NZ618904B2 - Pyridin-2(1h)-one derivatives as jak inhibitors - Google Patents

Pyridin-2(1h)-one derivatives as jak inhibitors Download PDF

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NZ618904B2
NZ618904B2 NZ618904A NZ61890412A NZ618904B2 NZ 618904 B2 NZ618904 B2 NZ 618904B2 NZ 618904 A NZ618904 A NZ 618904A NZ 61890412 A NZ61890412 A NZ 61890412A NZ 618904 B2 NZ618904 B2 NZ 618904B2
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Tana Jordi Bach
Paul Robert Eastwood
Santacana Lluis Miquel Pages
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Almirall Sa
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Abstract

Provided are pyridin-2(1H)-one derivative compounds of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include (5)-3-(4-( 1-( 5-fluoropyridin-2-yl)ethylamino)pyrimidin-2-ylamino)pyridin-2(1H)-one and 3-(5-{6-{[(1S)-1-(5-Fluoropyridin-2-yl)ethyl]amino}-2-[(2-oxo-1,2-dihydropyridin-3-yl)amino]pyrimidin-4-yl}-1,3-thiazol-2-yl)benzoic acid. The compounds are JAK inhibitors. The compounds may be useful in the treatment of cancers and immunological and inflammatory diseases. )ethyl]amino}-2-[(2-oxo-1,2-dihydropyridin-3-yl)amino]pyrimidin-4-yl}-1,3-thiazol-2-yl)benzoic acid. The compounds are JAK inhibitors. The compounds may be useful in the treatment of cancers and immunological and inflammatory diseases.

Description

PYRIDIN-2(1H)-ONE DERIVATIVES AS JAK INHIBITORS Cytokines have critical functions in regulating many aspects of immunity and inflammation, ranging from the development and differentiation of immune cells to the suppression of immune responses. Type I and type II cytokine receptors lack intrinsic enzymatic activity capable of mediating signal transduction, and thus require association with tyrosine kinases for this purpose. The JAK family of kinases comprises four different members, namely JAK1, JAK2, JAK3 and TYK2, which bind to type I and type II cytokine receptors for controlling signal transduction (Murray PJ, (2007). The JAK-STAT signalling pathway: input and output integration. J Immunol, 178: 2623).
Each of the JAK kinases is selective for the receptors of certain nes. In this , JAK-deficient cell lines and mice have validated the essential role of each JAK protein in receptor signalling: JAK1 in class II cytokine ors (IFN and IL-10 family), those sharing the gp130 chain (IL-6 family) and the common gamma chain (IL-2, IL-4, IL-7, IL-9, IL- 15 and IL-21) (Rodig et al. (1998). Disruption of the JAK1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biological response. Cell, 93:373; Guschin et al. (1995). A major role for the protein ne kinase JAK1 in the JAK/STAT signal uction pathway in response to interleukin-6. EMBO J. 14: 1421; Briscoe et al. (1996). Kinase-negative mutants of JAK1 can sustain intereferon-gamma-inducible gene expression but not an ral state. EMBO J. 15:799); JAK2 in hematopoietic factors (Epo, Tpo, GM-CSF, IL-3, IL-5) and type II IFNs (Parganas et al., . JAK2 is essential for signalling through a y of cytokine receptors. Cell, 93:385); JAK3 in receptors g the common gamma chain (IL-2 family) (Park et al., (1995). Developmental defects of id cells in JAK3 kinase-deficient mice. Immunity, 3:771; Thomis et al., (1995). Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3. e, 270:794; Russell et al., (1995). Mutation of JAK3 in a partient with SCID: Essential role of JAK3 in lymphoid development. Science, 270:797); and Tyk2 in the receptors of IL- 12, IL-23, IL-13 and type I IFNs hiosoff et al., . Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity, 13:549; Shimoda et al., (2000).
Tyk2 plays a restricted role in IFNg signaling, although it is required for ILmediated T cell function. Immunity, 13:561; Minegishi et al., (2006). Human Tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity, 25:745).
Receptor stimulation leads sequentially to JAK tion by phosphorylation, receptor orylation, STAT protein recruitment and STAT activation and dimerization. The STAT dimer then functions as a transcription factor, translocating to the nucleus and activating the transcription of multiple response genes. There are seven STAT proteins identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. Each particular cytokine receptor associates preferentially with a particular STAT protein.
Some associations are independent of cell type (ex: IFNg- STAT1) while others may be cell type dependent (Murray PJ, (2007). The JAK-STAT signaling y: input and output integration. J Immunol, 178: 2623).
The phenotype of deficient mice has provided insights on the function of each JAK and the cytokine ors signaling through them. JAK3 associates exclusively with the common gamma chain of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines. By virtue of this exclusive association, JAK3 knock out mice and common gamma chain deficient mice have an identical phenotype (Thomis et al., (1995). s in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3.
Science, 270:794; DiSanto et al., (1995). id development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. PNAS, 92:377). Moreover, this ype is shared to a great extent with SCID patients that hold mutations/defects in the common gamma chain or JAK3 genes (O’Shea et al., (2004).
JAK3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol, 41: 727). JAK3-deficient mice are viable but y abnormal lymphopoiesis which leads to a d thymus size (10-100 fold smaller than wild type). JAK3-deficient peripheral T cells are unresponsive and have an activated/memory cell phenotype (Baird et al., (1998). T cell development and activation in JAK3-deficient mice. J. Leuk.
Biol. 63: 669). The thymic defect in these mice strongly resembles that seen in IL-7 and IL-7 receptor knockout mice, suggesting that the absence of IL-7 signaling accounts for this defect in JAK3 -/-mice (von Freeden-Jeffry et al., (1995). Lymphopenia in Interleukin (IL)-7 Gene-deleted Mice Identifies IL-7 as a non-redundant ne. J Exp Med, 181:1519; Peschon et al, (1994). Early lymphocyte expansion is severely impaired in eukin 7 receptor-deficient mice. J Exp Med, 180: 1955). These mice, like SCID humans, have no NK cells, probably due to the absence of IL-15 signaling, a survival factor for these cells. JAK3 knockout mice, unlike SCID patients, show deficient B cell lymphopoiesis while in human patients, B cells are present in circulation but are not responsive g to obulinemia a et al., (2004). JAK3 and the pathogenesis of severe combined deficiency. Mol Immunol, 41: 727). This is explained by species-specific differences in IL-7 function in B and T cell development in mice and humans. On the other hand, Grossman et al. (1999. ulated myelopoiesis in mice lacking JAK3. Blood, 94:932:939) have shown that the loss of JAK3 in the T-cell tment drives the expansion of the myeloid lineages g to dysregulated myelopoiesis.
JAK2-deficient mice are embrionically , due to the e of definitive erythropoiesis. Myeloid progenitors fail to respond to Epo, Tpo, IL-3 or GM-CSF, while G-CSF and IL-6 signaling are not affected. JAK2 is not required for the generation, amplification or functional differentiation of lymphoid progenitors (Parganas et al., (1998). JAK2 is ial for signaling through a variety of cytokine receptors. Cell, 93:385).
JAK1-deficient mice die perinatally due to a nursing defect. JAK1 binds exclusively to the gp130 chain shared by the IL-6 cytokine family (i.e. LIF, CNTF, OSM, CT-1) and along with JAK3, is an essential component of the receptors sharing the common gamma chain, by binding to the non-shared or subunit. In this regard, JAK1- deficient mice show similar hematopoiesis defects as JAK3-deficient mice. In addition, they show defective responses to neurotrophic factors and to all interferons (class II cytokine receptors) (Rodig et al., (1998). Disruption of the JAK1 gene demonstrates obligatory and non-redundant roles of the JAKs in cytokine-induced biological response. Cell, 93:373).
Finally, Tyk2-deficient mice show an impaired response to IL-12 and IL-23 and only partially impaired to IFN-alpha (Karaghiosoff et al., (2000). Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity, 13:549; Shimoda et al., .
Tyk2 plays a restricted role in IFNg signaling, although it is required for ILmediated T cell function. Immunity, 13:561). However, human Tyk2 deficiency demonstrates that Tyk2 is involved in the signaling from IFN-α, IL-6, IL-10, IL-12 and IL-23 (Minegishi et al., (2006). Human ne kinase 2 ency reveals its requisite roles in multiple cytokine s involved in innate and acquired immunity. Immunity, 25:745).
The role of JAK kinases in transducing the signal from a myriad of cytokines makes them potential targets for the treatment of es in which nes have a enic role, such as inflammatory diseases, including but not limited to allergies and asthma, chronic obstructive pulmonary disease (COPD), sis, mune diseases such as rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sis, uveitis, transplant rejection, as well as in solid and hematologic malignancies such as myeloproliferative disorders, leukemia and lymphomas.
Inhibition of JAK kinases, especially JAK1 and JAK3, could give rise to potent immunosuppression which could be used therapeutically to prevent transplant ion. In this regard, the JAK inhibitor CP-690,550 (tofacitinib, formerly tasocitinib) has shown efficacy in several animal models of lantation (heretopic heart lantation in mice, cardiac allografts implanted in the ear of mice, renal allotransplantation in cynomolgous monkeys, aorta and tracheal transplantation in rats) by prolonging the mean al time of grafts (West K (2009). CP-690,550, a JAK3 tor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr. Op. . Drugs 10: 491).
In rheumatoid joints, an imbalance between pro and anti-inflammatory cytokine ties favours the induction of autoimmunity, followed by chronic mation and tissue destruction. In this regard, the pathogenic role of IL-6 in rheumatoid arthritis (RA) has been validated clinically by the use of the anti-IL-6R antibody tocilizumab. IL-6 activates the ription factor STAT3, through the use of JAK1 binding to the gp130 receptor chain (Heinrich et al., (2003). Principles of interleukin (IL)type cytokine signaling and its regulation. Biochem J. 374: 1). Constitutive STAT3 mediates the abnormal growth and survival properties of RA synoviocytes (Ivashkiv and Hu (2003).
The AT pathway in rheumatoid arthritis: pathogenic or protective? Arth & Rheum. 48:2092). Other cytokines that have been implicated in the pathogenesis of arthritis include IL-12 and IL-23, implicated in Th1 and Th17 cell eration, respectively; IL-15, and GM-CSF (McInnes and Schett, . Cytokines in the pathogenesis of rheumatoid arthritis. Nature Rew Immunol. 7:429.). The receptors for these cytokines also utilize JAK proteins for signal transduction, making JAK inhibitors potential pleiotropic drugs in this pathology. Consequently, administration of several JAK inhibitors in animal models of murine collagen-induced arthritis and rat adjuvant- induced arthritis has shown to reduce inflammation, and tissue destruction (Milici et al., (2008). Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arth. Res. 10:R14).
Inflammatory bowel disease (IBD) encloses two major forms of intestinal inflammation: ulcerative colitis and Crohn’s disease. Growing evidence has shown that multiple cytokines, including interleukins and interferons, are involved in the pathogenesis of IBD (Strober et al, (2002). The immunology of mucosal models of inflammation. Annu Rev Immunol. 20: 495). Activation of the IL-6/STAT3 cascade in lamina propia T cells has been shown to induce prolonged al of pathogenic T cells (Atreya et al, (2000). Blockade of interleukin 6 trans ing sses T-cell ance against apoptosis in c intestinal inflammation: Evidence in Crohn's disease and experimental colitis in vivo. Nature Med. 6:583). Specifically, STAT3 has been shown to be constitutively active in inal T cells of Crohn’s disease patients and a JAK inhibitor has been shown to block the constitutive activation of STAT3 in these cells (Lovato et al, (2003). Constitutive STAT3 activation in intestinal T cells from ts with Crohn’s disease. J Biol Chem. 278:16777). These observations indicate that the JAK-STAT pathway plays a pathogenic role in IBD and that a JAK inhibitor could be therapeutic in this setting.
Multiple sclerosis is an autoimmune demyelinating disease characterized by the formation of plaques in the white matter. The role of cytokines in the generation of multiple sclerosis has long been known. Potential therapies include blockade of IFN-g, IL-6, IL-12 and IL-23 (Steinman L. (2008). Nuanced roles of cytokines in three major human brain disorders. J Clin Invest. 118:3557), nes that signal through the JAKSTAT pathways. Use of tyrphostin, a JAK inhibitor, has been shown to inhibit IL induced phosphorylation of STAT3, and to reduce the incidence and severity of active and passive mental autoimmune encephalitis (EAE) (Bright et al., (1999) Tyrphostin B42 inhibits ILinduced tyrosine phosphorylation and activation of Janus kinase-2 and prevents mental allergic encephalomyelitis. J Immunol. 162:6255).
Another multikinase inhibitor, CEP701, has been shown to reduce secretion of TNF- alpha, IL-6 and IL-23 as well as the levels of phospho-STAT1, STAT3, and STAT5 in peripheral DCs of mice with EAE, significantly improving the clinical course of EAE in mice (Skarica et al, (2009). Signal transduction inhibition of APCs shes Th17 and Th1 responses in experimental autoimmune encephalomyelitis. J. Immunol. 182:4192.).
Psoriasis is a skin inflammatory disease which es a s of immune cell infiltration and tion that culminates in epithelial remodeling. The t theory behind the cause of psoriasis states the existence of a cytokine k that governs the interaction n immune and lial cells (Nickoloff BJ. (2007). Cracking the ne code in psoriasis, Nat Med, 13:242). In this , IL-23 produced by dendritic cells is found elevated in psoriatic skin, along with IL-12. IL-23 induces the formation of Th17 cells which in turn produce IL-17 and IL-22, the last one being responsible for epidermis thickening. IL-23 and IL-22 induce the phosphorylation of STAT-3, which is found abundantly in psoriatic skin. JAK inhibitors may thus be therapeutic in this setting. In accordance, a JAK1/3 inhibitor, R348, has been found to attenuate psoriasiform skin inflammation in a spontaneous T cell-dependent mouse model of psoriasis (Chang et al., (2009). JAK3 inhibition significantly attenuates psoriasiform skin inflammation on CD18 mutant PL/J mice. J Immunol. 183:2183).
Th2 cytokine-driven diseases such as allergy and asthma could also be a target of JAK tors. IL-4 promotes Th2 entiation, regulates B-cell function and immunoglobulin class ing, regulates eotaxin production, induces expression of IgE receptor and MHC II on B cells, and stimulates mast cells. Other Th2 cytokines like IL-5 and IL-13 can also contribute to eosinophil recruitment in bronchoalveolar lavage by stimulating eotaxin tion. Pharmacological inhibition of JAK has been shown to reduce the expression of IgE receptor and MHCII induced by IL-4 stimulation on B cells (Kudlacz et al., (2008). The JAK3 inhibitor CP-690,550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia. European J. Pharm. 582: 154). rmore, JAK3-deficient mice display poor eosinophil recruitment and mucus secretion to the airway lumen upon OVA challenge, as compared to wild type mice (Malaviya et al, (2000). Treatment of allergic asthma by targeting Janus kinase 3- ent riene synthesis in mast cells with 4-(3’, 5’- dibromo-4’- hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97). JPET 295:912.). In this regard, systemic administration of the ,550 JAK tor in mice has been shown to reduce the eosinophil count as well as the levels of n and IL13 in BAL in a murine model of pulmonary eosinophilia (Kudlacz et al., (2008). The JAK3 inhibitor CP-690,550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia. European J. Pharm. 582:154).
There is increasing evidence that cytokines play a pathogenetic role in ocular inflammatory disease such as uveitis or dry eye syndrome. Some cytokines implicated in experimental autoimmune uveitis, such as IL-2, IL-6, IL-12 and IFNg, would be amenable to JAK inhibition (Vallochi et al, (2007). The role of cytokines in the regulation of ocular autoimmune inflammation. Cytok Growth Factors Rev. ). In this regard, drugs or biologicals that interfere with IL-2 signaling such as cyclosporine or anti-IL-2 receptor antibody (daclizumab) have shown efficacy in the treatment of keratoconjuctivitis sicca and refractory uveitis, respectively (Lim et al, (2006). ic ies for inflammatory eye disease. Clin Exp Opht 34:365). Similarly, ic conjunctivitis, a common allergic eye e characterized by conjuctival congestion, mast cell activation and eosinophil infiltration, could benefit from JAK inhibition. STAT6- deficient mice, showing decreased TH2-mediated immune responses which are normally triggered by IL-4, do not develop the classical early and late phase responses, suggesting that IL-4 pathway abrogation through JAK inhibition may be therapeutic in this setting (Ozaki et al, (2005). The control of allergic conjunctivitis by suppression of cytokine signaling (SOCS)3 and SOCS5 in a murine model. J Immunol, 175:5489).
There is growing evidence of the critical role of STAT3 activity in processes involved in tumorigenesis like cell cycle dysregulation, promotion of uncontrolled growth, ion of survival s and inhibition of apoptosis (Siddiquee et al., (2008). STAT3 as a target for inducing apoptosis in solid and haematological tumors. Cell Res. 18: 254).
Antagonism of STAT3 by means of dominant-negative mutants or antisense oligonucleotides has shown to promote apoptosis of cancer cells, inhibition of angiogenesis and up-regulation of host competence. Inhibition of constitutively active STAT3 in human tumors by means of JAK inhibitors may provide a therapeutic option to the treatment of this disease. In this , the use of the JAK inhibitor tyrphostin has been shown to induce apoptosis of malignant cells and inhibit cell proliferation in vitro and in vivo (Meydan et al., (1996). Inhibition of acute lymphoblastic leukemia by a JAK-2 inhibitor. Nature, 379:645).
Hematological malignancies with dysregulated JAK-STAT pathways may benefit from JAK inhibition. Recent studies have implicated dysregulation of JAK2 kinase activity by chromosomal translocations and mutations within the pseudokinase domain (such as the JAK2V617F mutation) in a spectrum of myeloproliferative diseases (IhIe and Gililand, 2007), including polycythemia vera, myelofibrosis and essential thrombocythemia. In this regard, several JAK inhibitors that tackle JAK2 potently, such as 209 (Pardanani et al., (2007). TG101209, a small lar JAK2-selective inhibitor ly inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations Leukemia. 21:1658–68), TG101348 (Wernig et al, (2008).
Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell, 13: 311), CEP701, (Hexner et al, (2008). rtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative ers. Blood, 111: 5663), CP-690,550 (Manshouri et al, (2008).
The JAK kinase inhibitor CP-690,550 sses the growth of human polycythemia vera cells carrying the JAK2V617F mutation. Cancer Sci, 99:1265), and CYT387 (Pardanani et al., . CYT387, a selective JAK1/JAK2 inhibitor: invitro assessment of kinase ivity and preclinical studies using cell lines and primary cells from polycythemia vera ts. Leukemia, 23:1441) have been proposed for treating myeloproliferative diseases on the basis of their antiproliferative activity on cells carrying the 17F mutation. Similarly, T-cell leukemia due to human T-cell leukemia virus (HTLV-1) transformation is associated with JAK3 and STAT5 constitutive activation (Migone et al, . Constitutively activated JAK-STAT pathway in T cells transformed with HTLV-I. Science, 269: 79) and JAK inhibitors may be therapeutic in this setting (Tomita et al, . Inhibition of constitutively active JAK-STAT pathway suppresses cell growth of human T-cell ia virus type I- infected T cell lines and primary adult T-cell leukemia cells. Retrovirology, 3:22). JAK1- activating mutations have also been identified in adult acute lymphoblastic leukemia of T cell origin (Flex et al, (2008). Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J. Exp. Med. 205:751-8) pointing to this kinase as a target for the development of novel antileukemic drugs.
Conditions in which targeting of the JAK pathway or tion of the JAK kinases, particularly JAK1, JAK2 and JAK3 s, are contemplated to be therapeutically useful for the treatment or prevention of diseases include: neoplastic diseases (e.g. leukemia, lymphomas, solid tumors); transplant rejection, bone marrow lant applications (e.g., graft- versus-host disease); autoimmune diseases (e.g. diabetes, multiple sclerosis, rheumatoid tis, inflammatory bowel disease); respiratory inflammation diseases (e.g. asthma, chronic obstructive pulmonary disease), inflammation-linked ocular diseases or allergic eye diseases (e.g. dry eye, glaucoma, s, diabetic retinopathy, allergic ctivitis or age-related macular degeneration) and skin inflammatory diseases (e.g., atopic dermatitis or psoriasis).
