1111111111111111 IIIIII IIIII 111111111111111 111111111111111 IIIII IIIII IIIII 1111111111 11111111
`US 20140357650Al
`
`c19) United States
`c12) Patent Application Publication
`Jansen et al.
`
`(lo) Pub. No.: US 2014/0357650 Al
`Dec. 4, 2014
`(43) Pub. Date:
`
`(52)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`C07D417/12
`C07D413/12
`C07D401/12
`C07D403/12
`U.S. CI.
`CPC ............ C07D 487/04 (2013.01); C07D 401/12
`(2013.01); C07D 403/12 (2013.01); C07D
`417/12 (2013.01); C07D 413/12 (2013.01);
`C07D 471/04 (2013.01)
`USPC ... 514/259.31; 546/169; 514/314; 546/279.1 ;
`514/343; 546/156; 514/312; 548/314.7;
`514/397; 548/200; 514/365; 548/236; 514/374;
`546/208; 514/326; 546/118; 514/303; 544/263;
`546/123
`
`ABSTRACT
`(57)
`The present invention relates to novel inhibitors having high
`selectivity and specificity for FAP (fibroblast activation pro(cid:173)
`tein). Said inhibitors are useful as a human and/or veterinary
`medicine, in particular for the treatment and/or prevention of
`PAP-related disorders such as but not limited to proliferative
`disorders.
`
`(54) NOVEL FAP INHIBITORS
`
`(71) Applicants: , Antwerpen (BE); Fox Chase Cancer
`Center, Philadelphia, PA (US)
`
`(72)
`
`Inventors: Koen Jansen, Wilrijk (BE); Ingrid De
`Meester, Wilrijk (BE); Leen Heirbaut,
`Wilrijk (BE); Jonathan D. Cheng,
`Philadelphia, PA (US); Jurgen Joossens,
`Wilrijk (BE); Koen Augustyns, Wilrijk
`(BE); Pieter Van Der Veken, Wilrijk
`(BE)
`
`(73) Assignee: Fox Chase Cancer Center,
`Phliadelphia, PA (US)
`
`(21) Appl. No.:
`
`14/372,798
`
`(22) PCT Filed:
`
`Jan. 17, 2013
`
`(86) PCT No.:
`
`PCT /EP2013/050845
`
`§ 371 (c)(l),
`(2), ( 4) Date:
`
`Jul. 17, 2014
`
`(30)
`
`Foreign Application Priority Data
`
`Jan. 17, 2012
`Nov. 14, 2012
`
`(GB) ........ .............. ............. 1200705.0
`(GB) ................................... 1220458.2
`
`Publication Classification
`
`(51)
`
`Int. CI.
`C07D 487104
`C07D 471/04
`
`(2006.01)
`(2006.01)
`
`3/17/2025 16:29:54
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`Page 1 of 57
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`Petitioner GE Healthcare – Ex. 1044, p. 1
`
`

`

`US 2014/0357650 Al
`
`Dec. 4, 2014
`
`1
`
`NOVEL FAP INHIBITORS
`
`FIELD OF THE INVENTION
`
`[0001) The present invention relates to novel inhibitors
`having high selectivity and specificity for FAP (fibroblast
`activation protein). Said inhibitors are useful as a human
`and/or veterinary medicine, in particular for the treatment
`and/or prevention of FAP-related disorders such as but not
`limited to proliferative disorders.
`
`BACKGROUND TO THE INVENTION
`
`[0002) 1. Introduction
`[0003) Fibroblast activation protein (FAP, FAP-alpha,
`seprase, alpha2 antiplasmin converting enzyme) is a Clan SC
`protease of the prolyl oligopeptidase subfamily S9b, occur(cid:173)
`ring as a cell surface homodimer. FAP has been demonstrated
`to possess both dipeptidyl peptidase and endopeptidase activ(cid:173)
`ity, catalyzed by the same active center. Its expression is
`associated with activated stromal fibroblasts and pericytes of
`over 900/o of human epithelial tumors examined and with
`normal or excessive wound healing, e.g. in tissue remodeling
`sites or during chronic inflammation. The enzyme is gener(cid:173)
`ally not expressed in normal adult tissues and in nonmalig(cid:173)
`nant tumors. 1 Several studies have tried to map the physi(cid:173)
`ological substrate spectrum of FAP, including very recent
`reports that identify i.a. alpha2-antiplasmin, type I collagen
`and gelatin as in vitro substrates of the endopeptidase activity
`of FAP.2 Analogously, Neuropeptide Y, B-type natriuretic
`peptide, substance P and peptide YY have been identified as
`in vitro substrates of the dipeptidyl peptidase activity ofF AP. 3
`Nonetheless, the relevance of these findings under in vivo
`conditions remains debatable and the unambiguous definition
`of FAP's physiological
`substrate
`spectrum
`remains
`untouched matter so far.
