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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to certain compounds that function as inhibitors of inhibitory- ⁇ B kinase (IKK) activity, and especially the alpha subunit of IKK (IKK ⁇ ).
• the compounds of the present invention may therefore be used to treat disease or conditions mediated, at least in part, by aberrant or inappropriate IKK (and especially IKK ⁇ ) activity. Cancer is an example of condition associated with aberrant or inappropriate IKK (and especially IKK ⁇ ) activity.
• the invention furthermore relates to the use of the compounds as for treating diseases or conditions in which IKK (and especially IKK ⁇ ) activity is implicated, to processes for making these compounds and to pharmaceutical compositions comprising them.
• NF- ⁇ B Nuclear Factor kappa-B
• NF- ⁇ B Nuclear Factor kappa-B
• B- cells represents a family of five transcription factors involved in diverse biological responses that underpin phenotypic outcomes of inflammation, modulation of immune responses, cell growth, proliferation, apoptosis and aspects of differentiation and development [1-5].
• NF- ⁇ B signalling is now appreciated as either canonical (classical) or non-canonical (alternative) pathways via the mobilisation of both homo—and hetero-dimer complexes of these family members ( Figure 1; [1-5]).
• NF- ⁇ B proteins are five distinct isoforms; RelA (p65), RelB, c-Rel, NF- ⁇ B1 (p105/p50) and NF- ⁇ B2 (p100/p52) [1-5].
• I ⁇ B inhibitory- ⁇ B
• I ⁇ B proteins include isoforms of I ⁇ B ⁇ , I ⁇ B ⁇ , and I ⁇ B ⁇ and in the case of p105 and p100 proteins it is their intrinsic protein structure that maintains them in a self-bound inhibitory form by virtue of their C-terminal I ⁇ B-like structures (I ⁇ B ⁇ and I ⁇ B ⁇ respectively) composed of ankyrin repeats [1-5].
• Activation and liberation of NF- ⁇ B proteins occurs typically in response to a number of extracellular ligands, as well as agents that generate a DNA Damage response (DDR), resulting in the nuclear localisation of DNA-binding protein dimers following dissociation from I ⁇ B molecules [1-5].
• DDR DNA Damage response
• the canonical pathway can be activated in response to cytokines such as TNF ⁇ and IL-1 ⁇ , and pathogen-associated molecular profiles (PAMPs) such as the bacterial endotoxin lipopolysaccharide (LPS) [6, 7].
• cytokines such as TNF ⁇ and IL-1 ⁇
• PAMPs pathogen-associated molecular profiles
• LPS pathogen-associated molecular profiles
• IKK inhibitory- ⁇ B kinase
• IKK ⁇ / ⁇ / ⁇ inhibitory- ⁇ B kinase
• lymphotoxin- ⁇ (LT- ⁇ ), the related tumor necrosis factor superfamily member 14 (TNFSF14) known as LIGHT, TNF-like weak inducer of apoptosis (TWEAK), CD40 ligand (CD40L), Receptor-activator of NF- ⁇ B ligand (RANKL) and B-cell activating factor (BAFF) [1, 3, 4].
• LT- ⁇ lymphotoxin- ⁇
• TNFSF14 tumor necrosis factor superfamily member 14
• TWEAK TNF-like weak inducer of apoptosis
• CD40L CD40 ligand
• RNKL Receptor-activator of NF- ⁇ B ligand
• BAFF B-cell activating factor
• NIK NF- ⁇ B-inducing kinase
• MAP3K the 14 th member of the MAP kinase kinase kinase family
• IKK ⁇ the 14 th member of the MAP kinase kinase kinase family
• TRAF3 acts as the crucial regulator of NIK expression by controlling the extent of its proteasome-mediated degradation [16]. Upon receptor activation the focus of proteasome-mediated protein degradation switches from NIK to that of TRAF2 and TRAF3 which stabilises NIK expression to initiate the sequence of signalling events toward p100 processing [17-20].
• the cIAP proteins that function as ubiquitin ligases to ubiquitinate NIK then target TRAF3 for degradation to increase NIK protein levels.
• NIK protein stabilisation As the first component of the non-canonical NF- ⁇ B pathway it catalyses is the phosphorylation of IKK ⁇ and supports IKK ⁇ recruitment to and phosphorylation of p100 to drive subsequent p100 ubiquitination and proteasome-mediated degradation to liberate p52 [16].
• p100 exists typically in dimer complexes with RelB and upon stimulated degradation generates p52-RelB dimers able to translocate to the nucleus to initiate the transcription of distinct genes ( Figure 1).
• Both NIK and IKK ⁇ play critical roles in the phosphorylation of p100 to liberate mature p52-RelB protein dimers.
• NIK can stimulate the phosphorylation, ubiquitination and processing of p100 [23, 24], however recombinant NIK itself does not display any phosphorylation of p100 in vitro [24, 25].
• NIK mediates downstream signalling by engaging and activating IKK ⁇ resulting in the phosphorylation of the C-terminal region of p100 [25], and this is independent of the other IKK isoforms, ⁇ and ⁇ associated with canonical NF- ⁇ B activation [26, 27].
• IKK ⁇ phosphorylates p100 and regulated non-canonical NF- ⁇ B activation alone, it is not as effective at inducing p100 processing as NIK [23]. With these observations, further studies then identified NIK to have a critical role in regulating p100 processing via the recruitment of IKK ⁇ to and binding with p100 as a protein substrate [22].
• NIK-IKK ⁇ interaction with p100 results in the phosphorylation of p100 at specific serine residues, primarily Ser868/870 [24]. These sites are components of the phospho-degron within the p100 C- terminal NIK-responsive domain (NRD) and when phosphorylated lead to ⁇ TrCP binding as part of the SCF ⁇ TrCP ubiquitin ligase complex that drives the eventual processing of p100 to generate p52.
• NBD NIK-responsive domain
• IKK ⁇ via catalysed phosphorylation, regulates directly a number of cellular proteins that then either directly or indirectly regulate cellular transcription [6, 7].
• Additional substrates also include the Protein inhibitor of activated STAT1 (PIAS1) as a modulator of transcription/inflammation [36], the oestrogen (ER) [37] and androgen receptors (AR) [38] of the steroid hormone family receptor along with their associated steroid receptor co-factor (SRC)-3 [37, 39, 40] and Aurora kinase A [41, 42] that contributes to the mitotic process.
• PIAS1 Protein inhibitor of activated STAT1
• ER oestrogen
• AR androgen receptors
• SRC steroid receptor co-factor
• IKK ⁇ Direct modulation of the status of these proteins by IKK ⁇ has bearing on the transcription of additional regulatory proteins such as p53 [43, 44] and EZH2 [44] and additional mitotic kinase Polo-like kinase (PLK) 4 [45].
• IKK ⁇ therefore serves as a key switch in the coordinated regulation of both NF- ⁇ B-dependent and NF- ⁇ B-independent gene transcription and this underpins the outcomes associated with events that initiate and/or perpetuate the development of acquired characteristics, or phenotypes, we now recognise as cancer ‘Hallmarks’ as identified and defined by Hanahan & Weinberg [46, 47].
• the transcriptional modulation driven by IKK ⁇ -mediated signalling may be in excess of 200 genes and these gene/protein induction/repression events support the acquisition of characteristics of specific ‘Hallmarks’, particularly the ability of tumours to ‘sustain proliferative signalling’, ‘resist cell death’, ‘evade growth suppressors’ and encourage ‘genomic instability and mutation’.
• IKK ⁇ inducing angiogenesis’ and ‘activating invasion and metastasis’ by way of regulating cytokine (e.g. IL-1 ⁇ , IL-6 [48, 49]) and chemokine (e.g. CCL19, CCL21, CXCL12, CXCL13 and BAFF [27, 51, 52]) induction and modulation of adhesion molecule (e.g. VCAM; [48-50]), maspin [50; 53] and MMPs [50] expression in different cellular/tissue situations.
• cytokine e.g. IL-1 ⁇ , IL-6 [48, 49]
• chemokine e.g. CCL19, CCL21, CXCL12, CXCL13 and BAFF [27, 51, 52]
• tumour-stromal communication and matrix composition within the tumour microenvironment and define a better understanding of ‘tumour-promoting inflammation’.
• Varfolomeev E Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJ, Flygare JA, Fairbrother WJ, Deshayes K, Dixit VM, Vucic D.
• IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha- dependent apoptosis.
• Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol.2008 Dec;9(12):1371-8 [22] Xiao G, Fong A, Sun SC.
• Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation. J Biol Chem.2004 Jul 16;279(29):30099-105 [23] Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF- kappaB2 p100. Mol Cell.2001 Feb;7(2):401-9. [24] Liang C, Zhang M, Sun SC.
• beta-TrCP binding and processing of NF-kappaB2/p100 involve its phosphorylation at serines 866 and 870.
• Cell Signal.2006 Aug;18(8):1309-17 [25] Senftleben U, Cao Y, Xiao G, Greten FR, Krähn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science.2001 Aug 24;293(5534):1495-9. [26] Claudio E, Brown K, Park S, Wang H, Siebenlist U.
• Wharry CE Haines KM, Carroll RG, May MJ. Constitutive non-canonical NFkappaB signaling in pancreatic cancer cells. Cancer Biol Ther.2009 Aug;8(16):1567-76.
• Ammirante M Shalapour S, Kang Y, Jamieson CA, Karin M. Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc Natl Acad Sci U S A.2014 Oct 14;111(41):14776-81.
• Ammirante M Luo JL, Grivennikov S, Nedospasov S, Karin M.
• a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
• a method of inhibiting IKK ⁇ activity comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
• a method of treating a disease or disorder in which IKK ⁇ activity is implicated in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
• a method of treating a proliferative disorder in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
• a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use as a medicament.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer In a particular embodiment, the cancer is human cancer.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of IKK ⁇ activity is provided.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein for use in the treatment of a disease or disorder in which IKK ⁇ activity is implicated.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the manufacture of a medicament for the treatment of a proliferative disorder.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the manufacture of a medicament for the treatment of cancer.
• a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of IKK ⁇ activity there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which IKK ⁇ activity is implicated.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.
• novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.
• Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including optional, suitable and preferred features in relation to any other aspect of the invention.
• references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.
• “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
• a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
• the "therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. It should be understood that in, for example, a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount may be the amount required by the guidelines of the United States Food and Drug Administration (FDA) or equivalent foreign regulatory body, for the particular disease and subject being treated.
• FDA United States Food and Drug Administration
• subject(s) and “patient(s)” refer to animals (e.g. mammals), particularly humans.
• the “subject(s)” and “patient(s)” may be a non-human animal (e.g. livestock and domestic pets) or a human.
• “pharmaceutically acceptable” refers to materials that are generally chemically and/or physically compatible with other ingredients (such as, for example, with reference to a formulation), and/or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.
• alkyl includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only.
• (1-6C)alkyl includes (1-4C)alkyl, (1- 3C)alkyl, propyl, isopropyl and t-butyl.
• An “alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups.
• (1-6C)alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH2-), the ethylene isomers (– CH(CH3)– and –CH2CH2–), the propylene isomers (–CH(CH3)CH2–, –CH(CH2CH3)–, –C(CH3)2– , and –CH2CH2CH2–), pentylene (-CH2CH2CH2CH2CH2-), and the like.
• alkyenyl refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon double bond is present within the group.
• alkenyl groups include ethenyl, propenyl and but-2,3-enyl and includes all possible geometric (E/Z) isomers.
• alkynyl refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon triple bond is present within the group. Examples of alkynyl groups include acetylenyl and propynyl.
• (m-nC)cycloalkyl means a saturated hydrocarbon ring system containing from m to n number of carbon atoms.
• exemplary cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptyl.
• alkoxy refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy and t-butoxy.
• haloalkyl is used herein to refer to an alkyl group in which one or more hydrogen atoms have been replaced by halogen (e.g. fluorine) atoms.
• haloalkyl groups include -CH 2 F, -CHF 2 and -CF 3 .
• halo or “halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.
• Carbocyclyl means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbon-containing ring system(s).
• Monocyclic carbocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms.
• Bicyclic carbocycles contain from 6 to 17 member atoms, suitably 7 to 12 member atoms, in the ring.
• Bicyclic carbocyclic(s) rings may be fused, spiro, or bridged ring systems.
• carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl and spiro[3.3]heptanyl.
• heterocyclyl means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s).
• Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring.
• Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems.
• heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers.
• Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like.
• Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine.
• Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
• heterocycles containing sulfur the oxidized sulfur heterocycles containing SO or SO2 groups are also included.
• examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide.
• heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl.
• any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom.
• reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.
• bridged ring systems is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992.
• bridged heterocyclyl ring systems examples include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane and quinuclidine.
• spiro bi-cyclic ring systems we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom.
• spiro ring systems examples include 6- azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-6- azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7- azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.
• aromatic refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer.
• Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e. “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl”).
• An aromatic ring system can be substituted or unsubstituted.
• non-aromatic refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system.
• non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S.
• a non-aromatic ring system can be substituted or unsubstituted.
• heteroaryl or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur.
• heteroaryl includes both monovalent species and divalent species.
• heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members.
• the heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings.
• Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen.
• the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
• the heteroaryl ring contains at least one ring nitrogen atom.
• the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non- basic as in the case of an indole or pyrrole nitrogen.
• the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
• heteroaryl examples include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridin
• Heteroaryl also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur.
• partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2- dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.
• Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
• Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
• a bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazo
• bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.
• bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.
• aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms.
• aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In a particular embodiment, an aryl is phenyl.
• This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example (3-6C)cycloalkyl(m-nC)alkyl comprises (m-nC)alkyl substituted by (3- 6C)cycloalkyl.
• optional substituted refers to either groups, structures, or molecules that are substituted and those that are not substituted.
• the term “wherein a/any CH, CH 2 , CH 3 group or heteroatom (i.e. NH) within a R 1 group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R 1 group is substituted by a relevant stipulated group.
• optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups. In some embodiments, one or more refers to one, two or three. In another embodiment, one or more refers to one or two.
• one or more refers to one.
• the phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically.
• “About” when used herein in conjunction with a measurable value such as, for example, an amount or a period of time and the like, is meant to encompass reasonable variations of the value, for instance, to allow for experimental error in the measurement of said value.
