WO2013005057A1

WO2013005057A1 - New compounds

Info

Publication number: WO2013005057A1
Application number: PCT/GB2012/051606
Authority: WO
Inventors: Joaquín PASTOR FERNÁNDEZ; Sonia MARTÍNEZ GONZÁLEZ; Carmen BLANCO-APARICIO; Sonsóles RODRÍGUEZ-ARÍSTEGUI; Cristina Ana GÓMEZ DE LA OLIVA; Ana Isabel HERNÁNDEZ HIGUERAS; Esther GONZÁLEZ CANTALAPIEDRA; Nuria AJENJO DÍEZ
Original assignee: Centro Nacional De Investigaciones Oncológicas (Cnio)
Priority date: 2011-07-07
Filing date: 2012-07-06
Publication date: 2013-01-10

Abstract

There is provided compounds of formula I,wherein R¹ R², X, R³, X¹, X², X^a, X^b, X^c, X^d, X^f, X⁹ and R⁴have meanings given in the description (and which compounds are optionally substituted as indicated in the description), and pharmaceutically-acceptable esters, amides, solvates or salts thereof, which compounds are useful in the treatment of diseases in which inhibition of a protein or lipid kinase (e.g. a PIM family kinase, such as PIM-1, PIM-2 and/or PIM-3) is desired and/or required, and particularly in the treatment of cancer or a proliferative disease. There is also provided combinations comprising the compounds of formula I.

Description

NEW COMPOUNDS

Field of the Invention

This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of protein or lipid kinases (such as inhibitors of a member of the PIM family kinases, e.g. PIM-1 , PIM-2 or PIM-3). The invention also relates to the use of such compounds as medicaments, to the use of such compounds for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells (or associated pathological conditions), to pharmaceutical compositions containing them, and to synthetic routes for their production.

Background of the Invention

The malfunctioning of protein kinases (PKs) is the hallmark of numerous diseases. A large share of the oncogenes and proto-oncogenes involved in human cancers code for PKs. The enhanced activities of PKs are also implicated in many non-malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis. PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.

For a general reference to PKs malfunctioning or disregulation see, for instance, Current Opinion in Chemical Biology 1999, 3, 459 - 465. PIM-1 is the protooncogene activated by murine leucemia virus (Provirus Integration site for Moloney murine leucemia virus - MoMuLV) that induces T-cell lymphoma [Cuypers, H.T., et. al. Cell, 1984, 37, 141-150].

The expression of the protooncogene produces a non-transmembrane serine/threonine kinase of 313 residues, including a kinase domain consisting of 253 amino acid residues. Two isoforms are known through alternative initiation (p44 and p33) [Saris, C.J.M. et al. EMBO J. 1991, 10, 655-664].

PIM-1 , PIM-2 and PIM-3 phosphorylate protein substrates that are important in cancer neogenesis and progression. For example, PIM-1 phosphorylates inter alia p21, Bad, c-myb, Cdc 25A and elF4B (see e.g. Quian, K. C. et al, J. Biol. Chem. 2005, 280(7), 6130-6137, and references cited therein).

Two PIM-1 homologs have been described [Baytel, D. Biochem. Biophys. Acta 1998, 1442, 274-285; Feldman, J. et al. J. Biol. Chem. 1998, 273, 16535.16543]. PIM-2 and PIM-3 are respectively 58% and 69% identical to PIM-1 at the amino acid level. PIM-1 is mainly expressed in thymus, testis, and cells of the hematopoietic system [Mikkers, H.; Nawijn, M.; Allen, J.; Brouwers, C; Verhoeven, E.; Jonkers, J.; Berns, Mol. Cell. Biol. 2004, 24, 6104; Bachmann, M.; Moroy, T. Int. J. Biochem. Cell Biol. 2005, 37, 726-730. 6115]. PIM-1 expression is directly induced by STAT (Signal Transducers and Activators of Transcription) transcription factors, and PIM-1 expression is induced by many cytokine signalling pathways such as interleukins (IL), granulocyte-macrophage colony stimulating factor (GM-CSF), a- and γ-interferon, erythropoietin, and prolactin [Wang, Z et al.. J. Vet. Sci. 2001, 2, 167-179].

PIM-1 has been implicated in lymphoma development. Induced expression of PIM-1 and the protooncogene c-myc synergise to increase the incidence of lymphomagenesis [Breuer, M. et al. Nature 1989, 340, 61-63; van Lohuizen M. et al. Cell, 1991 , 65, 737-752]. PIM-1 functions in cytokine signalling pathways and has been shown to play a role in T cell development [Schmidt, T. et al. EMBO J. 1998, 17, 5349-5359; Jacobs, H. et al. JEM 1999, 190, 1059-1068]. Signalling through gp130, a subunit common to receptors of the IL-6 cytokine family, activates the transcription factor STAT3 and can lead to the proliferation of hematopioetic cells [Hirano, T. et al. Oncogene 2000, 19, 2548-2556]. A kinase- active PIM-1 appears to be essential for the gp130-mediated STAT3 proliferation signal. In cooperation with the c-myc PIM-1 can promote STAT3-mediated cell cycle progression and antiapoptosis [Shirogane, T. et si., immunity, 1999, 11 , 709-719]. PIM-1 also appears to be necessary for IL-3-stimulated growth in bone marrow-derived mast cells [Domen, J. et al., Blood, 1993, 82, 1445-1452] and survival of FDCP1 cells after IL-3 withdrawal [Lilly, M. et al., Oncogene, 1999, 18, 4022-4031].

Additionally, control of cell proliferation and survival by PIM-1 may be effected by means of its phosphorylation of the well-established cell cycle regulators cdc25 [Mochizuki, T. et al., J. Biol. Chem. 1999, 274, 18659-18666] and/or p21(Cip1/WAF1) [Wang Z. et al. Biochim. Biophys. Acta 2002, 1593, 45-55] or phosphorylation of heterochromatin protein 1 , a molecule involved in chromatin structure and transcriptional regulation [Koike, N. et al, FEBS Lett. 2000, 467, 17- 21].

Mice deficient for all three PIM genes showed an impaired response to hematopoietic growth factors and demonstrated that PIM proteins are required for efficient proliferation of peripheral T lymphocyes. In particular, it was shown that PIM function is required for efficient cell cycle induction of T cells in response to synergistic T-cell receptor and IL-2 signalling. A large number of interaction partners and substrates of PIM-1 have been identified, suggesting a pivotal role for PIM-1 in cell cycle control, proliferation, as well as in cell survival. The oncogenic potential of this kinase has been first demonstrated in E μ PIM-1 transgenic mice in which PIM-1 over-expression is targeted to the B-cell lineage which leads to formation of B-cell tumors [van Lohuizen, M.et al.; Cell 1989, 56, 673-682. Subsequently PIM-1 has been reported to be over-expressed in a number of prostate cancers, erythroleukemias, and several other types of human leukemias [Roh, M. et al., Cancer Res. 2003, 63, 8079-8084; Valdman, A. et al., Prostate 2004, 60, 367-371 ;

For example, chromosomal translocation of PIM-1 leads to overexpression of PIM-1 in diffuse large cell lymphoma. [Akasaka, H.et al.; Cancer Res. 2000, 60, 2335-2341]. Furthermore, a number of missense mutations in PIM-1 have been reported in lymphomas of the nervous system and AIDS-induced non-Hodgkins' lymphomas that probably affect PIM-1 kinase activity or stability [Pasqualucci, L. et al, Nature 2001, 412, 341-346; Montesinos-Rongen, M. et al., Blood 2004, 103, 1869-1875; Gaidano, G. et al., Blood 2003, 102, 1833-184]. Thus, the strong linkage between reported overexpression data and the occurrence of PIM-1 mutations in cancer suggests a dominant role of PIM-1 in tumorigenesis.

Several other protein kinases have been described in the literature, in which the activity and/or elevated activity of such protein kinases have been implicated in diseases such as cancer, in a similar manner to PIM-1, PIM-2 and PIM-3.

It has also been reported that PIM-1 has a role in pulmonary artery hypertension (PAH), see the journal article by Paulin et al, "Singal transducers and activators of transcription-3/PIM-1 axis plays a critical role in the pathogenesis of human pulmonary arterial hypertension".

There is a constant need to provide alternative and/or more efficacious inhibitors of protein kinases, and particularly inhibitors of PIM-1 , PIM-2 and/or PIM-3. Such modulators are expected to offer alternative and/or improved approaches for the management of medical conditions associated with activity and/or elevated activity of PIM-1 , PIM-2 and/or PIM-3 protein kinases.

For the treatment of cancer, targeted therapies are becoming more important. That is, therapy that has the effect of interfering with specific target molecules that are linked to tumor growth and/or carcinogenesis. Such therapy may be more effective than current treatments (e.g. chemotherapy) and less harmful to normal cells (e.g. because chemotherapy has the potential to kill normal cells as well as cancerous cells). This, and also the fact that targeted therapies may be selective (i.e. it may inhibit a certain targeted molecule more selectively as compared to other molecular targets, e.g. as described hereinafter), may have the benefit of reducing side effects and may also have the benefit that certain specific cancers can be treated (also selectively). The latter may in turn also reduce side effects.

Hence, it is a clear goal of current oncologists to develop targeted therapies (e.g. ones that are selective). In this respect, it should be pointed out that several different molecular targets may exist that are linked to certain diseases (e.g. cancer). However, one simply cannot predict if a therapy (e.g. a small molecule as a therapeutic) that interferes with or inhibits one target molecule could inhibit a different molecular target (be it one that will ultimately have the effect of treating the same disease or a different one).

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

Journal articles J. Med. Chem. 2005, 48, 1367-1383 by Russell ef al and J. Med. Chem. 2005, Vol 48, No. 23, 7089 by Carling et al both disclose inter alia triazolophthalazine compounds of potential use as GABA_A receptor agonists, which may be useful therefore as inter alia hypnotics (and therefore for treating sleep disorders) and muscle relaxants. However, these documents only relate to fused tricyclic compounds in which one of the cyclic moieties is bridged. Further, there is no mention that the compounds disclosed therein may be useful as kinase inhibitors.

International patent application WO 2005/041971 discloses inter alia fused tricyclic compounds that may bind to of α₂δ-1 sub-units of Ca channels, and may therefore be useful in the treatment of inter alia psychiatric and mood disorders. International patent applications WO 99/025353 and WO 98/04559 disclose various compounds that may act as ligands for GABA_A receptors, WO 98/04560 discloses those that may act as inverse agonists of GABA_A receptors, UK patent GB 2345443 discloses inter alia tricyclic compounds, which may be of use in treating premenstrual syndrome, and international patent application WO 2005/041971 discloses various tricyclic compounds for use in the treatment of bipolar diseases and the like. All of these documents only disclose fused tricyclic compounds that necessarily have oxy substituents, and do not disclose the use of those compounds as kinase inhibitors. US patent application US 5,011 ,835 discloses inter alia fused tricyclic compounds that may be useful as bronchodilators and antiallergic agents, but does not disclose tricyclic compounds that are substituted with an aromatic substituent, nor does it mention that the compounds may be useful as kinase inhibitors. European patents EP 0 104 506 and EP 0 029 130 both disclose inter alia tricyclic compounds that may be useful as bronchodilators, but does not disclose any that bear an aromatic substituent, nor does it disclose the potential use of those compounds as kinase inhibitors.

Journal article J. Het. Chem. 1988, 25(2), 393-8 by Branko et a/ discloses various tricyclic compounds, including those that contain an aromatic triazolopyridazine bicycle as an integral part of the tricycle. However, this journal article does not disclose that those compounds have a medical use, and further only discloses tricycles in which the 'third' ring fused to the triazolopyridazine bicycle contains an unsaturation (double bond).

European patent applications EP 0 548 923 and EP 0 562 439 disclose inter alia tricyclic compounds containing an aromatic imidazopyridazine bicyclic core or a [1 ,2,4]triazolo[1 ,5-b]pyridazine core. However, it does not disclose any tricyclic compounds containing a [1 ,2,4]triazolo[4,3-b]pyridazine core, nor does it mention that any of the compounds disclosed therein may be useful as kinase inhibitors.

European patent application EP 0 620 224 discloses inter alia [1,2,4]triazolo[4,3- b]pyridazines, but none in which such a bicycle is a sub-component of a fused tricyclic compound. Nor does this document disclose that the compounds therein may be useful as kinase inhibitors.

US patent application US 2003/0078277 discloses tricyclic compounds that may be useful as a corticotrophin, and therefore of use in the treatment of e.g. depression. However, this document does not primiarly relate to [1 ,2,4]triazolo[4,3-b]pyridazines, nor does it disclose that the compounds therein may be useful as kinase inhibitors. US patent application US 2007/0167453 discloses inter alia tricyclic compounds that may be useful as histamine-H3 receptor antagonists. However, this document does not specifically relate to [1,2,4]triazolo[4,3-b]pyridazines substituted with an amino moiety and an aromatic group. Further, this document does not mention that the compounds disclosed therein may be useful as kinase inhibitors. International patent application WO 99/06404 discloses various fused tricyclic compounds containing a triazolopyridazine core, for use as phosphodiesterase 4 inhibitors. However, this document only relates to fused tricyclic compounds in which each of the three rings is aromatic.

International patent application WO 2008/109104 discloses various triazolopyridazines for use as Akt kinase inhibitors, but this document does not disclose any fused tricyclic compounds.

International patent applications WO 2009/060197 and WO 2009/040552 disclose various imidazopyridazine-based and imidazolothiadiazolo-based compounds, for use as certain protein kinase inhibitors. However, these documents do not mention fused tricyclic compounds containing a bicyclic aromatic triazolopyridazine core fused to a non-aromatic ring.

Unpublished international patent application PCT/GB2010/002348 and unpublished European patent application EP 11382011.2 both disclose various tricyclic compounds for use as certain kinase inhibitors. However, neither of these documents specifically relates to compounds in which there is a quinolinyl (or variant) attached to the core tricyclic template. Further, these documents are also all substituted by an amino group.

International patent applications WO 2010/039825, WO 2010/022081 , WO 2010/022076, WO 2008/124323, WO 2008/121687 and US patent application US 2010/0144751 all disclose various compounds for use as medicaments, which compounds contain bicyclic moieties linked to other bicyclic moieties.

Disclosure of the Invention

According to the invention, there is now provided a compound of formula I,

wherein:

X¹ represents =N- or =C(R⁵)-;

R⁵ represents hydrogen, halo or C_1-3 alkyl optionally substituted by one or more substituents selected from fluoro and -CN;

X² represents =N- or =C(H)-;

X^a, X^b, X^c, X^d, X^f and X⁹ independently represent -C(R⁷)=, or, any one or two of X^a, X^b, X^c, X^d, X^f or X^g may represent -N=; each R⁷ independently represents hydrogen or a substituent selected from -F, -CI, -Br, -CN, -CH₂OH, C_1-3 alkyl (optionally substituted by one or more fluoro atoms) and -0-C_1-3 alkyl (optionally substituted by one or more fluoro atoms); the R¹, R² and X-containing ring is non-aromatic in which: R¹ and R² are independently selected from -0-, -S-, -S(O)-, -S(0)₂-, -C(R⁶)(R^6a)- and -N(R⁶)-; and

X represents C _-3 alkylene optionally substituted by one or more substituents selected from E²; each R⁶ and R^6a independently represents, on each occasion when used herein, H, -C(0)NHR^d1, -C(0)R^d2 or R^d3; R^d1, R and R independently represent C _-12 (e.g. C_1-6) alkyl optionally substituted by one or more substituents selected from E¹; R³ represents hydrogen or a substituent selected from -CI, -CN, -OH, -OCH₃ and C1-3 alkyl optionally substituted by one or more fluoro atoms;

R⁴ represents: -0-C_1-6alkyl-OCH₃; -0-C_1-6alkyl-NH₂; -0-C_1-6alkyl-N(H)(CH₃); -[0]o-i-(CH₂)_ni-heterocycloalkyl (in which n1 is 0, 1 , 2 or 3; and heterocycloalkyl is optionally substituted by one or more substituents selected from Q¹); -C(0)-[fragment IA]; -N(R^4a)-C(0)-R ^b; -(CH₂)_m-[fragment IA] (in which m represents 1 or 2); -(CH₂)_n2-OR^4c (in which n2 represents 0, 1 or 2); aryl (optionally substituted by one or more substitutents selected from E³); heteroaryl (optionally substituted by one or more substitutents selected from E³); or a fragment of formula IA;

R^4a represents hydrogen or C_1-6 alkyl optionally substituted by one or more substituents selected from halo; R^4b represents C_1-6 alkyl, heterocycloalkyl, aryl or heteroaryl (which latter four groups are optionally substituted by one or more substitutents selected from halo, C _-3 alkyl and -OC _-3 alkyl);

R^4c represents hydrogen, C_1-6 alkyl, heterocycloalkyl, aryl or heteroaryl (which latter four groups are optionally substituted by one or more substitutents selected from halo, C_1-3 alkyl and -OC_1-3 alkyl); each fragment of formula IA independently represents:

in which R^a and R^b independently represent H, -Z^1a-C_1-12 (e.g. C_1-8) alkyl, -Z^1b-heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =NOR^7a and Q¹), -Z^1c-aryl or -Z^1d-heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Q²); or R^a and R^b are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a (first) 3- to 7-membered cyclic group, optionally containing one further heteroatom selected from nitrogen, sulfur and oxygen, and which ring optionally:

(a) is fused to a second ring that is either a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen (preferably oxygen and nitrogen), a 3- to 12- membered saturated carbocyclic ring, or an unsaturated 5- to 12- membered carbocyclic or heterocyclic ring (in which the heteroatoms are preferably selected from sulfur and, especially, nitrogen and oxygen);

(b) comprises a linker group -(C(R^X)₂)_P- and/or -(C(R^x)₂)r-0-(C(R^x)₂)s- (wherein p is 1 or 2; r is 0 or 1 ; s is 0 or 1 ; and each R^x independently represents hydrogen or C_1-6 alkyl), linking together any two non-adjacent atoms of the first 3- to 7-membered ring (i.e. forming a bridged structure); or

(c) comprises a second ring that is either a 3- to 12-membered saturated carbocyclic ring or a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen and nitrogen, and which second ring is linked together with the first ring via a single carbon atom common to both rings (i.e. forming a spiro-cycle), all of which cyclic groups, defined by the linkage of R^a and R^b, are optionally substituted by one or more substituents selected from =0, =NOR^7b and E⁴; Z^1a, Z^1b, Z ^c and Z^1d independently represent a direct bond, -C(O)- or -S(0)₂-; each Q and Q² independently represents, on each occasion when used herein: halo, -CN, -N0₂, -N(R^10a)R^11a, -OR ^0a, -C(=Y)-R ^0a, -C(=Y)-OR^10a, -C(=Y)N(R ^0a)R^11a, -C(=Y)N(R^10a)-OR^11c, -OC(=Y)-R^10a, -OC(=Y)-OR^10a, -OC(=Y)N(R^10a)R^11a, -OS(O)₂OR^10a, -OP(=Y)(OR^10a)(OR^11a), -OP(OR^10a)(OR^11a), -N(R ^2a)C(=Y)R ^1a, -N(R ^2a)C(=Y)OR^11a, -N(R^12a)C(=Y)N(R^10a)R^{1 a},

-NR^12aS(O)₂R^10a, -NR^12aS(O)₂N(R^10a)R^{1 a}, -S(O)₂N(R^10a)R^11a, -SC(=Y)R^10a, -S(O)₂R^10a, -SR^10a, -S(O)R^10a, d.i2 alkyl, heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R^10a) and E⁵), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E⁶);

R^7a and R^7b independently represent hydrogen or C_1-6 alkyl optionally substituted by one or more fluoro atoms; each R ^1c independently represents, on each occasion when used herein, C_1-12 alkyl, heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R²⁰) and E⁷), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E⁸); each R^10a, R^11a and R^12a independently represent, on each occasion when used herein, hydrogen, C_1-12 alkyl, heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R²⁰) and E⁷), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E⁸); or any relevant pair of R ^0a, R^11a and R ^2a (for example, when attached to the same atom, adjacent atom (i.e. 1 ,2-relationship) or to atoms that are two atoms apart, i.e. in a 1 ,3-relationship) may be linked together to form (e.g. along with the requisite nitrogen atom to which they may be attached) a 4- to 20- (e.g. 4- to 12-) membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, e.g. (a) heteroatom(s) selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (e.g. double bonds), and which ring is optionally substituted by one or more substituents selected from =0, =S, =N(R²⁰) and E⁹; each E¹, E², E³, E⁴, E⁵, E⁶, E⁷, E⁸ and E⁹ independently represents, on each occasion when used herein:

(i) Q⁴; (ii) Ci-12 alkyl optionally substituted by one or more substituents selected from =0 and Q⁵; or any two E , E², E³, E⁴, E⁵, E⁶, E⁷, E⁸ or E⁹ groups, for example on C_1-12 alkyl groups or on aryl groups, e.g. when they are attached to the same or adjacent carbon atoms (e.g. two E³ groups may be attached to adjacent carbon atoms of an aryl group, so forming a fused bicycle), may be linked together to form a 3- to 12-membered ring (in which each of the atoms of the ring may be a carbon atom or a heteroatom), optionally containing one or more (e.g. one to three) unsaturations (e.g. double bonds), and which ring is optionally substituted by one or more substituents selected from =0 and J¹; each Q⁴ and Q⁵ independently represent, on each occasion when used herein: halo, -CN, -N0₂, -N(R²⁰)R²¹, -OR²⁰, -C(=Y)-R²⁰, -C(=Y)-OR²⁰, -C(=Y)N(R²⁰)R²¹, -C(=Y)N(R²⁰)-O-R^21a, -OC(=Y)-R²⁰, -OC(=Y)-OR²⁰, -OC(=Y)N(R²⁰)R²¹, -OS(0)₂OR²⁰, -OP(=Y)(OR²⁰)(OR²¹), -OP(OR²⁰)(OR²¹), -N(R²²)C(=Y)R²¹, -N(R²²)C(=Y)OR²¹, -N(R²²)C(=Y)N(R²⁰)R²¹, -NR^SiO^R²⁰, -NR²²S(O)₂N(R ⁰)R²¹, -S(O)₂N(R²⁰)R²¹, -SC(=Y)R²⁰, -S(0)₂R²°, -SR²⁰, -S(0)R²⁰, C_1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and J²), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from

J³); each Y independently represents, on each occasion when used herein, =0, =S, =NR²³ or =N-CN; each R^{2 a} independently represents, on each occasion when used herein, Ci_-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J⁴ and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J⁵); each R²⁰, R²¹, R²² and R²³ independently represent, on each occasion when used herein, hydrogen, C _-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J⁴ and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J⁵); or any relevant pair of R²⁰, R²¹ and R²², may (for example, when attached to the same atom, adjacent atom (i.e. 1 ,2-relationship) or to atoms that are two atoms apart, i.e. in a 1 ,3-relationship) be linked together to form (e.g. along with the requisite nitrogen atom to which they may be attached) a 4- to 20- (e.g. 4- to 12-) membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, e.g. (a) heteroatom(s) selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (e.g. double bonds), and which ring is optionally substituted by one or more substituents selected from J⁶ and =0; each J¹, J², J³, J⁴, J⁵ and J⁶ independently represents, on each occasion when used herein:

(i) Q⁷;

(ii) aryl, C_1-6 alkyl or heterocycloalkyl, both of which latter two groups are optionally substituted by one or more substituents selected from =0 and Q⁸; each Q⁷ and Q⁸ independently represents, on each occasion when used herein: halo, -N(R⁵⁰)R⁵¹, -OR⁵⁰, -C(=Y^a)-R⁵⁰, -C(=Y^a)-OR⁵⁰, -C(=Y^a)N(R⁵⁰)R⁵¹, -N(R⁵²)C(=Y^a)R⁵¹, -NR⁵²S(0)₂R⁵⁰, -S(0)₂R⁵°, -SR⁵⁰, -S(0)R⁵⁰ or C_1-6 alkyl optionally substituted by one or more fluoro atoms; each Y^a independently represents, on each occasion when used herein, =0, =S, =NR⁵³ or =N-CN; each R⁵⁰, R⁵ , R⁵² and R⁵³ independently represents, on each occasion when used herein, hydrogen or C_1-6 alkyl optionally substituted by one or more substituents selected from fluoro, -OR⁶⁰ and -N(R⁶¹)R⁶²; or

any relevant pair of R⁵⁰, R⁵¹ and R⁵² may (for example when attached to the same or adjacent atoms) be linked together to form, a 3- to 8-membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, heteroatoms selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (e.g. double bonds), and which ring is optionally substituted by one or more substituents selected from =0 and C_1-3 alkyl;

_R6o _R6i _anc| _R62 independently represent hydrogen or C_1-6 alkyl optionally substituted by one or more fluoro atoms, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, which compounds, esters, amides, solvates and salts are referred to hereinafter as "the compounds of the invention".

Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

By "pharmaceutically acceptable ester, amide, solvate or salt thereof, we include salts of pharmaceutically acceptable esters or amides, and solvates of pharmaceutically acceptable esters, amides or salts. For instance, pharmaceutically acceptable esters and amides such as those defined herein may be mentioned, as well as pharmaceutically acceptable solvates or salts. Specific salts that may be mentioned include HCOOH and HCI salts. Oxide salts, such as N-oxides (e.g. in which there is a "N⁺-0 " moiety present) may also be mentioned (for instance, when the nitrogen atom is an integral part of the compound of the invention).

Pharmaceutically acceptable esters and amides of the compounds of the invention are also included within the scope of the invention. Pharmaceutically acceptable esters and amides of compounds of the invention may be formed from corresponding compounds that have an appropriate group, for example an acid group, converted to the appropriate ester or amide. For example, pharmaceutically acceptable esters (of carboxylic acids of compounds of the invention) that may be mentioned include optionally substituted C_1-6 alkyl, C_5-10 aryl and/or C_5-io aryl-C_1-6 alkyl- esters. Pharmaceutically acceptable amides (of carboxylic acids of compounds of the invention) that may be mentioned include those of the formula -CiOJNfR^R²², in which R^z1 and R²² independently represent optionally substituted C _-6 alkyl, C^o aryl, or C_5-10 aryl-C_1-6 alkylene-. Preferably, Ci-e alkyl groups that may be mentioned in the context of such pharmaceutically acceptable esters and amides are not cyclic, e.g. linear and/or branched.

Further compounds of the invention that may be mentioned include carbamate, carboxamido or ureido derivatives, e.g. such derivatives of existing amino functional groups.

For the purposes of this invention, therefore, prodrugs of compounds of the invention are also included within the scope of the invention.

The term "prodrug" of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration.

Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent. Prodrugs include compounds of the invention wherein a hydroxy!, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively. Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs" p. 1-92, Elesevier, New York-Oxford (1985).

Compounds of the invention may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).

Compounds of the invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerisations. Valence tautomers include interconversions by reorganisation of some of the bonding electrons. Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.

All stereoisomers (including but not limited to diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope of the invention. In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.

The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.

The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ¹ C, ¹³C, ¹ C , ¹³N, ¹⁵0, ¹⁷0, ¹⁸0, ³²P, ³³P, ³⁵S, ⁸F, ³⁶CI, ¹²³l, and ¹²⁵l. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with ³H and ¹⁴C) are useful in compound and for substrate tissue distribution assays. Tritiated (³H) and carbon-14 (¹ C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as ¹⁵0, ³N, ¹C and ⁸F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Scheme 1 and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent. Unless otherwise specified, C_1-q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched- chain, and/or cyclic (so forming a C₃-q-cycloalkyl group). Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C₂._q alkenyl or a C_2-q alkynyl group). Unless otherwise stated, the term d^, alkylene (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be saturated or unsaturated (so forming, for example, an alkenylene or alkynylene linker group). Such C_1-q alkylene groups may be branched (if sufficient number of atoms), but are preferably straight-chained. In the case of the C _-3 alkylene groups that X may represent, these alkylene groups are straight-chained.

C_3-q cycloalkyl groups (where q is the upper limit of the range) that may be specifically mentioned may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups). Such cycloalkyl groups may be saturated or unsaturated containing one or more double bonds (forming for example a cycloalkenyl group). Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic. The term "halo", when used herein, preferably includes fluoro, chloro, bromo and iodo. Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is from 3 to 20 (such as between 3 and 20 (e.g. between three and ten, e.g between 3 and 8, such as 5- to 8-)). Such heterocycloalkyl groups may also be bridged. Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C_2-q heterocycloalkenyl (where q is the upper limit of the range) group. C_2-q heterocycloalkyl groups that may be mentioned include 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6- azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1 ,3-dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4- dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6- oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, non-aromatic pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1 ,2,3,4-tetrahydropyridyl and 1 ,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form. Heterocycloalkyl mentioned herein may be stated to be specifically monocyclic or bicyclic.

For the avoidance of doubt, the term "bicyclic" (e.g. when employed in the context of heterocycloalkyl groups) refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring. The term "bridged" (e.g. when employed in the context of cycloalkyl or heterocycloalkyl groups) refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).

Aryl groups that may be mentioned include C^o, such as (e.g. C_6-io) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have from 6 to 12 (such as between 6 and 12 (e.g. 6 and 10)) ring carbon atoms, in which at least one ring is aromatic. C_6-i₀ aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl. The point of attachment of aryl groups may be via any atom of the ring system. For example, when the aryl group is polycyclic the point of attachment may be via atom including an atom of a non- aromatic ring. However, when aryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring.