`[0004) Through structure-based design studies combined
`with extensive synthetic and biochemical effort, we were able
`to establish a Structure-Activity Relationship (SAR) of
`N-acylated aminoacyl pyrrolidine inhibitors of fibroblast
`activation protein. This has led to the discovery of a novel
`scaffold type that has the potential to deliver inhibitors ofFAP
`that combine low nanomolar activity with unprecedented
`selectivity toward related Clan SC proteases (dipeptidyl pep(cid:173)
`tidases IV, II, 8/9 and the endopeptidase prolyl oligopeptidase
`(PREP, PO). When compared to most other classes of
`reported inhibitors of F AP, inhibitors belonging to the scaf(cid:173)
`fold type described here have remarkable stability both in
`aqueous solution and in human plasma and retain activity and
`selectivity for FAP within the latter media. For example,
`WO2007085895, WO2007005991 , WO2010083570,
`WO2006125227 and WO0238590 all disclose FAP inhibitors
`having a general structure closely relating to the compounds
`of the present invention. However, none of them actually
`discloses compounds wherein
`
`0-·
`
`as defined in the present invention, is a 5 to 10-membered
`N-containing aromatic or non-aromatic mono- or bicyclic
`heterocycle, wherein there are exactly 2 ring atoms between
`
`the N atom and X. As further detailed herein below, in par(cid:173)
`ticular said feature is relevant for providing the compounds of
`the present invention with the FAP activity and selectivity as
`defined herein.
`[0005) Based on FAP's role in (patho-)fysiology, docu(cid:173)
`mented extensively in literature, we reasonably foresee
`potential applications of our inhibitors in disease domains
`characterised by: (a) proliferation (including but not limited
`to cancer) (b) tissue remodelling and/or chronic inflammation
`(including but not limited to fibrotic disease, wound healing,
`keloid formation, osteoarthritis, rheumatoid arthritis and
`related disorders involving cartilage degradation) and (c)
`endocrinological disorders (including but not limited to dis(cid:173)
`orders of glucose metabolism). The relationship ofFAP with
`said pathological processes is described in more detail here(cid:173)
`after.
`
`(a) FAP and Proliferative Diseases (Including but not Limited
`to Cancer).
`
`[0006) During the last decade, numerous reports have been
`published that claim an important role for FAP in tumor
`growth and proliferation. The exact mechanism by which
`FAP takes part in these processes is unknown, but direct
`modulation of tumor growth, angiogenesis or disease pro(cid:173)
`gression by proteolytic processing of growth factors, cytok(cid:173)
`ines, collagenase activity regulating proteins and even col(cid:173)
`lagen derived proteins, is currently the subject of intensive
`research.
`[0007) While awaiting the detailed functional characteriza(cid:173)
`tion of the enzyme in these processes, several groups cur(cid:173)
`rently focus on FAP's status as a potential cancer biomarker
`which presence or activity in tumors could also be used for
`site-directed delivery of oncology drugs.4 Equally important,
`FAP or its activity are being targeted by several groups as a
`direct way to reduce tumor growth and proliferation by means
`of immunotherapeutic and
`small molecule
`inhibitor
`approaches. 5 For the latter, a number of in vivo proof-of(cid:173)
`concept studies are present. These all involve the dipeptide
`derived boronic acid talabostat (PT-100, Val-boroPro) or
`close analogues, and report significant activity on tumor stro(cid:173)
`magenesis and growth. 6 In addition, talabostat has been
`evaluated as a drug in various clinical trials up to phase II, for
`the treatment of, i.a. metastatic kidney cancer, chronic lym(cid:173)
`phocytary leukemia, pancreatic adenocarcinoma and non(cid:173)
`small cell lung cancer. While talabostat in several of these
`trials was able to induce clinical response, questions were
`raised with regards to the safety profile of the compound,
`potentially related to its well-known lack of selectivity with
`respect to other Subfamily S9B proteases.7
`(b) FAP and Diseases Involving Tissue Remodeling and/or
`Chronic Inflammation (Including but not Limited to Fibrotic
`Disease, Wound Healing, Keloid Formation, Osteoarthritis,
`Rheumatoid Arthritis and Related Disorders Involving Carti(cid:173)
`lage Degradation, Atherosclerotic Disease and Chron's Dis(cid:173)
`ease)
`[0008) Multiple reports on occurrence of significantly
`increased FAP expression and/or activity both in physiologi(cid:173)
`cal processes and in several clearly distinct disease domains,
`indicate that the enzyme might play an important role during
`events characterized by tissue remodeling and/or inflamma(cid:173)
`tion. Although the exact mechanism by which FAP is alleged
`to do so has to date not been clarified, the most straightfor(cid:173)
`ward hypothesis involves the enzyme's capability of process(cid:173)
`ing collagenase activity regulating proteins and even collagen
`
`3/17/2025 16:29:54
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`Page 2 of 57
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`Petitioner GE Healthcare – Ex. 1044, p. 2
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`

`US 2014/0357650 Al
`
`Dec. 4, 2014
`
`2
`
`derived proteins, thereby altering the composition and struc(cid:173)
`ture of the extracellular matrix (ECM) of tissues. This effect
`could be supplemented by influences on the proteolytic pro(cid:173)
`cessing of peptide growth factors and cytokines. Similar argu(cid:173)
`ments are summoned to describe the ofFAP's role in prolif(cid:173)
`erative disease (vide supra).