In view of the numerous conditions that are plated to benefit by treatment involving modulation of the JAK pathway or of the JAK Kinases it is immediately apparent that new compounds that te JAK ys and use of these compounds should provide substantial therapeutic benefits to a wide variety of patients. ed herein are novel pyridin-2(1H)-one derivatives for use in the treatment of conditions in which targeting of the JAK pathway or inhibition of JAK kinases can be eutically useful.
The compounds described in the present invention are simultaneously potent JAK1, JAK2 and JAK3 inhibitors, i.e. pan-JAK inhibitors. This property makes them useful for the treatment or prevention of ogical conditions or diseases such as myeloproliferative disorders (such as polycythemia vera, essential thrombocythemia or myelofibrosis), leukemia, lymphomas and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as ulcerative colitis or s disease), inflammation-linked ocular diseases or allergic eye diseases (such as dry eye, uveitis, or allergic conjunctivitis), allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), and skin inflammatory diseases (such as atopic dermatitis or psoriasis).
It has now been found that certain pyridin-2(1H)-one derivatives are novel and potent JAK inhibitors and can therefore be used in the ent or prevention of these diseases; and/or at least provide the public with a useful choice.
In this specification where reference has been made to patent ications, other external documents, or other s of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be y identifiable by a person skilled in the art and may assist in g into ce the invention as defined in the claims of this application.
SUMMARY OF THE INVENTION The present invention is directed to compounds of formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof: NH Y O R2 (R3-C-R4)m W N A D Formula (I) wherein, m is 0, 1, 2 or 3; A and B each independently represent a nitrogen atom or a -CR7 group, n at least one of A and B ents a -CR7 group; D represents a nitrogen atom or a -CR5 group, wherein when one of A and B represents a en atom, D represents a -CR5 group; W represents a linker selected from a -NR8- group, a -(CR9R10)- group, -O- or -S-; R1 represents a hydrogen atom, a linear or ed C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or ic C6-C14 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkylsulfonyl group, a C3- C7 cycloalkyl group, a phenyl group, a pyridyl group, a dinyl group or a piperidyl group; R2 and R7 each independently represent a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- ed heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N, n the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- ed cycloalkyl or heterocyclyl group are unsubstituted or substituted by one or more substituents selected from a halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a C1-C4 kyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a monocyclic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N; a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a (O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -(CH2)n’-C(O)-(CH2)n- NR11R12 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a -(CH2)n’-S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2; said monocyclic or bicyclic C6-C14 aryl group being unsubstituted or further substituted by one or more carboxyl groups; R3 and R4 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group; R5 and R6 each independently ent a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14- ed heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 14- membered heterocyclyl group ning at least one heteroatom selected from O, S and N, a -(CH2)nOR11 group; a 12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -C(O)-(CH2)n-NR11R12 group; a (CH2)nR11 group; a -S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 lkyl, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0, 1 or 2; R8, R9 and R10 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or tuted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group; R11, R12 and R13 each ndently represent a hydrogen atom; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a 5-to 9- ed heterocyclyl group contaning one, two or three heteroatoms selected from O, S and N, which heterocyclyl group is unsubstituted or substituted by one or more tuents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group or a C1-C4 hydroxyalkyl group; or linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or tuted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a dyl group; wherein the compound of formula (I) is other than: a) 3-[[5-Chloro[[2,5-dimethyl(piperidinyl)phenyl]amino]pyrimidin yl]amino]pyridin-2(1H)-one; and b) 2-[7-[[5-Chloro[(2-oxo-1,2-dihydropyridinyl)amino]pyrimidinyl]amino] methoxy-1,2,4,5-tetrahydrobenzo[d]azepinyl]-N,N-dimethylacetamide.
Further described are tic processes and intermediates described herein, which are useful for preparing said compounds.
The invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
The invention also provides a pharmaceutical ition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.
The invention is also directed to a compound of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK). In particular, wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immunemediated diseases and inflammatory es; more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic ctive pulmonary disease (COPD), atopic dermatitis and psoriasis.
The invention is also ed to use of a compound of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK). In particular, wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid ancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases; more in ular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, , chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
Also bed is a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in ular wherein the pathological condition or e is selected from roliferative disorders, leukemia, lymphoid malignancies and solid ; bone marrow and organ transplant rejection; -mediated diseases and inflammatory diseases, more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease , atopic dermatitis and psoriasis; comprising administering a therapeutically effective amount of the compounds of the invention or a pharmaceutical composition of the invention to a subject in need of such treatment.
Generally described is a combination product comprising (i) the compounds of the invention as bed herein; and (ii) one or more additional active substances which are known to be useful in the ent of myeloproliferative disorders (such as polycythemia vera, essential ocythemia or ibrosis), leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune- mediated diseases and matory diseases, more in particular wherein the pathological condition or e is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as ulcerative colitis or Crohn’s disease), dry eye, uveitis, allergic conjunctivitis, allergic is, asthma, chronic obstructive pulmonary e (COPD), atopic dermatitis and psoriasis.
In one embodiment, the invention provides a combination product comprising (i) a compound of the invention; and (ii) another compound selected from: a) Dyhydrofolate reductase inhibitors; b) Dihydroorotate dehydrogenase (DHODH) inhibitors; c) Immunomodulators; d) tors of DNA sis and repair; e) Immunosuppressants; f) Anti-alpha 4 integrin antibodies; g) Alpha 4 integrin antagonists; h) Corticoids and glucocorticoids; i) Fumaric acid esters; j) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) antibodies; k) Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors; l) Anti-CD20 (lymphocyte protein) monoclonal antibodies; m) Anti-CD52 (lymphocyte protein) monoclonal antibodies' n) Anti-CD25 (lymphocyte protein) monoclonal antibodies; o) Anti-CD88 (lymphocyte protein) monoclonal antibodies; p) Anti-Interleukin 6 Receptor ) onal antibodies; q) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL- 23R) monoclonal antibodies; r) Calcineurin inhibitors; s) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors; t) Cannabinoid receptor agonists; u) Chemokine CCR1 antagonists; v) Chemokine CCR2 antagonists; w) Necrosis -kappaB ppaB or NFKB) Activation Inhibitors; x) Adenosine A2A agonists; y) osine-1 (S1P) phosphate receptor ts; z) Sphingosine-1 (S1P) liase inhibitors; aa) Spleen tyrosine kinase (Syk) inhibitors; bb) Protein Kinase Inhibitors (PKC) inhibitors; cc) Anti-cholinergic agents; dd) Beta adrenergic agonists; ee) Compounds having tional Muscarinic Antagonist-Beta2 Agonist activity (MABAs); ff) Histamine 1 (H1) receptor antagonists; gg) Chemoattractant receptor homologous molecule sed on TH2 cells ) inhibitors; hh) Vitamin D derivatives; ii) nflammatory agents; jj) Anti-allergic agents; kk) Anti-viral agents; ll) Phosphodiestearase (PDE) III tors; mm) Phosphosdiesterase (PDE) IV inhibitors; nn) Dual Phosphodiestearase (PDE) III/IV inhibitors; oo) Xanthine derivatives; pp) p38 Mitogen-Activated Protein Kinase (p38 MAPK) Inhibitors; qq) Mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor; rr) Phosphoinositide 3-Kinases (PI3Ks) inhibitors; ss) Interferons; and tt) Interferon alpha.
The ation product of the invention in one embodiment is for simultaneous, separate or sequential use in the treatment of the human or animal body.
The invention also provides a use of (i) a compound of the invention, and (ii) another compound selected from: a) Dyhydrofolate reductase inhibitors; b) Dihydroorotate dehydrogenase ) inhibitors; c) Immunomodulators; d) Inhibitors of DNA synthesis and repair; e) Immunosuppressants; f) Anti-alpha 4 integrin antibodies; g) Alpha 4 integrin antagonists; h) Corticoids and glucocorticoids; i) Fumaric acid ; j) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) antibodies; k) Soluble Tumor necrosis factor-alpha lpha) receptors; l) Anti-CD20 ocyte protein) monoclonal antibodies; m) Anti-CD52 (lymphocyte protein) monoclonal dies; n) Anti-CD25 (lymphocyte protein) monoclonal antibodies; o) Anti-CD88 (lymphocyte protein) monoclonal antibodies; p) Anti-Interleukin 6 Receptor (IL-6R) monoclonal antibodies; q) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R) onal antibodies; r) Calcineurin tors; s) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors; t) Cannabinoid receptor agonists; u) Chemokine CCR1 antagonists; v) Chemokine CCR2 antagonists; w) is factor-kappaB (NF-kappaB or NFKB) tion Inhibitors; x) Adenosine A2A agonists; y) Sphingosine-1 (S1P) phosphate receptor agonists; z) Sphingosine-1 (S1P) liase inhibitors; aa) Spleen tyrosine kinase (Syk) inhibitors; bb) Protein Kinase Inhibitors (PKC) inhibitors; cc) Anti-cholinergic agents; dd) Beta adrenergic agonists; ee) Compounds having bifunctional Muscarinic Antagonist-Beta2 Agonist activity (MABAs); ff) Histamine 1 (H1) receptor antagonists; gg) ttractant receptor homologous molecule sed on TH2 cells (CRTH2) inhibitors; hh) Vitamin D derivatives; ii) Anti-inflammatory ;, jj) llergic agents; kk) Anti-viral agents; ll) Phosphodiestearase (PDE) III inhibitors; mm) Phosphosdiesterase (PDE) IV tors; nn) Dual Phosphodiestearase (PDE) III/IV inhibitors; oo) Xanthine derivatives; pp) p38 Mitogen-Activated Protein Kinase (p38 MAPK) Inhibitors; qq) Mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor; rr) Phosphoinositide 3-Kinases (PI3Ks) inhibitors; ss) Interferons tt) Interferon alpha; in the manufacture of a medicament for simultaneously, separately or sequentially treating a disease or condition of the human or animal body.
Detailed Descritpion The term ising” as used in this specification means “consisting at least in part of”. When reting each ent in this specification that includes the term “comprising”, features other than that or those prefaced by the term may also be present. Related terms such as “comprise” and “comprises” are to be reted in the same manner.
As used herein the term C1-C6 alkyl embraces linear or branched radicals having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, npropyl , i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2- utyl, methylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, ylpentyl and iso-hexyl radicals.
As used , the term C1-C4 haloalkyl group is an alkyl group, for example a C1-C4 or C1-C2 alkyl group, which is bonded to one or more, preferably 1, 2 or 3 halogen atoms. Preferably, said haloakyl group is chosen from –CCl3, –CHF2 and –CF3.
As used herein, the term C1-C4 hydroxyalkyl embraces linear or branched alkyl radicals having 1 to 4 carbon atoms, any one of which may be substituted by one or more, preferably 1 or 2, more preferably 1 hydroxyl radicals. Examples of such ls include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.
As used herein, the term C1-C4 alkoxy (or alkyloxy) embraces linear or branched oxycontaining radicals each having alkyl portions of 1 to 4 carbon atoms. Examples of C1- C4 alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy or t-butoxy.
As used herein, the term C1-C4 alkylsulfonyl embraces radicals ning an optionally substituted, linear or branched alkyl radicals of 1 to 4 carbon atoms ed to a divalent –SO2- radical.
As used , the term C3-C10 cycloalkyl embraces saturated monocyclic or polycyclic yclic radicals having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms. An optionally tuted C3-C10 lkyl l is lly unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. When a C3- C10 cycloalkyl radical carries 2 or more substituents, the substituents may be the same or different. Typically the substituents on a C3-C10 cycloalkyl group are themselves unsubstituted. clic cycloalkyl radicals contains two or more fused cycloalkyl groups, ably two lkyl groups. Typically, polycyclic cycloalkyl radicals are selected from decahydronaphthyl yl), bicyclo[2.2.2]octyl, adamantly, camphyl or bornyl groups.
Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, entyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.
As used herein, the term C3-C10 cycloalkenyl embraces partially unsaturated carbocyclic radicals having from 3 to 10 carbon atoms, preferably from 3 to 7 carbon atoms. A C3-C10 cycloalkenyl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. When a C3-C10 cycloalkenyl radical carries 2 or more substituents, the substituents may be the same or different. Typically, the substituents on a cycloalkenyl group are themselves unsubstituted.
Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl and cyclodecenyl.
As used herein, the term C6-C14 aryl radical embraces typically a C6-C14, preferably C6- C10 monocyclic or bicyclic aryl radical such as , naphthyl, anthranyl and phenanthryl. Phenyl is preferred. A said optionally substituted C6-C14 aryl radical is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. When a C6-C14 aryl radical carries 2 or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents on a C6-C14 aryl group are typically themselves tituted.
As used herein, the term 5- to 14- membered heteroaryl radical embraces typically a 5- to 14- membered ring system, preferably a 5- to 10- membered ring system, more preferably a 5- to 6- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N. A 5- to 14- membered heteroaryl radical may be a single ring or two or more fused rings wherein at least one ring ns a heteroatom.
A said optionally substituted 5- to 14- membered heteroaryl l is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. When a 5- to 14- membered heteroaryl radical carries 2 or more substituents, the substituents may be the same or ent. Unless ise specified, the substituents on a 5- to 14- membered heteroaryl radical are typically lves unsubstituted.
Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, olyl, benzimidazolyl, thiazolyl, thiadiazolyl, l, pyrrolyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d] pyrimidinyl and the various pyrrolopyridyl radicals.
As used herein, the term 5- to 14-membered heterocyclyl radical embraces typically a non-aromatic, ted or rated C5-C14 carbocyclic ring system, preferably C5- C10 carbocyclic ring , more preferably C5-C6 carbocyclic ring system, in which one or more, for example 1, 2, 3 or 4 of the carbon atoms preferably 1or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S. A heterocyclyl radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom. When a 5 to 14-membered heterocyclyl radical carries 2 or more substituents, the substituents may be the same or different.
A said optionally substituted 5- to 14-membered heterocyclyl radical is typically unsubstituted or tuted by 1, 2 or 3 substituents which may be the same or different. Typically, the substituents on a 5 to 14-membered heterocyclyl l are themselves unsubstituted.
Examples of 5- to 14-membered heterocyclyl radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, quinuclidinyl, triazolyl, lyl, tetrazolyl, imidazolidinyl, imidazolyl, oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, hydro-oxazolyl, 2-benzofuran-1(3H)-one, 1,3-dioxolone, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-azathianyl, oxepanyl, thiephanyl, azepanyl, 1,4-dioxepnayl, athiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4- panyl, 1,4-diazepanyl, yl, (1S,5R)aza-bicyclo[3.1.0]hexyl, 3,4-dihydro- 2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 2,3-hydrobenzofuranyl, 1,2,3,4- tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, olinyl and indolinyl.
Where a 5- to 14-membered heterocyclyl radical carries 2 or more substituents, the substituents may be the same or different.
As used herein, the term bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or cyclyl group typically refers to a moiety containing a bond which is shared between a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group and a 5- to 9- membered cycloalkyl or heterocyclyl group, wherein said heteroaryl or heterocyclyl group contains at least one heteroatom selected from O, S and N. Typically said bicyclyl group is a phenyl or 5- or 6- membered heteroaryl group fused to a 5- or 6-, ably 6-, membered cycloalkyl or heterocyclyl group. Typically said heteroaryl or heterocyclyl group contains 1, 2 or 3, preferably 1 or 2, for example 1, heteroatom selected from O, S and N, preferably N. Examples include chromanyl groups or 1,2,3,4- tetrahydronaphthalenyl groups. 1,2,3,4-tetrahydronaphthalenyl groups are preferred.
As used herein, some of the atoms, radicals, moieties, chains and cycles present in the general structures of the invention are “optionally substituted”. This means that these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any position by one or more, for e 1, 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are ed by ally acceptable atoms, radicals, moieties, chains and cycles. When two or more substituents are t, each substituent may be the same or different. The substituents are typically themselves unsubstituted.
As used herein, the term halogen atom embraces chlorine, fluorine, bromine and iodine atoms. A halogen atom is typically a fluorine, chlorine or bromine atom, most preferably chlorine or fluorine. The term halo when used as a prefix has the same meaning. nds containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, in the form of racemic mixtures and in the form of mixtures enriched in one or more isomer. The scope of the invention as described and claimed encompasses the c forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
Conventional ques for the preparation/isolation of individual enantiomers include chiral synthesis from a le lly pure precursor or resolution of the racemate using, for e, chiral high pressure liquid tography (HPLC). atively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomehc mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, lly HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, lly heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. ochemistry of Organic nds" by Ernest L. ElieI (Wiley, New York, 1994).
As used herein, the term pharmaceutically able salt refers to a salt prepared from a base or acid which is acceptable for stration to a patient, such as a mammal. Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable nic or organic acids.
Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid; and organic acids, for example citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic acid, xinafoic (1-hydroxynaphthoic acid), napadisilic (1,5-naphthalenedisulfonic acid) and the like. Particularly preferred are salts derived from fumaric, hydrobromic, hydrochloric, acetic, ic, methanesulfonic, xinafoic, and tartaric acids.
Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts.
Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and ry amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, e, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, lamine, ethylenediamine, N- orpholine, N-ethylpiperidine, glucamine, amine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, zine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Other preferred salts according to the invention are quaternary ammonium compounds wherein an equivalent of an anion (X-) is associated with the positive charge of the N atom. X- may be an anion of various l acids such as, for e, chloride, bromide, iodide, sulphate, nitrate, ate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate. X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulphonate.
As used herein, an N-oxide is formed from the tertiary basic amines or imines present in the le, using a convenient oxidising agent.
The compounds of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is ed when said t is water. Examples of solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, romethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, lamine, or mixtures f. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. rmore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate. Additionally, it is specifically contemplated that [Link] /en.wikipedia.org/wiki/Stable_isotope [Link] http://en.wikipedia.org/wiki/Hydrogen in the present invention less than one solvent molecule may be associated with one molecule of the compounds of the present ion, such as a drate.
Furthermore, solvates of the t invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non- solvate form of the compounds.
The invention also includes ically-labeled nds of the ion, wherein one or more atoms is replaced by an atom having the same atomic , but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically-labeled compounds of the invention, for example, those incorporating a ctive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 3H, and carbon- 14, 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as ium, 2H, may afford certain eutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the beled reagent otherwise employed.
Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of the invention. As used herein, the term deuterated tive embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or 2H) is a stable isotope of en which is present at a natural abundance of 0.015 molar %.
[Link] http://en.wikipedia.org/wiki/Chemical_reaction [Link] http://en.wikipedia.org/wiki/Hydrogen [Link] http://en.wikipedia.org/wiki/Deuterium Hydrogen deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a ium atom. Said exchange (incorporation) reaction can be total or partial.
Typically, a deuterated derivative of a nd of the invention has an isotopic enrichment factor (ratio between the isotopic nce and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium t at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation).
In a preferred embodiment, the isotopic enrichment factor is at least 5000 (75% deuterium). In a more preferred embodiment, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In a most preferred embodiment, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from the other ation sites.
The isotopic enrichment factor can be determined using conventional analytical s known too en ry skilled in the art, including mass spectrometry (MS) and nuclear magnetic nce (NMR).
Prodrugs of the compounds described herein are also within the scope of the invention.
Thus n derivatives of the compounds of the present invention, which tives may have little or no pharmacological ty themselves, when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for e, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS ium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
Prodrugs in ance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
In the case of compounds that are solids, it is understood by those skilled in the art that the ive compounds and salts may exist in different crystalline or polymorphic forms, or in an amorphous form, all of which are ed to be within the scope of the present invention.
Typically, in the compound of formula (I), m, X, Y, W, A, B, D and R1 to R13 are as defined above; and n when D represents a nitrogen atom, A and B represent a - CR7 group, m is 0, R2 is other than a substituted 2,3,4,5-tetrahydro-1H- d]azepine group or a phenyl group substituted by a piperidinyl group.