Unless otherwise specified, the term "heteroaryl" when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which have from 5 to 20 (such as between 5 and 20) members (e.g. from 5 to 10 (such as between 5 and 10)) and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group). In the compounds of the invention, heteroaryl groups that may be mentioned are preferably monocyclic. When the heteroaryl group is polycyclic the point of attachment may be via any atom including an atom of a non-aromatic ring. However, when heteroaryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. Heteroaryl groups that may be mentioned include 3,4-dihydro-1/-/-isoquinolinyl, 1 ,3-dihydroisoindolyl, 1 ,3-dihydroisoindolyl (e.g. 3,4- dihydro-1H-isoquinolin-2-yl, 1 ,3-dihydroisoindol-2-yl, 1 ,3-dihydroisoindol-2-yl; i.e. heteroaryl groups that are linked via a non-aromatic ring), or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3- benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1 ,3- benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1 ,3- benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-1 ,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1 ,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1 ,6-naphthyridinyl or, preferably, 1 ,5-naphthyridinyl and 1 ,8-naphthyridinyl), oxadiazolyl (including

1.2.3- oxadiazolyl, 1 ,2,4-oxadiazolyl and 1 ,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1 ,2,3,4- tetrahydroquinolinyl and 5,6,7, 8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1 ,2,3-triazolyl,

1.2.4- triazolyl and 1,3,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heteroaryl groups may also be in the N- or S- oxidised form. Heteroaryl groups mentioned herein may be stated to be specifically monocyclic or bicyclic. When heteroaryl groups are polycyclic in which there is a non- aromatic ring present, then that non-aromatic ring may be substituted by one or more =0 group. It may be specifically stated that the heteroaryl group is monocyclic or bicyclic (although for the purposes of this invention, heteroaryl groups are preferably monocyclic). In the case where it is specified that the heteroaryl is bicyclic, then it may consist of a five-, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another a five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring).

Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur. For the avoidance of doubt, where it is stated herein that a group (e.g. a C_1-12 alkyl group) may be substituted by one or more substituents (e.g. selected from E⁵), then those substituents (e.g. defined by E⁵) are independent of one another. That is, such groups may be substituted with the same substituent (e.g. defined by E⁵) or different substituents (defined by E⁵).

For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which there is more than one e.g. Q¹ or Q², or, E¹ to E⁹ (such as E⁶) substituent present, then those Q¹ or Q², or, E¹ to E⁹ (e.g. E⁶) substituents may be the same or different. Further, in the case where there are e.g. Q¹ or Q², or, E¹ to E⁹ (such as E⁶) substituents present, in which one represents -OR ^0a (or e.g. -OR²⁰, as appropriate) and the other represents -C(O)₂R^10a (or e.g. -C(0)₂R²°, as appropriate), then those R^10a or R²⁰ groups are not to be regarded as being interdependent. Also, when e.g. there are two -OR^10a substituents present, then those -OR^10a groups may be the same or different (i.e. each R^10a group may be the same or different). For the avoidance of doubt, when a term such as 'Έ¹ to E⁹" is employed herein, this will be understood by the skilled person to mean E¹, E², E³, E⁴, E⁵, E⁶, E⁷, E⁸ and E⁹, inclusively.

All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).

The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity. Compounds of the invention that may be mentioned include those in which each J¹, J², J³, J⁴, J⁵ and J⁶ independently represents, on each occasion when used herein:

(i) Q⁷; or

(ii) C_1-6 alkyl or heterocycloalkyl, both of which are optionally substituted by one or more substituents selected from =0 and Q⁸.

Compounds of the invention that may be mentioned include those in which when R⁴ represents -C(0)-[fragment IA], then the fragment IA is one in which Z^1a, Z ^b, Z^1c and Z^1d each represent a direct bond.

For the avoidance of doubt, in compounds of the invention, the R , R² and X- containing ring may represent a 5-, 6- or 7-membered ring and hence a compound of one of the following formulae:

in which the squiggly lines represent the point of attachment to the remainder of the compound of formula I and R¹, R², R³, X¹ and X² are as hereinbefore defined. The most preferred compunds are those in which the R¹ and R²-containing ring is 5-, 6- or 7-membered, particularly those that are 6-membered. The -CH₂-, -CH₂CH₂- and -CH₂CH₂CH₂- moieities linking R¹ and R² are optionally substituted as defined herein (by one or more substituents selected from E²).

Compounds of the invention that may be mentioned include those in which:

when R^a or R^b represent alkyl (e.g. C_1-12 alkyl) or heterocycloalkyl, then such groups are optionally substituted by one or more substituents selected from =0 and Q¹;

when R^a and R^b are linked together to form a ring, then the/those rings formed by the linkage of R^a and R^b are optionally substituted by one or more substituents selected from =0 and E⁴; each Q¹ and Q² independently represents, on each occasion when used herein: halo, -CN, -N0₂, -N(R^10a)R ^1a, -OR^10a, -C(=Y)-R^10a, -C(=Y)-OR ^0a, -C(=Y)N(R^10a)R ^1a, -OC(=Y)-R^10a, -OC(=Y)-OR^10a, -OC(=Y)N(R^10a)R^{1 a}, -OS(O)₂OR^10a, -OP(=Y)(OR^10a)(OR^11a), -OP(OR^10a)(OR^11a), -N(R^12a)C(=Y)R^11a, -N(R ^2a)C(=Y)OR^{1 a}, -N(R^12a)C(=Y)N(R^10a)R^11a, -NR^12aS(O)₂R^10a,

-NR ^2aS(O)₂N(R^10a)R^11a, -S(O)₂N(R^10a)R^{1 a}, -SC(=Y)R ^0a, -S(O)₂R^10a, -SR^10a, -S(O)R^10a, Ci-i₂ alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R^10a) and E⁵), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E⁶); and/or

each Q⁴ and Q⁵ independently represent, on each occasion when used herein: halo, -CN, -N0₂, -N(R²⁰)R²¹, -OR²⁰, -C(=Y)-R²⁰, -C(=Y)-OR²⁰, -C(=Y)N(R²⁰)R²¹, -OC(=Y)-R²⁰, -OC(=Y)-OR²⁰, -OC(=Y)N(R²⁰)R²¹, -OS(0)₂OR²°, -OP(=Y)(OR²⁰)(OR²¹), -OP(OR²⁰)(OR²¹), -N(R²²)C(=Y)R²¹, -N(R²²)C(=Y)OR²¹, -N(R²²)C(=Y)N(R²⁰)R²¹, -NR²²S(0)₂R²⁰, -NR²²S(O)₂N(R²⁰)R²¹, -S(O)₂N(R²⁰)R²¹, -SC(=Y)R²⁰, -S(0)₂R²⁰, -SR²⁰, -S(0)R²⁰, C_1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and J²), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J³).

In an embodiment, preferred compounds of the invention include those in which: R¹ may not represent -N(R⁶)- (e.g. R¹ is selected from -0-, -S-, -S(O)-, -S(0)₂- and -C(R⁶)(R^6a)-), especially when R² represents -C(R⁶)(R^6a)-. Preferred monocyclic heteroaryl groups that R^a or R^b or Q¹, Q², Q⁴ or Q⁵ (if applicable) may independently represent include 5- or 6-membered rings, containing one to three (e.g. one or two) heteroatoms selected from sulfur, oxygen and nitrogen. Preferred bicyclic heteroaryl groups that R^a or R^b, or Q¹, Q², Q⁴ or Q⁵ may represent include 8- to 12- (e.g. 9- or 10-) membered rings containing one to four (e.g. one to three, or, preferably, one or two) heteroatoms selected from sulfur, oxygen and nitrogen (e.g. an indolyl group).

Preferred heterocycloalkyl groups that R^a or R^b or Q¹, Q², Q⁴ or Q⁵ may independently represent include 4- to 8-membered (e.g. 5- or 6-membered) heterocycloalkyl groups, which groups preferably contain one or two heteroatoms (e.g. sulfur or, preferably, nitrogen and/or oxygen heteroatoms), so forming for example, an optionally substituted azetidinyl, azepinyl, piperazinyl or tetrahydropyridinyl group or, particularly, an optionally substituted pyrrolidinyl, piperidinyl, morpholinyl or tetrahydropyranyl group.

Preferred C_3-6 cycloalkyl groups that R^a or R^b or Q¹, Q², Q⁴ or Q⁵ may independently represent include optionally substituted C3-8 (e.g. C^) cycloalkyl groups, such as cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl. Further preferred compounds of the invention include those in which:

each R^10a, R^11a and R^12a independently represent, on each occasion when used herein, hydrogen or C_1-12 (e.g. C_1-6) alkyl (which latter group is optionally substituted by one or more substituents selected from =0 and E⁷); or

any relevant pair of R^10a, R^{1 a} and R^12a may be linked together as defined herein (although they are preferably not linked);

each of E¹, E², E³, E⁴, E⁵, E⁶, E⁷, E⁸ and E⁹ independently represent, on each occasion when used herein, Q⁴ or C _-6 alkyl (e.g. C_1-3) alkyl optionally substituted by one or more substituents selected from =0 and Q⁵;

each Q⁴ and Q⁵ independently represent halo, -CN, -N0₂, -N(R²⁰)R²¹, -OR²⁰, -C(=Y)-R²⁰, -C(=Y)-OR²⁰, -C(=Y)N(R²⁰)R²¹, -N(R²²)C(=Y)R²¹, -N(R²²)C(=Y)OR²¹, -N(R²²)C(=Y)N(R²⁰)R²¹, -NR²²S(0)₂R²⁰, -NR²²S(O)₂N(R²⁰)R²¹, -S(O)₂N(R²⁰)R²¹, -S(0)₂R²⁰, -SR²⁰, -S(0)R²⁰, C_1-6 alkyl, heterocycloalkyl, aryl or heteroaryl (which latter four groups are optionally substituted as defined herein);

any two E¹, E², E³, E⁴, E⁵, E⁶, E⁷, E⁸ and/or E⁹ groups may be linked together (e.g. any two E³ substituents may also be linked together as defined herein, for example when attached to the same or, preferably, adjacent carbon atoms), but (e.g. any two E¹, E², E⁴, E⁵, E⁶, E⁷, E⁸ and/or E⁹) are preferably not linked together;

each R²⁰, R² , R²² and R²³ independently represent, on each occasion when used herein, aryl (e.g. phenyl; preferably unsubstituted, but which may be substituted by one to three J⁵ groups) or hydrogen or C₁.6 (e.g. d_-3) alkyl or heterocyclaolkyl, which latter two groups are optionally substituted by one or more substituents selected from =0 and J⁴; or

any pair of R²⁰ and R²¹, may, when attached to the same nitrogen atom, be linked together to form a 4- to 8-membered (e.g. 5- or 6-membered) ring, optionally containing one further heteroatom selected from nitrogen and oxygen, optionally containing one double bond, and which ring is optionally substituted by one or more substituents selected from J⁶ and =0;

each R⁵⁰, R⁵¹, R⁵² and R⁵³ substituent independently represents, on each occasion when used herein, hydrogen or C_1-6 (e.g. C-1.3) alkyl optionally substituted by one or more substituents selected from fluoro;

when any relevant pair of R⁵⁰, R⁵¹ and R⁵² are linked together, then those pairs that are attached to the same nitrogen atom may be linked together (i.e. any pair of R⁵⁰ and R⁵¹), and the ring so formed is preferably a 5- or 6-membered ring, optionally containing one further nitrogen or oxygen heteroatom, and which ring is optionally substituted by one or more substituents selected from =0 and d_-3 alkyl

(e.g. methyl);

R⁶⁰, R⁶¹ and R⁶² independently represent hydrogen or C _-3 (e.g. C_1-2) alkyl optionally substituted by one or more fluoro atoms.

Preferred compounds of the invention include those in which:

each R^10a, R^11a and R^12a independently represent phenyl (optionally substituted by one or more E⁸ substituents), preferably, heterocycloalkyl (optionally substituted by one or more =0 and/or E⁷ substituents) and, more preferably, hydrogen or (e.g. C _-6) alkyl (optionally substituted by one or more =0 and/or E⁷ substituents), or any pair of R^10a, R^11a and R^12a (e.g. any pair of R^10a and R^11a when attached to the same nitrogen atom) may be linked together to form a 4- to 10-membered (e.g. a 4- to 6-membered monocyclic) ring, optionally substituted by one or more substituents selected from =0 and E⁹ (although any pair of R^10a and R^11a are preferably not linked together);

each E¹, E², E³, E⁴, E⁵, E⁶, E⁷, E⁸ and E⁹ independently represents C_1-12 alkyl optionally substituted by one or more substituents selected from =0 and Q⁵, or, each E¹ to E⁹ independently represent Q⁴; or, any two E¹ to E⁹ substituents (e.g. when attached to the same or adjacent atoms) may be linked together to form a 3- to 8-membered ring, optionally containing one to three double bonds, one to three heteroatoms, and which ring may be substituted by one or more substituents selected from =0 and J¹ (however, any two E¹ to E⁹ groups are preferably not linked together);

each R²⁰, R²¹, R²² and R²³ (e.g. each R²⁰ and R²¹) independently represents heteroaryl, preferably, aryl (e.g. phenyl) (which latter two groups are optionally substituted by one or more substituents selected from J⁵), or, more preferably, hydrogen or C_1-6 (e.g. C^) alkyl optionally substituted by one or more substituents selected from =0 and J⁴; or

any relevant pair of R²⁰, R² and R²² (e.g. R²⁰ and R²¹) may (e.g. when both are attached to the same nitrogen atom) may be linked together to form a 3- to 8- (e.g. 4- to 8-) membered ring, optionally containing a further heteroatom, and optionally substituted by one or more substituents selected from =0 and J⁶;

each J¹, J², J³, J⁴, J⁵ and J⁶ independently represent heterocycloalkyl or C_1-6 alkyl (which latter two groups are optionally substituted by one or more substituents selected from Q⁸), or, J¹ to J⁶ more preferably represent a substituent selected from Q⁷;

each R⁵⁰, R⁵ , R⁵² and R⁵³ independently represents hydrogen or

(e.g. C_M) alkyl optionally substituted by one or more fluoro atoms;

each R⁶⁰, R⁶¹ and R⁶² independently represents hydrogen or C_1-2 alkyl (e.g. methyl).

More preferred compounds of the invention include those in which:

R^d , R^d2 and R^d3 independently represent Ci_₆ (e.g. C_1-4 or, particularly, C_1-3) alkyl optionally substituted by one or more substituents selected from E ;

when R^a and R^b are linked together, they may represent a 3- to 6-membered ring (e.g. a 5- or, preferably, 6-membered ring), optionally containing one further heteroatom selected from nitrogen and oxygen, which ring is optionally substituted by one or more (e.g. one or two) substituent(s) selected from =0 and, preferably, E⁴;

Q⁴ and Q⁵ independently represent -S(0)₂R²⁰ or, particularly, halo (e.g. fluoro), -OR²⁰, -N(R²⁰)R²¹, -C(=Y)R²⁰, -C(=Y)OR²⁰, -C(=Y)N(R²⁰)R²¹, -N(R²²)C(=Y)R²¹, -NR²²S(0)₂R²⁰, Ci_6 alkyl, heterocycloalkyl, aryl and/or heteroaryl (which latter four groups are optionally substituted with one or more substitutents selected from J² or J³, as appropriate);

each Y represents, on each occasion when used herein, =S, or preferably =0; each R²⁰, R²¹, R²² and R²³ (e.g. each R²⁰ and R²¹) independently represents hydrogen, C _-4 (e.g. C_1-3) alkyl or 4- to 8-membered heterocycloalkyl (which latter alkyl and heterocycloalkyl groups are optionally substituted by one or more (e.g. one) J⁴ substituent(s)) or aryl or heteroaryl (e.g. phenyl or a 5, 6, 9 or 10- membered heteroaryl group; which aryl and heteroaryl groups are optionally substituted by one or more J⁵ substituents); or

any relevant pair of R²⁰, R²¹ and R²² (e.g. R²⁰ and R²¹) may (e.g. when both are attached to the same nitrogen atom) may be linked together to form a 5- or, preferably, a 6-membered ring, optionally containing a further heteroatom (preferably selected from nitrogen and oxygen), which ring is preferably saturated, and optionally substituted by one or more substituents selected from =0 and J⁶;

R²² represents C_1-3 alkyl or hydrogen;

each J¹, J², J³, J⁴, J⁵ and J⁶ independently represent a substituent selected from Q⁷, or J¹ to J⁶ represents alkyl (e.g. C _-4 alkyl) or a 4- to 8-membered heterocycloalkyl group;

each Q⁷ and Q⁸ independently represent -S(0)₂R²° or, particularly, halo (e.g. fluoro), -N(R⁵⁰)R⁵¹, -OR⁵⁰, -C(=Y^a)-R⁵⁰, -C(=Y^a)-OR⁵⁰, -C(=Y^a)N(R⁵⁰)R⁵¹, -N(R⁵²)C(=Y^a)R⁵¹ or C_1-6 alkyl optionally substituted by one or more fluoro atoms; each Y^a independently represents =S or, preferably, =0;

each R⁵⁰, R⁵¹, R⁵² and R⁵³ independently represents H or C_1-4 alkyl.

More preferred compounds of the invention include those in which:

R¹ and R² independently represent -N(R⁶)-, -O- or -C(R⁶)(R^6a)- (and more preferably, R and R² independently represent -N(R⁶)- or -0-);

R⁶ and R^6a independently represent H or R^d3;

R^d3 represents Ci_-3 alkyl (e.g. methyl or ethyl) optionally substituted by one or two (e.g. one) substituent selected from E¹;

R ^a represents hydrogen or C _-4 alkyl (optionally substituted by one or more halo atoms);

R^4b represents C _-4 alkyl or a heterocycloalkyl group (which latter two groups are optionally substituted by one or more substituents selected from halo and C_1-2 alkyl);

R ^c represents hydrogen, C_1-4 alkyl or a heterocycloalkyl group (which latter two groups are optionally substituted by one or more substituents selected from halo and C_1-2 alkyl) and, more preferably, R^4c represents hydrogen or C_1-4 alkyl;

X represents C_2-3 alkylene optionally substituted by one or more (e.g. one or two) substituents selected from E²; Q¹ and Q² independently represent -N(R ^2a)C(=Y)R^11a, C_1-6 alkyl (optionally substituted by one or more subsitutents selected from =0 and E⁵) or, particularly, halo, -CN, -N(R^10a)R ^a, -OR^10a, -C(=Y)-R^10a, -C(=Y)-OR^10a, -C(=Y)N(R^10a)R ^1a, -S(O)₂R^10a, C_1-4 (e.g. C_1-3) alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more subsitutents selected from =0 and E⁵), aryl or heteroaryl (which latter two groups are optionally substituted by one or more subsitutents selected from E⁶);

E¹, E², E³, E⁴, E⁵, E⁶, E⁷, E⁸ and E⁹ independently represent Q⁴ or C_1-6 (e.g. C_M) alkyl optionally substituted by one or more (e.g. two or, preferably, one) substituent(s) selected from Q⁵;

preferably any two E¹ to E⁹ groups are not linked together;

more preferably E⁷, E⁸ and E⁹ independently represent Q⁴;

Q⁴ represents -N(R²²)C(=Y)R²¹ or, particularly, halo (e.g. fluoro), -CN, -OR²⁰,

-N(R²⁰)R²¹, -C(=Y)R²⁰, -C(=Y)OR²⁰, -N(R²²)S(0)₂R²⁰, -S(0)₂R²°, heterocycloalkyl (optionally substituted by one or more substituents selected from J²), aryl (e.g. phenyl) or heteroaryl (e.g. a monocyclic 5- or 6-membered group) (which aryl and heteroaryl groups are optionally substituted by one or more substituents selected from J³);

Q⁵ represents -C(=Y)-R²⁰, -C(=Y)-OR²⁰, -NR^SiO^R²⁰, -S(0)₂R²° or, particularly, C_1-6 alkyl (optionally substituted by one or more substituents selected from J²), halo (e.g. fluoro), -N(R²⁰)R²¹, -N(R²²)C(=Y)R²¹, -OR²⁰ or aryl (optionally substituted by one or more substituents selected from J³);

R^10a and R^11a independently represent H or, preferably, C_1-3 alkyl (e.g. methyl);

R²⁰ represents H, C_1-4 alkyl (optionally substituted by one or more J⁴ substituents), heterocycloalkyl (e.g. a 4- to 8-membered or preferably 5- or 6- membered heterocycloalkyl group; optionally substituted by one or more J⁴ substituents) or aryl (e.g. phenyl; optionally substituted by one or more J⁵ substituents);

R²¹ represents hydrogen or C_1-4 (e.g. C_1-3) alkyl;

R²² represents hydrogen;

Y represents =0;

J¹, J², J³, J⁴, J⁵ and J⁶ (e.g. J⁴) independently represent Q⁷ or a heterocycloalkyl group (e.g. a 4- to 8-membered such as a 5- or 6-membered heterocycloalkyl group); J¹, J², J³, J⁵ and J⁶ more preferably represent Q⁷ (e.g. in which Q⁷ represents halo);

Q⁷ represents halo, -N(R⁵⁰)R⁵¹, -OR⁵⁰ or -S(0)₂R⁵°;

Q⁸ represents halo (e.g. fluoro);

R⁵⁰ and R⁵¹ independently represent hydrogen or C _-2 alkyl;

R⁶⁰, R⁶¹ and R⁶² independently represent hydrogen or C _-2 alkyl.

Preferred X¹ and X²-containing bicyclic moieties of compounds of the invention in lude:

in which the squiggly lines represent the point of attachment to the remainder of the compound of formula I and R³ is as hereinbefore defined. Preferably, the X¹ and X²-containing bicycles contain at least three nitrogen atoms. The bicycles (at the X¹ position) are optionally substituted, i.e. R⁵ represents hydrogen or a substituent. Preferably, R⁵ represents hydrogen, halo or unsubstituted Ci_-2 alkyl. Most preferably R⁵ represents hydrogen.

In compounds of the invention, X^a to X⁹ (i.e. X^a, X^b, X^c, X^d, X^f and X⁹) may all represent -C(R⁷)= (so forming a naphthyl group) or any two may represent -N= (so forming e.g. a quinazolinyl, phthalazinyl or pyridinopyridine). Preferred X^a to X⁹-containing bicycles include those in which X^f and X⁹ independently represent -C(R⁷)=. Further preferred X^a to X⁹-containing bicycles include those in which X^a to X⁹ all represent -C(R⁷)= or, particularly, one of X^a, X^b, X°, X^d, X^f or X⁹ (e.g. one of X^a, X^b, X^c or X^d) represents -N= (and the others independently represent -C(R⁷)=) so forming, e.g. a quinolinyl or isoquinolinyl moiety (such as a 2-quinolinyl, 3-isoquinolinyl, 6-isoquinolinyl or 7-isoquinolinyl). Most preferred bicycles are the following:

in which the squiggly lines represent the point of attachment to the remainder of the compound of formula I and R⁴ is as hereinbefore defined. In the compounds of the invention each R⁷ preferably represents hydrogen or a substituent selected from -F, -CI, -Br, -CN, methyl, ethyl, methoxy, trifluoromethyl and triflouromethoxy (most preferably, each R⁷ represents hydrogen; and hence the X^a to X⁹- containing bicycle is only substituted with one substituent (the R⁴ substituent)).

Preferred compounds of the invention include those in which R⁴ represents:

a fragment of formula IA;

-CH₂-[fragment I A];

-C(0)-[fragment IA];

-[O]_0-1-(CH₂)ni-heterocycloalkyl (e.g. -0-(CH₂)_ni-heterocycloalkyl or -heterocyclo- alkyl), in which n1 represents 0 or 1 ;

-N(R^4a)-C(0)-R ^b;

aryl (optionally substituted by one or more substituents selected from E³); or heteroaryl (optionally substituted by one or more substituents selected from E³); in the fragment of formula IA, when R^a and R^b are linked together, then the ring so forming is preferably not fused to another ring (to form a bicycle) and preferably does not comprise a linker group (to form a bridged structure), nor does it comprise a second ring attached via a common carbon atom (to form a spiro cycle);

the ring formed by the linkage of R^a and R^b is optionally substituted by one or more substituents selected from =0 and E⁴;

when R⁴ represents aryl, it is preferably monocyclic e.g. phenyl, preferably substituted by one substituent (e.g. located at the meta or para-position) selected from E³;

when R⁴ represents heteroaryl, it is preferably a monocyclic 5- or 6-membered ring (e.g. containing one or two heteroatom(s) preferably selected from nitrogen and oxygen; so forming e.g. a pyridyl, furanyl, pyrazolyl or pyrimidinyl group, such as 4-pyridyl, 2-furanyl, 4-pyrazolyl or 5-pyrimidinyl);

when R⁴ represents -0-(CH₂)_ni-heterocycloalkyl, then that heterocycloalkyi group is preferably 4- to 8-membered (e.g. 5- or, preferably 6-membered), preferably containing one or two (e.g. one) heteroatom(s) (e.g. nitrogen) so forming a piperidinyl (e.g. 4-piperidinyl) group;

when R⁴ represents heterocycloalkyi, it preferably represents a 5- or 6-membered group optionally containing one or two (e.g. one) double bond(s) and preferably containing one or two (e.g. one) heteroatom, preferably selected from nitrogen, so forming e.g. piperidinyl containing an optional double bond;

when R⁴ represents -C(0)-[fragment IA], then R^a and R^b independently represent hydrogen, C_1-4 alkyl (e.g. ethyl) (preferably at least one of R^a and R^b represents hydrogen) or a substituent selected from R^aby (as defined hereinafter);

when R⁴ represents a fragment of formula IA or -CH₂-[fragment IA], then one of R^a and R^b represents hydrogen or d_-3 alkyl and the other represents hydrogen or a substituent selected from R^abx (as defined hereinafter); or R^a and R^b are linked together to form a 4- to 8-membered ring (e.g. a 5- or preferably 6-membered group containing one or two heteroatoms; e.g. a piperidinyl or piperazinyl group) optionally substituted by one or more substituents selected from E⁴.

Preferred compounds of the invention include those in which:

R^4a represents Ci.₃ alkyl or, preferably, hydrogen;

R^4b represents C_1-4 alkyl (e.g. d_-2 alkyl, such as methyl) or a 5- or 6-membered heterocycloalkyi group (e.g. in which there is one or two (e.g. one) heteroatom (s), preferably a nitrogen heteroatom; so forming e.g. piperidinyl, such as 4- piperidinyl);

R^aby and R^{a x} independently represent: acyclic C_1-4 alkyl (e.g. methyl or ethyl) optionally (and preferably) substituted by one or more (e.g. one) substituent(s) selected from Q¹; cycloalkyl (e.g. a 3- to 7-membered group, e.g. cyclohexyl) optionally (and preferably) substituted by one or more (e.g. one) substituent(s) selected from Q¹; or heterocycloalkyi (e.g. a 5-, 6- or 7-membered heterocycloalkyi group, containing one or two (e.g. one) heteroatom(s) in which one is preferably selected from nitrogen and oxygen; and hence may represent a piperidinyl group, e.g. 4-piperidinyl, a tetrahydropyranyl group, e.g. 4- tetrahydropyranyl or azepanyl, e.g. 4-azepanyl) optionally substituted by one or more subsitutents selected from Q ;

more preferably, R^aby and R^ab independently represent acyclic C_1-4 alkyl (e.g. methyl) optionally substituted by one or more (e.g. one) substituent(s) selected from Q¹; 5- or 6-membered cycloalkyl (e.g. cyclohexyl) optionally (and preferably) substituted by one or more (e.g. one) substituent(s) selected from Q¹; or heterocycloalkyl (e.g. a 6-membered heterocycloalkyl group, containing one heteroatom preferably selected from nitrogen; and hence may represent a piperidinyl group, e.g. 4-piperidinyl) and which heterocycloalkyl group is unsubstituted or substituted with one Q¹ substituent on a nitrogen atom.

