I 1111111111111111 11111 1111111111 11111 111111111111111 IIIII IIIIII IIII IIII IIII
`US009758524B2
`
`c12) United States Patent
`Barf et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,758,524 B2
`Sep.12,2017
`
`(54) 4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES
`AS BTK INHIBITORS
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`7,825,118 B2
`7,960,396 B2
`8,377,946 Bl
`8,658,794 B2
`9,290,504 B2 *
`2006/0084654 Al
`2008/0076921 Al
`2011/0257203 Al
`2012/0053189 Al
`2012/0095026 Al
`
`11/2010 Honigberg et al.
`6/2011 Honigberg et al.
`2/2013 Chen et al.
`2/2014 de Man et al.
`3/2016 Barf .
`4/2006 Beck et al.
`3/2008 Honigberg et al.
`10/2011 Honigberg et al.
`3/2012 Loury
`4/2012 Honigberg et al.
`(Continued)
`
`C07D 487/04
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`WO
`
`1/2013
`2548877 Al
`WO-0017203 Al
`3/2000
`(Continued)
`
`OTHER PUBLICATIONS
`
`Berge et al., "Pharmaceutical salts," 66(1) J. Pharm. Sci. 1-19
`(1977).
`
`(Continued)
`
`Primary Examiner - Galam M M Shameem
`(74) Attorney, Agent, or Firm - Covington & Burling
`LLP; Einar Stole; Melody Wu
`
`ABSTRACT
`(57)
`The present invention relates to 6-5 membered fused pyri(cid:173)
`dine ring compounds according to Formula (I)
`
`Formula (I)
`
`(71) Applicant: Merck Sharp & Dohme B.V., Haarlem
`(NL)
`
`(72)
`
`Inventors: Tjeerd A. Barf, Ravenstein (NL);
`Christiaan Gerardus Johannes Maria
`Jans, Cuijk (NL); Adrianus Petrus
`Antonius de Man, Hurwenen (NL);
`Arthur A. Oubrie, Wijchen (NL);
`Hans C. A. Raaijmakers, Eindhoven
`(NL); Johannes Bernardus Maria
`Rewinkel, Berghem (NL); Jan Gerard
`Sterrenburg, Renkum (NL); Jacobus
`C.H. M. Wijkmans, Oss (NL)
`
`(73) Assignee: Merck Sharp & Dohme B.V., Haarlem
`(NL)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.: 15/019,543
`
`(22) Filed:
`
`Feb. 9, 2016
`
`(65)
`
`Prior Publication Data
`
`US 2016/0151364 Al
`
`Jun. 2, 2016
`
`Related U.S. Application Data
`
`(62) Division of application No. 14/233,418, filed as
`application No. PCT/EP2012/063552 on Jul. 11,
`2012, now Pat. No. 9,290,504.
`
`(60) Provisional application No. 61/509,397, filed on Jul.
`19, 2011.
`
`(30)
`
`Foreign Application Priority Data
`
`Jul. 19, 2011
`
`(EP) ..................................... 11174578
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 3114985
`C07D 487104
`C07D 519100
`A61K 311501
`A61K 311506
`A61K 31155
`A61K 3115377
`(52) U.S. Cl.
`CPC ........ C07D 487104 (2013.01); A61K 3114985
`(2013.01); A61K 311501 (2013.01); A61K
`311506 (2013.01); A61K 3115377 (2013.01);
`A61K 31155 (2013.01); C07D 519100
`(2013.01)
`
`( 58) Field of Classification Search
`CPC .......................... A61K 31/4985; C07D 487/04
`See application file for complete search history.
`
`or a pharmaceutically acceptable salt thereof or to pharma(cid:173)
`ceutical 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 according to Formula (I) in the treatment of
`Bruton's Tyrosine Kinase (Btk) mediated disorders.
`
`14 Claims, No Drawings
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1005, p. 1 of 78
`
`

`

`US 9,758,524 B2
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2012/0129821 Al
`2012/0135944 Al
`2012/0165328 Al
`2013/0018032 Al
`2013/0079327 Al
`2014/0073593 Al
`2014/0206681 Al
`2014/0212425 Al
`
`5/2012 Honigberg et al.
`5/2012 Honigberg et al.
`6/2012 Honigberg et al.
`1/2013 Chen et al.
`3/2013 Yamamoto et al.
`3/2014 Conklin et al.
`7/2014 Kim et al.
`7/2014 Chang et al.