• the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula (I), shown below: (I) wherein: R 1 is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)alkynyl, (3-7C) cycloalkyl, aryl, heteroaryl and heterocyclyl, and wherein said (1-6C)alkyl, (2-6C)alkynyl, (3-7C) cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more R 100 substituents; wherein R 100 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH 2 ) z OR f , (CH 2 ) z C(O)R f , (CH 2 ) z C(O)OR f
• the present invention relates to compounds of formula I defined above, wherein R3 is selected from hydrogen, cyano, (1-8C)alkyl, (3-7C)cycloalkyl, (CH2)1-3(3- 7C)cycloalkyl, a carbon-linked 4 to 7 membered heterocyclyl, a carbon-linked 5 to 6 membered heteroaryl, -C(O)-(1-8C)alkyl, -C(O)(CH2)0-3(3-7C)cycloalkyl, -C(O)[5- or 6-membered heteroaryl], -C(O)phenyl, -C(O)O(1-8C)alkyl, -C(O)O(3-7C)cycloalkyl, -C(O)O(CH2)1-3(3- 7C)cycloalkyl, -C(O)NH2, -C(O)NH-(1-8C)alkyl, -C(O)
• Particular compounds of the invention include, for example, compounds of the Formula (I), or pharmaceutically acceptable salts, hydrates and/or solvates thereof, defined herein having one of the structural formulae (Ia), (Ib), (Ic), (Id) or (Ie) shown below: wherein R1, X, R3, R4, R5 and Q are each as defined herein.
• Particular compounds of the invention include, for example, compounds of the Formula (I) [including sub-formulae (Ia), (Ib), (Ic), (Id), (Ie) or (If)], or pharmaceutically acceptable salts, hydrates and/or solvates thereof, wherein, unless otherwise stated, each of R1, X, R2, R3, R4, X1, R5 and Q and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (43) hereinafter: (1) R1 is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, a 5 or 6-membered heteroaryl or a 4 to 7-membered heterocyclyl, wherein said (2-6C)alkynyl, (3-7C)cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted by one or more R100 substituents; and wherein
• R 1 is selected from hydrogen, halogen, (1-6C)alkyl, (2-6C)alkynyl, phenyl or a 5 or 6- membered heteroaryl, wherein said (2-6C)alkynyl, phenyl or heteroaryl are optionally substituted by one or more R 100 substituents; and wherein R 100 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH 2 ) z OR f , (CH 2 ) z C(O)R f , (CH 2 ) z C(O)OR f , (CH 2 ) z OC(O)R f , (CH 2 ) z C(O)N(R j )R h , (CH 2 ) z N(R g )C(O)R f , (CH 2 ) z S(O) y R
• R100 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORf, C(O)Rf, C(O)ORf, OC(O)Rf, C(O)N(Rj)Rh, N(Rg)C(O)Rf, S(O)yRf, SO2N(Rj)Rh, N(Rg)SO2Rf, NRjRh, (CH2)z-[4-6 membered heterocyclyl], or (CH2)zphenyl; and wherein: (i) Rf and Rg are each independently selected from hydrogen or (1- 2C)alkyl; and (ii) any (1-4C)alkyl
• R1 is selected from: (i) hydrogen; (ii) ethynyl, i.e. which is optionally substituted by R 100 ; (iii) phenyl, which is optionally substituted by R 100 ; (iv) a 5 or 6-membered heteroaryl; and wherein R 100 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH 2 ) z OR f , C(O)R f , C(O)OR f , OC(O)R f , C(O)N(R j )R h , N(R g )C(O)R f , S(O) y R f , SO 2 N(R j )R h , N(R g )SO 2 R f , NR j R h , (CH 2 ) z
• R100 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORf, C(O)Rf, C(O)ORf, OC(O)Rf, C(O)N(Rj)Rh, N(Rg)C(O)Rf, S(O)yRf, SO2N(Rj)Rh, NRjRh, (CH2)z-[4-6 membered heterocyclyl], or (CH2)zphenyl; and wherein: (i) R f and R g are each independently selected from hydrogen or (1- 2C)alkyl; and (ii) any (1-4C)alkyl, heterocyclyl or phenyl moiety in a
• R100 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORf, C(O)Rf, C(O)ORf, C(O)N(Rj)Rh, S(O)yRf, SO2N(Rj)Rh, NRjRh, (CH2)z-[4-6 membered heterocyclyl], or (CH2)zphenyl; and wherein: (i) Rf and Rg are each independently selected from hydrogen or (1- 2C)alkyl; and (ii) any (1-4C)alkyl, heterocyclyl or phenyl moiety in a R100 substituent group is optionally further substituted by one or more substituents selected from hal
• R 100 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH 2 ) z OR f , C(O)R f , C(O)OR f , C(O)N(R j )R h , S(O) y R f , SO 2 N(R j )R h , NR j R h , (CH 2 ) z -[4-6 membered heterocyclyl], or (CH 2 ) z phenyl; and wherein: (i) R f and R g are each independently selected from hydrogen or (1- 2C)alkyl; and (ii) any (1-4C)alkyl, hetero
• R200 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORm, (CH2)zC(O)Rm, (CH2)zC(O)ORm, (CH2)zOC(O)Rm, (CH2)zC(O)N(Ro)Rp, (CH2)zN(Rn)C(O)Rm, (CH2)zS(O)yRm, (CH2)zSO2N(Ro)Rp, (CH2)zN(Rn)SO2Rm, (CH2)zNRoRp, (CH2)z(3-7C)cycloalkyl, (CH2)zheterocyclyl, (CH2)z(3-7C)cycloalkyl, (CH2)zheterocyclyl, (CH2)z(3-7C)cycloalkyl, (CH2)zheterocyclyl, (CH2)z(3-7C
• R200 which is optionally substituted by R200; and wherein R200 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH2)zORm, (CH2)zC(O)Rm, (CH2)zC(O)ORm, (CH2)zOC(O)Rm, (CH2)zC(O)N(Ro)Rp, (CH2)zN(Rn)C(O)Rm, (CH2)zS(O)yRm, (CH2)zSO2N(Ro)Rp, (CH2)zN(Rn)SO2Rm, (CH2)zNRoRp, (CH2)z(3-7C)cycloalkyl, (CH2)zheterocyclyl, (CH2)zheteroaryl, or (CH2)zphenyl; and wherein: (i) Rm and Rn are each independently selected from hydrogen, (1-6C)alkyl
• R 200 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH 2 ) z OR m , (CH 2 ) z C(O)R m , (CH2)zC(O)N(Ro)Rp, (CH2)zN(Rn)C(O)Rm, (CH2)zS(O)yRm, (CH2)zNRoRp, (CH2)z(3- 7C)cycloalkyl, (CH2)zheterocyclyl, (CH2)zheteroaryl, or (CH2)zphenyl; and wherein: (i) Rm and Rn are each independently selected from hydrogen, (1-6C)alkyl or phenyl; Ro and Rp are each independently selected from hydrogen, (1-6C)alkyl or phenyl or Ro and Rp together with the nitrogen atom to
• R 200 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (1-4C)alkyl, (1-4C)hydroxyalkyl, (CH 2 ) z OR m , (CH 2 ) z NR o R p , (CH 2 ) z (3- 7C)cycloalkyl, (CH 2 ) z heterocyclyl, (CH 2 ) z heteroaryl, or (CH 2 ) z phenyl; and wherein: (i) R m and R n are each independently selected from hydrogen, (1-6C)alkyl or phenyl; R o and R p are each independently selected from hydrogen, (1-6C)alkyl or phenyl or R o and R p together with the nitrogen atom to which they are attached form a 3-6 membered ring; and (ii) any (3-7C)cycloalkyl, heterocyclyl, heterocyclyl, hetero
• R1 is as defined in any one of numbered paragraphs (5) to (9) above. Most suitably, R1 is as defined in any one of numbered paragraphs (7) to (9) above.
• X is as defined in any one of numbered paragraphs (10) to (18) above. More suitably, X is as defined in any one of numbered paragraphs (14) to (18) above. Most suitably, X is as defined in any one of numbered paragraphs (16) to (18) above.
• R2 is as defined in any one of numbered paragraphs (10) to (17) above
• R2 is as defined in any one of numbered paragraphs (14) to (17) above
• R2 is as defined in numbered paragraphs (16) or (17) above
• R3 is as defined in numbered paragraphs (20) or (21) above
• R4 is as defined in numbered paragraph (23) above.
• X1 is as defined in any one of numbered paragraphs (24) to (30) above. More suitably, X1 is as defined in numbered paragraphs (28) to (30) above. Most suitably, X1 is as defined in any one of numbered paragraphs (29) or (30) above.
• R 5 is as defined in any one of numbered paragraphs (28) to (30) above. More suitably, R 5 is as defined in numbered paragraphs (29) or (30) above. Most suitably, R 5 is as defined in numbered paragraph (30) above. [0076] Suitably, y is as defined in numbered paragraph (36) above. [0077] Suitably, x is as defined in numbered paragraph (40) above.
• particular compounds of the invention include, for example, compounds of the Formula (I), or pharmaceutically acceptable salts, hydrates and/or solvates thereof, defined herein having one of the structural formulae (Ia), (Ib), (Ic), (Id) or (Ie) shown below: wherein R1, X, R3, R4, R5 and Q are each as defined herein.
• compounds have a structure according to formula Ia (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and/or solvate thereof, wherein X, R4 and R5 each have any one of the definitions set out herein.
• X is as defined in any one of numbered paragraphs (10) to (18) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in any one of numbered paragraphs (28) to (30) above.
• X is as defined in any one of numbered paragraphs (14) to (18) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (29) or (30) above.
• X is as defined in numbered paragraph (14) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraph (28) above.
• X is as defined in numbered paragraph (15) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraph (28) above.
• X is as defined in numbered paragraph (16) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraph (29) above.
• X is as defined in numbered paragraph (17) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraph (30) above.
• compounds have a structure according to formula Ib (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and/or solvate thereof, wherein R 1 , R 3 , R 4 , and R 5 each have any one of the definitions set out herein.
• R 1 is as defined in any one of numbered paragraphs (1) to (9) above;
• R 3 is as defined in any one of numbered paragraphs (19) to (21) above (including (19a) and (20a));
• R 4 is as defined in numbered paragraph (23) above;
• R 5 is as defined in any one of numbered paragraphs (28) to (30) above.
• R1 is as defined in any one of numbered paragraphs (5) to (9) above;
• R 3 is as defined in any one of numbered paragraphs (19) to (21) above (including (19a) and (20a));
• R4 is as defined in numbered paragraph (23) above;
• R5 is as defined in numbered paragraphs (29) or (30) above.
• R1 is as defined in numbered paragraph (5) above; R3 is as defined in numbered paragraph (19) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (28) above.
• R1 is as defined in numbered paragraph (6) above; R3 is as defined in numbered paragraph (20) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (29) above.
• R 1 is as defined in numbered paragraph (7) above; R 3 is as defined in numbered paragraph (20) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (29) above.
• R 1 is as defined in numbered paragraph (8) above; R 3 is as defined in numbered paragraph (21) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (30) above.
• R 1 is as defined in numbered paragraph (9) above; R3 is as defined in numbered paragraph (21) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (30) above.
• R1, R4, and R5 each have any one of the definitions set out herein.
• R1 is as defined in any one of numbered paragraphs (1) to (9) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in any one of numbered paragraphs (28) to (30) above.
• R 1 is as defined in any one of numbered paragraphs (5) to (9) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (29) or (30) above.
• R 1 is as defined in numbered paragraph (5) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (28) above.
• R 1 is as defined in numbered paragraph (6) above; R 4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (29) above.
• R1 is as defined in numbered paragraph (7) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (29) above.
• R1 is as defined in numbered paragraph (8) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (30) above.
• R1 is as defined in numbered paragraph (9) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (30) above.
• compounds have a structure according to formula Id (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and/or solvate thereof, wherein R 1 , Q, R 4 , and R 5 each have any one of the definitions set out herein.
• R 1 is as defined in any one of numbered paragraphs (1) to (9) above;
• Q is as defined in any one of numbered paragraphs (32) to (35) above;
• R 4 is as defined in numbered paragraph (23) above;
• R 5 is as defined in any one of numbered paragraphs (28) to (30) above.
• R1 is as defined in any one of numbered paragraphs (5) to (9) above; Q is as defined in any one of numbered paragraphs (33) to (35) above; R 4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (29) or (30) above.
• R1 is as defined in numbered paragraph (5) above; Q is as defined in numbered paragraph (32) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (28) above.
• R1 is as defined in numbered paragraph (6) above; Q is as defined in numbered paragraph (33) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (29) above.
• R 1 is as defined in numbered paragraph (7) above; Q is as defined in numbered paragraph (33) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (29) above.
• R 1 is as defined in numbered paragraph (8) above; Q is as defined in numbered paragraph (34) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (30) above.
• R1 is as defined in numbered paragraph (9) above; Q is as defined in numbered paragraph (35) above; R 4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (30) above.
• compounds have a structure according to formula Ie (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and/or solvate thereof, wherein X, R3, R4 and R5 each have any one of the definitions set out herein.
• X is as defined in any one of numbered paragraphs (10) to (18) above; R3 is as defined in any one of numbered paragraphs (19) to (21) above (including (19a) and (20a)); R4 is as defined in numbered paragraph (23) above; and R5 is as defined in any one of numbered paragraphs (28) to (30) above.
• X is as defined in any one of numbered paragraphs (14) to (18) above; R 3 is as defined in any one of numbered paragraphs (19) to (21) above (including (19a) and (20a)); R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (29) or (30) above.
• X is as defined in numbered paragraph (14) above; R 3 is as defined in numbered paragraph (19) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (28) above.
• X is as defined in numbered paragraph (14) above; R 3 is as defined in numbered paragraph (20) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (29) above.
• X is as defined in numbered paragraph (15) above; R3 is as defined in numbered paragraph (20) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (29) above.
• X is as defined in numbered paragraph (16) above; R3 is as defined in numbered paragraph (21) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (30) above.
• X is as defined in numbered paragraph (17) above; R 3 is as defined in numbered paragraph (21) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (30) above.
• compounds have a structure according to formula If (which is a sub-definition of formula I), or a pharmaceutically acceptable salt, hydrate and/or solvate thereof, wherein R 1 , Q, R 4 , and R 5 each have any one of the definitions set out herein.
• R1 is as defined in any one of numbered paragraphs (1) to (9) above;
• Q is as defined in any one of numbered paragraphs (32) to (35) above;
• R4 is as defined in numbered paragraph (23) above;
• R5 is as defined in any one of numbered paragraphs (28) to (30) above.
• R1 is as defined in any one of numbered paragraphs (5) to (9) above; Q is as defined in any one of numbered paragraphs (33) to (35) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (29) or (30) above.
• R1 is as defined in numbered paragraph (5) above; Q is as defined in numbered paragraph (32) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (28) above.
