(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`24 January 2013 (24.01.2013)
`
`P O P C T
`
`(10) International Publication Number
`WO 2013/010868 Al
`
`(51) International Patent Classification:
`A61P 29/00 (2006.01)
`C07D 487/04 (2006.01)
`A61P 31/00 (2006.01)
`C07D 519/00 (2006.01)
`A61K 31/4985 (2006.01)
`A61P 35/00 (2006.01)
`A61P 19/08 (2006.01)
`A61P 37/00 (2006.01)
`
`(21) International Application Number:
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`PCT/EP2012/063552
`
`11 July 2012 ( 11.07.2012)
`
`English
`
`English
`
`(30) Priority Data:
`61/509,397
`11174578.2
`
`19 July 201 1 (19.07.201 1)
`19 July 201 1 (19.07.201 1)
`
`(71) Applicant
`OSS B.V.
`(NL).
`
`(for all designated States except US): MSD
`[NL/NL]; Kloosterstraat 6, NL-5349AB Oss
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BARF, Tjeerd A.
`[NL/NL]; St. Luciastraat 7, NL-5371AS Ravenstein (NL).
`JANS, Christiaan, Gerardus, Johannes, Maria [NL/NL];
`Heggerank 134, NL-5342CC Cuijk (NL). MAN, de Adri-
`anus, Petrus, Antonius [NL/NL]; N . V . Organon, H.W.
`Van Heelstraat 4, NL-5327AH Hurwenen (NL). OUBRIE,
`Arthur A. [NL/NL]; Saltshof 1106, NL-6604EB Wijchen
`(NL). RAAIJMAKERS, Hans C.A. [NL/NL]; Eikakker-
`hoven 26, NL-5242KK Eindhoven (NL). REWINKEL,
`Johannes, Bernardus, Maria [NL/NL]; Molenweg 16,
`NL-535 1EV Berghem (NL). STERRENBURG, Jan-Ger¬
`ard [NL/NL]; Grote Omloop 18, NL-6871TE Renkum
`(NL). WIJKMANS, Jacobus C.H.M. [NL/NL]; N . V . Or
`ganon, Oss, NL-5345LR Hurwenen (NL).
`
`(74) Agent: HORGAN, James Michael Frederic; Hertford
`Road, Hoddesdon Hertfordshire EN1 1 9BU (GB).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`
`[Continued on next page]
`
`(54) Title: 4 - IMIDAZOPYRIDAZIN- 1 -YL-BENZAMIDES AND 4 - IMIDAZOTRIAZIN- 1 - YL - BENZAMJDES AS BTK-
`INHIBITORS
`
`(57) Abstract: The present
`to 6-5
`relates
`invention
`membered fused pyridine ring compounds according to for
`mula (I) or a pharmaceutically acceptable salt thereof or to
`pharmaceutical compositions comprising these compounds
`and to their use in therapy. In particular,
`the present
`inven
`tion relates to the use of 6-5 membered fused pyridine ring
`compounds
`according to formula I
`in the treatment of
`Brutons Tyrosine Kinase (Btk) mediated disorders.
`
`(I)
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1006, p. 1 of 114
`
`