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`WO-0119828 A2
`WO-02080926 Al
`WO-03065995 A2
`WO-2005014599 Al
`WO-2005037836 A2
`WO-2005097800 Al
`WO-2007061737 A2
`WO-2007064883 A2
`WO-2007064993 A2
`WO-2007106503 A2
`WO-2008121742 A2
`WO-2009076170 A2
`WO-2010126960 Al
`WO-2011095556 Al
`WO-2011119663 Al
`WO-2011152351 Al
`WO-2011153514 A2
`WO-2012158843 A2
`WO-2013003629 A2
`WO-2013010380 Al
`WO-2013010868 Al
`WO-2013010869 Al
`WO-2013059738 A2
`WO-2014143807 A2
`WO-2014159745 Al
`WO-2014168975 Al
`WO-2015018522 Al
`
`3/2001
`10/2002
`8/2003
`2/2005
`4/2005
`10/2005
`5/2007
`6/2007
`6/2007
`9/2007
`10/2008
`6/2009
`11/2010
`8/2011
`9/2011
`12/2011
`12/2011
`11/2012
`1/2013
`1/2013
`1/2013
`1/2013
`4/2013
`9/2014
`10/2014
`10/2014
`2/2015
`
`OTHER PUBLICATIONS
`
`Bingham et al., "Over one hundred solvates of sulfathiazole,"
`Chem. Commun. 603-04 (2001).
`Caira et al., "Preparation and Crystal Characterization of a
`Polymorph, a Monohydrate, and an Ethyl Acetate Solvate of the
`Antifungal Fluconazole," 93(3) J. Pharma. Sci. 601-11 (2004).
`Davis et al., "Chronic active B-cell-receptor signalling in diffuse
`large B-cell lymphoma," 463 Nature 88-92 (2010).
`Dhar et al., "Synthesis and SAR of p38a MAP kinase inhibitors
`based on heterobicyclic scaffolds," 17 Bioorg. & Med. Chem. Lett.
`5019-24 (2007).
`Gaudet et al., "A Homogeneous Fluorescence Polarization Assay
`Adaptable for a Range of Protein Serine/Threonine and Tyrosine
`Kinases," 8(2) J. Biomol. Screening 164-75 (2003).
`Gennaro (ed.), Remington: The Science and Practice of Pharmacy,
`20th edition (2000).
`
`Gilfillan et al., "The tyrosine kinase network regulating mast cell
`activation," 288 Immun. Rev. 149-69 (2009).
`Gould, "Salt selection for basic drugs," 33 Int'! J. Pharmaceutics
`201-217 (1986).
`Greene & Wuts, Protective Groups in Organic Synthesis, 2d Edition
`(1991).
`Harder et al., "Gain- and Loss-of-Function Lyn Mutant Mice Define
`a Critical Inhibitory Role for Lyn in the Myeloid Lineage," 15
`Immunity 603-15 (2001).
`Hartz et al., "Synthesis and Evaluation of Imidazo[l,5-a]pyrazines
`as Corticotropin Releasing Hormone Receptor Ligands," 12 Bioorg.
`& Med. Chem. Lett. 291-94 (2002).
`Higuchi et al. (eds.), Pro-drugs as Novel Delivery Systems, 14
`A.C.S. Symposium Series (1975).
`Ji et al., "A novel, potent, and selective insulin-like growth factor-I
`receptor kinase inhibitor blocks insulin-like growth factor-I receptor
`signaling in vitro and inhibits insulin-like growth factor-I receptor(cid:173)
`dependent tumor growth in vivo," 6(8) Mo!. Cancer Ther. 2158-67
`(2007).
`King et al., "Nucleofugality effects in the pyridine promoted for(cid:173)
`mation of esters from 2-substituted ethanesulfonyl chlorides," 66
`Can. J. Chem. 1109-16 ( 1988).
`Klinghoffer et al., "Src family kinases are required for integrin but
`not PDGFR signal transduction," 18(9) EMBO J. 2459-71 (1999).
`Lim et al., "Anti-CD20 monoclonal antibodies: historical and future
`perspectives," 95(1) Haematologica 135-43 (2010).
`Lowell et al., "Deficiency of the Hck and Src Tyrosine Kinases
`Results in Extreme Levels of Extramedullary Hematopoiesis,"
`87(5) Blood 1780-92 (1996).
`Mitchell et al., Synthesis of C-nucleoside isosteres of 9-(2-
`hydroxyethoxymethyl)guanine (acyclovir), 21(3) J. Heterocyclic
`Chem. 697-99 (1984).