In a particular embodiment, the compound of formula (I) is one of formula (I’) NH Y O R2 (R3-C-R4)m W N B R5 Formula (I’) wherein, m is 0 or an integer from 1 to 3; X and Y each independently represent a nitrogen atom or a -CR6 group, wherein at least one of X and Y represents a -CR6 group; A and B each independently represent a nitrogen atom or a -CR7 group, wherein at least one of A and B represents a -CR7 group; W represents a linker selected from a -NR8- group, a -(CR9R10)- group, -O- or -S-; R1 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered cyclyl group containing at least one heteroatom selected from O, S and N, n the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkylsulfonyl group, a C3- C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group; R2 and R7 each independently represent a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 14- membered cyclyl group containing at least one atom selected from O, S and N, or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered aryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group ning at least one heteroatom ed from O, S and N, wherein the lkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups, and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered lkyl or cyclyl group are unsubstituted or substituted by one or more substituents selected from a halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a monocyclic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N; a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a (O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -C(O)-(CH2)n-NR11R12 group; a -S(O)2(CH2)nR11 group; a -S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; n each n is 0, 1 or 2; said monocyclic or bicyclic C6-C14 aryl group being unsubstituted or further substituted by one or more carboxyl groups.
R3 and R4 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group, a C3-C7 lkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group; R5 and R6 each independently represent a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14- membered heteroaryl group ning at least one heteroatom selected from O, S and N, a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, a -(CH2)nOR11 group; a -NR11R12 group; a (O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -C(O)-(CH2)n-NR11R12 group; a -S(O)2(CH2)nR11 group; a -S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more tuents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0, 1 or 2; R8, R9 and R10 each independently ent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or tuted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a dinyl group or a piperidyl group; R11, R12 and R13 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a linear or ed C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group.
Typically, in the compound of a (I) or formula (I’), X and Y each independently represent a nitrogen atom or a -CR6 group, n at least one of X and Y represents a -CR6 group.
In one ment, in the compound of formula (I) or formula (I’) X represents a nitrogen atom and Y represents a -CR6 group.
In other embodiment, in the compound of formula (I) or formula (I’) Y represents a en atom and X represents a -CR6 group.
In another embodiment, in the compound of formula (I) or formula (I’) both X and Y ents a -CR6 group.
For the avoidance of doubt, when two –CR6 groups are present, they may be the same or different.
Preferably, in the compound of formula (I) or formula (I’) both X and Y represents a - CR6 group.
In one ment, in the nd of formula (I) or formula (I’) A represents a nitrogen atom and B represents a -CR7 group.
In other embodiment, in the compound of formula (I) or formula (I’) B represents a nitrogen atom and A represents a -CR7 group.
In another embodiment, in the compound of formula (I) or formula (I’) A and B independently represent a -CR7 group.
For the avoidance of doubt, when two -CR7 groups are present, they may be the same or different.
Preferably, in the compound of formula (I) or formula (I’) A represents a nitrogen atom and B represents a -CR7 group.
Typically, in the compound of formula (I), D represents a nitrogen atom or a -CR5 group, wherein when one of A and B represents a nitrogen atom, D represents a -CR5 group.
In one embodiment, in the compound of formula (I) D represents a nitrogen atom when A and B independently represent a -CR7 group.
In another embodiment, in the compound of formula (I) D represents a -CR5 group when A ents a en atom and B represents a -CR7 group.
In r embodiment, in the compound of formula (I) D represents a -CR5 group when A represents a -CR7 group and B represents a nitrogen atom.
Typically, in the compound of a (I) or formula (I’) R1 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a dinyl group or a piperidyl group.
Preferably, in the compound of formula (I) or formula (I’) R1 represents a hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group or a pyridyl group.
More ably in the compound of formula (I) or formula (I’) R1 represents a hydrogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 kyl group or a C1-C3 hydroxyalkyl group. Most preferably R1 represents a hydrogen atom.
Typically, in the compound of formula (I) R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered aryl group containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms ed from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a clic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N; a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a (O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -(CH2)n’-C(O)-(CH2)n- NR11R12 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a -(CH2)n’-S(O)2(CH2)nNR11R12 group; a (O)2(CH2)nR12 group or a (O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2; and n R11, R12 and R13 are as defined above and said monocyclic or ic C6-C14 aryl group is unsubstituted or further substituted by one or more carboxyl .
Preferably in the compound of formula (I) R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a triazolyl group, a thiazolyl group, a idinyl group, or a piperidyl group; wherein the cycloalkyl, phenyl, pyridyl, dinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a triazolyl group, a thiazolyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)1-3CN group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a (CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -(CH2)n’-C(O)-(CH2)n-NR11R12 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a - (CH2)n’-S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a - NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2; and wherein R11, R12 and R13 are as d above.
More preferably, in the compound of formula (I) R2 represents a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group or a piperidinyl group, wherein the cycloalkyl, phenyl, pyridyl or pyrimidinyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group, a triazolyl group, a -(CH2)1-3CN group, a -(CH2)nOR11 group, a -C(O)-(CH2)1CN group, a -C(O)- (CH2)n-NR11R12 group or a -(CH2)n’-S(O)2(CH2)nR11; wherein each n’ and n are 0, 1 or 2; and wherein R11 and R12 each independently represent a hydrogen atom, a methyl group, or a piperidinyl group substituted by a hydroxyl group.
It is particulary red that in the compound of formula (I) the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups that R2 may represent are unsubstituted or substituted by one, two or three, preferably one or two, substituents selected from a halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a triazolyl group; a -(CH2)1-3CN group; a -C(O)-(CH2)1CN group; or a -(CH2)n’- S(O)2(CH2)nR11; wherein n’ is 0, 1 or 2 and R11 represents a piperidinyl group substituted by a hydroxyl group More preferably R2 represents a cyclohexyl group, a pyridyl group or a piperidyl group, wherein the cyclohexyl, pyridyl and piperidyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a triazolyl group, a -(CH2)1-3CN group, a (CH2)1CN group, or a -(CH2)n’-S(O)2(CH2)nR11; wherein n’ is 0, 1 or 2 and R11 ents a piperidinyl group substituted by a hydroxyl group.
Preferably, in the compound of formula (I) when R2 is a C3-C7 cycloalkyl group, it is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, which group is unsubstituted or tuted by one, two or three tuents selected from a halogen atom (preferably a fluorine atom or a chlorine atom), a linear or ed C1-C3 alkyl group, a C1-C3 haloalkyl group, a -(CH2)1-3CN group, a hydroxyl group or a -(CH2)n’-S(O)2(CH2)nR11; n n’ is 0, 1 or 2 and R11 represents a piperidinyl group substituted by a yl group. More preferably, when R2 is a C3-C7 cycloalkyl group, it is preferably a exyl group unsubstituted or substituted by one, two or three substituents selected from linear or branched C1-C3 alkyl group (preferably a methyl group), a -(CH2)1-3CN group, a hydroxyl group or a - (CH2)n’-S(O)2(CH2)nR11; n n’ is 0, 1 or 2 and R11 represents a piperidinyl group substituted by a hydroxyl group.
Preferably, in the compound of formula (I) when R2 is a C3-C7 cycloalkyl group m is 0.
In other words, when R2 is a C3-C7 cycloalkyl group it is directly bonded to the en atom of the –N-R1 group.
Preferably, in the compound of formula (I) when R2 is a pyridyl group, said group is linked to the rest of the molecule via a ring carbon atom, in other words they are linked to the group -(R3-C-R4)m-, which is bonded to the nitrogen atom of the –N-R1 group, via a ring carbon atom. Pyridyl groups are unsubstituted or tuted with one, two or three substituents selected from a halogen atom (preferably a fluorine atom or a chlorine atom), a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 haloalkyl group (preferably a -CHF2 group or a -CF3 group), a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -(CH2)n’-C(O)-(CH2)n-NR11R12 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a - (CH2)n’-S(O)2(CH2)nNR11R12 group; a (O)2(CH2)nR12 group or a - NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2; and wherein R11, R12 and R13 each independently represent a hydrogen atom or a linear or branched C1- C3 alkyl group. More preferably, pyridyl groups are substituted by one or two halogen atoms.
Preferably, in the compound of formula (I) when R2 is a piperidinyl group, it is linked to the rest of the le via a ring carbon atom. In this case, m is 0. In other words, when R2 is a dinyl group it is ly bonded to the nitrogen atom of the –N-R1 group.
Preferably, in the compound of formula (I) when R2 is a piperidinyl group, it is tituted or substituted by one, two or three substituents selected from a halogen atom (preferably a fluorine atom or a chlorine atom), a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 haloalkyl group (preferably a -CHF2 group or a - CF3 group), a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, a lyl group, a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a - C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -(CH2)n’-C(O)-(CH2)n-NR11R12 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a -(CH2)n’-S(O)2(CH2)nNR11R12 group; a - NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2; and wherein R11, R12 and R13 each ndently ent a hydrogen atom or a linear or branched C1-C3 alkyl group. Preferably when R2 is a piperidinyl group it is substituted by one or two substituents selected from a n atom, a - C(O)-(CH2)1CN group or a triazolyl group.
Typically, in the compound of formula (I’) R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the lkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or tuted by one or more substituents selected from a halogen atom; a cyano group; a linear or ed C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a monocyclic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N; a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a (CH2)n-NR11R12 group; a -S(O)2(CH2)nR11 group; a (CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; and wherein R11, R12 and R13 are as defined above and said monocyclic or ic C6-C14 aryl group is unsubstituted or further substituted by one or more carboxyl groups.
Preferably in the compound of a (I’) R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a triazolyl group, a lyl group, a pyrrolidinyl group, or a piperidyl group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or dyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a triazolyl group, a thiazolyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)1-3CN group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group; a (CH2)nR11 group; a -S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2 and wherein R11, R12 and R13 are as defined above.
More ably, in the compound of formula (I’) R2 represents a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group or a piperidinyl group, wherein the cycloalkyl, phenyl, pyridyl or pyrimidinyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group, a triazolyl group, a -(CH2)1-3CN group, a nOR11 group, a (CH2)1CN group or a - C(O)-(CH2)n-NR11R12 group; wherein each n is 0, 1 or 2; and wherein R11 and R12 each ndently represent a hydrogen atom or a methyl group.
It is particulary preferred that in the compound of formula (I’) the cycloalkyl, cycloalkenyl, aryl, aryl, and heterocyclyl groups that R2 may ent are unsubstituted or substituted by one, two or three, preferably one or two, substituents selected from a n atom; a cyano group; a linear or branched C1-C6 alkyl group; a triazolyl group; a -(CH2)1-3CN group; and a -C(O)-(CH2)1CN group.
More preferably R2 represents a cyclohexyl group, a pyridyl group or a piperidyl group, wherein the cyclohexyl, pyridyl and piperidyl groups are tituted or substituted by one, two or three substituents selected from a halogen atom, a triazolyl group, a -(CH2)1-3CN group or -C(O)-(CH2)1CN group.
Preferably, when R2 is a C3-C7 cycloalkyl group, it is a cyclopropyl group, a cyclobutyl group, a entyl group, a cyclohexyl group or a cycloheptyl group, which group is unsubstituted or substituted by one, two or three tuents selected from a halogen atom (preferably a fluorine atom or a chlorine atom), a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group, a -(CH2)1-3CN group or a hydroxy group. More preferably, when R2 is a C3-C7 cycloalkyl group, it is preferably a cyclohexyl group unsubstituted or substituted by one, two or three substituents selected from linear or branched C1-C3 alkyl group (preferably a methyl group), a -(CH2)1-3CN group or a hydroxy group.
Preferably, in the nd of formula (I’) when R2 is a C3-C7 cycloalkyl group m is 0.
In other words, when R2 is a C3-C7 cycloalkyl group it is directly bonded to the nitrogen atom of the –N-R1 group.
Preferably, in the compound of formula (I’) when R2 is a pyridyl group, said group is linked to the rest of the molecule via a ring carbon atom, in other words they are linked to the group -(R3-C-R4)m-, which is bonded to the nitrogen atom of the –N-R1 group, via a ring carbon atom. Pyridyl groups are unsubstituted or substituted with one, two or three substituents ed from a halogen atom (preferably a fluorine atom or a chlorine atom), a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 haloalkyl group (preferably a -CHF2 group or a -CF3 group), a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -C(O)-(CH2)n-NR11R12 group; a -S(O)2(CH2)nR11 group; a -S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a (O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; and wherein R11, R12 and R13 each independently ent a hydrogen atom or a linear or ed C1-C3 alkyl group. More preferably, pyridyl groups are tuted by one or two halogen atoms.
Preferably, in the compound of formula (I’) when R2 is a piperidinyl group, it is linked to the rest of the molecule via a ring carbon atom. In this case, m is 0. In other words, when R2 is a piperidinyl group it is directly bonded to the en atom of the –N-R1 group.
Preferably, in the compound of formula (I’) when R2 is a piperidinyl group, it is tituted or substituted by one, two or three substituents ed from a halogen atom (preferably a fluorine atom or a chlorine atom), a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 kyl group (preferably a -CHF2 group or a - CF3 group), a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, a triazolyl group, a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -C(O)-(CH2)n-NR11R12 group; a -S(O)2(CH2)nR11 group; a -S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; and wherein R11, R12 and R13 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group. Preferably when R2 is a piperidinyl group it is substituted by one or two tuents selected from a halogen atom, a -C(O)-(CH2)1CN group or a triazolyl group.
Typically, in the compound of formula (I) or formula (I’) R3 and R4 each independently represent a hydrogen atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group. Preferably, R3 and R4 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group.
More preferably, R3 and R4 each independently represent a hydrogen atom or a methyl group.
Typically, in the compound of formula (I) or formula (I’) R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; and wherein R11, R12 and R13 each independently represent a hydrogen atom or a linear or ed C1-C3 alkyl group.
Preferably, in the nd of formula (I) or a (I’) R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group or a -C(O)- (CH2)n-NR11R12 group; wherein n is 0, 1 or 2; and wherein R11 and R12 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group.
More preferably, in the compound of formula (I) or formula (I’) R5 ents a hydrogen atom, a halogen atom (preferably a fluorine atom or a chlorine atom), a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0 or 1; and wherein R11 and R12 each independently represent a hydrogen atom or a methyl group.
More preferably R5 represents a hydrogen atom, a halogen atom (preferably a fluorine atom or a ne atom), a linear or branched C1-C3 alkyl group or a -C(O)-(CH2)n- NR11R12 group; wherein n is 0 or 1; and wherein R11 and R12 ndently represent a hydrogen atom or a linear or branched C1-C3 alkyl group.
Typically, in the compound of formula (I) or formula (I’), R6 represents a en atom, a n atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a clic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, or a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or ed C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl, a phenyl group, a pyridyl group, a pyrimidinyl group, a dyl group, or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0, 1 or 2; and wherein R11 and R12 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group.
Preferably, in the compound of formula (I) or formula (I’) R6 represents a en atom, a halogen atom, a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrrolidinyl group, a piperidyl group, a tetrahydropyranyl group or a morpholinyl group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidyl, tetrahydropyranyl or morpholinyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or ed C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group.
More preferably, in the compound of formula (I) or formula (I’) R6 represents a hydrogen atom, a halogen atom (preferably a fluorine atom or a chlorine atom), a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, or a morpholinyl group.
More preferably, R6 represents a en atom or a n atom (preferably a fluorine atom or a chlorine atom).
Preferably, when R6 is a pyridyl group, it is linked to the rest of the molecule via a ring carbon atom. In other words, when R6 is pyridyl group it is bonded to the pyridin-2(1H)- one ring via a ring carbon atom of the pyridyl group.
Preferably, when R6 is a pyrimidinyl group or a morpholinyl group it is linked to the rest of the molecule via the ring nitrogen atom. In other words, when R6 is a pyrimidinyl group or a morpholinyl group it is bonded to the pyridin-2(1H)-one ring via the ring en atom of the pyrimidinyl group or the morpholinyl group.
Typically, in the compound of formula (I) or formula (I’), R7 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, or a 5- to 7- ed cyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the lkyl, aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one, two or three tuents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)1-3CN group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; and wherein R11, R12 and R13 each independently represent a hydrogen atom or a linear or ed C1-C3 alkyl group.
Preferably, in the compound of formula (I) or formula (I’), R7 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a triazolyl group, a thiazolyl group, a pyrrolidinyl group, a piperidyl group, a tetrahydropyranyl group or a morpholinyl group; wherein the lkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, piperidyl, tetrahydropyranyl or morpholinyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 yalkyl group, a C3-C7 lkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a triazolyl group, a thiazolyl group, a dinyl group, a piperidyl group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R12 group, a -C(O)-(CH2)n-NR11R12 group, a (CH2)nR12 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0 or 1; and wherein R11, R12 and R13 each independently represent a hydrogen atom or methyl group.
It is particularly preferred that the cycloalkyl, aryl, heteroaryl and heterocyclyl groups that R7 may represent are unsubstituted or substituted by one, two or three, preferably one or two, substituents selected from a halogen atom, a linear or branched C1-C6 alkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, and a - (CH2)nOR11 group wherein n is 0, 1 or 2 and wherein R11 represents a hydrogen atom or a linear or branched C1-C3 alkyl group.
Most preferably, R7 represents a en atom, piperidyl group, a thiazolyl group or a linyl group; n the piperidyl, thiazolyl and morpholinyl groups are unsubstituted or substituted by one or two substituents selected from a hydroxy group or a c acid.
Preferably, when R7 is a pyridyl group, a pyrimidinyl group, a triazolyl group or a lyl group, it is linked to the rest of the molecule via a ring carbon atom. In other words, when R7 is a pyridyl group, a pyrimidinyl group, a triazolyl group or a thiazolyl group it is bonded to the central ring of the compound of formula (I) or formula (I’) via a ring carbon atom of the pyridyl, pyrimidinyl, triazolyl or thiazolyl group.
Preferably, when R7 is a pyrimidinyl group or a morpholinyl group it is linked to the rest of the le via the ring nitrogen atom. In other words, when R7 is a dinyl group or a morpholinyl group it is bonded to the central ring of the compound of formula (I) via the ring nitrogen atom of the pyrimidinyl group or the morpholinyl group.
Typically, in the compound of formula (I) or formula (I’), m is 0, 1 or 2; preferably 0 or 1.
Typically, in the compound of formula (I) or formula (I’) n represents 0, 1 or 2.
Typically, in the compound of formula (I) n’ represents 0, 1 or 2.
Typically, in the nd of formula (I) or formula (I’) R8 represents a hydrogen atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group. ably R8 represents a hydrogen atom or a linear or branched C1-C3 alkyl group. More preferably R8 represents a hydrogen atom.
Typically, in the compound of formula (I) or formula (I’) R9 and R10 each independently represent a hydrogen atom or a linear or branched C1-C6 alkyl group. Preferably R9 and R10 each independently represent a en atom or a linear or branched C1-C3 alkyl group. More preferably R9 and R10 each represent a hydrogen atom.
Typically, in the compound formula (I) R11, R12 and R13 each independently represent a hydrogen atom, a linear or ed C1-C3 alkyl group, or a 5- to 7- membered heterocyclyl group ning one, two or three heteroatoms selected from O, S and N, which heterocyclyl group is tituted or substituted by one, two or three substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1- C4 alkyl group, a C1-C4 haloalkyl group or a C1-C4 hydroxyalkyl group. Preferably, in the compound formula (I) R11, R12 and R13 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group.
Typically, in the compound formula (I’) R11, R12 and R13 each independently ent a hydrogen atom or a linear or branched C1-C3 alkyl group.
Typically, in the compound of formula (I) or formula (I’), W ents a linker selected from a -NR8- group, a -(CR9R10)- group, -O- or -S-, wherein R8, R9 and R10 are as defined above. Preferably, in the compound of formula (I) or formula (I’), W represents a linker selected from a -NR8- group or a -(CR9R10)- group, n R8, R9 and R10 are as defined above. More preferably W represents a -NR8- group wherein R8 is as defined above. Even more preferably W represents a -NR8- group wherein R8 is a en atom or a C1-C3 alkyl group. Most preferably, W represents a -NR8- group wherein R8 is a hydrogen atom or a methyl group. Even more preferred, W represents a -NH- group.
When the cycloalkyl, lkenyl, aryl, heteroaryl and heterocyclyl groups that R2, R5, R6 and R7 may represent are substituted by one or more -NR11C(O)-(CH2)n-R12 groups or one or more -C(O)-(CH2)n-R11 groups, and n is 0, then it is preferred that R11 or R12 do not represent a hydrogen atom.