`

`w o 2013/010868
`
`A i
`
`1I II «III
`
`ill Hill III
`
`III
`
`I
`
`III
`
`M
`
`III
`
`II
`
`I
`
`II
`
`DZ,
`
`EC,
`
`EE,
`
`HN, HR, HU,
`
`KR, KZ,
`
`LA,
`
`EG,
`
`ID,
`
`LC,
`
`ES,
`
`FI, GB,
`
`GD, GE, GH,
`
`GM,
`
`GT,
`
`LV, MC, MK, MT, NL, NO,
`
`PL, PT, RO, RS,
`
`SE, SI, SK,
`
`IL,
`
`IN,
`
`IS,
`
`JP, KE, KG, KM, KN, KP,
`
`LK,
`
`LR,
`
`LS,
`
`LT,
`
`LU,
`
`LY, MA, MD,
`
`(BF,
`TR), OAPI
`SM,
`GW, ML, MR, NE,
`
`BJ, CF, CG, CI, CM, GA, GN, GQ,
`SN, TD, TG).
`
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`
`NO, NZ,
`
`OM,
`
`PE,
`
`PG,
`
`PH,
`
`PL,
`
`PT, QA,
`
`RO,
`
`Declarations
`
`under
`
`Rule
`
`4.17:
`
`SD,
`
`SE,
`
`SG,
`
`SK,
`
`SL,
`
`SM,
`
`ST,
`
`SV,
`
`SY, TH,
`
`TR,
`
`TT,
`
`TZ, UA, UG, US, UZ, VC,
`
`VN,
`
`RS, RU,
`TJ, — as to applicant's entitlement to applv for and be granted
`a patent (Rule 4.1 7(H))
`ZA,
`
`RW,
`
`TM,
`
`ZM,
`
`SC,
`
`TN,
`
`ZW.
`
`(84)
`
`(unless otherwise indicated, for every
`States
`Designated
`kind of regional protection available): ARIPO
`(BW,
`GH,
`SZ, TZ,
`SL,
`GM, KE,
`LR,
`LS, MW, MZ, NA,
`RW,
`SD,
`AZ, BY, KG, KZ, RU, TJ, — with international search report (Art. 21(3))
`(AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`
`— as to the applicant's entitlement to claim the priority of
`the earlier application (Rule 4.1 7(Hi))
`
`Published:
`
`UG,
`
`ZM,
`
`ZW),
`
`Eurasian
`
`(AM,
`
`TM),
`
`European
`
`EE,
`
`ES,
`
`FI,
`
`FR, GB, GR, HR, HU,
`
`IE,
`
`IS,
`
`IT, LT,
`
`LU,
`
`SANDOZ INC.
`
`IPR2023-00478
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`Ex. 1006, p. 2 of 114
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`

`

`4 -IMIDAZOPYRIDAZIN- 1 -YL-BENZAMIDES AND 4 -IMIDAZOTRIAZIN- 1 -YL -BENZAMIDES A S
`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
`
`a n 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 FCER 1 o n 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 a n 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 FcsR-mediated mast cell activation, Btk inhibitors may also
`
`show potential
`
`in the treatment of allergic responses
`
`[Gilfillan et al,
`
`Immunological Reviews 288 (2009)
`
`pp-1 49-1 69].
`
`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.
`
`SANDOZ INC.
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`IPR2023-00478
`
`Ex. 1006, p. 3 of 114
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`

`

`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 (201 0) pp1 35-1 43]. 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 (201 0) 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
`
`WO2001 0 19828 as IGF-1 R 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) pp1 491 - 1502]. Furthermore, aged Lyn knock-out mice develop severe
`
`splenomegaly
`
`(myeloid expansion) and disseminated monocyte/macrophage
`
`tumors [Harder et al,
`
`Immunity, 15 (2001 ) pp603-61 5]. 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) pp1 69-1 76].
`
`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 'Uck ' , two thirds of the mice die at birth, with surviving mice
`
`developing osteopetrosis, extramedullary hematopoiseis, anemia,
`
`leukopenia [Lowell et al, Blood , 87
`
`( 1996) pp1 780-1 792].
`
`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 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
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1006, p. 4 of 114
`
`

`

`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.
`
`More specifically, the present invention provides 6-5 membered fused pyridine ring compounds according
`
`to formula I or pharmaceutically acceptable salts thereof.
`
`In this formula the substituents are defined as
`
`Formula I
`
`X is CH, N , O or S ;
`
`Y is C(R6), N , O or S ;
`
`Z is CH, N or bond;
`
`A is CH or N ;
`
`B 1 is N or C(R7);
`
`B2 is N or C(R8);
`
`B3 is N or C(R9);
`
`B4 is N or C(R10);
`
`R 1 is R 11C(0), R12S(0), R13S0 2 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 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 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
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1006, p. 5 of 114
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`

`

`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 (6-1 0C)aryl or ( 1-9C)heteroaryl;
`
`R9 is H , halogen or ( 1-3C)alkoxy;
`
`R 10 is H , halogen, or ( 1-3C)alkoxy;
`
`R 11 is independently selected from a 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
`
`R 11 is ( 1-3C)alkyl-C(0)-S-(1 -3C)alkyl; or
`
`R 11 is ( 1-5C)heteroaryl optionally substituted with one or more groups selected from halogen or cyano.
`
`R 12 and R 13 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,
`
`(3-7C)cycloalkoxy,
`
`(6-1 0C)aryl,
`
`or
`
`(3-
`
`7C)heterocycloalkyl; or
`
`( 1-5C)heteroaryl optionally substituted with one or more groups selected from halogen or cyano;
`
`R 14 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,
`
`(6-1 0C)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
`
`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 ;
`
`0 to 2 atoms of B 1, 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.
`
`SANDOZ INC.
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`Ex. 1006, p. 6 of 114
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`