Other preferred compounds of the invention include those in which:

Q¹ (e.g. when present on an alkyl, e.g. acyclic alkyl, group) represents a heterocycloalkyl group or a heteroaryl group;

when Q¹ represents a heterocycloalkyl group, it is preferably a 4-, 5- or 6- membered heterocycloalkyl group (containing one or two (e.g. one) heteroatom(s) in which one is preferably selected from nitrogen and oxygen; and hence may represent a piperidinyl group, e.g. 4-piperidinyl, tetrahydropyranyl, e.g. 4-tetrahydropyranyl, azetidinyl, e.g. 3-azetidinyl group, or piperazinyl, e.g. 1- piperazinyl) optionally substituted by one or more subsitutents selected from E⁵ (although the heterocycloalkyl group is preferably unsubstituted);

when Q¹ represents a heteroaryl group, it is preferably a 5- or, especially, a 6- membered heteroaryl group, containing one or two (preferably one) heteroatom, preferably selected from nitrogen (so forming pyridyl, e.g. 4-pyridyl), which heteroaryl group is optionally substituted by one or more substituents selected from E⁶ (but is preferably unsubsubstituted);

Q¹ (e.g. when present on a cycloalkyl group) represents -N(R^10a)R ^1a (e.g. -NH₂); Q¹ (e.g. when present on the nitrogen atom of a heterocycloalkyl group) represents C_1-4 (e.g. C _-3) alkyl (e.g. methyl, ethyl or cyclopropyl; which alkyl group is optionally substituted by E⁵, so forming e.g. -CH₂CH₂-OCH₃) or -S(O)₂R^10a (e.g. -S(0)₂CH₃);

E³ represents Q⁴ or C_1-4 (e.g. C _-2) alkyl (e.g. ethyl) optionally substituted by one or two (e.g. one) substituents selected from Q⁵; E⁴ (which may be present on a nitrogen heteroatom) represents Q⁴ or C _-3 alkyl (e.g. methyl) optionally substituted by one or two (e.g. one) substituent(s) selected from Q⁵;

E⁵ (e.g. when present on a nitrogen heteroatom) represents C_1-2 alkyl (e.g. methyl) optionally substituted by one or two (e.g. one) Q⁵ substituent;

E⁵ (e.g. when present on an alkyl group) represents Q⁴;

when E³ represents Q⁴, then Q⁴ represents -N(R²⁰)R²¹, -OR²⁰ or -N(R²²)S(0)₂R²⁰; when E⁴ represents Q⁴, then Q⁴ represents -N(R ⁰)R²¹ or -S(0)₂R²°;

when E⁵ represents Q⁴, then Q⁴ represents -OR²⁰;

Q⁵ represents -N(R²⁰)R²¹, -OR²⁰ or aryl (e.g. unsubstituted phenyl);

R^10a and R^11a independently represent C _-3 alkyl or, preferably, hydrogen;

R²⁰ and R²¹ independently represent hydrogen, C_1-3 alkyl (e.g. methyl; which alkyl group is optionally substituted by one or more (e.g. one) substituent(s) selected from J⁴), heterocycloalkyl (e.g. a 5- or preferably 6-membered heterocycloalkyl group; preferably containing one or two (e.g. one) heteroatom; so forming e.g. a piperidinyl group) or aryl (e.g. unsubstituted phenyl);

J⁴ represents Q⁷ or a 5- or 6-membered heterocycloalkyl group, e.g. containing one or two (e.g. one) heteroatom (s), preferably selected from nitrogen (so forming e.g. a piperidinyl, e.g. 4-piperidinyl group);

Q⁷ represents -S(0)₂R⁵⁰;

R⁵⁰ represents C_1-4 alkyl (e.g. C _-2 alkyl, such as methyl);

preferred E³ substituents include amino (e.g. -NH₂, -N(CH₃)₂, -N(H)-[4-piperidinyl] and/or -N(H)-CH₂-[4-piperidinyl]), hydroxy (-OH), alkoxy (e.g. -OCH₃), alkylalkoxy (e.g. -CH₂CH₂OCH₃), sulfonamido (e.g. -N(H)S(0)₂CH₂CH₃) and substituted alkylamino (e.g. -CH₂-N(H)-CH₂CH₂-S(0)₂CH₃);

preferred E⁴ substituents (on cyclic groups formed by the linkage of R^a and R^b) include amino and alkylamino groups, e.g. -NH₂ and -CH₂-NH₂, alkylhydroxy groups (e.g. -CH₂CH₂OH) and alkylsulfonyl groups (e.g. -S(0)₂CH₃);

preferred E⁵ substituents (which may be present on a nitrogen heteroatom) include methyl and benzyl.

Preferred R⁴ groups of compounds of the invention include the following:

wherein the squiggly line represents the point of attachment to the requisite X^a to X⁹-containing bicycle of the compound of formula I, R³'" represents R^a or R^b, and the other integers (e.g. E³, E⁴, E⁵, E⁶ and Q¹; which are optional substituents that may be attached to specific atoms, or, may be depicted as 'floating', in which case the relevant group is optionally substituted by one or more of those E³/E⁴/Q /E⁵/E⁶ substituents) are as defined herein. The depiction of a substituent in brackets signifies that that substituent is optionally present, and may therefore be absent (i.e. N-(E⁵) may signify N-E⁵ or N-H).

Preferred R¹, R² and X-containing rings of the compounds of the invention include:

wherein the squiggly lines represent the point of attachment to the requisite X¹ and X²-containing bicycle of the compound of formula I, and the relevant atoms of the ring may be substituted by a substituent defined by R⁶ or R^6a (as appropriate) or by a substituent defined by E². The most preferred ring is the following:

Preferred R³ groups in the compounds of the invention include those in which: R³ represents hydrogen or a substituent selected from -CI, C_1-3 alkyl (preferably unsubstituted; e.g. methyl, cyclopropyl), -CN, -OH and -OCH₃.

Preferred compounds of the invention include those in which, in the R , R² and X- containing ring:

X preferably represents C₂-₃ alkylene (e.g. -CH₂-CH₂- or -CH₂CH₂CH₂-) optionally substituted by one or more (e.g. one or two) substituents selected from E² (for instance, one or two E² substituents may be located on the central carbon atom of a C₃ alkylene group so forming -CH₂C(E )(E²)CH₂-, e.g. -CH₂C(CH₃)2CH2-); E² represents C1-4 (e.g. C1.2) alkyl (e.g. methyl, preferably unsubstituted);

when R or R² represents -C(R⁶)(R^6a)-, then R⁶ and R^6a preferably represent hydrogen;

when R¹ or R² (e.g. R²) represents -N(R⁶)-, then R⁶ represents hydrogen or, preferably, a substituent selected from alkoxyalkyl (e.g. -CH₂CH₂-OCH₃, -(CH₂)₃-OCH₃), aryloxyalkyl (e.g. -CH₂CH₂-0-phenyl), C_1-4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl) or benzyl;

R⁶ represents R^d3;

R^d3 represents C_1-4 alkyl optionally substituted by one or more (e.g. one) substituent(s) selected from E¹;

E¹ represents Q⁴;

when E¹ represents Q⁴, then Q⁴ represents -OR²⁰ or aryl (e.g. phenyl);

R²⁰ represents C_1-4 alkyl (e.g. C_1-2 alkyl, such as methyl) or aryl (e.g. phenyl).

Particular compounds of the invention include compounds of formula Al,

wherein:

X¹ and X² independently represent =N- or =C(H)-;

X^a, X^b, X^c, X^d, X^f and X⁹ independently represent -C(R⁷)= or, any one of X^b or X^c may represent -N=; each R⁷ independently represents hydrogen or a substituent selected from -F, -CI, -Br; R² represents -O- or -N(R⁶)-;

X represents C_2-3 alkylene optionally substituted by one or more substituents selected from E²;

R⁶ represents C_1-4 alkyl optionally substituted by one or more substituents selected from E¹; R³ represents hydrogen or a substituent selected from -CI, -CN, -OH, -OCH₃ and C_1-3 alkyl;

R⁴ represents -[0]o-i-(CH₂)₀-i-heterocycloalkyl (which heterocycloalkyl is optionally substituted by one or more substituents selected from Q¹), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substitutents selected from E³); or R⁴ represents -[C(O)]_0-i-N(R^a)R^b;

R^a and R independently represent H, -[C(O)]_0-i-C_1-9 alkyl, -[C(0)]o-i-heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and Q ); or

R^a and R^b are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a (first) 3- to 7-membered cyclic group, optionally containing one further nitrogen atom, and which ring optionally comprises a second ring that is a 5- to 7-membered saturated heterocycloalkyl group containing one oxygen atom, and which second ring is linked together with the first ring via a single carbon atom common to both rings (i.e. forming a spiro- cycle), all of which cyclic groups, defined by the linkage of R^a and R^b, are optionally substituted by one or more substituents selected from E⁴; each Q¹ independently represents, on each occasion when used herein:

-N(R^10a)R ^1a, -OR ^0a, -N(R^12a)C(=0)R^11a, -S(O)₂R^10a, C_1-12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from E⁵), or heteroaryl (which latter group is optionally substituted by one or more substituents selected from E⁶); each R^10a, R^11a and R^12a independently represent, on each occasion when used herein, hydrogen, C^₂ alkyl (which latter group is optionally substituted by one or more substituents selected from E⁷); each E¹, E², E³, E⁴, E⁵, and E⁷ independently represents, on each occasion when used herein:

(i) Q⁴;

(ii) C₁.4 alkyl optionally substituted by one or more substituents selected from =0 and Q⁵; or any two E⁵ or E⁷ groups may be linked together to form a 4- to 6-membered ring (in which each of the atoms of the ring may be a carbon atom or a heteroatom); each Q⁴ and Q⁵ independently represent, on each occasion when used herein: halo, -N(R²⁰)R²¹, -OR²⁰, -C(=0)-R²⁰, -C(=0)-OR²⁰, -N(R²²)C(=0)R²¹, -NR²²S(0)₂R²⁰, -S(0)₂R²⁰ or aryl; each R²⁰, R²¹ and R²² independently represent, on each occasion when used herein, hydrogen, C₁-4 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J⁴) or aryl; each J⁴ independently represents, on each occasion when used herein:

(i) Q⁷;

(ii) aryl or heterocycloalkyl; each Q⁷ independently represents, on each occasion when used herein:

-N(R⁵⁰)R⁵¹ or -S(0)₂R⁵⁰; and each R⁵⁰ and R⁵¹ independently represents, on each occasion when used herein, hydrogen or C_1-2 alkyl; or a pharmaceutically acceptable ester, amide, solvate or salt thereof. Particular heterocycloalkyi groups that may be mentioned with respect to compounds of formula Al include non-aromatic monocyclic and bicyclic heterocycloalkyi groups in which one or two of the atoms in the ring system is other than carbon (i.e. a heteroatom), the total number of atoms in the ring system is from 4 to 10, and which groups may be saturated or unsaturated (i.e. contain one or more double and/or triple bonds, forming for example a C_2-q heterocycloalkenyl (where q is the upper limit of the range)). Particular compounds of the invention include compounds of formula All,

wherein: X¹ and X² independently represent =N- or =C(H)-;

X^a, X^b, X°, X^d, X^f and X⁹ independently represent -C(R⁷)=, or, any one of X^b or X^c may represent -N=; each R⁷ independently represents hydrogen or a substituent selected from -F, -CI, -Br;

R⁶ represents C_1-4 alkyl optionally substituted by one or more substituents selected from E¹; R³ represents hydrogen or a substituent selected from -CI, -CN, -OH, -OCH₃ and C _-3 alkyl;

R⁴ represents heterocycloalkyi (optionally substituted by one or more substituents selected from Q ), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substitutents selected from E³); or R⁴ represents

R^a and R^b independently represent H, -[C(O)]_0-i-C_1-9 alkyl, -[C(O)]₀-i-heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and Q¹); or

R^a and R are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a (first) 3- to 7-membered cyclic group, optionally containing one further nitrogen atom, and which ring optionally comprises a second ring that is a 5- to 7-membered saturated heterocycloalkyi group containing one oxygen atom, and which second ring is linked together with the first ring via a single carbon atom common to both rings (i.e. forming a spiro- cycle), all of which cyclic groups, defined by the linkage of R^a and R^b, are optionally substituted by one or more substituents selected from E⁴; each Q independently represents, on each occasion when used herein:

-N(R^10a)R ^1a, -OR^10a, -N(R ^2a)C(=0)R^11a, -S(O)₂R^10a, C_1-12 alkyl, heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from E⁵), or heteroaryl (which latter group is optionally substituted by one or more substituents selected from E⁶); each R^10a, R^11a and R ^2a independently represent, on each occasion when used herein, hydrogen, C _-12 alkyl (which latter group is optionally substituted by one or more substituents selected from E⁷); each E¹, E², E³, E⁴, E⁵, and E⁷ independently represents, on each occasion when used herein: (') Q⁴;

(ii) C _-4 alkyl optionally substituted by one or more substituents selected from =0 and Q⁵; or any two E⁵ or E⁷ groups may be linked together to form a 4- to 6-membered ring (in which each of the atoms of the ring may be a carbon atom or a heteroatom); each Q⁴ and Q⁵ independently represent, on each occasion when used herein: halo, -N(R²⁰)R²¹, -OR²⁰, -N(R² )C(=0)R²¹, -NR²²S(0)₂R²⁰ or aryl; each R²⁰, R²¹ and R²² independently represent, on each occasion when used herein, hydrogen, C_1-4 alkyl, heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from J⁴) or aryl; each J⁴ independently represents, on each occasion when used herein:

(i) Q⁷;

(ii) aryl or heterocycloalkyi; each Q⁷ independently represents, on each occasion when used herein:

-N(R⁵⁰)R⁵¹ or -S(0)₂R⁵°; and each R⁵⁰ and R⁵¹ independently represents, on each occasion when used herein, hydrogen or C _-2 alkyl; or a pharmaceutically acceptable ester, amide, solvate or salt thereof.

Particular heterocycloalkyi groups that may be mentioned with respect to compounds of formula All include non-aromatic monocyclic and bicyclic heterocycloalkyi groups in which one or two of the atoms in the ring system is other than carbon (i.e. a heteroatom), the total number of atoms in the ring system is from 4 to 10. In particular, the heterocycloalkyi group may be a piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl or azepinyl group. Particular compounds of the invention include compounds of formula AIM,

wherein:

R^a and R^b independently represent H or ^1-4 alkyl, (which alkyl group is optionally substituted by one or more substituents selected from Q¹); each Q independently represents, on each occasion when used herein, C_1-2 alkyl or heterocycloalkyi (which two groups are optionally substituted by one or more E⁵ substituents); and any two E⁵ groups may be linked together to form a 6-membered ring (in which each of the atoms of the ring may be a carbon atom or a heteroatom); or a pharmaceutically acceptable ester, amide, solvate or salt thereof.

Particular heterocycloalkyi groups that may be mentioned with respect to compounds of formula AMI include non-aromatic monocyclic and bicyclic heterocycloalkyi groups in which one or two of the atoms in the ring system is other than carbon (i.e. a heteroatom), the total number of atoms in the ring system is from 4 to 10. In particular, the heterocycloalkyi group may be a piperidinyl group. Particular compounds of the invention include compounds of formula AlV,

wherein:

X^b and X^c both represent -C(H)=, or one of X^b and X^c represents -N= and the other represents -C(H)=;

R⁶ represents d-4 alkyl optionally substituted by one or more substituents selected from E¹;

R³ represents hydrogen or a substituent selected from -CI and -CH₃;

R⁴ represents -[C(O)]₀- N(R^a)R^b;

R^a and R^b independently represent H, -[C(O)]₀-i-C_1-6 alkyl, or -[C(0)]o-i-heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from Q¹); or R^a and R^b are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a 6-membered cyclic group, optionally containing one further nitrogen atom, which cyclic groups, defined by the linkage of R^a and R^b, are optionally substituted by one or more substituents selected from

each Q independently represents, on each occasion when used herein: -NH₂, -OH, C_1-2 alkyl, or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from E⁵); each E¹, E⁴, and E⁵ independently represent, on each occasion when used herein:

(i) Q⁴;

(ii) C₁ alkyl optionally substituted by one or more substituents selected from Q⁵; or any two E⁵ groups may be linked together to form a 6-membered ring (in which each of the atoms of the ring may be a carbon atom or a heteroatom); and each Q⁴ and Q⁵ independently represents, on each occasion when used herein: halo, -NH₂ or aryl; or a pharmaceutically acceptable ester, amide, solvate or salt thereof.

Particular heterocycloalkyl groups that may be mentioned with respect to compounds of formula AlV include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which one or two of the atoms in the ring system is other than carbon (i.e. a heteroatom), the total number of atoms in the ring system is from 4 to 10. In particular, the heterocycloalkyl group may be a piperidinyl, piperazinyl, azetidinyl or azepinyl group.

Particularly preferred compounds of the invention include those of the examples described hereinafter.

Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter. According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I which process comprises:

(i) compounds of formula I in which R⁴ represents -0-C_1-6alkyl-OCH₃, -O-Cvealkyl-NHz, -0-C^alkyl-N(H)(CH₃), -0-(CH₂)_n -heterocycloalkyl, -OR^4c or a fragment of formula IA, may be prepared by reaction of a compound of formula II,

wherein L¹ represents a suitable leaving group, such as iodo, bromo, chloro or a sulfonate group (e.g. -OS(0)₂CF₃, -OS(0)₂CH₃ or -OS(0)₂PhMe), and R¹, R², X, R³, X¹, X², X^a, X^b, X°, X^d, X^f and X⁹ are as hereinbefore defined, with a compound of formula III,

R^4x-H III wherein R^4x represents represents -0-C_1-6alkyl-OCH₃, -0-C_1-6alkyl-NH₂,

-0-(CH₂)_ni-heterocycloalkyl, -OR ^c or a fragment of formula IA, under standard conditions, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc)₂, Cul (or Cul/diamine complex), copper tris(triphenyl- phosphine)bromide, Pd(OAc)₂, tris(dibenzylideneacetone)-dipalladium(0) (Pd₂(dba)₃) or NiCI₂ and an optional additive such as Ph₃P, 2,2'- bis(diphenylphosphino)-1 ,1'-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et₃N, pyridine, A/./V-dimethylethylenediamine, Na₂C0₃, K₂C0₃, K₃P0₄, Cs₂C0₃, f-BuONa or f-BuOK (or a mixture thereof, optionally in the presence of 4A molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, /V-methylpyrrolidinone, tetrahydrofuran or a mixture thereof). This reaction may be carried out under microwave irradiation reaction conditions or, alternatively, the reaction may be performed in the absence of other reagents such as catalyst, base and even solvent. Such a reaction may be accompanied by a rearrangement reaction, for instance if the compound of formula III is 2,7-diaza- spiro[3.5]nonane (or the 7-protected derivative thereof, e.g. the corresponding 7- carboxylic acid terf-butyl ester thereof), then such a spiro-cyclic amine may undergo ring-opening to form a 1-aza-bicyclo[2.2.1]hept-4-ylmethyl-amino moiety (i.e. a bridged amine) so forming a corresponding compound of formula I in which R⁴ represents 1-aza-bicyclo[2.2.1]hept-4-ylmethyl-amino;

(ii) reaction of a compound of formula IV,

wherein L³ represents a suitable leaving group such as one hereinbefore defined in respect of L¹ (e.g. halo, such as chloro or, preferably, bromo), and R , R², X, X¹, X² and R³ are as hereinbefore defined, with a compound of formula V,

wherein L⁴ represents a suitable group, such as -B(OH)₂, -BiOR^ or -SniR^, in which each R™* independently represents a C_1-6 alkyl group, or, in the case of -BiOR^, the respective R"* groups may be linked together to form a 4- to 6- membered cyclic group (such as a 4,4,5,5-tetramethyl-1 ,3_>2-dioxaborolan-2-yl group), thereby forming e.g. a pinacolato boronate ester group, (or L⁴ may represent iodo, bromo or chloro, provided that L³ and L⁴ are mutually compatible) and R⁴, X^a, X^b, X^c, X^d, X^f and X⁹ are as hereinbefore defined. The reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as Pd, Cul, Pd/C, PdCI₂, Pd(OAc)₂, Pd(Ph₃P)₂CI_2l Pd(Ph₃P)₄ (i.e. palladium tetrakistriphenylphosphine), Pd₂(dba)₃ and/or NiCI₂ (preferred catalysts include palladium) and a ligand such as PdCI₂(dppf).DCM, f-Bu₃P, (CeHnfeP, Ph₃P, AsPh₃, P(o-Tol)₃, 1 ,2- bis(diphenylphosphino)ethane, 2,2'-bis(di-feAf-butylphosphino)-1,1'-biphenyl, 2,2'- bis(diphenylphosphino)-1 , 1 '-bi-naphthyl, 1 , 1 '-bis(diphenyl-phosphino-ferrocene), 1,3-bis(diphenylphosphino)propane, xantphos, or a mixture thereof (preferred ligands include PdCI₂(dppf).DCM), together with a suitable base such as, Na₂C0₃, K₃P0₄, Cs₂C0₃, NaOH, KOH, K₂C0₃, CsF, Et₃N, (/-Pr)₂NEt, f-BuONa or i-BuOK (or mixtures thereof; preferred bases include Na₂C0₃ and K₂C0₃) in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, dimethoxyethane, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, /V-methylpyrrolidinone, tetrahydrofuran or mixtures thereof (preferred solvents include dimethylformamide and dimethoxyethane). The reaction may be carried out for example at room temperature or above (e.g. at a high temperature such as at about the reflux temperature of the solvent system). Alternative reaction conditions include microwave irradiation conditions, for example at elevated temperature of about 130°C;

(iii) for compounds of formula I in which X² represents -N=, reaction of a compound of formula VI,

wherein L¹ represents a suitable leaving group as hereinbefore defined, and X¹, R¹, R², R³ and X are as hereinbefore defined, with a compound of formula VII,

wherein R⁴, X^a, X^b, X°, X^d, X^f and X⁹ are as hereinbefore defined, under standard reaction conditions to promote the formation of the requisite triazolopyridazine bicyclic core, for example, in the presence of base, such as an organic base (e.g. triethylamine or the like), and/or an acid, such as an organic acid (e.g. para- toluenesulfonic acid or the like), and the base and acid are preferably in a ratio of about 1 :1. The reaction may also take place in the presence of a suitable solvent, such as a polar solvent (e.g. 1 ,4-dioxane and the like), which may be heated at room termperature, or, preferably, above room temperature, e.g. above 50°C, such as at about 100°C. In the case where reaction takes place with a compound of formula VI in which R⁴L¹ represents either L¹, then the reaction may be proceeded by reaction with a compound of formula III, for example as defined in respect of process step (i) above; (iv) for compounds of formula I in which R and R² are independently selected from -0-, -S- and -NR⁶-, reaction of a compound of formula VIII,

wherein R ^a and R^2a independently represent -0-, -S- and -NR⁶-, and R³, X¹, X², X^a, X^b, X^c, X^d, X^f, X⁹ and R⁴ are as hereinbefore defined, with a compound of formula IX, L⁵-X-L⁶ IX wherein L⁵ and L⁶ independently represent a suitable leaving group, such as one hereinbefore defined in respect of L¹ (e.g. halo, such as chloro), and X is as hereinbefore defined, under standard reaction conditions (to promote the nucleophilic substitution reactions), for example in the presence of a suitable base, such as Na₂C0₃, K₃P0₄, Cs₂C0₃, NaOH, KOH, K₂C0₃, CsF, Et₃N, (/- Pr)₂NEt, f-BuONa or f-BuOK (or mixtures thereof) in a suitable solvent such as dioxane, toluene, ethanol, terf-butanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N- methylpyrrolidinone, tetrahydrofuran or mixtures thereof. Preferred bases include f-BuOK;

(v) for compounds of formula I in which R⁴ represents optionally substituted aryl or heteroaryl, reaction of a compound of formula II as hereinbefore defined, with a compound of formula X,

R ^X1-L⁴ wherein L⁴ represents a suitable leaving group, as hereinbefore defined and R^{4 1} represents optionally substituted aryl or heteroaryl (which R⁴ may represent) under reaction conditions such as those hereinbefore described in respect of process step (ii) above;

(vi) for compounds of formula I in which one of R¹ and R² represents -0-, intramolecular reaction of a compound of formula XI,

wherein either T^1a represents -R -X-OH or T^2a represents -R²-X-OH and the other represents a suitable leaving group such as one defined hereinbefore by L¹ (e.g. chloro) and R³, X¹, X², X^a, X^b, X^c, X^d, X^f, X⁹ and R⁴ are as hereinbefore defined, under standard reaction conditions e.g. in the presence of base (e.g. a metal alkyl oxide, such as potassium terf-butoxide) in a suitable solvent (e.g. a polar aprotic solvent such as THF) under reflux reaction conditions; (vii) for compounds of formula I in which R¹ and R² both represent -O- (and preferably X represents C₂ or, especially, C₃ alkylene), reaction of a compound of formula XII,

wherein L^1a and L^2a each independently represent a suitable leaving group such as one defined hereinbefore by L¹ (e.g. chloro) and R³, X¹, X², X^a, X^b, X°, X^d, X^f, X⁹ and R⁴ are as hereinbefore defined, with a compound of formula XIII,

HO-X-OH XIII wherein X is as hereinbefore defined (preferably C₃ alkylene), under reaction conditions such as basic conditions, e.g. in the presence of an inorganic base (such as NaH or the like) in a suitable solvent (such as a polar aprotic solvent, e.g. DMF);

(viii) for compounds of formula I in which X represents alkylene substituted by a methyl group, an intramolecular addition reaction of a compound of formula XIV,

wherein either Q ^a or Q^2a represents -CH₂-CH₂=CH₂ and the other represents -OH (and R³, X¹, X², X^a, X^b, X^c, X^d, X^f, X⁹ and R⁴ are as hereinbefore defined), under addition reaction conditions, for instance in the presence of an organic acid (e.g. para-toluene sulfonic acid), in an appropriate solvent (e.g. an aromatic solvent, such as toluene) for instance under reflux reaction conditions;

(ix) for compounds of formula I in which X² represents -N=, reaction of a compound of formula XIVA,

wherein R¹, R², X, R³ and X¹ are as hereinbefore defined, with a compound of formula XIVB,

wherein X^a, X^b, X^c, X^d, X^f, X⁹ and R⁴ are as hereinbefore defined, in the presence of appropriate reaction conditions, such as reaction in the presence of a suitable solvent (e.g. an alcoholic solvent such as ethanol) for instance at elevated temperature (e.g. at reflux), which reaction mixture may then be concentrated and taken up in another solvent (e.g. dichloromethane) in the presence of a suitable reagent (e.g. iodobenzene diacetate) to allow reaction to continue. Compounds of formula II may be prepared by reaction of a compound of formula IV with a compound of formula XV,

wherein L¹, L⁴, X^a, X^b, X^c, X^d, X^f and X⁹ are as hereinbefore defined under reaction conditions such as those hereinbefore described in respect of process step (ii) above.

Compounds of formula IV may be prepared by reaction of a compound of formula XVI,

XVI

wherein R³, X¹, X², R¹, R² and X are as hereinbefore defined, for example by reaction in the presence of a source of halide (e.g. bromide) ions, for instance an electrophile that provides a source of iodide ions includes iodine, diiodoethane, diiodotetrachloroethane or, preferably, /V-iodosuccinimide, a source of bromide ions includes /V-bromosuccinimide and bromine, and a source of chloride ions includes N-chlorosuccinimide, chlorine and iodine monochloride, for instance in the presence of a suitable solvent, such as an alcohol (e.g. methanol) or, preferably a halogenated solvent (e.g. chloroform), and which reaction may take place under microwave irradiation conditions (e.g. at above 100°C, such as at about 120°C) or may alternatively take place in the presence of a suitable base, such as a weak inorganic base, e.g. sodium bicarbonate.

Compounds of formula VI may be prepared by reaction of a compound of formula XVII,

wherein L⁴ and L⁵ independently represent a suitable leaving group (e.g. chloro), and R³, L¹ are as hereinbefore defined, with a compound of formula XVIII,

H-R^1a-X-R^2a-H XVIII wherein R^1a, R^2a and X are as hereinbefore defined, under standard aromatic nucleophilic reaction conditions, for example in the presence of a base and solvent (such as one hereinbefore described in respect of process step (iv) above, e.g. NaOf-Bu in the presence of a solvent such as acetonitrile) or under reaction conditions such as those described in respect of process step (ii) above. Compounds of formula XVI may be prepared by reaction of a compound of formula VI as hereinbefore defined, with a compound of formula XIX, H-C(0)-N(H)-NH₂ XIX for example under reaction conditions described herein (e.g. process step (iii) above).

Other specific transformation steps (including those that may be employed in order to form compounds of formula I) that may be mentioned include:

(i) reductions, for example of a carboxylic acid (or ester) to either an aldehyde or an alcohol, using appropriate reducing conditions (e.g. -C(0)OH (or an ester thereof), may be converted to a -C(0)H or -CH₂-OH group, using DIBAL and UAIH₄, respectively (or similar chemoselective reducing agents));

(ii) reductions of an aldehyde (-C(O)H) group to an alcohol group (-CH₂OH), using appropriate reduction conditions such as those mentioned at point (i) above;

(iii) oxidations, for example of a moiety containing an alcohol group (e.g. -CH₂OH) to an aldehyde (e.g. -C(O)H), for example in the presence of a suitable oxidising agent, e.g. Mn0₂ or the like;

(iv) reductive amination of an aldehyde and an amine, under appropriate reaction conditions, for example in "one-pot" procedure in the presence of an appropriate reducing agent, such as a chemoselective reducing agent such as sodium cyanoborohydride or, preferably, sodium triacetoxyborohydride, or the like. Alternatively, such reactions may be performed in two steps, for example a condensation step (in the presence of e.g. a dehydrating agent such as trimethyl orthoformate or MgS0₄ or molecular sieves, etc) followed by a reduction step (e.g. by reaction in the presence of a reducing agent such as a chemoselective one mentioned above or NaBH₄, AIH₄, or the like), for instance the conversion of -NH₂ to -N(H)-isopropyl by condensation in the presence of acetone (H₃C-C(0)-CH₃) followed by reduction in the presence of a reducing agent such as sodium cyanaoborohydride (i.e. overall a reductive amination);

(iv) amide coupling reactions, i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example when R² represents -C(0)OH (or an ester thereof), it may be converted to a -C(O)N(R^10b)R^11b group (in which R^10b and R^11b are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. when R² represents -C(O)OH) be performed in the presence of a suitable coupling reagent (e.g. 1 ,1'-carbonyldiimidazole, Ν,Ν- dicyclohexylcarbodiimide, or the like) or, in the case when R² represents an ester (e.g. -C(0)OCH₃ or -C(0)OCH₂CH₃), in the presence of e.g. trimethylaluminium, or, alternatively the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula HN(R^10a)R^11a (in which R^10a and R ^1a are as hereinbefore defined), under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere);

(v) amide coupling reactions, i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example when R² represents -C(0)OH (or an ester thereof), it may be converted to a -C(O)N(R^10b)R^11b group (in which R^10b and R^{1 b} are as hereinbefore defined, and may be linked together, e.g. as defined above), and which reaction may (e.g. when R² represents -C(O)OH) be performed in the presence of a suitable coupling reagent (e.g. 1 ,1'-carbonyldiimidazole, Ν,Ν¹- dicyclohexylcarbodiimide, or the like) or, in the case when R² represents an ester (e.g. -C(0)OCH₃ or -C(0)OCH₂CH₃), in the presence of e.g. trimethylaluminium, or, alternatively the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula HN(R^10a)R^11a (in which R^10a and R^11a are as hereinbefore defined), under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere);

(vi) conversion of a primary amide to a nitrile functional group, for example under dehydration reaction conditions, e.g. in the presence of POCI₃, or the like;

(vii) nucleophilic substitution reactions, where any nucleophile replaces a leaving group, e.g. methylsulfonylpiperazine may replace a chloro leaving group;

(viii) transformation of a methoxy group to a hydroxy group, by reaction in the presence of an appropriate reagent, such as boron fluoride-dimethyl sulfide complex or BBr₃ (e.g. in the presence of a suitable solvent such as dichloromethane);

(ix) alkylation, acylation or sulfonylation reactions, which may be performed in the presence of base and solvent (such as those described hereinbefore in respect of preparation of compounds of formula I, process step (iv) above, for instance, a -N(H)- or -OH or -NH₂ (or a protected version of the latter) moiety may be alkylated, acylated or sulfonylated by employing a reactant that is an alkyl, acyl or sulfonyl moiety attached to a leaving group (e.g. d-s alkyl-halide (e.g. ethylbromide), alkyl-C(0)-halide (e.g. H₃C-C(0)CI), an anhydride (e.g. H₃C- C(0)-0-C(0)-CH₃, i.e. "-0-C(0)-CH₃" is the leaving group), dimethylformamide (i.e. -N(CH₃)₂ is the leaving group) or a sulfonyl halide (e.g. H₃C-S(0)₂CI) and the like);

(x) specific deprotection steps, such as deprotection of an ΛΖ-Boc protecting group by reaction in the presence of an acid, or, a hydroxy group protected as a silyl ether (e.g. a terf-butyl-dimethylsilyl protecting group) may be deprotected by reaction with a source of fluoride ions, e.g. by employing the reagent tetrabutylammonium fluoride (TBAF).