`Mukaiyama et al., "Synthesis and c-Src inhibitory activity of
`imidazo[l,5-a]pyrazine derivatives as an agent for treatment of
`acute ischemic stroke," 15 Bioorg. & Med. Chem. 868-85 (2007).
`Mulvihill et al., "1,3-Disubstituted-imidazo[l,5-a]pyrazines as
`insulin-like growth-factor-I receptor (IGF-IR)
`inhibitors," 17
`Bioorg. & Med. Chem. Lett. 1091-97 (2007).
`Mulvihill et al., "Novel 2-phenylquinolin-7-yl-derived imidazo[ 1,5-
`a ]pyrazines as potent insulin-growth factor-I receptor (IGF-IR)
`inhibitors," 16 Bioorg. & Med. Chem. 1359-75 (2008).
`Odom et al., "Negative Regulation oflmmunoglobulin E-dependent
`Allergic Responses by Lyn Kinase," 199(11) J. Exp. Med. 1491-
`1502 (2004).
`Pan et al., "Discovery of Selective Irreversible Inhibitors for
`Bruton's Tyrosine Kinase," 2 ChemMedChem 58-61 (2007).
`Roby et al., "Alterations in Reproductive Function in Src Tyrosine
`Kinase Knockout Mice," 26 Endocrine 169-76 (2005).
`Roche (ed.), Bioreversible Carriers in Drug Design, Pergamon
`Press (1987).
`Shinohara et al., "Tyrosine Kinases Btk and Tee Regulate Osteoclast
`Differentiation by Linking RANK and ITAM Signals," 132 Cell
`794-806 (2008).
`van Tonder et al., "Preparation and Physicochemical Characteriza(cid:173)
`tion of 5 Niclosamide Solvates and 1 Hemisolvate," 5(1) AAPS
`PharmSciTech Article 12 (2004).
`
`* cited by examiner
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1005, p. 2 of 78
`
`

`

`US 9,758,524 B2
`
`1
`4-IMIDAZOPYRIDAZIN-1-YL-BENZAMIDES
`AS BTK INHIBITORS
`
`RELATED APPLICATIONS
`
`This application is a divisional of U.S. patent application
`Ser. No. 14/233,418, which is the U.S. national stage of
`International Patent Application No. PCT/EP2012/063552
`filed Jul. 11, 2012, which claims priority to U.S. Patent
`Application No. 61/509,397 filed Jul. 19, 2011, and to EP 10
`Patent Application No. 11174578.2 filed Jul. 19, 2011, each
`of which is hereby incorporated by reference in its entirety
`herein.
`
`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 20
`membered fused pyridine ring compounds in the treatment
`of Bruton's Tyrosine Kinase (Btk) mediated disorders.
`
`BACKGROUND OF THE INVENTION
`
`2
`lymphoma, diffuse large B-cell lymphoma and chronic lym(cid:173)
`phocytic leukemia [Lim et al, Haematologica, 95 (2010) pp
`135-143]. The reported role for Btk in the regulation of
`proliferation and apoptosis of B cells indicates there is
`5 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) pp 88-92].
`Some classes of 6-5 membered fused pyridine ring com-
`pounds have been described as kinase inhibitors e.g. Imi(cid:173)
`dazo[l,5-f][l,2,4]triazine compounds have been described
`in WO2005097800 and WO2007064993. Imidazo[l,5-a]
`pyrazine
`compounds
`have
`been
`described m
`15 WO2005037836 and WO2001019828 as IGF-lR 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
`25 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
`30 allergy-associated traits [Odom et al, J. Exp. Med., 199
`(2004) pp 1491-1502]. Furthermore, aged Lyn knock-out
`mice develop severe splenomegaly (myeloid expansion) and
`disseminated monocyte/macrophage tumors [Harder et al,
`Immunity, 15 (2001) pp 603-615]. These observations are in
`35 line with hyperresponsive B cells, mast cells and 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) pp 169-17 6].
`and Src-1-Yes-1
`The double knockouts Src-1-Fyn-1
`-
`-
`show a severe phenotype with effects on movement and
`
`breathing. The triple knockouts Src-1-Fyn-1-Yes-1- die at
`day 9.5 [Klinghoffer et al, EMBO J., 18 (1999) pp 2459-
`
`2471]. For the double knockout Src-1-Hck-1-, two thirds of
`the mice die at birth, with surviving mice developing osteo(cid:173)
`petrosis, extramedullary hematopoiesis, anemia, and leuko(cid:173)
`penia [Lowell et al, Blood, 87 (1996) pp 1780-1792].