`[0009) Significant FAP expression has been confirmed for
`reactive fibroblasts in granulation tissue of healing wounds,
`on stellate cells at the tissue remodeling interface in hepatic
`cirrhosis, and in lung tissue in idiopathic pulmonary fibrosis. 8
`For hepatic cirrhosis (the pathological state characterized by
`fibrosis in which FAP's involvement has been best character(cid:173)
`ized) elevated expression ofFAP was observed regardless of
`the etiology of the disease ( viral hepatitis-induced, alcohol(cid:173)
`induced, biliary cirrhosis). This given might suggest broad
`applicability of PAP-targeted therapy, e.g. using small mol(cid:173)
`ecule inhibitors, in disease area's involving fibrotic liver
`degeneration. 9
`[0010) FAP expression was found to be significantly
`increased on keloid fibroblasts compared to normal skin
`fibroblasts and inhibition ofFAP activity with the albeit unse(cid:173)
`lective (with respect to phylogenetically related dipeptidyl
`peptidases) irreversible
`inhibitor Gly-Pro<Pl(OPh)2 was
`found to lead to a decrease in invasiveness. 10
`[0011) FAP expression and activity was also shown to be
`associated with rheumatoid arthritis and osteoarthritis: FAP(cid:173)
`activity on the surface of chondrocytes and elevated expres(cid:173)
`sion and activity in cartilage affected by osteoarthritis were
`demonstrated. FAP was also found to be present in synovial
`tissue of affected joints, and elevated expression is detected in
`the murine collagen induced arthritis model. An additional
`pathway by which FAP could be operating in the pathogen(cid:173)
`esis and progression of arthritis, has been proposed to imply
`proteolytic cleavage of alpha2-antiplasmin, ultimately lead(cid:173)
`ing to fibrin deposition in the joint. Notably, in a Phase 1
`clinical dosing study with a humanized anti-FAP antibody
`( si brotuzuma b) for advanced and metastatic cancer, the anti(cid:173)
`body in three patients not only localized to tumors, but also to
`the knees and shoulders. This observation has been connected
`to early-stage arthritis, offering initial support for the in vivo
`validation ofFAP as a target for arthritis and related diseases.
`11
`
`[0012) Recently, significantly increased expression ofFAP
`was reported for human Type IV-Type V aortic atheromata,
`compared to type III atheromata and healthy aortae. Addi(cid:173)
`tionally, thin-cap human coronary atheromata were found to
`contain more FAP than thick-cap lesions. The enzyme's
`occurrence was found to be concentrated on smooth muscle
`and endothelial cells, and it could not be detected on mac(cid:173)
`rophages. Nonetheless, macrophage burden did correlate
`with total FAP expression in the plaques. Furthermore, in
`vitro zymography revealed that PAP-mediated collagenase
`activity was neutralized by an antibody directed to the
`enzyme' s catalytic domain both in human atherosclerotic
`smooth muscle cells and in fibrous caps of atherosclerotic
`plaques. 2 6
`[0013)
`In a very recent publication, FAP was found to be
`overexpressed in enteric strictures of patients with Chron's
`disease (CD) and the protein was observed to be upregulated
`on strictured CD myofibroblasts by profibrogenic stimuli,
`leading the authors oftl1is study to propose FAP as a potential
`target for the treatment offibrostenosing CD. 12
`[0014)
`In general, no in vivo or clinical results (apart from
`the mentioned) have so far been disclosed dealing with the
`
`application of PAP-targeting small molecules or immuno(cid:173)
`therapeutic strategies in disease domains mentioned under
`this part. Nonetheless, mounting in vitro evidence from lit(cid:173)
`erature can certainly be considered compelling to initiate
`such investigations.
`
`(c) FAP and Diseases Involving Endocrinological Disorder
`(Including but not Limited
`to Disorders of Glucose
`Metabolism) and Diseases
`Involving Blood Clotting
`Disorders.