In a particularly preferred embodiment, in the compound of formula (I) m is 0, 1 or 2; X is a nitrogen atom and Y is a -CR6 group; or Y is a nitrogen atom and X is a -CR6 group; or both X and Y are a -CR6 group; A is a nitrogen atom, B is a -CR7 group and D is a -CR5 group; or B is a nitrogen atom, A is a -CR7 group and D is a -CR5 group; or both A and B are a -CR7 group and D is nitrogen atom or a -CR5 group; W represents a linker selected from a -NR8- group or a -(CR9R10)- group; preferably a -NR8- group; R1 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group; R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered cyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or tuted by one or more substituents ed from a halogen atom; a cyano group; a linear or ed C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a monocyclic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N; a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a 12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a-(CH2)n’-C(O)-(CH2)n- NR11R12 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a -(CH2)n’-S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2 and said clic or ic C6-C14 aryl group is unsubstituted or further substituted by one or more carboxyl groups.
R3 and R4 each independently represent a hydrogen atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; R5 ents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)nOR11 group, a -NR11R12 group, a (O)-(CH2)n-R12 group, a (O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R6 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a clic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a - to 7- membered cyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are tituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl, a phenyl group, a l group, a pyrimidinyl group, a piperidyl group, or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0, 1 or 2 R7 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a - to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and cyclyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)1-3CN group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a (O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R8 represents a en atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; R9 and R10 each independently represent a en atom or a linear or branched C1- C3 alkyl group; R11, R12 and R13 each independently represent a hydrogen atom, a linear or branched C1-C3 alkyl group, or a 5- to 7- ed heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, which heterocyclyl group is unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group or a C1- C4 yalkyl group.
In a further particular preferred embodiment, in the compound of formula (I): m is 0, 1 or 2; both X and Y ents a -CR6 group; A is a nitrogen atom, B is a -CR7 group and D is a -CR5 group; or B is a nitrogen atom, A is a -CR7 group and D is a -CR5 group; or both A and B are a -CR7 group and D is nitrogen atom or a -CR5 group; W represents a linker selected from a -NR8- group or a -(CR9R10)- group; preferably a -NR8- group; R1 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group; R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered aryl group containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms ed from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom; a cyano group; a linear or ed C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a monocyclic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N; a 5- to 14- membered heterocyclyl group containing at least one atom selected from O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a 12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a-(CH2)n’-C(O)-(CH2)n- 2 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a -(CH2)n’-S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2 and said monocyclic or ic C6-C14 aryl group is unsubstituted or further substituted by one or more carboxyl groups.
R3 and R4 each independently represent a hydrogen atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; R5 ents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R6 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms ed from O, S and N, a - to 7- membered heterocyclyl group containing one, two or three heteroatoms ed from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0, 1 or 2 R7 represents a en atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a clic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a - to 7- membered heterocyclyl group containing one, two or three atoms ed from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 yalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)1-3CN group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R8 represents a en atom or a linear or branched C1-C6 alkyl group, which alkyl group is tituted or substituted by a C1-C2 alkoxy group; R9 and R10 each independently represent a hydrogen atom or a linear or branched C1- C3 alkyl group; R11, R12 and R13 each independently represent a hydrogen atom, a linear or branched C1-C3 alkyl group, or a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, which heterocyclyl group is unsubstituted or substituted by one, two or three substituents ed from a halogen atom, a hydroxyl group, a linear or ed C1-C4 alkyl group, a C1-C4 haloalkyl group or a C1- C4 hydroxyalkyl group.
In a further particular preferred embodiment, in the compound of formula (I): m is 0 or 1; both X and Y ents a -CR6 group; A is a nitrogen atom, B is a -CR7 group and D is a -CR5 group; or B is a nitrogen atom, A is a -CR7 group and D is a -CR5 group; or both A and B are a -CR7 group and D is en atom or a -CR5 group; W represents a linker selected from a -NR8- group or a -(CR9R10)- group; preferably a -NR8- group; R1 represents a hydrogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group or a C1-C3 hydroxyalkyl group; R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a l group, a pyrimidinyl group, a triazolyl group, a lyl group, a idinyl group or a piperidyl group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a triazolyl group, a thiazolyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a-(CH2)n’-C(O)-(CH2)n- NR11R12 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a -(CH2)n’-S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2; R3 and R4 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group; R5 represents a en atom, a halogen atom, a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)1-3CN group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a (O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; n each n is 0, 1 or 2; R6 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 haloalkyl group, a C1-C4 yalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, a pyrrolidinyl group, a piperidyl group, a tetrahydropyranyl group or a morpholinyl group; R7 represents a hydrogen atom, a halogen atom, a cyano group, a linear or ed C1-C3 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a triazolyl group, a thiazolyl group, a pyrrolidinyl group, a piperidyl group, a tetrahydropyranyl group or a morpholinyl group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl, piperidyl, tetrahydropyranyl or morpholinyl groups are unsubstituted or tuted by one, two or three substituents selected from a halogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a triazolyl group, a thiazolyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a (CH2)n-R12 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR12 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R8 represents a en atom or a linear or branched C1-C3 alkyl group; R9 and R10 each independently represent a hydrogen atom or a linear or branched C1- C3 alkyl group; R11, R12 and R13 each ndently represent a hydrogen atom or a linear or branched C1-C3 alkyl group, or a 5- to 7- membered heterocyclyl group containing one, two or three atoms selected from O, S and N, which heterocyclyl group is unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group or a C1- C4 yalkyl group.
In a further particular preferred embodiment, in the nd of formula (I): m is 0 or 1; both X and Y represents a -CR6 group; A is a nitrogen atom, B is a -CR7 group and D is a -CR5 group; or B is a nitrogen atom, A is a -CR7 group and D is a -CR5 group; or both A and B are a -CR7 group and D is nitrogen atom or a -CR5 group; W ents a -NH- group or a -CH2- group; preferably a -NH- group; R1 represents a hydrogen atom, a C1-C3 haloalkyl group, a C1-C3 hydroxyalkyl group or a linear or branched C1-C3 alkyl group; R2 represents a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group or a morpholinyl group, wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, dinyl or morpholinyl group are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group, a triazolyl group, a -(CH2)1-3CN group, a -(CH2)0-2OR11 group or a -C(O)-(CH2)1CN group; R3 and R4 each independently represent a hydrogen atom or a methyl group; R5 represents a hydrogen atom, a halogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group, a C3-C7 cycloalkyl group or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0 or 1; R6 represents a hydrogen atom, a halogen atom, a linear or ed C1-C3 alkyl group, a C1-C3 haloalkyl group, a C3-C7 lkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group or a morpholinyl group, wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or morpholinyl group are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 kyl group, a triazolyl group, a -(CH2)1-3CN group or a -(CH2)0-2OR11 group; R7 represents a hydrogen atom, a halogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group or a morpholinyl group, n the cycloalkyl, phenyl, pyridyl, dinyl, piperidinyl or morpholinyl group are unsubstituted or tuted by one, two or three substituents selected from a halogen atom, a hydroxy group, a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group, a phenyl group, a phenyl group tuted by a carboxyl group, a triazolyl group, a -(CH2)1-3CN group or a -(CH2)0-2OR11 group; R8, R9 and R10 each independently represent a hydrogen atom or a methyl group; R11 and R12 each independently represent a hydrogen atom or a methyl group.
In yet a further particular preferred embodiment, in the nd of formula (I): m is 0 or 1; both X and Y represents a -CR6 group; A is a nitrogen atom, B is a -CR7 group and D is a -CR5 group; or B is a nitrogen atom, A is a -CR7 group and D is a -CR5 group; or both A and B are a -CR7 group and D is nitrogen atom or a -CR5 group; W represents a -NH- group or a -CH2- group; preferably a -NH- group; R1 represents a hydrogen atom; R2 represents a cyclohexyl group, a pyridyl group or a piperidyl group, wherein the cyclohexyl, pyridyl and piperidyl and groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a lyl group, a -(CH2)1-3CN group, -C(O)-(CH2)1CN group or a -(CH2)-S(O)2- pyrimidinyl group, which pyrimidinyl is unsubstituted or substituted by one, two or three yl groups; R3 and R4 each independently represent a hydrogen atom or a methyl group; R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a linear or branched C1-C3 alkyl group, a -OCH3 group or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0 or 1; and n R11 and R12 independently ent a hydrogen atom or a linear or branched C1-C3 alkyl group; R6 represents a hydrogen atom, a halogen atom or a pyrazolyl group; R7 represents a hydrogen atom, piperidyl group, a thiazolyl group or a morpholinyl group; wherein the piperidyl, thiazolyl and morpholinyl groups are unsubstituted or substituted by one or two substituents selected from a hydroxy group or a benzoic acid.
In a particularly red embodiment, in the compound of a (I’) m is 0, 1 or 2; X is a nitrogen atom and Y is a -CR6 group; or Y is a en atom and X is a -CR6 group; or both X and Y are a -CR6 group; A is a nitrogen atom and B is a -CR7 group; or B is a nitrogen atom and A is a -CR7 group; or both A and B are a -CR7 group; W represents a linker selected from a -NR8- group or a -(CR9R10)- group; R1 represents a hydrogen atom, a linear or ed C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group; R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered cyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the lkyl, lkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents ed from a halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a monocyclic or ic C6-C14 aryl group; a 5- to 14- ed heteroaryl group containing at least one heteroatom selected from O, S and N; a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; a -(CH2)1-3CN group; a nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -C(O)-(CH2)n-NR11R12 group; a -S(O)2(CH2)nR11 group; a -S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2 and said monocyclic or bicyclic C6-C14 aryl group is unsubstituted or further substituted by one or more carboxyl groups.
R3 and R4 each independently represent a hydrogen atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a (O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R6 represents a en atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a - to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one, two or three tuents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 lkyl, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0, 1 or 2 R7 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered aryl group containing one, two or three heteroatoms selected from O, S and N, a - to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, n the cycloalkyl, aryl, heteroaryl and cyclyl groups are unsubstituted or substituted by one, two or three substituents selected from a n atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a dinyl group, a piperidyl group, a -(CH2)1-3CN group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R8 represents a en atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; R9 and R10 each independently represent a hydrogen atom or a linear or branched C1- C3 alkyl group; R11, R12 and R13 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group.
In a further particular preferred embodiment, in the compound of formula (I’): m is 0 or 1; X and Y each independently are a -CR6 group; A is a nitrogen atom and B is a -CR7 group; or B is a nitrogen atom and A is a -CR7 group; or both A and B are a -CR7 group; W represents a linker selected from a -NR8- group or a -(CR9R10)- group; R1 represents a hydrogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 kyl group or a C1-C3 hydroxyalkyl group; R2 represents a linear or ed C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a triazolyl group, a lyl group, a pyrrolidinyl group or a piperidyl group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidyl groups are unsubstituted or tuted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a triazolyl group, a thiazolyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)nOR11 group, a 12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a (O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R3 and R4 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group; R5 represents a hydrogen atom, a n atom, a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a 1-3CN group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R6 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrrolidinyl group, a piperidyl group, a tetrahydropyranyl group or a morpholinyl group; R7 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a triazolyl group, a thiazolyl group, a pyrrolidinyl group, a piperidyl group, a tetrahydropyranyl group or a morpholinyl group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, lyl, pyrrolidinyl, piperidyl, tetrahydropyranyl or morpholinyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a triazolyl group, a thiazolyl group, a dinyl group, a piperidyl group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a (CH2)1CN group, a -C(O)-(CH2)n-R12 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR12 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; n each n is 0, 1 or 2; R8 represents a hydrogen atom or a linear or branched C1-C3 alkyl group; R9 and R10 each independently represent a hydrogen atom or a linear or branched C1- C3 alkyl group; R11, R12 and R13 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group.
In a further particular preferred ment, in the compound of formula (I’): m is 0 or 1; both X and Y represents a -CR6 group; A is a nitrogen atom and B is a -CR7 group; or B is a nitrogen atom and A is a -CR7 group; or both A and B are a -CR7 group; W represents a linker selected from a -NR8- group or a -(CR9R10)- group; R1 represents a en atom, a C1-C3 haloalkyl group, a C1-C3 hydroxyalkyl group or a linear or branched C1-C3 alkyl group; R2 represents a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group or a morpholinyl group, wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or morpholinyl group are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a linear or ed C1-C3 alkyl group, a C1-C3 haloalkyl group, a triazolyl group, a -(CH2)1-3CN group, a -(CH2)0-2OR11 group or a -C(O)-(CH2)1CN group; R3 and R4 each independently represent a hydrogen atom or a methyl group; R5 represents a hydrogen atom, a n atom, a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group, a C3-C7 cycloalkyl group or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0 or 1; R6 represents a hydrogen atom, a halogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 kyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a dinyl group, a piperidinyl group or a morpholinyl group, wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or morpholinyl group are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group, a triazolyl group, a -(CH2)1-3CN group or a -(CH2)0-2OR11 group; R7 ents a hydrogen atom, a halogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 haloalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a l group, a pyrimidinyl group, a piperidinyl group or a linyl group, wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, piperidinyl or morpholinyl group are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a hydroxy group, a linear or ed C1-C3 alkyl group, a C1-C3 haloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a triazolyl group, a -(CH2)1-3CN group or a -(CH2)0-2OR11 group; R8, R9 and R10 each independently represent a en atom or a methyl group; R11 and R12 each independently represent a hydrogen atom or a methyl group.
In yet a further particular red embodiment, in the nd of formula (I’): m is 0 or 1; both X and Y represents a -CR6 group; A is a nitrogen atom and B is a -CR7 group; or B is a nitrogen atom and A is a -CR7 group; or both A and B are a -CR7 group; W represents a -NH- group or a -CH2- group; R1 represents a hydrogen atom; R2 represents a cyclohexyl group, a pyridyl group or a piperidyl group, wherein the cyclohexyl, pyridyl and piperidyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a triazolyl group, a -(CH2)1-3CN group or -C(O)-(CH2)1CN group; R3 and R4 each independently represent a hydrogen atom or a methyl group; R5 represents a hydrogen atom, a halogen atom, a linear or branched C1-C3 alkyl group or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0 or 1; and wherein R11 and R12 independently ent a hydrogen atom or a linear or branched C1-C3 alkyl group; R6 represents a hydrogen atom or a halogen atom; R7 ents a hydrogen atom, piperidyl group, a thiazolyl group or a morpholinyl group; n the piperidyl, thiazolyl and linyl groups are unsubstituted or substituted by one or two substituents selected from a hydroxy group or a benzoic acid.
Particular individual compounds of the invention include: (4-(1-(5-fluoropyridinyl)ethylamino)pyrimidinylamino)pyridin-2(1H)-one; (S)(4-(1-(5-fluoropyridinyl)ethylamino)methylpyrimidinylamino)pyridin-2(1H)- one; (S)(5-chloro(1-(5-fluoropyridinyl)ethylamino)pyrimidinylamino)pyridin-2(1H)- one; (S)(4-(1-(5-fluoropyridinyl)ethylamino)methoxypyrimidinylamino)pyridin- 2(1H)-one; (S)(4-(1-(5-fluoropyridinyl)ethylamino)hydroxypyrimidinylamino)pyridin- 2(1H)-one; (S)(1-(5-fluoropyridinyl)ethylamino)(2-oxo-1,2-dihydropyridin ylamino)pyrimidinecarboxamide; (S)chloro(4-(1-(5-fluoropyridinyl)ethylamino)methylpyrimidin ylamino)pyridin-2(1H)-one; (S)(4-(1-(5-fluoropyridinyl)ethylamino)methylpyrimidinylamino)(1H- pyrazolyl)pyridin-2(1H)-one; (S)(4-(1-(5-fluoropyridinyl)ethylamino)(4-hydroxypiperidinyl)pyrimidin ylamino)pyridin-2(1H)-one; (S)(5-fluoro(1-(5-fluoropyridinyl)ethylamino)morpholinopyrimidin ylamino)pyridin-2(1H)-one; (S)(6-(1-(5-fluoropyridinyl)ethylamino)pyrazinylamino)pyridin-2(1H)-one; (S)(6-(1-(5-fluoropyridinyl)ethylamino)pyridinylamino)pyridin-2(1H)-one; 2-((1r,4r)(5-methyl(2-oxo-1,2-dihydropyridinylamino)pyrimidin ylamino)cyclohexyl)acetonitrile; (1r,4r)((3-hydroxypiperidinylsulfonyl)methyl)cyclohexylamino)pyrimidin ylamino)pyridin-2(1H)-one; (R)oxo(3-(2-(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino)piperidin yl)propanenitrile; (3-(5-methyl(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino)piperidin- 1-yl)oxopropanenitrile; (R)(3-(5-fluoro(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino)piperidin- 1-yl)oxopropanenitrile; (R)(4-(1-(4H-1,2,4-triazolyl)piperidinylamino)fluoropyrimidin ylamino)pyridin-2(1H)-one; (R)(3-(2-(5-chlorooxo-1,2-dihydropyridinylamino)methylpyrimidin ylamino)piperidinyl)oxopropanenitrile; (R)(3-(5-fluoromorpholino(2-oxo-1,2-dihydropyridinylamino)pyrimidin ylamino)piperidinyl)oxopropanenitrile; (R)(3-(5-methylmorpholino(2-oxo-1,2-dihydropyridinylamino)pyrimidin ylamino)piperidinyl)oxopropanenitrile; (R)(3-(5-methylmorpholino(2-oxo-1,2-dihydropyridinylamino)pyrimidin ylamino)piperidinyl)oxopropanenitrile; (R)(3-(4-(5-chlorooxo-1,2-dihydropyridinylamino)methyl morpholinopyrimidinylamino)piperidinyl)oxopropanenitrile; (R)(3-(5-chloro(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino)piperidin- 1-yl)oxopropanenitrile; 3-[(4-{[(1S)(5-Fluoropyridinyl)ethyl]amino}pyrimidinyl)methyl]pyridin-2(1H)-one; (S)(5-(6-(1-(5-fluoropyridinyl)ethylamino)(2-oxo-1,2-dihydropyridin ylamino)pyrimidinyl)thiazolyl)benzoic acid; or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer or deuterated derivative thereof.
In an embodiment, ular individual compounds of the ion include: (S)(4-(1-(5-fluoropyridinyl)ethylamino)pyrimidinylamino)pyridin-2(1H)-one; (S)(4-(1-(5-fluoropyridinyl)ethylamino)methylpyrimidinylamino)pyridin-2(1H)- one; (S)chloro(4-(1-(5-fluoropyridinyl)ethylamino)methylpyrimidin ylamino)pyridin-2(1H)-one; (S)(1-(5-fluoropyridinyl)ethylamino)(2-oxo-1,2-dihydropyridin ylamino)pyrimidinecarboxamide; (R)oxo(3-(2-(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino)piperidin yl)propanenitrile; (R)(3-(5-methyl(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino)piperidin- 1-yl)oxopropanenitrile; (R)(3-(5-fluoro(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino)piperidin- 1-yl)oxopropanenitrile; (R)(4-(1-(4H-1,2,4-triazolyl)piperidinylamino)fluoropyrimidin o)pyridin-2(1H)-one; (R)(3-(2-(5-chlorooxo-1,2-dihydropyridinylamino)methylpyrimidin ylamino)piperidinyl)oxopropanenitrile; (S)(6-(1-(5-fluoropyridinyl)ethylamino)pyrazinylamino)pyridin-2(1H)-one; 2-((1r,4r)(5-methyl(2-oxo-1,2-dihydropyridinylamino)pyrimidin ylamino)cyclohexyl)acetonitrile; (S)(4-(1-(5-fluoropyridinyl)ethylamino)(4-hydroxypiperidinyl)pyrimidin ylamino)pyridin-2(1H)-one; 3-[(5-Chloro{[(1S)(5-fluoropyridinyl)ethyl]amino}pyrimidinyl)amino] pyridin- 2(1H)-one; (S)((4-(1-(5-fluoropyridinyl)ethylamino)pyrimidinyl)methyl)pyridin-2(1H)-one; (S)((5-fluoro(1-(5-fluoropyridinyl)ethylamino)morpholinopyrimidin yl)methyl)pyridin-2(1H)-one; 3-[(6-{[(1S)(5-Fluoropyridinyl)ethyl]amino}pyridinyl)amino]pyridin-2(1H)-one; (S)(5-(6-(1-(5-fluoropyridinyl)ethylamino)(2-oxo-1,2-dihydropyridin ylamino)pyrimidinyl)thiazolyl)benzoic acid; or a pharmaceutically acceptable salt, or solvate, or e, or stereoisomer or deuterated derivative thereof.