`Hence, an inhibitor that inhibits multiple or all kinases of
`the Src-family kinases simultaneously may cause serious
`adverse effects.
`
`B lymphocyte activation is key in the generation of
`adaptive immune responses. Derailed B lymphocyte activa(cid:173)
`tion is a hallmark of many autoimmune diseases and modu(cid:173)
`lation of this immune response is therefore of therapeutic
`interest. Recently the success of B cell therapies in autoim(cid:173)
`mune diseases has been established. Treatment of rheuma(cid:173)
`toid 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 mul(cid:173)
`tiple sclerosis (RRMS) and systemic lupus erythematosus
`(SLE) patients. This success supports the potential for future
`therapies in autoimmune diseases targeting B cell immunity.
`Bruton's tyrosine kinase (Btk) is a Tee family non(cid:173)
`receptor protein kinase, expressed in B cells and myeloid 40
`cells. The function ofBtk in signaling pathways activated by
`the engagement of the B cell receptor (BCR) and FcERl 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 humans results in 45
`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 50
`classes. These findings support the key role for Btk in the
`regulation of the production of auto-antibodies in autoim(cid:173)
`mune 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 55
`in the treatment of autoimmune diseases.
`With the regulatory role reported for Btk in FcER-medi(cid:173)
`ated mast cell activation, Btk inhibitors may also show
`potential in the treatment of allergic responses [Gilfillan et
`al, Immunological Reviews 288 (2009) pp 149-169].
`Furthermore, Btk is also reported to be implicated in
`RANKL-induced osteoclast differentiation [Shinohara et al,
`Cell 132 (2008) pp 794-806] and therefore may also be of
`interest for the treatment of bone resorption disorders.
`Other diseases with an important role for dysfunctional B 65
`cells are B cell malignancies. Indeed anti-CD20 therapy is
`used effectively in the clinic for the treatment of follicular
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The object of the present invention is to provide 6-5
`membered fused pyridine ring compounds, to pharmaceuti-
`60 cal 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.
`More specifically, the present invention provides 6-5
`membered fused pyridine ring compounds according to
`Formula (I) or pharmaceutically acceptable salts thereof.
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1005, p. 3 of 78
`
`

`

`US 9,758,524 B2
`
`3
`
`Formula (I)
`
`In this formula the substituents are defined as
`X is CH, N, 0 or S;
`Y is C(R6), N, 0 or S;
`Z is CH, N or a bond;
`A is CH or N;
`Bl is Nor C(R7);
`B2 is N or C(RS);
`B3 is N or C(R9);
`B4 is Nor C(Rl0);
`Rl is Rll C(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 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;
`R5 is H, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy, (3-6C)
`cycloalkyl; all alkyl groups of RS are optionally substituted
`with one or more halogen; or RS is (6-l0C)aryl or (2-6C)
`heterocycloalkyl;
`R6 is Hor (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;
`RS is Hor (1-3C)alkyl; or
`R7 and RS form, together with the carbon atom they are
`attached to, a (6-l0C)aryl or (1-9C)heteroaryl;
`R9 is H, halogen or (1-3C)alkoxy;
`RIO is H, halogen, or (1-3C)alkoxy;
`Rl 1 is independently selected from a group consisting of 55
`(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)cy(cid:173)
`cloalkyl, [(1-4C)alkyl]amino, di[(l-4C)alkyl]amino, (1-3C)
`alkoxy, (3-7C)cycloalkoxy, (6-l0C)aryl or (3-7C)heterocy- 60
`cloalkyl; or
`Rll is (1-3C)alkyl-C(O)-S-(1-3C)alkyl; or
`Rll is (1-5C)heteroaryl optionally substituted with one or
`more groups selected from halogen or cyano.
`R12 and R13 are independently selected from a group 65
`consisting of (2-6C)alkenyl or (2-6C)alkynyl both option(cid:173)
`ally substituted with one or more groups selected from
`
`45
`
`15
`
`20
`
`4
`[(1-4C)alkyl]
`(3-7C)cycloalkyl,
`(1-4C)alkyl,
`hydroxyl,
`amino, di[(l-4C)alkyl]amino,
`(1-3C)alkoxy,
`(3-7C)cy(cid:173)
`cloalkoxy, (6-l0C)aryl, or (3-7C)heterocycloalkyl; or
`(1-5C)heteroaryl optionally substituted with one or more
`5 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]
`10 amino, di[(l-4C)alkyl]amino,
`(1-3C)alkoxy,
`(3-7C)cy(cid:173)
`cloalkoxy, (6-l0C)aryl, (1-5C)heteroaryl or (3-7C)heterocy(cid:173)
`cloalkyl.