• R 1 is as defined in numbered paragraph (6) above; Q is as defined in numbered paragraph (33) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (29) above.
• R 1 is as defined in numbered paragraph (7) above; Q is as defined in numbered paragraph (33) above; R 4 is as defined in numbered paragraph (23) above; and R 5 is as defined in numbered paragraphs (29) above.
• R 1 is as defined in numbered paragraph (8) above; Q is as defined in numbered paragraph (34) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (30) above.
• R1 is as defined in numbered paragraph (9) above; Q is as defined in numbered paragraph (35) above; R4 is as defined in numbered paragraph (23) above; and R5 is as defined in numbered paragraphs (30) above.
• Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following: 5-(2-aminopyridin-4-yl)-7-chloro-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-methyl-1H-indazol-3-amine; 5-(2-aminopyridin-4-yl)-7-(trifluoromethyl)-1H-indazol-3-amine; 7-chloro-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine; 7-ethynyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-
• the various functional groups and substituents making up the compounds of the Formula (I), or sub-formulae (Ia) to (Ie), are typically chosen such that the molecular weight of the compound of the formula (I) does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less.
• a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
• an inorganic or organic acid for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
• a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
• an alkali metal salt for example a sodium or potassium salt
• an alkaline earth metal salt for example a calcium or magnesium salt
• an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
• stereoisomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
• stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
• enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
• An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
• a chiral compound can exist as either individual enantiomer or as a mixture thereof.
• a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
• the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
• the present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions.
• H may be in any isotopic form, including 1H, 2H(D), and 3H (T);
• C may be in any isotopic form, including 12C, 13C, and 14C; and
• O may be in any isotopic form, including 16O and18O; and the like.
• certain compounds of the Formula (I), or sub-formulae (Ia) to (Ie) may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess activity.
• tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
• keto/enol Illustrated below
• imine/enamine imine/enamine
• amide/imino alcohol amidine/amidine
• nitroso/oxime thioketone/enethiol
• nitro/aci-nitro k eto enol enolate
• a reference herein to a compound of the Formula (I), or sub- formulae (Ia) to (Ie), that contains an amine function also includes the N-oxide.
• a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide.
• Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
• N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages.
• N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
• mCPBA m-chloroperoxybenzoic acid
• the compounds of Formula (I), or sub-formulae (Ia) to (Ie) may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention.
• a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
• a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property- modifying group can be attached.
• pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I), or sub-formulae (Ia) to (Ie), and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I), or sub- formulae (Ia) to (Ie).
• the present invention includes those compounds of the Formula (I), or sub-formulae (Ia) to (Ie), as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I), or sub-formulae (Ia) to (Ie), that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I), or sub-formulae (Ia) to (Ie), may be a synthetically-produced compound or a metabolically-produced compound.
• a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (Ia) to (Ie), is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
• Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H.
• Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S.
• a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (Ia) to (Ie), that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
• An in vivo cleavable ester of a compound of the Formula I, or sub-formulae (Ia) to (Ie), containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or parent alcohol.
• Suitable pharmaceutically acceptable esters for carboxy include (1-6C)alkyl esters such as methyl, ethyl and tert-butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters, (1- 6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3- 8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1- cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo- 1,3-dioxolen-4-ylmethyl esters and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.
• a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (Ia) to (Ie), that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
• An in vivo cleavable ester or ether of a compound of the Formula (I), or sub-formulae (Ia) to (Ie), containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
• Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1- 6C) 2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
• inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
• Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacet
• Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
• a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (Ia) to (Ie), that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (1- 4C)alkylamine such as methylamine, a [(1-4C)alkyl] 2 amine such as dimethylamine, N-ethyl-N- methylamine or diethylamine, a (1-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
• an amine such as ammonia
• a (1- 4C)alkylamine such as methylamine
• a [(1-4C)alkyl] 2 amine such as dimethylamine, N-e
• a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae (Ia) to (Ie), that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
• Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with (1-10C)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
• ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(1-4C)alkyl)piperazin-1-ylmethyl.
• the in vivo effects of a compound of the Formula (I), or sub-formulae (Ia) to (Ie), may also be exerted by way of metabolism of a precursor compound (a pro-drug).
• the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
• the present invention excludes any individual compounds not possessing the biological activity defined herein. Synthesis [00149]
• the compounds of the present invention can be prepared by any suitable technique known in the art.
• protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons).
• Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.
• reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
• a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
• the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
• a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
• a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
• the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
• an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
• a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
• Resins may also be used as a protecting group.
• the methodology employed to synthesise a compound of Formula (I), or sub-formulae (Ia) to (Ie), will vary depending on the nature of R 1 , R 2 , R 3 , R 4 , R 6 and R 10 and any substituent groups or subgroups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples.
• the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I) into another compound of Formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.
• An example of (ii) above is when a compound of Formula (I) is synthesised and then one or more of the groups may be further reacted to change the nature of the group and provide an alternative compound of Formula (I).
• the resultant compounds of Formula (I), or sub-formulae (Ia) to (Ie), can be isolated and purified using techniques well known in the art.
• the compounds of Formula (I) may be synthesised by the synthetic routes shown in the Examples section below.
• Biological Activity The biological assays described in the Examples section herein may be used to measure the pharmacological effects of the compounds of the present invention.
• the compounds of the invention were found to be active in the IKK-alpha in vitro assay described in the Examples section, with preferred compounds showing selectivity for IKK-alpha over IKK-beta.
• compositions which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
• compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
• oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
• compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
• compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
• An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
• the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration.
• a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
• active agent more suitably from 0.5 to 100 mg, for example from 1 to 30 mg
• excipients which may vary from about 5 to about 98 percent by weight of the total composition.
• the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
• a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
• a parenteral route is employed.
• a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
• a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
• Oral administration may also be suitable, particularly in tablet form.
• unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
• the present invention provides compounds that function as inhibitors of IKK activity, particularly IKK ⁇ activity. Accordingly, the compounds of the present invention are suitable for the treatment of any disease or condition in which the inhibition of IKK ⁇ activity is potentially beneficial.
• IKK ⁇ activity is known to play a role in cancer. The role of IKK ⁇ in cancer IKK ⁇ in solid tumours [00175] In recent years the role of the non-canonical NF- ⁇ B pathway and IKK ⁇ within it have increasingly been implicated in the development and progression of multiple solid tumours.
• the non-canonical NF- ⁇ B pathway has been associated with poor prognosis in glioblastoma [57] and mouse orthotopic models have demonstrated that up-regulation of this pathway is associated with an aggressive glioblastoma subtype [57].
• nuclear localisation of RelB is associated with higher grade tumours [58] and treatment of prostate cancer cells with androgens induces accumulation of nuclear p52 [59].
• silencing of IKK ⁇ reduces androgen receptor activity and gene expression, providing evidence that IKK ⁇ is associated with prostate cancer growth [58]. Therefore, IKK ⁇ is an attractive target for prostate cancer as the androgen receptor is the main driver of prostate cancer proliferation and inhibition of cell death.
• the non-canonical NF- ⁇ B pathway is constitutively activated and associated with increased cell proliferation [60].
• NIK is elevated in pancreatic cancer and associated with increased proliferation [61, 62] and up-regulation of RelB and p52 are associated with mutated KRAS pancreatic cancer [63] with IKK ⁇ -dependent gene expression being observed.
• NF- ⁇ B2 DCT/DCT mice develop tumours spontaneously, providing evidence that p100/p52 drives oncogenesis in this setting [64].
• members of the non-canonical NF- ⁇ B pathway are associated with poor prognosis, increased disease stage and decreased local inflammation [65].
• RelB is associated with shorter overall survival, differentiation, tumour invasion, lymph node metastasis, distant metastasis and ‘tumour, node, metastasis’ (TNM) stage [68].
• TPM tumor necrosis
• bladder cancer up-regulation of RelB and p52 correlate with histological grade, stage and lymph node metastasis [69].
• IKK ⁇ , RelB and p52 are associated with decreased cancer specific survival in ER-positive breast disease [70, 71].
• Bcl3 can form a DNA-binding complex with p52 and has been observed as over expressed in breast cancer samples.
• IKK ⁇ is demonstrated to play an essential role in the proliferation of mammary epithelium and it is therefore not surprising that aberrant IKK ⁇ signalling has been reported in breast cancer [72].
• Yang et al. 2013 reports that in HER2 positive epithelial cells nuclear IKK ⁇ can promote progression to tumourogenesis via p27 [73].
• overexpression of p100/52 results in a delay of mammary gland development, which is accompanied with over expression of cyclin D1, MMP2, MMP9 and COX-2 expression and results in the mice developing multiple tumours [74].
• constitutive RANK signalling causes elevation of non-canonical NF- ⁇ B signalling in breast cancer cell lines, which subsequently stimulates cell proliferation via increased transcription of cyclin D1 [75-77] and nuclear IKK ⁇ expression is observed in invasive ductal carcinoma and associated with disease free survival.
• Immuno-histochemical studies have demonstrated that the p52 subunit is expressed at a higher level in the breast cancer tissue compared to normal adjacent tissue [78] and Western blots of nuclear fractions extracted from cancerous and adjacent normal breast tissue confirm an increase in p52 levels in the tumour cells [78]. This is accompanied by an increase in mRNA levels of p52, Bcl-3 and cyclin D1, all genes regulated by IKK ⁇ [78].
• IKK ⁇ has been demonstrated in cervical, lung, prostate and pancreatic cell lines to regulate mTORC1 and mTORC2 which control tumour cell proliferation [79].
• IKK ⁇ signalling independent of NF- ⁇ B pathways in solid tumours [00178]
• IKK ⁇ plays in NF- ⁇ B pathways, it is also reported to have a role independent of both the canonical and non-canonical NF- ⁇ B pathways.
• IKK ⁇ accumulates in the nucleus, where it can phosphorylate a variety of substrates including histone H3, SMRT and nuclear co-repressor (NCoR) [80]. In colorectal cancer, IKK ⁇ phosphorylates SMRT, resulting in increased expression of Notch dependent genes [80]. In addition, IKK ⁇ has been reported to be associated with NOTCH activation in the presence of anti-oestrogens in breast cancer, resulting in up-regulation of ER-dependent gene expression and providing a mechanism for hormone resistance in an NF- ⁇ B independent manner [81, 82]. Bennett et al.
• IKK ⁇ independent of the non-canonical NF- ⁇ B pathway in colorectal cancer and cutaneous squamous cell carcinoma have centred on a truncated form of IKK ⁇ (p45 IKK ⁇ ) that is constitutively active and specifically resides in the nucleus [55, 56]. Bennett et al. observed that nuclear IKK ⁇ in breast cancer has a stronger predictive power than cytoplasmic IKK ⁇ , and proposed that this could be due to detection of the truncated activated form of p45 IKK ⁇ as the antibody employed was unable to distinguish between full length IKK ⁇ and the truncated p45 IKK ⁇ form [71].
• IKK ⁇ signalling independent of the non-canonical NF- ⁇ B pathway in colorectal cancer provide additional evidence that IKK ⁇ binds to Notch-dependent gene promoters to upregulate them and release chromatin-bound SMRT, which can be restored by inhibition IKK ⁇ and results in colorectal cancer xenografts shrinking in size [56]. It has been reported that the truncated p45 IKK ⁇ , forms a complex with full length IKK ⁇ and NEMO and is responsible for regulating phosphorylation of SMRT and histone H3 in an NF- ⁇ B- independent fashion.
• IKK ⁇ may be phosphorylated in a TAK1-dependent but NF- ⁇ B-independent manner in BRAF V600E mutant colorectal tumours [56], so supporting a role for nuclear IKK ⁇ independent of non-canonical NF- ⁇ B signalling.
• the nuclear role of IKK ⁇ is consistently reported as being independent of NF- ⁇ B, by activating alternative pathways such as NOTCH [85]. This has been observed in breast cancer, skin cancer and osteosarcoma [86].
• Hepatitis B virus X protein down- regulates maspin expression via nuclear IKK ⁇ resulting in chemoresistance, suggesting that targeting IKK ⁇ could re-sensitise HCC tumours to chemotherapy [87].
• IKK ⁇ transgenic adenocarcinoma of the mouse prostate (TRAMP) models of prostate cancer IKK ⁇ can translocate to the nucleus to promote metastasis and development of castrate resistant disease in a maspin dependent manner, which is accompanied by a local inflammatory response [88]. Similar to breast cancer, in prostate cancer nuclear IKK ⁇ appears to provide a mechanism for hormone resistance as IKK ⁇ is associated with development of castrate resistant prostate cancer [53] and deletion of BAG3 which is required for IKK ⁇ nuclear translocation delays development of castrate resistant disease [89]. IKK ⁇ association with Hallmarks of cancer in human tumours [00181] The NF- ⁇ B pathways regulate the transcription of a wide range of genes involved in the inflammation, proliferation and apoptosis.
• IKK ⁇ functions as a member of the non-canonical NF- ⁇ B pathway or in its NF- ⁇ B-independent roles, it is clear that it is involved with multiple hallmarks of cancer including key roles in innate and adaptive immune responses, cell survival, cell death and inflammation [90, 91].
• the non-canonical NF- ⁇ B pathway has key roles in regulating processes including production of lymphoid organs (responsible for B and T lymphocyte production), B-cell development and survival, dendritic cell function and bone metabolism [92] and has been reported to promote development and progression of cancers via promotion of inflammatory infiltrate.
• Mouse model studies have demonstrated that mice with a dominant-negative, catalytically-inactive IKK ⁇ , have reduced adenoma formation, smaller colorectal tumours with a lower proliferation index when treated with a carcinogen and this was associated with increased recruitment of macrophages and other immune cell types [93]. In skin cancer studies, IKK ⁇ has been demonstrated to induce inflammation-related genes [94].
• IKK ⁇ is also associated with promoting expression of pro-inflammatory cytokines such as IL-8 in prostate cancer [95].
• DRC1 breast cancer 1
• PCR array-based gene transcriptional profiling experiments demonstrated that reducing cellular IKK ⁇ expression had a significant impact on increased expression of genes associated with induction of apoptosis, in particular BAK1 and BBC3, providing evidence that IKK ⁇ is involved regulating both cell proliferation and apoptosis in ER positive breast cancer.
• Dan et al. demonstrates that IKK ⁇ via mTORC can induce cell proliferation in cervical, lung, prostate and pancreatic cell lines [79] and in basal cell carcinoma IKK ⁇ is associated with proliferation and EMT [94].