`
`[0015) A recent patent application by Gorrell et al. claims
`the utility ofFAP inhibitors in the prevention and treatment of
`metabolic abnormalities characterized by abnormal glucose
`metabolism, including diabetes mellitus and new onset dia(cid:173)
`betes. This claim is however not otherwise documented in the
`literature. 13
`[0016) Finally, blocking the activity of the soluble form of
`FAP ( alpha2-antiplasmin cleaving enzyme, APCE) occurring
`in plasma, using small molecule inhibitors was found to cause
`enhanced fibrinolysis and to lead to a decrease of plasmino(cid:173)
`gen activator induced clot lysis time. This observation Jed the
`authors to state thatAPCE-inhibition might constitute a novel
`approach in tlrrombolytic therapy without significant risk of
`bleeding.14
`
`2. Inhibitor Design
`
`[0017) The prime aim underlying our effort to establish
`detailed SAR data for N-acylated aminoacyl pyrrolidine
`inhibitors of FAP, was to identify compounds with signifi(cid:173)
`cantly improved (a) chemical stability and (b) selectivity
`characteristics when compared to known FAP inhibitors,
`while retaining high affinity for the target enzyme.
`(a) Umited chemical stability due to intramolecular cyclisa(cid:173)
`tion is a well known problem of several currently available
`highly potent dipeptide derived boronic acids (e.g. Val-boro(cid:173)
`Pro ). This property, caused by the combined presence of a
`nucleophilic amino terminus and an electrophilic boronic
`acid, puts constraints e.g. on the applicability of this com(cid:173)
`pound and its analogues at physiological pH both in vitro and
`in vivo. 15
`(b) Selectivity with respect to related S9b proteases (DPP IV,
`DPPS/9, DPP II, PREP) is a potential point of concern for all
`FAP inhibitors. Due to the high degree of phylogenetic rela(cid:173)
`tionship between the S9b proteases, pharmacophores of their
`inhibitors generally display substantial overlap. This problem
`is well documented for a numberof described FAP inhibitors,
`including the well known ValboroPro. Noteworthy however,
`for most reported FAP inhibitors incomplete and in some
`cases even no selectivity data have been reported, rendering
`existing knowledge as a starting point for selective FAP
`inhibitor discovery inadequate. Nonetheless, taking into
`account the importance of inhibitor selectivity in the frame(cid:173)
`work of potential compound toxicity and off-target effects,
`we deemed the preparation of selective compounds an impor(cid:173)
`tant goal of our endeavours. With the number of reported
`PAP-inhibitors being small and most of them belonging to the
`class ofboronic acids, we initially decided to focus on com(cid:173)
`pounds that contain a carbonitrile warhead in place of the
`boronic acid, but conserve an overall di peptide derived archi(cid:173)
`tecture. The latter is a hallmark of most chemotypes of pub(cid:173)
`lished Subfamily S98 inhibitors. The carbonitrile function
`itself is also a popular affinity-enhancing moiety in reported
`series of inhibitors ofDPP IV, DPP8, DPP9 and PREP. Com-
`
`3/17/2025 16:29:54
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`Page 3 of 57
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`Petitioner GE Healthcare – Ex. 1044, p. 3
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`

`

`US 2014/0357650 Al
`
`Dec. 4, 2014
`
`3
`
`pared to other warheads that are used in serine protease
`inhibitor design (e.g. - B(OH)2 , - CHO, chloromethylke(cid:173)
`tones, ketoamides, .
`. ) the relatively mildly electroph.ilic
`carbonitrile could account for making the inhibitor more
`selective in vivo, a hypothesis that has been raised in literature
`earlier.' In addition, the projected structures' overall archi(cid:173)
`tecture does in principle not impose fundamental limitations
`with respect to in vivo use, as e.g. illustrated by the EMA(cid:173)
`approved vildagliptin and the FDA approved saxagliptin,
`both inhibitors ofDPP IV. Three other publications are known
`to us that also contain carbonitrile-based inhibitors ofF AP, all
`of them including incomplete FAP affinity and selectivity
`data or, in one case, even no affinity at all. 16
`[0018] Using the boundary assumptions described above,
`we decided to start an in depth investigation of the Structure(cid:173)
`Activity Relationship (SAR) of N-acylaminoacyl(2-cyan(cid:173)
`opyrrolidines) as inhibitors of FAP and their selectivity
`toward dipeptidyl peptidases and PREP. Three main struc(cid:173)
`tural fragments with.in this structure were marked for inves(cid:173)
`tigation and elaboration of the SAR:
`
`Val-boroPro
`talabostat
`
`Pl
`
`R3
`\
`
`N
`
`~
`R 1 I ~ o
`,,L
`
`P3 [
`
`,,)t..
`
`toward dipeptidyl peptidases to be smaller, blocking the
`amino terminus does substantially increase the risk of selec(cid:173)
`tivity problems with respect to the endopeptidase PREP.
