NZ620085B2 - 4-imidazopyridazin-1-yl-benzamides and 4-imidazotriazin-1-yl-benzamides as btk-inhibitors - Google Patents
4-imidazopyridazin-1-yl-benzamides and 4-imidazotriazin-1-yl-benzamides as btk-inhibitors Download PDFInfo
- Publication number
- NZ620085B2 NZ620085B2 NZ620085A NZ62008512A NZ620085B2 NZ 620085 B2 NZ620085 B2 NZ 620085B2 NZ 620085 A NZ620085 A NZ 620085A NZ 62008512 A NZ62008512 A NZ 62008512A NZ 620085 B2 NZ620085 B2 NZ 620085B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- benzamide
- pyrazinyl
- amino
- imidazo
- pyridinyl
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title abstract description 15
- NBOUQRHNEKKMCI-UHFFFAOYSA-N N1(N=CC=C2C1=NC=N2)C1=CC=C(C(=O)N)C=C1 Chemical class N1(N=CC=C2C1=NC=N2)C1=CC=C(C(=O)N)C=C1 NBOUQRHNEKKMCI-UHFFFAOYSA-N 0.000 title abstract 2
- RFMXXXSWDWZODI-UHFFFAOYSA-N N1(N=NC=C2C1=NC=N2)C1=CC=C(C(=O)N)C=C1 Chemical class N1(N=NC=C2C1=NC=N2)C1=CC=C(C(=O)N)C=C1 RFMXXXSWDWZODI-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 328
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- 125000004432 carbon atoms Chemical group C* 0.000 claims description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
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- 125000003118 aryl group Chemical group 0.000 claims description 20
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Abstract
Provided are 4-imidazopyridazin-1-yl-benzamides and 4-imidazotriazin-1-yl-benzamides of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include (S)-4-(3-(1-Acryloylpyrrolidin-2-y1)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide and (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-phenylpyridin-2-yl)benzamide. The compounds are inhibitors of Brutons Tyrosine Kinase (Btk). The compounds may be used to treat immune, autoimmune, inflammatory, infectious, bone resorption and proliferative diseases mediated by this kinase. ide and (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-phenylpyridin-2-yl)benzamide. The compounds are inhibitors of Brutons Tyrosine Kinase (Btk). The compounds may be used to treat immune, autoimmune, inflammatory, infectious, bone resorption and proliferative diseases mediated by this kinase.
Description
-IMIDAZOPYRIDAZINYL-BENZAMIDES AND 4-IMIDAZOTRIAZINYL-BENZAMIDES AS BTK-
INHIBITORS
Field of the invention
The present invention relates to 6-5 membered fused pyridine ring compounds, to pharmaceutical
compositions comprising these compounds and to their use in therapy. In particular, the present invention
relates to the use of 6-5 membered fused pyridine ring compounds in the treatment of Bruton’s Tyrosine
Kinase (Btk) mediated disorders.
Background of the invention
B lymphocyte activation is key in the generation of adaptive immune responses. Derailed B lymphocyte
activation is a hallmark of many autoimmune diseases and modulation of this immune response is
therefore of therapeutic interest. Recently the success of B cell therapies in autoimmune diseases has
been established. Treatment of rheumatoid arthritis (RA) patients with Rituximab (anti-CD20 therapy) is
an accepted clinical therapy by now. More recent clinical trial studies show that treatment with Rituximab
also ameliorates disease symptoms in relapsing remitting multiple sclerosis (RRMS) and systemic lupus
erythematosus (SLE) patients. This success supports the potential for future therapies in autoimmune
diseases targeting B cell immunity.
Bruton tyrosine kinase (Btk) is a Tec family non-receptor protein kinase, expressed in B cells and myeloid
cells. The function of Btk in signaling pathways activated by the engagement of the B cell receptor (BCR)
and FcεR1 on mast cells is well established. In addition, a function for Btk as a downstream target in Toll
like receptor signaling was suggested. Functional mutations in Btk in human results in the primary
immunodeficiency disease called XLA which is characterized by a defect in B cell development with a
block between pro- and pre-B cell stage. This results in an almost complete absence of B lymphocytes in
human causing a pronounced reduction of serum immunoglobulin of all classes. These finding support
the key role for Btk in the regulation of the production of auto-antibodies in autoimmune diseases. In
addition, regulation of Btk may affect BCR-induced production of pro-inflammatory cytokines and
chemokines by B cells, indicating a broad potential for Btk in the treatment of autoimmune diseases.
With the regulatory role reported for Btk in FcεR-mediated mast cell activation, Btk inhibitors may also
show potential in the treatment of allergic responses [Gilfillan et al, Immunological Reviews 288 (2009)
pp149-169].
Furthermore, Btk is also reported to be implicated in RANKL-induced osteoclast differentiation [Shinohara
et al, Cell 132 (2008) pp794-806] and therefore may also be of interest for the treatment of bone
resorption disorders.
Other diseases with an important role for dysfunctional B cells are B cell malignancies. Indeed anti-CD20
therapy is used effectively in the clinic for the treatment of follicular lymphoma, diffuse large B-cell
lymphoma and chronic lymphocytic leukemia [Lim et al, Haematologica, 95 (2010) pp135-143]. The
reported role for Btk in the regulation of proliferation and apoptosis of B cells indicates there is potential
for Btk inhibitors in the treatment of B cell lymphomas as well. Inhibition of Btk seems to be relevant in
particular for B cell lymphomas due to chronic active BCR signaling [Davis et al, Nature, 463 (2010) pp88-
94].
Some classes of 6-5 membered fused pyridine ring compounds have been described as kinase inhibitors
e.g. Imidazo[1,5-f][1,2,4]triazine compounds have been described in WO2005097800 and
WO2007064993;. Imidazo[1,5-a]pyrazine compounds have been described in WO2005037836 and
WO2001019828 as IGF-1R enzyme inhibitors.
Some of the Btk inhibitors reported are not selective over Src-family kinases. With dramatic adverse
effects reported for knockouts of Src-family kinases, especially for double and triple knockouts, this is
seen as prohibitive for the development of Btk inhibitors that are not selective over the Src-family kinases.
Both Lyn-deficient and Fyn-deficient mice exhibit autoimmunity mimicking the phenotype of human lupus
nephritis. In addition, Fyn-deficient mice also show pronounced neurological defects. Lyn knockout mice
also show an allergic-like phenotype, indicating Lyn as a broad negative regulator of the IgE-mediated
allergic response by controlling mast cell responsiveness and allergy-associated traits [Odom et al, J.
Exp. Med., 199 (2004) pp1491-1502]. Furthermore, aged Lyn knock-out mice develop severe
splenomegaly (myeloid expansion) and disseminated monocyte/macrophage tumors [Harder et al,
Immunity, 15 (2001) pp603-615]. These observations are in line with hyperresponsive B cells, mast cells
and myeloid cells, and increased Ig levels observed in Lyn-deficient mice.
Female Src knockout mice are infertile due to reduced follicle development and ovulation [Roby et al,
Endocrine, 26 (2005) pp169-176].
-/- -/- -/- -/-
The double knockouts Src Fyn and Src Yes show a severe phenotype with effects on movement and
-/- -/- -/-
breathing. The triple knockouts Src Fyn Yes die at day 9.5 [Klinghoffer et al, EMBO J., 18 (1999)
-/- -/-
pp2459-2471]. For the double knockout Src Hck , two thirds of the mice die at birth, with surviving mice
developing osteopetrosis, extramedullary hematopoiseis, anemia, leukopenia [Lowell et al, Blood, 87
(1996) pp1780-1792].
Hence, an inhibitor that inhibits multiple or all kinases of the Src-family kinases simultaneously may cause
serious adverse effects.
Detailed description of the invention
The present invention provides 6-5 membered fused pyridine ring compounds and pharmaceutical
compositions comprising these compounds. Also described herein is the use of such compounds in
therapy, and in particular the use of 6-5 membered fused pyridine ring compounds in the treatment of
Bruton’s Tyrosine Kinase (Btk) mediated disorders.
More specifically, the present invention provides 6-5 membered fused pyridine ring compounds according
to formula I or pharmaceutically acceptable salts thereof.
Formula I
In this formula the substituents are defined as
X is CH, N, O or S;
Y is C(R6), N, O or S;
Z is CH, N or a bond;
A is CH or N;
B1 is N or C(R7);
B2 is N or C(R8);
B3 is N or C(R9);
B4 is N or C(R10);
R1 is R11C(O), R12S(O), R13SO or (1-6C)alkyl optionally substituted with R14;
R2 is H, (1-3C)alkyl or (3-7C)cycloalkyl;
R3 is H, (1-6C)alkyl or (3-7C)cycloalkyl); or
R2 and R3 form, together with the N atom that R2 is attached to and the C atom that R3 is attached to, a
(3-7C)heterocycloalkyl optionally substituted with one or more fluorine, hydroxyl, (1-3C)alkyl, (1-3C)alkoxy
or oxo;
R4 is H or (1-3C)alkyl;
R5 is H, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy, (3-6C)cycloalkyl; all alkyl groups of R5 are optionally
substituted with one or more halogen; or R5 is (6-10C)aryl or (2-6C)heterocycloalkyl;
R6 is H or (1-3C)alkyl; or
R5 and R6 together may form a (3-7C)cycloalkenyl, or (2-6C)heterocycloalkenyl; each optionally
substituted with (1-3C)alkyl, or one or more halogen;
R7 is H, halogen or (1-3C)alkoxy;
R8 is H or (1-3C)alkyl; or
R7 and R8 form, together with the carbon atom they are attached to a (6-10C)aryl or (1-9C)heteroaryl;
R9 is H, halogen or (1-3C)alkoxy;
R10 is H, halogen, or (1-3C)alkoxy;
R11 is independently selected from the group consisting of (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl
each alkyl, alkenyl or alkynyl optionally substituted with one or more groups selected from hydroxyl, (1-
4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-
10C)aryl or (3-7C)heterocycloalkyl; or
R11 is (1-3C)alkyl-C(O)-S-(1-3C)alkyl; or
R11 is (1-5C)heteroaryl optionally substituted with one or more groups selected from halogen or cyano.
R12 and R13 are independently selected from the group consisting of (2-6C)alkenyl or (2-6C)alkynyl both
optionally substituted with one or more groups selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, [(1-
4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl, or (3-
7C)heterocycloalkyl; or
(1-5C)heteroaryl optionally substituted with one or more groups selected from halogen or cyano;
R14 is independently selected from the group consisting of halogen, cyano or (2-6C)alkenyl or (2-
6C)alkynyl both optionally substituted with one or more groups selected from hydroxyl, (1-4C)alkyl, (3-
7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl, (1-
5C)heteroaryl or (3-7C)heterocycloalkyl.
With the proviso that:
- 0 to 2 atoms of X, Y, Z can simultaneously be a heteroatom;
- when one atom selected from X, Y is O or S, then Z is a bond and the other atom selected from X, Y
cannot be O or S;
- when Z is CH or N then Y is C(R6) or N and X is CH or N;
- 0 to 2 atoms of B1, B2, B3 and B4 are N.
The terms as used herein refer to the following:
(1-2C)Alkyl means an alkyl group having 1 to 2 carbon atoms, being methyl or ethyl.
(1-3C)Alkyl means a branched or unbranched alkyl group having 1-3 carbon atoms, being methyl, ethyl,
propyl or isopropyl.
(1-4C)Alkyl means a branched or unbranched alkyl group having 1-4 carbon atoms, being methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, (1-3C)alkyl groups being preferred.
(1-5C)Alkyl means a branched or unbranched alkyl group having 1-5 carbon atoms, for example methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and isopentyl, (1-4C)alkyl groups being
preferred.
(1-6C)Alkyl means a branched or unbranched alkyl group having 1-6 carbon atoms, for example methyl,
ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. (1-5C)alkyl groups are preferred, (1-
4C)alkyl being most preferred.
(1-2C)Alkoxy means an alkoxy group having 1-2 carbon atoms, the alkyl moiety having the same
meaning as previously defined.
(1-3C)Alkoxy means an alkoxy group having 1-3 carbon atoms, the alkyl moiety having the same
meaning as previously defined. (1-2C)alkoxy groups are preferred.
(1-4C)Alkoxy means an alkoxy group having 1-4 carbon atoms, the alkyl moiety having the same
meaning as previously defined. (1-3C)alkoxy groups are preferred, (1-2C)alkoxy groups being most
preferred.
(2-4C)Alkenyl means a branched or unbranched alkenyl group having 2-4 carbon atoms, such as ethenyl,
2-propenyl, isobutenyl or 2-butenyl.
(2-6C)Alkenyl means a branched or unbranched alkenyl group having 2-6 carbon atoms, such as ethenyl,
2-butenyl, and n-pentenyl. (2-4C)alkenyl groups are preferred.
(2-4C)Alkynyl means a branched or unbranched alkynyl group having 2-4 carbon atoms, such as ethynyl,
2-propynyl or 2-butynyl.
(2-6C)Alkynyl means a branched or unbranched alkynyl group having 2-6 carbon atoms, such as ethynyl,
propynyl, n-butynyl, n-pentynyl, isopentynyl, isohexynyl or n-hexynyl. (2-4C)alkynyl groups are preferred.
(3-6C)Cycloalkyl means a cycloalkyl group having 3-6 carbon atoms, being cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl.
(3-7C)Cycloalkyl means a cycloalkyl group having 3-7 carbon atoms, being cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl.
(2-6C)Heterocycloalkyl means a heterocycloalkyl group having 2-6 carbon atoms, preferably 3-5 carbon
atoms, and one or two heteroatoms selected from N, O and/or S, which may be attached via a
heteroatom if feasible, or a carbon atom. Preferred heteroatoms are N or O. Preferred are piperidine,
morpholine, pyrrolidine and piperazine. Most preferred (2-6C)heterocycloalkyl is pyrrolidine. The
heterocycloalkyl group may be attached via a heteroatom if feasible.
(3-7C)Heterocycloalkyl means a heterocycloalkyl group having 3-7 carbon atoms, preferably 3-5 carbon
atoms, and one or two heteroatoms selected from N, O and/or S. Preferred heteroatoms are N or O.
Preferred (3-7C) heterocycloalkyl groups are azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or
morpholinyl. More preferred (3-7C)heterocycloalkyl groups are piperidine, morpholine and pyrrolidine.
The heterocycloalkyl group may be attached via a heteroatom if feasible.
(3-7C)Cycloalkoxy means a cycloalkyl group having 3-7 carbon atoms, with the same meaning as
previously defined, attached via a ring carbon atom to an exocyclic oxygen atom.
(6-10C)Aryl means an aromatic hydrocarbon group having 6-10 carbon atoms, such as phenyl, naphthyl,
tetrahydronaphthyl or indenyl. The preferred (6-10C)aryl group is phenyl.
(1-5C)Heteroaryl means a substituted or unsubstituted aromatic group having 1-5 carbon atoms and 1-4
heteroatoms selected from N, O and/or S. The (1-5C)heteroaryl may optionally be substituted. Preferred
(1-5C)heteroaryl groups are tetrazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidyl, triazinyl, thienyl or furyl,
more preferred (1-5C)heteroaryl is pyrimidyl.
(1-9C)Heteroaryl means a substituted or unsubstituted aromatic group having 1-9 carbon atoms and 1-4
heteroatoms selected from N, O and/or S. The (1-9C)heteroaryl may optionally be substituted. Preferred
(1-9C)heteroaryl groups are quinoline, isoquinoline and indole.
[(1-4C)Alkyl]amino means an amino group, monosubstituted with an alkyl group containing 1-4 carbon
atoms having the same meaning as previously defined. Preferred [(1-4C)alkyl]amino group is
methylamino.
Di[(1-4C)alkyl]amino means an amino group, disubstituted with alkyl group(s), each containing 1-4 carbon
atoms and having the same meaning as previously defined. Preferred di[(1-4C)alkyl]amino group is
dimethylamino.
Halogen means means fluorine, chlorine, bromine or iodine
(1-3C)Alkyl-C(O)-S-(1-3C)alkyl means an alkyl-carbonyl-thio-alkyl group, each of the alkyl groups having
1 to 3 carbon atoms with the same meaning as previously defined.
(3-7C)Cycloalkenyl means a cycloalkenyl group having 3-7 carbon atoms, preferably 5-7 carbon atoms.
Preferred (3-7C)cycloalkenyl groups are cyclopentenyl or cyclohexenyl. Cyclohexenyl groups are most
preferred.
(2-6C)Heterocycloalkenyl means a heterocycloalkenyl group having 2-6 carbon atoms, preferably 3-5
carbon atoms; and 1 heteroatom selected from N, O and/or S. Preferred (2-6C)heterocycloalkenyl groups
are oxycyclohexenyl and azacyclohexenyl group.
In the above definitions with multifunctional groups, the attachment point is at the last group.
When, in the definition of a substituent, is indicated that “all of the alkyl groups” of said substituent are
optionally substituted, this also includes the alkyl moiety of an alkoxy group.
A circle in a ring of Formula I indicates that the ring is aromatic.
Depending on the ring formed, the nitrogen, if present in X or Y, may carry a hydrogen.
The term “substituted” means that one or more hydrogens on the designated atom/atoms is/are replaced
with a selection from the indicated group, provided that the designated atom’s normal valency under the
existing circumstances is not exceeded, and that the substitution results in a stable compound.
Combinations of substituents and/or variables are permissible only if such combinations result in stable
compounds. “Stable compound” or “stable structure” is defined as a compound or structure that is
sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation
into an efficacious therapeutic agent.
The term “optionally substituted” means optional substitution with the specified groups, radicals or
moieties.
Aspects of the invention
In one aspect the invention relates to a compound according to formula I wherein B1 is C(R7); B2 is
C(R8); B3 is C(R9) and B4 is C(R10).
In another aspect the invention relates to a compound according to formula I wherein B1 is C(R7); B2 is
C(R8); B3 is C(R9); B4 is C(R10); R7, R9, and R10 each are H; and R8 is selected from a group
consisting of hydrogen and methyl.
In one aspect the invention relates to a compound according to formula I wherein R8 is hydrogen or
methyl, in particular R8 is hydrogen.
In another aspect the invention relates to a compound according to formula I wherein R7 is hydrogen,
fluorine or (1-3C)alkoxy. In particular, R7 is hydrogen, fluorine or methoxy. Even more particularly, an
aspect of the invention relates to a compound according to formula I wherein R7 is hydrogen.
In yet another aspect the invention relates to a compound according to formula I wherein R9 is hydrogen,
fluorine or (1-3C)alkoxy. In particular, R9 is hydrogen, fluorine or methoxy. Even more particularly, an
aspect of the invention relates to a compound according to formula I wherein R9 is hydrogen.