• Studies in vitro demonstrate that ovarian cancer epithelial cell proliferation, migration and an invasive phenotype of the cancer were promoted via up-regulation of IKK ⁇ .
• NIK levels have been associated with regulating both cell proliferation and apoptosis in colorectal cancer, demonstrating that the non-canonical NF- ⁇ B pathway is involved in cell viability and tumour growth [97].
• IKK ⁇ in haematological malignancies Aberrant NF- ⁇ B signalling and associated gene transcription that modulate cellular processes involved in the initiation, maintenance and progression of human malignancies are also common to haematological cells and cancers. In this regard, many B-cell leukaemias and lymphomas display abnormal NF- ⁇ B activation, implicating this family of transcription factors in these diseases and suggesting regulation of these proteins may represent promising therapeutic targets.
• CLL Chronic lymphocytic leukaemia
• NF- ⁇ B is constitutively activated in many CLL patients and this is associated with more aggressive disease [106, 107].
• a number of recurrent genetic mutations in NF- ⁇ B-associated genes have been described in CLL. The most common of these is an inactivating mutation in NF ⁇ BIE that encodes I ⁇ B ⁇ , a negative NF- ⁇ B regulator. These NF ⁇ BIE aberrations are found in approximately 7% of CLL cases and predominantly occur in poor-prognostic subgroups. This may be causal as mutations in NF ⁇ BIE result in increased nuclear translocation of RelA [108].
• NOTCH1 mutations occur at an even higher frequency in CLL ( ⁇ 11%). These activating mutations are associated with poor response to chemotherapy [109] and this may be caused by NOTCH1-mediated NF- ⁇ B pathway activation [110-112].
• BIRC3 mutations are found in a smaller proportion of CLL patients ( ⁇ 4%) but they impact upon the non-canonical NF- ⁇ B pathway due to the premature truncation of the BIRC3-encoded protein product, cIAP2, resulting in the loss of its E3 ubiquitin ligase activity that is essential for NIK proteasomal degradation.
• NIK levels increase leading to the phosphorylation of IKK ⁇ , NF- ⁇ B2, the processing of p100 to p52 and the constitutive activation of non-canonical NF- ⁇ B signalling [113].
• BIRC3 mutations are associated with loss of sensitivity to chemotherapy and poor prognosis [114].
• the lymph node microenvironment plays a critical role in modulating the natural pathology of this disease.
• BCR B-cell receptor
• TLR toll-like receptors
• CD40 proliferation-inducing ligand
• APRIL proliferation-inducing ligand
• Diffuse large B-cell lymphomas are the most common types of non-Hodgkin lymphoma. They are divided into three molecular sub-types: ABC (activated B-cell), GCB (germinal centre B-cell) and PMBL (primary mediastinal B-cell lymphoma).
• ABC activated B-cell
• GCB germinal centre B-cell
• PMBL primary mediastinal B-cell lymphoma
• NF- ⁇ B activation in the ABC sub-type can result from mutations in components of the BCR signalling cascade, which results in chronic BCR activation. These mutations often occur in the immunoreceptor tyrosine-based motif (ITAM) but also in the coiled-coil domain of the CARD11/CARMA1 gene [124]. Finally, MYD88 gene mutations are found in approximately 30% of the ABC sub-type resulting in spontaneous activation of the downstream IRAK complex and NF- ⁇ B activation [125].
• ITAM immunoreceptor tyrosine-based motif
• MM Multiple myeloma
• Disease progression involves clonal expansion of transformed plasma cells in the bone marrow.
• genetic abnormalities leading to constitutive NF- ⁇ B activity have been found in approximately 20% of MM patients and 40% of MM cell lines [127-129].
• CD40 is a cell surface marker not usually expressed on normal plasma cells but has been shown to be increased in the early stages of MM [132]. Furthermore, blocking the interaction of CD40 with CD40L decreases NF- ⁇ B activation [127]. This results in the inhibition of IL-6 and vascular endothelial growth factor (VEGF) secretion, which in turn leads to growth arrest and cell death of MM cells [133]. Furthermore, the bone marrow stromal cells (BMSC) found in the MM tumour microenvironment have also been found to express high levels of NF- ⁇ B activation that helps to support the proliferation, survival and drug resistance of malignant plasma cells within the bone marrow niche [134].
• BMSC bone marrow stromal cells
• Non-canonical nf-kb signaling drives the aggressive invasiveness of glioblastoma Neuro-oncology 201416 (Suppl 5), v2.
• IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell.2001 Dec 14;107(6):763-75.
• Yang Z Wang XL, Bai R, Liu WY, Li X, Liu M, Tang H. miR-23a promotes IKK ⁇ expression but suppresses ST7L expression to contribute to the malignancy of epithelial ovarian cancer cells. Br J Cancer.2016 Sep 6;115(6):731-40.
• Non-conventional functions for NF-kappa B members the dark side of NF-kappa B. Oncogene.2015 Apr 30: 34:2279-87.
• BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF- kappaB2.
• Immunity.2002 Oct;17(4):515-24 [103] Novack DV, Yin L, Hagen-Stapleton A, Schreiber RD, Goeddel DV, Ross FP, Teitelbaum SL.The IkappaB function of NF-kappaB2 p100 controls stimulated osteoclastogenesis. J Exp Med.2003 Sep 1;198(5):771-81 [104] Sun S.C. The non-canonical NF- ⁇ B pathway. Immunol. Rev.2012; 246:125–140.
• TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs. Proc Natl Acad Sci U S A.2005; 102(8):2874-9.
• a method of inhibiting IKK ⁇ activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
• a method of treating a disease or disorder in which IKK ⁇ activity is implicated in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
• a method of treating a proliferative disorder in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
• a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy for use in therapy.
• a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative disorder for use in the treatment of a proliferative disorder.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer In a particular embodiment, the cancer is human cancer.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of IKK ⁇ activity there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which IKK ⁇ activity is implicated.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the manufacture of a medicament for the treatment of a proliferative disorder.
• a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the manufacture of a medicament for the treatment of cancer.
• a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of IKK ⁇ activity is provided.
• a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.
• proliferative disorder is suitably cancer
• the cancer is suitably a human cancer.
• the compounds of the present invention will be useful for the treatment of any cancer in which a mis-match repair inhibition is beneficial.
• Any suitable cancer may be targeted (e.g. adenoid cystic carcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendix cancer, astrocytoma, ataxia-telangiectasia, Beckwith-Wiedemann Syndrome, bile duct cancer (cholangiocarcinoma), Birt-Hogg-Dubé Syndrome, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, Carney Complex, central nervous system tumors, cervical cancer, colorectal cancer, Cowden Syndrome, craniopharyngioma, desmoplastic infantile ganglioglioma, ependymoma, esophageal cancer, Ewing sarcoma, eye cancer, eyelid cancer, familial adenomatous polyposis, familial GIST, familial malignant melanoma, familial non-VHL clear cell renal cell carcinoma, familial pancreatic cancer, gallbladder cancer, gastrointestinal stromal tumor – GIST
• Kaposi or soft tissue skin cancer, small bowel cancer, stomach cancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis complex, uterine cancer, vaginal cancer, Von Hippel-Lindau syndrome, vulvar cancer, Waldenstrom’s macroglobulinemia, Werner syndrome, Wilms Tumor and xeroderma pigmentosum).
• haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), multiple myeloma, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, gastro-oesophageal cancer, neuroendocrine cancers, osteosarcomas, prostate cancer, pancreatic cancer, small intestine cancer, bladder cancer, rectal cancer, cholangiocarcinoma, CNS cancer, thyroid cancer, head and neck cancer, oesophageal cancer, and ovarian cancer.
• lymphomas including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphom
• IKK ⁇ inhibition is anticipated to be beneficial
• cancers in which IKK ⁇ inhibition is anticipated to be beneficial include advanced prostate cancer, multiple myeloma, pancreatic cancer, colorectal cancer (especially metastatic colorectal cancer) and breast cancer (especially triple negative breast cancer).
• Prostate cancer is of particular interest as potential therapeutic target for IKK ⁇ inhibitors.
• the effective targeting of IKK ⁇ may enhance androgen deprivation therapy (ADT) chemotherapy responses by concurrently inhibiting androgen-driven and androgen-independent AR (androgen receptor) activity.
• IKK ⁇ inhibition may also abrogate inflammatory microenvironment signalling and eliminate tumour-promoting stimuli from adjacent stroma and infiltrating monocytes.
• IKK ⁇ inhibitors therefore have the potential to alter disease course, restore/prolong sensitivity to AR- targeted therapy and improve survival. Moreover, their use in hormone-sensitive de novo metastatic disease may significantly extend the benefit duration of conventional therapies and reduce the overall incidence of castration-resistant prostate cancer (CRPC).
• CRPC castration-resistant prostate cancer
• a IKK ⁇ inhibitor may find use in clinical scenarios such as: • the last-line therapy in patients with CRPC that have failed standard-of-care treatment • combination therapy with ADT to prevent the emergence of CRPC/prolong sensitivity to ADT • combination therapy in CRPC patients to restore sensitivity to ADT/reduce resistance development to chemotherapy • single-agent therapy to prevent the emergence of CRPC Routes of Administration [00210]
• the compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically, peripherally or topically (i.e., at the site of desired action).
• Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including intratumoral, subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratrache
• the compounds of the present invention may be administered as a sole therapy or may involve, in addition to a compound of the invention, conventional surgery or radiotherapy or chemotherapy or a targeted agent.
• chemotherapy or targeted agent may include one or more of the following categories: (i) Antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as, but not limited to, alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin
• inhibitors of growth factor function such as, but not limited to, growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al.
• growth factor antibodies and growth factor receptor antibodies for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al.
• inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3- chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)- quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors
• vascular damaging agents such as, but not limited to, Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
• an endothelin receptor antagonist for example zibotentan (ZD4054) or atrasentan;
• antisense therapies such as, but not limited to, those directed to targets listed above, such as ISIS 2503, an anti-ras antisense;
• immunotherapy approaches including for example cancer vaccines, antibody, viral (oncolytic viruses) and small molecule or cell therapy approaches to increase the immunogenicity of patient tumour cells and/or facilitate a cell mediated anti-tumour response.
• Such therapies could include, but are not limited to, OX40 agonists, cGAS- STING agonists, A2a receptor antagonists, PI3 kinase inhibitors, TLR7/8 agonists, IDO inhibitors, Arginase inhibitors, BTK inhibitors and Bromodomain inhibitors; transduction with microbial vectors of cancer antigens, direct transduction of cancer antigens into antigen presenting cells, treatment with immune cells specific for cancer antigens (e.g. CAR-T), treatment with antibodies, antibody fragments and antibody drug conjugates that enable the immune system to recognise tumour cells.
• OX40 agonists e.g., cGAS- STING agonists, A2a receptor antagonists, PI3 kinase inhibitors, TLR7/8 agonists, IDO inhibitors, Arginase inhibitors, BTK inhibitors and Bromodomain inhibitors
• transduction with microbial vectors of cancer antigens direct transduction of cancer antigens into antigen presenting cells,
• the compounds of the present invention are anticipated to be particularly useful in combination with androgen deprivation therapies (ADTs) and standard chemotherapy used to treat prostate cancer and, in particular, castrate-resistant prostate cancer (CRPC).
• ADTs androgen deprivation therapies
• CRPC castrate-resistant prostate cancer
• Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
• Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
• a combination for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof, and an anti-tumour agent.
• a proliferative condition such as cancer (for example a cancer involving a solid tumour)
• a pharmaceutically acceptable salt or solvate thereof comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt or solvate thereof, and any one of the anti-tumour agents listed herein above.
• a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.
• a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of cancer in combination with a tyrosine kinase inhibitor, optionally selected from one listed herein above.
• a tyrosine kinase inhibitor optionally selected from one listed herein above.
• “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
• a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.
• TLC Thin-layer chromatography
• Alignment chromatography was carried out on aluminium- backed SiO 2 plates (Merck, silica gel 60, F 254 ) and spots visualised using ultra-violet light (254 nm) or by staining with potassium permanganate. All tested compounds were determined to be ⁇ 95 % purity by LC-MS and analytical HPLC unless otherwise stated.
• General procedures All commercially available reagents and solvents used were obtained from Sigma-Aldrich, Fluorochem Fisher Scientific, Acros, Alfa Aesar, Apollo scientific and Advanced ChemBlocks and used without further purification.Air- or moisture-sensitive reactions were carried out under argon or nitrogen atmosphere. Microwave reactions were carried out using a Biotage Initiator system.
• Flash chromatography was performed using a Biotage SP4 automated chromatography system using silica stationary phase (Fisher Scientific, 60 ⁇ , 35-70 micron; detection wavelength: 254 nm; monitoring: 280 nm) and the mobile phase used are detailed in the text.
• Reverse phase HPLC purifications were conducted on Shimadzu Prominance HPLC using a semi-preparative (50 x 21.2 mm) Luna 5 ⁇ m C18 column at 40 °C; flow rate: 6 ml/min; detection wavelength: 254 nm eluting with an acetonitrile/water gradient with 0.1% TFA.
• NMR spectra were recorded on either a Bruker Avance3/DPX400 (400 MHz), Bruker DRX500 (500 MHz), Bruker AV400 (400 MHz), Bruker AV500HD (500 MHz) or Bruker AV600 (600 MHz) instrument and analysed using Advanced Chemistry Development Labs (ACD/labs) NMR processor 12.00 or MestReNova 10.0 software.
• Chemical shifts ( ⁇ ) are recorded in parts per million (ppm) relative to an internal solvent reference (tetramethylsilane) and coupling constants (J) in Hertz (Hz). Splitting patterns were indicated as singlet (s), broad singlet (br.
• LCMS was carried out on an Agilent Technologies 1220 series LC system with Agilent 6100 series quadrupole mass spectrometer in ESI/APCI mode. Separation was achieved with an Agilent Eclipse C18 4.6x50 mm column; flow rate:1 ml/min; detection:254 nm; sample volume:10 ⁇ l; mobile phase: acetonitrile/ 5mM ammonium acetate :water/5mM ammonium acetate; 5%, 1.48 min; 5-100%, 8 min; 100%, 13.5 min; 100-5%, 16.5 min; 18 min.
• Section 2 compounds of the formula: Example 4 7-Chloro-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.291 g, 1.50 mmol) along with 7-chloro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (0.502 g, 1.5 mmol), dioxane (8 ml) and potassium phosphate (4 ml of 1M solution)) were placed in a 20ml ml microwave vial. The solution was then degassed with N2 for 10 min.
