PA 1894726
`
`~4'1:Gls,'\l~Ji'W!IQM{'IIHiE,Stz l~HESE~~ Smdffi,~OMIE!~
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`
`August 28, 2012
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`THE RECORDS OF THE UNITED ST ATES PATENT AND TRADEMARK
`OFFICE OF THOSE PAPERS OF THE BELOW IDENTIFIED PATENT
`APPLICATION THAT MET THE REQUIREMENTS TO BE GRANTED A
`FILING DATE UNDER35 USC 111.
`
`APPLICATION NUMBER: 61/509,397
`FILING DATE: July 19, 2011
`
`THE COUNTRY CODE AND NUMBER OF YOUR PRIORITY
`APPLICATION, TO BE USED FOR FILING ABROAD UNDER THE PARIS
`CONVENTION, IS US61/509,397
`
`By Authority of the
`Under Secretary of Commerce for Intellectual Property
`and Director of the United States Patent and Trade ark Office
`
`Certifying Officer
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1007, p. 1 of 121
`
`

`

`Electronic Acknowledgement Receipt
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`EFSID:
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`Application Number:
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`10552594
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`61509397
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`International Application Number:
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`Confirmation Number:
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`3679
`
`Title of Invention:
`
`BTK INHIBITORS
`
`First Named Inventor/Applicant Name:
`
`Tjeerd A. Barf
`
`Customer Number:
`
`67706
`
`Filer:
`
`Barry H. JacobsenNirginia Finno-Sorrentino
`
`Filer Authorized By:
`
`Barry H. Jacobsen
`
`Attorney Docket Number:
`
`2011.182
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`19-JUL-2011
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`IPR2023-00478
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`Copy provided by USPTO from the IFW Image Database on 08/22/2012
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1007, p. 4 of 121
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`

`

`2011.182
`
`BTK inhibitors
`
`Field of the invention
`
`5
`
`to
`fused pyridine ring compounds,
`to 6-5 membered
`invention relates
`The present
`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
`
`15
`
`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 Tee 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 FctR1 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 FctR-mediated mast cell activation, Btk inhibitors
`35 may also show potential in the treatment of allergic responses [Gilfillan et al, Immunological
`Reviews 288 (2009) pp149-169].
`
`20
`
`25
`
`30
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`Copy provided by USPTO from the IFW Image Database on 08/22/2012
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`- 2 -
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`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.
`
`5 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 8 cell lymphomas as
`10 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. lmidazo[1,5-f][1,2,4]triazine compounds have been described in WO2005097800
`and WO2007064993;.
`lmidazo[1,5-a]pyrazine compounds have been described
`in
`WO2005037836 and WO2001019828 as IGF-1R enzyme inhibitors.
`
`15
`
`20
`
`25
`
`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
`lgE-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
`30 myeloid cells, and increased lg 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) pp169-176J.
`The double knockouts Src+Fyn_,_ and Src-1-Yes_,_ show a severe phenotype with effects on
`movement and breathing. The triple knockouts Src-1-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.
`
`35
`
`Copy provided by USPTO from the IFW Image Database on 08/22/2012
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1007, p. 6 of 121
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`- 3 -
`
`Detailed description of the invention
`The object of the present invention is to provide 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
`
`5
`
`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.
`
`10
`
`Formula I
`
`In this formula the substituents are defined as
`Xis CH, N, 0 or S;
`15 Y is C(R6), N, 0 or S;
`Z is CH, N or bond;
`A is CH orN;
`B1 is N or C(R7);
`82 is N or C(R8);
`20 B3 is N or C(R9);
`B4 is Nor 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;
`25 R3 is H, (1-6C)alkyl or (3-7C)cycloalkyl); or
`
`Copy provided by USPTO from the IFW Image Database on 08/22/2012
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`SANDOZ INC.
`
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`Ex. 1007, p. 7 of 121
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`- 4 -
`
`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 fluorine, hydroxyl, (1-3C)alkyl, (1-3C)alkoxy or oxo;
`R4 is Hor (1-3C)alkyl;
`RS is H, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy, (3-6C)cycloalkyl; all alkyl groups of R5 are
`s optionally substituted with one or more halogen; or RS is (6-1 0C)aryl or (2-6C)heterocycloalkyl;
`R6 is Hor (1-3C)alkyl; or
`RS 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;
`10 R8 is Hor (1-3C)alkyl; or
`R7 and RS 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;
`15 R11 is independently selected from a group consisting of (1-SC)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
`20 R11 is {1-SC)heteroaryl optionally substituted with one or more groups selected from halogen
`orcyano.
`R12 and R13 are independently selected from a 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,
`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 a 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-SC)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 can not be O or S;
`when Z is C or N then Y is C(R6) or N and X is C or N;
`Oto 2 atoms of B1, B2, B3 and B4 are N.
`
`35
`
`The terms as used herein refer to the following:
`
`Copy provided by USPTO from the IFW Image Database on 08/22/2012
`
`25
`
`30
`
`(3-
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`SANDOZ INC.
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`Ex. 1007, p. 8 of 121
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`