In another aspect the invention relates to a compound according to formula I wherein R10 is hydrogen
fluorine or (1-3C)alkoxy. In particular, R10 is hydrogen, fluorine or methoxy. Even more particularly, an
aspect of the invention relates to a compound according to formula I wherein R10 is hydrogen.
In still another aspect the invention relates to a compound according to formula I wherein R7 and R8
form, together with the carbon atom they are attached to, an indole or quinoline or naphtyl.
In another aspect the invention relates to a compound according to formula I wherein B1 is C(R7); B2 is
C(R8); B3 is C(R9); B4 is C(R10) and R7, R8, R9, and R10 each are H;
In yet another aspect the invention relates to a compound according to formula I wherein R4 is hydrogen
or methyl. In particular, R4 is hydrogen.
In still another aspect the invention relates to a compound according to formula I wherein A is N.
In another aspect the invention relates to a compound according ot formula I wherein A is CH.
In another aspect the invention relates to a compound according to formula I wherein the ring containing
X, Y and Z is selected from a group consisting of pyridyl, pyrimidyl, pyridazyl, triazinyl, thiazolyl, oxazolyl,
and isoxazolyl. In particular, the invention relates to a compound according to formula I wherein the ring
containing X, Y and Z is selected from a group consisting of pyridyl, pyrimidyl and thiazolyl. The definition
of R5 and R6 is independent from the selection of X, Y, and Z. The place of attachment of R5 and
optionally of R6 to these heteroaryl rings follows from formula I.
The invention further relates to a compound according to formula I wherein R5 is selected from a group
consisting of hydrogen, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy and (3-6C)cycloalkyl. All of the alkyl
groups of R5 are optionally substituted with one or more halogen. In particular, the (1-4C)alkyl group in
R5 is optionally substituted with one or more halogen.
In another aspect the invention relates to a compound according to formula I wherein R5 is selected from
a group consisting of hydrogen, fluorine, chlorine, (1-3C)alkyl and (1-2C) alkoxy, all of the alkyl groups of
R5 are optionally substituted with one or more halogen. In particular, the (1-3C)alkyl group in R5 is
optionally substituted with one or more fluoro. Even more particularly, the invention relates to a compound
according to formula I wherein R5 is hydrogen, fluorine, methyl, ethyl, propyl, methoxy or trifluoromethyl.
In yet another aspect the invention relates to a compound according to formula I wherein R5 is pyrrolidine
or phenyl.
In another aspect, the invention relates to a compound according to formula I wherein R6 is hydrogen or
(1-3C)alkyl, preferably R6 is hydrogen.
In yet another aspect the invention relates to a compound according to formula I wherein R5 and R6
together form a (3-7C)cycloalkenyl or a (2-6C)heterocycloalkenyl both optionally substituted with (1-
3C)alkyl or one or more halogen. In particular, (3-7C)cycloalkenyl groups are cyclohexenyl and
cyclopentenyl. In particular, (2-6C)heterocycloalkenyl groups are azacyclohexenyl and oxocyclohexenyl.
Even more in particularly, the invention relates to a compound according to formula I wherein the (3-
7C)cycloalkenyl in R5 is cyclohexenyl..
In another aspect, the invention relates to a compound according to formula I wherein R2 is hydrogen or
(1-3C)alkyl. In particular, R2 is hydrogen or methyl. R2 is hydrogen being most preferred.
In yet another aspect the invention relates to a compound according to formula I wherein R3 is (1-
6C)alkyl. In particular, R3 is (1-3C)alkyl. R3 is methyl being most preferred.
In another aspect the invention relates to a compound according to formula I wherein R3 is (3-
7C)cycloalkyl.
In another aspect the invention relates to a compound according to formula I wherein R2 is hydrogen or
(1-3C)alkyl and R3 is (1-6C)alkyl. In particular, R2 is hydrogen or methyl and R3 is (1-3C)alkyl. Even
more particularly, the invention relates to a compound according to formula I wherein R2 is hydrogen and
R3 is methyl.
In yet another aspect the invention relates to a compound according to formula I wherein R2 or R3 are
independently selected from a group consisting of cyclopropyl, cyclobutyl and cyclopentyl.
In another aspect the invention relates to a compound of formula I wherein,R2 and R3 form, together with
the N and C atom they are attached to, a (3-7C)heterocycloalkyl optionally substituted with one or more
halogen, hydroxyl, (1-3C)alkyl. In particular, R2 and R3 form, together with the N and C atom they are
attached to an azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl ring each optionally
substituted with one or more halogen, hydroxyl, (1-3C)alkyl, (1-3C)alkoxy or oxo, preferred halogen
substituent being fluoro.
In yet another aspect the invention relates to a compound of formula I wherein, R2 and R3 form together
with the N and C atom they are attached to an azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or
morpholinyl ring each optionally substituted with fluoro, hydroxyl, (1-3C)alkyl, (1-3C)alkoxy or oxo. In
particular, R2 and R3 together with the N and C atom they are attached to form a pyrrolidinyl, piperidinyl,
morpholinyl or homopiperidinyl ring.
In yet another aspect the invention relates to a compound according to formula I wherein, R1 is R11C(O)
and R11 is (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl each optionally independently substituted with one
or more groups selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, (3-7C)heterocycloalkyl, [(1-
4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl, (1-5C)heteroaryl or
(1-3C)alkyl-S-C(O)-(1-3C)alkyl. In particular, the (1-5C)heteroaryl group is pyrimidyl or triazinyl optionally
substituted with one or more groups selected from halogen or cyano. In particular, the (3-
7C)heterocycloalkyl is pyrrolidinyl. Even more particularly, the invention relates to a compound according
to formula I wherein the (3-7C)cycloalkyl substituent of R11 is cyclopropyl. In particular, the (6-10C)aryl
substituent of R11 is phenyl.
In yet another aspect the invention relates to a compound according to formula I wherein,
R1 is C(O)R11 and R11 is (2-6C)alkenyl or (2-6C)alkynyl each optionally substituted with one or more
groups selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, (3-7C)heterocycloalkyl, (di)[(1-
4C)alkyl]amino, (1-3C)alkoxy or (3-7C)cycloalkoxy. In particular, the (3-7C)heterocycloalkyl substituent of
R11 is pyrrolidinyl and the (3-7C)cycloalkyl substituent of R11 is cyclopropyl.
In another aspect the invention relates to a compound according to formula I wherein, R1 is C(O)R11 and
R11 is (2-4C)alkenyl or (2-4C)alkynyl each optionally substituted with one or more groups selected from
(1-4C)alkyl, (3-7C)cycloalkyl, (3-7C)heterocycloalkyl, (di)[(1-4C)alkyl]amino or (1-3C)alkoxy. In particular,
the (3-7C)heterocycloalkyl substituent of R11 is pyrrolidinyl and the (3-7C)cycloalkyl substituent is
cyclopropyl. Even more particularly, R11 is (2-4C)alkenyl or (2-4C)alkynyl each optionally substituted with
one or more groups selected from methyl, ethyl, cyclopropyl, pyrrolidinyl, dimethylamino, methoxy or
ethoxy.
In a further aspect the invention relates to compounds according to formula I wherein R1 is C(O)R11
wherein R11 is (1-5C)heteroaryl optionally substituted with one or more groups selected from halogen or
cyano. In particular, the (1-5C)heteroaryl substituent is pyrimidyl or triazinyl, pyrimidyl rings being
preferred, optionally substituted with one or more groups selected from halogen or cyano. In particular,
the halogen substituent is chlorine.
In another aspect, the invention relates to compounds according to formula I wherein R1 is R13SO ,
wherein R13 is (2-6C)alkenyl or (2-6C)alkynyl. In particular, R13 is (2-4C)alkenyl. Even more particularly,
R13 is ethenyl.
In another aspect, the invention relates to compounds according to formula I wherein R1 is R12S(O),
wherein R12 is (2-6C)alkenyl or (2-6C)alkynyl. In particular, R13 is (2-4C)alkenyl. Even more particularly,
R12 is ethenyl.
In yet another aspect, the invention relates to compounds according to formula I wherein R1 is (1-3C)alkyl
optionally substituted with R14 wherein R14 is (2-4C)alkenyl or (2-4C)alkynyl.
In yet another aspect the invention relates to a compound according to formula I selected from the group
consisting of
(S)(3-(1-Acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S,E)(8-amino(1-(4-(pyrrolidinyl)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin-
2-yl)benzamide,
(S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-
(pyridinyl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin-
2-yl)benzamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
fluoropyridinyl)benzamide,
(S)(8-Amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-methylpyridin
yl)benzamide,
(S,E)(8-Amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
propylpyridinyl)benzamide,
(S)(8-Amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridin
yl)benzamide,
(S,E)(8-Amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-ethylpyridin-
2-yl)benzamide,
(S)(8-Amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4,5,6,7-
tetrahydrobenzo[d]thiazolyl)benzamide,
(S)(3-(1-Acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)fluoro-N-(pyridinyl)benzamide,
(S)(3-(1-Acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)methoxy-N-(pyridin
yl)benzamide,
(S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(thiazol-
2-yl)benzamide,
(S,E)(8-Amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide,
(S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridinyl)benzamide,
(S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-cyanopyridinyl)benzamide,
(S)(8-Amino(1-(vinylsulfonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridin
yl)benzamide,
(S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyrimidinyl)benzamide,
(S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-methylpyrimidin
yl)benzamide,
(S)(8-Amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyrimidinyl)benzamide,
(S)(8-Amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridazinyl)benzamide,
(S)(8-Amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(isoxazolyl)benzamide,
(S,E)(8-Amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(5-ethylthiazol-
2-yl)benzamide,
(S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)fluoro-N-(4-propylpyridin
yl)benzamide,
(S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)
methoxy-N-(4-propylpyridinyl)benzamide,
4-(8-Amino((S)butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)methyl-N-(pyridin
yl)benzamide,
4-(3-(Acrylamidomethyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S)(8-Amino(1-butynamidoethyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S)-S(2-(8-Amino(4-(pyridinylcarbamoyl)phenyl)imidazo[1,5-a]pyrazinyl)pyrrolidinyl)
oxoethyl ethanethioate,
(S)(8-Amino(1-(4-hydroxymethylpentynoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-
(pyridinyl)benzamide,
(S)(8-Amino(1-(6-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin-
2-yl)benzamide,
(S)(8-Amino(1-pentynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S)(8-Amino(1-(3-cyclopropylpropioloyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide,
(S)(8-Amino(1-hexynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
4-(3-(1-Acryloylazepanyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(R)(8-Amino(4-butynoylmorpholinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S)(8-amino(1-(N-methylbutynamido)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4-
(trifluoromethyl)pyridinyl)benzamide,
(S)(8-Amino(1-(4-(dimethylamino)butynoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide,
(S)(8-Amino(1-(4-methoxybutynoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide,
(S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridinyl)benzamide,
(S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-(pyrrolidinyl)pyridin
yl)benzamide,
(S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridin
yl)benzamide,
(S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S)(3-(1-acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-propylpyridin
yl)benzamide,
(S,E)(8-amino(1-(4-methoxy-N-methylbutenamido)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4-
propylpyridinyl)benzamide,
(S)(8-amino(1-(vinylsulfonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-propylpyridin
yl)benzamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)fluoro-N-(pyridin
yl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
methoxypyridinyl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)fluoro-N-(4-
methoxypyridinyl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridin-
2-yl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(isoxazol
yl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyrimidin
yl)benzamide,
4-(8-amino((S)(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)methyl-N-
(pyridinyl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
methylpyridinyl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
isopropylpyridinyl)benzamide,
(S,E)(8-amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
methylpyridinyl)benzamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(thiazolyl)benzamide,
(S)(3-(1-acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-propylpyridinyl)benzamide,
(S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridin
yl)benzamide,
(S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridin
yl)benzamide,
(S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-propylpyridin
yl)benzamide,
(S,E)(8-amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
isopropylpyridinyl)benzamide,
4-(8-amino((S)(vinylsulfonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)methyl-N-(pyridin
yl)benzamide,
(S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)fluoro-N-(4-propylpyridin
yl)benzamide,
4-(3-((S)acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)methyl-N-(pyridinyl)benzamide,
(E)(8-amino((4-(dimethyl amino)butenamido)methyl) imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide,
(S)(8-amino(1-(2-chloro pyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
isopropylpyridinyl)benzamide,
(S)(8-amino(1-(2-chloro pyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4,5,6,7-
tetrahydrobenzo[d]thiazolyl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridazin
yl)benzamide,
(S,E)(8-amino(1-(4-(dimethylamino)butenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-
(pyridazinyl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridazin-
3-yl)benzamide,
(S,E)(8-amino(1-(4-methoxy-N-methylbutenamido)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4-
(trifluoromethyl)pyridinyl)benzamide,
(S,E)(8-amino(1-(4-(dimethylamino)-N-methylbutenamido)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4-
propylpyridinyl)benzamide,
(S,E)(8-amino(1-(4-(pyrrolidinyl)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
propylpyridinyl)benzamide,
(S,E)(8-amino(1-(4-(dimethylamino)butenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin-
2-yl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
propylpyridinyl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
fluoropyridinyl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridin-
2-yl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4,5,6,7-
tetrahydrobenzo[d]thiazolyl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)methoxy-
N-(pyridinyl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)fluoro-N-
(pyridinyl)benzamide,
4-(8-amino((S)((E)methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)methyl-N-
(pyridinyl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyrimidin
yl)benzamide,
4-(8-amino((S)((E)methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)methyl-N-(4-
propylpyridinyl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
methylpyrimidinyl)benzamide,
(S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-methylpyrimidin
yl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyrimidin-
2-yl)benzamide,
(S)(8-amino(1-methacryloylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S)(8-amino(1-(2-(trifluoromethyl)acryloyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide,
(S,E)(8-amino(1-butenoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S)(8-amino(1-(cyanomethyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(E)(8-amino((4-methoxybutenamido)methyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-(pyrrolidinyl)pyridin
yl)benzamide,
(E)(8-amino(1-(4-methoxybutenoyl)azepanyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
cyanopyridinyl)benzamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)methoxy-N-(pyridin
yl)benzamide,
(S)(3-(1-acrylamidoethyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(thiazolyl)benzamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-isopropylpyridin
yl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)methoxy-N-
(pyridinyl)benzamide,
(S,E)(8-amino(1-cinnamoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S)-N-(1-(8-amino(4-(pyridinylcarbamoyl)phenyl)imidazo[1,5-a]pyrazinyl)ethyl)
chloropyrimidinecarboxamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridin
yl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
propylpyridinyl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
(trifluoromethyl)pyridinyl)benzamide,
(S)(3-(1-acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridin
yl)benzamide,
(S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)methoxy-N-(4-propylpyridin
yl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)methoxy-N-(4-
propylpyridinyl)benzamide,
4-(8-amino(butynamidomethyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide,
(S)(8-amino(1-(N-methylbutynamido)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4-propylpyridin
yl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)fluoro-N-(4-
propylpyridinyl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
(trifluoromethyl)pyridinyl)benzamide,
(S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(5-ethylthiazol
yl)benzamide,
(S)(3-(1-acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(5-ethylthiazolyl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(5-
ethylthiazolyl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
(trifluoromethyl)pyridinyl)benzamide,
(R,E)(8-amino(4-(4-methoxybutenoyl)morpholinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-propylpyridin-
2-yl)benzamide,
(S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-cyanopyridinyl)benzamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-methoxypyridin
yl)benzamide,
(S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-methylpyridinyl)benzamide,
(S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-propylpyridinyl)benzamide,
(S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-ethylpyridinyl)benzamide,
(S,E)(8-amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin-
2-yl)benzamide,
(S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
(trifluoromethyl)pyridinyl)benzamide,
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
methylpyridinyl)benzamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-cyanopyridin
yl)benzamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-ethylpyridin
yl)benzamide,
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-phenylpyridin
yl)benzamide, and
(S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-phenylpyridinyl)benzamide.
The invention also relates to those compounds wherein all specific definitions for R1 through R14 and all
substituent groups in the various aspects of the inventions defined here above occur in any combination
within the definition of the 6-5 membered fused pyridine ring compounds i.e. 8-amino-imidazo[1,5-
a]pyrazine and 4-amino-imidazo[1,5-f][1,2,4]triazine compounds of formula I.
The 6-5 membered fused pyridine ring compounds like 8-amino-imidazo[1,5-a]pyrazine and 4-amino-
imidazo[1,5-f][1,2,4]triazine compounds of the invention inhibit the Btk kinase activity. All compounds of
the invention have an EC50 of 10 µM or lower.
In another aspect the invention relates to compounds of formula I which have an EC50 of less than 100
nM. In yet another aspect the invention relates to compounds of formula I which have an EC50 of less
than 10 nM.
The term EC50 means the concentration of the test compound that is required for 50% inhibition of its
maximum effect in vitro.
Inhibition of kinase activity can be measured using the Immobilized Metal Assay for Phosphochemicals
(IMAP) assay. IMAP is a homogeneous fluorescence polarization (FP) assay based on affinity capture of
phosphorylated peptide substrates. IMAP uses fluorescein-labeled peptide substrates that, upon
phosphorylation by a protein kinase, bind to so-called IMAP nanoparticles, which are derivatized with
trivalent metal complexes. Binding causes a change in the rate of the molecular motion of the peptide,
and results in an increase in the FP value observed for the fluorescein label attached to the substrate
peptide (Gaudet et al. A homogeneous fluorescence polarization assay adaptable for a range of protein
serine/threonine and tyrosine kinases. J. Biomol. Screen (2003) 8, 164-175).
The compounds of Formula (I) can form salts which are also within the scope of this invention. Reference
to a compound of Formula (I) herein is understood to include reference to salts thereof, unless otherwise
indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or
organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a
compound of Formula (I) contains both a basic moiety, such as, but not limited to a pyridine or imidazole,
and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be
formed and are included within the term "salt(s)" as used herein. Such acidic and basic salts used within
the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable)
salts. Salts of the compounds of Formula (I) may be formed, for example, by reacting a compound of
Formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in
which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates,
borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides,
hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates
(also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the
formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for
example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and
Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P.
Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration,
Washington, D.C. on their website). These disclosures are incorporated herein by reference.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium
salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for
example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such
as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such
as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates
(e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides,
bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
The compounds of Formula I may contain asymmetric or chiral centers, and, therefore, exist in different
stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well
as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the
present invention embraces all geometric and positional isomers. For example, if a compound of Formula
(I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are
embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their
physical chemical differences by methods well known to those skilled in the art, such as, for example, by
chromatography and/or fractional crystallization. Enantiomers can be separated by converting the
enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active
compound (e.g. chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the
diastereomers and converting (e.g. hydrolyzing) the individual diastereomers to the corresponding pure
enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g. substituted biaryls)
and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC
column.