• Example 5 7-Bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.291 g, 1.50 mmol) along with 7-bromo-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (0.502 g, 1.5 mmol), dioxane (8 ml) and potassium phosphate (4 ml of 1M solution)) were placed in a 20ml ml microwave vial. The solution was then degassed with N 2 for 10 min.
• Example 6 7-Ethynyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine 7-Bromo-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine (0.200 g, 0.61 mmol) and ethynyltrimethylsilane (0.169 ml, 1.2 mmol) were added to a sealable vial containing triethylamine (2 ml) and DMF (2 ml)and the solution degassed with N2 for 10 min.
• Example 7 7-Phenyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine
• a 2-5 mL MW tube was charged with a mixture of 7-chloro-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H- indazol-3-amine (Example 4) (57 mg, 0.2 mmol, 1 eq.), phenylboronic acid (49 mg, 1.2 eq., 2 eq.), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) catalyst (6.5 mg, 5mol%) in 1,4-dioxane (1.2 mL) was stirred under argon before adding 1 M aq.
• Example 8 5-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine
• 4-chloro-2-methyl-7-azaindole 0.058 g, 0.35 mmol
• 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (0.136 g, 0.53 mmol)
• 1M potassium phosphate solution (0.87 ml, 0.87 mmol
• [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) catalyst 0.011 g, 0.0175 mmol
• 1.5 ml ethanol/water (1:1) was deoxygenated with nitrogen in sealed tube and the mixture allowed to stir at 90-100 °C for 18 h.
• Example 10 4-(3-Amino-1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid
• the purification by HPLC of the reaction for the synthesis of 4-(3-amino-1H-indazol-5-yl)-N- isopentyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Example 237) afforded also the title compound as a yellow solid (0.0091 g, 0.0175 mmol, 22%).
• Example 12 5-[2-(Ethylamino)pyridin-4-yl]-1H-indazol-3-amine
• the reaction was placed in a microwave and irradiated at 160 ⁇ C for 40 min. Once cooled to room temperature the reaction mixture was concentrated under reduced pressure then suspended in EtOH (2 mL). To this suspension was added hydrazine hydrate (57 ⁇ L, 1.17 mmol) and NaHCO3 (0.030 g). The resulting suspension was heated to 80 °C for 2 d at which point additional hydrazine hydrate (28.5 ⁇ L, 2.5 eq.) and EtOH (1 mL) were added. Heating was continued for 1.5 d. The reaction mixture was then cooled down to 40 °C, diluted with water (6 mL), stirred at room temperature for 30 min and left in the fridge overnight.
• Example 14 5-(2-(Isopropylamino)pyridin-4-yl)-1H-indazol-3-amine
• 4-bromo-N-isopropylpyridin-2-amine 0.050 g, 0.23 mmol
• 3-cyano-4- fluorophenylboronic acid pinacol ester 0.115 g, 0.5 mmol
• [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) catalyst 0.030 g, 0.05 mmol
• IPA/H 2 O (2:1 mL) was degassed with nitrogen.
• Example 16 5-(2-(Isopentylamino)pyridin-4-yl)-1H-indazol-3-amine
• 4-bromo-N-isopentylpyridin-2-amine 0.05 g, 0.23 mmol
• 3-cyano-4- fluorophenylboronic acid pinacol ester (0.115 g, 0.50 mmol
• [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) catalyst 0.030 g, 0.05 mmol
• IPA/H2O 3:1.5 mL
• Example 19 4-Bromo-N-(trans-4-methylcyclohexyl)pyridin-2-amine 4-Bromo-2-fluoropyridine (0.1 mL, 0.98 mmol), triethylamine (0.50 mL, 3.59 mmol), trans-4- methylcyclohexanamine (0.4 mL , 2.98 mmol) in 1,4-dioxane (2.5 mL) was heated in the microwave at 160 ⁇ C for30 min. Once cooled to room temperature the reaction mixture was concentrated under reduced pressure.
• Example 23 5-((4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)amino)pentan-1-ol
• [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) catalyst (0.047 g, 0.072 mmol) in IPA/H 2 O (3:1.5 mL) was degassed for 5 min using a steady stream of nitrogen.
• Example 25 5-(2-((2-Methoxyethyl)amino)pyridine-4-yl)-1H-indazol-3-amine
• 4-bromo-N-(2-methoxyethyl)pyridin-2-amine 0.040 g, 0.17 mmol
• 3-cyano-4- fluorophenylboronic acid 0.075 g, 0.30 mmol
• [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) catalyst 0.15 g, 0.02 mmol
• IPA/H 2 O 3:1.5 mL
• Example 26 5-(2-((3-Methoxypropyl)amino)pyridine-4-yl)-1H-indazol-3-amine
• 4-bromo-N-(3-methoxypropyl)pyridine-2-amine 0.030 g, 0.12 mmol
• 3-cyano- 4-fluorophenylboronic acid 0.056 g, 0.23 mmol
• [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) catalyst 0.13 g, 0.02 mmol
• IPA/H 2 O 3:1.5 mL
• Example 36 1-(4-Chloropyridin-2-yl)-3-ethylurea
• 4-chloropyridin-2-amine (437 mg, 3.40 mg, 1 eq.) and chloroform (1.6 mL)
• isocyanatoethane (483 mg, 538 ⁇ L, 6.80 mmol, 2 eq.).
• the reaction mixture was heated to 100 °C under microwave irradiation for 1 hour.
• the resulting light yellow solution was cooled to room temperature, diluted by dropwise addition of hexane (8 mL) and left overnight.
• Example 38 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-isopentylurea
• ethyl (4-(3-amino-1H-indazol-5-yl)pyridin-2- yl)carbamate (Example 35) (0.030 g, 0.10 mmol, 1 eq.), 3-methylbutan-1-amine (0.264 g, 352 ⁇ L, 3.03 mmol, 30 eq.) and dioxane (650 ⁇ L), was sealed with an aluminium crimp cap fitted with a disposable PTFE/silicon septum, and purged with nitrogen.
• the reaction mixture was heated to 180 °C under microwave irradiation for 30 minutes.
• the reaction mixture was then cooled to ca. 40 °C and diluted by dropwise addition of water (5 mL) via syringe.
• the mixture was stirred and sonicated for 30 minutes and allowed to cool to room temperature.
• the cap was then removed and a solid was filtered, washed with water (2 ⁇ 4 mL) and dried to afford the title compound.
• Example 40 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-cyclohexylurea 1-(4-Bromopyridin-2-yl)-3-cyclopentylurea (0.157 g, 0.53 mmol) along with 2-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.132 g, 0.53 mmol), and t-butylamine (150 ⁇ l) were placed in a 5 ml microwave vial to which IPA:H2O (2:1) (4 ml) was added. The solution was then degassed with N2 for 10 min.
• Example 41 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-hydroxyethyl)urea
• ethyl (4-(3-amino-1H-indazol-5-yl)pyridin-2- yl)carbamate (Example 35) (0.030 g, 0.10 mmol, 1 eq.), 2-aminoethanol (0.025 g, 24.4 ⁇ L, 0.40 mmol, 4 eq.) and dioxane (650 ⁇ L), was sealed with an aluminium crimp cap fitted with a disposable PTFE/silicon septum, and purged with nitrogen.
• the reaction mixture was heated to 160 °C under microwave irradiation for 90 minutes.
• the reaction mixture was then concentrated in vacuo and the resulting crude was dissolved in water (3 mL).
• the mixture was stirred and sonicated for 30 minutes, then the solid was filtered, washed with water (2 ⁇ 3 mL) and dried to afford the title compound.
• the reaction mixture was heated to 180 °C under microwave irradiation for 40 minutes.
• the reaction mixture was then cooled to ca. 40 °C and diluted by dropwise addition of water (5 mL) via syringe.
• the mixture was stirred and sonicated for 30 minutes and allowed to cool to room temperature.
• the cap was then removed and a solid was filtered, washed with water (2 ⁇ 4 mL) and dried to afford the title compound.
• the reaction mixture was heated to 180 °C under microwave irradiation for 30 minutes.
• the reaction mixture was then cooled to ca. 40 °C and diluted by dropwise addition of water (5 mL) via syringe.
• the mixture was stirred and sonicated for 30 minutes and allowed to cool to room temperature.
• the cap was then removed and a solid was filtered, washed with water (2 ⁇ 4 mL) and dried to afford the title compound.
• Example 46 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenethylurea 1-(4-Bromopyridin-2-yl)-3-phenethylurea (0.169 g, 0.53 mmol) along with 2-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.132 g, 0.53 mmol), and t-butylamine (150 ⁇ l) were placed in a 5 ml microwave vial to which IPA:H 2 O (2:1) (4 ml) was added. The solution was then degassed with N 2 for 10 min.
• Example 47 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-(pyridin-2-ylmethyl)urea
• ethyl (4-(3-amino-1H-indazol-5-yl)pyridin-2- yl)carbamate (Example 35) (0.030 g, 0.10 mmol, 1 eq.)
• pyridin-2-ylmethanamine 0.044 g, 41.6 ⁇ L, 0.40 mmol, 4 eq.
• dioxane 650 ⁇ L
• the reaction mixture was heated to 180 °C under microwave irradiation for 40 minutes.
• the reaction mixture was then concentrated in vacuo and the resulting crude was dissolved in water (3 mL).
• the mixture was stirred and sonicated for 30 minutes, then the solid was filtered, washed with water (2 ⁇ 3 mL) and dried to afford the title compound.
• the reaction mixture was heated to 180 °C under microwave irradiation for 40 minutes.
• the reaction mixture was then cooled to ca. 40 °C and diluted by dropwise addition of water (5 mL) via syringe.
• the mixture was stirred and sonicated for 30 minutes and allowed to cool to room temperature.
• the cap was then removed and a solid was filtered, washed with water (2 ⁇ 4 mL) and dried to afford the title compound.
• the reaction mixture was heated to 180 °C under microwave irradiation for 40 minutes.
• the reaction mixture was then cooled to ca. 40 °C and diluted by dropwise addition of water (5 mL) via syringe.
• the mixture was stirred and sonicated for 30 minutes and allowed to cool to room temperature.
• the cap was then removed and a solid was filtered, washed with water (2 ⁇ 4 mL) and dried to afford the title compound.
• Example 50 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-phenylurea Ethyl (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate (EXAMPLE 35) (0.050 g, 0.17 mmol) and analine (16 ⁇ l, 0.20 mmol, 1.2 eq) were placed in a 0.5-2 ml microwave vial with dioxane (2 ml).
• Example 51 1-(4-(3-Amino-1H-indazol-5-yl)pyridine-2-yl)-3-(3-fluorophenyl)urea
• ethyl (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate 0.050 g, 0.17 mmol
• 3-fuoroanaline 60 ⁇ L
• dioxane 3 ml
• Bismuth triflate (0.008 g ) was added and the mixture was heated in the microwave at 120 °C for 80 min.
• Example 53 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-isopropyl)phenyl)urea
• EXAMPLE 35 A suspension of ethyl [4-(3-amino-1H-indazol-5-yl)pyridin-2-yl]carbamate (EXAMPLE 35) (0.050 g, 0.17 mmol), bismuth(III)trifluoromethanesulfonate (0.030 g, 0.05 mmol), 3- isopropoxyaniline (0.050 mL, 0.36 mmol) in 1,4-dioxane (4 mL) was degassed for 5 min using a steady stream of nitrogen.
• Example 54 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-(hydroxymethyl)phenyl)urea Ethyl (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate (EXAMPLE 35) (0.050 g, 0.17 mmol) and (3-aminophenyl)methanol (0.025 g, 0.20 mmol, 1.2 eq) were placed in a 0.5-2 ml microwave vial with dioxane (2 ml).
• Example 56 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-phenoxyphenyl)urea
• EXAMPLE 35 A suspension of ethyl [4-(3-amino-1H-indazol-5-yl)pyridin-2-yl]carbamate (EXAMPLE 35) (0.051 g, 0.17 mmol), bismuth(III)trifluoromethanesulfonate (0.037 g, 0.056 mmol), 3- phenoxyaniline (0.068 g, 0.37 mmol) in 1,4-dioxane (4 mL) was degassed for 5 min using a steady stream of nitrogen.
• Example 58 1-(4-(3-Amino-1H-indazol-5-yl)pyridin2-yl)-3-(3-((4-fluorobenzyl)oxy)phenyl)urea
• EXAMPLE 35 0.056 g, 0.19 mmol
• bismuth(III)trifluoromethanesulfonate 0.052 g, 0.08 mmol
• 3-(4- fluorobenzyloxy)phenylamine (0.21 mL, 0.96 mmol) in 1,4-dioxane (4 mL) was degassed for 5 min using a steady stream of nitrogen.
• Example 59 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-(3-((3-fluorobenzyl)oxy)phenyl)urea
• EXAMPLE 35 0.054 g, 0.18 mmol
• bismuth(III)trifluoromethanesulfonate 0.050 g, 0.08 mmol
• 3-(3- fluorobenzyloxy)phenylamine (0.20 g, 0.91 mmol) in 1,4-dioxane (4 mL) was degassed for 5 min using a steady stream of nitrogen.
• Example 62 1-(4-(3-Amino-1H-indazol-5-yl)pyridine-2-yl)-3-(4-fluorophenyl)urea
• EXAMPLE 35 ethyl (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate (EXAMPLE 35) (0.050 g, 0.17 mmol), 4-fuoroanaline (60 ⁇ L), in dioxane (3 ml) was degassed with nitrogen.
• Bismuth triflate (0.008 g ) was added and the mixture was heated in the microwave at 120 °C for 80 min.
• Example 63 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-chlorophenyl)urea
• Ethyl (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate (EXAMPLE 35) (0.050 g, 0.17 mmol) and 4-chloroaniline (0.026 g, 0.20 mmol, 1.2 eq) were placed in a 0.5-2 ml microwave vial with dioxane (2 ml).
• Example 64 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-(tert-butyl)phenyl)urea Ethyl (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate (EXAMPLE 35) (0.050 g, 0.17 mmol) and 4-t-butylaniline (32 ⁇ l, 0.20 mmol, 1.2 eq) were placed in a 0.5-2 ml microwave vial with dioxane (2 ml).
• Example 65 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-(4-(methylsulfonyl)phenyl)urea Ethyl (4-(3-amino-1H-indazol-5-yl)pyridin-2-yl)carbamate (EXAMPLE 35) (0.050 g, 0.17 mmol) and 4-(methylsulfonyl)aniline (0.034 g, 0.20 mmol, 1.2 eq) were placed in a 0.5-2 ml microwave vial with dioxane (2 ml).