`

`l
`~bon atoms, being methyl or ethyl.
`'\yl group having 1-3 carbon atoms, being
`
`\
`
`\, group having 1-4 carbon atoms, being
`\utyl and tert-butyl, (1-3C)alkyl groups
`\
`\
`I
`\
`\roup having 1-5 carbon atoms, for
`\,. sec-butyl, tert-butyl, pentyl and
`
`\ 11p having 1-6 carbon atoms, for
`\ \ ,,s, the alkyl moiety having the
`
`\
`1-pentyl and n-hexyl. ( 1-5C)alkyl
`
`\the alkyl moiety having the
`~rred.
`\e alkyl moiety having the
`
`"e-4 carbon atoms, such
`
`\\d. (1-2C)alkoxy groups
`\
`) carbon atoms, such
`\ 1
`\
`·frbon atoms, such
`\
`\ ibon atoms, such
`\1. (2-4C)alkynyl
`\-
`
`\ cyclopropyl,
`
`\yclopropyl,
`
`\\erably 3-
`may be
`\ or 0.
`\d (2-
`\. 11a a
`\
`
`-------
`
`---------------· ..
`
`_,,.,·uatabase on 08/22/2012
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1007, p. 9 of 121
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`

`- 6 -
`
`(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, 0 and/or S. Preferred
`heteroatoms are N or 0. 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, tetrahyclronaphthyl 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, 0 and/or S. The (1-5C)heteroaryl may optionally
`be substituted. Preferred (1-5C)heteroaryl groups are tetrazolyl, imidazolyl, thiadiazolyl, pyridyl,
`pyrimidyl, triazinyl, thienyl orfuryl, 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, 0 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)alkyIJamino means an amino group, disubstituted with alkyl group{s), each containing
`1-4 carbon atoms and having the same meaning as previously defined. Preferred diI(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, 0 and/or S. Preferred (2-
`6C)heterocycloalkenyl groups are oxycyclohexenyl and azacyclohexenyl group.
`
`s
`
`10
`
`15
`
`20
`
`25
`
`30
`
`In the above definitions with multifunctional groups, the attachment point is at the last group.
`35 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.
`
`Copy provided by USPTO from the IFW Image Database on 08/22/2012
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`SANDOZ INC.
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`Ex. 1007, p. 10 of 121
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`- 7 -
`
`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.
`
`5
`
`The term "optionally substituted" means optional substitution with the specified groups, radicals
`or moieties.
`
`Io
`
`Aspects of the invention
`
`In one aspect the invention relates to a compound according to formula I wherein 81 is C(R7);
`B2 is C(R8); B3 is C(R9) and B4 is C(R10).
`
`15
`
`In another aspect the invention relates to a compound according to formula I wherein B 1 is
`C(R7); B2 is C{R8); B3 is C(R9}; 84 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.
`
`20
`
`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
`25 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
`30 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
`35 more particularly, an aspect of the invention relates to a compound according to formula I
`wherein R 1 0 is hydrogen.
`
`Copy provided by USPTO from the IFW Image Database on 08/22/2012
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`SANDOZ INC.
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`Ex. 1007, p. 11 of 121
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`