`

`( 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.
`
`(6-1 0C)Aryl means an aromatic hydrocarbon group having 6-1 0 carbon atoms, such as phenyl, naphthyl,
`
`tetrahydronaphthyl or indenyl. The preferred (6-1 0C)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
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1006, p. 7 of 114
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`

`

`( 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(0)-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.
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1006, p. 8 of 114
`
`

`

`Aspects of the invention
`
`In one 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) and B4 is C(R1 0).
`
`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); B4 is C(R1 0); R7, R9, and R 10 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 R 10 is hydrogen
`
`fluorine or ( 1-3C)alkoxy.
`
`In particular, R 10 is hydrogen, fluorine or methoxy. Even more particularly, an
`
`aspect of the invention relates to a compound according to formula I wherein R 10 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 B 1 is C(R7); B2 is
`
`C(R8); B3 is C(R9); B4 is C(R1 0) and R7, R8, R9, and R 10 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
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1006, p. 9 of 114
`
`

`

`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.
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1006, p. 10 of 114
`
`

`

`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, R 1 is R 1 1C(0)
`
`and R 11 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,
`
`(6-1 0C)aryl,
`
`( 1-5C)heteroaryl or
`
`( 1-3C)alkyl-S-C(0)-(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 R 1 1 is cyclopropyl.
`
`In particular, the (6-1 0C)aryl
`
`substituent of R 11 is phenyl.
`
`In yet another aspect the invention relates to a compound according to formula I wherein,
`
`R 1 is C(0)R1 1 and R 11 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
`
`R 11 is pyrrolidinyl and the (3-7C)cycloalkyl substituent of R 11 is cyclopropyl.
`
`In another aspect the invention relates to a compound according to formula I wherein, R 1 is C(0)R1 1 and
`
`R 1 1 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 R 1 1 is pyrrolidinyl and the (3-7C)cycloalkyl substituent
`
`is
`
`cyclopropyl. Even more particularly, R 11 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.
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1006, p. 11 of 114
`
`

`

`In a further aspect the invention relates to compounds according to formula I wherein R 1 is C(0)R1 1
`
`wherein R 1 1 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 R 1 is R13S0 2,
`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 R 1 is R12S(0),
`
`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 R 1 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)-4-(3-(1-Acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-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)
`
`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)-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)-N-(py
`
`2-yl)benzamide,
`
`(S)-4-(8-amino-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-e^
`
`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,
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1006, p. 12 of 114
`
`

`

`(S,E)-4-(8-Amino-3-(1-(4-methoxybut-2-enoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4
`
`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-Acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-2-fluoro-N-(pyridin-2-yl)ben
`
`(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,^
`
`2-yl)benzamide,
`
`(S,E)-4-(8-Amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]pyrazin-1^
`
`yl)benzamide,
`
`(S)-4-(3-(1-Acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(4-fluoropyri^
`
`(S)-4-(3-(1-Acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(4-cyanopyri
`
`(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-(pyrimidi
`
`(S)-4-(3-(1-Acryloylpiperidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(4-methylpy
`
`yl)benzamide,
`
`(S)-4-(8-Amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1 ,5-a]pyrazin-1-yl)-N-(pyrimidin-4-yl)benzamide,
`
`(S)-4-(8-Amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1 ,5-a]pyrazin-1-yl)-N-(pyridazin-3-yl)benzamide,
`
`(S)-4-(8-Amino-3-(1-but-2-ynoylpiperidin-2-yl)imidazo[1 ,5-a]pyrazin-1-yl)-N-(isoxazol-3-yl)benzamide,
`
`(S,E)-4-(8-Amino-3-(1-(4-methoxybut-2-enoyl)piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(5-ethylt^
`
`2-yl)benzamide,
`
`(S)-4-(3-(1-