Intermediate compounds described herein are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. Further, processes to prepare compounds of formula I may be described in the literature, for example in:

Werber.G. et al.; J. Heterocycl. Chem.; EN; 14; 1977; 823-827;

Andanappa K. Gadad et al. Bioorg. Med. Chem. 2004, 12, 5651-5659;

Paul Heinz et al. Monatshefte fur Chemie, 1977, 108, 665-680;

M.A. El-Sherbeny et al. Boll. Chim. Farm. 1997, 136, 253-256;

Nicolaou, K. C; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 2-49;

Bretonnet et al. J. Med. Chem. 2007, 50, 1872 ;

Asuncion Marin et al. Farmaco 1992, 47 (1), 63-75;

Severinsen, R. et al. Tetrahedron 2005, 61, 5565-5575;

Nicolaou, K. C; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 2-49;

M. Kuwahara et al., Chem. Pharm Bull., 1996, 44, 122;

Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65(20), 6319-6337;

Shintani, R.; Okamoto, K. Org. Lett. 2005, 7 (21), 4757-4759;

Nicolaou, K. C; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 2-49;

J. Kobe et al., Tetrahedron, 1968, 24, 239 ;

P.F. Fabio, A.F. Lanzilotti and S.A. Lang, Journal of Labelled Compounds and Pharmaceuticals, 1978, 15, 407;

F.D. Bellamy and K. Ou, Tetrahedron Lett, 1985, 25, 839; M. Kuwahara et al., Chem. Pharm Bull., 1996, 44, 122;

A.F. Abdel-Magid and C.A Maryanoff. Synthesis, 1990, 537;

M. Schlosser et al. Organometallics in Synthesis. A Manual, (M. Schlosser, Ed.), Wiley &Sons Ltd: Chichester, UK, 2002, and references cited therein;

L. Wengwei et al. , Tetrahedron Lett. , 2006, 47, 1941 ;

M. Plotkin et al. Tetrahedron Lett., 2000, 41, 2269;

Seyden-Penne, J. Reductions by the Alumino and Borohydrides, VCH, NY, 1991;

O. C. Dermer, Chem. Rev., 1934, 14, 385;

N. Defacqz, et al., Tetrahedron Lett., 2003, 44, 9111 ;

S.J. Gregson et al., J. Med. Chem., 2004, 47, 1161;

A. M. Abdel Magib, et ai, J. Org. Chem., 1996, 61, 3849;

A.F. Abdel-Magid and C.A Maryanoff. Synthesis, 1990, 537;

T. Ikemoto and M. Wakimasu, Heterocycles, 2001, 55, 99;

E. Abignente et al., II Farmaco, 1990, 45, 1075;

T. Ikemoto et al., Tetrahedron, 2000, 56, 7915;

T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley,

NY, 1999;

S. Y. Han and Y.-A. Kim. Tetrahedron, 2004, 60, 2447;

J. A. H. Lainton et al., J. Comb. Chem., 2003, 5, 400; or

Wiggins, J. M. Synth. Commun., 1988, 18, 741.

The substituents R¹, R², R³, R⁴ and X in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.

For example, when substituents in the compounds of the invention such as C0₂Et, CHO, CN and/or CH₂CI, are present, these groups can be further derivatized to other fragments described (e.g. by those integers mentioned above) in compounds of the invention, following synthetic protocols very well know to the person skilled in the art and/or according to the experimental part described in the patent. Other specific transformation steps that may be mentioned include: the reduction of a nitro or azido group to an amino group; the hydrolysis of a nitrile group to a carboxylic acid group; and standard nucleophilic aromatic substitution reactions, for example in which an iodo-, preferably, fluoro- or bromo-phenyl group is converted into a cyanophenyl group by employing a source of cyanide ions (e.g. by reaction with a compound which is a source of cyano anions, e.g. sodium, copper (I), zinc or potassium cyanide, optionally in the presence of a palladium catalyst) as a reagent (alternatively, in this case, palladium catalysed cyanation reaction conditions may also be employed).

Other transformations that may be mentioned include: the conversion of a halo group (preferably iodo or bromo) to a 1-alkynyl group (e.g. by reaction with a 1- alkyne), which latter reaction may be performed in the presence of a suitable coupling catalyst (e.g. a palladium and/or a copper based catalyst) and a suitable base (e.g. a tri-(C_1-6 alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine); the introduction of amino groups and hydroxy groups in accordance with standard conditions using reagents known to those skilled in the art; the conversion of an amino group to a halo, azido or a cyano group, for example via diazotisation (e.g. generated in situ by reaction with NaN0₂ and a strong acid, such as HCI or H₂S0₄, at low temperature such as at 0°C or below, e.g. at about -5°C) followed by reaction with the appropriate nucleophile e.g. a source of the relevant anions, for example by reaction in the presence of a halogen gas (e.g. bromine, iodine or chlorine), or a reagent that is a source of azido or cyanide anions, such as NaN₃ or NaCN; the conversion of -C(0)0H to a -NH₂ group, under Schmidt reaction conditions, or variants thereof, for example in the presence of HN₃ (which may be formed in by contacting NaN₃ with a strong acid such as H₂S0₄), or, for variants, by reaction with diphenyl phosphoryl azide ((PhO)₂P(0)N₃) in the presence of an alcohol, such as tert-butanol, which may result in the formation of a carbamate intermediate; the conversion of -C(0)NH₂ to -NH_2> for example under Hofmann rearrangement reaction conditions, for example in the presence of NaOBr (which may be formed by contacting NaOH and Br₂) which may result in the formation of a carbamate intermediate; the conversion of -C(0)N₃ (which compound itself may be prepared from the corresponding acyl hydrazide under standard diazotisation reaction conditions, e.g. in the presence of NaN0₂ and a strong acid such as H₂S0₄ or HCI) to -NH₂, for example under Curtius rearrangement reaction conditions, which may result in the formation of an intermediate isocyanate (or a carbamate if treated with an alcohol); the conversion of an alkyl carbamate to -NH₂, by hydrolysis, for example in the presence of water and base or under acidic conditions, or, when a benzyl carbamate intermediate is formed, under hydrogenation reaction conditions (e.g. catalytic hydrogenation reaction conditions in the presence of a precious metal catalyst such as Pd); halogenation of an aromatic ring, for example by an electrophilic aromatic substitution reaction in the presence of halogen atoms (e.g. chlorine, bromine, etc, or an equivalent source thereof) and, if necessary an appropriate catalyst/Lewis acid (e.g. AICI₃ or FeCI₃).

Compounds of the invention bearing a carboxyester functional group may be converted into a variety of derivatives according to methods well known in the art to convert carboxyester groups into carboxamides, N-substituted carboxamides, Ν,Ν-disubstituted carboxamides, carboxylic acids, and the like. The operative conditions are those widely known in the art and may comprise, for instance in the conversion of a carboxyester group into a carboxamide group, the reaction with ammonia or ammonium hydroxide in the presence of a suitable solvent such as a lower alcohol, dimethylformamide or a mixture thereof; preferably the reaction is carried out with ammonium hydroxide in a methanol/dimethyl- formamide mixture, at a temperature ranging from about 50°C to about 100°C. Analogous operative conditions apply in the preparation of N-substituted or N,N- disubstituted carboxamides wherein a suitable primary or secondary amine is used in place of ammonia or ammonium hydroxide. Likewise, carboxyester groups may be converted into carboxylic acid derivatives through basic or acidic hydrolysis conditions, widely known in the art. Further, amino derivatives of compounds of the invention may easily be converted into the corresponding carbamate, carboxamido or ureido derivatives.

Compounds of the invention may be isolated from their reaction mixtures using conventional techniques (e.g. recrystallisations). It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods (and the need can be readily determined by one skilled in the art). Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethyleneoxycarbonyl (Fmoc) and 2,4,4-trimethylpentan-2-yl (which may be deprotected by reaction in the presence of an acid, e.g. HCI in water/alcohol (e.g. MeOH)) or the like. The need for such protection is readily determined by one skilled in the art.

The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.

Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.

The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3^rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).

Medical and Pharmaceutical Uses Compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined, for use as a pharmaceutical.

Compounds of the invention may inhibit protein or lipid kinases, such as a PI M family kinase such as PIM-1 , PIM-2 and/or PIM-3, for example as may be shown in the tests described below and/or in tests known to the skilled person. Thus, the compounds of the invention may be useful in the treatment of those disorders in an individual in which the inhibition of such protein or lipid kinases (e.g. a PIM family kinase such as PIM-1, PIM-2 and/or PI -3) is desired and/or required.

The term "inhibit" may refer to any measurable reduction and/or prevention of catalytic kinase (e.g. a PIM family kinase such as PIM-1, PIM-2 and/or PIM-3) activity. The reduction and/or prevention of kinase activity may be measured by comparing the kinase activity in a sample containing a compound of the invention and an equivalent sample of kinase (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) in the absence of a compound of the invention, as would be apparent to those skilled in the art. The measurable change may be objective (e.g. measurable by some test or marker, for example in an in vitro or in vivo assay or test, such as one described hereinafter, or otherwise another suitable assay or test known to those skilled in the art) or subjective (e.g. the subject gives an indication of or feels an effect).

Compounds of the invention may be found to exhibit 50% inhibition of a protein or lipid kinase (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) at a concentration of 100 μΜ or below (for example at a concentration of below 50 μΜ, or even below 10 μΜ, such as below 1 μΜ), when tested in an assay (or other test), for example as described hereinafter, or otherwise another suitable assay or test known to the skilled person. Compounds of the invention are thus expected to be useful in the treatment of a disorder in which a protein or lipid kinase (e.g. a PIM family kinase such as PIM- 1 , PIM-2 and/or PIM-3) is known to play a role and which are characterised by or associated with an overall elevated activity of that protein kinase (due to, for example, increased amount of the kinase or increased catalytic activity of the kinase). Compounds of the invention (alone or in combination with another active) may be shown to be active e.g. in the biochemical assays described herein, may be shown to have predictive activity based on e.g. the phosphorylation assay described herein, and/or may reduce the rate of cell proliferation e.g. as may be shown in the cell proliferation assays described herein (for instance using cancer cell lines (e.g. known commercially available ones), such as those described herein).

Hence, compounds of the invention are expected to be useful in the treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with the protein or lipid kinase (e.g. a PIM family kinase such as PIM- 1 , PIM-2 and/or PIM-3). Such conditions/disorders include cancer, immune disorders, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders and neurological disorders. Compounds of the invention (particular PIM-1 inhibitors) may also be useful in the treatment of pulmonary artery hypertension (PAH).

The disorders/conditions that the compounds of the invention may be useful in treating hence includes cancer (such as lymphomas, solid tumours or a cancer as described hereinafter), obstructive airways diseases, allergic diseases, inflammatory diseases (such as asthma, allergy and Chrohn's disease), immunosuppression (such as transplantation rejection and autoimmune diseases), disorders commonly connected with organ transplantation, AIDS- related diseases and other associated diseases. Other associated diseases that may be mentioned (particularly due to the key role of kinases in the regulation of cellular proliferation) include other cell proliferative disorders and/or non- malignant diseases, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, bone disorders, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis. Other disease states that may be mentioned include cardiovascular disease, stroke, diabetes, hepatomegaly, Alzheimer's disease, cystic fibrosis, hormone- related diseases, immunodeficiency disorders, destructive bone disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukaemia, liver disease, pathologic immune conditions involving T cell activation and CNS disorders.

As stated above, the compounds of the invention may be useful in the treatment of cancer. More, specifically, the compounds of the invention may therefore be useful in the treatment of a variety of cancer including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including non-small cell cancer and small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, skin, squamous cell carcinoma, testis, genitourinary tract, larynx, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma, lung adenocarcinoma, bone, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papilliary carcinoma, seminona, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukaemia; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.

Further, the protein or lipid kinases (e.g. a PIM family kinase such as PIM-1 , PIM- 2 and/or PIM-3) may also be implicated in the multiplication of viruses and parasites. They may also play a major role in the pathogenesis and development of neurodegenerative disorders. Hence, compounds of the invention may also be useful in the treatment of viral conditions, parasitic conditions, as well as neurodegenerative disorders.

Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.

According to a further aspect of the present invention, there is provided a method of treatment of a disease (e.g. cancer or another disease as mentioned herein) which is associated with the inhibition of protein or lipid kinase (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) is desired and/or required (for example, a method of treatment of a disease/disorder arising from abnormal cell growth, function or behaviour associated with protein or lipid kinases, e.g. a PIM family kinase such as PIM-1, PIM-2 and/or PIM-3), which method comprises administration of a therapeutically effective amount of a compound of the invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition. "Patients" include mammalian (including human) patients. Hence, the method of treatment discussed above may include the treatment of a human or animal body.

The term "effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (e.g. measurable by some test or marker) or subjective (e.g. the subject gives an indication of or feels an effect).

Compounds of the invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.

Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. The type of pharmaceutical formulation may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.

Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques and/or in accordance with standard and/or accepted pharmaceutical practice.

According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.

Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.

The amount of compound of the invention in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.

The invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.

Compounds of the invention may also be combined with other therapeutic agents that are inhibitors of protein or lipid kinases (e.g. a PIM family kinase such as PIM-1 , PIM-2 and/or PIM-3) and/or useful in the treatment of a cancer and/or a proliferative disease. Compounds of the invention may also be combined with other therapies (e.g. radiation).

For instance, compounds of the invention may be combined with one or more treatments independently selected from surgery, one or more anti-cancer/anti- neoplastic/anti-tumoral agent, one or more hormone therapies, one or more antibodies, one or more immunotherapies, radioactive iodine therapy, and radiation. More specifically, compounds of the invention may be combined with an agent that modulates the Ras/Raf/Mek pathway (e.g. an inhibitor of MEK), the Jak Stat pathway (e.g. an inhibitor of Jak), the PI3K/Akt pathway (e.g. an inhibitor of Akt), the DNA damage response mechanism (e.g. an inhibitor of ATM or ATR) or the stress signaling pathway (an inhibitor of p38 or NF- B).

For instance, compounds of the invention may be combined with:

(i) a targeted kinase inhibitor;

(ii) a receptor tyrosine kinase (RTK) inhibitor;

(iii) an Akt or PI3-K inhibitor, such as GDC-0941;

(iv) an Flt-3 inhibitor;

(v) an EGFR or HER2 inhibitor, such as lapatanib;

(vi) a therapeutic monoclonal antibody, such as the HER2 inhibitor trastuzumab;

(vii) a MEK inhibitor, such as PD-0325901;

(vii) a BRaf inhibitor, such as GDC-0879;

(viii) an anthracyclin, such as doxorubicin;

(ix) a taxane, such as paclitaxel or, particularly, docetaxel (Taxotere);

(x) a platin, such as carboplatin or, particularly, cisplatin;

(xi) a nucleotide analog, such as 5-fluorouracil (5-FU) or gemcitabine);

(xii) an alkylating agent, such as temozolomide;

(xiii) a hormone therapeutic agent, such as an estrogen receptor antagonist e.g. tamoxifen;

(xiv) an anti-tumour compound that has potential radiosensitising and/or chemosensitising effects, such as chloroquine;

(xv) an mTOR inhibitor, such as rapamycin;

(xvi) a JAK inhibitor;

(xvii) a cyclin dependent kinase inhibitor (e.g. a CDK6 or CDK4 inhibitor, such as PD-0332991); and/or (xviii) an agent that modulates the DNA damage response mechanism and/or the stress signaling pathway, e.g. an inhibitor of ATM or ATR, an inhibitor of p38 and/or NF- B. According to a further aspect of the invention, there is provided a combination product comprising:

(A) a compound of the invention, as hereinbefore defined; and

(B) another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease (e.g. another therapeutic agent as described herein, for instance in the examples),

wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).

Thus, there is further provided:

(1) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(2) a kit of parts comprising components:

(a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

In a particularly preferred aspect of the invention, compounds of the invention may be combined with other therapeutic agents (e.g. chemotherapeutic agents) for use as medicaments (e.g. for use in the treatment of a disease or condition as mentioned herein, such as one in which the inhibition of growth of cancer cells are required and/or desired e.g. for treating hyperproliferative disorders such as cancer (e.g. specific cancers that may be mentioned herein, e.g. in the examples) in mammals, especially humans). Such active ingredients in combinations may act in synergy.

In particular, compounds of the invention may be combined with known chemotherapeutic agents (as may be demonstrated by the examples, for instance where a compound of the examples is employed in combination and inhibits cellular proliferative in vitro), for instance:

(i) a PI3K inhibitor, such as GDC-0941 ;

(ii) an EGFR inhibitor, such as Lapatinib;

(iii) a BRaf inhibitor such as GDC-0879;

(iv) docetaxel (Taxotere®, Sanofi-Aventis);

(v) a MEK inhibitor, such as PD-0325901 ; and/or

(vi) a CDK4 inhibitor, such as PD-0332991.

The MEK inhibitor PD-0325901 (CAS RN 391210-10-9, Pfizer) is a second- generation, non-ATP competitive, allosteric MEK inhibitor for the potential oral tablet treatment of cancer (US6960614; US 6972298; US 2004/1147478; US 2005/085550). Phase II clinical trials have been conducted for the potential treatment of breast tumors, colon tumors, and melanoma. PD-0325901 is named (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benz- amide, and has the structure:

Docetaxel (TAXOTERE®, Sanofi-Aventis) is used to treat breast, ovarian, and NSCLC cancers (US 4814470; US 5438072; US 5698582; US 5714512; US 5750561 ; Mangatal et al (1989) Tetrahedron 45:4177; Ringel et al (1991) J. Natl. Cancer Inst. 83:288; Bissery et al(1991) Cancer Res. 51 :4845; Herbst et al (2003) Cancer Treat. Rev. 29:407-415; Davies et al (2003) Expert. Opin. Pharmacother. 4:553-565). Docetaxel is named as (2R,3S)-N-carboxy-3- phenylisoserine, N-tert-butyl ester, 13-ester with 5, 20-epoxy-1 , 2, 4, 7, 10, 13- hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate (US 4814470; EP 253738; CAS Reg. No. 114977-28-5) (or named as 1 ,7 ,10 -trihydroxy-9-oxo- SP^O-epoxytax-H-ene^dAISa-triyl 4-acetate 2-benzoate 13-{(2R,3S)-3-[(terf- butoxycarbonyl)amino -2-hydroxy-3-phenylpropanoate}) and has the structure:

Lapatinib (TYKERB®, GW572016, Glaxo SmithKline) has been approved for use in combination with capecitabine (XELODA®, Roche) for the treatment of patients with advanced or metastatic breast cancer whose tumors over-express HER2 (ErbB2) and who have received prior therapy including an anthracycline, a taxane and trastuzumab. Lapatinib is an ATP-competitive epidermal growth factor (EGFR) and HER2/neu (ErbB-2) dual tyrosine kinase inhibitor (US 6727256; US 6713485; US 7109333; US 6933299; US 7084147; US 7157466; US 7141576) which inhibits receptor autophosphorylation and activation by binding to the ATPbinding pocket of the EGFRIHER2 protein kinase domain. Lapatinib is named as N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2-(methylsulfonyl)ethylamino)- methyl)furan-2-yl)quinazolin-4-amine (or alternatively named as /V-[3-chloro-4-[(3- fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl] quinazolin-4-amine), and has the structure:

The invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with the other therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier. By "bringing into association", we mean that the two components are rendered suitable for administration in conjunction with each other.

Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components "into association with" each other, we include that the two components of the kit of parts may be:

(i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or

(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

Depending on the disorder, and the patient, to be treated, as well as the route of administration, compounds of the invention may be administered at varying therapeutically effective doses to a patient in need thereof. However, the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease. Administration may be continuous or intermittent (e.g. by bolus injection). The dosage may also be determined by the timing and frequency of administration. In the case of oral or parenteral administration the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of the invention. In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Compounds of the invention may have the advantage that they are effective inhibitors of protein or lipid kinases (e.g. a PIM family kinase such as PIM-1 , PIM- 2 and/or PIM-3). Advantagouesly, when compounds of the invention are employed in combination with known chemotherapeutic agents (such as those described herein), the components of the combinations may act in a synergistic manner.

Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above- stated indications or otherwise.

Compounds of the invention may be beneficial as they are medicaments with targeted therapy, i.e. which target a particular molecular entity by inferring or inhibiting it (e.g. in this case by inhibiting one or more protein or lipid kinases as hereinbefore described). Compounds of the invention may therefore also have the benefit that they have a new effect (for instance as compared to known compounds in the prior art), for instance, the new effect may be a particular mode of action or another effect resultant of the targeted therapy. Targeted therapies may be beneficial as they may have the desired effect (e.g. reduce cancer, by reducing tumor growth or carcinogenisis) but may also have the advantage of reducing side effects (e.g. by preventing the killing of normal cells, as may occur using e.g. chemotherapy).

Furthermore, compounds of the invention may selectively target particular protein or lipid kinases (e.g. the ones described herein) compared to other known protein or lipid kinases (as may be shown experimentally hereinafter). Accordingly, compounds of the invention may have the advantage that certain, specific, cancers may be treated selectively, which selective treatment may also have the effect of reducing side effects. Examples/Biological Tests

PIM-1 biochemical assay

The biochemical assay to measure PIM-1 activity relies on the ADP Hunter assay kit (DiscoveRx Corp., Cat. # 90-0077), that determines the amount of ADP as direct product of the kinase enzyme activity.

The enzyme has been expressed and purified in-house as a recombinant human protein with a C-terminal histidine tag. The protein is active and stable.

Assay conditions were as indicated by the kit manufacturers with the following adaptations for the kinase activity step:

Kinase assay buffer and assay volume stay as recommended (15 mM HEPES, pH 7.4, 20 mM NaCI, 1 mM EGTA, 0.02% Tween 20, 10 mM MgCI₂ and 0.1 mg/ml bovine y-globulins/75 μΙ assay volume)

Incubation time and temperature: 60 min at 30°C

PIM-1 concentration: 50 pg/μΙ

ATP concentration: 100 μΜ

PIM-1 substrate peptide: PIMtide (ARKRRRHPSGPPTA) • Peptide concentration: 60 μΜ

• Positive control for kinase activity inhibition: 1-10 μΜ Staurosporine

• DMSO concentration have to stay below 2% during the kinase reaction Assays were performed in either 96 or 384-well plates. The final outcome of the coupled reactions provided by the kit is the release of the fluorescent product Resorufin and has been measured with a multilabel HTS counter VICTOR V (PerkinElmer) using an excitation filter at 544 nm and an emission filter at 580 nm.

PIM-2 biochemical assay

The biochemical assay to measure PIM-2 activity relies on the ADP Hunter assay kit (DiscoveRx Corp., Cat. # 90-0077), that determines the amount of ADP as direct product of the kinase enzyme activity.

The enzyme has been expressed and purified in-house as a recombinant human protein with a N-terminal histidine tag. The protein is active and stable.

• Kinase assay buffer and assay volume stay as recommended (15 mM HEPES, pH 7.4, 20 mM NaCI, 1 mM EGTA, 0.02% Tween 20, 10 mM MgCI₂ and 0.1 mg/ml bovine y-globulins/20 μΙ assay volume)

• Incubation time and temperature: 30 min at 30°C

• PIM-2 concentration: 350 pg/μΙ

• ATP concentration: 100 μΜ

• PIM-1 substrate peptide: PIMtide (ARKRRRHPSGPPTA)

· Peptide concentration: 100 μΜ

• Positive control for kinase activity inhibition: 1-10 μΜ Staurosporine

• DMSO concentration have to stay below 2% during the kinase reaction

Assays were performed in either 96 or 384-well plates. The final outcome of the coupled reactions provided by the kit is the release of the fluorescent product Resorufin and has been measured with a multilabel HTS counter VICTOR V (PerkinElmer) using an excitation filter at 544 nm and an emission filter at 580 nm. PIM-3 biochemical assay

The biochemical assay to measure PIM-3 activity relies on the ADP Hunter assay kit (DiscoveRx Corp., Cat. # 90-0077), that determines the amount of ADP as direct product of the kinase enzyme activity.

The enzyme has been bought from Millipore (# 14-738). The protein is active and stable.

· Incubation time and temperature: 30 min at 30°C

• PIM-3 concentration: 250 pg/μΙ

• ATP concentration: 100 μΜ

• PIM-1 substrate peptide: PIMtide (ARKRRRHPSGPPTA)

• Peptide concentration: 60 μΜ

· Positive control for kinase activity inhibition: 1-10 μΜ Staurosporine

• DMSO concentration have to stay below 2% during the kinase reaction

Assays were performed in either 96 or 384-well plates. The final outcome of the coupled reactions provided by the kit is the release of the fluorescent product Resorufin and has been measured with a multilabel HTS counter VICTOR V (PerkinElmer) using an excitation filter at 544 nm and an emission filter at 580 nm. BAD S112 Phosphorylation inhibition assay

Efficacy of compounds of the invention on the inhibition of Bad phosphorylation was measured by an In Cell ELISA. EC50 values were established for the tested compounds.

Assay conditions:

Cells: H1299 cells overexpressing Pim1 (H1299Pim1)

DMSO Plates: 96-well- Polystyrene, Untreated, Round-Bottom plates from Costar (Cat #3797)

Cell Plates: 96-Flat bottom biocoated with Poly-D-Lysin plates with lid from Becton Dickinson (Cat#354651)

Cell Culture Medium: DMEM high glucose, 10% Fetal Bovine Serum, 2mM L- Glutamine, P/S

Antibodies: phosphor Bad S112 antibody from Cell Signaling (cat. #9291S), anti rabbit conjugated with peroxidise from Amersham (cat.#3619)

Reagent: SuperSignal ELISA femto from Pierce (cat.#1001110)

Procedure:

Cells were seeded in 15000 cells per 200 μΙ per well into 96-well plates and incubated for 16 h at 37°C, 5% C0₂. On day two, nine serial 1 :2 compound dilutions were made in DMSO in a 96-well plate. The compounds were added to duplicate wells in 96-well cell plates using a FX BECKMAN robot (Beckman Coulter) and were incubated at 37°C under C0₂ atmosphere in medium without FBS. After 4 hours, relative levels of Bad S112 phosphorylation were measured in Cell ELISA using SuperSignal ELISA Femto substrate (Pierce) and read on VICTOR (Perkin Elmer). EC50 values were calculated using ActivityBase from IDBS. MTT in vitro cell proliferarion assay

Proliferation assays (MTT) were performed as described in:

"Chemical interrogation of FOX03a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases", W. Link, J. Oyarzabal, B.G. Serelde, M.I. Albarran, O. Rabal, A. Cebria.P. Alfonso, J. Fominaya, O. Renner, S. Peregrina, D. Soilan, P.A. Ceballos, A.I. Hernandez, M. Lorenzo, P. Pevarello, T.G. Granda, G. Kurz, A. Carnero, J.R. Bischoff, J. Biol. Chem. 284 (2009) 28392-28400. Combination assay

The combination index (CI) of combinations of certain example compounds and various chemotherapeutic agents in the MTT in vitro cell proliferarion assays were tested. A combination index score was calculated by the Chou and Talalay method (CalcuSyn software, Biosoft). The strength of synergy was scored using the ranking system Chou and Talalay: CI less than 0.8 indicates synergy, CI between 0.8 and 1.2 indicates additivity and CI greater than 1.2 indicates antagonism.

The EC50 values of representative combinations were also calculated. The individually measured EC50 values of the chemotherapeutic agent and the example compounds were compared to the EC50 value of the combination. The cell lines were characterised by tumor type.