It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such
forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine
forms of the compounds are included in the invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present
compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the
salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on
various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric
carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of
this invention, as are positional isomers. Individual stereoisomers of the compounds of the invention may,
for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with
all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R
configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate",
“ester”, "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of
enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the
inventive compounds.
A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems
(1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward
B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term “prodrug” means a
compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a
pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by
various mechanisms (e.g. by metabolic or chemical processes), such as, for example, through hydrolysis
in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as
Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug
Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
The compounds of the invention may form hydrates or solvates. It is known to those of skill in the art that
charged compounds form hydrated species when lyophilized with water, or form solvated species when
concentrated in a solution with an appropriate organic solvent. The compounds of this invention include
the hydrates or solvates of the compounds listed.
One or more compounds of the invention may exist in unsolvated as well as solvated forms with
pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the
invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a
compound of this invention with one or more solvent molecules. This physical association involves
varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the
solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in
the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable
solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
"Hydrate" is a solvate wherein the solvent molecule is H O.
The present invention also relates to a pharmaceutical composition comprising 6-5 membered fused
pyridine ring compounds like imidazopyrazine and imidazotriazine compounds or pharmaceutically
acceptable salts thereof having the general formula I in admixture with pharmaceutically acceptable
auxiliaries and optionally other therapeutic agents. The auxiliaries must be “acceptable” in the sense of
being compatible with the other ingredients of the composition and not deleterious to the recipients
thereof.
The invention further includes a compound of formula I in combination with one or more other drug(s).
Compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular,
nasal, local, or rectal administration, and the like, all in unit dosage forms for administration.
For oral administration, the active ingredient may be presented as discrete units, such as tablets,
capsules, powders, granulates, solutions, suspensions, and the like.
For parenteral administration, the pharmaceutical composition of the invention may be presented in unit-
dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials
and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition
of sterile liquid carrier, e.g. water, prior to use.
Mixed with such pharmaceutically acceptable auxiliaries, e.g. as described in the standard reference,
Gennaro, A.R. et al., Remington: The Science and Practice of Pharmacy (20th Edition., Lippincott
Williams & Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing), the active agent may be
compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
By means of pharmaceutically acceptable liquids the active agent can be applied as a fluid composition,
e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a
nasal spray.
For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric
binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not
interfere with the function of the active compounds can be used. Suitable carriers with which the active
agent of the invention can be administered as solid compositions include lactose, starch, cellulose
derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration,
aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing
pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or
butylene glycol.
The invention further includes a pharmaceutical composition, as hereinbefore described, in combination
with packaging material suitable for said composition, said packaging material including instructions for
the use of the composition for the use as hereinbefore described.
The exact dose and regimen of administration of the active ingredient, or a pharmaceutical composition
thereof, may vary with the particular compound, the route of administration, and the age and condition of
the individual subject to whom the medicament is to be administered.
In general parenteral administration requires lower dosages than other methods of administration which
are more dependent upon absorption. However, a dosage for humans preferably contains 0.0001-25 mg
per kg body weight. The desired dose may be presented as one dose or as multiple subdoses
administered at appropriate intervals throughout the day, or, in case of female recipients, as doses to be
administered at appropriate daily intervals throughout the menstrual cycle. The dosage as well as the
regimen of administration may differ between a female and a male recipient.
In the compounds of generic Formula I, the atoms may exhibit their natural isotopic abundances, or one
or more of the atoms may be artificially enriched in a particular isotope having the same atomic number,
but an atomic mass or mass number different from the atomic mass or mass number predominantly found
in nature. The present invention is meant to include all suitable isotopic variations of the compounds of
generic Formula I. For example, different isotopic forms of hydrogen (H) include protium ( H) and
deuterium ( H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium
may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage
requirements, or may provide a compound useful as a standard for characterization of biological samples.
Isotopically-enriched compounds within generic Formula I can be prepared without undue
experimentation by conventional techniques well known to those skilled in the art or by processes
analogous to those described in the Schemes and Examples herein using appropriate isotopically-
enriched reagents and/or intermediates.
The compounds according to the invention can be used in therapy.
Also described herein is the use of 6-5 membered fused pyridine ring compounds or a pharmaceutically
acceptable salt thereof, having the general formula I for the manufacture of a medicament to be used for
the treatment of Btk-mediated diseases or Btk-mediated conditions.
Also described herein is the use of 6-5 membered fused pyridine ring compounds or a pharmaceutically
acceptable salt thereof having the general formula I for the manufacture of a medicament to be used for
the treatment of chronic B cell disorders in which T cells play a prominent role.
Also described herein is the use of 6-5 membered fused pyridine ring compounds like 8-amino-
imidazo[1,5-a]pyrazine and 4-amino-imidazo[1,5-f][1,2,4]triazine compounds having the general formula I
for the manufacture of a medicament to be used for the treatment of Btk-mediated diseases or conditions.
These include, but are not limited to, the treatment of B cell lymphomas resulting from chronic active B
cell receptor signaling.
Thus, the compounds according to the invention can be used in therapies to treat or prevent diseases
Bruton’s Tyrosine Kinase (Btk) mediated disorders. Btk mediated disorders or Btk mediated condition as
used herein, mean any disease state or other deleterious condition in which B cells, mast cells, myeloid
cells or osteoclasts play a central role. These diseases include but are not limited to, immune,
autoimmune and inflammatory diseases, allergies, infectious diseases, bone resorption disorders and
proliferative diseases.
Immune, autoimmune and inflammatory diseases that can be treated or prevented with the compounds of
the present invention include rheumatic diseases (e.g. rheumatoid arthritis, psoriatic arthritis, infectious
arthritis, progressive chronic arthritis, deforming arthritis, osteoarthritis, traumatic arthritis, gouty arthritis,
Reiter’s syndrome, polychondritis, acute synovitis and spondylitis), glomerulonephritis (with or without
nephrotic syndrome), autoimmune hematologic disorders (e.g. hemolytic anemia, aplasic anemia,
idiopathic thrombocytopenia, and neutropenia), autoimmune gastritis, and autoimmune inflammatory
bowel diseases (e.g. ulcerative colitis and Crohn’s disease), host versus graft disease, allograft rejection,
chronic thyroiditis, Graves’ disease, schleroderma, diabetes (type I and type II), active hepatitis (acute
and chronic), pancreatitis, primary billiary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus
erythematosis, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns, vasculitis (e.g.
Behcet’s disease) chronic renal insufficiency, Stevens-Johnson syndrome, inflammatory pain, idiopathic
sprue, cachexia, sarcoidosis, Guillain-Barré syndrome, uveitis, conjunctivitis, kerato conjunctivitis, otitis
media, periodontal disease, pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis,
pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema, pulmonary fibrosis,
silicosis, chronic inflammatory pulmonary disease (e.g. chronic obstructive pulmonary disease) and other
inflammatory or obstructive disease on airways.
Allergies that can be treated or prevented include, among others, allergies to foods, food additives, insect
poisons, dust mites, pollen, animal materials and contact allergans, type I hypersensitivity allergic
asthma, allergic rhinitis, allergic conjunctivitis.
Infectious diseases that can be treated or prevented include, among others, sepsis, septic shock,
endotoxic shock, sepsis by Gram-negative bacteria, shigellosis, meningitis, cerebral malaria, pneumonia,
tuberculosis, viral myocarditis, viral hepatitis (hepatitis A, hepatitis B and hepatitis C), HIV infection,
retinitis caused by cytomegalovirus, influenza, herpes, treatment of infections associated with severe
burns, myalgias caused by infections, cachexia secondary to infections, and veterinary viral infections
such as lentivirus, caprine arthritic virus, visna-maedi virus, feline immunodeficiency virus, bovine
immunodeficiency virus or canine immunodeficiency virus.
Bone resorption disorders that can be treated or prevented include, among others, osteoporosis,
osteoarthritis, traumatic arthritis, gouty arthritis and bone disorders related with multiple myeloma.
Proliferative diseases that can be treated or prevented include, among others, non-Hodgkin lymphoma
(in particular the subtypes diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)), B
cell chronic lymphocytic leukemia and acute lymphoblastic leukemia (ALL) with mature B cell, ALL in
particular.
In particular compounds of the invention can be used for the treatment of B cell lymphomas resulting from
chronic active B cell receptor signaling.
Inhibition of kinase activity can be measured using the Immobilized Metal Assay for Phosphochemicals
(IMAP) assay. IMAP is a homogeneous fluorescence polarization (FP) assay based on affinity capture of
phosphorylated peptide substrates. IMAP uses fluorescein-labeled peptide substrates that, upon
phosphorylation by a protein kinase, bind to so-called IMAP nanoparticles, which are derivatized with
trivalent metal complexes. Binding causes a change in the rate of the molecular motion of the peptide,
and results in an increase in the FP value observed for the fluorescein label attached to the substrate
peptide.
The Btk activity can also be determined in B cell lines such as Ramos cells or in primary cell assays, e.g
PBMC or whole blood from human, monkey, rat or mouse or isolated splenocytes from monkey, rat or
mouse. Inhibition of Btk activity can be investigated measuring anti-IgM-induced MIP1β production
(Ramos, PBMC, splenocytes), H O -induced Btk and PLCγ2 phosphorylation (Ramos cells), or anti-IgM-
induced B cell proliferation or CD86 expression on primary B cells (PBMC and splenocytes).
Regulation of Btk activity can also be determined on human, monkey, rat or mouse mast cells following
activation FcεR induced degranulation, cytokine production and CD63 induced cell surface expression.
Furthermore, regulation of Btk activity can be determined on CD14+ monocytes differentiated following
treatment with M-CSF to osteoclasts and activated with RANKL.
Activity of Btk inhibitors can be investigated in mouse splenocytes following administration in vivo. In a
typical experiment mice can be euthanized 3h following compound administration. Spleens can be
extracted from the treated mice for splenocyte isolation. Splenocytes can be plated in 96 well culture
plates and stimulated with anti-IgM, without further addition of compounds. Anti-IgM-induced B cell
stimulation and inhibition thereof by Btk inhibitors can be measured by B cell proliferation, MIP1β
production or CD86 expression on CD19+ splenocyte B cells.
Efficacy of Btk inhibitors can also be investigated in the mouse collagen induced arthritis model using a
therapeutic protocol with start of treatment following onset of disease, measuring disease score, X-ray
analysis of bone destruction, cartilage breakdown and histology of joints
Efficacy of Btk inhibitors on the regulation of activated mast cells can be investigated in vivo using the
passive cutaneous anaphylaxis model.
The effect of Btk inhibitors on bone resorption in vivo can be investigated using the rat OVX model. In this
model ovariectomized animals develop symptoms of osteoporosis that may be regulated using a Btk
inhibitor.
General Synthesis
The 8-amino-imidazo[1,5-a]pyrazine and 4-amino-imidazo[1,5-f][1,2,4]triazine derivatives of the present
invention can be prepared by methods well known in the art of organic chemistry. See, for example, J.
March, ‘Advanced Organic Chemistry’ 4 Edition, John Wiley and Sons. During synthetic sequences it
may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules
concerned. This is achieved by means of conventional protecting groups, such as those described in
T.W. Greene and P.G.M. Wutts ‘Protective Groups in Organic Synthesis’ 3 Edition, John Wiley and
Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using
methods well known in the art.
The products of the reactions are optionally isolated and purified, if desired, using conventional
techniques, but not limited to, filtration, distillation, crystallization, chromatography and the like. Such
materials are optionally characterized using conventional means, including physical constants and
spectral data.
8-amino-imidazo[1,5-a]pyrazine compounds of formula I, wherein R -R have the previously defined
meanings, can be prepared by the general synthetic route shown in scheme I
Cl Cl Cl Cl
N N NH N NH Pg N
N N N N N Bromination
Raney-Ni
POCl
reagent
Pg-N(R )C(R R )COOH R2
Hydrogen 2 3 4
Coupling reagent
R4 R3
V R3
R5 R5
X N X N
R5 Y
NH NH
VIII
3 B B
1 B B
B 4 4
Cl NH B NH B B
2 2 2 2 2 2
Br Br
N N N N
Deprotection
N N N N
NH /i-PrOH
N 3 N N N
Pd catalysts
base
Functionalisation
Pg R1
Pg Pg
Boronic acid
R4 R4 R4 R4
R3 R3 R3 R3
R2 R2 R2 R2
Scheme I
Reduction of 3-chloropyrazinecarbonitrile (II) can be accomplished by hydrogenation in the presence of
a suitable catalysts system and solvent, for example Raney-Nickel to provide (3-chloropyrazin
yl)methanamine (III). This can then be reacted with an appropriately amine protected amino acid. The
reaction of Cbz-N(R2)CR3R4)COOH can be carried out in a solvent such as DMF, THF or DCM in the
presence of a base such as DIPEA, N-methylmorpholine, 4-DMAP or triethylamine and in the presence of
a coupling reagent such as PyBOP, TBTU, EDCI or HATU to form N-((3-chloropyrazinyl)methyl)amide
IV. Cyclisation chloropyrazine IV can be performed using condensation reagents like
phosphorousoxychloride under heating conditions to provide the 8-chloroimidazo[1,5-a]pyrazine
derivatives V. Subsequent bromination can be accomplished using bromine or N-bromosuccinimide in a
suitable solvent like DCM or DMF at appropriate temperature to obtain compounds of formula VI. 8-
Aminoimidazo[1,5-a]pyrazine derivatives (VII) can be prepared from compounds VI using ammonia(gas)
in isopropanol at elevated temperature in a pressure vessel (>4 atm). Compounds of formula IX can be
prepared from compounds of formula VII using an appropriate boronic acid or pinacol ester (VIII), in the
presence of a suitable palladium catalyst system and solvent, for example
bis(diphenylphosphino)ferrocene palladium(II)chloride complex or
tetrakis(triphenylphosphine)palladium(0) in the presence of potassium carbonate in dioxane/water provide
compounds of formula IX. Finally, cleaving the protective group of compounds with the formula IX give
the unprotected amine which after functionalisation, using methods well known in the art, with appropriate
warheads with previously defined meanings, provided compounds of formula I. An example of such
protective strategy is the use of the benzyloxycarbonyl protecting group to protect the amine from the
amino acids used, and after deprotection with 33% HBr/HOAc or conc. HCl gave the resulting amines.
The amino acids HN(R2)CR3R4)COOH are either commercially available or they can be readily prepared
using methods well known to the skilled organic chemist, to introduce protecting groups like
benzyloxycarbonyl or tert-butyloxycarbonyl.
Palladium catalysts and conditions to form either the pinacol esters or to couple the boronic acids or
pinacol esters with the 1-bromoimidazo[1,5-a]pyrazinamine are well known to the skilled organic
chemist – see, for example, Ei-ichi Negishi (Editor), Armin de Meijere (Associate Editor), Handbook of
Organopalladium Chemistry for Organic Synthesis, John Wiley and Sons, 2002.
4-Amino-imidazo[1,5-f][1,2,4]triazine compounds of formula I, wherein R -R have the previously defined
meanings, can be prepared by the general synthetic route shown in scheme II
HN NH HN NH Pg HN HN
Iodination
POCl
N N N N
Pg-N(R )C(R R )COOH reagent
2 3 4
H N N H N N O H N N H N N
R2 2 2
Coupling reagent Pg Pg
R4 R4
R4 R3
XI R2 R2
XII XIII
R5 R5
X NH X NH
X NH
NH NH
VIII
B B B
O NH B NH B NH B
2 2 2 2
POCl ,triazole B
pyridine OH
HN N N N
Deprotection
NH /i-PrOH
N 3 N
Pd catalysts
base N N
Functionalisation
Pg R1
Pg Pg
Boronic acid
R4 R4 R4
R3 R3 R3 R3
R2 R2 R2 R2
XV XVI I
Scheme
Starting material 3-amino(aminomethyl)-1,2,4-triazin-5(4H)-one X can be prepared via a condensation
reaction of ethyl bromopyruvate, dibenzylamine, and aminoguanidine carbonate, followed by
debenzylation via hydrogenation over Pd-C catalyst [Mitchel, W.L.et al, J. Heterocycl. Chem. 21 (1984)
pp697].This can then be reacted with an appropriately amine protected amino acid. The reaction of Cbz-
N(R )CR R )COOH can be carried out in a solvent such as DMF, THF or DCM in the presence of a base
2 3 4
such as DIPEA, N-methylmorpholine, 4-DMAP or triethylamine and in the presence of a coupling reagent
such as PyBOP, TBTU, EDCI or HATU to form N-((3-aminooxo-4,5-dihydro-1,2,4-triazin
yl)methyl)amide XI. Cyclisation of the amino-triazinone XI can be performed using condensation reagents
like phosphorousoxychloride under heating conditions to provide the 2-aminoimidazo[1,5-f][1,2,4]triazin-
4(3H)-one derivatives XII. Subsequent iodination can be accomplished using iodine or N-iodosuccinimide
in a suitable solvent like DCM or DMF at appropriate temperature to obtain compounds of formula XIII.
Removal of the 2-amino group in the 2-aminoimidazo[1,5-f][1,2,4]triazin-4(3H)-one derivatives XIII can be
perfomed using t-butyl nitrite in solvents like DMF/THF at room temperature to form imidazo[1,5-
f][1,2,4]triazin-4(3H)-one derivatives XIV. 4-Amino-imidazo[1,5-f][1,2,4]triazine derivatives (XV) can be
prepared from compounds XIV using phosphorousoxychloride, 1,2,4-triazole in pyridine and subsequent
ammonolysis with ammonia(gas) in isopropanol at room temperature. Compounds of formula XVI can be
prepared from compounds of formula XV using an appropriate boronic acid or pinacol ester (VIII), in the
presence of a suitable palladium catalyst system and solvent, for example
bis(diphenylphosphino)ferrocene palladium(II)chloride complex or
tetrakis(triphenylphosphine)palladium(0) in the presence of potassium carbonate in dioxane/water provide
compounds of formula XVI. Finally, cleaving the protective group of compounds with the formula XVI give
the unprotected amine which after functionalisation, using methods well known in the art, with appropriate
warheads with previously defined meanings, provided compounds of formula I. An example of such
protective strategy is the use of the benzyloxycarbonyl protecting group to protect the amine from the
amino acids used, and after deprotection with 33% HBr/HOAc or conc. HCl gave the resulting amines.
The amino acids HN(R )CR R )COOH are either commercially available or they can be readily prepared
2 3 4
using methods well known to the skilled organic chemist, to introduce protecting groups like
benzyloxycarbonyl or tert-butyloxycarbonyl.