`With the proviso that:
`0 to 2 atoms ofX, Y, Z can simultaneously be a heteroa(cid:173)
`tom;
`when one atom selected from X, Y is O or S, then Z is a
`bond and the other atom selected from X, Y camiot be
`0 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 Bl, 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
`25 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.
`( l -4C)Alky 1 means a branched or unbranched alky 1 group
`30 having 1-4 carbon atoms, being methyl, ethyl, propyl, iso(cid:173)
`propyl, butyl, isobutyl, sec-butyl and tert-butyl, (1-3C)alkyl
`groups being preferred.
`(1-5C)Alkyl means a branched or unbranched alkyl group
`35 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.
`( l -6C)Alky 1 means a branched or unbranched alky 1 group
`having 1-6 carbon atoms, for example methyl, ethyl, propyl,
`40 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 previ(cid:173)
`ously defined.
`(1-3C)Alkoxy means an alkoxy group having 1-3 carbon
`atoms, the alkyl moiety having the same meaning as previ(cid:173)
`ously 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 previ-
`50 ously 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-hexy(cid:173)
`nyl. (2-4C)alkynyl groups are preferred.
`(3-6C)Cycloalkyl means a cycloalkyl group having 3-6
`carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl or
`cyclohexyl.
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1005, p. 4 of 78
`
`

`

`US 9,758,524 B2
`
`6
`When, in the definition of a substituent, it 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
`10 on the designated atom/atoms is/are replaced with a selec(cid:173)
`tion 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 permis(cid:173)
`sible 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,
`20 and formulation into an efficacious therapeutic agent.
`The term "optionally substituted" means optional substi(cid:173)
`tution with the specified groups, radicals or moieties.
`
`Aspects of the Invention
`
`5
`(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 5
`one or two heteroatoms selected from N, 0 and/or S, which
`may be attached via a heteroatom if feasible, or a carbon
`atom. Preferred heteroatoms are N or 0. Preferred are
`piperidine, morpholine, pyrrolidine and piperazine. Most
`preferred (2-6C)heterocycloalkyl is pyrrolidine. The hetero(cid:173)
`cycloalkyl 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 15
`one or two heteroatoms selected from N, 0 and/or S.
`Preferred heteroatoms are N or 0. Preferred (3-7C) hetero(cid:173)
`cycloalkyl groups are azetidinyl, pyrrolidinyl, piperidinyl,
`homopiperidinyl or morpholinyl. More preferred (3-7C)
`heterocycloalkyl groups are piperidine, morpholine and pyr(cid:173)
`rolidine. 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 25
`atom.
`(6-l0C)Aryl means an aromatic hydrocarbon group hav(cid:173)
`ing 6-10 carbon atoms, such as phenyl, naphthyl, tetrahy(cid:173)
`dronaphthyl or indenyl. The preferred (6-l0C)aryl group is
`phenyl.
`(1-5C)Heteroaryl means a substituted or unsubstituted
`aromatic group having 1-5 carbon atoms and 1-4 heteroa(cid:173)
`toms selected from N, 0 and/or S. The (1-5C)heteroaryl may
`optionally be substituted. Preferred (1-5C)heteroaryl groups 35
`are tetrazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidyl,
`triazinyl, thienyl or fury!, 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 heteroa- 40
`toms 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, monosubsti(cid:173)
`tuted with an alkyl group containing 1-4 carbon atoms 45
`having the same meaning as previously defined. Preferred
`[(1-4C)alkyl]amino group is methylamino.
`Di[(l-4C)alkyl]amino means an amino group, disubsti(cid:173)
`tuted with alkyl group(s), each containing 1-4 carbon atoms
`and having the same meaning as previously defined. Pre- 50
`ferred di[(l-4C)alkyl]amino group is dimethylamino.
`Halogen means fluorine, chlorine, bromine or iodine.
`(1-3C)Alkyl-C(O)-S-(1-3C)alkyl means an alkyl-carbo(cid:173)
`nyl-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 cyclohex(cid:173)
`enyl. 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 oxycyclo(cid:173)
`hexenyl and azacyclohexenyl groups.