Compounds of general formula (I) may be ed from compounds of formula (II) as illustrated in Scheme 1.
X X N Y R2 HN Y R2 O (R3 C R4)m O (R3 C R4)m W N N W N N R1 R1 A D A D B B (II) (I) Scheme 1 When the defined R groups are susceptible to chemical reaction under the ions of the hereinbefore described ses or are incompatible with said processes, conventional protecting groups may be used in accordance with standard practice, for e see T. W. Greene and P. G. M. Wuts in 'Protective Groups in Organic Synthesis', 3rd Edition, John Wiley & Sons (1999). It may be that deprotection will form the last step in the synthesis of compounds of formula (I).
The term amino-protecting group refers to a protecting group suitable for preventing undesired reactions at amino nitrogen. entative amino-protecting groups e, but are not limited to, formyl; acyl groups, for example yl groups such as acetyl; alkoxycarbonyl groups such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS); trimethylsiloxyethoxymethyl (SEM) and the like.
The term hydroxy-protecting group refers to a protecting group suitable for preventing undesired reactions at a hydroxy group. Representative hydroxy-protecting groups include, but are not limited to, alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, for e alkanoyl groups, such as acetyl; arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); Tetrahydropyranyl ethers (THP ethers) such as methoxy-THP or ethoxy-THP; silyl groups, such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS); trimethylsiloxyethoxymethyl (SEM) and the like.
Treatment of compounds of formula (II) with a suitable t, such as a mixture of trimethylsilyl chloride and sodium iodide in a solvent such as acetonitrile at temperatures ranging from ambient temperature to reflux or with an aqueous solution of hydrogen bromide at 100 ºC gives rise to compounds of a (I).
In the particular case of formula (II) where W = NH, compounds of subformula (II-a) may be prepared by the synthetic approach as shown in Scheme 2: R2 X N Y (R3 C R4)m X R2 O HN N Y R2 Cl N Cl R1 NH2 (R3 C R4)m O (R3 C R4)m (IV) Cl N N (VI) A D R1 HN N N B R1 A D B A D (III) (V) (II-a) Scheme 2 Compounds of formula (III) may be reacted with amines of formula (IV), in the presence of a base, such as N,N-diisopropylethylamine or triethylamine, in a solvent such as tetrahydrofuran, acetonitrile, ethanol, n-butanol, 1-methylpyrrolidinone or N,N’- dimethylformamide at temperatures ranging from t temperature to 180 ºC to furnish compounds of formula (V). ent of compounds of formula (V) with amines of formula (VI) in the presence of a suitable catalyst, such as the catalytic species generated from tris (dibenzylideneacetone)dipalladium(0) and 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene, and a base such as cesium ate in a solvent such as 1,4-dioxane at temperatures g from 80–120 ºC gives rise to compounds of formula (II-a).
In the particular case of formula (V) where A = N and B ents a –CR7 group (R7 is as defined in the claims section) and D represents a -CR5 group, compounds of subformula (V-a) may be prepared by the synthetic approach as shown in Scheme 3: (R3 C R4)m HN R2 Cl N Cl (IV) (R3 C R4)m N Cl N N Cl N (VII) (VIII) R6 H R6 H (IX) (IX) (R3 C R4)m HN R2 Cl N Cl (R3 C R4)m (IV) Cl N N N R1 R6 R5 (X) (V-a) Scheme 3 Pyrimidines of formula (VII) may be reacted with amines of formula (IV), in the presence of a base, such as N,N-diisopropylethylamine in a solvent such as ethanol at temperatures g from ambient temperature to reflux to furnish compounds of formula (VIII).
Compounds of formula (VIII) when treated with an appropriate nucleophile of formula (IX), such as 4-(tert-butyl-dimethylsilanyloxy)piperidine, in the presence of a base, such as cesium carbonate, in a solvent such as N,N’-dimethylformamide at atures ranging from t temperature to 130 ºC gives rise to nds of formula (V-a).
In another synthetic pathway, reaction of pyrimidines of formula (VII) with an appropriate nucleophile of formula (IX), such as morpholine, in a solvent such as ethanol at temperatures ranging from -78 ºC to ambient temperature gives rise to compounds of formula (X).
Compounds of formula (X) may be converted to compounds of formula (V-a) by treatment with amines of formula (IV) in the presence of a base, such as N,N’- diisopropylethylamine, in a solvent such ethanol or n-butanol, at temperatures ranging from ambient temperature to 130 ºC.
Compounds of formula (I), (II) or (V) in which the residue –(R3-C-R4)m-R2, R5 or R7 (in the particular case where B = CR7 and D = CR5) contains a “protected” atom, such as nitrogen or oxygen, may be “deprotected” by removal of the protecting group to give compounds of formula (I), (II) or (V) in which the residue –(R3-C-R4)m-R2, R5 or R7 contains the “deprotected” heteroatom. Typical examples of protecting groups for heteroatoms, such as nitrogen and oxygen, and their removal (deprotection) may be found in several textbooks, for example: Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540. rmore said “deprotected” heteroatoms may be further functionalized by, for example, alkylation, ion, sulfonamidation or arylation under standard reaction conditions.
Compounds of formula (I), (II) or (V) in which the e –(R3-C-R4)m-R2, R5 or R7 (in the particular case where B = CR7 and D = CR5) contains a carboxylic acid moiety functionalized with an appropriate protecting group such as an ethyl ester, may be ected at the carboxylic acid moiety under standard conditions (Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540). The corresponding carboxylic acid may then be further functionalized under standard conditions to give the corresponding .
Starting compounds are commercially available or may be obtained following the conventional synthetic methods already known in the art.
EXAMPLES The synthesis of the nds of the invention and of the intermediates for use therein are illustrated by the following Examples (1-26) (including ation es (Preparations 1-28)) and are given in order to provide a person skilled in the art with a sufficiently clear and te explanation of the present invention, but should not be considered as limiting of the ial aspects of its subject, as set out in the preceding portions of this description.
Preparations PREPARATION 1 (S)-N4-(1-(5-Fluoropyridinyl)ethyl)-N2-(2-methoxypyridinyl)pyrimidine-2,4- diamine a) (S)Chloro-N-(1-(5-fluoropyridinyl)ethyl)pyrimidinamine A solution of (S)(5-fluoropyridinyl)ethanamine (prepared as described in WO2006/123113, 235 mg, 1.68 mmol) in tetrahydrofuran (2 mL) was added to a stirred solution of 2,4-dichloropyrimidine (250 mg, 1.68 mmol) in tetrahydrofuran (2 mL) at ambient temperature. A solution of triethylamine (0.23 mL, 1.68 mmol) in tetrahydrofuran (2 mL) was then added dropwise and the reaction mixture was heated overnight at 55 ºC. After cooling to ambient temperature, the reaction e was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The residue was ed by reverse phase chromatography (C-18 silica from , water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (43 mg, 10%) as an oil.
LRMS (m/z): 253 (M+1)+. 1H-NMR  (CDCl 3): 1.54 (d, 3H), 5.16 (br s, 1H), 6.16 -6.35 (m, 2H), 7.29 (dd, 1H), 7.39 (t, 1H), 7.97 (d, 1H), 8.40 (d, 1H). b) (S)-N4-(1-(5-Fluoropyridinyl)ethyl)-N2-(2-methoxypyridinyl)pyrimidine-2,4- diamine An oven-dried resealable Schlenk tube was charged with (S)chloro-N-(1-(5- fluoropyridinyl)ethyl)pyrimidinamine (Preparation 1a, 43 mg, 0.17 mmol), 2- ypyridinamine (23 mg, 0.19 mmol), cesium carbonate (111 mg, 0.34 mmol) and 1,4-dioxane (3 mL). The Schlenk tube was subjected to three cycles of evacuation- backfilling with argon then tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.02 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (10 mg, 0.02 mmol) were added. After three further cycles of tion-backfilling with argon, the Schlenk tube was capped and then stirred and heated to 100 ºC. After 24 hours the e was cooled to ambient ature and the t was evaporated under reduced pressure. Ethyl acetate was added and the organic solution was washed with water (x3) and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure.
The residue was purified by reverse phase tography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid ed] 0% to 100%) to give the title compound (11 mg, 19%) as a solid.
LRMS (m/z): 341 (M+1)+.
ATION 2 (S)-N4-(1-(5-Fluoropyridinyl)ethyl)-N2-(2-methoxypyridinyl)methyl pyrimidine-2,4-diamine a) (S)Chloro-N-(1-(5-fluoropyridinyl)ethyl)methylpyrimidinamine A mixture of (S)(5-fluoropyridinyl)ethanamine dihydrochloride (prepared as described in WO2006/123113, 560 mg, 2.63 mmol), 2,4-dichloromethylpyrimidine (620 mg, 2.63 mmol) and diisopropylethylamine (1.4 mL, 7.9 mmol) in n-butanol (1 mL) was stirred and heated for 45 min at 110 ºC in a microwave oven. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The c solution was washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The e was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (427 mg, 61%) as a yellow oil.
LRMS (m/z): 267 (M+1)+. 1H-NMR  (CDCl 3): 1.56 (d, 3H), 1.65 (s, 3H), 5.43 (t, 1H), 6.37 (br s, 1H), 7.28- 7.37 (m, 1H), 7.38-7.50 (m, 1H), 7.83 (s, 1H), 8.43 (d, 1H). b) (S)-N4-(1-(5-Fluoropyridinyl)ethyl)-N2-(2-methoxypyridinyl)methyl pyrimidine-2,4-diamine Obtained as a yellow oil (69%) from chloro-N-(1-(5-fluoropyridinyl)ethyl) methylpyrimidinamine (Preparation 2a) and 2-methoxypyridinamine following the experimental procedure as described in Preparation 1b.
LRMS (m/z): 355 (M+1)+. 1H-NMR  (CDCl 3): 1.60 (d, 3H), 1.65 (s, 3H), 4.02 (s, 3H), 5.40 (q, 1H), 5.77 (d, 1H), 6.86 (dd, 1H), 7.35 (ddd, 2H), 7.70 (dd, 1H), 7.77 (s, 1H), 8.45 (d, 1H), 8.59 (dd, 1H).
PREPARATION 3 (S)Chloro-N4-(1-(5-fluoropyridinyl)ethyl)-N2-(2-methoxypyridinyl) pyrimidine-2,4-diamine a) (S)-2,5-Dichloro-N-(1-(5-fluoropyridinyl)ethyl)pyrimidinamine Obtained as a colourless oil (57%) from 2,4,5-trichloropyrimidine and (S)(5- fluoropyridinyl)ethanamine ochloride (prepared as described in WO2006/123113) following the experimental procedure as described in Preparation 2a followed by purification of the crude product by flash chromatography % ethyl e in hexanes).
LRMS (m/z): 287 (M+1)+. 1H-NMR  (CDCl 3): 1.55 (d, 3H), 5.33 -5.42 (m, 1H), 7.06 (br s, 1H), 7.31 (dd, 1H), 7.40-7.46 (m, 1H), 8.03 (s, 1H), 8.44 (d, 1H). b) (S)Chloro-N4-(1-(5-fluoropyridinyl)ethyl)-N2-(2-methoxypyridinyl) pyrimidine-2,4-diamine Obtained as a colourless oil (50%) from (S)-2,5-dichloro-N-(1-(5-fluoropyridin yl)ethyl)pyrimidinamine ration 3a) and 2-methoxypyridinamine following the experimental procedure as described in Preparation 1b followed by purification of the crude product by flash chromatography % ethyl acetate in hexanes).
LRMS (m/z): 375 (M+1)+. 1H-NMR  (CDCl 3): 1.61 (d, 3H), 4.02 (s, 3H), 5.30-5.39 (m, 1H), 6.42 (br s, 1H), 6.86 (dd, 1H), 7.28-7.42 (m, 3H), 7.74 (dd, 1H), 7.95 (s, 1H), 8.41-8.56 (m, 1H).
PREPARATION 4 (S)-N4-(1-(5-Fluoropyridinyl)ethyl)methoxy-N2-(2-methoxypyridinyl) pyrimidine-2,4-diamine a) (S)Chloro-N-(1-(5-fluoropyridinyl)ethyl)methoxypyrimidinamine Obtained as a white solid (91%) from 2,4-dichloromethoxypyrimidine and (S)(5- fluoropyridinyl)ethanamine dihydrochloride (prepared as described in WO2006/123113) following the experimental procedure as described in Preparation 2a followed by purification of the crude t by flash chromatography (0-100% ethyl acetate in hexanes).
LRMS (m/z): 283 (M+1)+. 1H-NMR  (CDCl 3): 1.57 (d, 3H), 3.84 (s, 3H), 5.31 -5.43 (m, 1H), 6.84 (d, 1H), .47 (m, 2H), 7.52 (s, 1H), 8.43 (d, 1H). b) (S)-N4-(1-(5-Fluoropyridinyl)ethyl)methoxy-N2-(2-methoxypyridinyl) pyrimidine-2,4-diamine Obtained as a yellow solid (79%) from (S)chloro-N-(1-(5-fluoropyridinyl)ethyl) methoxypyrimidinamine (Preparation 4a) and oxypyridinamine following the experimental procedure as described in Preparation 1b followed by purification of the crude product by flash chromatography (0-100% ethyl acetate in hexanes).
LRMS (m/z): 371 (M+1)+. 1H-NMR  (CDCl 3): 1.59 (d, 3H), 3.85 (s, 3H), 4.01 (s, 3H), 5.25 -5.42 (m, 1H), 6.20 (d, 1H), 6.83 (dd, 1H), 7.20 (s, 1H), .34 (m, 1H), 7.54 (s, 1H), 7.67 (dd, 1H), 8.45 (d, 1H), 8.53 (dd, 1H).
PREPARATION 5 (S)(1-(5-Fluoropyridinyl)ethylamino)(2-methoxypyridinylamino) pyrimidinecarboxamide a) (S)-Ethyl 2-chloro(1-(5-fluoropyridinyl)ethylamino)pyrimidine carboxylate A solution of ethyl 2,4-dichloropyrimidinecarboxylate (prepared as described in /131687, 0.29 g, 1.31 mmol), (S)(5-fluoropyridinyl)ethanamine hloride (prepared as described in WO2006/123113, 0.28 g, 1.59 mmol) and diisopropylethylamine (0.69 mL, 3.96 mmol) in acetonitrile (3 mL) was stirred overnight at ambient temperature. Water was then added and the reaction mixture was extracted with diethyl ether. The organic phase was washed with water and brine, dried (MgSO4), ed and the solvents evaporated under reduced pressure to yield the title compound (0.49 g, 85%) as an oil.
LRMS (m/z): 325 (M+1)+. 1H-NMR  (CDCl 3): 1.41 (t, 3H), 1.58 (d, 3H), 4.39 (q, 2H), 5.42 -5.55 (m, 1H), 7.31 (dd, 1H), 7.39 (dd, 1H), 8.49 (d, 1H), 8.69 (s, 1H), 9.37 (d, 1H). b) (S)Chloro(1-(5-fluoropyridinyl)ethylamino)pyrimidinecarboxylic acid A solution of lithium hydroxide monohydrate (633 mg, 15.09 mmol) in water (6 mL) was added to a solution of (S)-ethyl 2-chloro(1-(5-fluoropyridinyl)ethylamino)pyrimidine carboxylate (Preparation 5a, 490 mg, 1.51 mmol) in a e of methanol (6 mL) and ydrofuran (2 mL) and the reaction mixture was stirred at ambient temperature for 3 hours. The solvents were evaporated under reduced pressure and water was added to the resulting residue. The pH was then adjusted to ca. 6 with 2M s hydrochloric acid and the aqueous suspension was extracted with diethyl ether (x3).
The organic phase was washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure to give the title compound (0.21 g, 41%) as a semi-solid.
LRMS (m/z): 297 (M+1)+. c) (S)(1H-Benzo[d][1,2,3]triazolyloxy)(1-(5-fluoropyridinyl)ethylamino) dinecarboxamide N-(3-Dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride (177 mg, 0.92 mmol) and 1-hydroxybenzotriazole (125 mg, 0.93 mmol) were added to a solution of (S) chloro(1-(5-fluoropyridinyl)ethylamino)pyrimidinecarboxylic acid (Preparation 5b, 210 mg, 0.62 mmol) in N,N’-dimethylformamide (5 mL) and the mixture was stirred for 30 min at ambient temperature. 0.5M a solution in 1,4-dioxane (3 mL) was then added and the on mixture was stirred overnight at ambient temperature. The solvents were evaporated and the resulting residue was taken up in diethyl ether. The c solution was washed with water and brine, dried (Na2SO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by e phase chromatography (C-18 silica from , water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to yield the title compound (30 mg, 12%) as a solid.
LRMS (m/z): 395 (M+1)+. d) (S)(1-(5-Fluoropyridinyl)ethylamino)(2-methoxypyridinylamino) pyrimidinecarboxamide A solution of (S)(1H-benzo[d][1,2,3]triazolyloxy)(1-(5-fluoropyridinyl) ethyl amino)pyrimidinecarboxamide (Preparation 5c, 30 mg, 0.08 mmol), 2-methoxy pyridinamine (14 mg, 0.11 mmol) and p-toluenesulfonic acid hydrate (15 mg, 0.08 mmol) in 1,4-dioxane (3 mL) was heated at 120 ºC for 4 hours. The solvent was evaporated under reduced pressure and the resulting residue was ed by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (21 mg, 72%) as a solid.
LRMS (m/z): 384 (M+1)+.
PREPARATION 6 -Chloromethoxypyridinamine a) 5-Chloromethoxynitropyridine A solution of sodium methoxide (0.84 g, 16.6 mmol) in methanol (4 mL) was added dropwise to a solution of 2,5-dichloronitropyridine (1.00 g, 5.2 mmol) in methanol (10 mL) and the mixture was stirred and heated to reflux. After 7 hours, the mixture was cooled and diluted with water and the precipitate was filtered, washed with water and dried to give the title compound (0.95 g, 97%) as a white solid. 1H NMR  (CDCl 3): 4.11 (s, 3H), 8.23 (s, 1H), 8.32 (s, 1H). b) 5-Chloromethoxypyridinamine Zinc bromide (0.27 g, 1.2 mmol) and 10% platinum on carbon (0.58 g, 2.97 mmol) were added to a solution of 5-chloromethoxynitropyridine (Preparation 6a, 1.13 g, 5.99 mmol) in ethyl acetate (20 mL) and the resulting mixture was hydrogenated in a Parr apparatus at 10 psi for 2 hours. The e was then ed through diatomaceous earth (Celite®) and the filter cake was washed with ethyl acetate. The combined te and washings were concentrated to give the title compound (0.95 g, 100%) as an oil which was used in the next synthetic step without further purification.
LRMS (m/z): 159 (M+1)+. 1H NMR  (CDCl 3): 3.97 (s, 3H), 6.98 (s, 1H), 7.50 (s, 1H).
PREPARATION 7 (S)-N2-(5-Chloromethoxypyridinyl)-N4-(1-(5-fluoropyridinyl)ethyl)methyl pyrimidine-2,4-diamine ed as a yellow solid (62%) from (S)chloro-N-(1-(5-fluoropyridinyl)ethyl) methylpyrimidinamine ration 2a) and 5-chloromethoxypyridinamine (Preparation 6b) following the experimental procedure as described in Preparation 1b followed by purification of the crude product by flash chromatography (2:1 s/ethyl acetate).
LRMS (m/z): 389 (M+1)+. 1H-NMR  (CDCl 3): 1.62 (d, 3H), 2.06 (br s, 3H), 4.01 (s, 3H), 5.44 (t, 2H), 6.03 (d, 2H), 7.30-7.47 (m, 2H), 7.65 (d, 1H), 7.78 (s, 1H), 8.44 (d, 1H), 8.88 (d, 1H).