• Example 66 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-(o-tolyl)urea
• EXAMPLE 35 ethyl [4-(3-amino-1H-indazol-5-yl)pyridin-2-yl]carbamate (EXAMPLE 35) (0.060 g, 0.20 mmol), bismuth(III)trifluoromethanesulfonate (0.043 g, 0.067 mmol), o-toluidine (0.1 mL, 0.94 mmol) in 1,4-dioxane (4 mL) was degassed for 5 min using a steady stream of nitrogen.
• Example 67 1-(4-(3-Amino-1H-indazol-5-yl)pyridin-2-yl)-3-(2-ethylphenyl)urea
• EXAMPLE 35 0.054 g, 0.18 mmol
• bismuth(III)trifluoromethanesulfonate 0.050 g, 0.08 mmol
• 2-ethylaniline 0.11 mL, 0.89 mmol
• General procedure A A suspension of required chloroaryl (1 eq.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazol-3-amine (1.2-1.5 eq.), base (2 eq.) in 1:3 of solvent was deoxygenated with nitrogen in sealed tube. Then [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) catalyst (0.05 eq.) was added then the tube was sealed and the mixture allowed to stirred at 90-100 °C for 18 h. After the reaction was cooled to room temperature, EtOAc and water were added.
• Example 70 4-Chloro-3-((triisopropylsilyl)ethynyl)pyridin-2-amine
• reaction mixture was heated to 80 °Cfor 4 hours.
• the resulting mixture was diluted with EtOAc, filtered through silica, concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether 60-80%/acetone 7:3) to give the product as a brown solid. (0.62 g, 41%).
• Example 71 4-Chloro-3-(cyclopropylethynyl)pyridin-2-amine A solution of 4-chloro-3-iodopyridin-2-amine (1.00 g, 3.9 mmol), copper (I) iodide (38 mg, 0.2 mmol) and bis(triphenylphosphine) palladium(II) chloride (0.28 g, 0.4 mmol) in 16 ml of N,N- dimethyformamide-triethylamine (4:1) was degassed in sealed tube followed by addition of ethynylcyclopropane (1.35 mL, 16.0 mmol). The reaction mixture was heated to 80 °C for 5 hours.
• reaction mixture was heated to 80 °C for 4 hours.
• the resulting mixture was diluted with EtOAc, filtered through silica, concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether 60-80%/acetone 7:3) to give the product as a dark yellow solid.
• N-(4-Chloro-3-iodopyridin-2-yl)pivalamide To a solution of N-(4-chloropyridin-2-yl)pivalamide (8.0g, 37.72 mmol) in anhydrous THF flushed with argon and cooled to -78 o C was added n-BuLi (38 mL, 94.4mmol of 2.5 M soln in hexanes).
• reaction mixture was stirred at 80 °C for 4 h.
• the reaction mixture was then diluted with EtOAc and washed with 1M sodium carbonate. Extracted organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the residue purified by column chromatography (50% EtOAc and 1% triethylamine in petroleum ether 60-80%) to give the product as a brown solid (0.061 g, 47%).
• reaction mixture was then diluted with EtOAc and washed with 1M sodium carbonate. Extracted organic layer was washed with brine and dried over magnesium sulfate and concentrated under reduced pressure and the residue purified by column chromatography (50% EtOAc and 1% triethylamine in petroleum ether 60-80%) to give the product as a light brown solid( 0.181 g 75%).
• reaction mixture was stirred at 80 °C for 4 h.
• the reaction mixture was then diluted with EtOAc and extracted with 1M sodium carbonate.
• the extracted organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the residue purified by column chromatography (50% EtOAc and 1% triethylamine in petroleum ether 60- 80%) to give the product as a light brown solid (0.22 g, 93%).
• reaction mixture was stirred at 80 °C for 4 h.
• the reaction mixture was then diluted with EtOAc and extract with 1M sodium carbonate.
• the extracted organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the residue purified by column chromatography (50% EtOAc and 1% triethylamine in petroleum ether 60-80%) to give the product as a dark brown solid ( 0.215 g, 70 %).
• Example 83 3-(2-Amino-4-chloropyridin-3-yl)prop-2-yn-1-ol
• 4-chloro-3-iodo-pyridine-2-amine 0.3 g, 1.181 mmol
• copper (I) iodide 0.023 g, 0.1181 mmol
• bis(triphenylphosphine) palladium(II) chloride 0.083 g, 0.1181 mmol
• 5 ml of N,N-dimethyformamide-triethylamine (1:4) was degassed in sealed tube followed by addition of propagyl alcohol (0.0795 g, 0.083 mL, 1.42 mmol).
• reaction mixture was stirred at 80 °C for 4 h.
• the reaction mixture was then diluted with EtOAc and extracted with 1M sodium carbonate.
• the extracted organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the residue purified by column chromatography (50% EtOAc and 1% triethylamine in petroleum ether 60- 80%) to give the product as a dark brown solid ( 0.087 g, 40 %).
• reaction mixture was stirred at 80 °C for 4 h.
• the reaction mixture was then diluted with EtOAc and extracted with 1M sodium carbonate.
• the extracted organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the residue purified by column chromatography (50% EtOAc and 1% triethylamine in petroleum ether 60-80%) to give the product as a brown solid (0.184 g, 79%).
• reaction mixture was stirred at 80 °C for 4 h.
• the reaction mixture was then diluted with EtOAc and washed with 1M sodium carbonate.
• the extracted organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the residue purified by column chromatography (50% EtOAc and 1% triethylamine in petroleum ether 60-80%) to give the product as a brown solid (0.192 g, 77%).
• the resulting suspension was purged with nitrogen for 5 minutes before adding 1 M aq. K 3 PO 4 (1.8 mL).
• the reaction mixture was heated to 110 °C for 16 hrs.
• the reaction mixture was then allowed to cool to room temperature, before being diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL).
• the combined organic fractions were then dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure.
• the crude product was then purified by HPLC to give the desired product as a pale yellow solid (23 mg).
• Example 89 1-((2-Amino-4-chloropyridin-3-yl)ethynyl)cyclopentan-1-ol
• 4-chloro-3-iodo-pyridine-2-amine (0.105, 0.416 mmol)
• copper (I) iodide 0.0079 g, 0.0416 mmol
• bis(triphenylphosphine) palladium(II) chloride 0.029 g, 0.0416 mmol
• 5 ml of N,N-dimethyformamide-triethylamine (1:4) was degassed in sealed tube followed by addition of 1-ethynylcyclopentan-1-ol (0.055 g, 0.49 mmol).
• reaction mixture was stirred at 80 °C for 4 h.
• the reaction mixture was then diluted with EtOAc and washed with 1M sodium carbonate.
• the extracted organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the residue purified by column chromatography (50% EtOAc and 1% triethylamine in petroleum ether 60-80%) to give the product as a brown solid (0.088 g, 90%).
• reaction mixture was stirred at 80 °C for 4 h.
• the reaction mixture was then diluted with EtOAc and extract with 1M sodium carbonate.
• the extracted organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the residue purified by column chromatography (50% EtOAc and 1% triethylamine in petroleum ether 60-80%) to give the product as a light brown solid (0.282 g, 71%).
• reaction mixture was stirred at 80 °C for 4 h.
• the reaction mixture was then diluted with EtOAc and extracted with 1M sodium carbonate.
• the extracted organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the residue purified by column chromatography (50% EtOAc and 1% triethylamine in petroleum ether 60-80%) to give the product as a light brown solid (0.251 g, 63%).
• Example 94 4-Chloro-3-(5-morpholinopent-1-yn-1yl)pyridin-2-amine
• 4-chloro-3-iodo-pyridine-2-amine (0.15 g, 0.6 mmol)
• copper (I) iodide 0.005 g, 0.03 mmol
• bis(triphenylphosphine) palladium(II) chloride 0.02 g, 0.03 mmol
• 4 ml of N,N-dimethyformamide-triethylamine (1:4) was degassed in sealed tube followed by addition of 4-(but-3-yn-1-yl)morpholine (122) (0.12 ml, 0.88 mmol).
• reaction mixture was stirred at 80 °C for 3 h.
• the reaction mixture was diluted with EtOAc and extracted with 1 M sodium carbonate.
• the extracted organic layer was washed with brine and dried over magnesium sulfate and concentrated under reduced pressure and the residue purified by column chromatography (80% EtOAc and 1% triethylamine in petroleum ether 60-80%) to give the product as yellow oil (0.139 g, 89%),.
• Example 95 4-Chloro-3-(5-chloropent-1-yn-1yl)pyridin-2-amine
• 4-chloro-3-iodo-pyridine-2-amine (0.15 g, 0.6 mmol), copper (I) iodide (0.005 g, 0.03 mmol) and bis(triphenylphosphine) palladium(II) chloride (0.02 g, 0.03 mmol) in 4 ml of tetrahydrofuran – triethylamine (1:4) was degassed in sealed tube followed by addition of 5- chloro-1-pentyne (0.1 ml, 0.9 mmol). The reaction mixture was stirred at room temperature for 16 h.
• Example 96 4-Chloro-3-(5-morpholinopent-1-yn-1yl)pyridin-2-amine
• a mixture of 4-chloro-3-(5-chloropent-1-yn-1yl)pyridin-2-amine 0.1 g, 0.4 mmol
• morpholine 0.5 ml
• potassium iodide 0.04 g, 0.22 mmol
• N,N-dimethylamide 1.5 ml
• the resulting suspension was purged with nitrogen for 5 minutes before adding 1 M aq. K 3 PO 4 (1.8 mL).
• the reaction mixture was heated to 110 °C for 16 hrs.
• the reaction mixture was then allowed to cool to room temperature, before being diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL).
• the combined organic fractions were then dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure.
• the crude product was then purified by HPLC to give the desired product as a pale yellow solid (14 mg).
• Example 100 5-(2-Amino-3-cyclopropylpyridin-4-yl)-1H-indazol-3-amine
• a 0.5-2 mL MW tube was charged with a mixture of 4-chloro-3-cyclopropylpyridin-2-amine (29.5 mg, 0.175 mmol, 1 eq.) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (59 mg, 0.228 mmol, 1.3 eq.), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) catalyst 5.7 mg, 0.00875 mmol, in EtOH (0.7 mL) was stirred under argon before adding 1 M aq.
• Example 101 4-(2-Amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)butan-1-ol
• 4-(2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)but-3-yn-1-ol (Example 84 SU1503) (42 mg, 0.14 mmol) in 1.2 ml of dry MeOH was added 10% Pd/C (20 mg, 0.19 mmol). The reaction was stirred at RT, o/n under a hydrogen atmosphere.
• Example 102 1-(2-(2-Amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethyl)cyclohexan-1-ol To a solution of 1-((2-amino-4-(3-amino-1H-indazol-5-yl)pyridin-3-yl)ethynyl)cyclohexan-1-ol (Example 90) (90 mg, 0.26 mmol) in 2.7 ml of dry MeOH was added 10% Pd/C (40 mg, 0.38 mmol).
• Example 104 5-(2-Aminopyridin-4-yl)-7-phenyl-1H-indazol-3-amine 5-(2-Aminopyridin-4-yl)-7-chloro-3-amino-1H-indazole (Example 1) (0.050 g, 0.19 mmol), phenylboronic acid (0.046 g, 0.38 mmol) and [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) catalyst (0.006 g, 0.01 mmol) were placed in a 2-5 mL microwave vial which was sealed and purged with nitrogen.
• Example 105 5-(2-Aminopyridin-4-yl)-7-(3-fluorophenyl)-1H-indazol-3-amine This compound was prepared using an analogous procedure for Example 104 using 3- fluorophenylboronic acid (0.062 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off- white solid (0.017 g, 27 %).
• Example 106 5-(2-Aminopyridin-4-yl)-7-(3-(trifluoromethyl)phenyl)-1H-indazol-3-amine This compound was prepared using an analogous procedure for Example 104 using 3- trifluoromethyl phenylboronic acid (0.072 g, 0.38 mmol).
• Example 109 5-(2-Aminopyridin-4-yl)-7-(3-methoxyphenyl)-1H-indazol-3-amine This compound was prepared using an analogous procedure for Example 104 using 3- methoxyphenylboronic acid (0.057 g, 0.38 mmol).
• Example 111 3-(3-Amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzaldehyde This compound was prepared using an analogous procedure for Example 104 using 3- formylphenylboronic acid (0.072 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off- white solid (0.021 g, 32 %).
• Example 112 Ethyl 3-(3-amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzoate This compound was prepared using an analogous procedure for Example 104 using (3- (ethoxycarbonyl)phenyl)boronic acid (0.072 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.024 g, 34 %).
• Example 113 3-(3-Amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzamide This compound was prepared using an analogous procedure for Example 104 using (3- carbamoylphenyl)boronic acid (0.075 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.011 g, 16 %).
• Example 114 3-(3-Amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzenesulfonamide This compound was prepared using an analogous procedure for Example 104 using (3- sulfamoylphenyl)boronic acid (0.076 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.023 g, 24 %).
• Example 115 5-(2-Aminopyridin-4-yl)-7-(4-(methylsulfonyl)phenyl)-1H-indazol-3-amine
• This compound was prepared using an analogous procedure for Example 104 using (3- (methylsulfonyl)phenyl)boronic acid (0.074 g, 0.38 mmol).
• Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.036 g, 32 %).
• Example 118 4-(3-Amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenyl)methanol This compound was prepared using an analogous procedure for Example 104 using 3- hydroxymethylphenylboronic acid (0.072 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.012 g, 22 %).
• Example 119 5-(2-Aminopyridin-4-yl)-7-(4-(dimethylamino)phenyl)-1H-indazol-3-amine
• This compound was prepared using an analogous procedure for Example 104 using (4- (dimethylamino)phenyl)boronic acid (0.064 g, 0.38 mmol).
• Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.016 g, 25 %).
• Example 120 4-(3-Amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzamide This compound was prepared using an analogous procedure for Example 104 using (4- carbamoylphenyl)boronic acid (0.062 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.013 g, 21 %).
• Example 121 4-(3-Amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)benzenesulfonamide This compound was prepared using an analogous procedure for Example 104 using (4- sulfamoylphenyl)boronic acid(0.076 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.011 g, 13 %).
• Example 122 5-(2-Aminopyridin-4-yl)-7-(4-(morpholinomethyl)phenyl)-1H-indazol-3-amine This compound was prepared using an analogous procedure for Example 104 using (4- (morpholinomethyl)phenyl)boronic acid (0.051 g, 0.23 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.020 g, 21 %).
• reaction was then sealed and stirred at 90 °C for 18 hours.