Combination assays were performed as described in:

"Pirn 1 kinase inhibitor ETP-45299 suppresses cellular proliferation and synergizes with PI3K inhibition". Blanco-Aparicio, Carmen; Collazo, Ana Maria

Garcia; Oyarzabal, Julen; Leal, Juan F.; Albaran, Maria Isabel; Lima, Francisco

Ramos; Pequeno, Belen; Ajenjo, Nuria; Becerra, Mercedes; Alfonso, Patricia;

Reymundo, Maria Isabel; Palacios, Irene; Mateos, Genoveva; Quinones, Helena; Corrionero, Ana; Carnero, Amancio; Pevarello, Paolo; Lopez, Ana Rodriguez;

Fominaya, Jesus; Pastor, Joaquin; Bischoff, James R. Cancer Letters (Shannon,

Ireland) 2011, 300(2), 145-153.

The invention is illustrated by way of the following examples.

The compound names given herein were generated with MDL ISIS/DRAW 2.5 SP 2, Autonom 2000. Experimental part:

The compound names given herein were generated with MDL ISIS/DRAW 2.5 SP 2, Autonom 2000.

Herein after, the term "AIBN" means 2,2'-azobis(2-methylpropionitrile), "BOP" means (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, "DCM" means dichloromethane, "DCE" means dichloroethane, "MeOH" means methanol, "THF" means tetrahydrofuran, "DMF" means dimethylformamide, "DME" means 1 ,2-dimethoxyethane, "EtOAc" means ethyl acetate, "DIPEA" means diisopropylethylamine, "TEA" means triethylamine, "BINAP" means (R i+J^^'-bisidiphenylphosphinoJ-l .l'-binaphtyl, "eq" means equivalents, "EtOH" means ethanol, "nBuOH" means n-butanol, "tBuOH" means tert-butanol, "DIAD" means diethylazodicarboxylate, "DavePhos" means 2- dicyclohexylphosphino-2'-(n,n-dimethylamino)biphenyl, "HATU" means 0-(7- azabenzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate, "Pd(PPh₃)₄" means tetrakis(triphenylphosphine)palladium, "Pd₂(dba)₃" means tris(dibenzylideneacetone)dipalladium(0), "Pd(dppf)CI₂.DCM" means 1 ,1'- bis(diphenylphosphino)ferrocenepalladium(ll) dichloride, dichloromethane, "NCS" means N-chlorosuccinimide, "NBS" means N-bromosuccinimide, "mw" means microwave, "RT" means room temperature, "CCTLC" means centrifugal circular thin-layer chromatography, "min" means minutes, "h" means hours.

General Procedure

NMR spectra were recorded in a Bruker Avance II 300 spectrometer and Bruker Avance II 700 spectrometer fitted with 5 mm QXI 700 S4 inverse phase, Z- gradient unit and variable temperature controller.

The HPLC measurements were performed using a HP 1100 from Agilent Technologies comprising a pump (binary) with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source or API/APCI. Nitrogen was used as the nebulizer gas. Data acquisition was performed with ChemStation LC/MSD quad, software.

Method 1

Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um). Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 5% to 100% of B within 8 min at 50 °C, DAD.

Method 2

Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um).

Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 5% to 40% of B within 8 min at 50 °C, DAD.

Method 3

Reversed phase HPLC was carried out on a Gemini-NX C18 (100 x 2.0 mm; 5um).

Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 0% to 30% of B within 8 min at 50 °C, DAD.

Method 4

Reversed phase HPLC was carried out on a Gemini C18 column (50 x 2 mm, 3 urn).

Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 10% to 95% of B within 4 min at 50°C, DAD.

Method 5

Reversed phase HPLC was carried out on a Gemini C18 column (50 x 2 mm, 3 urn). Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. Gradient: 0% to 30% of B within 4 min at 50°C, DAD.

"Found mass" refers to the most abundant isotope detected in the HPLC-MS.

GENERAL SYNTHETIC PROCEDURE FOR THE SYNTHESIS OF FINAL PRODUCTS BOC deprotection of the amino group was carried out using standard protocols, very well known for a person skilled in the art, such as reaction in acidic media, by using hydrochloric acid or trifluoroacetic acid, in the presence of an appropriate solvent or using an acid resin such as amberlyst. General Synthetic Procedure A

Example: Synthesis of final product 1

A mixture of intermediate I-2 (100 mg, 0.25 mmol), 1-Boc-4-(aminomethyl)piperidine (70 mg, 0.33 mmol), Pd₂(dba)₃ (100 mg, 0.12 mmol), Cs₂C0₃ (100 mg, 0.3 mmol), BINAP (16 mg, 0.02 mmol) in toluene (2 mL), was heated in a pressure tube under reflux for 48 h. The dark mixture was filtrated through a Celite pad and the filtrate was concentrated in vacuo. The dark residue was purified by Biotage flash column chromatography eluting with a solvent system of MeOH/DCM (from 0% to 10% on MeOH). Required product intermediate 1-1 (35 mg) was recovered as bright yellow solid.

A mixture of intermediate 1-1 (35 mg, 0.06 mmol) in MeOH (1.5 mL) with Amberlyst (200 mg) was slowly stirred at RT for 20 h. Solvent was removed and the resin was unbound by stirring three times with a 7 N solution of NH₃ in MeOH. Combined methanolic layers were concentrated in vacuo, leaving a bright yellow solid that was purified by preparative HPLC to obtain a yellow solid as final product 1, as a salt of formic acid (8 mg).

Example: Synthesis of final product 123

A mixture of intermediate I-2 (100 mg, 0.25 mmol), 7-oxa-2-azaspiro[3.5]nonane hydrochloride (70 mg, 0.3 mmol), Pd₂(dba)₃ (25 mg), DavePhos (20 mg) and tBuONa (60 mg, 0.20 mmol), in 1 ,4-dioxane (2 mL) was heated under microwave irradiation for 60 min at 130 °C. On cooling, the mixture was filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH/DCM, 0:100 to 15:85) to give final product 123 (10 mg). xample: Synthesis of final product 126

I-2 124 126

A mixture of tricycle I-2 (60 mg, 0.15 mmol), (3R,4S)-benzyl 4-(aminomethyl)-3- fluoropiperidine-1-carboxylate (60 mg, 0.21 mmol), Pd₂(dba)₃ (12 mg), BINAP (15 mg) and Cs₂C0₃ (75 mg, 0.22 mmol), in toluene (2 mL) was heated at reflux in a high pressure vial for 18 h. The dark mixture was cooled down to rt, filtered through a Celite pad and concentrated under reduced pressure. The dark crude was absorbed in silica and purified by Biotage flash column chromatography (25-S) eluting with a solvent system of MeOH/DCM (from 0% to 15% on MeOH). Required product was obtained as yellow-brown solid (20 mg) of final compound 124.

A solution of Final Product 124 (20 mg, 0.02 mmol) in TFA (0.8 mL) was heated at 70 °C for 1 h. On cooling, TFA was removed in vacuo. The residue was taken up in DCM/MeOH (5 mL 1 mL), NH₃ 7 M in MeOH was added to pH 7 and the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (Isolute Si II 5 g), (MeOH:DCM 0:100 to 5:95 and after with NH₃ 7 M in MeOH:DCM 3:97 to 5:95) and by prep-HPLC to give Final Product 126 (8 mg, 53%).

General Synthetic Procedure B

Example; Synthesis of final product 3

1-3 3

A mixture of intermediate 1-3 (17 mg, 0.05 mmol), aq. NaOH (0.5 M, 100 pL, 0.05 mmol) and H₂0₂ (35%, 20 pL, 0.17 mmol) in EtOH (0.5 mL) was heated at 50 °C for 1 h. The mixture was neutralised with aq. H₂S0₄ (5%) and extracted with DCM (3 x 10 mL). Combined organic layers were washed with brine (30 mL), dried over Na₂S0₄ and concentrated. The yellow residue was purified employing a chromatotron apparatus and eluting with a solvent system of MeOH/DCM (from 0% to 10% MeOH). Final product 3 was recovered as bright yellow solid (3 mg).

General Synthetic Procedure C

A mixture of intermediate I-2 (60 mg, 0.15 mmol), 4-(dimethylamino)phenylboronic acid (50 mg, 0.30 mmol), 2M aq. solution of Na₂C0₃ (0.5 mL), Pd(PPh₃)₄ (cat.) in a mixture of solvents, DME (1 mL), EtOH (0.25 mL) and water (0.65 mL) was heated under microwave irradiation at 100 °C for 10 min. Reaction mixture was partitioned between DCM (30 mL) and water (30 mL). Different layers were separated and the aqueous layer was re-extracted with DCM (3 x 10 mL). Combined organic layers were washed with sat. aq. NaHC0₃ (40 mL), brine (30 mL), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by Biotage flash column chromatography eluting with a solvent system of MeOH/DCM (from 0% to 20% on MeOH). Recovered required product was triturated with diethyl ether leaving a bright yellow solid as final product 6 (23 mg, 35%).

General Synthetic Procedure D

Example: Synthesis of final product 7

To a suspension of final product 8 (30 mg, 0.07 mmol) in DCM (2 mL) was added boron fluoride-dimethyl sulfide complex (120 μί, 1 mmol). The mixture turned dark red and was stirred at RT for 16 h. Aq. sat. solution of NaHC0₃ was added to the mixture until effervescense stopped, and the mixture was extracted with DCM (3 x 15 mL). Combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified employing a chromatotron apparatus and eluting with MeOH/DCM (from 0% to 5% on MeOH). Required final product was recovered as cream solid that was triturated with MeOH to afford final product 7 (3 mg). General Synthetic Procedure E

Example: Synthesis of final product 8

A mixture of intermediate 1-2 (100 mg, 0.25 mmol), 4-methoxyphenylboronic acid (46 mg, 0.30 mmol), PdCI₂(dppf) (cat. amount) and aq. sat. solution of K₂C0₃ (0.4 mL) in DME (2 mL) was heated under microwave irradiation at 140 °C for 45 min. Solvent was removed in vacuo and the residue was purified by Biotage flash column chromatography eluting with a solvent system of MeOH/DCM (from 0% to 15% on MeOH). Required product was recovered as cream solid (90 mg). 60 mg were tritured with MeOH, filtered and dried in vacuo, leaving a whiter solid, as final product 8 (45 mg).

General Synthetic Procedure F

Example: Synthesis of final product 10

1-6 10

A mixture of I-4 (150 mg, 0.8 mmol), I-5 (300 mg, 0.9 mmol) in EtOH (3 mL) was heated under reflux until reagents were consumed. Reaction mixture was cooled down to rt and solvents were removed in vacuo. The residue was re-dissolved in DCM (4 mL) and iodobenzene diacetate (270 mg, 0.8 mmol) was added. The resulting mixture was stirred at rt for 3 h. The mixture was quenched by adding sat. aq. solution of Na₂S₂0₃ and extracted with DCM (3 x 25 mL). Combined organic layers were washed with brine (30 mL), dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by Biotage flash column chromatography (25-S) eluting with a solvent system of MeOH/DCM (from 0% to 10% on MeOH) to obtain 35 mg of a yellow solid as intermediate I-6 and 45 mg of unreacted starting material 1-5. A mixture of intermediate 1-6 (35 mg, 0.07mmol) with Amberlyst (300 mg) in MeOH was slowly shaken for 24 h. Solvent was removed and the resin was unbound with MeOH/NH₃, stirring three times with a 7 M solution of NH₃ in MeOH. Combined methanolic layers were concentrated in vacuo, leaving a yellow residue that was purified to obtain 45 mg of final product 10.

General Synthetic Procedure G

Example: Synthesis of final product 12

To a suspension of intermediate I-7 (300 mg, 0.897 mmol) in THF (10.6 mL) at RT were added n-Boc-4-piperidinemethanol (212 mg, 0.987 mmol), triphenylphosphine (353 mg, 1.346 mmol), and DIAD (265 mg, 1.346 mmol). The resulting mixture was stirred for 2 days. The resulting mixture was partitioned between saturated NaHC0₃ and ethyl acetate. The combined organics were dried over Na₂S0₄, filtered and concentrated under reduced pressure to afford a yellow solid which was purified by biotage (DCM/MeOH) twice, to obtain 40 mg of intermediate 1-8.

1 mL of a 4N solution of HCI in dioxane was added to a solution of intermediate 1-8 (0.04 g, 0.075 mmol) in dioxane (1 mL). The reaction was stirred for 18 h at rt. Solvents were evaporated to dryness. Residue was azeotropically dried with toluene. The solid was purified on C18 (Water-ACN/Water) affording 12 mg of final compound, as a solid, final product 12.

Intermediate I-7 is synthesised following a similar procedure used for intermediate I- 2, using 8-hydroxyquinoline-2-carboxaldehyde and I-4 as starting material. General Synthetic Procedure H

Example: Synthesis of final product 22

1-16 22

To a mixture of Intermediate 1-16 (40 mg, 0.11 mmol) in DMF (3 mL) with HATU (50 mg, 0.13 mmol) and DIPEA (60 uL, 0.33mmol) stirred for 10 min at rt, was added ethylamine in a 2M solution if THF (61 uL, 0.12 mmol). The resulting mixture was stirred at rt for 4 h. Solvents were removed in vacuo. The residue was purified by biotage flash column chromatography (25-S) eluting with MeOH/DCM (from 0% to 10% on MeOH). Required product was recovered as a light yellow solid which was tritured with MeOH, filtered and dried, leaving a brighter yellow solid, (3 mg) as final product 22.

General Synthetic Procedure I

Example: Synthesis of final product 1

A solution of intermediate 1-17 (720 mg, 1.661 mmol) with Amberlyst (1.767 mg) in MeOH (50 mL) was shaked at rt for 24 h. Solvent was removed and the resin was unbound shaking it with a mixture of NH₃ 7 N in MeOH (20 mL) three times. Methanolic layers were mixed and concentrated in vacuo, leaving a yellow solid (intermediate 1-19) that was used further without additional purification (550 mg), 99% yield.

A mixture of intermediate 1-19 (200 mg, 0.6 mmol), 1-Boc-4-piperidinecarboxaldehyde (0.166 mL, 0.78 mmol) and AcOH (72 mg, 1.2 mmol) in DCE (7 mL) was stirred at rt for 30 min. Then NaBH(OAc)₃ (191 mg, 0.9 mmol) was added. The reaction mixture was stirred at rt for 24 h and quenched by adding aq. 2 M NaOH. The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na₂S0₄, filtered and evaporated. The residue was purified by column chromatography (DCM:MeOH 100:0 to 80:20) affording 220 mg (70% yield) of a yellow compound. A solution of this compound (220 mg, 0.415 mmol) with Amberlyst (0.441 g) in MeOH (10 mL) was shaked at rt for 24 h. Solvent was removed and the resin was unbound shaking it with a mixture of NH₃ 7 N in MeOH (20 mL) three times. Methanolic layers were mixed and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH 10:1) affording 71 mg of compound 1 (40% yield, yellow solid). General Synthetic Procedure J

Example: Synthesis of final product 33

A mixture of final product 27 (57 mg, 0.122 mmol), 1-Boc-4-piperidinone (24 mg, 0.122 mmol) and acetic acid (0.014 mL, 0.244mmol) in DCE (1.4 mL) was stirred at room temperature for 30 minutes under Argon, then NaBH(OAc)₃ (31 mg, 0.146 mmol) was added to the mixture. The reaction was stirred at room temperature for 16 h. Excess of reagents were added and the reaction was allow to stir at room temperature until completion of the reaction. The reaction mixture was diluted with DCM and washed with 2N KOH and H₂0. The organic layer was dried (Na₂S0₄), filtered and concentrated to obtain a residue which was treated for Boc deprotection. Amberlyst-15 (465 mg) was added to a solution of this residue (124 mg, 0.222 mmol) in MeOH (5.2 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction was filtered and the amberlyst was washed with MeOH (3 times). Amberlyst was stirred at room temperature with 7N NH₃ in MeOH for 1 h, then filtered and washed with MeOH. This process was repeated 3 times, until no more deprotected compound was observed. The solvent was evaporated under vacuum. The residue was purified by column chromatography (Isolute/Flash, Sill, 0% to 20% MeOH in DCM then 10% 7N NH₃ in MeOH) to give the desired product 33 as a yellow solid (60 mg, 59%). General Synthetic Procedure K

Example: Synthesis of final product 50

1-35 50

A mixture of intermediate 1-35 (33 mg, 0.058 mmol) and NaCN (4 mg, 0.088 mmol) in DMF (0.3 mL) was heated in a sealed tube in a sea sand bath at 150°C for 16 h. The solvent was evaporated under vacuum. The residue was diluted with DCM and washed with water. The organic layer was dried (Na₂S0₄), filtered and concentrated.

The residue was triturated from Et₂0 to give the desired final product, Boc-protected.

Boc deprotection with Amberlyst and further treatment of the resin with 7 N NH₃ in MeOH afforded the desired product which was purified by automated chromatography in DCM/MeOH 100:0 to 80:20 to obtain the final product 50 pure.

Intermediate I-35 was synthesised following a similar synthetic route to general procedure I but without the Boc deprotection and using in the beginning of the synthesis the precursor intermediate 1-23.

General Synthetic Procedure L

Example: Synthesis of final product 51

I-35 51 To a solution of intermediate I-35 (36 mg, 0.0637 mmol) in MeOH (1.2 mL) was added sodium methoxide (10 mg, 0.191 mmol). The mixture was stirred at rt for 2h and then heated under MW irradiation at 140 °C for 45 min. The compound was further deprotected with Amberlyst to obtain the desired product 51 which was purified by automated chromatography in the presence of DCM/MeOH 100 to 80:20. General Synthetic Procedure M

Example: Synthesis of final product 52

A mixture of final product 25 (65 mg, 0.17 mmol), HATU (130 mg, 0.34 mmol) and DIPEA (90 μΙ_, 0.51 mmol) in DMF was stirred for 10 min. N-Boc-isonipecotic acid (100 mg, 0.43 mmol) was added and the mixture was stirred at rt for 2 days. Solvent was removed in vacuo. The brown residue was purified by flash column chromatography (Biotage) eluting with a gradient system of MeOH/DCM 0:100 to 10:90. The product recovered (150 mg) was suspended in MeOH (6 ml_) with Amberlyst (550 mg) and was slowly shaken at rt for 24 h. The solvent was removed and the resin was unbound shaking it with a mixture of NH₃ 7 N in MeOH (8 mL) three times. Methanolic layers were mixed and concentrated in vacuo. The residue was purified by flash chromatography (Isolute Si II 5 g) eluting with a solvent system of MeOH/DCM 0:100 to 5:95 and NH₃ 7 N in MeOH/DCM 5:95 to 10:90 to afford final product 52 (35 mg) as yellow solid.

Example: Synthesis of final product 99

A mixture of (S)-(-)-2-acetoxypropionic acid (40 mg, 0.3 mmol), BOP (133 mg, 0.3 mmol) and TEA (0.07 mL, 0.5 mmol) in DMF (3 mL) was stirred for 1 h at RT. A solution of Intermediate 10 (100 mg, 0.25 mmol) in DMF (2 mL) was then added. The reaction mixture was stirred for 18 h at 60 °C. On cooling, the solvent was removed in vacuo, and the residue was purified by column chromatography (EtOAc/MeOH 100:0 to 80:20) to give the ester (65 mg). It was dissolved in EtOH (5 mL), the mixture was cooled to 0 °C and LiOH (1 , 3 mL) was added. The reaction mixture was stirred for 1 h at RT, cooled to 0 °C, and AcOH was added dropwise up to pH ~6. EtOH was carefully removed in vacuo and the resulting brown solid was filtered and washed with water. After recrystallization from EtOAc, Final Product 99 (31 mg, 26%) was obtained as yellow solid.

Example: Synthesis of final product 103

A solution of final product 24 (75 mg, 0.16 mmol), Boc-L-alanyl-L-alanine (50 mg, 0.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (39 μί, 0.222 mmol), 4- dimethylaminopyridine (2 mg, 0.016 mmol), 1-hydroxybenzotriazole hydrate (29 mg, 0.19 mmol) and triethylamine (44 pL, 0.317 mmol) in DCM (1.6 mL) was stirred at RT overnight. The solvent was removed in vacuo, the residue was diluted with EtOAc and washed with saturated KHS0₄ (x2), NaHC0₃ and brine. The organic layers were dried over MgS0_4> filtered and evaporated. The residue (108 mg, 95% yield) was deprotected by treatment with Amberlyst in MeOH to give Final Product 103 (46 mg, 53%).

General Synthetic Procedure N

Example: Synthesis of final product 61

1-36 61 A mixture of intermediate 1-36 (40 mg, 0.066 mmol) and aq. NaOH 2 M (0.350 mL) in acetonitrile (2 mL) was heated under microwave irradiation at 110 °C for 30 min. Aq. NaOH 5 M (0.200 mL) was added and the mixture was heated at 115 °C for 15 min. Solvent was removed in vacuo, and the residue was taken up in sat. aq. NaHC0₃ and DCM. The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated in vacuo to give the hydroxy product (19 mg). A mixture of this product (19 mg, 0.032 mmol) and Amberlyst (100 mg) in MeOH (3 mL) was shaken at RT for 20 h. The mixture was filtered and the resin was treated with 7 N NH₃ in MeOH (8 mL) three times. Methanolic layers were mixed and concentrated in vacuo. The residue was purified by flash chromatography (Isolute Si II 5 g) eluting with a solvent system of 7 N NH₃ in MeOH:DCM 0:100 to 50:50 affording the desired compound 61 (5 mg, 31%) as yellow solid. General Synthetic Procedure O

Example: Synthesis of final product 82

1-7 1-37 82

To a solution of Intermediate 1-7 (200 mg, 0.598 mmol) in dry pyridine (2 mL) was added portionwise p-toluenesulfonyl chloride (137 mg, 0.718 mmol). The reaction mixture was heated at 45°C for 24 h and at 65°C for 24 h. More p-toluenesulfonyl chloride (319 mg, 1.67 mmol) was added, and the mixture was heated at 65°C for 3 h. On cooling, the mixture was quenched with water and extracted with DCM. The organic layer was dried over Na₂S0₄, filtered and concentrated. The residue was purified by column chromatography (Biotage, MeOH:DCM 0:100 to 20:80) to give Intermediate I-37 (187 mg, 65%) as yellow solid.

To a mixture of Pd(OAc)₂ (3 mg, 0.013 mmol), XPhos (7 mg, 0.015 mmol), potassium (4-teri-butoxycarbonylpiperazin-1-yl)methyltrifluoroborate (58 mg, 0.189 mmol) and Cs₂C0₃ (123 mg, 0.378 mmol) was added dropwise a solution of Intermediate I-37 (50 mg, 0.126 mmol) in THF/H₂0 (1.1/0.4 mL). The reaction mixture was heated under microwave irradiation at 110 °C for 3 h. On cooling, the mixture was purified by column chromatography (Biotage, MeOH:DCM 5:95 to 10:90) to give Boc-protected final product 82 (27 mg, 41.5%) as yellow solid. After treatment with Amberlyst, Final Product 82 was obtained.

General Synthetic Procedure P

Example: Synthesis of final product 84

A mixture of Intermediate 1-38 (50 mg, 0.11 mmol), 2-chloroethanol (18 μΙ_, 0.26 mmol) and K₂C0₃ (23 mg, 0.16 mmol) in acetonitrile (3 mL) was heated at 100 °C for 24 h. More 2-chloroethanol (18 μί.) and K₂C0₃ (15 mg) were added and the mixture was refluxed for 24 h. On cooling, the mixture was evaporated. The residue was purified by column chromatography (Isolute Si II 5 g; MeOH/DCM 0:100 to 5:95 and 7N NH₃ in MeOH/DCM 10:90) to give Final Product 84 (16 mg, 29%) as yellow solid.

Example: Synthesis of final product 95

A mixture of Intermediate 10 (100 mg, 0.25 mmol), K₂C0₃ (104 mg, 0.75 mmol) and 3-bromo-1 ,1,1-trifluoropropane (0.040 mL, 0.375 mmol) in DMF (2 mL) and ACN (3 mL) was heated for 18 h at 90 °C in a sealed tube. On cooling, the solvent was removed in vacuo and the residue was purified by column chromatography (EtOAc/MeOH 100:0 to 95:5) and triturated from Et₂0 to afford Final Product 95 (67 mg, 54%) as yellow solid. General Synthetic Procedure Q

Example: Synthesis of final product 85

1-50 85

A mixture of Intermediate 1-50 (30 mg, 0.066 mmol), ethanesulfonyl chloride (8 μΙ_, 0.08 mmol) and Cs₂C0₃ (43 mg, 0.13 mmol) in acetonitrile (3 mL) was heated at 100 °C for 7 h. More ethanesulfonyl chloride (5 μΙ_) was added and the heating was continued for 18 h. Ethanesulfonyl chloride (10 μΙ_) and Cs₂C0₃ (20 mg) were added and the mixture was refluxed for 3 h. On cooling, the mixture was evaporated. The residue was purified by column chromatography (Isolute Si II 5 g; EtOAc/cHex, 75:25 to 100:0 and MeOH/EtOAc, 0:100 to 10:90) to give Final Product 85 (13 mg, 36%) as cream solid.

Example: Synthesis of final product 100

A mixture of Intermediate 10 (100 mg, 0.25 mmol) and TEA (0.07 mL, 0.50 mmol) in DCE (5 mL) and DMF (2 mL) was cooled to 0 °C. Then, methanesulfonyl chloride (0.023 mL, 0.3 mmol) was added and the mixture was stirred for 18 h at RT. The solvents were removed in vacuo, water (5 mL) was added followed by 33% aqueous NH₄OH up to pH~8, and the mixture was extracted with DCE (4 x 25 mL). The combined organic fractions were dried, filtered and evaporated. The residue was purified by column chromatography (EtOAc/MeOH 100:0 to 60:40) and triturated from MeOH/Et₂0 to afford Final Product 100 (24 mg, 20%) as yellow solid. General Synthetic Procedure R

Example: Synthesis of final product 5-01

I-54 5-01

To a suspension of Intermediate I-54 (70 mg, 0.198 mmol) and 4-amino-1-Boc- piperidine (79 mg, 0.397 mmol) in dry "BuOH (5 mL) was added triethylamine (55 μΙ_, 0.397 mmol). The mixture was heated under microwave irradiation at 180°C for 6h. On cooling, the mixture was evaporated and the residue was purified by column chromatography (Biotage, DCM/MeOH 100:0 to 80:20) to afford Final Product 5-01 (38 mg; 46%).

Example: Synthesis of final product 6-01

I -64 6-01

A mixture of Intermediate I-64 (20 mg, 0.056 mmol), cyclohexylamine (0.010 mL, 0.086 mmol), Pd(OAc)₂ (4 mg, 0.018 mmol), X-Phos (21 mg, 0.052 mmol) and Cs₂C0₃ (36 mg, 0.114 mmol) in 1 ,4-dioxane (0.8 mL) was heated in a sealed tube at 140°C for 18 h. On cooling, the solvent was evaporated. The residue was purified by column chromatography (Isolute/Flash, Sill, CHCI₃) and by preparative HPLC to give Final Product 6-01 (6 mg, 26%) as pale yellow solid. xample: Synthesis of final product 6-02

1-64 6-02

A mixture of Intermediate 1-64 (50 mg, 0.142 mmol), 4-aminomethyltetrahydropyran (25 mg, 0.213 mmol), Pd(OAc)₂ (6 mg, 0.028 mmol), BrettPhos (31 mg, 0.057 mmol) and Cs₂C0₃ (93 mg, 0.284 mmol) in 1,4-dioxane (1.1 ml_) was heated in a sealed tube at 110°C for 20 h. Additional amounts of Pd(OAc)₂ (6 mg) and BrettPhos (15 mg) were added and the reaction mixture was heated at 120°C for 4 h. On cooling, the solvent was evaporated and the residue was purified by column chromatography (Isolute/Flash, Sill, CHCI₃) and by preparative HPLC to give Final Product 6-02 (30 mg, 49%) as yellow solid.

General Synthetic Procedure S

Example: Synthesis of final product 101

A mixture of Intermediate 10 (80 mg, 0.2 mmol) and Ac₂0 (2 mL) in dry pyridine (2 mL) was stirred overnight at RT. The solvents were removed in vacuo and the residue was was taken up in water (5 mL). Aqueous NH₄OH (33%) was added up to pH ~8. The resulting solid was filtered, washed with water and dried to afford Final Product 101 (51 mg, 58%) as yellow solid. General Synthetic Procedure T

Example: Synthesis of final product 126

To a mixture of final compound 125 (85 mg, 0.18 mmol) in dry acetone (2 mL), was added aqueous HCI 1 M (2 mL). The mixture was stirred at room temperature for 20 h. After that, three portions of HCI 2 M (2 mL) were added to the mixture. Then, three subsequent additions of HCI 6 M (2 mL) were made, and finally concentrated HCI (8 mL) was added, and the mixture was heated at 70 °C for 6 h. The orange mixture was cooled down to RT. A mixture of saturated aqueous K₂C0₃ and ice was added until the effervescence stopped, and resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated in vacuo affording 70 mg (90%) of de-protected compound as a yellow solid. To a cooled solution of de-protected compound (70 mg, 0.16 mmol) at 0 °C was added a 3 M solution of methylmagnesium chloride in THF (0.250 mL, 0.65 mmol). The resulting mixture was stirred at RT for 18 h. The mixture was quenched by adding saturated aqueous NH₄CI solution and extracted with DC (3 x 25 mL). The combined organic layers were washed with saturated aqueous NaHC0₃ (30 mL), brine (30 mL), dried over Na₂S0₄ and concentrated in vacuo. The solid was purified by column chromatography (Biotage, MeOH:EtOAc 0:75) to give Final Product 126 (4 mg, 6%) as yellow solid.