ATION 8 -(1-Benzyl-1H-pyrazolyl)methoxypyridinamine a) 5-(1-Benzyl-1H-pyrazolyl)methoxynitropyridine An oven-dried resealable Schlenk tube was charged with 5-bromomethoxy nitropyridine (3.58 g, 15.36 mmol), 1-benzyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole (5.23 g, 18.43 mmol), potassium carbonate (4.24 g, 30.72 mmol), 1,4-dioxane (50 mL) and water (5 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and is(triphenylphosphine)palladium(0) (1.77 g, 1.53 mmol) was added. After three further cycles of tion-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 100 ºC. After 3 days, the mixture was , filtered through diatomaceous earth (Celite®) and the filter cake was washed with methylene chloride (300 mL). The combined filtrate and washings were concentrated in vacuo and the residue was purified by flash chromatography (20-50% ethyl acetate in hexanes) to give the title compound (3.70 g, 84%) as a yellow solid. 1H-NMR  (CDCl 3): 4.11 (s, 3H), 5.36 (s, 2H), 7.33 (m, 5H), 7.64 (d, 1H), 7.81 (d, 1H), 8.30 (d, 1H), 8.49 (d, 1H). b) 5-(1-Benzyl-1H-pyrazolyl)methoxypyridinamine A suspension of 5-(1-benzyl-1H-pyrazolyl)methoxynitropyridine (Preparation 8a, 3,5 g, 11.28 mmol) in acetic acid (50 mL) was added to a cooled (10 ºC) suspension of zinc (3.67 g, 56.25 g) in acetic acid (50 mL) and the resulting mixture was stirred at ambient ature for 1.5 hours. The mixture was filtered and the solid washed with methylene chloride (50 mL). The combined filtrate and washings were evaporated and the residue was purified by flash chromatography (20-40% ethyl acetate in hexanes) to give a brown oil which was treated with a 1:1 mixture of hexanes/diethyl ether (40 mL). The resulting solid was filtered, washed with hexane and dried to yield the title compound (2.33 g, 74%) as a beige solid. 1H-NMR  (CDCl 3): 3.79 (br s, 2H), 3.98 (s, 3H), 5.32 (s, 2H), 6.95 (d, 1H), 7.22- 7.40 (m, 5H), 7.52 (d, 1H), 7.68 (d, 1H), 7.72 (d, 1H).
PREPARATION 9 (S)-N4-(1-(5-Fluoropyridinyl)ethyl)-N2-(2-methoxy(1H-pyrazolyl)pyridin methylpyrimidine-2,4-diamine a) (S)-N2-(5-(1-Benzyl-1H-pyrazolyl)methoxypyridinyl)-N4-(1-(5-fluoro pyridinyl)ethyl)methylpyrimidine-2,4-diamine Obtained as a white foam (69%) from (S)chloro-N-(1-(5-fluoropyridinyl)ethyl) methylpyrimidinamine ration 2a) and 5-(1-benzyl-1H-pyrazolyl)methoxy pyridinamine (Preparation 8b) following the mental procedure as described in Preparation 1b.
LRMS (m/z): 511 (M+1)+. 1H-NMR  (CDCl 3): 1.54 (d, 3H), 2.05 (s, 3H), 4.03 (s, 3H), 5.37 (s, 2H), 5.39 - .52 (m, 1H), 5.97 (d, 1H), 7.18 (dd, 1H), 7.24 (d, 1H), 7.28-7.37 (m, 5H), 7.69 (s, 1H), 7.77 (d, 1H), 7.82 (d, 1H), 7.85 (d, 1H), 8.38 (d, 1H), 8.91 (d, 1H). b) (S)-N4-(1-(5-Fluoropyridinyl)ethyl)-N2-(2-methoxy(1H-pyrazolyl)pyridin- 3-yl)methylpyrimidine-2,4-diamine 5N Aqueous hydrochloric acid solution (0.126 mL, 0.63 mmol) and 20% palladium hydroxide on carbon (0.07 g, 0.50 mmol) were added to a solution of (S)-N2-(5-(1- benzyl-1H-pyrazolyl)methoxypyridinyl)-N4-(1-(5-fluoropyridinyl)ethyl) methylpyrimidine-2,4-diamine (Preparation 9a, 0.214 g, 0.42 mmol) in a 1:1 mixture of ol/tetrahydrofuran (4 mL) and the reaction mixture was stirred at 50 ºC overnight under a hydrogen atmosphere. Further 5N aqueous hydrochloric acid solution (0.126 mL, 0.63 mmol) and palladium catalyst (0.07 g) were then added and the mixture was stirred overnight under a hydrogen atmosphere. The mixture was then ed through diatomaceous earth (Celite®) and the filter cake was washed with methanol. The combined filtrate and washings were evaporated and a 1:1 mixture of methanol/tetrahydrofuran (4 mL) was added to the residue. 5N s hydrochloric acid on (0.126 mL, 0.63 mmol) and 20% ium hydroxide on carbon (0.07 g, 0.50 mmol) were then added to the resulting solution and the reaction mixture was stirred at 50 ºC overnight under a hydrogen atmosphere. The mixture was then filtered through Celite® and the filter cake was washed with methanol. The combined filtrate and washings were evaporated to give the title compound (0.166 g, 70%) as a white foam that was used in the next synthetic step without further purification.
LRMS (m/z): 421 (M+1)+. 1H-NMR  (CDCl 3): 1.49 (d, 3H), 2.15 (s, 3H), 4.02 (s, 3H), 5.25 -5.28 (m, 1H), 7.07 (dd, 1H), .34 (m, 1H), 7.59 (d, 1H), 7.82 (s, 2H), 8.08 (d, 1H), 8.36 (d, 1H), 8.41 (d, 1H).
PREPARATION 10 3-[(4-(4-{[Tert-butyl(dimethyl)silyl]oxy}piperidinyl){[(1S)(5-fluoropyridin yl)ethyl]amino}pyrimidinyl)amino]pyridin-2(1H)-one a) chloro-N-[(1S)(5-fluoropyridinyl)ethyl]pyrimidinamine (S)(5-Fluoropyridinyl)ethanamine hydrochloride (prepared as described in WO2006/123113, 1.05 g, 4.91 mmol) and N,N’-diisopropylethylamine (2.80 mL, 16.36 mmol) were added to a solution of 2,4,6-trichloropyrimidine (0.75 g, 4.09 mmol) in ethanol (15 mL) and the resulting mixture was stirred and heated to 80 ºC in a sealed tube for 1 hour. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate (x3). The ed organic layers were washed with water and brine, dried (MgSO4), filtered and the solvent ated under d pressure. The residue was purified by flash chromatography (hexanes to 1:1 hexanes/ethyl acetate) to give the title compound (0.66 g, 57%) as a white solid. 1H-NMR  (DMSO-d 6): 1.45 (d, 3H), 5.18 -5.27 (m, 1H), 6.63 (s, 1H), 7.46 (dd, 1H), 7.70 (td, 1H), 8.53 (d, 1H), 8.70 (d, 1H). b) 6-(4-{[Tert-butyl(dimethyl)silyl]oxy}piperidinyl)chloro-N-[(1S)(5-fluoro pyridinyl)ethyl]pyrimidinamine A mixture of 2,6-dichloro-N-[(1S)(5-fluoropyridinyl)ethyl]pyrimidinamine (Preparation 10a, 0.66 g, 2.31 mmol), 4-(tert-butyl-dimethylsilanyloxy)piperidine (prepared as described in WO2004/006926, 0.60 g, 2.77 mmol) and cesium carbonate (1.13 g, 3.46 mmol) in N,N’-dimethylformamide (15 mL) was stirred and heated to 130 ºC in a sealed tube for 2 hours. After cooling to ambient ature, water was added and the resulting mixture was extracted with ethyl acetate (x3). The combined organic extract was washed with water and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes to 6:4 hexanes/ethyl acetate) to give the title nd (0.53 g, 50%) as a white solid. 1H-NMR  (DMSO-d 6): 0.04 (s, 6H), 0.85 (s, 9H), 1.02 -1.36 (m, 2H), 1.40 (d, 3H), 1.48-1.65 (m, 2H), 3.11-3.29 (m, 2H), .94 (m, 3H), 5.03 (m, 1H), 5.84 (s, 1H), 7.37 (dd, 1H), 7.64 (td, 1H), 7.79 (d, 1H), 8.47 (d, 1H). c) 6-(4-{[Tert-butyl(dimethyl)silyl]oxy}piperidinyl)-N4-[(1S)(5-fluoropyridin yl)ethyl]-N2-(2-methoxypyridinyl)pyrimidine-2,4-diamine Obtained as a white solid (59%) from 6-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidinyl)- 2-chloro-N-[(1S)(5-fluoropyridinyl)ethyl]pyrimidinamine (Preparation 10b) and 2-methoxypyridinamine ing the experimental procedure as described in ation 1b followed by purification of the crude product by flash chromatography (10-40% ethyl acetate/hexanes). 1H-NMR  (CDCl 3): 0.09 (s, 6H), 0.91 (s, 9H), 1.52 (d, 3H), 1.67 -1.84 (m, 2H), 3.45 (m, 2H), 3.92 (m, 1H), 3.98 (s, 3H), 3.96-4.14 (m, 2H), 4.90 (m, 1H), 5.01 (s, 1H), 5.16 (d, 1H), 6.60 (s, 1H), 6.82 (dd, 1H), 7.34 (dd, 2H), 7.70 (dd, 1H), 8.27 (dd, 1H), 8.40 (s, 1H). d) 3-[(4-(4-{[Tert-butyl(dimethyl)silyl]oxy}piperidinyl){[(1S)(5-fluoropyridin yl)ethyl]amino}pyrimidinyl)amino]pyridin-2(1H)-one Trimethylsilyl chloride (0.285 mL, 2.25 mmol) and sodium iodide (337 mg, 2.25 mmol) were added to a stirred solution of 6-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidinyl)-N4- [(1S)(5-fluoropyridinyl)ethyl]-N2-(2-methoxypyridinyl)pyrimidine-2,4-diamine (Preparation 10c, 415 mg, 0.75 mmol) in acetonitrile (5 mL) and the reaction mixture was heated at 80 ºC for 4.5 hours. After cooling to ambient temperature, water was added and the e was extracted with ethyl acetate (x3). The pH was then adjusted to ca. 6 with 2M aqueous sodium ide solution and the aqueous phase was extracted with ethyl acetate (x3). The combined organic extract was washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under d pressure to give the title compound (0.52 g, 100%) as a brown oil which was used in the next synthetic step without further purification.
LRMS (m/z): 539 (M+1)+.
PREPARATION 11 (S)Fluoro-N4-(1-(5-fluoropyridinyl)ethyl)-N2-(2-methoxypyridinyl) morpholinopyrimidine-2,4-diamine a) 4-(2,6-Dichlorofluoropyrimidinyl)morpholine A solution of morpholine (1.5 mL, 17.05 mmol) in ethanol (25 mL) was added to a cooled (-20 ºC) solution of 2,4,6-trichlorofluoropyrimidine (3.00 g, 14.93 mmol) in l (150 mL) and the resulting mixture was stirred at -20 ºC for 30 minutes and at ambient temperature for 3 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water and ene chloride. The c layer was separated, dried and the solvent evaporated under reduced re. The resulting white solid was triturated with ethanol, then filtered and dried to give the title compound (2.0 g, 53%).
LRMS (m/z): 252/254 (M+1)+. 1H-NMR  (CDCl 3): 3.77-3.80 (m, 4H), 3.82-3.85 (m, 4H). b) (S)Chlorofluoro-N-(1-(5-fluoropyridinyl)ethyl)morpholinopyrimidin amine A e of 4-(2,6-dichlorofluoropyrimidinyl)morpholine (Preparation 11a, 1.18 g, 4.68 mmol), (S)(5-fluoropyridinyl)ethanamine hydrochloride (prepared as described in WO2006/123113, 1.00 g, 4.69 mmol) and N,N’-diisopropylethylamine (3.27 mL, 18.77 mmol) in n-butanol (20 mL) was heated at 130 ºC for two days. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (0-5% ethyl acetate in hexanes to 5:94:1 ethyl acetate/hexanes/triethylamine) to give the title compound (0.700 g, 42%) as one major regioisomer. The chemical structures of both regioisomers were confirmed by NMR experiments AD and gHMBCAD).
LRMS (m/z): 8 (M+1)+. 1H-NMR  (CDCl 3): 1.54 (3H, dd), 3.60-3.75 (8H, m), .37 (1H, m), 6.07 (1H, br d), 7.24-7.32 (1H, m), 7.36-7.42 (1H, m), 8.42 (1H, t) c) Fluoro-N4-(1-(5-fluoropyridinyl)ethyl)-N2-(2-methoxypyridinyl) morpholinopyrimidine-2,4-diamine Obtained (69%) from (S)chlorofluoro-N-(1-(5-fluoropyridinyl)ethyl) morpholinopyrimidinamine (Preparation 11b) and 2-methoxypyridinamine following the experimental procedure as described in Preparation 1b followed by purification of the crude product by flash tography (0-20% methanol in dichloromethane).
LRMS (m/z): 444 (M+1)+. 1H-NMR  (CDCl 3): 1.58 (3H, s), 3.63 (4H, m) 3.77 (4H, m), 4.02 (3H, s), 5.30 (1H, m), 5.65 (1H, br d) 6.83 (1H, dd), 7.10 (1H, s), 7.33 (2H, m), 7.68 (1H, dd), 8.42 (1H, dd).
ATION 12 N-[(1S)(5-Fluoropyridinyl)ethyl]-N'-(2-methoxypyridinyl)pyrazine-2,6- diamine a) 6-Chloro-N-[(1S)(5-fluoropyridinyl)ethyl]pyrazinamine N,N’-Diisopropylethylamine (2.50 mL, 14.35 mmol) was added dropwise to a solution of 2,6-dichloropyrazine (525 mg, 3.52 mmol) and (S)(5-fluoropyridinyl)ethanamine hydrochloride (prepared as described in WO2006/123113, 750 mg, 3.52 mmol) in 1- methylpyrrolidinone (4 mL) and the resulting mixture was d and heated for 6 hours at 180 ºC in a microwave oven. After cooling to ambient temperature, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (7:3 hexanes/ethyl acetate) to give the title compound (520 g, 57%) as a brown oil.
LRMS (m/z): 253 (M+1)+. 1H-NMR  (CDCl 3): 1.54 (d, 3H), 5.14 (m, 1H), 5.97 (d, 1H), 7.29-7.42 (m, 2H), 7.78 (d, 2H), 8.42 (d, 1H). b) N-[(1S)(5-Fluoropyridinyl)ethyl]-N'-(2-methoxypyridinyl)pyrazine-2,6- diamine ed as a yellow solid (64%) from 6-chloro-N-[(1S)(5-fluoropyridinyl)ethyl] pyrazinamine (Preparation 12a) and oxypyridinamine following the experimental procedure as described in Preparation 1b followed by purification of the crude product by flash chromatography (95:5 chloroform/methanol).
LRMS (m/z): 341 (M+1)+. 1H-NMR  (CDCl 3): 1.59 (d, 3H), 4.03 (s, 3H), 5.05 (m, 1H), 5.35 (d, 1H), 6.85 (m, 1H) 7.34 (m, 3H), 7.39 (s, 1H), 7.48 (s, 1H), 7.73 (m, 2H).
PREPARATION 13 (S)-N2-(1-(5-Fluoropyridinyl)ethyl)-N6-(2-methoxypyridinyl)pyridine-2,6- diamine a) (S)Chloro-N-(1-(5-fluoropyridinyl)ethyl)pyridinamine (S)(5-Fluoropyridinyl)ethanamine hydrochloride (prepared as described in WO2006/123113, 0.291 g, 1.37 mmol) was added to a solution of 2,6-dichloropyridine (0.203 g, 1.38 mmol) in N,N’-diisopropylethylamine (1.2 mL, 6.89 mmol) and the resulting mixture was stirred and heated to reflux for two days. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (0-10% ethyl acetate in hexanes) to yield the title compound (127 mg, 36%) as a yellow solid.
LRMS (m/z): 252 (M+1)+. 1H-NMR  (CDCl 3): 1.53 (d, 3H), 4.87 -5.04 (m, 1H), 5.55 (d, 1H), 6.18 (d, 1H), 6.56 (d, 1H), 7.27 (dd, 1H), 7.32-7.45 (m, 2H), 8.34-8.43 (m, 1H). b) (S)-N2-(1-(5-Fluoropyridinyl)ethyl)-N6-(2-methoxypyridinyl)pyridine-2,6- diamine Obtained as an orange oil (90%) from (S)chloro-N-(1-(5-fluoropyridinyl)ethyl) namine (Preparation 13a) and 2-methoxypyridinamine following the experimental ure as described in Preparation 1b followed by purification of the crude product by flash tography (0-100% ethyl acetate in s).
LRMS (m/z): 340 (M+1)+. 1H-NMR  (CDCl 3): 1.57 (d, 3H), 4.01 (s, 3H), 4.93 -5.06 (m, 1H), 5.06 (d, 1H), .84 (d, 1H), 6.01-6.13 (m, 1H), 6.74 (s, 1H), 6.83 (dd, 1H), 7.19-7.27 (m, 1H), 7.28-7.43 (m, 2H), 7.68 (dd, 1H), 8.38 (dd, 1H), 8.40-8.44 (m, 1H).
PREPARATION 14 2-((1r,4r)Aminocyclohexyl)acetonitrile a) Tert-Butyl (1r,4r)(hydroxymethyl)cyclohexylcarbamate Di-tert-butyl dicarbonate (3.04 g, 13.9 mmol) was added to a stirred solution of ((1r,4r)- 4-aminocyclohexyl)methanol (1.50 g, 11.6 mmol) in tetrahydrofuran (20 mL). After stirring overnight at ambient temperature, the mixture was evaporated and partitioned between ethyl e and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and ated. The residue was treated with hexanes and the sion was filtered to give the title compound (2.11 g, 79%) as a white solid.
LRMS (m/z): 228 (M-H)+. 1H NMR  (DMSO-d 6): 0.84-0.95 (m, 2H), 1.05-1.18 (m, 2H), 1.20-1.29 (m, 2H), 1.40 (s, 9H), 1.71-1.80 (m, 3H), 3.14 (m, 1H), 3.21 (t, 2H), 4.41 (t, 1H), 6.73 (d, 1H). b) ((1r,4r)(Tert-Butoxycarbonylamino)cyclohexyl)methyl 4-methylbenzenesulfonate A solution of 4-methylbenzenesulfonyl chloride (2.28 g, 11.96 mmol) in dichloromethane was added to a solution of tert-butyl (1r,4r)(hydroxymethyl) cyclohexylcarbamate (Preparation 14a, 2.11 g, 9.2 mmol) and triethylamine (1.59 mL, 11.4 mmol) in dichloromethane (50 mL) and the resulting mixture was d overnight at ambient temperature. The mixture was washed with 1M aqueous sodium hydroxide solution and the organic layer was dried (MgSO4), the solvent was evaporated and the residue was purified by flash tography (diethyl ether/hexanes) to give the title compound (2.91 g, 83%) as a white solid.
LRMS (m/z): 382 (M-H)+. 1H NMR  (CDCl 3): 0.90-1.12 (m, 4H), 1.43 (s, 3H), 1.78 (dd, 2H), 1.99 (d, 2H), 3.34 (m, 1H), 3.46 (t, 1H), 3.81 (d, 2H), 4.37 (m, 1H), 7.34 (d, 2H), 7.77 (d, 2H). c) Tert-Butyl (1r,4r)(cyanomethyl)cyclohexylcarbamate Sodium cyanide (0.38 g, 7.8 mmol) was added to a solution of r)(tertbutoxycarbonylamino )cyclohexyl)methyl 4-methylbenzene-sulfonate ration 14b, 1.00 g, 2.6 mmol) in dimethylsulphoxide (10 mL) and the mixture was stirred and heated to 55 oC. After stirring for 20 hours, the mixture was diluted with ethyl acetate and washed with saturated aqueous potassium carbonate solution, water and brine, dried (MgSO4) and ated. The residue was purified by flash chromatography (100% dichloromethane to 95:5 dichloromethane/methanol) to give the title compound (0.450 g, 72%) as a white solid.
LRMS (m/z): 239 (M+H)+. 1H NMR  (CDCl 3): 1.06-1.25 (m, 4H), 1.44 (s, 9H), 1.65 (m, 1H), 1.90 (d, 2H), 2.06 (d, 2H), 2.25 (d, 2H), 3.39 (m, 1H), 4.38 (m, 1H). d) 2-((1r,4r)Aminocyclohexyl)acetonitrile hydrochloride A mixture of tert-butyl (1r,4r)(cyanomethyl)cyclohexylcarbamate (Preparation 14c, 0.348 g, 1.46 mmol) and 4M hydrogen chloride solution in oxane (3.65 mL) was stirred ght at ambient temperature. The solvent was evaporated in vacuo and the residue was treated with diethyl ether. The ant suspension was filtered to give the title compound (0.226 g, 89%) as a white solid.