• the cooled reaction was then diluted with EtOAc (30 mL) and washed with water (30 mL) and brine (10 mL).
• the organic layer was then concentrated under reduced pressure and purified by flash column chromatography eluting from 50 -100% petroleum ether: EtOAc to afford the desired compound as a light brown solid (1.05 g, 64%).
• the reaction was then sealed and stirred at 90 °C for 18 hours.
• the cooled reaction was then treated with TBAF to deprotect, diluted with EtOAc (30 mL) and washed with water (30 mL) and brine (10 mL).
• the organic layer was then concentrated under reduced pressure and purified by HPLC to give the desired compound as a yellow powder (0.012 g, 11 %).
• Example 124 5-(2-Aminopyridin-4-yl)-7-(2-chlorophenyl)-1H-indazol-3-amine This compound was prepared using an analogous procedure for Example 104 using 2- chlorophenylboronic acid (0.060 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off- white solid (0.028 g, 25 %).
• Example 125 2-(3-Amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)phenyl)methanol This compound was prepared using an analogous procedure for Example 104 using 2- hydroxymethylphenylboronic acid (0.072 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.017 g, 14 %).
• Example 126 4-(3-Amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)-3-methylbenzenesulfonamide This compound was prepared using an analogous procedure for Example 104 using (2-methyl- 4-sulfamoylphenyl)boronic acid(0.074 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.024 g, 16 %).
• Example 127 5-(2-Aminopyridin-4-yl)-7-(pyridin-4-yl)-1H-indazol-3-amine This compound was prepared using an analogous procedure for Example 104 using pyridin-3- ylboronic acid (0.046 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.031 g, 27 %).
• Example 128 5-(2-Aminopyridin-4-yl)-7-(pyridin-4-yl)-1H-indazol-3-amine This compound was prepared using an analogous procedure for Example 104 using pyridin-4- ylboronic acid (0.075 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.010 g, 11 %).
• Example 129 5-(2-Aminopyridin-4-yl)-7-(furan-3-yl)-1H-indazol-3-amine This compound was prepared using an analogous procedure for Example 104 using furan-3- ylboronic acid (0.056 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.022 g, 25 %).
• Example 130 5-(2-Aminopyridin-4-yl)-7-(thiophen-3-yl)-1H-indazol-3-amine This compound was prepared using an analogous procedure for Example 104 using thiophen- 3-ylboronic acid (0.058 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off- white solid (0.042 g, 48 %).
• Example 131 5-(2-Aminopyridin-4-yl)-7-(thiophen-2-yl)-1H-indazol-3-amine This compound was prepared using an analogous procedure for Example 104 using thiophen- 2-ylboronic acid (0.058 g, 0.38 mmol). HLPC purification (see general experimental section) yielded product as off-white solid (0.031 g, 27 %).
• Example 132 5-(2-Aminopyridin-4-yl)-7-(thiazol-5-yl)-1H-indazol-3-amine This compound was prepared using an analogous procedure for Example 104 using thiazol-5- ylboronic acid (0.049 g, 0.38 mmol). Chromatographic purification (Biotage SP4, 50 g cartridge, solvent system: EtOAc/methanol, 0-10%, 8 CV; 10%, 4 CV) yielded product as off-white solid (0.034 g, 27 %).
• Example 133 5-(2-Aminopyridin-4-yl)-7-(1H-pyrazol-5-yl)-1H-indazol-3-amine
• a 2-5 mL MW tube was charged with a mixture of 5-(2-aminopyridin-4-yl)-7-chloro-1H-indazol- 3-amine (Example 1) (52 mg, 0.2 mmol, 1 eq.), potassium trifluoro(1H-pyrazol-5-yl)borate (52 mg, 0.2 mmol, 1.5 mmol, 1.5 eq.), XphosG2 (7.9 mg, 0.01 mmol, 5mol%) in 1,4-dioxane (oxygen-free, 1.8 mL) was heated to 60 °C under a gentle flow of nitrogen for 5 minutes, then 1 M aq.
• Example 134 5-(2-Aminopyridin-4-yl)-7-(3-methylbut-1-yn-1-yl)-1H-indazol-3-amine
• a solution of 5-(2-aminopyridin-4-yl)-7-bromo-1H-indazol-3-amine (0.03 g, 0.09 mmol)
• copper (I) iodide 0.0008 g, 0.0045 mmol
• [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst (0.003 g, 0.0045 mmol) in 0.27 ml of tetrahydrofuran:triethylamine (1:4) was degassed followed by addition of 3-methylbut-1- yne (0.013 ml, 0.13 mmol) .
• Example 135 4-Iodopyridin-2-amine In a sealed 25 mL microwave vial, equipped with a magnetic stir bar, 2-fluoro-4-iodopyridine (1.5 g, 6.72 mmol, 1 Eq) was dissolved in 2 mL of Dioxane.
• Example 136 tert-Butyl (4-iodopyridin-2-yl)carbamate To a solution of 4-iodopyridin-2-amine (1 g, 4.54 mmol, 1 Eq) in dioxane (10 mL) was added DMAP (666.13 mg, 5.45 mmol, 1.2 Eq) under a blanket of argon followed by the addition of Boc2O (1.04 g, 4.77 mmol, 1.05 Eq). The resulting reaction mixture was stirred at 80 °C overnight. The reaction was then cooled and quenched by pouring into water (10 mL), extracted with EtOAc (3 x 15 mL) and washed with brine (10 mL).
• tert-butyl (4-(3-amino-7-bromo-1H-indazol-5-yl)pyridin-2-yl)carbamate To a solution of 7-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (1.353 g, 4.00 mmol, 1.1 Eq) in a degassed 9:1 solution of dioxane/water (10 mL), were added tert-butyl (4-iodopyridin-2-yl)carbamate (1.3 g, 3.64 mmol, 1 Eq), cesium carbonate (3.557 g, 10.92 mmol, 3 Eq) and bis(triphenylphosphine)palladium chloride (255.49 mg, 0.364 mmol, 0.1 Eq) under argon atmosphere.
• Example 138 5-(2-Aminopyridin-4-yl)-7-(phenylethynyl)-1H-indazol-3-amine 5-(2-Aminopyridin-4-yl)-7-bromo-3-amino-1H-indazole (0.030 g, 0.1 mmol), phenylacetylene (37 ⁇ L, 0.34 mmol) and Tetrakis(triphenylphosphine)palladium(0) catalyst (0.012 g, 0.01 mmol) and CuI (0.002 g, 0.01 mmol) were placed in a 2-5 mL microwave vial which was sealed and purged with nitrogen.
• Example 139 4-(3-Amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)but-3-yn-1-ol 5-(2-Aminopyridin-4-yl)-7-bromo-3-amino-1H-indazole (0.030 g, 0.1 mmol), but-3-yn-1-ol (31 ⁇ L, 0.34 mmol) and Pd(PPh 3 ) 4 (0.012 g, 0.01 mmol) and CuI (0.002 g, 0.01 mmol) were placed in a 2-5 mL microwave vial which was sealed and purged with nitrogen.
• Example 140 4-(3-Amino-5-(2-aminopyridin-4-yl)-1H-indazol-7-yl)-2-methylbut-3-yn-2-ol
• a 2-5 mL MW tube was charged with a mixture of 5-(2-aminopyridin-4-yl)-7-bromo-1H-indazol-3- amine (50 mg, 0.15 mmol, 1 eq.), 2-methylbut-3-yn-2-ol (30 uL, 0.3 mmol, 2 eq.), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst (16mg mg, 0.02 mmol, 15 mol%) and CuI (4.2 mg 0.02 mmol, 15 mol%) in DMF (1 mL) and triethylamine (1 mL).
• the tube was then heated to 85 °C under nitrogen for 16 hrs.
• the reaction mixture was then cooled to room temperature, diluted with water (10 mL), the mixture was extracted with ethyl acetate (3 x 10 mL) and the organic fractions combined and dried over anhydrous magnesium sulfate, filtered and the solvent removed under high vacum.
• the resulting residue was purified by HPLC to give the desired product as a yellow solid (22 mg, 0.05 mmol, 37 %).
• Example 141 5-(2-Aminopyridin-4-yl)-7-((3-methyloxetan-3-yl)ethynyl)-1H-indazol-3-amine
• a solution of 5-(2-aminopyridin-4-yl)-7-bromo-1H-indazol-3-amine 0.05 g, 0.15 mmol
• copper (I) iodide 0.0014 g, 0.0075 mmol
• [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst (0.005 g, 0.0075 mmol) in 0.45 ml of tetrahydrofuran:triethylamine (1:4) was degassed followed by addition of 3-ethynyl-3- methyloxetane (0.02 ml, 0.22 mmol) .
• reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with EtOAc and extracted with water. Extracted organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was then purified by HPLC to give the titled compound as yellow solid (41.8 mg, 84 %).
• Example 147 5-(2-Aminopyridin-4-yl)-7-phenethyl-1H-indazol-3-amine Pd/C 5% (10 mg, 10%) was added to a solution of 5-(2-aminopyridin-4-yl)-7-(phenylethynyl)- 1H-indazol-3-amine (100 mg, 0.31 mmol) in MeOH (5 mL). The reaction mixture was allowed to stir under H 2 atmosphere at rt for 18 h. Pd/C was filtered off through celite. The organic solvent was removed under reduced pressure.
• Example 148 5-(2-Amino-5-fluoropyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3-amine
• a 0.5-2 mL MW tube was charged with a mixture of 5-(2-amino-5-fluoropyridin-4-yl)-7-chloro- 1H-indazol-3-amine (33 mg, 0.12 mmol, 1 eq.), (3,3-dimethylbut-1-yn-1-yl)trifluoroborate (36 mg, 0.92 mmol, 1.6 eq.), XphosG2 (4.7 mg, 0.006 mmol, 5mol%) in 1,4-dioxane (oxygen-free, 1.1 mL) was heated to 60 °C under a gentle flow of nitrogen for 5 minutes, then 2 M aq.
• reaction was then sealed and stirred at 90 °C for 18 hours.
• the cooled reaction was then diluted with EtOAc (30 mL) and washed with water (30 mL) and brine (10 mL).
• the organic layer was then concentrated under reduced pressure and purified by flash column chromatography eluting from 50 -100% petroleum ether: EtOAc to afford the desired compound as a light brown solid (0.31 g, 76 %).
• the reaction was then sealed and heated at 90 °C for 18 hours.
• the cooled reaction was diluted with EtOAc and washed with water (20 mL) and brine (10 mL).
• the organic layer was concentrated under reduced pressure and purified by flash column chromatography utilising NH silica cartridges from Biotage eluting with 50-100% petroleum ether: EtOAc followed by preparative HPLC to afford the target compound as a cream coloured powder (0.065 g. 21 %).
• Example 151 4-Iodopyridine-2,6-diamine To a solution of 2, 6-difluoro-4-iodopyridine (0.5 g, 4.77 mmol) in dioxane (5mL) was added Ammonium Hydroxide (10mL 28% in H 2 O) the reaction was the flushed with argon, sealed and stirred at 130°C for 3 hours by microwave irradiation. The reaction was cooled, partitioned between EtOAc and H 2 O and the aqueous layer washed a further 2 times with EtOAc (2 x 30 mL). The combined organic layers were washed with brine and concentrated under reduced pressure.
• Ammonium Hydroxide 10mL 28% in H 2 O
• reaction was then sealed and stirred at 90 °C for 18 hours.
• the cooled reaction was then diluted with EtOAc (30 mL) and washed with water (30 mL) and brine (10 mL).
• the organic layer was then concentrated under reduced pressure and purified by flash column chromatography NH silica cartridges from Biotage eluting from 50 -100% petroleum ether - EtOAc + 10% MeOH to afford the desired compound as a grey solid (0.487 g, 90 %).
• the reaction was then sealed and heated at 90 °C for 18 hours.
• the cooled reaction was diluted with EtOAc and washed with water (20 mL) and brine (10 mL).
• the organic layer was concentrated under reduced pressure and purified by flash column chromatography utilising NH silica cartridges from Biotage eluting with 50-100% petroleum ether - EtOAc + 10% MeOH to afford the target compound as a greyish brown solid (0.274 g, 56 %).
• Example 153 N-Cyclopropyl-4-iodopyridin-2-amine To a solution of 2-fluoro-4-iodopyridine (0.45 g, 2.02 mmol) in dioxane (5mL) was added cyclopropylamine (0.28 mL, 4.05 mmol) the reaction was the flushed with argon, sealed and stirred at 130 for 3 hours. The reaction was cooled, partitioned between EtOAc and H 2 O and the aqueous layer washed a further 2 times with EtOAc (2 x 30 mL). The combined organic layers were washed with brine and concentrated under reduced pressure.
• reaction was then sealed and stirred at 90 °C for 18 hours.
• the cooled reaction was then diluted with EtOAc (30 mL) and washed with water (30 mL) and brine (10 mL).
• the organic layer was then concentrated under reduced pressure and purified by flash column chromatography eluting from 50 -100% petroleum ether: EtOAc to afford the desired compound as a a yellow solid (0.032 g, 12 %).
• the reaction was then sealed and heated at 90 °C for 18 hours.
• the cooled reaction was diluted with EtOAc and washed with water (20 mL) and brine (10 mL).
• the organic layer was concentrated under reduced pressure and purified by HPLC to afford the target compound as a yellow (0.012 g. 4 %).
• Example 154 N-Cyclobutyl-4-iodopyridin-2-amine
• 2-fluoro-4-iodopyridine 200 mg, 0.89 mmol, 1 Eq
• cyclobutylamine 255.16 mg, 0.3 mL, 3.58 mmol, 4 Eq
• EtOAc 10 mL
• organic layer was washed with water (2 X 5 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure.
• the reaction was then sealed and heated at 90 °C for 18 hours.
• the cooled reaction was diluted with EtOAc and washed with water (20 mL) and brine (10 mL).
• the organic layer was concentrated under reduced pressure and purified by flash column chromatographyutilising NH silica cartridges from Biotage eluting with 50-100% petroleum ether: EtOAc to afford the target compound as a yellow solid (0.018 g.18 %).
• Example 157 N-(Cyclopropylmethyl)-4-iodopyridin-2-amine
• 2-fluoro-4-iodopyridine 200 mg, 0.89 mmol, 1 Eq
• cyclopropylmethylamine 126.59 mg, 0.154 mL, 1.78 mmol, 2 Eq
• EtOAc 10 mL
• the organic layer was washed with water (2 X 5 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure.