Palladium catalysts and conditions to form either the pinacol esters or to couple the boronic acids or
pinacol esters with the 5-iodoimidazo[1,5-f][1,2,4]triazinamine are well known to the skilled organic
chemist – see, for example, Ei-ichi Negishi (Editor), Armin de Meijere (Associate Editor), Handbook of
Organopalladium Chemistry for Organic Synthesis, John Wiley and Sons, 2002.
The present invention also includes within its scope all stereoisomeric forms of the 8-amino-imidazo[1,5-
a]pyrazine and 4-amino-imidazo[1,5-f][1,2,4]triazine derivatives according to the present invention
resulting, for example, because of configurational or geometrical isomerism. Such stereoisomeric forms
are enantiomers, diastereoisomers, cis and trans isomers etc. For example where azepanecarboxylic
acid is used as amino acid, there exists a mixture of two enantiomers. In the case of the individual
stereoisomers of compounds of formula I or salts or solvates thereof, the present invention includes the
aforementioned stereoisomers substantially free, i.e., associated with less than 5%, preferably less than
2% and in particular less than 1% of the other stereoisomer. Mixtures of stereoisomers in any proportion,
for example a racemic mixture comprising substantially equal amounts of two enantiomers are also
included within the scope of the present invention.
For chiral compounds, methods for asymmetric synthesis whereby the pure stereoisomers are obtained
are well known in the art, e.g. synthesis with chiral induction, synthesis starting from chiral intermediates,
enantioselective enzymatic conversions, separation of stereoisomers using chromatography on chiral
media. Such methods are described in Chirality In Industry (edited by A.N. Collins, G.N. Sheldrake and J.
Crosby, 1992; John Wiley). Likewise methods for synthesis of geometrical isomers are also well known in
the art.
The8-amino-imidazo[1,5-a]pyrazine and 4-amino-imidazo[1,5-f][1,2,4]triazine derivatives of the present
invention, which can be in the form of a free base, may be isolated from the reaction mixture in the form
of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by
treating the free base of formula I with an organic or inorganic acid such as hydrogen chloride, hydrogen
bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic
acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic
acid, and ascorbic acid.
The8-amino-imidazo[1,5-a]pyrazine and 4-amino-imidazo[1,5-f][1,2,4]triazine derivatives of the present
invention also exist as amorphous forms. Multiple crystalline forms are also possible. All the physical
forms are included within the scope of the present invention.
Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci.,
93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl
acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are
described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et
al, Chem. Commun. 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive
compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher
than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then
isolated by standard methods. Analytical techniques such as, for example IR spectroscopy, show the
presence of the solvent (or water) in the crystals as a solvate (or hydrate).
The present invention also embraces isotopically-labelled compounds of the present invention which are
identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having
an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into compounds of the invention include isotopes of
2 3 13 14 15 17
hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as H, H, C, C, N, O,
18 31 32 35 18 36
O, P, P, S, F, and Cl, respectively.
3 14
Certain isotopically-labelled compounds of Formula I (e.g. those labeled with H and C) are useful in
3 14
compound and/or substrate tissue distribution assays. Tritiated (i.e., H) and carbon-14 (i.e., C) isotopes
are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier
isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater
metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be
preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared
by following procedures analogous to those disclosed in the Schemes and/or in the Examples herinbelow,
by substituting an appropriate isotopically labeled reagent for a non-isotoplically labeled reagent.
The invention is illustrated by the following examples.
Examples
The following examples are illustrative embodiments of the invention, not limiting the scope of the
invention in any way. Reagents are commercially available or are prepared according to procedures in
the literature.
Mass Spectrometry: Electron Spray spectra were recorded on the Applied Biosystems API-165 single
quad mass spectrometer in alternating positive and negative ion mode using Flow Injection. The mass
range was 120-2000 Da and scanned with a step rate of 0.2 Da. and the capillary voltage was set to 5000
V. N2-gas was used for nebulisation.
LC-MS spectrometer (Waters) Detector: PDA (200-320 nm), Mass detector: ZQ
Eluens : A: acetonitrile with 0.05% trifluoroacetic acid , B: acetronitrile / water = 1/9 (v/v) with 0.05%
trifluoroacetic acid
Methode LCMS (A)
Column 1: Chromolith Performance, RP-18e, 4.6x100 mm,
Gradient method: Flow: 4 mL/min
Time (min) A (%) B (%)
0.00 100 0
3.60 0 100
4.00 0 100
4.05 100 0
6.00 100 0
Methode LCMS (B)
Column 2: XBridge C18, 3.5µm, 4.6x20mm
Gradiënt methoden: Flow: 4 ml/min
Time (min.) A (%) B (%)
0.0 100 0
1.60 0 100
3.10 0 100
3.20 100 0
.00 100 0
UPLC : Water acquity UPLC system; Column : BEH C18 1.7 µm, 2.1 x 100 mm, Detector: PDA (200-320
nm), Mass detector: SQD
Eluens : A: acetonitrile with 0.035% trifluoroacetic acid , B: acetronitrile / water = 1/9 (v/v) with 0.035%
trifluoroacetic acid
Methode UPLC (A) UPLC (B) UPLC (C)
Method 60_100 Method 40_80 Method 0_60
Flow: 0.75 mL/min Flow: 0.65 mL/min Flow: 0.60 mL/min
Time (min) A (%) B (%) A (%) B (%) A (%) B (%)
0.0 40 60 60 40 100 0
3.00 0 100 20 80 40 60
3.20 0 100 0 100 0 100
3.69 0 100 0 100 0 100
3.70 40 60 60 40 100 0
Preparative HPLC was conducted on a column (50 x 10 mm ID, 5μm, Xterra Prep MS C18) at a flow rate
of 5 ml/min, injection volume 500 μl, at room temperature and UV Detection at 210 nm.
The following abbreviations are used throughout the application with respect to chemical terminology:
HATU O-(7-Azabenzotriazolyl)-1,1,3,3-tetramethyluroniumhexafluoro phosphate
Cbz Benzyloxycarbonyl
DMF N,N-Dimethylformamide
DCM Dichloromethane
EtOAc Ethyl acetate
DIPEA N,N-Diisopropylethylamine
THF Tetrahydrofuran
EtOH Ethanol
EDCI.HCl 1-(3-Dimethylaminopropyl)ethylcarbodiimide. hydrochloride
4-DMAP 4-Dimethylamino pyridine
PyBOP O-Benzotriazoleyl-oxy-trispyrrolidinophosphonium
hexafluorophosphate
TBTU O-Benzotriazolyl-N,N,N’,N’-tetramethyluronium tetrafluoroborate
HBr Hydrogen bromide
HCl Hydrogen chloride
HOAc Acetic acid
Z Benzyloxycarbonyl
Pro Proline
POCl Phosphorous oxychloride
HPLC High Pressure Liquid Chromatography
UPLC
LiHMDS Lithium hexamethyldisilazide
MeOH Methanol
Gly Glycine
Ala Alanine
n-BuLi n-Butyllithium
CO Carbondioxide
The names of the final products in the examples are generated using Chemdraw Ultra (version 9.0.7).
Intermediate 1
Cl Cl Cl
N N NH N NH
N N N
Cl Cl NH
Br Br
N N N
N N N
N N N
Cbz Cbz Cbz
N N N
(S)-Benzyl 2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate
(a) (3-Chloropyrazinyl)methanamine.hydrochloride
To a solution of 3-chloropyrazinecarbonitrile (160 g, 1.147 mol) in acetic acid (1.5 L) was added Raney
Nickel (50% slurry in water, 70 g, 409 mmol). The resulting mixture was stirred under 4 bar hydrogen at
room temperature overnight. Raney Nickel was removed by filtration over decalite and the filtrate was
concentrated under reduced pressure and co-evaporated with toluene. The remaining brown solid was
dissolved in ethyl acetate at 50°C and cooled on an ice-bath. 2M hydrogen chloride solution in diethyl
ether (1.14 L) was added in 30 min. The mixture was allowed to stir at room temperature over weekend.
The crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure at
40°C. The product brown solid obtained was dissolved in methanol at 60°C. The mixture was filtered and
partially concentrated, cooled to room temperature and diethyl ether (1000 ml) was added. The mixture
was allowed to stir at room temperature overnight. The solids formed were collected by filtration, washed
with diethyl ether and dried under reduced pressure at 40°C to give 153.5 g of (3-chloropyrazin
yl)methanamine.hydrochloride as a brown solid (74.4 %, content 77 %).
(b) (S)-benzyl 2-((3-chloropyrazinyl)methylcarbamoyl)pyrrolidinecarboxylate
To a solution of (3-chloropyrazinyl)methanamine.HCl (9.57 g, 21.26 mmol, 40% wt) and Z-Pro-OH (5.3
g, 21.26 mmol) in dichloromethane (250 mL) was added triethylamine (11.85 mL, 85 mmol) and the
reaction mixture was cooled to 0°C. After 15 min stirring at 0°C, HATU (8.49 g, 22.33 mmol) was added.
The mixture was stirred for 1 hour at 0°C and then overnight at room temperature. The mixture was
washed with 0.1 M HCl-solution, 5% NaHCO3, water and brine, dried over sodium sulfate and
concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate =
1/4 v/v%) to give 5 g of (S)-benzyl 2-((3-chloropyrazinyl)methylcarbamoyl)pyrrolidinecarboxylate
(62.7%).
(c) (S)-Benzyl 2-(8-chloroimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate
(S)-Benzyl 2-((3-chloropyrazinyl)methylcarbamoyl)pyrrolidinecarboxylate (20.94 mmol, 7.85 g) was
dissolved in acetonitrile (75 ml), 1,3-dimethylimidazolidinone (62.8 mmol, 6.9 ml, 7.17 g) was added
and the reaction mixture was cooled to 0ºC before POCl3 (84 mmol, 7.81 ml, 12.84 g) was added drop
wise while the temperature remained around 5ºC. The reaction mixture was refluxed at 60-65°C
overnight. The reaction mixture was poured carefully in ammonium hydroxide 25% in water (250
ml)/crushed ice (500 ml) to give a yellow suspension (pH ~8-9) which was stirred for 15 min until no ice
was present in the suspension. Ethyl acetate was added, layers were separated and the aqueous layer
was extracted with ethyl acetate (3x). The organic layers were combined and washed with brine, dried
over sodium sulfate, filtered and evaporated to give 7.5 g crude product. The crude product was purified
using silica gel chromatography (heptane/ethyl acetate = 1/4 v/v%) to give 6.6 g of (S)-benzyl 2-(8-
chloroimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (88%).
(d) (S)-Benzyl 2-(1-bromochloroimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate
N-Bromosuccinimide (24.69 mmol, 4.4 g) was added to a stirred solution of (S)-benzyl 2-(8-
chloroimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (24.94 mmol, 8.9 g) in DMF (145 mL). The
reaction was stirred 3 h at rt. The mixture was poored (slowly) in a stirred mixture of water (145 mL), ethyl
acetate (145 mL) and brine (145 mL). The mixture was then transferred into a separating funnel and
extracted. The water layer was extracted with 2x145 mL ethyl acetate. The combined organic layers were
washed with 3x300 mL water, 300 mL brine, dried over sodium sulfate, filtered and evaporated. The
product was purified using silica gel chromatography (ethyl acetate/heptane = 3/1 v/v%) to give 8.95 g of
(S)-benzyl 2-(1-bromochloroimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (82.3%).
(e) (S)-Benzyl 2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate
(S)-Benzyl 2-(1-bromochloroimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (20.54 mmol, 8.95 g)
was suspended in 2-propanol (113 ml) in a pressure vessel. 2-propanol (50 ml) was cooled to -78ºC in a
pre-weighed flask (with stopper and stirring bar) and ammonia gas (646 mmol, 11 g) was lead through for
minutes. The resulting solution was added to the suspension in the pressure vessel. The vessel was
closed and stirred at room temperature and a slight increase in pressure was observed. Then the
suspension was heated to 110 °C which resulted in an increased pressure to 4.5 bar. The clear solution
was stirred at 110 ºC, 4.5 bar overnight. After 18h the pressure remained 4 bar. The reaction mixture was
concentrated in vacuum, the residue was suspended in ethyl acetate and subsequent washed with water.
The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate and
concentrated to give 7.35 g of (S)-benzyl 2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidine
carboxylate (86%).
Intermediate 2
NH NH NH
2 2 2
N N N
N N N
N N N
Cbz Cbz
N N NH
(S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
(a) (S)-Benzyl 2-(8-amino(4-(pyridinylcarbamoyl)phenyl)imidazo[1,5-a]pyrazinyl)pyrrolidine
carboxylate
(S)-benzyl 2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (0.237 mmol, 98.5
mg) and 4-(pyridinyl-aminocarbonyl)benzeneboronic acid (0.260 mmol, 63.0 mg) were suspended in a
mixture of 2N aqueous potassium carbonate solution (2.37 mmol, 1.18 mL) and dioxane (2.96 mL).
Nitrogen was bubbled through the mixture, followed by the addition of 1,1'-
bis(diphenylphosphino)ferrocene palladium (ii) chloride (0.059 mmol, 47.8 mg). The reaction mixture was
heated for 20 minutes at 140°C in the microwave. Water was added to the reaction mixture, followed by
an extraction with ethyl acetate (2x). The combined organic layer was washed with brine, dried over
magnesium sulfate and evaporated. The product was purified using silicagel and
dichloromethane/methanol = 9/1 v/v% as eluent to afford 97.1 mg of (S)-benzyl 2-(8-amino(4-(pyridin-
2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (77%).
(b) (S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
To (S)-benzyl 2-(8-amino(4-(pyridinylcarbamoyl)phenyl)imidazo[1,5-a]pyrazinyl)pyrrolidine
carboxylate (0.146 mmol, 78 mg) was added a 33% hydrobromic acid/acetic acid solution (11.26 mmol, 2
ml) and the mixture was left at room temperature for 1 hour. The mixture was diluted with water and
extracted with dichloromethane. The aqueous phase was neutralized using 2N sodium hydroxide
solution, and then extracted with dichloromethane. the organic layer was dried over magnesium sulfate,
filtered and evaporated to give 34 mg of (S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-
(pyridinyl)benzamide (58%).
Example 1
(S)(3-(1-Acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
To a solution of (S)(8-amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
(0.626 mmol, 250 mg) in dichloromethane (25 ml) at 0 °C was added triethylamine (0.626 mmol, 0.087
ml, 63.3 mg) and, drop wise, acryloyl chloride (0.657 mmol, 0.053 ml, 59.5 mg). The resulting mixture was
stirred at 0 °C for 2 hours. The mixture was washed with water, dried over magnesium sulfate. After
evaporation, the residue was purified by preparative HPLC. Fractions containing product were collected
and lyophilized to afford 126 mg of (S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-
N-(pyridinyl)benzamide (44.4% yield). Data: UPLC (C) Rt : 1.50 min; m/z 454.3 (M+H) .
Example 2
(S,E)(8-amino(1-(4-(pyrrolidinyl)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin-
2-yl)benzamide
To a solution of (S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
(intermediate 2b, 19.7 mg, 0.049 mmol), triethylamine (20 mg, 0.197 mmol, 0.027 mL) and (E)
(pyrrolidinyl)butenoic acid hydrochloride (9.45 mg, 0.049 mmol) in dichloromethane (2 mL) was
added HATU (18.75 mg, 0.049 mmol). The mixture was stirred for 30 min at room temperature. The
mixture was washed with water dried over magnesium sulfate and concentrated in vacuo. The residue
was purified by preparative HPLC. Fractions containing product were collected and reduced to dryness to
afford 7.1 mg of (S,E)(8-amino(1-(4-(pyrrolidinyl)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazin-
1-yl)-N-(pyridinyl)benzamide (26.8 % yield). Data: UPLC (C) R : 1.25 min; m/z 537.4 (M+H) .
Example 3
(S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-
(pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 2b and (E)(dimethylamino)butenoic acid, to afford the title compound
(11.8 mg, 46.6%). Data: UPLC (C) Rt : 1.29 min; m/z 511.0 (M+H) .
Intermediate 3
(E)Methoxybutenoic acid
Sodium methoxide (30%/Methanol, 30.3 mmol, 5.68 mL) was added via a glass syringe to a stirred
solution of 4-bromocrotonic acid (6.06 mmol, 1 g) in methanol (60 mL) at room temperature. The light
yellow solution was stirred for 30 min at room temperature and 2 h. at reflux. After cooling the reaction
mixture, the solvent was removed under reduced pressure. The residue was partitioned between water
(50 mL) and diethyl ether (50 mL). 2M aq. hydrochloride solution (3.5 mL) was added until pH was ~pH 1.
The waterlayer was separated and extracted with diethyl ether (3 x 20 mL). The combined organic layers
were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo, to give 650 mg of
(E)Methoxybutenoic acid (92%).
Example 4
(S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 2b and (E)methoxybutenoic acid (Intermediate 3), to afford the title
compound (11 mg, 29.9%). Data: UPLC (C) Rt : 1.58 min; m/z 498.3 (M+H) .
Example 5
(S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin-
2-yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 2b and 2-chloropyrimidinecarboxylic acid, to afford the title compound (8.3
mg, 40.4%). Data: UPLC (C) R : 1.64 min; m/z 540.1 (M+H) .
Example 6
(S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 2b and 2-butynoic acid, to afford the title compound (10.5 mg, 18.0%). Data:
LCMS (B) Rt : 2.08 min; m/z 466.1 (M+H) .
Intermediate 4
OH Cl
N-(4-fluoropyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
(a) 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)benzoyl chloride
To a cold (0°C) solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoic acid (40.3 mmol, 10.01
g) in dichloromethane (206 mL) was added a catalytic amount of DMF. A solution of oxalyl chloride (101
mmol, 8.66 mL, 12.8 g) was added drop wise. After stirring for 30 min at 0°C, the reaction mixture was
allowed to warm up to room temperature and the mixture was stirred for an additional 3 hours. The
reaction mixture was concentrated to give 10.9 g. of crude 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)benzoyl chloride (101%).
(b) N-(4-fluoropyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoyl chloride (1.688 mmol, 450 mg) in
acetonitrile (24.8 mL) was added 2-aminofluoropyridine (4.22 mmol, 473 mg). The reaction mixture
was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to a small volume, 3%
aq. citric acid solution (18 mL) was added and the mixture was extracted with dichloromethane (2 x 15
mL). The combined organic layer was washed with 3% aq. citric acid solution, dried over magnesium
sulfate, filtered and evaporated to afford 542.2 mg of N-(4-fluoropyridinyl)(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)benzamide (94%) as an off-white solid.
Intermediate 5
(S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 2b, from (S)-
benzyl 2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (Intermediate 1e) and N-
(4-fluoropyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (intermediate 4b) to afford
the title compound (331 mg, 93%).