General Synthetic Procedure U

Example: Synthesis of final product 128

128

General procedure A was used to obtain intermediate I-75 (58%). Then, to a mixture of I-75 (50 mg, 0.09 mmol) in DCM (2 ml_) with TEA (13 uL, 0.1 mmol) was added acetyl chloride (7 uL, 0.1 mmol). The resulting mixture was stirred at RT for 1 h. Water was added to the mixture. Different layers were separated and the organic layer was washed with saturate solution of NaHC0₃ (10 ml_), water (10 ml_) and brine (10 ml_). After being dried with Na₂S0₄, the solvent was removed under reduced pressure to give intermediate I-76 (40 mg, 74%) as yellow solid.

A solution of I-76 (40 mg, 0.07 mmol) in MeOH (5 mL) was slowly stirred with amberlyst 15 (200 mg) for 18 h. Methanol was removed, and the resin was unbound stirring it with 7 M NH₃ in MeOH (3 x 20 mL). The combined methanol/NH₃ layers were concentrated under reduced pressure. The solid was purified by flash column chromatography (Isolute/Flash, Sill, DCM/MeOH 100:0 to 95:5% and then NH₃ (7 M in MeOH)/DCM 95:5% to 90:10%). Required final product 128 (15 mg, 45%) was recovered as yellow solid.

GENERAL SYNTHETIC PROCEDURES FOR INTERMEDIATE SYNTHESIS

Syntesis of Intermediate I-5

1-12 I-5

Two mixtures of 8-bromo-2-methylquinoline (1.250 g, 5.5 mmol), 1-Boc-piperazine (1.050 g, 5.5 mmol), Pd₂(dba)₃ (200 mg), DavePhos (300 mg, 0.8 mmol), tBuOK (900 mg, 8 mmol) in dioxane (7 mL) was heated under microwave irradiation at 120 °C for 20 min (Biotage, Abs. Level Normal). The dark mixtures were combined and filtered through a Celite pad, washing with DCM. Filtrate was concentrated, and residue was purified by Biotage flash column chromatography eluting with a solvent system of cyclohexane/EtOAc (from 0% to 40% on EtOAc). Required product 1-12 was recovered as yellow oil, (2 g, 55%).

To a solution of Se0₂ (550 mg, 5 mmol) in dioxane (5 mL) heated at 50°C was added a solution of intermediate 1-12 (1 g, 3 mmol) in dioxane (6 mL). The resulting mixture was heated at 60 °C until starting material was consumed. The dark red mixture was cooled down to rt, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Biotage) eluting with EtOAc/cyclohexane (from 0% to 30% on EtOAc). Required intermediate 1-5 was recovered as dark yellow oil (1.5 g, 72%).

This methodology can be applied to synthesise analogues to I-5 with other amines instead of the piperazine fragment.

Synthesis of intermediate 1-9

To a suspension of selenium dioxide (2.5 g, 23.0 mmol) in dioxane (15 mL) at 60 °C was added a solution of 8-bromo-2-methylquinoline (3 g, 13.5 mmol) in dioxane (15 mL). Resulted mixture turned dark brown after 30 min at 60 °C. The heating continued until reagents were consumed. The mixture was cooled down to rt, filtered and concentrated in vacuo. The cream solid was used without additional purification

(3.1 g).

Following the same procedure the following Intermediates were prepared: intermediate 1-72

Yield: 52%. ynthesis of intermediate 1-2

1-2

A mixture of intermediate 1-4 (0.735 g, 4 mmol) and intermediate 1-9 (0.930 g, 4 mmol) in EtOH (20 mL) was heated at reflux for 2 h, until starting materials were consumed. Solvent was removed in vacuo leaving a brown-orange solid that was re- dissolved in DCM (20 mL). lodobenzene diacetate (1.7 g, 4 mmol) was added, and the resulting mixture was stirred at rt for 1 h. The reaction was quenched by adding aqueous Na₂S0₃ and extracted with DCM (3 x 15 mL). Combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated in vacuo. The brown residue was purified by Biotage flash column chromatography (40-S) eluting with solvent system of MeOH/DCM (from 0% to 25% on MeOH) to obtain intermediate I- 2, 700 mg.

Following the same procedure the following Intermediates were prepared: Intermediate 1-54

1-54

Intermediate 1-73

1-73

Yield: 29% ynthesis of intermediate 1-3

A mixture of intermediate 1-4 (510 mg, 2.8 mmol) with intermediate 1-13 (600 mg, 2.8 mmol) in tBuOH (5 mL) was heated under microwave irradiation at 150 °C for 3 h (Abs. Level VH). Solvent was removed in vacuo. The dark crude was purified by Biotage flash column chromatography (25-M) eluting with a solvent sytem of MeOH/DCM (from 0% to 15% on MeOH). The resulting product was tritured with diethyl ether/DCM, leaving a clean light orange solid product as intermediate 1-3. Synthesis of intermediate 1-16

To a suspension of intermediate I-3 (160 mg, 0.46 mmol) in water (6 mL) was added dropwise cone. H₂S0₄ (2 mL) dropwise. The dark mixture was heated at 150 °C for 8 h. The mixture was cooled down to rt. The mixture was diluted with water (30 mL) and solid Na₂C0₃ was added until effervescence ceased. The mixture was extracted with DCM (3 x 15 mL). Combined organic layers were washed with brine, dried and concentrated in vacuo. Required product was obtained as bright yellow solid, intermediate 1-16 (90 mg) that was used in the next step without additional purification.

ynthesis of intermediate 1-13

A mixture of intermediate 1-14 (5 g, 15 mmol), Zn(CN)₂ (1.550 g, 13.5 mmol), Pd(PPh₃)₄ ( 0.8 g) and DMF (40 mL) was heated at 120 °C for 48h. Excess of Zn(CN)₂ (0.6 g) and Pd(PPh₃)₄ (0.3 g) as added until completion of the reaction. The reaction mixtre was cooled down, water (75 mL) was added, followed by aqueous H₂S0₄ (2 M, 20 mL). The mixture was extracted with EtOAc (3 x 60 mL). Combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated. The crude was purified by Biotage flash column chromatography (40-M) eluting with a solvent system of EtOAc/cyclohexane (from 0% to 100% on EtOAc). Required compound was recovered as cream solid (1.8 g, intermediate 1-13).

Synthesis of intermediate 1-14

To a mixture of intermediate 1-15 (200 mg, 0.9 mmol) in THF (3 mL) and DMF (0.5 mL) with TEA (310 pL, 2.1 mmol) was added N- phenylbis(trifluoromethanesulfonimide) (300 mg, 2.1 mmol). The mixture was stirred at rt for 18 h and diluted with DCM/water. The layers were separated and aqueous layer was extracted with DCM (2 x 10 mL). Combined organic layers were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by Biotage flash column chromatography eluting with a solvent system of EtOAc/cyclohexane (from 30% to 100% on EtOAc). Required product was recovered as colourless oil (165 mg, intermediate 1-14).

Synthesis of intermediate 1-15

To a suspension of 8-hydroxyquinoline-2-carboxylic acid (1.8 g, 9.5 mmol) in MeOH (30 mL) cooled to 0 °C was added dropwise thionyl chloride (1.1 mL, 15.2 mmol). The yellow suspension was warmed to rt and heated at 65 °C for 4 h. Solvent was removed in vacuo, leaving a bright orange solid (2 g, intermediate 1-15). ynthesis of intermediate 1-63

To a refluxing mixture of NBS (529 mg, 2.972 mmol) and AIBN (37 mg, 0.226 mmol) in CCI₄ (11 mL) was added a solution of 1-chloro-7-methylnaphthalene (500 mg, 2.831 mmol) in CCI₄ (11 mL). The reaction mixture was refluxed for 4 h. The mixture was cooled to RT and the solid was filtered off. The filtrate was concentrated in vacuo and dissolved in CHCI₃ (22 mL). Hexamethylenetetramine (476 mg, 3.397 mmol) was added and the mixture was refluxed for 3 h and stirred at RT overnight. The solvent was evaporated and the residue was dissolved in HOAc:H₂0 (1:1 ; 18 mL) and cone. HCI (4.4 mL). The mixture was refluxed for 3 h, cooled to RT, and partitioned between H₂0 and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried (Na₂S0₄), filtered and concentrated. The residue was purified by column chromatography (Isolute/Flash, Sill, DCM) to give Intermediate 1-63 as a yellow solid (270 mg, 50%).

Synthesis of intermediate 1-70

To a solution of 8-amino-2-methylquinoline (1 g, 6.32 mmol) in CH₃CN (46 mL) was added N-bromosuccinimide (0.563 g, 3.16 mmol). After stirring for 15 min, a second portion of N-bromosuccinimide (619 mg, 3.48 mmol) was added. After stirring for 30 min, the mixture was concentrated. EtOAc was added, and the mixture was washed with water and with saturated NaCI. The organic phases were dried over MgS0₄, filtered and evaporated. The residue was purified by column chromatography (Biotage, cHex/EtOAc 90:10) to give Intermediate I-70 (1.3 g, 87%).

Synthesis of intermediate 1-71

To a solution of Intermediate I-70 (1.32 g, 5.56 mmol) in 1,4-dioxane (11 mL) was added di-tert-butyl dicarbonate (1.7 g, 7.79 mmol). The reaction mixture was heated at 90°C for 24 h. More di-tert-butyl dicarbonate (0.6 g) was added and the mixture was heated for 48 h. On cooling, the mixture was evaporated and the residue was purified by column chromatography (Biotage, cHex EtOAc, 100:0 to 50:50) to give Intermediate 1-71 (629 mg, 34%). Synthesis of intermediate 1-17

1-17

A mixture of intermediate I-4 (0.5 g, 2.76 mmol) and intermediate 1-18 (te/t-butyl 2-formylquinolin-8-ylcarbamate, CAS: 380153-78-6) (0.827 g, 3.035 mmol) in EtOH (15 mL) was heated at reflux for 2 h. Solvent was removed in vacuo leaving a brown-orange solid that was re-dissolved in DCM (20 mL). lodobenzene diacetate (0.725 g, 2.759 mmol) was added, and the resulting mixture was stirred at rt for 1 h. The reaction was quenched by adding aqueous Na₂S0₃ and extracted with DCM (3 x 15 mL). Combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated in vacuo. The brown residue was purified by Biotage flash column chromatography eluting with a solvent system of MeOH/DCM (from 0% to 25% on MeOH) to obtain 720 mg of intermediate 1-17.

Intermediate I-53

[2-(6-Methyl-6,7,8,9-tetrahydro-10-oxa-1 ,2,3a,4,6-pentaaza- cyclohepta[e]inden-3-yl)-quinolin-8-yl]-carbamic acid tert-butyl ester

I-53

HPLC-MS (method 4): Rt= 4.7 min, [M+H]⁺ m/z 448.

Yield: 99% Intermediate 1-61

{2-[6-(2-Trityloxy-ethyl)-7,8-dihydro-6H-9-oxa-1,2,3a,4,6-pentaaza- cyclopenta[a]naphthalen-3-yl]-quinolin-8-yl}-carbamic acid tert-butyl ester

1-61

HPLC- S (method 4): Rt= 5.3 min, [M+H]⁺ m/z 706.

Yield: 44%

Intermediate I-64

3-(8-Chloro-naphthalen-2-yl)-6-methyl-7,8-dihydro-6H-9-oxa-1,2,3a,4,6- pentaaza-cyclopenta[a]naphthalene

1-64

¹H-NMR (300 MHz, CDCI₃) δ 9.46 (d, J = 0.7 Hz, 1H), 8.57 (dd, J = 8.7, 1.7 Hz, 1H), 8.23 (s, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.58 (dd, J = 7.4, 1.0 Hz, 1 H), 7.45 - 7.36 (m, 1 H), 4.54 (m, 2H), 3.49 (m, 2H), 3.03 (s, 3H). HPLC-MS (method 4): Rt= 5.0 min, [M+H]⁺ m/z 352.

Yield: 40%

Intermediate 1-4 (176 mg, 10.775 mmol) and 2-quinolinecarboxaldehyde, 8-[[(1,1- dimethylethyl)dimethylsilyl]oxy] (3.09 g, 10.775 mmol) were heated to reflux in EtOH (52 mL) for 1h. Then, EtOH was evaporated and the corresponding residue was used without further purification. This residue (3.22 g, 7.146 mmol) was dissolved in DCM (31 mL) and iodobenzene diacetate (2.302 g, 7.146 mmol) was added. After stirring at rt for 8 h, the reaction mixture was partitioned between DCM (500 mL) and aq saturated Na₂S₂0₃ (400 mL). The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was purified by flash chromatography Biotage, with a gradient DCM/MeOH 100 to 80/20, to yield a yellow solid, 872 mg.

Deprotection of silyl ether was afforded in acidic media. To a solution of the yellow solid (0.761 g, 1.696 mmol) in THF (89 mL) was added 1N HCI (17 mL). After stirring at rt for 2h 1 N HCI (55 mL) was added and the reaction mixture was stirred for 16 h. The mixture was neutralized with 1 NaOH and diluted with EtOAc. The yellow solid precipitated (470 mg) was collected. The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue (yellow solid, 300 mg) was used without further purfication. Synthesis of Intermediate 1-62

1-61 I -62

A mixture of Intermediate 1-61 (220 mg, 0.312 mmol) and Amberlyst (332 mg) in MeOH (8 mL) was shacked at RT for 24 h. The mixture was filtered. The resin was treated with NH₃ 7 N in MeOH (10 mL) at RT for 1 h and filtered. This process was repeated three times. The fitrates were concentrated to give Intermediate I-62 (105 mg) as yellow solid.

HPLC-MS (method 4): R_t= 3.27 min, [M+H]⁺ 364 m/z.

Yield: 93%

ynthesis of Intermediate 1-65

1-65

A mixture of 6-fluoro-2-methylquinolin-8-amine (500 mg, 2.838 mmol) with di-tert- butyl dicarbonate (867 mg, 3.973 mmol) in dioxane (3.4 ml.) was refluxed for 48h. More di-tert-butyl dicarbonate (867 mg, 3.973 mmol) was added and the mixture was refluxed for 24h. On cooling, the mixture was evaporated and the residue was purified by column chromatography (Biotage, cHex/DCM: 100:0 to 60:40) to give Intermediate 1-65 (681 mg).

HPLC-MS (method 4): R_t= 5.2 min, [M+H]⁺ 277 m/z.

¹H NMR (300 MHz, CDCI₃) δ 9.02 (s, 1H), 8.16 (d, J = 10.6 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.87 (dd, J = 8.8, 2.7 Hz, 1H), 2.64 (s, 3H), 1.57 (s, 9H).

Yield: 87%

Synthesis of Intermediate I-66

I-65 |-66

To a stirred suspension of selenium dioxide (492 mg, 4.43 mmol) in dioxane (15 mL) at 55°C was added a solution of Intermediate I-65 (681 mg, 2.46 mmol) in dioxane (15 mL). The reaction mixture was stirred at 90°C overnight. On cooling, the mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (Biotage, cHex:DCM, 100:0 to 80:20) to give Intermediate 1-66 (424 mg).

¹H NMR (300 MHz, CDCI₃) δ 10.23 (d, J = 0.5 Hz, 1H), 9.03 (s, 1H), 8.35 (dd, J = 11.3, 2.2 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.10 (dd, J = 8.5, 2.7 Hz, 1H), 1.62 (s, 9H).

Yield: 59%

Synthesis of Intermediate 1-67

To a solution of Intermediate 1-66 (424 mg, 1.46 mmol) in EtOH (15 mL) was added a solution of Intermediate I-4 (265 mg, 1.46 mmol) in EtOH (30 mL). The mixture was refluxed for 1 h. On cooling, the mixture was evaporated, and DCM (30 mL) was added followed by lodobenzene diacetate (470 mg, 1.46 mmol). The reaction mixture was stirred at RT for 2h. More lodobenzene diacetate (236 mg) was added and the mixture was stirred for 1h. Aqueous Na₂S₂0₃ was added and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was purified by column chromatography (Biotage, DCM:MeOH, 100:0 to 96:4) to give Intermediate I-67 (197 mg) as yellow solid.

HPLC-MS (method 4): R_t= 4.8 min, [M+H]⁺ 452 m/z.

Yield: 30%

ynthesis of Intermediate 1-68

To a solution of Intermediate 1-67 (197 mg, 0.436 mmol) in MeOH (5 mL) was added amberlyst (465 mg). The reaction mixture was stirred at RT for 24 h. The resin was filtered off and treated with NHa MeOH (7N) (5 mL) for 2h (3 times). After filtration, the solvent was evaporated and the residue was purified by column chromatography (Biotage, DCM:MeOH, 100:0 to 90:10) to give Intermediate 1-68 (46 mg).

HPLC-MS (method 4): R_t= 3.94 min, [M+H]⁺ 352.1 m/z.

Yield: 30%

SYNTHESIS OF INTERMEDIATE 1-4 AND OTHER BICYCLES ANALOGUES

Synthesis of Intermediate 1-55

To a solution of diethanolamine (1.82 mL, 19.02 mmol) in acetonitrile (19 mL), K₂C0₃ (5.25 g, 38.04 mmol) and benzyl chloroformate (2.72 mL, 19.02 mmol) were added. The suspension was stirred vigorously for 3h at RT. The mixture was extracted with DCM and the organic layer was dried, filtered and concentrated to afford Intermediate 1-55 (4.32 g, 95%) as clear oil. It was used in the next experiment without further treatment.

HPLC-MS (method 4): Rt =2.9, [M+H]⁺ 340.

¹H NMR (300 MHz, CDCI₃) δ 7.35 - 7.21 (m, 5H), 5.06 (s, 2H), 3.84 - 3.60 (m, 4H), 3.46 - 3.31 (m, 4H). Synthesis of Intermediate 1-56

To a solution of Intermediate 1-55 (4.32 g, 18.05 mmol) in DCM (180 mL) at 0°C were added imidazole (1.23 g, 18.05 mmol) and trityl chloride (4.76 mL, 18.05 mmol). The reaction mixture was stirred at 0°C for 45 min and at RT for 90 min. The mixture was washed with sat. NH₄CI, the organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (Biotage, c- Hex/EtOAc 100:0 to 50:50) to give Intermediate 1-56 (3.7 g, 42%) as colourless oil.

1H NMR (300 MHz, CDCI₃) δ 7.38 - 7.06 (m, 20H), 4.98 (s, 2H), 3.68 (s, 2H), 3.51 - 3.45 (m, 2H), 3.41 (t, J = 5.6 Hz, 2H), 3.17 (t, J = 5.4 Hz, 2H).

Synthesis of Intermediate I-57

I-56 I-57

To a solution of Intermediate 1-56 (3.7 g, 7.68 mmol) in methanol (20 mL) was added Pd(OH)₂/C (225 mg, 20 wt.%). The mixture was stirred under hydrogen atmosphere (balloon pressure) for 16h at RT. The reaction mixture was filtered over celite and the filtrate was concentrated to give Intermediate I-57 (2.4 g, 90%). It was used in the next experiment without further purification.

1H NMR (300 MHz, DMSO) δ 7.45 - 7.18 (m, 15H), 3.43 (t, J = 5.3 Hz, 2H), 3.02 (t, J = 7.7 Hz„ 2H), 2.71 (t, J = 7.8 Hz, 2H), 2.55 (t, J = 5.7 Hz, 2H).

General procedure for chlorine substitution for different amines

To a solution of 3,4,5-trichloropyridazine (1 eq) in MeOH (1 mL/mmol) was added dropwise a solution of the appropriate aminoalcohol (ex: 2-methylamino-ethanol) (3 eq) in MeOH (1 mL mmol) for 1h at RT. The solvent was removed in vacuo to give a brown oil which was purified by Biotage flash column chromatography (eluent: 70% EtOAc in cyclohexane to 100% EtOAc) to give the desired product (ex: 2-[(5,6-Dichloro-pyridazin-4-yl)-methyl-amino]-ethanol). Example: Synthesis of Intermediate 1-10

-pyridazin-4-yl)-methyl-amino]-ethanol:

¹H NMR (300 MHz, CDCI₃) δ 8.60 (s, 1H), 3.90 (t, J = 5.4 Hz, 2H), 3.72 (m, 2H), 3.20 (s, 3H).

Synthesis of Intermediate 1-58

To a solution of 3,4,5-trichloropyridazine (880 mg, 4.80 mmol) in EtOH (10 mL) was slowly added a solution of Intermediate I-57 (2 g, 5.76 mmol) and DIPEA (2.5 mL, 14.40 mmol) in EtOH (10mL). The reaction mixture was refluxed for 6h and evaporated. The residue was dissolved in DCM and washed with water. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (Biotage, DCM/MeOH 100:0 to 80:20) to yield Intermediate 1-58 (1.3 g, 55%) as yellow solid. It was used in later experiments without further purification.

¹H NMR (300 MHz, CDCI₃) δ 8.67 (s, 1H), 7.36 - 7.16 (m, 15H), 3.84 (m, 4H), 3.64 (t, J = 5.4 Hz, 2H), 3.33 (t, J = 5.1 Hz, 2H).

General procedure for cvclization reaction

The appropriate dichloropyridazine (1.0 eq) was dissolved in THF (20 mL/mmol). When the solution reached reflux, 'BuOK (1.2 eq) was added portionwise. The reaction mixture was refluxed for 2 h. On cooling, a saturated aqueous solution of NH₄CI was added and the layers were separated. The aqueous phase was extracted twice with EtOAc. The combined organic layers were dried (Na₂S0₄), filtered and evaporated. The residue was triturated with Et₂0-DCM 9:1 and filtered off to afford the desired product (ex: 8-Chloro-4-methyl-3,4-dihydro-2H- pyridazino[4,5-b]-1 ,4-oxazine).

Examples: Synthesis of Intermediate 1-11 and analogues

Intermediate 1-11

methyl-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine

¹H NMR (300 MHz, CDCI₃) δ 8.47 (s, 1 H), 4.42 (m, 2H), 3.46 (m, 2H), 3.06 (s, 3H).

Intermediate I-33

8-Chloro-4-propyl-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine

¹H NMR (300 MHz, CDCI₃) δ = 8.42 (s, 1H), 4.31 (dd, J=5.5, 3.3, 2H), 3.44 (m, 2H), 3.28 (m, 2H), 1.61 (m, 2H), 0.91 (t, J=7.4, 3H).

Intermediate 1-32

8-Chloro-4-benzyl-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine

¹H NMR (300 MHz, CDCI₃) δ = 8.46 (s, 1 H), 7.27 (m, 3H), 7.17 (m, 2H), 4.51 (s, 4.34 (m, 2H), 3.45 (dd, J=5.8, 3.1 , 2H).

Intermediate 1-31

8-Chloro-4-butyl-3,4-dihydro-2H-pyridazino[4,5-b][1 ,4]oxazine

H NMR (300 MHz, CDCI₃) δ 8.50 (s, 1 H), 4.37 (m, 2H), 3.49 (m, 2H), 3.37 (m, 2H), 1.64 (m, 2H), 1 .38 (dq, J = 14.5, 7.3 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H).

Intermediate 1-30

8-Chloro-4-isobutyl-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine

¹H NMR (300 MHz, CDCI₃) δ 8.23 (s, 1 H), 4.1 1 (m, 2H), 3.27 (m, 2H), 2.92 (d, J=7.5, 2H), 1.80 (m, 1 H), 0.71 (d, J=5.7, 6H).

Intermediate I-29

8-Chloro-4-methoxyethyl-3,4-dihydro-2H-pyridazino[4,5-b][1 ,4]oxazine

¹H NMR (300 MHz, CDCI₃) δ 8.47 (s, 1H), 4.28 (m, 2H), 3.60 (m, 6H), 3.26 (s, 3H).

Intermediate 1-28

8-Chloro-4-ethyl-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine

¹H NMR (300 MHz, CDCI₃) δ 8.41 (s, 1H), 4.31 (m, 2H), 3.40 (m, 4H), 1.17 (m, 3H). Intermediate 1-27

8-Chloro-4-isopropyl-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine

1H NMR (300 MHz, CDCI₃) δ 8.51 (s, 1H), 4.29 (m, 2H), 4.10 (m, 1H), 3.33 (m, 2H), 1,21 (s, 3H), 1.17 (s, 3H).

Intermediate I-26

8-Chloro-4-(3-methoxy-propyl)-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine

1H NMR (300 MHz, CDCI₃) δ 8.52 (s, 1H), 4.38 - 4.29 (m, 2H), 3.46 (m 4H), 3.38 (t, J = 5.5 Hz, 2H), 3.29 (s, 3H), 1.85 (m, 2H). Intermediate 1-25

8-Chloro-4-{3-phenoxyethyl)-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine

H NMR (300 MHz, CDCI₃) δ 8.57 (s, 1 Η), 7.24 (m, 2H), 6.93 (m, 1H), 6.79 (m, 2H),4.32 (m, 1 Η), 4.14(m, 4H), 3.74 (m, 1 Η), 3.61 (m, 2H).

Intermediate 1-59

8-Chloro-4-(2-trityloxy-ethyl)-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine

HPLC-MS (method 4): Rt= 4.78 min, [M+Hf m/z 458.2.

Yield: 100%

Intermediate 1-24

4-Chloro-7,7.9-trimethyl-6,7,8,9-tetrahydro-5-oxa-2,3,9-triaza- benzocycloheptene

HPLC-MS (method 4): Rt= 3.68 min, [M+H]⁺ m/z 228.1.

¹H NMR (300 MHz, CDCI₃) δ 8.46 (s, 1 H), 4.04 (s, 2H), 3.24 (s, 2H), 3.05 (s, 3H), 1.09 (s, 6H).

Yield: 52% for two steps Intermediate 1-51

4-Chloro-9-methyl-6,7,8,9-tetrahydro-5-oxa-2,3,9-triaza-benzocycloheptene

HPLC-MS (method 4): Rt= 2.01 min, [M+H]⁺ m/z 200.1.

1H NMR (300 MHz, CDCI₃) δ 8.52 (s, 1 H), 4.46 (t, J = 6.2 Hz, 2H), 3.60 (m, 2H), 3.09 (s, 3H), 2.21 (m, 2H).

Yield: 96%

General Procedure for O. O cycles.

Example: Synthesis of Intermediate 1-34

5,8-Dichloro-2,3-dihydro-[1,4]dioxino[2,3-d]pyridazine

A mixture of 3,4,5,6-tetrachloropyridazine (5.0 g, 22.9 mmol), ethylene glycol (1.49 mL) and sodium hydride (60% in mineral oil, 1.1 g) in dry DMF (250 mL) was stirred for 18 h at room temperature. Then, more sodium hydride (60% in mineral oil, 1,1 g) was added and the mixture was stirred at 60 °C for 3 h and at RT for 18 h. The solvents were removed under vacuum and the residue purified by flash chromatography (EtOAc/hexanes 1:10 to 1:1) to give compound 5,8- dichloro-2,3-dihydro-[1,4]dioxino[2,3-d]pyridazine as a yellow solid (758 mg, 16% yield). HPLC-MS (method 4): Rt= 2.52 min, [M+H]⁺ m/z 206.9.

1H NMR (300 MHz, CDCI₃) δ 4.54 (s, 4H).

General Procedure for chlorine substitution for hydrazine

Example: Synthesis of Intermediate 1-4 and analogues

8-hydrazine-4-methyl-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine

Hydrazine hydrate (10.775 mL) was added to intermediate 1-11 (2 g, 10.775 mmol). The reaction mixture was heated in MW at 150°C 30 min. Then, hydrazine was evaporated and the residue was purified by Biotage DCM/MeOH to obtain a yellow solid, 1.885 g, 96% yield.

Other bicycles hydrazine-4-R1substituent-3,4-dihydro-2H-pyridazino[4,5- b][1 ,4]oxazine were synthesised following a similar synthetic procedure.

Intermediate 1-52

(9-Methyl-6,7,8,9-tetrahydro-5-oxa-2,3,9-triaza-benzocyclohepten-4-yl- hydrazine

1-52

HPLC-MS (method 4): Rt= 0.4 min, [M+H]⁺ m/z 196.

Yield: 18% Intermediate 1-60

[4-(2-Trityloxy-ethyl)-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazin-8-yl]- hydrazine

HPLC-MS (method 4): Rt= 3.5 min, [M+H]⁺ m/z 454.

Yield: 82% eneral Procedure for chlorination

A mixture of the appropriate bicyclic chloropyrazines (1.0 eq) in acetonitrile (5 mlJmmol) was heated at 50°C. Then, NCS (1.2 eq) was added and the reaction mixture was heated at 50°C for 3 h. The solvent was removed in vacuum. The residue was taken up into DCM and washed with a saturated solution of NaHC0₃. The organic layer was dried (Na₂S0₄), filtered and evaporated to give an orange solid which was purified by column chromatography (Biotage, DC /EtOAc 20%) to afford the desired product (ex: 5,8-Dichloro-4-methyl-3,4-dihydro-2H- pyridazino[4,5-b][1 ,4]oxazine).

Example: Synthesis of Intermediate 1-20

5,8-Dichloro-4-methyl-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazine

'-20

HPLC-MS (method 4): Rt =3.1min, [M+H]⁺ 220.0, 222.0.

¹H NMR (300 MHz, CDCI₃) δ 4.36 (m, 2H), 3.31 (m, 2H), 3.14 (s, 3H).

General Procedure for coupling reaction in the presence of Palladium in dichloro bicycles

To a mixture of the appropriate bicyclic dichloropyridazines (1.0 eq) in 1 ,2- dimethoxyethane (5 mlJmmol), R-boronic acid or boronate pinacol ester, Palladium catalyst as PdCI₂(dppf) (0.1 eq), and an inorganic base as K₂C0₃ aqueous solution was added. The mixture was heated at the appropriate temperature, for example at 140°C, for the appropriate time, for example 24h, in a seal tube. The mixture was extracted with DCM. The organic layer was dried, filtered and evaporated. The residue was purified by flash column chromatography (Biotage) using gradient MeOH:DCM 0:100 to 10:90 to afford the desired product (ex.: 8-Chloro-4,5-dimethyl-3,4-dihydro-2 H-pyridazino[4,5- b][1 ,4]oxazine).