`- 8 -
`
`In still another aspect the invention relates to a compound according to formula J 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 81 is
`5 C(R7); B2 is C(RB); 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
`10 N.
`In another aspect the invention relates to a compound according ot formula I wherein A.is CH.
`
`15
`
`20
`
`25
`
`30
`
`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 a~achment of RS and optionally of R6 to these
`heteroaryl rings follows from formula I.
`The invention further relates to a compound according to formula I wherein RS 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 RS are optionally substituted with one or more halogen.
`In particular, the (1-4C)alkyl group in RS is optionally substituted with one or more halogen.
`In another aspect the invention relates to a compound according to formula I wherein RS is
`selected from a group consisting of hydrogen, fluorine, chlorine, (1-3C)alkyl and (1-2C) alkoxy,
`all of the alkyl groups of RS are optionally substituted with one or more halogen. In particular,
`the (1-3C)alkyl group in RS is optionally substituted with one or more fluoro. Even more
`particularly, the invention relates to a compound according to formula I wherein RS is
`hydrogen, fluorine, methyl, ethyl, propyl, methoxy or trifluoromethyl.
`
`In yet another aspect the invention relates to a compound according to formula I wherein RS 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.
`
`35
`
`In yet another aspect the invention relates to a compound according to formula I wherein RS
`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
`
`Copy provided by USPTO from the IFW Image Database on 08/22/2012
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1007, p. 12 of 121
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`- 9 -
`
`In particular, (2-6C)heterocycloalkenyl groups are
`are cyclohexenyl and cyclopentenyl.
`azacyclohexenyl and oxocyclohexenyl. Even more in particularly, the invention relates to a
`compound according to formula I wherein the (3-7C)cycloalkenyl in RS is cyclohexenyl ..
`
`s
`
`10
`
`15
`
`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-
`?C)cyc/oalkyl.
`
`In another aspecf: 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
`20 R3 are independently selected from a group consisting of cyclopropyl, cyclobutyl and
`cyclopentyl.
`
`25
`
`30
`
`35
`
`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. 1n 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, R 1 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-?C)cycloalkyl, (3-
`?C)heterocycloalkyl, [(1-4C)alkyl]amino, di[(1-4C)alkyl]amino, (1-3C)alkoxy, (3-?C)cycloalkoxy,
`(6-10C)aryl,
`(1-5C)heteroaryl or (1-3C)alkyl-S-C(O)-(1-3C)alkyl.
`In particular,
`the
`(1-
`
`Copy pfoviaed-6y USPTO from the IFW Image Database on 08/22/2012
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1007, p. 13 of 121
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`