Example 7
(S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
fluoropyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 5 and (E)(dimethylamino)butenoic acid, to afford the title compound (33.4
mg, 54.1%). Data: UPLC (C) Rt : 1.72 min; m/z 529.3 (M+H) .
Intermediate 6
N-(4-Methylpyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
To a stirred solution of 4-methylpyridinamine (7.86 mmol, 850 mg) in THF (50 mL) was added
dropwise a solution of 1M LiHMDS in THF (8.0 mmol, 8 mL) at room temperature. After the reaction
mixture turned dark green, a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoyl chloride
(9.6 mmol, 2.56 g) in dichloromethane (55 mL) was added dropwise. The mixture was stirred at room
temperature for 2.5 h and was then concentrated. 3% aq. Citric acid solution (18 mL) was added and the
mixture was extracted with dichloromethane (2 x 15 mL). The combined organic layer was washed with
3% aq. citric acid solution, dried over magnesium sulfate, filtered and evaporated. The residue was
dissolved in THF (15 mL) and 6M NaOH solution (15 mL) was added. The mixture was stirred for 4 h. at
room temperature. Ethyl acetate was added and the layers were separated. The organic layer was
washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified
by chromatography on silica (eluent: DCM/MeOH=98/2 to DCM/MeOH=95/5) to yield 1.1 g of N-(4-
methylpyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (40.7%).
Intermediate 7
(S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-methylpyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 2, from (S)-benzyl
2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (Intermediate 1e) and N-(4-
methylpyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (intermediate 6) to afford the
title compound (125.5 mg, 82%).
Example 8
(S)(8-Amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-methylpyridin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-methylpyridinyl)benzamide (intermediate 7) and 2-
butynoic acid, to afford the title compound (6.3 mg, 27.2%). Data: UPLC (C) R : 1.56 min; m/z 480.3
(M+H) .
Intermediate 8
N-(4-Propylpyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 6, starting from 4-
propylpyridinamine, to afford the title compound (371.5 mg, 54.1%).
Intermediate 9
(S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-propylpyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 2, from (S)-benzyl
2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (Intermediate 1e) and N-(4-
Propylpyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (intermediate 8) to afford the
title compound (147.8 mg, 93%).
Example 9
(S,E)(8-Amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-
propylpyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-propylpyridinyl)benzamide (intermediate 9) and (E)-
4-methoxybutenoic acid (Intermediate 3), to afford the title compound (30.9 mg, 65.7%). Data: UPLC
(C) R : 2.73 min; m/z 566.3 (M+H) .
Intermediate 10
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)-N-(4-(trifluoromethyl)pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 6, starting from 4-
(trifluoromethyl)pyridinamine, to afford the title compound (657.2 mg, 89%).
Intermediate 11
(S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 2, from (S)-benzyl
2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (Intermediate 1e) and 4-(4,4,5,5-
Tetramethyl-1,3,2-dioxaborolanyl)-N-(4-(trifluoromethyl)pyridinyl)benzamide (intermediate 10) to
afford the title compound (163 mg, 87%).
Example 10
(S)(8-Amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridinyl)benzamide (intermediate
11) and 2-butynoic acid, to afford the title compound (7.1 mg, 31.1%). Data: UPLC (C) Rt : 2.63 min; m/z
534.2 (M+H) .
Intermediate 12
N-(4-Ethylpyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 4, starting from 4-
ethylpyridinamine, to afford the title compound (334.5 mg, 50.6%).
Intermediate 13
(S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-ethylpyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 2, from (S)-benzyl
2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (Intermediate 1e) and N-(4-
ethylpyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (intermediate 12) to afford the
title compound (133.8 mg, 89%).
Example 11
(S,E)(8-Amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-ethylpyridin-
2-yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-ethylpyridinyl)benzamide (intermediate 13) and (E)-
4-methoxybutenoic acid (Intermediate 3), to afford the title compound (10.6 mg, 28.8%). Data: UPLC
(C) R : 1.60 min; m/z 526.3 (M+H) .
Intermediate 14
O O O
Cl N N
Br Br B
N-(4,5,6,7-Tetrahydrobenzo[d]thiazolyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
(a) 4-Bromo-N-(4,5,6,7-tetrahydrobenzo[d]thiazolyl)benzamide
4-Bromobenzoyl chloride (1.5 g, 6.83 mmol) and 4,5,6,7-Tetrahydro-1,3-benzothiazolamine (1.054 g,
6.83 mmol) were dissolved in Pyridine (15 ml) and stirred at 50°C for 1.5 h. The reaction mixture was
cooled to room temperature and poured in water. The solid formed was filtered, washed with water. The
solids were co-evaporated with toluene twice to afford 1.8 g of 4-bromo-N-(4,5,6,7-
tetrahydrobenzo[d]thiazolyl)benzamide (78%) as a yellow solid.
(b) N-(4,5,6,7-Tetrahydrobenzo[d]thiazolyl)(4,4,5,5-tetramethyl-1,3,2-dioxaboro-lanyl)benzamide
To a solution of 4-bromo-N-(4,5,6,7-tetrahydrobenzo[d]thiazolyl)benzamide (1.8 g, 5.34 mmol) dioxane
(40 ml) was added bis(pinacolato)diboron (1.762 g, 6.94 mmol) and potassium acetate (1.048 g, 10.68
mmol). The reaction mixture was degassed with nitrogen. Subsequently 1,1'-
bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.218 g, 0.267 mmol) added and the reaction
mixture was stirred at 80°C for 5 days. The mixture was cooled to room temperature and after addition of
water extracted three times with EtOAC. The organic layers were combined , washed with brine, dried
over sodium sulfate, filtered and evaporated. The crude product was purified using silica gel
chromatography (heptane/ethyl acetate 3/7 to 7/3 v/v%) to give 600 mg of N-(4,5,6,7-
tetrahydrobenzo[d]thiazolyl)(4,4,5,5-tetramethyl-1,3,2-dioxaboro-lanyl)benzamide (29.3%).
Intermediate 15
(S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4,5,6,7-tetrahydrobenzo[d]thiazol
yl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 2, from (S)-benzyl
2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (Intermediate 1e) and N-(4,5,6,7-
tetrahydrobenzo[d]thiazolyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (intermediate
14b) to afford the title compound (260 mg, 60%).
Example 12
(S)(8-Amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4,5,6,7-
tetrahydrobenzo[d]thiazolyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4,5,6,7-tetrahydrobenzo[d]thiazolyl)benzamide
(intermediate 15) and 2-butynoic acid, to afford the title compound (7 mg, 19.2%). Data: UPLC (C) R :
2.41 min; m/z 526.3 (M+H) .
Intermediate 16
2-Fluoro-N-(pyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 14, starting from 4-
bromofluorobenzoic acid, to afford the title compound (2.54 g, 76%).
Intermediate 17
(S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)fluoro-N-(pyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 2, from (S)-benzyl
2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (Intermediate 1e) and 2-Fluoro-
N-(pyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (intermediate 16) to afford the
title compound (160 mg, 76%).
Example 13
(S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)fluoro-N-(pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 1, from (S)(8-amino-
3-(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)fluoro-N-(pyridinyl)benzamide (intermediate 17) and
acryloylchloride, to afford the title compound (13 mg, 38.4%). Data: UPLC (C) R : 1.67 min; m/z 472.3
(M+H) .
Intermediate 18
2-Methoxy-N-(pyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 14, starting from 4-
bromomethoxybenzoic acid, to afford the title compound (2.6 g, 90%).
Intermediate 19
(S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)methoxy-N-(pyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 2, from (S)-benzyl
2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (Intermediate 1e) and 2-methoxy-
N-(pyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (intermediate 18) to afford the
title compound (175 mg, 56.6%).
Example 14
(S)(3-(1-Acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)methoxy-N-(pyridin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 1, from (S)(8-amino-
3-(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)methoxy-N-(pyridinyl)benzamide (intermediate 19) and
acryloylchloride, to afford the title compound (14 mg, 35.5%). Data: UPLC (C) R : 1.74 min; m/z 484.3
(M+H) .
Intermediate 20
(S)(8-Amino(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(thiazolyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 2, from (S)-benzyl
2-(8-aminobromoimidazo[1,5-a]pyrazinyl)pyrrolidinecarboxylate (Intermediate 1e) and
commercially available Nthiazolyl 4-boronobenzamide to afford the title compound (229 mg, 73.1%).
Example 15
(S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(thiazol-
2-yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(thiazolyl)benzamide (intermediate 20) and (E)
(dimethylamino)butenoic acid, to afford the title compound (18.9 mg, 29.7%). Data: UPLC (C) R : 1.38
min; m/z 517.3 (M+H) .
Intermediate 21
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with commercially available 4-(pyridinyl-
aminocarbonyl)benzeneboronic acid, analogues as described for intermediate 2 afforded the title
compound (491 mg, 91%).
Example 16
(S,E)(8-Amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide (intermediate 21) and (E)
methoxybutenoic acid (intermediate 3), to afford the title compound (21.1 mg, 54.3%). Data: LCMS (B)
Rt : 2.22 min; m/z 512.3 (M+H) .
Intermediate 22
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with N-(4-fluoropyridinyl)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)benzamide (Intermediate 4), analogues as described for intermediate
2 afforded the title compound (160 mg, 71.8%).
Example 17
(S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 1, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridinyl)benzamide (intermediate 22) and
acryloylchlroide, to afford the title compound (12 mg, 42.7%). Data: UPLC(C) R : 2.29 min; m/z 486.3
(M+H) .
Intermediate 23
N-(4-Cyanopyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 4, starting from 2-
aminoisonicotinonitrile, to afford the title compound (1.3 g, 99%).
Intermediate 24
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-cyanopyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with N-(4-cyanopyridinyl)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)benzamide (Intermediate 23), analogues as described for
intermediate 2 afforded the title compound (82 mg, 35.7%).
Example 18
(S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-cyanopyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 1, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-cyanopyridinyl)benzamide (intermediate 24) and
acryloylchloride, to afford the title compound (4.8 mg, 10.4%). Data: UPLC(C) Rt : 2.31 min.
Intermediate 25
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-N-(4-(trifluoromethyl)pyridinyl)benzamide (Intermediate 10), analogues as described
for intermediate 2 afforded the title compound (144 mg, 59.1%).
Example 19
(S)(8-Amino(1-(vinylsulfonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 1, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridinyl)benzamide (intermediate 25)
and ethenesulfonyl chloride prepared according to procedures described by King et.al. in Can. J. Chem.
66 (1988) pp1109-1116, to afford the title compound (6.1 mg, 20.5%). Data: UPLC(B) Rt : 1.24 min; m/z
572.2 (M+H) .
Intermediate 26
N-(Pyrimidinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 14, starting from 2-
aminopyrimidine, to afford the title compound (855 mg, 42.6%).
Intermediate 27
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyrimidinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with N-(pyrimidinyl)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)benzamide (Intermediate 26), analogues as described for
intermediate 2 afforded the title compound (100.8 mg, 95.4%).
Example 20
(S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyrimidinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 1, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyrimidinyl)benzamide (intermediate 27) and
acryloylchloride, to afford the title compound (5.9 mg, 26.2%). Data: UPLC(C) Rt : 1.70 min; m/z 469.3
(M+H) .
Intermediate 28
N-(4-Methylpyrimidinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 14, starting from 2-
aminomethylpyrimidine, to afford the title compound (420 mg, 60.6%).
Intermediate 29
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-methylpyrimidinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with N-(4-methylpyrimidinyl)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)benzamide (Intermediate 28), analogues as described for
intermediate 2 afforded the title compound (83 mg, 50.4%).
Example 21
(S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-methylpyrimidin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 1, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-methylpyrimidinyl)benzamide (intermediate 29) and
acryloylchloride, to afford the title compound (4.5 mg, 27.4%). Data: UPLC(C) R : 1.79 min; m/z 483.3
(M+H) .
Intermediate 30
N-(Pyrimidinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 14, starting from 4-
aminopyrimidine, to afford the title compound (1 g, 59.4%).
Intermediate 31
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyrimidinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with N-(pyrimidinyl)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)benzamide (Intermediate 30), analogues as described for
intermediate 2 afforded the title compound (66 mg, 42.8%).
Example 22
(S)(8-Amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyrimidinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyrimidinyl)benzamide (intermediate 31) and 2-butynoic
acid, to afford the title compound (10.3 mg, 26.9%). Data: UPLC(C) Rt : 1.91 min; m/z 481.3 (M+H) .
Intermediate 32
N-(Pyridazinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 14, starting from 3-
aminopyridazine, to afford the title compound (1.25 g, 71.3%).
Intermediate 33
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridazinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with N-(pyridazinyl)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)benzamide (Intermediate 32) and deprotection, analogues as
described for intermediate 2 afforded the title compound (258 mg, 85%).
Example 23
(S)(8-Amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridazinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridazinyl)benzamide (intermediate 33) and 2-butynoic
acid, to afford the title compound (11 mg, 31.8%). Data: UPLC(C) R : 1.92 min; m/z 481.3 (M+H) .
Intermediate 34
N-(Isoxazolyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 14, starting from 3-
aminoisoxazole, to afford the title compound (1.64 g, 95%).
Intermediate 35
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(isoxazolyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with N-(isoxazolyl)(4,4,5,5-tetramethyl-
1,3,2-dioxaborolanyl)benzamide (Intermediate 34) and deprotection, analogues as described for
intermediate 2 afforded the title compound (72 mg, 129%).
Example 24
(S)(8-Amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(isoxazolyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(isoxazolyl)benzamide (intermediate 35) and 2-butynoic
acid, to afford the title compound (2 mg, 6.6%). Data: UPLC(C) R : 2.23 min; m/z 470.3 (M+H) .
Intermediate 36
N-(5-Ethylthiazolyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 4, starting from 5-
ethylthiazolamine, to afford the title compound (191 mg, 34.2%).
Intermediate 37
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(5-ethylthiazolyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with N-(5-ethylthiazolyl)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)benzamide (Intermediate 36) and deprotection, analogues as
described for intermediate 2 afforded the title compound (146 mg, 52.4%).
Example 25
(S,E)(8-Amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(5-ethylthiazol-
2-yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(5-ethylthiazolyl)benzamide (intermediate 37) and (E)
methoxybutenoic acid (Intermediate 3), to afford the title compound (11.7 mg, 47.6%). Data: UPLC(C)
Rt : 2.59 min; m/z 546.3 (M+H) .
Intermediate 38
2-Fluoro-N-(4-propylpyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 4, starting from
commercially available 2-fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoic acid and 4-propyl-
pyridinylamine, to afford the title compound (830 mg, 63.3%).
Intermediate 39
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)fluoro-N-(4-propylpyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with 2-fluoro-N-(4-propylpyridinyl)
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamid (Intermediate 38) and deprotection, analogues as
described for intermediate 2 afforded the title compound (75.4 mg, 62%).
Example 26
(S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)fluoro-N-(4-propylpyridin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)fluoro-N-(4-propylpyridinyl)benzamide (intermediate 39)
and acrylic acid, to afford the title compound (5.9 mg, 28.9%). Data: UPLC(C) Rt : 2.41 min; m/z 528.4
(M+H) .
Intermediate 40
2-Methoxy-N-(4-propylpyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 14, starting from
commercially available 4-bromomethoxybenzoic acid and 4-propyl-pyridinylamine, to afford the title
compound (240 mg, 15.1%).
Intermediate 41
(S)(8-Amino(piperidinyl)imidazo[1,5-a]pyrazinyl)methoxy-N-(4-propylpyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with 2-methoxy-N-(4-propylpyridinyl)
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (Intermediate 40) and deprotection, analogues as
described for intermediate 2 afforded the title compound (74.5 mg, 75%).
Example 27
(S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)
methoxy-N-(4-propylpyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(piperidinyl)imidazo[1,5-a]pyrazinyl)methoxy-N-(4-propylpyridinyl)benzamide (intermediate
41) and (E)(dimethylamino)butenoic acid, to afford the title compound (13.1 mg, 38.4%). Data:
UPLC(C) R : 1.86 min; m/z 597.4 (M+H) .
Intermediate 42
3-Methyl-N-(pyridinyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide
This compound was prepared, in an analogues manner as described in Intermediate 14, starting from
commercially available 4-bromomethylbenzoic acid and 2-aminopyridine, to afford the title compound
(2.5 g, 71.3%).
Intermediate 43
4-(8-Amino((S)-piperidinyl)imidazo[1,5-a]pyrazinyl)methyl-N-(pyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)piperidinecarboxylic acid to obtain (S)-benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)piperidinecarboxylate. Subsequent reaction with 3-methyl-N-(pyridinyl)(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)benzamide (Intermediate 42) and deprotection, analogues as
described for intermediate 2 afforded the title compound (150 mg, 71.7%).
Example 28
4-(8-Amino((S)butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)methyl-N-(pyridin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from 4-(8-amino
((S)-piperidinyl)imidazo[1,5-a]pyrazinyl)methyl-N-(pyridinyl)benzamide (intermediate 43) and
2-butynoic acid, to afford the title compound (13.7 mg, 59.1%). Data: UPLC(C) Rt : 2.28 min; m/z 494.3
(M+H) .
Intermediate 44
4-(8-Amino(aminomethyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from Z-Gly-OH
to obtain benzyl (8-aminobromoimidazo[1,5-a]pyrazinyl)methylcarbamate. Subsequent reaction with
commercially available 4-(pyridinyl-aminocarbonyl)benzeneboronic acid, analogues as described for
intermediate 2 afforded the title compound (261 mg, 81%).
Example 29
4-(3-(Acrylamidomethyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 1, from 4-(8-amino
(aminomethyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide (intermediate 44) and
acryloylchloride, to afford the title compound (1.7 mg, 4%). Data: UPLC(C) R : 1.22 min; m/z 414.2
(M+H) .
Intermediate 45
(S)(8-Amino(1-aminoethyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from Z-Ala-OH
to obtain benzyl (S)-benzyl 1-(8-aminobromoimidazo[1,5-a]pyrazinyl)ethylcarbamate. Subsequent
reaction with commercially available 4-(pyridinyl-aminocarbonyl)benzeneboronic acid and deprotection
with 33%HBr/HOAc, analogues as described for intermediate 2 afforded the title compound (133.6 mg,
80%).
Example 30
(S)(8-Amino(1-butynamidoethyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(1-aminoethyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide (intermediate 45) and 2-butynoic
acid, to afford the title compound (9.5 mg, 26.9%). Data: UPLC(C) Rt : 1.38 min; m/z 440.3 (M+H) .
Example 31
(S)-S(2-(8-Amino(4-(pyridinylcarbamoyl)phenyl)imidazo[1,5-a]pyrazinyl)pyrrolidinyl)
oxoethyl ethanethioate
This compound was prepared, in an analogues manner as described in Example 1, from the compound
described in intermediate 2b and 2,5-dioxopyrrolidinyl 2-(acetylthio)acetate, to afford the title
compound (12.3 mg, 31.8%). Data: UPLC (C) Rt : 1.51 min; m/z 516.3 (M+H) .