Example: Synthesis of Intermediate 1-21

,5-dimethyl-3,4-dihydro-2 H-pyridazino[4,5-b][1,4]oxazine

HPLC-MS (method 4): Rt =1.032 min, [M+H]⁺ 200.2.

¹H NMR (300 MHz, CDCI₃) δ 4.54 - 4.18 (m, 2H), 3.26 - 3.09 (m, 2H), 2.87 (s, 3H), 2.56 (s, 3H).

Example: Synthesis of Intermediate I-22

-cyclopropyl-4-methyl-3,4 -dihydro-2H-pyridazino[4,5-b][1 ,4]oxazine

HPLC-MS (method 4): Rt =3.0, [M+H]⁺ 226. One peak but mixture of both regioisomers used in next reaction step, being the depicted compound the major regioisomer.

General Procedure for hydrazine substitution

Example: Synthesis of Intermediate I-23

5-Chloro-4-methyl-3,4-dihydro-2H-pyridazino[4,5-b][1 ,4]oxazin-8-yl)-hyd

1-20 ,.23

Hydrazine hydrate (1.6 mL) was added to intermediate I-20 (300 mg, 1.363 mmol), the reaction mixture was heated in MW at 150°C 30 min. The hydrazine was evaporated and the residue was purified by automated chromatography in a gradient DCM/MeOH 100/0 to 80/20, to obtain a mixture of two regioisomers. After a second purification in a mixture of DCM/MeOH 100/0 to 90:10, the desired compound was obtained as unique regioisomer (210 mg).

H NMR (300 MHz, CDCI₃) δ 4.25 - 4.18 (m, 2H), 3.18 - 3.10 (m, 2H), 2.92 (s, 3H).

SYNTHESIS OF M.2.41TRIAZ0L0r4.3-a1PYRIDINE DERIVATIVES

Synthesis of Intermediate 1-38

1-38

To a solution of n-butyllithium (5.51 mL, 13.78 mmol, 2.5M in hexane) in dry Et₂0 (30 mL) cooled at -78°C, under a Argon atmosphere, was added dropwise 2,2,6,6-tetramethylpiperidine (2.326 mL, 13.785 mmol). The mixture was stirred at -78°C for 10 min, and then a solution of 2,3-dichloropyridine (2 g, 13.51 mmol) in dry THF (15 mL) was added dropwise. The mixture was stirred at -78°C for 30 min. A solution of iodine (5.14 g, 20.27 mmol) in dry THF (15 mL) was added. The reaction mixture was allowed to warm to rt and stirred overnight. Sat. Sol. Na₂S₂0₃ was added and the mixture was extracted with EtOAc. The combined organic layers were washed with sat. sol. NaHC0₃, dried, filtered and concentrated. The residue was precipitated with heptane, filtered off and dried to yield Intermediate 1-38 (2.63 g, 71%) as a cream solid.

HPLC-MS (method 4): Rt =4.5, [M+H]⁺ 274. Synthesis of Intermediate 1-39

1-38 1-39

To solution of Intermediate 1-38 (1 g, 3.65 mmol) in 1 ,4-dioxane (60 mL) was added hydrazine hydrate (1.07 mL, 21.91 mmol). The reaction mixture was heated in a sealed tube at 70°C for 16 h. On cooling, NH₄OH (32% aq. sol.) was added (10 mL) and the resulting mixture was concentrated. The residue was taken up in EtOH, the mixture was heated and filtered off. The filtrate was evaporated and the residue was taken up in EtOH, heated and filtered off. This procedure was repeated 3 times. The solids were mixed to give Intermediate 1-39 (0.86 g, 88%) as white solid.

HPLC-MS (method 4): Rt =0.6, [M+H]⁺ 270.

Synthesis of Intermediate 1-40

I -40

A mixture of Intermediate 1-39 (700 mg, 2.59 mmol) and te/ -butyl 2- formylquinolin-8-ylcarbamate (778 mg, 2.85 mmol) in EtOH (13 mL) was refluxed for 2 h. On cooling, the mixture was evaporated. The residue was purified by column chromatography (Biotage, cHex/EtOAc 100:0 to 50:50; twice) to give Intermediate I-40 (470 mg, 35%).

HPLC-MS (method 4): Rt =5.2, [M+H]⁺ 524. Synthesis of Intermediate 1-41

1-41

To a solution of Intermediate I-40 (470 mg, 0.897 mmol) in DCM (5 mL) was added iodobenzene diacetate (289 mg, 0.897 mmol). The reaction mixture was stirred at rt for 5 h. Sat. aq. sol. Na₂S₂0₃ was added and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried, filtered and evaporated. The residue was purified by column chromatography (Biotage, cHex/EtOAc 100:0 to 50:50) to give Intermediate 1-41 (350 mg, 75%). HPLC-MS (method 4): Rt =5.1, [M+H]⁺ 522.

1H NMR (300 MHz, CDCI₃) δ 9.29 (d, J = 7.3 Hz, 1H), 8.59 (d, J = 8.6 Hz, 1H), 8.52 - 8.40 (m, 2H), 8.33 (d, J = 8.6 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.51 (dd, J = 8.2, 1.3 Hz, 1 H), 7.32 (d, J = 7.3 Hz, 1 H), 1.61 (s, 9H).

Synthesis of Intermediate I-42

1-41 I-42

To a solution of Intermediate 1-41 (250 mg, 0.479 mmol) in toluene (2 mL) 2- (methylamino)ethanol (0.054 mL, 0.671 mmol), Pd(OAc)₂ (5 mg, 0.024 mmol), Cs₂C0₃ (234 mg, 0.719 mmol) and BINAP (224 mg, 0.359 mmol) were added. The reaction mixture was heated at 90 °C for 16 h in a sealed tube. On cooling, the mixture was evaporated. The residue was purified by column chromatography (Biotage, cHex/EtOAc 100:0 to 0:100) to give Intermediate 1-42 (115 mg, 54%) as yellow solid. HPLC-MS (method 4): Rt =4.2, [M+H]⁺ 433.

Synthesis of Intermediate 1-43

1-43

1-42

To a solution of Intermediate 1-42 (100 mg, 0.231 mmol) in MeOH (6 mL) was added Amberlyst (250 mg). The reaction mixture was shacked at rt for 24 h and filtered. The resin was treated with 7N NH₃ in MeOH (20 mL), stirred at rt for 1 h and filtered (three times). The filtrates were mixed and concentrated in vacuum to give Intermediate I-43 (55 mg, 72%) as yellow solid.

HPLC-MS (method 4): Rt =3.1, [M+H]⁺ 333.

SYNTHESIS OF IMIDAZOM.2-b1PYRIDAZINE DERIVATIVES

Synthesis of Intermediate 1-44

I -4 I-44

A mixture of Intermediate 1-4 (1.1 g, 6.071 mmol) and Ni Raney (3 pipets) in EtOH (100 mL) was stirred at RT under H₂ atmosphere (balloon presure) for 16 h. The mixture was filtered through Celite and washed with EtOH. The filtrate was evaporated and the residue was purified by column chromatography (Biotage, MeOH:DCM 0:100 to 30:70) to give Intermediate I-44 (650 mg, 64%) as yellow solid.

HPLC-MS (method 4): Rt =0.4, [M+H]⁺ 167.

H NMR (300 MHz, CDCI₃) δ 8.17 (s, 1H), 4.60 (s, 2H), 4.37 - 4.32 (m, 2H), 3.38 - 3.33 (m, 2H), 2.96 (s, 3H). ynthesis of Intermediate 1-45

1-45

To a suspension of (methoxymethyl)triphenylphosphonium chloride (100 mg, 0.367 mmol) in THF (3.4 mL) at -10°C was added LDA (1.8 M in THF/hexane/ethylbenzene, 0.55 mL, 0.771 mmol). The resulting red solution was stirred at -10°C for 1 h. Then, a solution of ferf-butyl 2-formylquinolin-8- ylcarbamate (100 mg, 0.367 mmol) in THF (2 mL) was added and the reaction mixture was stirred at RT for 16 h. The mixture was poured into water and extracted with DCM. The combined organic layers were dried (Na₂S0₄), filtered and concentrated. The residue was purified by column chromatography (Biotage, DCM:cHex, 50:50 to 100:0) to give Intermediate I-45 (69 mg, 63%) (mixture of E and Z isomers) as yellow solid.

HPLC-MS (method 4): Rt =4.9 & 5.0, [M+H]⁺ 301.

Synthesis of Intermediate 1-46

To a solution of (methoxymethyl)triphenylphosphonium chloride (160 mg, 0.466 mmol) in THF (4.7 mL) at 0°C was added dropwise K^fBuO (57 mg, 0.508 mmol) in THF (1 mL). The mixture was stirred at RT for 30 min. A solution of 8- bromoquinoline-2-carbaldehyde (100 mg, 0.424 mmol) in THF (1 mL) was added dropwise to the generated ylide at RT and the reaction mixture was stirred at RT for 16 h. More ylide (1.1 eq) was added, and the reaction mixture was stirred at RT for 19 h, heated at 50°C for 6 h, and then refluxed for 16 h. More ylide (1.1 eq) was added and the reaction was heated at 50°C for 3 days. On cooling, the mixture was evaporated. The residue was triturated from Et₂0 and filtered. The filtrate was evaporated and the residue was purified by column chromatography (Biotage, MeOH:DCM, 0:100 to 6:94) to give Intermediate I-46 (23 mg, 21%) (mixture of E and Z isomers) as yellow solid.

HPLC-MS (method 4): Rt =4.3, [M+H]⁺ 264. ynthesis of Intermediate 1-47

1-47

A mixture of Intermediate 1-45 (19 mg, 0.063 mmol) and NBS (12 mg, 0.066 mmol) in THF (0.4 mL) and H₂0 (0.08 mL) was stirred at RT for 1 h. Intermediate I-44 (11 mg, 0.066 mmol) was added, and the mixture was heated at 85°C for 32h. On cooling, the mixture was evaporated. The residue was purified by column chromatography (Biotage, MeOH:DCM, 0:100 to 30:70) to give the Intermediate I- 47 (10 mg, 37%).

HPLC-MS (method 4): Rt =4.1, [M+H]⁺ 433.

Following the same procedure Intermediate 1-48 was prepared.

1-48

HPLC-MS (method 4): Rt =3.4, [M+H]⁺ 396-398.

¹H NMR (300 MHz, CDCI₃) δ 8.68 (d, J = 8.7 Hz, 1H), 8.61 (s, 1H), 8.23 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.03 (dd, J = 7.5, 1.2 Hz, 1H), 7.75 (dd, J = 8.1 , 1.1 Hz, 1 H), 7.36 - 7.28 (m, 1 H), 4.63 - 4.53 (m, 2H), 3.46 - 3.33 (m, 2H), 3.05 (s, 3H). Synthesis of Intermediate 1-49

1-44 1-49

A mixture of Intermediate 1-44 (50 mg, 0.301 mmol) and chloroacetaldehyde (50% in water, 0.16 mL, 0.632 mmol) in THF (0.3 mL) was heated in a sealed tube at 85°C for 21 h. On cooling, the mixture was evaporated. The residue was purified by column chromatography (Biotage, MeOH:DCM, 0:100 to 30:70) to give Intermediate 1-49 (60 mg, 100%) as yellow solid.

HPLC-MS (method 4): Rt =0.4, [M+H]⁺ 191.

¹H NMR (300 MHz, MeOD) δ 8.56 (s, 1 H), 8.02 (s, 1 H), 7.76 (s, 1 H), 4.62 - 4.54 (m, 2H), 3.61 - 3.55 (m, 2H), 3.17 (s, 3H).

Alternative Synthesis of intermediate I -48

I-48

A mixture of Intermediate I-49 (60 mg, 0.315 mmol), 2,8-dibromoquinoline (95 mg, 0.331 mmol), Pd(PPh₃)₄ (18 mg, 0.016 mmol), Pd(OAc)₂ (4 mg, 0.016 mmol) and K₂C0₃ (87 mg, 0.631 mmol) in dioxane (1.3 mL) and H₂0 (0.012 mL) was heated at 100°C in a sealed tube for 18 h. On cooling, DCM was added and the mixture was filtered off and washed with DCM. The filtrate was evaporated. The residue was purified by column chromatography (Biotage, MeOH:DCM, 0:100 to 10:90) to give Intermediate i-48 (32 mg, 26%) as yellow solid.

Table 1 : Compounds, Analytical data, PIM activity, synthetic methodology -

R_t means retention time (in minutes), [M+H]⁺ means the protonated mass of the compound, method refers to the method used for (LC)MS. Biological activity in PIM1 , PIM2 and PIM3 for certain examples is represented by quantitative results, IC50 in nM and for certain examples is represented by semi-quantative results: IC50 >1μΜ (·), IC50 <100 nM (-), 100 nM<IC50<1 μΜ («). Synthetic method column refers to the general synthetic method used to generate the compounds following a similar protocol to the one described for one or some examples. Column of salt indicates whether the compound is in the free base form or salt form, sometimes this depends on the purification method in HPLC.

DMSO δ 11.61 (t,

J=5.9, 1H), 8.80 - 8.7 Method

(m, 2H), 8.68 (s, 2 Rt=

1H),8.60 (d, J=8.7, 1H), 7.494

CON(H) ***

8.25 (dd, J=8.1, 1.5, min >1000 ** H No (Et) 66

1H), 7.81 (t, J=7.7, 1H), [M+H]⁺

4.63 (m, 2H), 3.50 (m, m/z

2H), 3.14 (s, 3H), 1.24 391.2.

(t, 3H).

DMSO 5 8.46 (d, J =

8.6 Hz, 1H), 8.39 (s,

1H), 8.19 (m, 1H), 7.41

(t, J = 7.9 Hz, 1H), 7.05

Method

(d, J = 7.8 Hz, 1H),

1 Rt=

H 1 6.71 (t, J = 5.5 Hz, 1H),

3.70

6.66 (d, J = 7.7 Hz, ***

H min >1000 *** I No

1H), 4.52 (m, 2H), 3.50 7.8

H [M+Hf

(m, 2H), 3.40 (m, 2H),

mz

3.27 (m, 2H), 3.17 (m,

473.3

2H), 2.70 (m, 2H), 1.97

(m, 3H), 1.65 (m, 2H),

1.43 (m, 4H), 0.99 (m,

3H).

CDCfe δ 8.44 (d, J =

8.6 Hz, 1 H), 8.26 (s,

1H), 8.18 (d, J = 8.7

Hz, 1 H), 7.41 (t, J = 7.9

Method

Hz, 1H), 7.05 (d, J =

1 Rt=

HN¼ 7.7 Hz, 1H), 6.71 (d, J

3.64

= 7.4 Hz, 1 H), 6.47 (d, ***

H min 248 3.6 A

J = 7.5 Hz, 1H), 4.54 0.3 No

[M+Hf

NH₂ (m, 2H), 3.51 (m, 2H),

mz

3.42 (m, 2H), 2.86 (m,

473.4

1H), 2.34 (m, 2H), 2.03

(m, 2H), 1.69 (m, 2H),

1.43 (m, 6H), 1.02 (t, J

= 7.3 Hz, 3H).

DMSO δ 11.25 (d, J =

7.6 Hz, 1H), 9.11 (s, Method

1H), 8.70 (m, 3H), 8.25 1 Rt=

_{HN 0} (d, J = 8.0 Hz, 1H), 2.98

Me H 7.80 (t, J = 7.7 Hz, 1H), min >1000 - H No

w 4.58 (m, 2H), 4.21 (m, [M+Hf

H

1H), 3.49 (m, 2H), 3.15 mz

(m, 5H), 2.75 (m, 2H), 445.1

1.91 (s,4H).

DMSO δ 8.82 (s, 1H),

8.64 (d, J = 8.6 Hz,

1H), 8.30 (d, J = 8.5

Method

Hz, 1H), 8.07 (d, J =

1 Rt=

8.0 Hz, 1H), 7.85 (m,

3.53

1H), 7.77 (m, 1H), 7.55 **

Me H min >1000 - E No

(broad s, 2H), 7.21 (m,

[M+Hf

2H), 7.12 (d, J = 7.7

mz

Hz, 1H), 6.65 (d, J =

410.3

7.8 Hz, 1H), 4.57 (m,

2H), 3.47 (m, 2H), 3.11

(s, 3H).

DMSO δ 11.15 (d, J =

7.9 Hz, 1H), 8.73 (m,

3H), 8.58 (d, J = 8.7 Method

Hz, 1H), 8.26 (dd, J = 1 Rt=

8.1, 1.4 Hz, 1H), 7.81 2.93

Me H (m, 1H), 4.58 (m, 2H), min >1000 H No

3.90 (m, 1H), 3.53 (m, [M+Hf

2H), 3.10 (S, 3H), 2.71 mz

(m, 1H), 1.98 (m, 2H), 459.1

1.88 (m, 2H), 1.53 (m,

2H), 1.25 (m,2H).

DMSO δ 8.85 (s, 1H),

8.66 (d, J = 3.3 Hz,

1H), 8.59 (d, J = 8.7

Method

Hz, 1H), 8.51 (d, J =

1 Rt=

8.7 Hz, 1H), 8.26 (dd, J

3.10

= 7.5, 1.3 Hz, 1 H), 7.94

min **

H (dd, J = 8.2, 1.3 Hz, >1000 - 1 No

[M+Hf 119

1H), 7.72 (m, 1H), 6.58

mz

(d, J = 3.3 Hz, 1H),

564.3

4.47 (m, 2H), 3.86 (s,

2H), 3.76 (m, 2H), 3.61

(m, 4H), 3.28 (m, 5H),

3.01 (m, 5H).

DMSO δ 9.59 (s, 1H),

8.86 (s, 1H), 8.56 (d, J

= 8.7 Hz, 1H), 8.43 (d,

J = 8.6 Hz, 1H), 8.38

Method

(s, 1H), 8.21 (d, J = 7.3

1 Rt=

Hz, 1H), 7.88 (d, J =

4.65

8.0 Hz, 1H), 7.66 (t, J =

min ***

H 7.7 Hz, 1H), 4.48 (t, J = >1000 ** E No

[M+H]⁺ 67

3.7 Hz, 2H), 4.40 (t, J =

mz

5.1 Hz, 2H), 3.77 (t, J =

487.2

5.1 Hz, 2H), 3.71 (t, J =

5.0 Hz, 2H), 3.66 - 3.55 (m, 4H), 3.30 (s,

3H), 3.23 (s, 3H).

DMSO δ 8.69 (s, 1H),

8.48 (d, J = 8.6 Hz,

1H), 8.26 (d, J = 8.6

Method

Hz, 1 H), 7.57 (dt, J =

1 Rt=

15.4, 7.7 Hz, 2H), 7.21

4.48

(d, J = 7.2 Hz, 1 H),

0 min **

H 4.46 (t, J = 3.7 Hz, 2H), >1000

ψ [M+Hf 137 - Q No 3.68 (d, J = 4.4 Hz,

0 mz

5H), 3.57 (d, J = 4.7

525.2

Hz, 4H), 3.44 (s, 4H),

3.27 (s, 3H), 2.96 (s,

3H).

DMSO δ 8.62 (s, 1H),

8.39 (d, J = 8.7 Hz,

1H), 8.34 (d, J = 8.6

Hz, 1H), 7.45 (t, J = 7.9 method

Hz, 1H), 7.15 (d, J = 1 Rt=

5.78

7.5 Hz, 1H), 6.88 (d, J min *** >100 **

112 Me H I No

= 7.5 Hz, 1 H), 6.56 (d, [M+Hf 0

mz

F ? F J = 8.4 Hz, 1H), 4.55 452.2

(m, 2H), 3.83 (m, 1H),

3.45 (m, 2H), 3.08 (s,

3H), 2.11 (m, 6H), 1.70

(m, 2H).

DMSO δ 8.63 (s, 1H),

8.37 (d, J = 8.7 Hz,

1H), 8.33 (d, J = 8.6

Hz, 1H), 7.42 (t, J = 7.9

method

Hz, 1H), 7.10 (m, 1H),

1 Rt=

HN½ 6.77 (d, J = 7.4 Hz, 6.70

min *** >100 >100

113 Me H 1H), 6.53 (d, J = 8.1 I No

[M+Hf 0 0

Hz, 1 H), 4.55 (m, 2H), mz

444.3

3.52 (m, 1H), 3.44 (m,

2H), 3.08 (S, 3H), 1.94

(m, 2H), 1.46 (m, 6H),

0.98 (s, 3H), 0.97 (s,

3H).

MeOD δ 8.49 (d, J =

8.6 Hz, 1H), 8.42 (s,

1H), 8.16 (d, J = 8.7

Hz, 1 H), 7.41 (t, J = 7.9 method

Hz, 1H), 7.02 (d, J = 1 Rt=

4.94

8.1 Hz, 1 H), 6.71 (d, J min *** >100

116 Me H ** I No

= 7.7 Hz, 1H), 4.54 (m, [M+Hf 68 0

mz

2H), 3.62 (t, J = 6.2 Hz, 406.3

2H), 3.43 (m, 4H), 3.39

(s, 3H), 3.08 (s, 3H),

2.08 (p, J = 6.5 Hz,

2H).

S nthesis of Final Products 114 a

14 114 115 To a solution of Final Product 14 (47 mg, 0.1 mmol) in MeOH:DC 1:2 (1.5 mL) was added NCS (13 mg, 0.1 mmol). The reaction mixture was stirred at RT for 2 h. Water was added and the mixture was extracted with DCM. The organic layer was washed with NaCI, dried over sodium sulfate, filtered and evaporated. The residue was purified by prep-HPLC to give Final Product 114 (9 mg, 18%) and Final Product 115 (10 mg, 20%).

Final Product 114:

¹H-NMR (300 MHz, CDCI₃)□ 8.60-8.39 (m, 2H), 8.18 (d, J= 8.4 Hz, 1H), 7.39 (d, J= 8.5 Hz, 1H), 7.17 (d, J= 8.7 Hz, 1H), 4.49 (s, 2H), 3.75 (d, J= 5.3 Hz, 2H), 3.67-3.49 (m, 7H), 3.34 (s, 4H), 2.75 (s, 2H), 2.04 (d, J= 11.3 Hz, 2H), 1.87 (s, 1H), 1.65 (d, J= 11.2 Hz, 2H) ppm.

LC-MS (method 1) R 3.32 min [M+H]⁺ m/z 509.2.

Biological activity in PIM1 : IC₅₀ = 43 nM; PIM2: IC₅₀ >1000 nM; PIM3: IC₅₀ = 94 nM. Final Product 115 :

¹H-NMR (300 MHz, CDCI₃) D8.64 (d, J = 8.9 Hz, 1H), 8.46 (d, J = 8.9 Hz, 1H), 8.43 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 4.40 (s, 2H), 3.51 (m, 7H), 3.25 (m, 8H), 2.79 (m, 1H), 2.01 (m, 2H), 1.51 (m, 2H).

LC-MS (method 1) R 3.61 min [M+H]⁺ m/z 509.2. Biological activity in PIM1: IC₅₀ = 374 nM;

Synthesis of Final Product 117

To a solution of Intermediate I-68 (46 mg, 0.131 mmol) in DCE (5 mL) was added cyclohexanone (44 pL, 0.393 mmol) and AcOH (24 μ!_, 0.393 mmol). The mixture was stirred at RT for 30 min, then NaBH(OAc)₃ (83 mg, 0.393 mmol) was added. The reaction mixture was refluxed overnight. More cyclohexanone (88 pL), AcOH (48 pL) and, after stirring 30 min, NaBH(OAc)₃ (160 mg) were added, and the reaction was refluxed for 4h (SM was still detected). The reaction mixture was placed in a pressure tube and cyclohexanone (0.5 mL), AcOH (0.1 mL) and NaBH(OAc)₃ (160 mg) were added. The mixture was refluxed for 4h (still SM left). On cooling, the mixture was evaporated and the residue was purified by column chromatography (Biotage, DCM:MeOH 100:0 to 98:2) and by HPLC affording Final Product 117 (5 mg, 8%).

¹H-NMR (300 MHz, MeOD) δ 8.35 (m, 2H), 8.00 (m, 1H), 6.53 (m, 1H), 6.38 (m, 1H), 4.52 (s, 2H), 3.43 (m, 3H), 3.04 (s, 3H), 2.15 (m, 2H), 1.86 (m, 2H), 1.73 (m, 1H), 1.58 - 1.22 (m, 5H).

LC-MS (method 1) R 6.43 min [M+H]⁺ 434.2 m/z. Biological activity in PIM1 : IC₅₀ = 38 nM; PIM2: IC₅₀ >1000 nM; PIM3: IC₅₀ nM.

The following Final Products were prepared using the same procedure:

Final Product 122:

I-74 122

Yield : 68%.

¹H-NMR (300 MHz, CDCI₃) δ 8.55 (d, J = 8.9 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 8.28 (s, 1 H), 7.62 (d, J = 8.3 Hz, 1 H), 6.66 (d, J = 8.4 Hz, 1 H), 4.61 (m, 2H), 3.53 (m, 1H), 3.48 (m, 2H), 3.13 (s, 3H), 2.17 (m, 2H), 1.87 (m, 2H), 1.69 (m, 1H), 1.46 (m, 5H).

LC-MS (method 1) R_f= 6.98 min; [M+H]⁺ m/z 494.1, 496.1

89 130 131

To a solution of Final Product 14 (40 mg, 0.09 mmol) in DCM was added NCS (1 eq). The reaction mixture was stirred at RT for 2 h. Water was added and the mixture was extracted with DCM. The organic layer was washed with NaCI, dried over sodium sulfate, filtered and evaporated. The residue was purified by prep- HPLC to give Final Product 130 (8 mg) and Final Product 131 (8 mg).

130 ¹H-NMR (300 MHz, DMSO-d6) 8.75 (s, 1 H), 8.53 - 8.48 (m, 2H), 7.57 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.64 (t, J = 6.2 Hz, 1H), 4.62 (t, J = 3.9 Hz, 2H), 4.17 (dd, J = 20.0, 6.3 Hz, 2H), 3.60 - 3.46 (m, 2H), 3.15 (s, 3H), 2.87 - 2.66 (m, 4H), 1.97 - 1.66 (m, 4H).

LC-MS (method 1) Rr=3.1 min [M+H]⁺ 483 m/z.

131

¹H-NMR (300 MHz, DMSO-d6) 8.65 (s, 3H), 8.58 (d, J = 8.8 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 6.96 - 6.80 (m, 2H), 4.56 (t, J = 4.1 Hz, 2H), 3.58 (dd, J = 19.0, 6.0 Hz, 2H), 3.50 - 3.43 (m, 5H), 3.08 (s, 3H), 2.97 - 2.71 (m, 4H), 1.86 (d, J = 11.8 Hz, 2H).

LC-MS (method 1) R_/=3.4 min [M+H]⁺ 483 m/z.

Synthesis of Final Products 132

132

Compound 132 was synthesized by a coupling reaction using a tricycle intermediate (80 mg) and the corresponding amine following synthetic procedure A, and further BOC deprotection to obtain desired product (40 mg).

1H NMR (300 MHz, CDCI₃) δ 8.52 (d, J = 8.8 Hz, 1H), 8.42 (dd, J = 8.8, 4.3 Hz, 1H), 8.27 (d, 1H), 7.09 (m, 1H), 6.65 (m, 1H), 6.57 (m, 1H), 4.58 (m, 2H), 3.52 (m, 2H), 3.43 (m, 2H), 3.18 (m, 2H), 3.09 (s, 3H), 2.87 (m, 1H), 2.40 (m, 1H), 2.04 (m, 4H).

LC-MS (method 1), rt = 3.2 min. MS: [467] [M+H] Biological activity in PIM1 : IC₅₀ = 28 nM; PIM2: IC₅₀ >1000 nM; PIM3: IC₅₀ = 14 nM. ynthesis of Final Products 133

Compound 133 was synthesized by a coupling reaction using tricycle intermediate (300 mg) and the corresponding amine following synthetic procedure A, and further BOC deprotection to obtain desired product (110 mg). ¹H NMR (300 MHz, DMSO) δ 8.61 - 8.33 (m, 3H), 6.85 (m, 1 H), 6.73 (t, 1 H), 4.47 (m, 2H), 3.53 (m, 2H), 3.35 (m, 2H), 2.99 (s, 3H), 2.83 (m, 4H), 2.18 (m, 1 H), 1.82 (m, 1 H), 1.66 (m, 1 H).

LC-MS (method 1), rt = 3.4 min. MS: [485] [M+H]

Synthesis of Final Products 136

Compound 136 was synthesized by coupling reaction of a tricycle intermediate (80 mg) and the corresponding amine following synthetic procedure A.

¹H NMR (300 MHz, DMSO) δ 8.73 (s, 1 H), 8.47 (q, J = 8.8 Hz, 2H), 7.34 - 7.20 (m, 1H), 6.67 (m, 1 H), 4.52 (m, 2H), 3.43 (m, 3H), 3.05 (s, 3H), 1.82 (m, 2H), 1.67 (m, 4H), 1.50 (m, 2H), 1.16 (s, 3H). Synthesis of Final Products 137

137

Compound 137 was synthesized by coupling reaction of a tricycle intermediate (80 mg) and the corresponding amine following synthetic procedure A.