• Example 158 4-Iodo-N-(2,2,2-trifluoroethyl)pyridin-2-amine Lithium bis(trimethylsilyl)amide (1M in hexane, 4.5 mL, 4.48 mmol, 2 Eq) was added dropwise to a solution of 2,2,2-trifluoroethan-1-amine (0.33 g, 0.3 mL, 3.36 mmol, 1.5 Eq) in anhydrous THF (5 mL) at -78 oC. The reaction mixture was allowed to stir at -78 oC for 30 min.
• N 1 -(4-(3-Amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)ethane-1,2- diamine SU1698 A solution of 7-(3,3-dimethylbut-1-yn-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazol-3-amine (0.5 g, 1.47 mmol, 1 Eq), N 1 -(4-iodopyridin-2-yl)ethane-1,2-diamine (0.39 g, 1.47 mmol, 1 Eq), cesium carbonate (1.4 g, 4.41 mmol, 3 Eq) and bis(triphenylphosphine)palladium chloride (157 mg, 0.22 mmol, 0.15 Eq) in dioxane (4 mL) and water (1 mL) was stir
• Example 162 4-iodo-N-(2-methoxyethyl)pyridin-2-amine
• 2-fluoro-4-iodopyridine 200 mg, 0.89 mmol, 1 Eq
• 2-methoxyethylamine 133.69 mg, 0.155 mL, 1.78 mmol, 2 Eq
• EtOAc 10 mL
• the organic layer was washed with water (2 X 5 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure.
• Example 163 4-Iodo-N-(3-methoxypropyl)pyridin-2-amine To anhydrous THF cooled to -78 °C was added nBuLi 4.5 mL (1 eq, 1M solution in THF) followed by DIA 0.633 mL (1eq) dropwise and then a solution of 2-fluoro-3-iodopyridine (1.0 g, 4.48 mmol) slowly. The reaction was allowed to warm up to room temperature and aged for 30 minutes at this temperature before cooling back down to -78 °C and quenching by pouring over ice: H2O (20 mL).
• the reaction was then sealed and heated at 90 °C for 18 hours.
• the cooled reaction was diluted with EtOAc and washed with water (20 mL) and brine (10 mL).
• the organic layer was concentrated under reduced pressure and purified by flash column chromatographyutilising NH silica cartridges from Biotage eluting with 50-100% petroleum ether: EtOAc to afford the target compound as a yellow solid (0.044 g. 25 %).
• Acetyl Chloride (0.18 g, 0.16 mmol) was then added dropwise and the resulting reaction mixture allowed to warm up to room temperature and stirred at this temperature for 3 hours. The reaction was then quenched by pouring over ice/water 20 mL, extracted with EtOAc (3 x 30 mL) and washed with brine (10 mL). The combined organic layers were concentrated and purified by flash eluting with a gradient of EtOAc:Petroleum Ether (50-100%) to afford the target compound as an off white solid ( 0.40 g, 67%).
• the reaction was then sealed and heated at 90 °C for 18 hours.
• the cooled reaction was diluted with EtOAc and washed with water (20 mL) and brine (10 mL).
• the organic layer was concentrated under reduced pressure and purified by flash column chromatography utilising NH silica cartridges from Biotage eluting with 50-100% petroleum ether: EtOAc (plus NH3 in MeOH 7M) (50-100%) to afford the target compound as a cream coloured solid (0.38 g. 76 %).
• Example 165 N-(4-Iodopyridin-2-yl)propionamide
• 4-iodopyridin-2-amine 500 mg, 2.27 mmol, 1 Eq
• triethylamine 1.38 g, 2 mL, 13.65 mmol, 1 Eq
• propionyl chloride 252.02 mg, 0.238 mL, 2.72 mmol, 1.2 Eq
• N-(4-(3-Amino-7-bromo-1H-indazol-5-yl)pyridin-2-yl)propionamide To a solution of 7-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (472.2 mg, 1.39 mmol, 1.1 Eq) in a degassed 9:1 solution of dioxane/water (5 mL), were added N-(4-iodopyridin-2-yl)propionamide (350 mg, 1.27 mmol, 1 Eq), cesium carbonate (1.241 g, 3.81 mmol, 3 Eq) and bis(triphenylphosphine)palladium chloride (89.14 mg, 0.127 mmol, 0.1 Eq) under argon atmosphere.
• N-(4-(3-Amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)propionamide 250 mg, 0.694 mmol, 1 Eq
• N-(4-(3-amino-7-bromo-1H-indazol-5-yl)pyridin-2-yl)propionamide 250 mg, 0.694 mmol, 1 Eq
• copper(I) iodide 26.43 mg, 0.138 mmol, 0.2 Eq
• [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst 50.78 mg, 0.069 mmol, 0.1 Eq
• 3,3-dimethylbut-1-yne 85.50 mg, 0.128 mL, 1.041 mmol, 1.5 Eq
• the reaction mixture was allowed to stir at 50 oC for 18 h.
• the reaction mixture was extracted between EtOAc (10 mL) and water (5 mL).
• the organic layer was washed with brine (2 ⁇ 5 mL), dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure.
• the crude residue was purified using column chromatography (90% EtOAc in petroleum ether) to give the titled product as yellow solid (0.3 g, 0.6 mmol, 60%).
• tert-Butyl(tert-butoxycarbonyl)(7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-(3,3,3- trifluoropropanamido)pyridin-4-yl)-1H-indazol-3-yl)carbamate A solution of tert-butyl(5-(2-aminopyridin-4-yl)-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-3- yl)(tert-butoxycarbonyl)carbamate (0.5 g, 0.6 mmol, 1 Eq), (1-[bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (274 mg, 0.72 mmol, 1.2 Eq), N,N-diisopropylethylamine (155 mg, 0.2 mL,
• Trifluoroacetic acid (1.49 g, 1 mL, 13.1 mmol, 82 Eq) was added to a solution of tert-butyl(tert- butoxycarbonyl)(7-(3,3-dimethylbut-1-yn-1-yl)-5-(2-(3,3,3-trifluoropropanamido)pyridin-4-yl)-1H- indazol-3-yl)carbamate (100 mg, 0.16 mmol, 1 Eq) in DCM (4 mL) at 0 oC.
• N-(4-(3-Amino-7-bromo-1H-indazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide To a solution of 7-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (796.30 mg, 2.35 mmol, 1.1 Eq) in a degassed 9:1 solution of dioxane/water (5 mL), were added N-(4-iodopyridin-2-yl)cyclopropanecarboxamide (617 mg, 2.14 mmol, 1 Eq), cesium carbonate (2.09 g, 6.42 mmol, 3 Eq) and bis(triphenylphosphine)palladium chloride (150.32 mg, 0.214 mmol, 0.1 Eq) under argon atmosphere.
• N-(4-(3-Amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)cyclopropane carboxamide 200 mg, 0.53 mmol, 1 Eq
• N-(4-(3-amino-7-bromo-1H-indazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide 200 mg, 0.53 mmol, 1 Eq
• copper(I) iodide (20.46 mg, 0.11 mmol, 0.2 Eq)
• [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst 39.31 mg, 0.053 mmol, 0.1 Eq
• 3,3-dimethylbut-1-yne 66.20 mg, 0.099 mL, 0.80 mmol, 1.5
• Example 168 tert-Butyl (4-iodopyridin-2-yl)carbamate To a solution of 4-iodopyridin-2-amine (2.7 g 12.27 mmol) in dioxane (10 mL) was added DMAP (1.79 g, 14.72 mmol) under a blanket of argon followed by Boc 2 O (2.812 g, 12.88 mmol). The resulting reaction mixture was stirred at 80 °C for 12 hours. The reaction was then cooled and quenched by pouring into water 20 mL, extracted with EtOAc (3 x 30 mL) and washed with brine (10 mL).
• reaction was then sealed and stirred at 90 °C for 18 hours.
• the cooled reaction was then diluted with EtOAc (30 mL) and washed with water (30 mL) and brine (10 mL).
• the organic layer was then concentrated under reduced pressure and the crude product used directly in the subsequent reaction.
• N-(4-(3-amino-7-bromo-1H-indazol-5-yl)pyridin-2-yl)isobutyramide was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst (0.089 g, 0.121 mmol) and 3,3- dimethylbut-1-yne (0.099 g, 0.146 mL, 1.21 mmol), under an atmosphere of argon.
• the reaction was then sealed and heated at 90 °C for 18 hours.
• the cooled reaction was diluted with EtOAc and washed with water (20 mL) and brine (10 mL).
• the organic layer was concentrated under reduced pressure and purified by flash column chromatographyutilising NH silica cartridges from Biotage eluting with 50-100% petroleum ether: EtOAc to afford the target compound as a yellow (0.035 g.8 % over two steps).
• reaction was then sealed and stirred at 90 °C for 18 hours.
• the cooled reaction was then diluted with EtOAc (30 mL) and washed with water (30 mL) and brine (10 mL).
• the organic layer was then concentrated under reduced pressure and the crude product used directly in the subsequent reaction.
• N-(4-(3-Amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2-yl)pivalamide To a solution of N-(4-(3-amino-7-bromo-1H-indazol-5-yl)pyridin-2-yl)pivalamide in a degassed 4:1 solution of DMF:triethylamine (5 mL) was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst (0.0674 g, 0.092 mmol) copper iodide (0.035 g, 0.184 mmol) and 3,3-dimethylbut-1-yne (0.0756 g, 0.113 mL, 0.921 mmol), under an atmosphere of argon.
• the reaction was then sealed and heated at 90 °C for 18 hours.
• the cooled reaction was diluted with EtOAc and washed with water (20 mL) and brine (10 mL).
• the organic layer was concentrated under reduced pressure and purified by flash column chromatographyutilising NH silica cartridges from Biotage eluting with 50-100% petroleum ether: EtOAc to afford the target compound as a yellow solid (0.014 g, 4 % over two steps).
• Example 171 N-(4-Iodopyridin-2-yl)-3-methylbutanamide To a solution of tert-butyl (4-iodopyridin-2-yl)carbamate (0.5 g, 1.56 mmol) in dioxane (2 mL) was added NaHMDS (1.2 eq, 1M solution in THF) at 0 °C under a blanket of argon followed by 3-methylbutyryl chloride (0.207 g, 0.213 mL 1.716 mmol) and the resulting reaction mixture allowed to warm up to room temperature and stirred at this temperature for 12 hours.
• NaHMDS 1.2 eq, 1M solution in THF
• reaction was then sealed and stirred at 90 °C for 18 hours.
• the cooled reaction was then diluted with EtOAc (30 mL) and washed with water (30 mL) and brine (10 mL).
• the organic layer was then concentrated under reduced pressure and the crude product used directly in the subsequent reaction.
• N-(4-(3-amino-7-bromo-1H-indazol-5-yl)pyridin-2-yl)-3-methylbutanamide was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst (0.07697 g, 0.1052 mmol) and 3,3-dimethylbut-1-yne (0.0864 g, 0.129 mL, 1.052 mmol), under an atmosphere of argon.
• the reaction was then sealed and heated at 90 °C for 18 hours.
• the cooled reaction was diluted with EtOAc and washed with water (20 mL) and brine (10 mL).
• the organic layer was concentrated under reduced pressure and purified by flash column chromatographyutilising NH silica cartridges from Biotage eluting with 50-100% petroleum ether: EtOAc to afford the target compound as a yellow (0.013 g. 3% over two steps).
• N-(4-(3-Amino-7-bromo-1H-indazol-5-yl)pyridin-2-yl)cyclobutanecarboxamide To a solution of 7-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (615.35 mg, 1.82 mmol, 1.1 Eq) in a degassed 9:1 solution of dioxane/water (5 mL), were added N-(4-iodopyridin-2-yl)cyclopropanecarboxamide (500 mg, 1.65 mmol, 1 Eq), cesium carbonate (1.61 g, 4.95 mmol, 3 Eq) and bis(triphenylphosphine)palladium chloride (115.81 mg, 0.165 mmol, 0.1 Eq) under argon atmosphere.
• N-(4-(3-Amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2- yl)cyclobutanecarboxamide 300 mg, 0.776 mmol, 1 Eq
• N-(4-(3-amino-7-bromo-1H-indazol-5-yl)pyridin-2-yl)cyclobutanecarboxamide 300 mg, 0.776 mmol, 1 Eq
• copper(I) iodide 29.58 mg, 0.155 mmol, 0.2 Eq
• [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst 56.34 mg, 0.077 mmol, 0.1 Eq
• 3,3-dimethylbut-1-yne 95.61 mg, 0.143 mL, 1.164 mmol
• Example 173 N-(4-Iodopyridin-2-yl)cyclopentanecarboxamide To a solution of tert-butyl (4-iodopyridin-2-yl)carbamate (0.5 g, 1.56 mmol) in dioxane (2 mL) was added NaHMDS (1.2 eq, 1M solution in THF) at 0 °C under a blanket of argon followed by cyclopentanoyl chloride (0.2275 g, 1.716 mmol) and the resulting reaction mixture allowed to warm up to room temperature and stirred at this temperature for 12 hours.
• NaHMDS 1.2 eq, 1M solution in THF
• reaction was then sealed and stirred at 90 °C for 18 hours.
• the cooled reaction was then diluted with EtOAc (30 mL) and washed with water (30 mL) and brine (10 mL).
• the organic layer was then concentrated under reduced pressure and the crude product used directly in the subsequent reaction.
• N-(4-(3-Amino-7-(3,3-dimethylbut-1-yn-1-yl)-1H-indazol-5-yl)pyridin-2- yl)cyclopentanecarboxamide To a solution of N-(4-(3-amino-7-bromo-1H-indazol-5-yl)pyridin-2-yl)cyclopentanecarboxamide in a degassed 4:1 solution of DMF:triethylamine (5 mL) was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst (0.067 g, 0.0917 mmol) copper iodide (0.0349 g, 0.1834 mmol) and 3,3-dimethylbut-1-yne (0.0753 g, 0.917 mmol), under an atmosphere of argon.
• the reaction was then sealed and heated at 90 °C for 18 hours.
• the cooled reaction was diluted with EtOAc and washed with water (20 mL) and brine (10 mL).
• the organic layer was concentrated under reduced pressure and purified by flash column chromatographyutilising NH silica cartridges from Biotage eluting with 50-100% petroleum ether: EtOAc to afford the target compound as a yellow solid (0.018 g.5 %).
• the reaction mixture was allowed to stir at 60 oC for 18 h.
• the reaction mixture was extracted between EtOAc (10 mL) and water (5 mL).
• the organic layer was washed with brine (2 ⁇ 5 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure.
• the crude residue was purified using column chromatography (90% EtOAc in petroleum ether) to give the titled product as green solid (0.2 g, 0.49 mmol, 40%).

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