Example 32
(S)(8-Amino(1-(4-hydroxymethylpentynoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-
(pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 2b and 4-hydroxymethylpentynoic acid, to afford the title compound (8.0
mg, 25.1%). Data: UPLC (C) Rt : 1.53 min; m/z 510.3 (M+H) .
Example 33
(S)(8-Amino(1-(6-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin-
2-yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 2b and 6-chloropyrimidinecarboxylic acid, to afford the title compound (2.5
mg, 6.2%). Data: UPLC (C) Rt : 1.64 min; m/z 540.3 (M+H) .
Example 34
(S)(8-Amino(1-pentynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 2b and pentynoic acid, to afford the title compound (7.4 mg, 24.7%). Data:
UPLC (C) Rt : 1.73 min; m/z 480.3 (M+H) .
Example 35
(S)(8-Amino(1-(3-cyclopropylpropioloyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 2b and 3-cyclopropylpropiolic acid, to afford the title compound (8 mg, 26%).
Data: UPLC (C) Rt : 1.73 min; m/z 492.3 (M+H) .
Example 36
(S)(8-Amino(1-hexynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 2b and hexynoic acid, to afford the title compound (8.1 mg, 26.2%). Data:
UPLC (C) R : 1.94 min; m/z 494.3 (M+H) .
Intermediate 46
4-(8-Amino(azepanyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from 1-
(benzyloxycarbonyl)azepanecarboxylic acid to obtain benzyl 2-(8-aminobromoimidazo[1,5-
a]pyrazinyl)azepanecarboxylate. Subsequent reaction with commercially available 4-(pyridinyl-
aminocarbonyl)benzeneboronic acid, analogues as described for intermediate 2 afforded the title
compound (436 mg, quantitative, crude).
Example 37
4-(3-(1-Acryloylazepanyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 1, from 4-(8-amino
(azepanyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide (intermediate 46) and acryloylchloride,
to afford the title compound (11 mg, 32.6%). Data: UPLC(C) R : 1.88 min; m/z 482.3 (M+H) .
Intermediate 47
(R)(8-Amino(morpholinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
(benzyloxycarbonyl)morpholinecarboxylic acid to obtain (R)-benzyl 3-(8-aminobromoimidazo[1,5-
a]pyrazinyl)morpholinecarboxylate. Subsequent reaction with commercially available 4-(pyridinyl-
aminocarbonyl)benzeneboronic acid, analogues as described for intermediate 2 and subsequent
deprotection using TFA at 60°C, afforded the title compound (62 mg, 69.5%).
Example 38
(R)(8-Amino(4-butynoylmorpholinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (R)(8-amino-
3-(morpholinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide (intermediate 47) and 2-butynoic
acid, to afford the title compound (4.9 mg, 14.1%). Data: UPLC(C) R : 1.38 min; m/z 482.3 (M+H) .
Intermediate 48
(S)(8-Amino(1-(methylamino)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridin
yl)benzamide
This intermediate was prepared, in an analogues manner as described for intermediate 1, from (S)
((benzyloxycarbonyl)(methyl)amino)propanoic acid to obtain (S)-benzyl 1-(8-aminobromoimidazo[1,5-
a]pyrazinyl)ethyl(methyl)carbamate. Subsequent reaction with 4-(4,4,5,5-Tetramethyl-1,3,2-
dioxaborolanyl)-N-(4-(trifluoromethyl)pyridinyl)benzamide (Intermediate 10), analogues as described
for intermediate 2 afforded the title compound (71 mg, 64.7%).
Example 39
(S)(8-amino(1-(N-methylbutynamido)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4-
(trifluoromethyl)pyridinyl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from (S)(8-amino-
3-(1-(methylamino)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridinyl)benzamide
(intermediate 48) and 2-butynoic acid, to afford the title compound (11.5 mg, 33.4%). Data: UPLC(C) R :
2.54 min; m/z 522.2 (M+H) .
Intermediate 49
4-(Dimethylamino)butynoic acid
n-BuLi in hexane (2.5M, 24.06 mmol, 9.62 mL) was slowly added to a solution of N,N-dimethylpropyn-
1-amine (24.06 mmol, 2,59 mL, 2 g) in dry THF (10 mL) at -78°C. The mixture was stirred for 1 h at -
78°C, then crushed CO (241 mmol, 10.59 g) was added in one portion and the reaction mixture was
stirred for an additional 10 min. The resulting solution was poured into water and washed with ethyl
acetate. The aqueous layer was evaporated in vacuo to give the crude amino acid. This was dissolved in
methanol, and the insoluble salts were removed via filtration. The filtrate was evaporated to give 3.25 g of
4-(dimethylamino)butynoic acid (106%).
Example 40
(S)(8-Amino(1-(4-(dimethylamino)butynoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 2b and 4-(dimethylamino)butynoic acid (Intermediate 49), to afford the title
compound (5.6 mg, 12%). Data: UPLC (C) R : 0.97 min; m/z 509.3 (M+H) .
Intermediate 50
4-Methoxybutynoic acid
n-BuLi in hexane (2.5M, 28.5 mmol, 11.41 mL) was slowly added to a solution of 3-methoxypropyne
(28.5 mmol, 2,41 mL, 2 g) in dry THF (10 mL) at -78°C. The mixture was stirred for 1 h at -78°C, then
crushed CO (285 mmol, 12.56 g) was added in one portion and the reaction mixture was stirred for an
additional 10 min. The resulting solution was poured into water and washed with ethyl acetate. The
aqueous layer was evaporated in vacuo to give the crude amino acid. This was dissolved in methanol,
and the insoluble salts were removed via filtration. The filtrate was evaporated to give 3.35 g of 4-
methoxybutynoic acid (103%).
Example 41
(S)(8-Amino(1-(4-methoxybutynoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin
yl)benzamide
This compound was prepared, in an analogues manner as described in Example 2, from the compound
described in intermediate 2b and 4-methoxybutynoic acid (Intermediate 50), to afford the title
compound (9.1 mg, 24.7%). Data: UPLC (C) R : 1.44 min; m/z 496.2 (M+H) .
The following Examples were synthesized following the methods described for example 1-41.
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
(S)(3-(1-acryloylpyrrolidinyl)-
42 472.3 2.25 min
H 8-aminoimidazo[1,5-a]pyrazinyl)-
NH N-(4-fluoropyridinyl)benzamide
43 N (S)(3-(1-acryloylpyrrolidinyl)- 523.3 1.72 min
8-aminoimidazo[1,5-a]pyrazinyl)-
N-(4-(pyrrolidinyl)pyridin
yl)benzamide
44 (S)(8-amino(1-but 498.3 2.47 min
ynoylpiperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-fluoropyridin
O yl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
45 (S)(8-amino(1-but 480.3 2.26 min
ynoylpiperidinyl)imidazo[1,5- LCMS (B)
a]pyrazinyl)-N-(pyridin
yl)benzamide
46 (S)(3-(1-acryloylpiperidinyl) 468.3 2.49 min
aminoimidazo[1,5-a]pyrazinyl)-
N-(pyridinyl)benzamide
47 (S)(8-amino(1-but 508.3 2.00 min
N ynoylpyrrolidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-propylpyridin-
2-yl)benzamide
(S,E)(8-amino(1-(4-methoxy-
48 528.3 1.89 min
HN N-methylbut
enamido)ethyl)imidazo[1,5-
a]pyrazinyl)-N-(4-propylpyridin-
2-yl)benzamide
49 (S)(8-amino(1- 546.3 2.15 min
N (vinylsulfonyl)piperidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
propylpyridinyl)benzamide
50 (S)(8-amino(1-but 484.3 1.84 min
ynoylpyrrolidinyl)imidazo[1,5-
a]pyrazinyl)fluoro-N-(pyridin-
2-yl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
51 (S,E)(8-amino(1-(4- 528.4 1.60 min
methoxybutenoyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
methoxypyridinyl)benzamide
52 (S,E)(8-amino(1-(4- 516.3 1.79 min
methoxybutenoyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)
fluoro-N-(4-methoxypyridin
yl)benzamide
53 (S,E)(8-amino(1-(4- 516.3 2.31 min
methoxybutenoyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
fluoropyridinyl)benzamide
54 (S,E)(8-amino(1-(4- 502.3 2.01 min
methoxybutenoyl)piperidin
yl)imidazo[1,5-a]pyrazinyl)-N-
(isoxazolyl)benzamide
(S,E)(8-amino(1-(4-
55 513.3 1.79 min
methoxybutenoyl)piperidin
yl)imidazo[1,5-a]pyrazinyl)-N-
(pyrimidinyl)benzamide
56 4-(8-amino((S)(2- 568.3 2.23 min
chloropyrimidine
carbonyl)piperidinyl)imidazo[1,5-
a]pyrazinyl)methyl-N-(pyridin-
2-yl)benzamide
57 (S,E)(8-amino(1-(4- 512.4 1.67 min
methoxybutenoyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
methylpyridinyl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
58 (S,E)(8-amino(1-(4- 540.3 1.74 min
methoxybutenoyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
isopropylpyridinyl)benzamide
59 (S,E)(8-amino(1-(4- 525.4 1.11 min
(dimethylamino)but
2 enoyl)pyrrolidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-methylpyridin-
2-yl)benzamide
60 (S)(8-amino(1-but 472.0 2.24 min
ynoylpyrrolidinyl)imidazo[1,5-
a]pyrazinyl)-N-(thiazol
yl)benzamide
61 (S)(3-(1-acryloylpiperidinyl) 510.3 2.11 min
N aminoimidazo[1,5-a]pyrazinyl)-
N-(4-propylpyridinyl)benzamide
F (S)(3-(1-acryloylpyrrolidinyl)-
62 522.0 2.37 min
8-aminoimidazo[1,5-a]pyrazinyl)-
N-(4-(trifluoromethyl)pyridin
yl)benzamide
63 (S)(8-amino(1-but 548.3 1.09 min
ynoylpiperidinyl)imidazo[1,5- UPLC (B)
a]pyrazinyl)-N-(4-
(trifluoromethyl)pyridin
yl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
64 (S)(8-amino(1-but 522.3 2.29 min
ynoylpiperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-propylpyridin-
2-yl)benzamide
65 (S,E)(8-amino(1-(4- 553.3 1.31 min
(dimethylamino)but
enoyl)pyrrolidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-
isopropylpyridinyl)benzamide
66 4-(8-amino((S) 518.3 2.20 min
(vinylsulfonyl)piperidin
yl)imidazo[1,5-a]pyrazinyl)
methyl-N-(pyridinyl)benzamide
67 (S)(8-amino(1-but 540.3 2.56 min
N ynoylpiperidinyl)imidazo[1,5-
a]pyrazinyl)fluoro-N-(4-
propylpyridinyl)benzamide
68 4-(3-((S)acryloylpiperidinyl) 482.2 1.98 min
aminoimidazo[1,5-a]pyrazinyl)
methyl-N-(pyridinyl)benzamide
69 (E)(8-amino((4-(dimethyl 471.2 1.16 min
amino)butenamido)methyl)
imidazo[1,5-a]pyrazinyl)-N-
(pyridinyl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
70 (S)(8-amino(1-(2-chloro 582.2 1.89 min
pyrimidinecarbonyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
isopropylpyridinyl)benzamide
71 (S)(8-amino(1-(2-chloro 600.2 2.49 min
pyrimidinecarbonyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-
(4,5,6,7-tetrahydrobenzo[d]thiazol-
2-yl)benzamide
72 (S,E)(8-amino(1-(4- 513.3 1.84 min
methoxybutenoyl)piperidin
yl)imidazo[1,5-a]pyrazinyl)-N-
(pyridazinyl)benzamide
73 (S,E)(8-amino(1-(4- 526.4 1.26 min
(dimethylamino)but
enoyl)piperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(pyridazin
yl)benzamide
74 (S)(8-amino(1-(2- 555.3 1.96 min
chloropyrimidine
carbonyl)piperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(pyridazin
yl)benzamide
75 (S,E)(8-amino(1-(4-methoxy- 554.2 2.47 min
N-methylbut
enamido)ethyl)imidazo[1,5-
a]pyrazinyl)-N-(4-
(trifluoromethyl)pyridin
yl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
76 (S,E)(8-amino(1-(4- 541.3 1.41 min
(dimethylamino)-N-methylbut
enamido)ethyl)imidazo[1,5-
a]pyrazinyl)-N-(4-propylpyridin-
2-yl)benzamide
77 (S,E)(8-amino(1-(4- 579.3 1.64 min
HN (pyrrolidinyl)but
enoyl)pyrrolidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-propylpyridin-
2-yl)benzamide
78 (S,E)(8-amino(1-(4- 525.3 2.10 min
(dimethylamino)but LCMS (B)
enoyl)piperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(pyridin
yl)benzamide
79 (S)(8-amino(1-(2- 582.3 1.95 min
chloropyrimidine
carbonyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
N propylpyridinyl)benzamide
80 (S)(8-amino(1-(2- 572.3 2.45 min
chloropyrimidine
carbonyl)piperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-fluoropyridin
yl)benzamide
(S,E)(8-amino(1-(4-
81 530.3 2.38 min
H methoxybutenoyl)piperidin
NH yl)imidazo[1,5-a]pyrazinyl)-N-(4-
fluoropyridinyl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
82 (S,E)(8-amino(1-(4- 558.3 2.33 min
methoxybutenoyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-
(4,5,6,7-tetrahydrobenzo[d]thiazol-
2-yl)benzamide
83 (S)(8-amino(1-(2- 570.3 2.01 min
chloropyrimidine
carbonyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)
methoxy-N-(pyridinyl)benzamide
84 (S)(8-amino(1-(2- 558.2 1.95 min
chloropyrimidine
carbonyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)
fluoro-N-(pyridinyl)benzamide
4-(8-amino((S)((E)
85 526.3 2.12 min
methoxybutenoyl)piperidin
yl)imidazo[1,5-a]pyrazinyl)
methyl-N-(pyridinyl)benzamide
86 (S,E)(8-amino(1-(4- 513.3 1.83 min
methoxybutenoyl)piperidin
yl)imidazo[1,5-a]pyrazinyl)-N-
(pyrimidinyl)benzamide
87 4-(8-amino((S)((E) 554.4 1.86 min
methoxybutenoyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)
methyl-N-(4-propylpyridin
yl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
88 (S,E)(8-amino(1-(4- 527.3 1.88 min
methoxybutenoyl)piperidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
methylpyrimidinyl)benzamide
89 (S)(8-amino(1-but 495.3 1.97 min
H ynoylpiperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-
methylpyrimidinyl)benzamide
90 (S)(8-amino(1-(2- 555.3 1.91 min
chloropyrimidine
carbonyl)piperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(pyrimidin
yl)benzamide
91 (S)(8-amino(1- 468.4 1.61 min
methacryloylpyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-
(pyridinyl)benzamide
92 (S)(8-amino(1-(2- 522.3 1.99 min
(trifluoromethyl)acryloyl)pyrrolidin-
2-yl)imidazo[1,5-a]pyrazinyl)-N-
(pyridinyl)benzamide
(S,E)(8-amino(1-but
93 468.4 1.59 min
enoylpyrrolidinyl)imidazo[1,5-
a]pyrazinyl)-N-(pyridin
yl)benzamide
94 (S)(8-amino(1- 439.3 1.55 min
(cyanomethyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-
(pyridinyl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
95 (E)(8-amino((4-methoxybut 458.2 1.35 min
enamido)methyl)imidazo[1,5-
a]pyrazinyl)-N-(pyridin
yl)benzamide
96 N (S)(8-amino(1-but 535.3 2.27 min
ynoylpyrrolidinyl)imidazo[1,5- LCMS (B)
a]pyrazinyl)-N-(4-(pyrrolidin
yl)pyridinyl)benzamide
(E)(8-amino(1-(4-methoxybut-
97 526.3 1.97 min
2-enoyl)azepanyl)imidazo[1,5-
a]pyrazinyl)-N-(pyridin
yl)benzamide
98 (S,E)(8-amino(1-(4- 523.3 2.12 min
methoxybutenoyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
N cyanopyridinyl)benzamide
99 (S)(8-amino(1-but 496.3 1.87 min
ynoylpyrrolidinyl)imidazo[1,5-
a]pyrazinyl)methoxy-N-
(pyridinyl)benzamide
(S)(3-(1-acrylamidoethyl)
100 428.3 1.15 min
aminoimidazo[1,5-a]pyrazinyl)-
N-(pyridinyl)benzamide
101 (S)(3-(1-acryloylpyrrolidinyl)- 460.2 2.03 min
8-aminoimidazo[1,5-a]pyrazinyl)-
N-(thiazolyl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
102 (S)(8-amino(1-but 507.8 1.82 min
ynoylpyrrolidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-
isopropylpyridinyl)benzamide
103 (S,E)(8-amino(1-(4- 528.3 1.84 min
methoxybutenoyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)
methoxy-N-(pyridinyl)benzamide
104 (S,E)(8-amino(1- 530.4 2.09 min
cinnamoylpyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-
(pyridinyl)benzamide
105 (S)-N-(1-(8-amino(4-(pyridin 514.3 1.56 min
ylcarbamoyl)phenyl)imidazo[1,5-
a]pyrazinyl)ethyl)
chloropyrimidinecarboxamide
106 (S)(8-amino(1-but 484.2 2.38 min
ynoylpyrrolidinyl)imidazo[1,5-
2 a]pyrazinyl)-N-(4-fluoropyridin
yl)benzamide
107 (S)(8-amino(1-(2- 596.3 2.19 min
chloropyrimidine
carbonyl)piperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-propylpyridin-
2-yl)benzamide
108 (S,E)(8-amino(1-(4- 580.3 1.03 min
methoxybutenoyl)piperidin UPLC (B)
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
O (trifluoromethyl)pyridin
yl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
109 (S)(3-(1-acryloylpiperidinyl) 536.3 1.02 min
aminoimidazo[1,5-a]pyrazinyl)- UPLC (B)
N-(4-(trifluoromethyl)pyridin
yl)benzamide
110 (S)(8-amino(1-but 552.4 2.57 min
N ynoylpiperidinyl)imidazo[1,5-
a]pyrazinyl)methoxy-N-(4-
propylpyridinyl)benzamide
111 (S,E)(8-amino(1-(4- 584.4 2.49 min
N methoxybutenoyl)piperidin
yl)imidazo[1,5-a]pyrazinyl)
methoxy-N-(4-propylpyridin
yl)benzamide
112 4-(8-amino(but 426.2 1.35 min
ynamidomethyl)imidazo[1,5-
a]pyrazinyl)-N-(pyridin
yl)benzamide
113 (S)(8-amino(1-(N-methylbut- 496.3 1.94 min
2-ynamido)ethyl)imidazo[1,5-
a]pyrazinyl)-N-(4-propylpyridin-
2-yl)benzamide
114 (S,E)(8-amino(1-(4- 572.4 2.48 min
N methoxybutenoyl)piperidin
yl)imidazo[1,5-a]pyrazinyl)
fluoro-N-(4-propylpyridin
yl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
115 (S)(8-amino(1-(2- 622.2 1.15 min
chloropyrimidine UPLC (B)
carbonyl)piperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-
N (trifluoromethyl)pyridin
yl)benzamide
116 (S)(8-amino(1-but 514.3 2.68 min
ynoylpiperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(5-ethylthiazol
yl)benzamide
117 (S)(3-(1-acryloylpiperidinyl) 502.3 2.53 min
aminoimidazo[1,5-a]pyrazinyl)-
N-(5-ethylthiazolyl)benzamide
118 (S)(8-amino(1-(2- 588.3 2.71 min
chloropyrimidine
carbonyl)piperidinyl)imidazo[1,5-
a]pyrazinyl)-N-(5-ethylthiazol
yl)benzamide
119 (S)(8-amino(1-(2- 608.2 2.68 min
chloropyrimidine
carbonyl)pyrrolidin
N yl)imidazo[1,5-a]pyrazinyl)-N-(4-
(trifluoromethyl)pyridin
Cl yl)benzamide
120 (R,E)(8-amino(4-(4- 514.3 1.34 min
methoxybutenoyl)morpholin
yl)imidazo[1,5-a]pyrazinyl)-N-
(pyridinyl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
121 (S,E)(8-amino(1-(4- 554.4 2.07 min
methoxybutenoyl)piperidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
propylpyridinyl)benzamide
122 (S)(3-(1-acryloylpyrrolidinyl)- 479.0 1.86 min
8-aminoimidazo[1,5-a]pyrazinyl)-
N-(4-cyanopyridinyl)benzamide
123 (S)(8-amino(1-but 496.3 1.50 min
ynoylpyrrolidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-
N methoxypyridinyl)benzamide
(S)(3-(1-acryloylpyrrolidinyl)-
124 468.1 1.37 min
8-aminoimidazo[1,5-a]pyrazinyl)-
N-(4-methylpyridinyl)benzamide
125 (S)(3-(1-acryloylpyrrolidinyl)- 496.1 1.76 min
8-aminoimidazo[1,5-a]pyrazinyl)-
N-(4-propylpyridinyl)benzamide
126 (S)(3-(1-acryloylpyrrolidinyl)- 482.1 1.53 min
H 8-aminoimidazo[1,5-a]pyrazinyl)-
NH N-(4-ethylpyridinyl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
127 (S,E)(8-amino(1-(4- 511.0 1.29 min
(dimethylamino)but
enoyl)pyrrolidinyl)imidazo[1,5-
a]pyrazinyl)-N-(pyridin
yl)benzamide
128 (S,E)(8-amino(1-(4- 566.3 2.73 min
N methoxybutenoyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
N (trifluoromethyl)pyridin
yl)benzamide
129 (S)(8-amino(1-(2- 554.2 1.38 min
H chloropyrimidine
NH carbonyl)pyrrolidin
yl)imidazo[1,5-a]pyrazinyl)-N-(4-
N methylpyridinyl)benzamide
130 (S)(8-amino(1-but 491.2 2.20 min
ynoylpyrrolidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-cyanopyridin
yl)benzamide
131 (S)(8-amino(1-but 494.3 1.65 min
H ynoylpyrrolidinyl)imidazo[1,5-
NH a]pyrazinyl)-N-(4-ethylpyridin
yl)benzamide
132 (S)(8-amino(1-but 542.3 2.57 min
ynoylpyrrolidinyl)imidazo[1,5-
a]pyrazinyl)-N-(4-phenylpyridin-
2-yl)benzamide
Example Structure Name (M+H)+ UPLC (C)
m/z Rt
133 (S)(3-(1-acryloylpyrrolidinyl)- 530.3 2.38 min
8-aminoimidazo[1,5-a]pyrazinyl)-
N-(4-phenylpyridinyl)benzamide
Example 134 Assay Methods
Btk enzyme activity
Btk enzyme activity is measured using the IMAP (immobilized metal ion affinity-based fluorescence
polarization) assay as outlined below.