¹H NMR (300 MHz, DMSO) δ 8.71 (s, 1 H), 8.47 (dd, 2H), 7.38 (dd, J = 8.8 Hz, 2H), 6.56 (d, J = 10.2 Hz, 1H), 4.55 (m, 2H), 4.13 (m, 2H), 3.46 (m, 2H), 3.08 (s, 3H), 1.65 (m, 6H), 1.38 (m, 2H), 1.13 (s, 3H).

Table 2: Compounds, Analytical data, PIM activity, synthetic methodology -

R_t means retention time (in minutes), [M+H]⁺ means the protonated mass of the compound, method refers to the method used for (LC)MS. Biological activity in PIM1 , PIM2 & PIM3 for certain examples is represented by quantitative results, IC50 in nM and for certain examples is represented by semi-quantative results: IC50 >1μΜ (.), IC50 <100 nM (-«), 100 nM<IC50<1 μΜ (..). Synthetic method column refers to the general synthetic method used to generate the compounds following a similar protocol to the one described for one or some examples. Column of salt indicates whether the compound is in the free base form or salt form, sometimes this depends on the purification method in HPLC.

General Synthetic Procedure I

Synthesis of Final Product 3-01

I-43 I-44 3-01

A mixture of Intermediate I-43 (55 mg, 0.165 mmol), 1-Boc-4- piperidinecarboxaldehyde (71 mg, 0.331 mmol) and AcOH (0.025 mL, 0.331 mmol) in DCE (2 mL) was stirred at RT for 30 min. NaBH(OAc)₃ (77 mg, 0.364 mmol) was added and the reaction mixture was stirred at rt for 16 h. 2 M NaOH was added and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried, filtered and evaporated. The residue was purified by flash chromatography (Chromatotron, EtOAc) to give Intermediate 1-44 (40 mg, 42%) as yellow solid.

To a solution of Intermediate 1-44 (40 mg, 0.076 mmol) in MeOH (2 mL) was added Amberlyst (79 mg). The reaction mixture was shacked at RT for 24 h. The mixture was filtered off and the resin was treated with 7N NH₃ in MeOH (20 mL) at RT for 1 h. The mixture was filtered and the treatment was repeated three times. The filtrates were mixed and evaporated to give Final Product 3-01 (22 mg, 68%) as yellow solid.

LC-MS (method 1 ) R 2.46 min [M+H]⁺ mz 430.2.

¹H NMR (300 MHz, DMSO) δ 9.29 (d, J = 7.6 Hz, 1 H), 8.37 (m, 2H), 7.43 (t, J = 7.9 Hz, 1 H), 7.11 (m, 2H), 6.81 (d, J = 7.6 Hz, 1H), 6.13 (t, J = 5.7 Hz, 1 H), 4.43 (m, 2H), 3.46 (m, 2H), 3.26 (m, 2H), 3.01 (m, 5H), 2.54 (m, 2H), 1.86 (m, 1 H), 1.74 (m, 2H), 1.28 (m, 2H).

Biological activity PIM1 : IC₅₀ = 1 nM; PIM2: IC₅₀ = 479 nM; PIM3: IC₅₀ = 12 nM.

Table 3: Compounds, Analytical data, PIM activity, synthetic methodology -

R_t means retention time (in minutes), [M+H]⁺ means the protonated mass of the compound, method refers to the method used for (LC)MS. Biological activity in PIM1 , PIM2 and PIM3 for certain examples is represented by quantitative results, IC50 in nM and for certain examples is represented by semi-quantative results: IC50 >1μΜ 0, IC50 <100 nM («), 100 nM<IC50<1 μΜ (..). Synthetic method column refers to the general synthetic method used to generate the compounds following a similar protocol than the one described for one or some examples. Column of salt indicates whether the compound is in the free base form or salt form, sometimes this depends on the purification method in HPLC.

General Synthetic Procedure E

Synthesis of Final Product 4-01

I-48 4-01

A mixture of Intermediate I-48 (82 mg, 0.207 mmol), 2-aminopyrimidine-5-boronic acid, pinacol ester (55 mg, 0.248 mmol), PdCI₂(dppf) (34 mg, 0.041 mmol) and sat. sol. Na₂C0₃ (0.44 mL) in DME (1 ml.) was heated under microwave irradiation at 140°C for 30 min. On cooling, the mixture was filtered through Celite and washed with DCM. The filtrate was evaporated and the residue was purified by column chromatography (Biotage, MeOH:DCM, 0:100 to 10:90) to give Final Product 4-01 (30 mg, 35%) as yellow solid.

LC-MS (method 4) R 3.06 min [M+H]⁺ mz 411.1.

H NMR (300 MHz, DMSO) δ 8.93 (s, 1H), 8.56 (d, J = 8.9 Hz, 1H), 8.31 (d, J = 11.7 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.73 (m, 1H), 7.49 (m, 4H), 4.58 (m, 2H), 3.39 (m, 2H), 3.06 (s, 3H).

Table 4: Compounds, Analytical data, PIM activity, synthetic methodology -

R_t means retention time (in minutes), [M+H]⁺ means the protonated mass of the compound, method refers to the method used for (LC)MS. Biological activity in PIM1 , PIM2 & PIM3 for certain examples is represented by quantitative results, IC50 in nM and for certain examples is represented by semiquantitative results, IC50 >1μΜ (.), IC50 <100 nM (-.), 100 nM<IC50<1 μΜ («). Synthetic method column refers to the general synthetic method used to generate the compounds following a similar protocol than the one described for one or some examples. Column of salt indicates whether the compound is in the free base form or salt form, sometimes this depends on the purification method in HPLC.

Table 5: Compounds, Analytical data, PIM activity, synthetic methodology -

R_t means retention time (in minutes), [M+H]⁺ means the protonated mass of the compound, method refers to the method used for (LC)MS. Biological activity in PIM1, PIM2 & PIM3 for certain examples is represented by quantitative results, IC50 in nM and for certain examples is represented by semi-quantative results: IC50 >1μΜ («), IC50 <100 nM («.), 100 nM<IC50<1 μΜ (..). Synthetic method column refers to the general synthetic method used to generate the compounds following a similar protocol than the one described for one or some examples. Column of salt indicates whether the compound is in the free base form or salt form, sometimes this depends on the purification method in HPLC.

IC50 IC50 IC50 Synth.

R1 R2 R3 ¹H-NMR (300 MHz) LC/MS Salt

PIM1 PIM2 PIM3 Method

MeOD 5 8.80 (s, 1 H),

8.14 (dd, J = 8.6, 1.3

Hz, 1H), 8.07 (s, 1H),

7.83 (d, J = 5.7 Hz,

1H), 7.49 (d, J = 8.7 method 3

Hz, 1H), 6.99 (d, J = Rt= 3.91

Me H 5.8 Hz, 1H), 4.45 (m, min 18 No

2H), 3.64 (m, 2H), [M+H]+

3.37 (m, 2H), 3.00 (s, mz 417.2

3H), 2.81 (m, 3H),

1.93 (m, 2H), 1.67

(m, 2H).

Table 6: Compounds, Analytical data, PIM activity, synthetic methodology -

R_t means retention time (in minutes), [M+H]⁺ means the protonated mass of the compound, method refers to the method used for (LC)MS. Biological activity in PIM1, PIM2 & PIM3 for certain examples is represented by quantitative results, IC50 in nM and for certain examples is represented by semi-quantative results: IC50 >1μΜ (·), IC50 <100 nM (.«), 100 nM<IC50<1 μΜ («). Synthetic method column refers to the general synthetic method used to generate the compounds following a similar protocol than the one described for one or some examples. Column of salt indicates whether the compound is in the free base form or salt form, sometimes this depends on the purification method in HPLC.

Combination assays

Combination index (CI) calculated for the combination of compound 14 of the invention and various chemotherapeutic agents in the MTT in vitro cell 5 proliferation assays [CI < 0.1 (++++), 0.KCK 0.3 (+++), 0.3<CI<0.7 (++), 0.7<CI<1.2 (+)] are depicted in Table 7 below.

Table 7: Combination Studies

Data: BadP S112 inhibition by cell ELISA in H1299Pim1 cells

Efficacy of compounds of the examples to inhibit the Bad phosphorylation is represented in Table 8 by quantative results. Assay was performed in absence of FBS:

Claims

A compound of formula I,

wherein:

X¹ represents =N- or =C(R⁵)-; R⁵ represents hydrogen, halo or C-,.3 alkyl optionally substituted by one or more substituents selected from fluoro and -CN;

X² represents =N- or =C(H)-; X^a, X^b, X°, X^d, X^f and X⁹ independently represent -C(R⁷)= or, any one or two of X^a, X^b, X^c, X^d, X^f or X⁹ may represent -N=; each R⁷ independently represents hydrogen or a substituent selected from -F, -CI, -Br, -CN, -CH₂OH, C_1-3 alkyl (optionally substituted by one or more fluoro atoms) and -0-C_1-3 alkyl (optionally substituted by one or more fluoro atoms); the R¹, R² and X-containing ring is non-aromatic in which:

R¹ and R² are independently selected from -0-, -S-, -S(O)-, -S(0)₂-, -C(R⁶)(R^6a)- and -N(R⁶)-; and X represents C_1-3 alkylene optionally substituted by one or more substituents selected from E²; each R⁶ and R^6a independently represents, on each occasion when used herein, H, -C(0)NHR^d1, -C(0)R^d2 or R^d3;

R^d1, R^d2 and R^d3 independently represent C_1-12 (e.g. C_1-6) alkyl optionally substituted by one or more substituents selected from E¹; R³ represents hydrogen or a substituent selected from -CI, -CN, -OH, -OCH₃ and C _-3 alkyl optionally substituted by one or more fluoro atoms;

R^4a represents hydrogen or C _-6 alkyl optionally substituted by one or more substituents selected from halo; R⁴ represents d_-6 alkyl, heterocycloalkyl, aryl or heteroaryl (which latter four groups are optionally substituted by one or more substitutents selected from halo, C_1-3 alkyl and -OCi_-3 alkyl);

in which R^a and R independently represent H, -Z^1a-C_1-12 alkyl, -Z^1b-heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0, =NOR^7a and Q ), -Z^1c-aryl or -Z^1d-heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from Q²); or

R^a and R^b are linked together, along with the requisite nitrogen atom to which they are necessarily attached, to form a (first) 3- to 7-membered cyclic group, optionally containing one further heteroatom selected from nitrogen, sulfur and oxygen, and which ring optionally:

(a) is fused to a second ring that is either a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen, a 3- to 12-membered saturated carbocyclic ring, or an unsaturated 5- to 12-membered carbocyclic or heterocyclic ring;

(b) comprises a linker group -(C(R^X)₂)_P- and/or -(C(R )2)r-0-(C(R^x)₂)_s- (wherein p is 1 or 2; r is 0 or 1 ; s is 0 or 1 ; and each R^x independently represents hydrogen or C_1-6 alkyl), linking together any two non-adjacent atoms of the first 3- to 7-membered ring (i.e. forming a bridged structure); or

(c) comprises a second ring that is either a 3- to 12-membered saturated carbocyclic ring or a 3- to 7-membered saturated heterocycloalkyl group containing one to four heteroatoms selected from oxygen and nitrogen, and which second ring is linked together with the first ring via a single carbon atom common to both rings (i.e. forming a spiro-cycle), all of which cyclic groups, defined by the linkage of R^a and R^b, are optionally substituted by one or more substituents selected from =0, =NOR^7b and E⁴; _z ⁱa _z ⁱb _zic _{and z}w independently represent a direct bond, -C(O)- or -S(0)₂-; each Q and Q² independently represents, on each occasion when used herein: halo, -CN, -N0₂, -N(R^10a)R^{1 a}, -OR ^0a, -C(=Y)-R^10a, -C(=Y)-OR^10a, -C(=Y)N(R ^0a)R^11a, -C(=Y)N(R ^0a)-OR ^c, -OC(=Y)-R ^0a, -OC(=Y)-OR^10a, -OC(=Y)N(R^10a)R^{1 a}, -OS(O)₂OR^10a, -OP(=Y)(OR ^0a)(OR^11a), -OP(OR^10a)(OR^11a), -N(R^12a)C(=Y)R^11a, -N(R^12a)C(=Y)OR^11a, -N(R^12a)C(=Y)N(R^10a)R^11a,

-NR^12aS(O)₂R^10a, -NR^12aS(O)₂N(R^10a)R^11a, -S(O)₂N(R ^0a)R^11a, -SC(=Y)R^10a, -S(O)₂R^10a, -SR ^0a, -S(O)R^10a, C_1-12 alkyl, heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R ^0a) and E⁵), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E⁶);

R^7a and R^7b independently represent hydrogen or C_1-6 alkyl optionally substituted by one or more fluoro atoms; each R ^1c independently represents, on each occasion when used herein, C _-12 alkyl, heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R²⁰) and E⁷), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E⁸); each R^10a, R^11a and R ^2a independently represent, on each occasion when used herein, hydrogen, Ci_{- 2} alkyl, heterocycloalkyi (which latter two groups are optionally substituted by one or more substituents selected from =0, =S, =N(R²⁰) and E⁷), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from E⁸); or any relevant pair of R^10a, R^11a and R ^2a may be linked together to form a 4- to 20- membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from =0, =S, =N(R²⁰) and E⁹; each E¹, E², E³, E⁴, E⁵, E⁶, E⁷, E⁸ and E⁹ independently represents, on each occasion when used herein:

(i) Q⁴; (ii) C_1-12 alkyl optionally substituted by one or more substituents selected from =0 and Q⁵; or any two E , E², E³, E⁴, E⁵, E⁶, E⁷, E⁸ or E⁹ groups may be linked together to form a 3- to 12-membered ring (in which each of the atoms of the ring may be a carbon atom or a heteroatom), optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from =0 and J¹; each Q⁴ and Q⁵ independently represent, on each occasion when used herein: halo, -CN, -N0₂, -N(R²⁰)R²¹, -OR²⁰, -C(=Y)-R²⁰, -C(=Y)-OR²⁰, -C(=Y)N(R²⁰)R²\ -C(=Y)N(R²⁰)-O-R^21a, -OC(=Y)-R²°, -OC(=Y)-OR²⁰, -OC(=Y)N(R²⁰)R²¹, -OS(0)₂OR²⁰, -OP(=Y)(OR²⁰)(OR²¹), -OP(OR²⁰)(OR²¹), -N(R²²)C(=Y)R²¹, -N(R²²)C(=Y)OR²¹, -N(R²²)C(=Y)N(R²⁰)R²¹, -NR ²S(0)₂R²⁰, -NR²²S(O)₂N(R²⁰)R²¹, -S(O)₂N(R²⁰)R²¹, -SC(=Y)R²⁰, -S(0)₂R²⁰, -SR²⁰, -S(0)R²⁰, Ci-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and J²), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from

J³); each Y independently represents, on each occasion when used herein, =0, =S, =NR²³ or =N-CN; each R^21a independently represents, on each occasion when used herein, C_1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J⁴ and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J⁵); each R²⁰, R²¹, R²² and R²³ independently represent, on each occasion when used herein, hydrogen, C_1-6 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J⁴ and =0), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from J⁵); or any relevant pair of R²⁰, R²¹ and R²², may be linked together to form a 4- to 20- membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from J⁶ and =0; each J¹, J², J³, J⁴, J⁵ and J⁶ independently represents, on each occasion when used herein:

0) Q⁷;

(ii) aryl, C_1-6 alkyl or heterocycloalkyl, both of which latter two groups are optionally substituted by one or more substituents selected from =0 and Q⁸; each Q⁷ and Q⁸ independently represents, on each occasion when used herein: halo, -N(R⁵⁰)R⁵¹, -OR⁵⁰, -C(=Y^a)-R⁵⁰, -C(=Y^a)-OR⁵⁰, -C(=Y^a)N(R⁵⁰)R⁵¹, -N(R⁵²)C(=Y^a)R⁵¹, -NR⁵²S(0)₂R⁵⁰, -S(0)₂R⁵⁰, -SR⁵⁰, -S(0)R⁵⁰ or C_1-6 alkyl optionally substituted by one or more fluoro atoms; each Y^a independently represents, on each occasion when used herein, =0, =S, =NR⁵³ or =N-CN; each R⁵⁰, R⁵¹, R⁵² and R⁵³ independently represents, on each occasion when used herein, hydrogen or Ci_-6 alkyl optionally substituted by one or more substituents selected from fluoro, -OR⁶⁰ and -N(R⁶¹)R⁶²; or

any relevant pair of R⁵⁰, R⁵¹ and R⁵² may be linked together to form, a 3- to 8- membered ring, optionally containing one or more heteroatoms, optionally containing one or more unsaturations, and which ring is optionally substituted by one or more substituents selected from =0 and C_1-3 alkyl;

R⁶⁰, R⁶ and R⁶² independently represent hydrogen or Ci_-6 alkyl optionally substituted by one or more fluoro atoms, or a pharmaceutically acceptable ester, amide, solvate or salt thereof.

2. A compound as claimed in Claim 1 , wherein:

the X¹ and X²-containing bicyclic moieties of compounds of the invention represent:

in which the squiggly lines represent the point of attachment to the remainder of the compound of formula I and R³ is as defined in Claim 1 ;

the X^a to X⁹-containing bicycles represent those in which optionally one of X^a, X , X^c, X^d, X^f or X⁹ represents -N= (and the others independently represent -C(R⁷)=) so formin , e.g. the following:

in which the squiggly lines represent the point of attachment to the remainder of the compound of formula I and R⁴ is as defined in Claim 1.

3. A compound as claimed in Claim 1 or Claim 2, wherein: Preferred compounds of the invention include those in which R⁴ represents:

a fragment of formula IA;

-CH₂-[fragment IA];

-C(0)-[fragment IA];

-[0]o-i-(CH₂)ni-heterocycloalkyl (e.g. -0-(CH₂)_ni-heterocycloalkyl or -heterocyclo- alkyl), in which n1 represents 0 or 1 ;

-N(R^4a)-C(0)-R^4b;

aryl (optionally substituted by one or more substituents selected from E³); or heteroaryl (optionally substituted by one or more substituents selected from E³), or wherein R⁴ represents one of the following:

wherein the squiggly line represents the point of attachment to the requisite X^a to X^d-containing bicycle of the compound of formula I, represents R^a or R^b, and the other integers (e.g. E³, E⁴, E⁵, E⁶ and Q¹; which are optional substituerits that may be attached to specific atoms, or, may be depicted as 'floating', in which case the relevant group is optionally substituted by one or more of those E³/E⁴/Q¹/E⁵/E⁶ substituents) are as defined in Claim 1 (and the depiction of a substituent in brackets signifies that that substituent is optionally present, and may therefore be absent).

4. A compound as claimed in any one of the preceding claims, wherein: Q¹ and Q² independently represent halo, -CN, -N(R ^0a)R^11a, -OR^10a, -C(=Y)-R ^0a, -C(=Y)-OR^10a, -C(=Y)N(R^10a)R^11a, -S(O)₂R ^0a, -N(R^12a)C(=Y)R^11a , C_1-6 (e.g. C_1-3) alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more subsitutents selected from =0 and E⁵), aryl or heteroaryl (which latter two groups are optionally substituted by one or more subsitutents selected from E⁶); E¹, E², E³, E⁴, E⁵, E⁶, E⁷, E⁸ and E⁹ independently represent Q⁴ or C_1-6 (e.g. C_1-4) alkyl optionally substituted by one or more (e.g. two or, preferably, one) substituent(s) selected from Q⁵;

Q⁴ represents -C(=Y)-R²⁰, -C(=Y)OR²⁰, -N(R²⁰)R²¹, -OR²⁰, -N(R²²)S(0)₂R²⁰ or -S(0)₂R²⁰;

Q⁵ represents -N(R²⁰)R²¹, -OR²⁰ or aryl (e.g. unsubstituted phenyl);

R^10a and R^11a independently represent Ci_-3 alkyl or, preferably, hydrogen;

R²⁰ and R²¹ independently represent hydrogen, C _-3 alkyl (e.g. methyl; which alkyl group is optionally substituted by one or more (e.g. one) substituent(s) selected from J⁴), heterocycloalkyl (e.g. a 5- or preferably 6-membered heterocycloalkyl group; preferably containing one or two (e.g. one) heteroatom; so forming e.g. a piperidinyl group) or aryl (e.g. unsubstituted phenyl);

J⁴ represents Q⁷ or a 5- or 6-membered heterocycloalkyl group, e.g. containing one or two (e.g. one) heteroatom(s), preferably selected from nitrogen (so forming e.g. a piperidinyl, e.g. 4-piperidinyl group);

Q⁷ represents -N(R⁵⁰)R⁵¹ or -S(0)₂R⁵°;

R⁵⁰ represents hydrogen or C_1-4 alkyl (e.g. C_1-2 alkyl, such as methyl);

R³ represents hydrogen or a substituent selected from -CI, C _-3 alkyl (preferably unsubstituted; e.g. methyl, cyclopropyl), -CN, -OH and -OCH₃;

the R¹, R² and X-containing rings represent:

wherein the squiggly lines represent the point of attachment to the requisite X¹ and X²-containing bicycle of the compound of formula I, and the relevant atoms of the ring may be substituted e.g. by one or more substitutents selected from E², where E² is as defined in Claim 1.

5. A compound of formula Al,

wherein:

X¹ and X² independently represent =N- or =C(H)-;

X^a, X^b, X^c, X^d, X^f and X⁹ independently represent -C(R⁷)= or, any one of X^b or X^c may represent -N=; each R⁷ independently represents hydrogen or a substituent selected from -F, -CI, -Br; R² represents -O- or -N(R⁶)-; X represents C_2-3 alkylene optionally substituted by one or more substituents selected from E²;

R⁶ represents C _-4 alkyl optionally substituted by one or more substituents selected from E¹;

R³ represents hydrogen or a substituent selected from -CI, -CN, -OH, -OCH₃ and Ci_-3 alkyl; R⁴ represents -[0]₀-i-(CH₂)o-i-heterocycloalkyl (which heterocycloalkyl is optionally substituted by one or more substituents selected from Q¹), aryl or heteroaryl (which latter two groups are optionally substituted by one or more substitutents selected from E³); or R⁴ represents -[C(0)]o-i-N(R^a)R^b; R^a and R^b independently represent H, -[C(O)]₀-i-C_1-9 alkyl, -[C(O)]₀-i-heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from =0 and Q¹); or

-N(R^10a)R^11a, -OR^10a, -N(R^12a)C(=0)R^11a, -S(O)₂R^10a, C_1-12 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from E⁵), or heteroaryl (which latter group is optionally substituted by one or more substituents selected from E⁶); each R^10a, R^11a and R ^2a independently represent, on each occasion when used herein, hydrogen, d.₁₂ alkyl (which latter group is optionally substituted by one or more substituents selected from E⁷); each E¹, E², E³, E⁴, E⁵, and E⁷ independently represents, on each occasion when used herein:

(i) Q⁴;

(ii) C_1-4 alkyl optionally substituted by one or more substituents selected from =0 and Q⁵; or any two E⁵ or E⁷ groups may be linked together to form a 4- to 6-membered ring (in which each of the atoms of the ring may be a carbon atom or a heteroatom); each Q⁴ and Q⁵ independently represent, on each occasion when used herein: halo, -N(R²⁰)R²¹, -OR²⁰, -C(=0)-R²⁰, -C(=0)-OR²°, -N(R²²)C(=0)R²¹, -NR²²S(0)2R²⁰, -S(0)₂R²⁰ or aryl; each R²⁰, R²¹ and R²² independently represent, on each occasion when used herein, hydrogen, C_1-4 alkyl, heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J⁴) or aryl; each J⁴ independently represents, on each occasion when used herein:

(i) Q⁷;

-N(R⁵⁰)R⁵¹ or -S(0)₂R⁵⁰; and each R⁵⁰ and R⁵¹ independently represents, on each occasion when used herein, hydrogen or C _-2 alkyl; or a pharmaceutically acceptable ester, amide, solvate or salt thereof.

6. A compound of formula I as defined in any one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, for use as a pharmaceutical.

7. A pharmaceutical formulation including a compound of formula I, as defined in any one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

8. A compound, as defined in any one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, for use in the treatment of a disease in which inhibition of PIM-1, PIM-2 and/or PIM-3 is desired and/or required.

9. Use of a compound of formula I, as defined in any one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, for the manufacture of a medicament for the treatment of a disease in which inhibition of PIM-1, PIM-2 and/or PIM-3 is desired and/or required.

10. A compound as claimed in Claim 8 or a use as claimed in Claim 9, wherein the disease is cancer, an immune disorder, a cardiovascular disease, a viral infection, inflammation, a metabolism/endocrine function disorder, a neurological disorder, an obstructive airways disease, an allergic disease, an inflammatory disease, immunosuppression, a disorder commonly connected with organ transplantation, an AIDS-related disease, benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, a bone disorder, atherosclerosis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis, restenosis, stroke, diabetes, hepatomegaly, Alzheimer's disease, cystic fibrosis, a hormone-related disease, an immunodeficiency disorder, a destructive bone disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukaemia, liver disease, a pathologic immune condition involving T cell activation, CNS disorders, pulmonary artery hypertension (PAH), and other associated diseases.

11. A method of treatment of a disease in which inhibition of PIM-1, PIM-2 and/or PIM-3 is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound of formula I as defined in any one of Claims 1 to 5, or a pharmaceutically-acceptable ester, amide, solvate or salt thereof, to a patient suffering from, or susceptible to, such a condition.

12. A combination product comprising:

(A) a compound of formula I as defined in any one of Claims 1 to 5, or a pharmaceutically-acceptable ester, amide, solvate or salt thereof; and

(B) another therapeutic agent that is useful in the treatment of in the treatment of cancer and/or a proliferative disease,

13. A process for the preparation of a compound of formula I as defined in Claim 1 , which process comprises:

(i) for compounds of formula I in which R⁴ represents -0-C_1-6alkyl-OCH₃, -0-C_1-6alkyl-NH₂, -0-C_1-6alkyl-N(H)(CH₃), -0-(CH₂)_ni-heterocycloalkyl, -OR^4c or a fragment of fo

wherein L¹ represents a suitable leaving group, and R¹, R², X, R³, X¹, X², X^a, X^b, X^c, X^d, X^f and X⁹ are as defined in Claim 1, with a compound of formula III,

R^4x-H III

wherein R^4x represents represents -O-C^alkyl-OCHa, -0-C_1-6alkyl-NH₂, -0-C_1-6alkyl-N(H)(CH₃), -0-(CH₂)_ni-heterocycloalkyl, -OR^4c or a fragment of formula IA;

(ii) reaction of a compound of formula IV,

wherein L³ represents a suitable leaving group, and R¹, R², X, X¹ and X² and R³ are as defined in Claim 1 , with a compound of formula V,

wherein L⁴ represents a mutually suitable group to effect the coupling, and R⁴, X^a, X^b, X^c, X^d, X^f and X⁹ are as defined in Claim 1;

wherein L¹ represents a suitable leaving group as defined above, and X¹, R¹, R², R³ and X are as defined in Claim 1, with a compound of formula VII,

wherein R⁴, X^a, X^b, X^c, X^d, X^f and X⁹ are as defined in Claim 1;

(iv) for compounds of formula I in which R¹ and R² are independently selected from -0-, -S- and -NR⁶-, reaction of a compound of formula VIII,

wherein R^1a and R^2a independently represent -0-, -S- and -NR⁶-, and R³, X¹, X², X^a, X^b, X^c, X^d, X^f, X⁹ and R⁴ are as defined in Claim 1, with a compound of formula IX,

L⁵-X-L⁶ IX

wherein L⁵ and L⁶ independently represent a suitable leaving group, and X is as defined in Claim 1 ;

R ^x1-L⁴ X

wherein L⁴ represents a suitable leaving group, as defined above and R^{4 1} represents optionally substituted aryl or heteroaryl (which R⁴ may represent in Claim 1);

wherein either T^1a represents -R¹-X-OH or T^2a represents -R²-X-OH and the other represents a suitable leaving group and R³, X¹, X², X^a, X^b, X^c, X^d, X^f, X⁹ and R⁴ are as defined in Claim 1 ;

(vii) for compounds of formula I in which R and R² both represent -O- (and preferably X represents C₃ alkylene), reaction of a compound of formula XII,

wherein L ^a and L^2a each independently represent a suitable leaving group and R³, X¹, X², X^a, X^b, X^c, X^d, X^f, X⁹ and R⁴ are as defined in Claim 1 , with a compound of formula XIII,

HO-X-OH XIII

wherein X is as defined in Claim 1 ;

(viii) for compounds of formula I in which X represents Ci alkylene substituted by a methyl group, an intramolecular addition reaction of a compound of formula XIV,

wherein either Q^1a or Q^2a represents -CH₂-CH₂=CH₂ and the other represents -OH (and R³, X¹, X², X^a, X^b, X^c, X^d, X^f, X⁹ and R⁴ are as defined in Claim 1);

wherein R¹, R², X, R³ and X¹ are as defined in Claim 1 , with a compound of formula XIVB,

wherein X^a, X^b, X^c, X^d, X^f, X⁹ and R⁴ are as defined in Claim 1.

14. A process for the preparation of a pharmaceutical formulation as defined in Claim 7, which process comprises bringing into association a compound of formula I, as defined in any one of one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with a pharmaceutically- acceptable adjuvant, diluent or carrier.

15. A process for the preparation of a combination product as defined in Claim 12, which process comprises bringing into association a compound of formula I, as defined in any one of Claims 1 to 5, or a pharmaceutically acceptable ester, amide, solvate or salt thereof with the other therapeutic agent that is useful in the treatment of cancer and/or a proliferative disease, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.