`Again, very limited literature information was present deal(cid:173)
`ing with FAP to PREP selectivity of inhibitors with an acy(cid:173)
`lated P2 amine function. 1
`
`(b) the P2 Moiety:
`
`[0020] while several acylated glycyl(2-borono )pyrro(cid:173)
`lidines have been reported in literature, almost no data exist
`on the influence of other amino acid residues at the P2 posi(cid:173)
`tion in acylated compounds. At the outset of our activities,
`substrate kinetics studies nonetheless indicated a rather strict
`preference of PAP for a P2-glycine residue in substrates con(cid:173)
`taining an acylated P2 amino function . Th.is given is in sharp
`contrast with a series of dipeptide-derived substrates and/or
`inhibitors (e.g. ValboroPro) with a free amino terminus,
`where the number of tolerated P2 residues is known to be
`much larger.
`
`(c) The Pl Moiety:
`
`[0021] We decided to investigate the influence on activity
`and selectivity of substituting the pyrrolidine ring in com(cid:173)
`pounds with structure 1. To th.is end, we selected a number of
`different functional groups with different bulk size and elec(cid:173)
`tronic effects.
`[0022]
`In addition, we expected the obtained SAR-infor(cid:173)
`mation poised to be applicable to analogous inhibitor types
`containing specific other warhead types or even no warhead,
`a hypothesis that we later on showed to be correct.
`[0023] We have now surprisingly found that PAP-inhibitors
`of fonnula I exhibit good chemical stability and high selec(cid:173)
`tivity for FAP, rendering them very suitable for the prepara(cid:173)
`tion of a medicine for the treatment of various PAP-related
`disorders. In addition, our invention has the potential to
`deliver compounds with high solubility and low LogD-val(cid:173)
`ues, a feature that is far from evident for dipeptide-derived
`compounds lacking a basic amino terminus and that is
`accounted for by the presence of heteroatoms introduced at
`specific positions of the P3 substituent.
`
`SUMMARY OF THE INVENTION
`
`[0024]
`In a first aspect, the present invention provides a
`compound of Formula I or a stereoisomer, tautomer, racemic,
`metabolite, pro- or predrug, salt, hydrate, or solvate thereof,
`
`Wherein
`
`[0025] R, and R2 are each independently selected from the
`group comprising - H, OH, -halo, C1_6alkyl , -O- C1_
`6alkyl, S-C1_6alkyl;
`
`R2
`
`P2
`
`Generic structure of
`N-acyl-glycyl(2-cyru10 )pyrrolidines
`R 1 = alkanoyl-, aryl oyl-, arylalkanoyl, arylsulfonyl, R2 = alkyl-, aryl-, arylalkyl , R3 =
`methyl-, ethyl-, methylideen-, flu oro-, difluoro-,
`
`(a) the P3 Moiety:
`
`[0019] By attaching this moiety (via an acyl linkage) to the
`aminoacyl(2-cyanopyrrolidine) backbone of the inhibitor, we
`wanted to make the P2 residue non-basic and 11011-nucleo(cid:173)
`philic, thus increasing the likeliness of inhibitor selectivity
`and higher stability with respect to the S9b dipeptidyl pepti(cid:173)
`dases. Some literature evidence existed for peptide derived
`boronic acid inhibitors that this approach might be viable,
`although no systematic studies in th.is direction have been
`carried out. In addition, a substantial number of these litera(cid:173)
`ture FAP inhibitors have been reported with only limited or
`even without selectivity data for the related dipeptidyl pepti(cid:173)
`dases. Additionally, while one might anticipate affinity
`
`3/17/2025 16:29:54
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`Page 4 of 57
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`Petitioner GE Healthcare – Ex. 1044, p. 4
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`

`

`US 2014/0357650 Al
`
`Dec. 4, 2014
`
`4
`
`[0026] R3 is selected from the group comprising - H,
`----CN, - B(OH)2 , ----C(O)alkyl, - C(O)aryl-, ----C= C(cid:173)
`----C= C--S(O) 2aryl,
`----CO2 H,
`- SO3 H,
`C(O)aryl,
`- SO 2 NH 2
`, - PO 3 H 2
`, and 5-tetrazolyl;