Btk enzyme (His-Btk (Millipore catalog# 14-552), is diluted to 0.4 U/mL in KR buffer (10 mM Tris-HCl, 10
mM MgCl2, 0.01% Tween-20, 0.05% NaN3, 1 mM DTT, 2 mM MnCl2, pH 7.2).
Serial dilution log10 from 2 mM to 63.2 nM of test compounds are made in 100% DMSO. The dilutions in
DMSO are then diluted 50-fold in KR-buffer. Final compound concentration range in the assay from 10
μM to 0.316 nM.
μL/well of test compound in KR buffer (final DMSO concentration in the assay is 1%) is mixed with 5
μl/well of 0.4 U/mL Btk enzyme (final concentration in the assay is 0.1 U/mL). Test compounds and Btk
enzyme are pre-incubated 60 minutes at room temperature, before adding 5 μL/well of 200 nM Fluorescin
labeled substrate peptide (Blk/Lyntide substrate, e.g. #R7188/#R7233, Molecular Devices) in KR-buffer.
Final peptide substrate concentration in assay is 50 nM. The kinase assay is started by adding 5 μL/well
of 20 μM ATP in KR-buffer (final ATP concentration is 5 μM ATP, Km ATP in Btk IMAP assay). Following
incubation for 2h at room temperature the enzyme reaction is stopped by adding 40 μL/well IMAP
Progressive Binding Solution (according to suppliers (Molecular Devices) protocol using 75% 1x buffer A
and 25% 1x buffer B with 1:600 Progressive Binding Solution). After 60 min incubation at room
temperature in the dark the FP signal is read. Fluorescence at 535 nm is measured using parallel and
perpendicular filters to determine differences in rotation due to binding of the phosphorylated substrate
peptide to the beads. Values are calculated as percentage of the difference in readout (ΔmPi) of the
controls with and without ATP. EC50 values are determined by curve fitting of the experimental results
using Activity Base.
All examples have an EC50 of 10 µM or lower.
Table 1 EC50 Btk activity values
EC50 Example
≥1μM 91,
≥100nM
<1μM 52, 53, 54, 55, 68, 72, 74, 85, 86, 87, 88, 90, 92, 93, 94, 104
≥10nM 2, 4, 5, 7, 11, 24, 40, 41, 50, 51, 56, 57, 58, 59, 60, 69, 70, 71, 73, 80, 81, 82, 83,
<100nM 84, 89, 95, 96, 97, 98, 99, 103, 105, 106, 112, 113, 114, 119
1, 3, 6, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29,
<10 nM 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 42, 43, 44, 45, 46, 47, 48, 49, 61, 62, 63,
64, 65, 66, 67, 75, 76, 77, 78, 79, 100, 101, 102, 107, 108, 109, 110, 111, 115,
116, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,
Lck enzyme activity
Lck enzyme activity is measured using the IMAP (immobilized metal ion affinity-based fluorescence
polarization) assay as outlined below.
Lck enzyme (Millipore catalog# 14-442), is diluted to 0.4 U/mL in KR buffer (10 mM Tris-HCl, 10 mM
MgCl2, 0.01% Tween-20, 0.05% NaN3, 1 mM DTT, 2 mM MnCl2, pH 7.2).
Serial dilution log10 from 2 mM to 63.2 nM of test compounds are made in 100% DMSO. The dilutions in
DMSO are then diluted 50-fold in KR-buffer of which 5 μl is used in the assay, leading to a final
compound concentration range in the assay from 10 μM to 0.316 nM.
μL/well of test compound in KR buffer (final DMSO concentration in the assay is 1%) is mixed with 5
μl/well of 0.4 U/mL Lck enzyme (final concentration in the assay is 0.1 U/mL). Test compounds and Lck
enzyme are pre-incubated 60 minutes at room temperature, before adding 5 μL/well of 400 nM Fluorescin
labeled substrate peptide (p34cdc2 substrate peptide, e.g. #R7157/#R7172, Molecular Devices) in KR-
buffer. Final peptide substrate concentration in assay is 100 nM. The kinase assay is started by adding 5
μL/well of 24 μM ATP in KR-buffer (final ATP concentration is 6 μM ATP, Km ATP in Lck IMAP assay).
Following incubation for 2h at room temperature the enzyme reaction is stopped by adding 40 μL/well
IMAP Progressive Binding Solution (according to suppliers (Molecular Devices) protocol using 75% 1x
buffer A and 25% 1x buffer B with 1:600 Progressive Binding Solution). After 60 min incubation at room
temperature in the dark the FP signal is read. Fluorescence at 535 nm is measured using parallel and
perpendicular filters to determine differences in rotation due to binding of the phosphorylated substrate
peptide to the beads. Values are calculated as percentage of the difference in readout (ΔmPi) of the
controls with and without ATP. EC50 values are determined by curve fitting of the experimental results
using Activity Base.
Table 2 EC50 Lck activity values
EC50 Example
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 63, 65, 66, 67, 68, 69,
≥1μM 70, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,
92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 105, 106, 107, 108, 109, 110,
111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 123, 127, 128, 129, 130,
≥100nM
<1μM 60, 62, 64, 76, 104, 122, 124, 125, 126, 132, 133
Src enzyme activity
Src enzyme activity is measured using the IMAP (immobilized metal ion affinity-based fluorescence
polarization) assay as outlined below.
Src enzyme (Millipore catalog# 14-326), is diluted to 0.8 U/mL in KR buffer (10 mM Tris-HCl, 10 mM
MgCl2, 0.01% Tween-20, 0.05% NaN3, 1 mM DTT, 2 mM MnCl2, pH 7.2).
Serial dilution log10 from 2 mM to 63.2 nM of test compounds are made in 100% DMSO. The dilutions in
DMSO are then diluted 50-fold in KR-buffer of which 5 μl is used in the assay, leading to a final
compound concentration range in the assay from 10 μM to 0.316 nM.
μL/well of test compound in KR buffer (final DMSO concentration in the assay is 1%) is mixed with 5
μl/well of 0.8 U/mL Src enzyme (final concentration in the assay is 0.2 U/mL). Test compounds and Src
enzyme are pre-incubated 60 minutes at room temperature, before adding 5 μL/well of 400 nM Fluorescin
labeled substrate peptide (p34cdc2 substrate peptide, e.g. #R7157/#R7172, Molecular Devices) in KR-
buffer. Final peptide substrate concentration in assay is 100 nM. The kinase assay is started by adding 5
μL/well of 16 μM ATP in KR-buffer (final ATP concentration is 4 μM ATP, Km ATP in Src IMAP assay).
Following incubation for 2h at room temperature the enzyme reaction is stopped by adding 40 μL/well
IMAP Progressive Binding Solution (according to suppliers (Molecular Devices) protocol using 75% 1x
buffer A and 25% 1x buffer B with 1:600 Progressive Binding Solution). After 60 min incubation at room
temperature in the dark the FP signal is read. Fluorescence at 535 nm is measured using parallel and
perpendicular filters to determine differences in rotation due to binding of the phosphorylated substrate
peptide to the beads. Values are calculated as percentage of the difference in readout (ΔmPi) of the
controls with and without ATP. EC50 values are determined by curve fitting of the experimental results
using Activity Base.
Table 3 EC50 Src activity values
EC50 Example
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,
≥1μM 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,
88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,
107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122,
123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133
FynT enzyme activity
FynT enzyme activity is measured using the IMAP (immobilized metal ion affinity-based fluorescence
polarization) assay as outlined below.
FynT enzyme (Biomol catalog# SE-287), is diluted to 0.5 μg/mL in KR buffer (10 mM Tris-HCl, 10 mM
MgCl , 0.01% Tween-20, 0.05% NaN , 1 mM DTT, 2 mM MnCl , pH 7.2).
2 3 2
Serial dilution log10 from 2 mM to 63.2 nM of test compounds are made in 100% DMSO. The dilutions in
DMSO are then diluted 50-fold in KR-buffer of which 5 μl is used in the assay, leading to a final
compound concentration range in the assay from 10 μM to 0.316 nM.
μL/well of test compound in KR buffer (final DMSO concentration in the assay is 1%) is mixed with 5
μl/well of 0.5 μg/mL FynT enzyme (final concentration in the assay is 125 ng/mL). Test compounds and
FynT enzyme are pre-incubated 60 minutes at room temperature, before adding 5 μL/well of 400 nM
Fluorescin labeled substrate peptide (p34cdc2 substrate peptide, e.g. #R7157/#R7172, Molecular
Devices) in KR-buffer. Final peptide substrate concentration in assay is 100 nM. The kinase assay is
started by adding 5 μL/well of 0.8 μM ATP in KR-buffer (final ATP concentration is 0.2 μM ATP, Km ATP
in FynT IMAP assay). Following incubation for 2h at room temperature the enzyme reaction is stopped by
adding 40 μL/well IMAP Progressive Binding Solution (according to suppliers (Molecular Devices)
protocol using 75% 1x buffer A and 25% 1x buffer B with 1:600 Progressive Binding Solution). After 60
min incubation at room temperature in the dark the FP signal is read. Fluorescence at 535 nm is
measured using parallel and perpendicular filters to determine differences in rotation due to binding of the
phosphorylated substrate peptide to the beads. Values are calculated as percentage of the difference in
readout (ΔmPi) of the controls with and without ATP. EC values are determined by curve fitting of the
experimental results using Activity Base.
Table 4 EC50 FynT activity values
EC50 Example
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,
≥1μM 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,
88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,
107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122,
123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133
Lyn enzyme activity
Lyn enzyme activity is measured using the IMAP (immobilized metal ion affinity-based fluorescence
polarization) assay as outlined below.
Lyn enzyme (Millipore catalog# 14-510), is diluted to 250 mU/mL in KR buffer (10 mM Tris-HCl, 10 mM
MgCl , 0.01% Tween-20, 0.05% NaN , 1 mM DTT, 2 mM MnCl , pH 7.2).
2 3 2
Serial dilution log10 from 2 mM to 63.2 nM of test compounds are made in 100% DMSO. The dilutions in
DMSO are then diluted 50-fold in KR-buffer of which 5 μl is used in the assay, leading to a final
compound concentration range in the assay from 10 μM to 0.316 nM.
μL/well of test compound in KR buffer (final DMSO concentration in the assay is 1%) is mixed with 5
μl/well of 250 mU/mL Lyn enzyme (final concentration in the assay is 62.5 mU/mL). Test compounds and
Lyn enzyme are pre-incubated 60 minutes at room temperature, before adding 5 μL/well of 400 nM
Fluorescin labeled substrate peptide (Blk/Lyntide substrate, e.g. #R7188/#R7233, Molecular Devices) in
KR-buffer. Final peptide substrate concentration in assay is 100 nM. The kinase assay is started by
adding 5 μL/well of 8 μM ATP in KR-buffer (final ATP concentration is 2 μM ATP, Km ATP in Lyn IMAP
assay). Following incubation for 2h at room temperature the enzyme reaction is stopped by adding 40
μL/well IMAP Progressive Binding Solution (according to suppliers (Molecular Devices) protocol using
75% 1x buffer A and 25% 1x buffer B with 1:600 Progressive Binding Solution). After 60 min incubation at
room temperature in the dark the FP signal is read. Fluorescence at 535 nm is measured using parallel
and perpendicular filters to determine differences in rotation due to binding of the phosphorylated
substrate peptide to the beads. Values are calculated as percentage of the difference in readout (ΔmPi) of
the controls with and without ATP. EC values are determined by curve fitting of the experimental results
using Activity Base.
Table 5 EC50 Lyn activity values
EC50 Example
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67,
≥1μM 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,
89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107,
108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123,
127, 128, 129, 130, 131, 132
≥100nM
<1μM 60, 124, 125, 126, 133
Claims (57)
1. A compound according to Formula (I) Formula (I) or a pharmaceutically acceptable salt thereof, wherein: X is CH, N, O or S; Y is C(R6), N, O or S; 15 Z is CH, N or a bond; A is CH or N; B1 is N or C(R7); B2 is N or C(R8); 20 B3 is N or C(R9); B4 is N or C(R10); R1 is R11C(O), R12S(O), R13SO2 or (1-6C)alkyl optionally substituted with R14; R2 is H, (1-3C)alkyl or (3-7C)cycloalkyl; R3 is H, (1-6C)alkyl or (3-7C)cycloalkyl); or R2 and R3 form, together with the N atom that R2 is attached to and the C atom that R3 is attached to, a (3-7C)heterocycloalkyl optionally substituted with one or more fluorine, hydroxyl, (1-3C)alkyl, (1-3C)alkoxy or oxo; R4 is H or (1-3C)alkyl; 5 R5 is H, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy, (3-6C)cycloalkyl, any alkyl group of which is optionally substituted with one or more halogen; or R5 is (6-10C)aryl or (2-6C)heterocycloalkyl; R6 is H or (1-3C)alkyl; or R5 and R6 together may form a (3-7C)cycloalkenyl, or (2-6C)heterocycloalkenyl; each optionally substituted with (1-3C)alkyl, or one or more halogen; 10 R7 is H, halogen or (1-3C)alkoxy; R8 is H or (1-3C)alkyl; or R7 and R8 form, together with the carbon atom they are attached to a (6-10C)aryl or (1- 9C)heteroaryl; R9 is H, halogen or (1-3C)alkoxy; 15 R10 is H, halogen or (1-3C)alkoxy; R11 is independently selected the group consisting of (1-6C)alkyl, (2-6C)alkenyl and (2- 6C)alkynyl each alkyl, alkenyl or alkynyl optionally substituted with one or more groups selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1- 3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl or (3-7C)heterocycloalkyl; or 20 R11 is (1-3C)alkyl-C(O)-S-(1-3C)alkyl; or R11 is (1-5C)heteroaryl optionally substituted with one or more groups selected from halogen or cyano; R12 and R13 are independently selected from the group consisting of (2-6C)alkenyl or (2- 6C)alkynyl both optionally substituted with one or more groups selected from hydroxyl, (1- 25 4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3- 7C)cycloalkoxy, (6-10C)aryl or (3-7C)heterocycloalkyl; or (1-5C)heteroaryl optionally substituted with one or more groups selected from halogen or cyano; R14 is independently selected from the group consisting of halogen, cyano or (2-6C)alkenyl or (2- 6C)alkynyl both optionally substituted with one or more groups selected from hydroxyl, (1- 30 4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3- 7C)cycloalkoxy, (6-10C)aryl, (1-5C)heteroaryl or (3-7C)heterocycloalkyl; with the proviso that - 0 to 2 atoms of X, Y, Z can simultaneously be a heteroatom; - when one atom selected from X, Y is O or S, then Z is a bond and the other atom 35 selected from X, Y cannot be O or S; - when Z is CH or N then Y is C(R6) or N and X is CH or N; - 0 to 2 atoms of B1, B2, B3 and B4 are N.