`- 10 -
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`SC)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 (6-1 0C)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)alkyIJamino,
`(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
`R 11 is cyclopropyl.
`
`5
`
`10
`
`In another aspect the invention relates to a compound according to formula I wherein, R1 is
`15 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.
`
`20
`
`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.
`
`25
`
`In another aspect, the invention relates to compounds according to formula I wherein R1 is
`R13SO2 , wherein R13 is (2-6C)alkenyl or (2-6C)alkynyl. In particular, R13 is (2-4C)alkenyl.
`30 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.
`
`35
`
`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.
`
`Copyprovicieatiy CJSPTO from the IFW Image Database on 08/22/2012
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1007, p. 14 of 121
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`- 11 -
`
`In yet another aspect the invention relates to a compound according to formula I selected from
`the group consisting of
`( S)-4-(3-{1-Acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(pyrid in-2-
`yl)benzamide,
`( S,E)-4-(8-amino-3-{1-(4-(pyrrolidin-1-yl}but-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)(cid:173)
`N-(pyridin-2-yl)benzamide,
`
`(S,E)-4-(8-Amino-3-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)(cid:173)
`N-(pyridin-2-yl)benzamide,
`( S,E)-4-(8-amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo{ 1,5-a]pyrazin-1-yl)-N-
`(pyridin-2-yl)benzamide,
`( S)-4-(8-amino-3-( 1-(2-chloropyrimidine-4-carbonyl}pyrrolidin-2-yl) imidazo[1 ,5-a )pyrazin-1-yl)(cid:173)
`N-(pyridin-2-yl}benzamide,
`( S)-4-(8-am ino-3-( 1-but-2-ynoylpyrrolidin-2-yl)imidazo[ 1, 5-a]pyrazin-1-yl)-N-(pyridin-2-
`yl)benzamide,
`( S,E)-4-(8-Amino-3-(1-( 4-( dimethylamino )but-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-aJpyrazin-1-yl)(cid:173)
`N-( 4-fluoropyridin-2-yl)benzamide,
`(S)-4-(8-Amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo{1,5-a]pyrazin-1-yl)-N-(4-methylpyridin-2-
`yl)benzamide,
`{ S,E)-4-(8-Amino-3-(1-{ 4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[ 1, 5-a]pyrazin-1-yl)-N-{ 4-
`propylpyridin-2-yl}benzamide,
`( S)-4-{8-Amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-
`(trifluoromethyl)pyridin-2-yl)benzamide,
`(S,E)-4-(8-Amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-aJpyrazin-1-yl)-N-(4-
`ethylpyridin-2-yl)benzamide,
`( S)-4-(8-Amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl}-N-( 4,5, 6, 7-
`tetrahydrobenzo{d]thiazol-2-yl)benzamide,
`( S)-4-(3-( 1-Acry/oylpyrrolidin-2-yl)-8-aminoimidazo[ 1, 5-aJpyrazin-1-yl)-2-fluoro-N-(pyridin-2-
`yl)benzamide,
`( S)-4-(3-( 1-Acryloylpyrrolidin-2-yl)-8-aminoimidazo{ 1 , 5-a]pyrazin-1-yl)-2-methoxy-N-{pyridin-2-
`yl)benzamide,
`( S,E)-4-(8-Amino-3-( 1-( 4-( dimethylamino )but-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a)pyrazin-1-yl)(cid:173)
`N-(thiazol-2-yl)benzamide,
`{ S, E)-4-(8-Amino-3-( 1-( 4-methoxybut-2-enoyl}piperid in-2-yl)imidazo{1, 5-a]pyrazin-1-yl}-N(cid:173)
`(pyridin-2-yl)benzamide,
`( S)-4-(3-( 1-Acryloylpiperidin-2-yl}-8-aminoim idazo[1, 5-a]pyrazin-1-yl)-N-( 4-fluoropyridin-2-
`yl)benzamide,
`( S)-4-(3-( 1-Acryloylpiperidin-2-yl)-8-aminoimidazo{1, 5-a]pyrazin-1-yl)-N-( 4-cyanopyridin-2-
`yl)benzamide,
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Copy provided by USPTO from the IFW Image Database on 08/22/2012
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1007, p. 15 of 121
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`

`

`- 12 -
`
`5
`
`IO
`
`15
`
`20
`
`25
`
`30
`
`35
`
`( S)-4-(8-Amino-3-( 1-(vinylsulfonyl)piperidin-2-yl)imidazo[ 1, 5-a]pyrazin-1-yl}-N-( 4-
`(trifluoromethyl)pyridin-2-yl)benzamide,
`{ S)-4-(3-( 1-Acryloylpiperidin-2-yl}-8-aminoimidazo[1,5-a}pyrazin-1-yl)-N-(pyrimidin-2-
`yl)benzamide,
`( S)-4-(3-(1-Acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-aJpyrazin-1-yl)-N-( 4-methylpyrimidin-2-
`
`yl)benzamide,
`( S)-4-(8-Amino-3-( 1-but-2-ynoylpiperidin-2-yl)imidazol1 , 5-a]pyrazin-1-yl)-N-(pyrimidin-4-
`
`yl)benzamide,
`( S)-4-{8-Amino-3-( 1-but-2-ynoylpiperidin-2-yl}imidazo[ 1,5-aJpyrazin-1-yl)-N-(pyridazin-3-
`yl)benzamide,
`( S)-4-(8-Amino-3-( 1-but-2-ynoylpiperidin-2-