`[0027] R4 is selected from the group comprising - H,
`----C 1_6alkyl, -O----C 1 _6alkyl, - S- C 1_6alkyl, - Ar1 , and
`----C 1_6aralkyl; each of said ----C 1_6alkyl being optionally
`substituted with from 1 to 3 substituents selected from
`-OH, -halo
`[0028] R5 , R6 and R7 are each independently selected from
`the group comprising -H, -OH, -oxo, -halo, ----C 1 _
`63lkyl, -O-C 1_6alkyl, -S-C 1_6alkyl, -NR8R9 ,
`-OR12 -Het2 and -Ar2 ; each of said C1_6alkyl being
`optionally substituted with from 1 to 3 substituents
`selected from - OH, -halo R8 , R9 and R 12 are each inde(cid:173)
`pendently selected from the group comprising - H, -OH,
`-halo, ----C 1 _6alkyl, - 0----C 1 _6alkyl, - S----C 1_6alk.')'l, and
`- Ar3
`[0029] R 10, R 11 , R 13 and R 14 are each independently
`selected from the group comprising - H, - OH, -halo,
`----C 1_6alkyl, -O- C1 _6alkyl, and - S----C 1_6alkyl ;
`[0030] Ari, Ar2 and Ar3 are each independently a 5- or
`6-membered aromatic monocycle optionally comprising 1
`or 2 heteroatoms selected from 0 , N and S; each of said
`Ar1 , Ar2 and Ar3 being optionally and independently sub(cid:173)
`stituted with from 1 to 3 substituents selected from
`-NR10R 11 ,
`----C 1 _6alkyl, -O-C 1_6alkyl, -S----C 1_
`63lkyl;
`[0031] Het2 is a 5- or 6-membered non-aromatic mono(cid:173)
`cycle optionally comprising 1 or 2 heteroatoms selected
`from 0, N and S; said Het2 being optionally substituted
`with from 1 to 3 substituents selected from - NR13R14,
`----C 1_6alkyl, -O- C1 _6alkyl, - S- C 1_6alkyl;
`[0032] n is 0, 1, 2, or 3
`
`0-•
`
`represents a 5 to IO-membered N-containing aromatic or
`non-aromatic mono- or bicyclic heterocycle, wherein there
`are exactly 2 ring atoms between the N atom and X; said
`heterocycle optionally further comprising 1, 2 or 3 heteroat(cid:173)
`oms selected from 0, N and S; and
`[0033] X represents a C atom
`[0034]
`In a preferred embodiment, the present invention
`provides a compound according to formula I, wherein
`[0035] R 1 and R2 are each independently selected from the
`group comprising - H, and -halo;
`[0036] R3 is - CN, or - B(OH)2
`[0037] R4 is selected from the group comprising - H or
`----C 1_6alkyl ; eachofsaid - C 1_6alkyl being optionally sub(cid:173)
`stituted with from 1 to 3 substituents selected from -OH;
`[0038] R5 , R6 and R7 are each independently selected from
`the group comprising - H, -OH, -oxo, -halo, ----C 1 _
`6alk.')'l, -O- C 1_6alk.')'l, Ar2 and - NR8R9 ; each of said
`C1 _6alkyl being optionally substituted with from 1 to 3
`substituents selected from -OH, -halo;
`[0039] R8 and R9 are each independently selected from the
`group comprising - H and - Ar 3
`
`[0040] Ar2 andAr3 are each independently -phenyl option(cid:173)
`ally substituted with from I to 3-O----C 1 _6alkyl;
`[0041] n is O or 1
`
`0-·
`
`represents a 5 to IO-membered N-containing aromatic or
`non-aromatic mono- or bicyclic heterocycle, wherein there
`are exactly 2 ring atoms between the N atom and X; said
`heterocycle optionally further comprising 1, 2 or 3 heteroat(cid:173)
`oms selected from 0 , N and S; and
`[0042] X represents a C atom
`[0043]
`In yet another preferred embodiment, the present
`invention provides a compound according to formula I,
`wherein
`[0044] R1 and R2 are each independently selected from the
`group comprising - H, and - F;
`[0045] R3 is -CN, and -B(OH)2
`[0046] R4 is -H;
`[0047] R5 , R6 and R7 are each independently selected from
`the group comprising - H, -oxo, -halo, - C 1 _6alkyl, and
`-O- CF3 ;
`[0048] n is O;
`
`0-•
`
`represents a 5 to IO-membered N-containing aromatic or
`non-aromatic mono- or bicyclic heterocycle, wherein there
`are exactly 2 ring atoms between the N atom and X; said
`heterocycle optionally further comprising 1, 2 or 3 heteroat(cid:173)
`oms selected from 0 , N and S; and
`[0049] X represents a C atom
`[0050] The current invention further provides a compound