2. The compound according to claim 1 wherein B1 is C(R7); B2 is C(R8); B3 is C(R9); B4 is C(R10); R7 is H, R9 is H, and R10 is H; and R8 is selected from the group consisting of hydrogen and methyl. 5
3. The compound according to any one of claims 1 and 2 wherein R4 is selected from the group consisting of hydrogen and methyl.
4. The compound according to any one of claims 1 to 3 wherein the ring containing X, Y and Z is selected from the group consisting of pyridyl, pyrimidyl, pyridazyl, triazinyl, thiazolyl, oxazolyl, and 10 isoxazolyl.
5. The compound according to any one of claims 1 to 4 wherein the ring containing X, Y and Z is selected from the group consisting of pyridyl, pyrimidyl, and thiazolyl. 15
6. The compound according to any one of claims 1 to 5 wherein R5 is selected from the group consisting of hydrogen, fluorine, chlorine, (1-3C)alkyl and (1-2C) alkoxy; the (1-3C)alkyl group of which is optionally substituted with one or more halogen.
7. The compound according to any one of claims 1 to 6 wherein R5 is selected from the group 20 consisting of hydrogen, fluorine, methyl, ethyl, propyl, methoxy and trifluoromethyl.
8. The compound according to any one of claims 1 to 7 wherein R2 is hydrogen or (1-3C)alkyl; and R3 is (1-6C)alkyl. 25
9. The compound according to any one of claims 1 to 7 wherein R2 and R3 form, together with the N atom that R2 is attached to and the C atom that R3 is attached to, a heterocycloalkyl ring selected from azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl, optionally substituted with one or more fluoro, hydroxyl, (1-3C) alkyl, (1-3C)alkoxy, or oxo. 30
10. The compound according to any one of claims 1 to 9 wherein R1 is R11C(O) and R11 is independently selected from the group consisting of (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl each optionally substituted with one or more groups selected from hydroxyl, (1-4C)alkyl, (3- 7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6- 10C)aryl or (3-7C)heterocycloalkyl; or R11 is (1-5C)heteroaryl optionally substituted with one or 35 more groups selected from halogen or cyano.
11. The compound according to any one of claims 1 to 10 wherein R1 is R11C(O) and R11 is selected from the group consisting of (2-6C)alkenyl or (2-6C)alkynyl each optionally substituted with one or more groups selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, di[(1- 40 4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy or (3-7C)heterocycloalkyl.
12. The compound according to claim 1 selected from the group consisting of (S)(3-(1-Acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide; (S,E)(8-amino(1-(4-(pyrrolidinyl)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- 5 (pyridinyl)benzamide; (S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)- N-(pyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; 10 (S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin yl)benzamide; (S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)- 15 N-(4-fluoropyridinyl)benzamide; (S)(8-Amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-methylpyridin yl)benzamide; (S,E)(8-Amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- propylpyridinyl)benzamide; 20 (S)(8-Amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; (S,E)(8-Amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- ethylpyridinyl)benzamide; (S)(8-Amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4,5,6,7- 25 tetrahydrobenzo[d]thiazolyl)benzamide; (S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)fluoro-N-(pyridin yl)benzamide; (S)(3-(1-Acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)methoxy-N-(pyridin yl)benzamide; 30 (S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)- N-(thiazolyl)benzamide; (S,E)(8-Amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; (S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridin 35 yl)benzamide; (S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-cyanopyridin yl)benzamide; (S)(8-Amino(1-(vinylsulfonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; (S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyrimidin yl)benzamide ; (S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-methylpyrimidin yl)benzamide ; 5 (S)(8-Amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyrimidin yl)benzamide ; (S)(8-Amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridazin yl)benzamide ; (S)(8-Amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(isoxazol 10 yl)benzamide ; (S,E)(8-Amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(5- ethylthiazolyl)benzamide; (S)(3-(1-Acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)fluoro-N-(4-propylpyridin- 2-yl)benzamide; 15 (S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl) methoxy-N-(4-propylpyridinyl)benzamide; 4-(8-Amino((S)butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)methyl-N-(pyridin yl)benzamide; 4-(3-(Acrylamidomethyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide; 20 (S)(8-Amino(1-butynamidoethyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide; (S)-S(2-(8-Amino(4-(pyridinylcarbamoyl)phenyl)imidazo[1,5-a]pyrazinyl)pyrrolidin yl)oxoethyl ethanethioate; (S)(8-Amino(1-(4-hydroxymethylpentynoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)- N-(pyridinyl)benzamide; 25 (S)(8-Amino(1-(6-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; (S)(8-Amino(1-pentynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin yl)benzamide; (S)(8-Amino(1-(3-cyclopropylpropioloyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin- 30 2-yl)benzamide; (S)(8-Amino(1-hexynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin yl)benzamide; 4-(3-(1-Acryloylazepanyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide; (R)(8-Amino(4-butynoylmorpholinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin 35 yl)benzamide ; (S)(8-amino(1-(N-methylbutynamido)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; (S)(8-Amino(1-(4-(dimethylamino)butynoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; (S)(8-Amino(1-(4-methoxybutynoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin- 2-yl)benzamide; (S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridin yl)benzamide; 5 (S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-(pyrrolidinyl)pyridin- 2-yl)benzamide; (S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridin yl)benzamide; (S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin 10 yl)benzamide; (S)(3-(1-acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-propylpyridin yl)benzamide; (S,E)(8-amino(1-(4-methoxy-N-methylbutenamido)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4- 15 propylpyridinyl)benzamide; (S)(8-amino(1-(vinylsulfonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-propylpyridin yl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)fluoro-N-(pyridin yl)benzamide; 20 (S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- methoxypyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)fluoro- N-(4-methoxypyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- 25 fluoropyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- (isoxazolyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyrimidinyl)benzamide; 30 4-(8-amino((S)(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl) methyl-N-(pyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- methylpyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- 35 isopropylpyridinyl)benzamide; (S,E)(8-amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (4-methylpyridinyl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(thiazol yl)benzamide; (S)(3-(1-acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-propylpyridin yl)benzamide; (S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; 5 (S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; (S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-propylpyridin yl)benzamide; (S,E)(8-amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- 10 (4-isopropylpyridinyl)benzamide; 4-(8-amino((S)(vinylsulfonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)methyl-N-(pyridin yl)benzamide; (S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)fluoro-N-(4- propylpyridinyl)benzamide; 15 4-(3-((S)acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)methyl-N-(pyridin yl)benzamide; (E)(8-amino((4-(dimethyl amino)butenamido)methyl) imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; (S)(8-amino(1-(2-chloro pyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- 20 (4-isopropylpyridinyl)benzamide; (S)(8-amino(1-(2-chloro pyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (4,5,6,7-tetrahydrobenzo[d]thiazolyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridazinyl)benzamide; 25 (S,E)(8-amino(1-(4-(dimethylamino)butenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridazinyl)benzamide; (S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridazinyl)benzamide; (S,E)(8-amino(1-(4-methoxy-N-methylbutenamido)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4- 30 (trifluoromethyl)pyridinyl)benzamide; (S,E)(8-amino(1-(4-(dimethylamino)-N-methylbutenamido)ethyl)imidazo[1,5-a]pyrazin yl)-N-(4-propylpyridinyl)benzamide; (S,E)(8-amino(1-(4-(pyrrolidinyl)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (4-propylpyridinyl)benzamide; 35 (S,E)(8-amino(1-(4-(dimethylamino)butenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; (S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (4-propylpyridinyl)benzamide; (S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- 40 (4-fluoropyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- fluoropyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (4,5,6,7-tetrahydrobenzo[d]thiazolyl)benzamide; 5 (S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl) methoxy-N-(pyridinyl)benzamide; (S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl) fluoro-N-(pyridinyl)benzamide; 4-(8-amino((S)((E)methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl) 10 methyl-N-(pyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyrimidinyl)benzamide; 4-(8-amino((S)((E)methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl) methyl-N-(4-propylpyridinyl)benzamide; 15 (S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- methylpyrimidinyl)benzamide; (S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-methylpyrimidin yl)benzamide; (S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- 20 (pyrimidinyl)benzamide; (S)(8-amino(1-methacryloylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin yl)benzamide; (S)(8-amino(1-(2-(trifluoromethyl)acryloyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; 25 (S,E)(8-amino(1-butenoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin yl)benzamide; (S)(8-amino(1-(cyanomethyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin yl)benzamide; (E)(8-amino((4-methoxybutenamido)methyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin 30 yl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-(pyrrolidin yl)pyridinyl)benzamide; (E)(8-amino(1-(4-methoxybutenoyl)azepanyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin yl)benzamide; 35 (S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- cyanopyridinyl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)methoxy-N-(pyridin yl)benzamide; (S)(3-(1-acrylamidoethyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide; 40 (S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(thiazolyl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-isopropylpyridin yl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl) methoxy-N-(pyridinyl)benzamide; 5 (S,E)(8-amino(1-cinnamoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin yl)benzamide; (S)-N-(1-(8-amino(4-(pyridinylcarbamoyl)phenyl)imidazo[1,5-a]pyrazinyl)ethyl) chloropyrimidinecarboxamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-fluoropyridin 10 yl)benzamide; (S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- (4-propylpyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; 15 (S)(3-(1-acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-(trifluoromethyl)pyridin- 2-yl)benzamide; (S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)methoxy-N-(4- propylpyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl) 20 methoxy-N-(4-propylpyridinyl)benzamide; 4-(8-amino(butynamidomethyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide; (S)(8-amino(1-(N-methylbutynamido)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4-propylpyridin- 2-yl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)fluoro- 25 N-(4-propylpyridinyl)benzamide; (S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- (4-(trifluoromethyl)pyridinyl)benzamide; (S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(5-ethylthiazol yl)benzamide; 30 (S)(3-(1-acryloylpiperidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(5-ethylthiazol yl)benzamide; (S)(8-amino(1-(2-chloropyrimidinecarbonyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- (5-ethylthiazolyl)benzamide; (S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- 35 (4-(trifluoromethyl)pyridinyl)benzamide; (R,E)(8-amino(4-(4-methoxybutenoyl)morpholinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- propylpyridinyl)benzamide; (S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-cyanopyridin yl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-methoxypyridin yl)benzamide; 5 (S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-methylpyridin yl)benzamide; (S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-propylpyridin yl)benzamide; (S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-ethylpyridin 10 yl)benzamide; (S,E)(8-amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; 15 (S)(8-amino(1-(2-chloropyrimidinecarbonyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (4-methylpyridinyl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-cyanopyridin yl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-ethylpyridin 20 yl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4-phenylpyridin yl)benzamide and (S)(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(4-phenylpyridin yl)benzamide.
13. The compound of claim 1, wherein X is CH; Y is CH; Z is CH; 30 B1 is C(R7); B2 is C(R8); B3 is C(R9); B4 is C(R10); R1 is R11C(O); 35 R2 and R3 form, together with the N atom that R2 is attached to and the C atom that R3 is attached to, a pyrrolidinyl; R4 is H; R7 is H; R9 is H; 40 R10 is H; and R8 is H or methyl.
14. The compound according to claim 1 selected from the group consisting of: (S)(3-(1-Acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide; 5 (S,E)(8-Amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)- N-(pyridinyl)benzamide; (S,E)(8-amino(1-(4-methoxybutenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; (S)(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin 10 yl)benzamide; (S)(8-Amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; (S)(8-Amino(1-(4-hydroxymethylpentynoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)- N-(pyridinyl)benzamide; 15 (R)(8-Amino(4-butynoylmorpholinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin yl)benzamide; (S)(8-Amino(1-(4-(dimethylamino)butynoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide; (S,E)(8-Amino(1-(4-methoxybutenoyl)piperidinyl)imidazo[1,5-a]pyrazinyl)-N- 20 (pyridinyl)benzamide; (S)(8-amino(1-(N-methylbutynamido)ethyl)imidazo[1,5-a]pyrazinyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; (S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin yl)benzamide; and 25 (S)(8-amino(1-butynoylpiperidinyl)imidazo[1,5-a]pyrazinyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide.
15. A combination of a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a further therapeutic agent.
16. A pharmaceutical composition comprising a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
17. A compound of Formula (I) according to claim 1: or a pharmaceutically acceptable salt thereof, wherein: X is CH or S; 5 Y is C(R6); Z is CH or a bond; A is CH; B1 is N or C(R7); B2 is N or C(R8); 10 B3 is N or CH; B4 is N or CH; R1 is R11C(=O), R2 is (1-3C)alkyl; R3 is (1-3C)alkyl; or 15 R2 and R3 form a (3-7C)heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, optionally substituted with one or more fluorine, hydroxyl, (1-3C)alkyl, or (1-3C)alkoxy; R4 is H; R5 is H, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy, or (3-6C)cycloalkyl, any alkyl group of which is optionally substituted with one or more halogen; R6 is H or (1-3C)alkyl; or 5 R5 and R6 together may form a (3-7C)cycloalkenyl or (2-6C)heterocycloalkenyl, each optionally substituted with (1-3C)alkyl or one or more halogen; R7 is H, halogen or (1-3C)alkoxy; R8 is H or (C1–3)alkyl; or R7 and R8 form, together with the carbon atom that R7 is attached to and the carbon atom that 10 R8 is attached to, a (6-10C)aryl or (1-9C)heteroaryl; R11 is independently selected from the group consisting of (2-6C)alkenyl and (2-6C)alkynyl, wherein each alkenyl or alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(1- 4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-10C)aryl and (3-7C)heterocycloalkyl; 15 with the proviso that 0 to 2 atoms of B1, B2, B3 and B4 are N.
18. A compound of Formula (I) according to claim 1: 20 or a pharmaceutically acceptable salt thereof, wherein: the ring containing X, Y and Z is selected from the group consisting of pyridyl, pyrimidyl, pyridazyl, triazinyl, thiazolyl, oxazolyl and isoxazolyl; A is CH; B1 is CH; B2 is CH; B3 is CH; 5 B4 is CH; R1 is C(O)R11; R2 and R3 form, together with the N atom that R2 is attached to and the C atom that R3 is attached to, a (3-7C)heterocycloalkyl ring selected from azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl, each optionally substituted with fluoro, hydroxyl, (1-3C)alkyl, (1- 10 3C)alkoxy or oxo; R4 is hydrogen; R5 is H, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy, or (3-6C)cycloalkyl, any alkyl group of which is optionally substituted with one or more halogen; R11 is (2-6C)alkenyl or (2-6C)alkynyl, each optionally substituted with one or more groups 15 selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3- 7C)cycloalkoxy, or (3-7C)heterocycloalkyl.
19. A compound according to claim 1, which is (S)(3-(1-acryloylpyrrolidinyl) aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide, having the structure: 20 .
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 19. 5
21. A pharmaceutically acceptable salt of a compound according to claim 1, the compound being (S)- 4-(3-(1-acryloylpyrrolidinyl)aminoimidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide and having the structure: 10
22. The pharmaceutically acceptable salt of claim 21, wherein the salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate.
23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 21.
24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and 20 the pharmaceutically acceptable salt of claim 22.
25. A compound according to claim 1, which is (S,E)(8-amino(1-(4-(dimethylamino)but enoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide, having the structure:
26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and t he compound of claim 25.
27. A pharmaceutically acceptable salt of a compound according to claim 1, the compound being (S,E)(8-amino(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N- (pyridinyl)benzamide and having the structure:
28. The pharmaceutically acceptable salt of claim 27, wherein the salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, 5 salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate.
29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 27. 10
30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 28.
31. A compound according to claim 1, which is (S)(8-amino(1-butynoylpyrrolidin yl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide, having the structure: 15 .
32. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 31. 20
33. A pharmaceutically acceptable salt of a compound according to claim 1, the compound being (S)- 4-(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide and having the structure:
34. The pharmaceutically acceptable salt of claim 33, wherein the salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, 5 camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate.
35. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and 10 the pharmaceutically acceptable salt of claim 33.
36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 34. 15
37. A compound according to claim 1, which is (S)(8-amino(1-(3- cyclopropylpropioloyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide, having the structure:
38. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 37.
39. A pharmaceutically acceptable salt of a compound according to claim 1, the compound being (S)- 5 4-(8-amino(1-(3-cyclopropylpropioloyl)pyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridin yl)benzamide and having the structure:
40. The pharmaceutically acceptable salt of claim 39, wherein the salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, 10 camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate.
41. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and 5 the pharmaceutically acceptable salt of claim 39.
42. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 40. 10
43. A compound according to claim 1, which is (S)(8-amino(1-hexynoylpyrrolidin yl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide, having the structure:
44. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and 15 the compound of claim 43.
45. A pharmaceutically acceptable salt of a compound according to claim 1, the compound being (S)- 4-(8-amino(1-hexynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)-N-(pyridinyl)benzamide and having the structure:
46. The pharmaceutically acceptable salt of claim 45, wherein the salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, 5 camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate.
47. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and 10 the pharmaceutically acceptable salt of claim 45.
48. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 46. 15
49. A compound according to claim 1, which is (S)(8-amino(1-butynoylpyrrolidin yl)imidazo[1,5-a]pyrazinyl)methoxy-N-(pyridinyl)benzamide, having the structure:
50. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent of the compound of claim 49.
51. A pharmaceutically acceptable salt of a compound according to claim 1, the compound being (S)- 5 4-(8-amino(1-butynoylpyrrolidinyl)imidazo[1,5-a]pyrazinyl)methoxy-N-(pyridin yl)benzamide and having the structure:
52. The pharmaceutically acceptable salt of claim 51, wherein the salt is selected from the group 10 consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate. 15
53. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 51.
54. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 52.
55. A compound of any one of claims 1 to 14, 17 and 18 substantially as herein described with reference to any example thereof.
56. A combination according to claim 15 substantially as herein described with reference to any 25 example thereof.
57. A pharmaceutical composition according to claim 16 substantially as herein described with reference to any example thereof.
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NZ716110A NZ716110B2 (en) | 2011-07-19 | 2012-07-11 | 4-imidazopyridazin-1-yl-benzamides and 4-imidazotriazin-1-yl-benzamides as btk-inhibitors |
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EP11174578 | 2011-07-19 | ||
PCT/EP2012/063552 WO2013010868A1 (en) | 2011-07-19 | 2012-07-11 | 4 - imidazopyridazin- 1 -yl-benzamides and 4 - imidazotriazin- 1 - yl - benzamides as btk- inhibitors |
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