LRMS (m/z): 139 (M+H)+. 1H NMR  (DMSO-d6): 1.14 (ddd, 2H), 1.37 (ddd, 2H), 1.60 (m, 1H), 1.83 (d, 2H), 1.99 (d, 2H), 2.50 (d, 2H), 2.94 (m, 1H), 8.08 (br s, 2H).
PREPARATION 15 2-((1r, 4r)(2-(2-Methoxypyridinyl)amino)methylpyrimidinyl)amino) cyclohexyl)acetonitrile a) 2-((1r, 4r)(2-Chloromethylpyrimidinyl)amino)cyclohexyl)acetonitrile N,N’-Diisopropylethylamine (0.72 mL, 4.13 mmol) was added dropwise to a stirred solution of 2,4-dichloromethylpyrimidine (187 mg, 1.15 mmol) and 2-((1r,4r) aminocyclohexyl) acetonitrile hydrochloride (Preparation 14d, 200 mg, 1.15 mmol) in N,N’-dimethylformamide (1.5 mL) and the resulting mixture was stirred and heated for 3 hours at 90 ºC. After cooling to t ature, water was added and the resulting e was extracted with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO4), ed and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (140 g, 46%) as a solid.
LRMS (m/z): 265 (M+1)+. 1H-NMR  (CDCl 3): 1.15-1.40 (m, 4H), 1.72 (m, 1H), 1.97 (m, 5H), 2.19 (m, 2H), 2.31 (d, 2H), 4.05 (m, 1H), 4.46 (bd, 1H), 7.81 (s, 1H). b) 2-((1r, 4r)(2-(2-Methoxypyridinyl)amino)methylpyrimidinyl)amino) exyl)acetonitrile Obtained as a white solid (48%) from 2-((1r, 4r)(2-chloromethylpyrimidinyl) amino)cyclohexyl)acetonitrile (Preparation 15a) and 2-methoxypyridinamine following the experimental procedure as described in Preparation 1b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).
LRMS (m/z): 353 (M+1)+. 1H-NMR  (CDCl 3): .45 (m, 4H), 1.76 (m, 1H), 1.99 (m, 5H), 2.27 (d, 2H), 2.35 (d, 2H), 4.03 (m, 4H), 4.34 (bd, 1H), 6.87 (dd, 1H), 7.71 (dd, 1H), 7.74 (d, 1H), 8.70 (dd, 1H).
PREPARATION 16 ((1r,4r)(1,3-dioxoisoindolinyl)cyclohexyl)methanesulfonyl chloride a) (1r,4r)-Ethyl 4-aminocyclohexanecarboxylate hydrochloride Concentrated aqueous hloric acid (7 mL) was added to a suspension of )- ocyclohexanecarboxylic acid (6.32 g, 35.2 mmol) in ethanol (100 mL) and the mixture was stirred and heated to 60 oC. After 20 hours, the mixture was evaporated in vacuo and the residue was co-evaporated with further ethanol and then e to give the title compound (7.20 g, 99%) as a white solid. 1H NMR  (DMSO-d6): 1.17 (t, 3H), 1.26 -1.46 (m, 4H), 1.87-1.98 (m, 4H), 2.23 (m, 1H), 2.95 (m, 1H), 4.04 (q, 2H), 8.06 (br s, 3H). b) ((1r,4r)Aminocyclohexyl)methanol A suspension of (1r,4r)-ethyl 4-aminocyclohexanecarboxylate hydrochloride (Preparation 16a, 7.20 g, 34.7 mmol) in ydrofuran (200 mL) was added portion wise to a cooled (ice-bath), d 1M solution of lithium aluminium hydride in tetrahydrofuran (69 mL, 69.0 mmol). After 1 hour, the ice-bath was removed and the mixture was stirred at ambient temperature for 1 hour then allowed to stand overnight.
The stirred mixture was cooled in an ice bath and water (6. 9 mL), 15% aqueous sodium hydroxide solution (21 mL) and water (21 mL) were added dropwise sequentially with due care. After additional 30 s of agitation at ambient temperature, the mixture was filtered through a plug of Celite® and the filter cake was washed with tetrahydrofuran. The combined filtrate and washings were evaporated to give the title compound (4.50 g, 100%) as a white solid. 1H NMR  (DMSO-d 6): 0.78-1.01 (m, 4H), 1.23 (m, 1H), 1.65-1.75 (m, 4H), 2.41 (m, 1H), 3.18 (d, 2H), 4.36 (br s, 1H). c) 2-((1r,4r)(Hydroxymethyl)cyclohexyl)isoindoline-1,3-dione Triethylamine (4.46 mL, 32.0 mmol) was added to a suspension of ((1r,4r) yclohexyl)methanol (Preparation 16b, 1.00 g, 7.74 mmol) and isobenzofuran- one (1.15 g, 7.76 mmol) in e (50 mL) and the mixture was stirred and heated to 50 oC. After 20 hours, the e was evaporated and the residue was taken up in ethyl acetate and washed with 2M aqueous sodium hydroxide solution, water, brine, dried (MgSO4) and evapor ated to give the title compound (1.68 g, 84%) as a white solid.
LRMS (m/z): 260 (M+1)+. 1H NMR  (CDCl 3): 1.15 (dq, 1H), 1.31 (t, 1H), 1.64 (m, 1H), 1.81 (m, 2H), 1.96 (m, 2H), 2.30 (dq, 1H), 3.52 (t, 2H), 4.13 (tt, 1H), 7.70 (m, 2H), 7.82 (m, 2H). d) ((1r,4r)(1,3-Dioxoisoindolinyl)cyclohexyl)methyl methanesulfonate Methanesulphonyl chloride (0.31 mL, 4.01 mmol) was added dropwise to a stirred, cooled (ice bath) solution of 2-((1r,4r)(hydroxymethyl)cyclohexyl)isoindoline-1,3- dione (Preparation 16c, 1.00 g, 3.86 mmol) and triethylamine (0.59 mL, 4.23 mmol) in dichloromethane (20 mL). After 20 hours, the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4) and evaporated to give the title compound (1.25 g, 96%) as a white solid.
LRMS (m/z): 338 (M+1)+. 1H NMR  (CDCl 3): 1.24 (m, 2H), 1.80-2.02 (m, 5H), 2.32 (dq, 2H), 3.04 (s, 3H), 4.08-4.18 (m, 3H), 7.71 (m, 2H), 7.83 (m, 2H). e) S-((1r,4r)(1,3-Dioxoisoindolinyl)cyclohexyl)methyl ethanethioate A mixture of ((1r,4r)(1,3-dioxoisoindolinyl)cyclohexyl)methyl esulfonate (Preparation 16d, 1.25 g, 3.70 mmol) and potassium thioacetate (1.27 g, 11.1 mmol) in N,N’-dimethylformamide (15 mL) was d and heated to 50 oC. After 4 hours, the e was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4) and evaporated to give the title compound (1.13 g, 96%) as a white solid.
LRMS (m/z): 318 (M+1)+. 1H NMR  (CDCl 3): 1.15 (dq, 2H), 1.64 (m, 1H), 1.76 (m, 2H), 1.96 (m, 2H), 2.27 (dq, 2H), 2.36 (s, 3H), 2.85 (d, 2H), 4.11 (tt, 1H), 7.70 (m, 2H), 7.81 (m, 2H). f) ((1r,4r)(1,3-Dioxoisoindolinyl)cyclohexyl)methanesulfonic acid 30% Aqueous hydrogen peroxide (0.88 mL, 8.6 mmol) was added dropwise over 7 minutes to a stirred sion of S-((1r,4r)(1,3-dioxoisoindolinyl)cyclohexyl) methylethanethioate (Preparation 16e, 0.50 g, 1.6 mmol) in formic acid (4 mL). A highly rmic reaction ensued g a solution which then rapidly deposited a solid.
After 1 hour, the mixture was concentrated in vacuo and the residue was triturated with diethyl ether to give a solid which was filtered and dried to give the title compound (0.46 g, 90%) as a white solid.
LRMS (m/z): 322 (M-1)+. 1H NMR  (DMSO-d6): 1.03 (m, 2H), 1.68 (m, 3H), 2.08 (m, 4H), 2.38 (d, 2H), 3.94 (m, 1H), 7.80-7.86 (m, 4H). g) ((1r,4r)(1,3-Dioxoisoindolinyl)cyclohexyl)methanesulfonyl chloride Thionyl chloride (0.27 mL, 3.63 mmol) was added to a mixture of ((1r,4r)(1,3- soindolinyl)cyclohexyl)methanesulfonic acid (Preparation 16f, 0.333 g, 1.03 mmol) in dichloromethane (5 mL) and N,N’-dimethylformamide (0.1 mL) and the mixture was stirred and heated to 40 oC in a Schlenck tube. After 4 hours, the mixture was cooled and evaporated and the residue was taken up in ethyl acetate. The organic extract was washed with saturated aqueous sodium hydrogen ate solution and brine, dried (MgSO4) and evaporated to give the title compound (0.294 g, 84%) as a white solid. 1H NMR  (DMSO-d6): 1.04 (m, 2H), 1.68 (m, 3H), 2.08 (m, 4H), 2.41 (d, 2H), 3.94 (m, 1H), 7.79-7.86 (m, 4H). h) ((1r,4r)(1,3-Dioxoisoindolinyl)cyclohexyl)methanesulfonyl chloride native ation) 2M Aqueous hydrochloric acid (3.3 mL) was added to a cooled (ice bath), stirred suspension of S-((1r,4r)(1,3-dioxoisoindolinyl)cyclohexyl)methyl ethanethioate (Preparation 16e, 2.05 g, 6.5 mmol) in acetonitrile (18 mL). N-Chlorosuccinimide (3.45 g, 25.8 mmol) was added portion wise to the above mixture after which the ice-bath was removed. An exothermic reaction ensued and the temperature was maintained at < 20 oC by ic cooling in an ice-water bath. A homogenous solution formed followed by precipitation of a white solid. After 20 minutes, the thick e was diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium en carbonate solution and brine, dried (MgSO4) and evaporated to give the title compound (2.53 g, ca. 85% by 1H NMR) as a white solid pure enough to be used as such in subsequent ons.
PREPARATION 17 1-(((1r,4r)Aminocyclohexyl)methylsulfonyl)piperidinol a) 2-((1r,4r)((3-Hydroxypiperidinylsulfonyl)methyl)cyclohexyl)isoindoline- Piperidinol (0.89 g, 8.80 mmol) was added to a stirred solution of ((1r,4r)(1,3- dioxoisoindolinyl)cyclohexyl)methanesulfonyl chloride (Preparation 16g, 1.00 g, 2.49 mmol) in dichloromethane (20 mL). After 1 hour, the mixture was concentrated in vacuo and the resulting e was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give the title compound (0.98 g, 97%) as a white solid.
LRMS (m/z): 407 (M+1)+. 1H NMR  ): 1.24 (dq, 2H), 1.55 -1.69 (m, 3H), 1.7595 (m, 4H), 2.08- 2.20 (m, 2H), 2.35 (dq, 2H), 2.83 (m, 2H), 3.07 (dd, 1H), 3.17 (m, 1H), 3.32 (m, 1H), 3.50 (dd, 1H), 3.89 (m, 1H), 4.12 (tt, 1H), 7.71 (m, 2H), 7.83 (m, 2H). b) 1-(((1r,4r)Aminocyclohexyl)methylsulfonyl)piperidinol hydrochloride salt Hydrazine (0.44 mL, 9.0 mmol) was added to a stirred suspension of 2-((1r,4r)((3- hydroxypiperidinylsulfonyl)methyl)cyclohexyl)isoindoline-1,3-dione (Preparation 17a, 0.98 g, 2.4 mmol) in ethanol (45 mL) and the mixture was heated to 60 oC. After 6 hours, the mixture was cooled and evaporated. The solid residue was treated with 2M aqueous hydrochloric acid (20 mL) and filtered. The filtrate was lyophilized to give the title compound (0.74 g, 98%) as an off-white solid.
LRMS (m/z): 277 (M+1)+. 1H NMR  (DMSO-d 6):1.06-1.45 (m, 6H), 1.65-2.00 (m, 6H), 2.57 (m, 1H), 2.76 (m, 1H), 2.90 (m, 2H), 3.30 (m, 1H), 3.47 (m, 2H), 8.02 (br s, 3H) (remaining 2 s hidden under residual solvent peak).
PREPARATION 18 1-(((1r,4r)(2-(2-Methoxypyridinylamino)pyrimidinylamino)cyclohexyl) methylsulfonyl)piperidinol a) 1-(((1r,4r)(2-Chloropyrimidinylamino)cyclohexyl)methylsulfonyl)piperidin- 3-ol N,N’-Diisopropylethylamine (0.51 mL, 2.95 mmol) and 2,4-dichloropyrimidine (0.200 g, 1.34 mmol) were added to a suspension of 1-(((1r,4r) aminocyclohexyl)methylsulfonyl) piperidinol hloride salt (Preparation 17b, 0.408 g, 1.48 mmol) in N,N’-dimethylformamide (5 mL) in a Kimble vial. The vial was sealed and the suspension was shaken and heated to 90 ºC overnight. After g to ambient temperature, the on e was diluted with water and extracted with methylene chloride. The organic layer was washed with water and brine, dried (MgSO4) and the solvent was ated under reduced pressure. The crude product was purified by flash chromatography (0-5% methanol in methylene chloride) to give the title compound (0.118 g, 21%) as an oil. 1H NMR  (CDCl 3): 1.30 (m, 4H) 1.61 (m, 2H) 1.80-2.20 (m, 8H), 2.81 (m, 2H), 3.02 (dd, 1H), 3.11 (m, 1H), 3.30 (m, 1H), 3.50 (dd, 1H), 3.91 (m, 1H), 5.02 (s, 1H), 6.21 (d, 1H), 8.04 (m, 1H). b) 1-(((1r,4r)(2-(2-Methoxypyridinylamino)pyrimidinylamino)cyclohexyl) methylsulfonyl)piperidinol Obtained as a solid (56%) from r,4r)(2-chloropyrimidinylamino)cyclohexyl) methylsulfonyl)piperidinol (Preparation 18a) and oxypyridinamine following the experimental procedure as described in Preparation 1b followed by purification of the crude product by flash chromatography (0-5% methanol in methylene chloride). 1H NMR  (CDCl3): 1.24 -1.30 (m, 4H), 1.55-1.62 (m, 2H), 1.84-2.25 (m, 8H), 2.82 (m, 2H), 3.03 (dd, 1H), 3.11 (m, 1H), 3.30 (m, 1H), 3.51 (dd, 1H), 3.88 (m, 1H), 4.02 (s, 3H), 4.73 (s, 1H), 5.84 (d, 1H), 6.84 (dd, 1H), 7.37 (s, 1H), 7.73 (d, 1H), 7.92 (d, 1H), 8.70 (d, 1H).
PREPARATION 19 (R)(4-(Piperidinylamino)pyrimidinylamino)pyridin-2(1H)-one a) (R)-Tert-butyl 3-(2-chloropyrimidinylamino)piperidinecarboxylate A solution of 2,4-dichloropyrimidine (2.0 g, 13.4 mmol), (R)-tert-butyl 3- aminopiperidinecarboxylate (2.7 g, 13.5 mmol) and N,N’-diisopropylethylamine (2.3 mL, 13.4 mmol) in N,N’-dimethylformamide (15 mL) was stirred and heated overnight at 90 ºC. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (2:1 s/ethyl acetate) to give the title compound (2.87 g, 68%) as a yellow oil.
LRMS (m/z): 313 (M+1)+. 1H-NMR  (CDCl 3): 1.45 (s, 9H), 1.54 -1.81 (m, 4H), 1.94 (br s, 1H), 3.05-3.59 (m, 3H), 3.72 (br s, 1H), 5.13-5.31 (m, 1H), 6.28 (br s, 1H), 8.04 (br s, 1H). b) (R)-Tert-butyl 3-(2-(2-methoxypyridinylamino)pyrimidinylamino)piperidine carboxylate Obtained as a white solid (43%) from (R)-tert-butyl 3-(2-chloropyrimidinylamino) piperidinecarboxylate (Preparation 19a) and 2-methoxypyridinamine following the mental procedure as described in Preparation 1b ed by purification of the crude product by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%).
LRMS (m/z): 401 (M+1)+. 1H-NMR  (CDCl 3): 1.44 (s, 9H), 1.54-1.81 (m, 2H), 1.86-2.03 (m, 1H), 2.95 (m, 2H), 3.16-3.39 (m, 2H), 3.50 (m, 1H), 3.82 (d, 1H), 4.02 (s, 3H), 5.03 (m, 1H), .91 (d, 1H), 6.87 (dd, 1H), 7.77 (dd, 1H), 7.93 (d, 1H), 8.23 (s, 1H), 8.57 (d, 1H). c) (4-(Piperidinylamino)pyrimidinylamino)pyridin-2(1H)-one A suspension of rt-butyl 3-(2-(2-methoxypyridinylamino)pyrimidinylamino) piperidinecarboxylate (Preparation 19b, 340 mg, 0.85 mmol) in 48% aqueous hydrogen bromide solution (2.9 mL, 25.46 mmol) was stirred and heated at 100 ºC for 4 hours. After cooling to ambient ature the solid that formed was filtered and dried to give the hydrobromide salt of the title compound (243 mg, 100%) as an offwhite solid.
LRMS (m/z): 287 (M+1)+. 1H-NMR  (DMSO-d 6): 1.58 (d, 1H), 1.75-1.97 (m, 2H), 2.07 (dd, 1H), 2.86-3.10 (m, 2H), 3.24 (d, 1H), 3.31-3.50 (m, 1H), 4.33 (dd, 1H), 6.34 (d, 1H), 6.45 (t, 1H), 7.25 (br s, 1H), 8.00 (d, 1H), 8.20 (d, 1H), 8.78-8.92 (m, 1H), 8.94-9.08 (m, 1H), 9.32 (d, 1H), 9.76 (s, 1H), 12.19 (br s, 1H).
PREPARATION 20 (R)(5-Methyl(piperidinylamino)pyrimidinylamino)pyridin-2(1H)-one a) rt-butyl 3-(2-chloromethylpyrimidinylamino)piperidine-1 - ylate Obtained as an oil (100%) from 2,4-dichloromethylpyrimidine and (R)-tert-butyl 3- aminopiperidinecarboxylate following the experimental procedure as described in Preparation 19a.
LRMS (m/z): 327 (M+1)+. b) (R)-Tert-butyl 3-(2-(2-methoxypyridinylamino)methylpyrimidinylamino) piperidinecarboxylate Obtained as a solid (36%) from (R)-tert-butyl 3-(2-chloromethylpyrimidinylamino) piperidinecarboxylate (Preparation 20a) and 2-methoxypyridinamine ing the experimental procedure as described in Preparation 1b ed by purification of the crude t by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%).
LRMS (m/z): 415 (M+1)+. c) (R)(5-Methyl(piperidinylamino)pyrimidinylamino)pyridin-2(1H)-one Obtained as hydrobromide salt (63%) from (R)-tert-butyl 3-(2-(2-methoxypyridin o)methylpyrimidinylamino)piperidinecarboxylate (Preparation 20b) ing the mental procedure as described in Preparation 19c.
LRMS (m/z): 381 (M+1)+.
PREPARATION 21 2,4-Dichlorofluoropyrimidine To a stirred mixture of 5-fluoropyrimidine-2,4(1H,3H)-dione (3.0 g, 23 mmol) and phosphorous pentachloride (14.41 g, 69 mmol) was added phosphorous oxychloride (12.6 mL, 130 mmol). The reaction mixture was stirred and heated to reflux for 5 hours and then cooled to ambient temperature and stirred overnight. The mixture was carefully poured onto ice/water (600 mL) and then stirred for 1 hour. Sodium chloride was added and the product was extracted into dichloromethane. The combined organic layer was dried (MgSO4), filtered and evaporated to give the title compound (84%) as a yellow solid.