`of Formula II or a stereoisomer, tautomer, racemic, metabo(cid:173)
`lite, pro- or predrug, salt, hydrate, or solvate thereof,
`
`II
`
`wherein
`[0051] R1 and R2 are each independently selected from the
`group comprising - H, OH, -halo, C1_6alkyl , -O- C 1_
`6alkyl, S----C 1 _6alkyl;
`[0052] R3 is selected from the group comprising -H,
`-CN, -B(OH)2 , ----C(O)alkyl, ----C(O)aryl-, ----C=C(cid:173)
`C(O)aryl,
`----C=C- S(O) 2aryl,
`----CO2 H,
`- SO3 H,
`- SO2NH2 , - PO3H2 , and 5-tetrazolyl
`[0053] R4 is selected from the group comprising - H,
`- C 1_6alkyl, - O----C 1 _6alkyl, - S----C1 _6alkyl, - Ari, and
`- C 1_6aralkyl; each of said ----C 1 _6alkyl being optionally
`substituted with from 1 to 3 substituents selected from
`- OH, -halo
`
`3/17/2025 16:29:54
`
`Page 5 of 57
`
`Petitioner GE Healthcare – Ex. 1044, p. 5
`
`

`

`US 2014/0357650 Al
`
`Dec. 4, 2014
`
`5
`
`N~ •
`
`,,
`
`I
`
`N-N
`
`[0054] Rs, R6 and R7 are each independently selected from
`the group comprising - H, - OH, -oxo, -halo, -C 1 _
`6alkyl, -O-C 1 _6alkyl, - S-C 1_6alkyl, - NRsR9 , and
`- Ar2 ; each of said C 1_6alkyl being optionally substituted
`with from 1 to 3 substituents selected from -OH, -halo
`[0055] Rs and R9 , R 10 and R 11 are each independently
`selected from the group comprising -H, -OH, -halo,
`-C 1_6alkyl, -O-C1 _6alkyl, and -S-C 1_6alkyl;
`[0056] R 10 and R 11 are each independently selected from
`the group comprising -H, -OH, -halo, -C 1_6alkyl,
`-0-C 1 _6alkyl, - S-C1 _6alkyl, and - Ar3Ari, Ar2 and
`Ar3 are each independently a 5- or 6-membered aromatic
`monocycle optionally comprising 1 or 2 heteroatoms
`selected from 0 , N and S; each of said Ari, and Ar2 being
`optionally and independently substituted with from 1 to 3
`substituents selected from
`- NR10Rw - C 1_6alkyl,
`-O-C 1 _6alkyl, - S-C 1_6alkyl ;
`[0057] n is 0, 1, 2, or3
`[0058] mis 1 or 2
`
`m represents a 5 to 6-membered N-containing aromatic or
`non-aromatic monocyclic heterocycle optionally further
`comprising 1 or 2 heteroatoms selected from 0 , N and S.
`[0059]
`In a preferred embodiment, the current invention
`provides a compound according to formula II, wherein
`[0060] R 1 and R2 are each independently selected from the
`group comprising - H, OH, -halo, C 1_6alkyl, - O-C 1 _
`6alkyl, S-C 1 _6alkyl;
`[0061] R3 is selected from the group comprising - H,
`-CN, and - B(OH)2
`[0062] R4 is - H;
`[0063] Rs, R6 and R7 are each independently selected from
`the group comprising - H, - OH, -oxo, -halo, -C 1 _
`@lkyl, -0-C 1 _6alkyl, - S-C 1_6alkyl, - NRsR9 , and
`-Ar2 ; each of said C 1_6alkyl being optionally substituted
`with from 1 to 3 substituents selected from -OH, -halo
`[0064] Rs,~, R 10 and R 11 are each independently selected
`from the group comprising-H, -OH, -halo, -C 1_6alkyl,
`-0-C 1 _6alkyl, and -S-C 1 _6alkyl;
`[0065] Ar2 is a 5- or 6-membered aromatic monocycle
`optionally comprising 1 or 2 heteroatoms selected from 0,
`N and S; Ar2 being optionally and independently substi(cid:173)
`tuted with from 1 to 3 substituents selected from
`-NR10R 11 , -C 1 _6alkyl, -O-C 1_6alkyl, -S-C 1_
`@lkyl;
`[0066] n is 0, 1, 2, or 3
`[0067] 5 mis 1 or 2
`
`[0068]
`In said embodiment, preferably, Rs and R6 are each
`-H; R7 is selected from the group comprising -H, -OH,
`-oxo, -halo, -C 1_6alkyl, -0-C 1 _6alkyl, - S- C 1_6alkyl,
`- NRs~, and - Ar2 ; each of said C 1 _6alkyl being optionally
`substituted with from 1 to 3 substituents selected from - OH,
`-halo; and
`[0069] R7 is attached to position 2 or 3, in particular posi(cid:173)
`tion 2, as represented in
`
`.. -~ ..
`,
`'
`'
`'
`2© t -
`HN'' _,'
`
`1
`
`m
`
`.
`
`[0070]
`In yet a further embodiment, the present invention
`provides a compound of formula Illa, IIIb or Ille or a stere(cid:173)
`oisomer, tautomer, racemic, metabolite, pro- or predrug, salt,
`hydrate, or solvate thereof,
`
`R1
`
`R2
`
`\/'-..j..