`In the above definitions with multifunctional groups, the
`attachment point is at the last group.
`
`55
`
`30
`
`In one aspect the invention relates to a compound accord(cid:173)
`ing to Formula (I) wherein Bl is C(R7); B2 is C(RS); B3 is
`C(R9) and B4 is C(Rl0).
`In another aspect the invention relates to a compound
`according to Formula (I) wherein Bl is C(R7); B2 is C(RS);
`B3 is C(R9); B4 is C(Rl0); R7, R9, and RIO each are H; and
`RS is selected from a group consisting of hydrogen and
`methyl.
`In one aspect the invention relates to a compound accord(cid:173)
`ing to Formula (I) wherein RS is hydrogen or methyl, in
`particular RS 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 RIO is hydrogen fluorine
`or (1-3C)alkoxy. In particular, RIO is hydrogen, fluorine or
`methoxy. Even more particularly, an aspect of the invention
`relates to a compound according to Formula (I) wherein RIO
`is hydrogen.
`In still another aspect the invention relates to a compound
`according to Formula (I) wherein R7 and RS form, together
`with the carbon atom they are attached to, an indole or
`quinoline or naphthyl.
`In another aspect the invention relates to a compound
`60 according to Formula (I) wherein Bl is C(R7); B2 is C(RS);
`B3 is C(R9); B4 is C(Rl0) and R7, RS, R9, and RIO each
`are H;
`In yet another aspect the invention relates to a compound
`according to Formula (I) wherein R4 is hydrogen or methyl.
`65 In particular, R4 is hydrogen.
`In still another aspect the invention relates to a compound
`according to Formula (I) wherein A is N.
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1005, p. 5 of 78
`
`

`

`US 9,758,524 B2
`
`7
`In another aspect the invention relates to a compound
`according of 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, 5
`pyrimidyl, pyridazyl, triazinyl, thiazolyl, oxazolyl, and isox(cid:173)
`azolyl. 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 RS and R6 is 10
`independent from the selection of X, Y, and Z. The place of
`attachment of RS and optionally of R6 to these heteroaryl
`rings follows from Formula (I).
`The invention further relates to a compound according to 15
`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 option(cid:173)
`ally substituted with one or more halogen. In particular, the
`(1-4C)alkyl group in RS is optionally substituted with one or 20
`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 option- 25
`ally 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 hydro(cid:173)
`gen, fluorine, methyl, ethyl, propyl, methoxy or trifluorom- 30
`ethyl.
`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 35
`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 RS and R6 together form
`a (3-7C)cycloalkenyl or a (2-6C)heterocycloalkenyl both 40
`optionally substituted with (1-3C)alkyl or one or more
`halogen. In particular, (3-7C)cycloalkenyl groups are cyclo(cid:173)
`hexenyl and cyclopentenyl. In particular, (2-6C)heterocy(cid:173)
`cloalkenyl groups are azacyclohexenyl and oxycyclohex(cid:173)
`enyl. Even more in particularly, the invention relates to a 45
`compound according to Formula (I) wherein the (3-7C)
`cycloalkenyl in RS 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 hydro- 50
`gen 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 60
`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 indepen- 65
`dently selected from a group consisting of cyclopropyl,
`cyclobutyl and cyclopentyl.
`
`8
`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, pyrrolidi-
`nyl, piperidinyl, homopiperidinyl or morpholinyl ring each
`optionally substituted with one or more halogen, hydroxyl,
`(1-3C)alkyl, (1-3C)alkoxy or oxo, preferred halogen sub(cid:173)
`stituent 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, pyrrolidi(cid:173)
`nyl, 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, Rl is RllC(O) and Rll
`is (1-6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl each option(cid:173)
`ally independently substituted with one or more groups
`selected from hydroxyl, (1-4C)alkyl, (3-7C)cycloalkyl,
`(3-7C)heterocycloalkyl,
`[(1-4C)alkyl]amino,
`di[(l-4C)
`alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-l0C)aryl,
`(1-SC)heteroaryl or (1-3C)alkyl-S-C(O)-(1-3C)alkyl. In
`particular, the (1-SC)heteroaryl group is pyrimidyl or triazi(cid:173)
`nyl optionally substituted with one or more groups selected
`from halogen or cyano. In particular, the (3-7C)heterocy(cid:173)
`cloalkyl is pyrrolidinyl. Even more particularly, the inven-
`tion relates to a compound according