`
`" ~~ \~
`~ N
`Ii
`(CH2)n
`
`R3
`
`0
`
`Rs
`
`HN
`
`f
`
`~ w ' ' R1
`,
`'
`
`m
`
`Illa
`
`Illb
`
`Ilic
`
`mis a 5- or 6-membered aromatic or non-aromatic monocylic
`heterocycle optionally further comprising 1 or 2 heteroatoms
`selected from 0 , N and S; selected from the list comprising
`
`wherein
`[0071] R1 and R2 are each independently selected from the
`group comprising - H, OH, -halo, C1_6alkyl , -O- C 1_
`6alkyl, S-C 1 _6alkyl;
`[0072] R3 is selected from the group comprising - H,
`- CN, - B(OH)2 , -C(O)alkyl, -C(O)aryl-, -C= C(cid:173)
`C(O)aryl, -C= C- S(O)2aryl, -CO2 H,
`- SO3 H,
`-SO2NH2 , - PO3H2 , and 5-tetrazolyl
`
`3/17/2025 16:29:54
`
`Page 6 of 57
`
`Petitioner GE Healthcare – Ex. 1044, p. 6
`
`

`

`US 2014/0357650 Al
`
`Dec. 4, 2014
`
`6
`
`is a 9- or IO-membered aromatic or non-aromatic bicyclic
`heterocycle optionally further comprising 1 or 2 heteroatoms
`selected from 0 , N and S; selected from the list comprising
`
`~ ~ y ~N / 1
`
`(YNJ (NYNJ (NYNJ
`.
`.
`.
`Cye¢(:¢
`
`.
`
`[0073] R4 is selected from the group comprising - H,
`-C 1_6alkyl, -O-C 1 _6alkyl, - S- C 1_6alkyl, - Ari, and
`-C 1_6aralkyl; each of said -C 1_6alkyl being optionally
`substituted with from 1 to 3 substituents selected from
`-OH, -halo ;
`[0074] Rs, R6 and R7 are each independently selected from
`the group comprising - H, - OH, -oxo, -halo, -C 1 _
`6alkyl, -O-C 1 _6alkyl, - S-C 1_6alkyl, - NRsR9 , and
`-Ar2 ; each of said C 1_6alkyl being optionally substituted
`with from 1 to 3 substituents selected from -OH, -halo
`[0075] Rs and R9 , are each independently selected from the
`group comprising - H, -OH, -halo, - C 1_6alkyl,
`-O-C 1 _6alkyl, - S-C 1_6alkyl , and - Ar3
`[0076] R 10 and R 11 are each independently selected from
`the group comprising -H, -OH, -halo, -C 1_6alkyl,
`-0-C 1 _6alkyl, and - S-C 1 _6alkyl;
`[0077] Ari, Ar2 and Ar3 are each independently a 5- or
`6-membered aromatic monocycle optionally comprising 1
`or 2 heteroatoms selected from 0 , N and S; each of said
`Ar1 , and Ar2 being optionally and independently substi(cid:173)
`tuted with from 1 to 3 substituents selected from
`- NR10Ru, -C 1 _6alkyl, - 0 -C 1_6alkyl, - S-C 1_
`Galkyl;
`[0078] n is 0, 1, 2, or 3
`[0079] m is 1 or 2
`
`HNg - • and HNB - ru1d g_~
`0
`0
`· 0
`·
`
`m
`
`m
`
`m
`
`represent a 9 to 10-membered N-containing aromatic or non(cid:173)
`aromatic bicyclic heterocycle optionally further comprising 1
`or 2 heteroatoms selected from 0 , N and S.
`[0080]
`In a preferred embodiment, the present invention
`provides a compound according to fonnula III, wherein
`[0081] R 1 and R2 are each independently selected from the
`group comprising - H, OH, -halo, C 1_6alkyl, - O-C 1 _
`6alkyl, S-C 1 _6alkyl;
`[0082] R3 is selected from the group comprising -H,
`-CN, and -B(OH)2 ;
`[0083] R4 is-H;
`[0084] Rs, R6 and R7 are each independently selected from
`the group comprising - H, -OH, -oxo, -halo, -C 1 _
`6alk-yl, -0-C 1 _6alkyl, - S-C1 _6alkyl, - NRsR9 , and
`- Ar2 ; each of said C 1_6alkyl being optionally substituted
`with from 1 to 3 substituents selected from -OH, -halo
`[0085] Rs,~, R10 and R11 are each independently selected
`from the group comprising - H, -OH, -halo, - C 1_6alkyl,
`-0-C 1 _6alkyl, and - S-C 1 _6alkyl;
`[0086] Ar2 is a 5- or 6-membered aromatic monocycle
`optionally comprising I or 2 heteroatoms selected from 0,
`N and S; Ar2 being optionally and independently substi(cid:173)
`tuted wit