LRMS (m/z): 167 (M+1)+. 1H-NMR  (CDCl 3): 8.49 (s, 1H).
PREPARATION 22 (R)(5-Fluoro(piperidinylamino)pyrimidinylamino)pyridin-2(1H)-one a) rt-butyl 3-(2-chlorofluoropyrimidinylamino)piperidinecarboxylate Obtained as an oil (100%) from 2,4-dichlorofluoropyrimidine (Preparation 21) and (R)-tert-butyl 3-aminopiperidinecarboxylate ing the experimental procedure as described in ation 19a.
LRMS (m/z): 331 (M+1)+. b) (R)-Tert-butyl 3-(5-fluoro(2-methoxypyridinylamino)pyrimidinylamino) piperidinecarboxylate Obtained as a solid (32%) from (R)-tert-butyl 3-(2-chlorofluoropyrimidinylamino) piperidinecarboxylate (Preparation 22a) and 2-methoxypyridinamine following the experimental procedure as described in Preparation 1b followed by purification of the crude product by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%).
LRMS (m/z): 419 (M+1)+. c) (R)(5-Fluoro(piperidinylamino)pyrimidinylamino)pyridin-2(1H)-one Obtained as hydrobromide salt (94%) from (R)-tert-butyl 3-(5-fluoro(2-methoxy pyridinylamino)pyrimidinylamino)piperidinecarboxylate (Preparation 22b) following the experimental procedure as described in ation 19c.
LRMS (m/z): 385 (M+1)+.
PREPARATION 23 (R)Chloro(5-methyl(piperidinylamino)pyrimidinylamino)pyridin- 2(1H)-one a) (R)-Tert-butyl 3-(2-(5-chloromethoxypyridinylamino)methylpyrimidin ylamino)piperidinecarboxylate Obtained as a solid (14%) from (R)-tert-butyl 3-(2-chloromethylpyrimidinylamino) piperidinecarboxylate (Preparation 20a) and 5-chloromethoxypyridinamine (Preparation 6b) following the experimental procedure as described in Preparation 1b ed by cation of the crude product by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%).
LRMS (m/z): 449 (M+1)+. b) (R)Chloro(5-methyl(piperidinylamino)pyrimidinylamino)pyridin- 2(1H)-one Obtained as romide salt (73%) from (R)-tert-butyl 3-(2-(5-chloromethoxy pyridinylamino)methylpyrimidinylamino)piperidinecarboxylate (Preparation 23a) following the experimental procedure as described in Preparation 19c.
LRMS (m/z): 335 (M+1)+.
ATION 24 (R)(5-Fluoromorpholino(piperidinylamino)pyrimidinylamino)pyridin- 2(1H)-one a) (R)-tert-Butyl 3-(2-chlorofluoromorpholinopyrimidinylamino)piperidine- 1-carboxylate rt-Butyl 3-aminopiperidinecarboxylate (1.60 g, 7.99 mmol) was added to a solution of 4-(2,6-dichlorofluoropyrimidinyl)morpholine (Preparation 11a, 1.01 g, 4.00 mmol) in ethanol (48 mL) and the resulting mixture was stirred and heated to reflux for 3 days. After cooling to ambient temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between water and methylene de. The organic layer was separated, washed with water, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (0-100% ethyl acetate in hexanes) to give the title compound (0.810 g, 47%) as a white foam.
LRMS (m/z): 416 (M+1)+. 1H-NMR  (CDCl 3): 1.44 (s, 9H), 1.62 -1.70 (m, 2H), 1.85-1.90 (m, 1H), 3.40- 3.41 (m, 3H), 3.63-3.66 (m, 4H), 3.74-3.77 (m, 4H), 4.08-4.13 (m, 2H), 4.86 (br s, 1H). b) (R)-tert-Butyl 3-(5-fluoro(2-methoxypyridinylamino)morpholino pyrimidinylamino)piperidinecarboxylate ed as a white foam (87%) from (R)-tert-butyl 3-(2-chlorofluoromorpholino pyrimidinylamino)piperidinecarboxylate (Preparation 24a) and 2-methoxypyridin- 3-amine ing the experimental procedure as described in Preparation 1b followed by purification of the crude product by flash chromatography (0-100% ethyl e in hexanes).
LRMS (m/z): 504 (M+1)+. 1H-NMR  (CDCl 3): 1.43 (s, 9H), 1.63 -1.79 (m, 3H), 1.93-2.01 (m, 1H), 3.22- 3.34 (m, 3H), 3.49-3.55 (m, 1H), .64 (m, 4H), .81 (m, 4H), 4.70 (br s, 1H), 6.86 (dd, 1H), 7.15 (s, 1H), 7.69 (dd, 1H), 8.57 (dd, 1H). c) (R)(5-Fluoromorpholino(piperidinylamino)pyrimidinylamino) pyridin-2(1H)-one A mixture of (R)-tert-butyl 3-(5-fluoro(2-methoxypyridinylamino)morpholino pyrimidinylamino)piperidinecarboxylate (Preparation 24b, 0.099 g, 0.30 mmol) and a 4N solution of hydrogen chloride in 1,4-dioxane (70 mL) was stirred at ambient temperature for 3 hours. The solvent was evaporated under d pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated and the aqueous phase was washed with ethyl acetate (X2). The combined organic extracts were dried (Na2SO4) and the solvent evaporated under reduced pressure to give the title compound (0.088 g, 93%) as a yellow foam that was used in the next synthetic step without further purification.
LRMS (m/z): 390 (M+1)+.
PREPARATION 25 (R)-tert-Butyl 3-(2-chloromethylmorpholinopyrimidinylamino)piperidine carboxylate and (R)-tert-butyl 3-(4-chloromethylmorpholinopyrimidin ylamino)piperidinecarboxylate a) 4-(2,6-Dichloromethylpyrimidinyl)morpholine Obtained as the major isomer (white solid, 47%) from 2,4,6-trichloromethyl pyrimidine and line following the experimental procedure as described in Preparation 11a followed by purification of the crude product by flash tography (0-100% ethyl acetate in hexanes).
LRMS (m/z): 249 (M+1)+. 1H-NMR  (CDCl 3): 2.22 (s, 3H), 3.43-3.52 (m, 4H), .83 (m, 4H). b) (R)-tert-Butyl 3-(2-chloromethylmorpholinopyrimidinylamino)piperidine carboxylate and (R)-tert-butyl 3-(4-chloromethylmorpholinopyrimidin ylamino)piperidinecarboxylate ed from 4-(2,6-dichloromethylpyrimidinyl)morpholine (Preparation 25a) and (R)-tert-butyl 3-aminopiperidinecarboxylate following the experimental procedure as bed in Preparation 24a followed by purification by flash chromatography (0-100% ethyl acetate in hexanes). The chemical structures of the two regioisomers were assigned based on NMR nOe studies: (R)-tert-butyl 3-(2-chloromethyl morpholinopyrimidinylamino)piperidinecarboxylate was obtained as the minor isomer (25%, orange foam) and (R)-tert-butyl 3-(4-chloromethyl morpholinopyrimidinylamino)piperidinecarboxylate was obtained as the major isomer (59%, colourless oil).
(R)-tert-Butyl 3-(2-chloromethylmorpholinopyrimidinylamino)piperidine- 1-carboxylate (minor ): LRMS (m/z): 413 (M+1)+. 1H-NMR  (CDCl 3): 1.43 (s, 9H), 1.59-1.71 (m, 4H), 1.89 (m, 3H), 3.21 (m, 4H), 3.30-3.64 (m, 4H), 3.78 (m, 4H), 4.16 (br s, 1H).
(R)-tert-Butyl 3-(4-chloromethylmorpholinopyrimidinylamino)piperidine- 1-carboxylate (major isomer): LRMS (m/z): 413 (M+1)+. 1H-NMR  (CDCl 3): 1.41 (s, 9H), 1.55 (m, 2H), 1.73 (m, 1H), 1.90 (m, 1H), 2.10 (s, 2H), 2.16 (s, 3H), 3.33 (m, 4H), 3.86 (m, 4H), 4.89 (br s, 1H).
ATION 26 (R)(5-Methylmorpholino(piperidinylamino)pyrimidinylamino)pyridin- 2(1H)-one a) (R)-tert-Butyl 3-(2-(2-methoxypyridinylamino)methylmorpholino pyrimidinylamino)piperidinecarboxylate Obtained as an orange foam (79%) from (R)-tert-butyl 3-(2-chloromethyl morpholinopyrimidinylamino)piperidinecarboxylate ration 25b) and 2- methoxypyridinamine following the experimental procedure as described in Preparation 1b followed by purification of the crude product by flash chromatography (0-100% ethyl acetate in hexanes).
LRMS (m/z): 500 (M+1)+. 1H-NMR  (CDCl 3): .28 (m, 1H), 1.58 (s, 3H), 1.73 (m, 3H), 1.90 (s, 3H), 3.20 (t, 4H), 3.43 (m, 4H), 3.83 (t, 4H), 4.03 (s, 3H), 4.13 (br s, 1H), 6.87 (dd, 1H), 7.21 (br s, 1H), 7.68 (dd, 1H), 8.73 (dd, 1H). b) (R)(5-Methylmorpholino(piperidinylamino)pyrimidinylamino) pyridin-2(1H)-one Methanol was added to a stirred mixture of (R)-tert-butyl 3-(2-(2-methoxypyridin ylamino)methylmorpholinopyrimidinylamino)piperidinecarboxylate (Preparation 26a, 0.212 g, 0.42 mmol) and 4N solution of hydrogen chloride in 1,4- dioxane (4 mL) in a sealed tube at ambient temperature until a clear solution was formed. After stirring for an additional 3 hours, further 4N hydrogen chloride solution in 1,4-dioxane (3 mL) was added and the resulting mixture was d and heated at 40 ºC overnight. The solvents were evaporated under d pressure and the residue was partitioned between ethyl acetate and an saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated and the aqueous phase was washed with ethyl acetate (X2). The combined organic extracts were dried (Na2SO4) and the solvent ated under reduced re to give the title compound (0.082 g, 37%) as an orange foam that was used in the next synthetic step without further purification.
LRMS (m/z): 386 .
PREPARATION 27 (R)(5-Methylmorpholino(piperidinylamino)pyrimidinylamino)pyridin- 2(1H)-one a) (R)-tert-Butyl 3-(4-(2-methoxypyridinylamino)methylmorpholino dinylamino)piperidinecarboxylate Obtained as a yellow oil (60%) from (R)-tert-butyl 3-(4-chloromethyl morpholinopyrimidinylamino)piperidinecarboxylate (Preparation 25b) and 2- methoxypyridinamine following the experimental procedure as described in Preparation 1b followed by cation of the crude product by flash chromatography (0-100% ethyl acetate in hexanes).
LRMS (m/z): 500 (M+1)+. 1H-NMR  (CDCl 3): 1.40 (9H, br s), 1.52-1.80 (4H, m), 2.05 (3H, s), 3.22 (6H, s), 3.60 (2H, m), 3.78-3.95 (5H, m), 4.05 (3H, s), 4.70 (1H, br d), 6.88 (2H, m), 7.73 (1H, dd), 8.73 (1H, dd). b) (R)(5-Methylmorpholino(piperidinylamino)pyrimidinylamino) pyridin-2(1H)-one A mixture of (R)-tert-butyl 3-(4-(2-methoxypyridinylamino)methylmorpholino pyrimidinylamino)piperidinecarboxylate ration 27a, 0.523 g, 1.05 mmol) and a 4N solution of hydrogen chloride in 1,4-dioxane (10 mL) was d at ambient temperature for 3 days. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. Solid ium carbonate was added to the aqueous phase until a basic pH was reached and the aqueous solution was extracted with ene de (X3). The combined organic extracts were dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (0.110 g, 23%) as a yellow solid that was used in the next synthetic step without further purification.
LRMS (m/z): 386 . 1H-NMR  (CDCl 3): 1.50-1.83 (4H, m), 2.08 (3H, s), 2.57-2.75 (2H, m), 2.87- 2.95 (2H, m), 3.17-3.30 (4H, m), 3.71 (1H, s), 3.75-3.84 (4H, m), 4.85 (1H, br d), 6.34 (1H, t), 6.91 (1H, dd), 8.64 (1H, dd) PREPARATION 28 (R)Chloro(5-methylmorpholino(piperidinylamino)pyrimidin ylamino)pyridin-2(1H)-one a) (R)-tert-Butyl 3-(4-(5-chloromethoxypyridinylamino)methyl morpholinopyrimidinylamino)piperidinecarboxylate ed as a yellow foam (83%) from (R)-tert-butyl 3-(4-chloromethyl morpholinopyrimidinylamino)piperidinecarboxylate (Preparation 25b) and 52-methoxypyridinamine (Preparation 6b) following the experimental procedure as described in ation 1b followed by purification of the crude product by flash chromatography (0-100% ethyl e in hexanes).
LRMS (m/z): 534/536 (M+1)+. 1H-NMR  (CDCl 3): 1.39 (9H, br s), 1.60-1.80 (4H, m), 2.05 (3H, s), 3.20 (4H, s), 3.20-3.35 (2H, m), 3.50-3.60 (2H, m), 3.80 (4H, m), 3.92 (1H, br s), 4.05 (3H, s), 6.85 (1H, s), 7.65 (1H, d), 8.88 (1H, br s). b) (R)Chloro(5-methylmorpholino(piperidinylamino)pyrimidin ylamino)pyridin-2(1H)-one Methanol was added to a mixture of (R)-tert-butyl 3-(4-(5-chloromethoxypyridin ylamino)methylmorpholinopyrimidinylamino)piperidinecarboxylate (Preparation 28a, 0.332 g, 0.62 mmol) and a 4N solution of hydrogen chloride in 1,4- dioxane (6 mL) at ambient temperature until a clear solution was formed. After 3 days, solvents were evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium encarbonate. The organic layer was separated and the aqueous phase was washed with ethyl acetate (X2). The combined organic extracts were dried (Na2SO4) and the solvent evaporated under reduced pressure to give the title compound (0.175 g, 63%) as a yellow solid that was used in the next synthetic step without r purification.
LRMS (m/z): 420/422 (M+1)+. 1H-NMR  (CDCl 3): 1.57 (2H, m), 1.80 (2H, m), 2.07 (3H, s), .80 (2H, m), 2.90-3.00 (2H, m), .33 (4H, m), 3.76-3.84 (4H, m), 3.90 (1H, m), 4.90 (1H, br d), 6.95 (1H, d), 7.68 (1H, s), 8.71 (1H, s).
Examples EXAMPLE 1 (S)(4-(1-(5-fluoropyridinyl)ethylamino)pyrimidinylamino)pyridin-2(1H)-one A suspension of (S)-N4-(1-(5-fluoropyridinyl)ethyl)-N2-(2-methoxypyridinyl) pyrimidine-2,4-diamine (Preparation 1b, 11 mg, 0.03 mmol) in 48% aqueous hydrogen bromide solution (2 mL) was stirred and heated to 100 ºC for 5 hours. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The pH of the aqueous phase was then adjusted to ca. 8 with 2M aqueous sodium hydroxide solution and extracted (x3) with dichloromethane. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and the t evaporated under reduced pressure to yield the title compound (4 mg, 38%) as a solid.
LRMS (m/z): 327 (M+1)+. 1H-NMR  (CDCl 3): 1.57 (d, 3H), 5.19 (br s, 1H), 5.79 (d, 1H), 5.91 (d, 1H), 6.32 (d, 1H), 6.93 (dd, 1H), 7.29-7.47 (m, 3H), 7.96 (d, 2H), 8.43 (d, 2H), 11.76 (br s, 1H).
EXAMPLE 2 (S)(4-(1-(5-fluoropyridinyl)ethylamino)methylpyrimidinylamino)pyridin- 2(1H)-one Trimethylsilyl chloride (0.20 mL, 1.58 mmol) and sodium iodide (235 mg, 1.57 mmol) were added to a d solution of (S)-N4-(1-(5-fluoropyridinyl)ethyl)-N2-(2- methoxypyridinyl)methylpyrimidine-2,4-diamine ration 2b, 185 mg, 0.52 mmol) in acetonitrile (5 mL) and the mixture was stirred and heated at 80 ºC for 45 min.
After g to ambient temperature, the mixture was concentrated and treated with saturated aqueous sodium thiosulphate solution. After stirring for 10 minutes, the precipitate was filtered, washed with water and diethyl ether and dried to give the title compound (179 mg, 100%) as a solid.
LRMS (m/z): 341 (M+1)+. 1H-NMR  (DMSO-d 6): 1.63 (d, 3H), 2.14 (s, 3H), 5.22 -5.47 (m, 1H), 6.17-6.31 (m, 1H), 7.06 (br s, 1H), 7.55 (dd, 1H), 7.71 (br s, 1H), 7.87 (s, 2H), 7.96 (d, 2H), 8.60 (br s, 1H), 11.98 (br s, 1H).
EXAMPLE 3 3-[(5-chloro{[(1S)(5-fluoropyridinyl)ethyl]amino}pyrimidinyl)amino] pyridin-2(1H)-one A e of (S)chloro-N4-(1-(5-fluoropyridinyl)ethyl)-N2-(2-methoxypyridinyl) dine-2,4-diamine (Preparation 3b, 0.184 g, 0.49 mmol) and 48% aqueous hydrogen bromide solution (1.6 mL) was heated to 100 ºC for 3 hours. The solvent was evaporated under reduced pressure and the residue was treated with a saturated s solution of potassium carbonate and then extracted with ethyl acetate (X3).
The combined organic extracts were dried (Na2SO4) and the solvent evaporated to yield the title compound (0.154 g, 91%) as a white solid.
LRMS (m/z): 361 (M+1)+. 1H-NMR  (CDCl 3): 1.60 (d, 3H), 5.33-5.37 (m, 1H), 6.28-6.33 (m, 1H), 6.43 (d, 1H), 6.92 (d, 1H), 7.31-7.45 (m, 2H), 7.98 (s, 1H), 8.02 (s, 1H), 8.35 (dd, 1H), 8.46 (d, 1H), 11.07 (br s, 1H).
EXAMPLE 4 3-[(4-{[(1S)(5-fluoropyridinyl)ethyl]amino}methoxypyrimidinyl)amino] pyridin-2(1H)-one Obtained as a white solid (33%) from (S)-N4-(1-(5-fluoropyridinyl)ethyl)methoxy- N2-(2-methoxypyridinyl)-pyrimidine-2,4-diamine (Preparation 4b) following the mental procedure as described in e 3.
LRMS (m/z): 357 (M+1)+. 1H-NMR  (CDCl 3): 1.58 (d, 3H), 3.85 (s, 3H), 5.42 -5.26 (m, 1H), 6.21 (d, 1H), 6.29 (dd, 1H), 6.90 (dd, 1H), 7.56 (s, 1H), 7.41-7.29 (m, 2H), 7.85 (br s, 1H), 8.38 (dd, 1H), 8.45 (d, 1H), 12.03 (s, 1H).
EXAMPLE 5 3-[(4-{[(1S)(5-fluoropyridinyl)ethyl]amino}hydroxypyrimidinyl)amino] pyridin-2(1H)-one A mixture of (S)-N4-(1-(5-fluoropyridinyl)ethyl)methoxy-N2-(2-methoxypyridin yl)pyrimidine-2,4-diamine (Preparation 4b, 0.200 g, 0.54 mmol) and 48% aqueous hydrogen bromide solution (1.8 mL) was stirred and heated to 100 ºC overnight. The solvent was evaporated under d pressure and the residue was treated with a saturated aqueous solution of potassium carbonate and then extracted with ethyl acetate (X3). Concentrated s hydrogen chloride solution was then added to the aqueous solution until an acidic pH was reached and the white solid that formed was filtered and dried to give the title compound (0.047 g, 25%).
LRMS (m/z): 343 (M+1)+. 1H-NMR  (CD 3OD): 1.68 (d, 3H), 5.37-5.44 (m, 1H), 6.34-6.49 (m, 1H), 7.15 (d, 1H), 7.35 (s, 1H), .67 (m, 2H), 8.05 (d, 1H), 8.48 (d, 1H).
EXAMPLE 6 (S)(1-(5-fluoropyridinyl)ethylamino)(2-oxo-1,2-dihydropyridinylamino) pyrimidinecarboxamide Obtained as a white solid (60%) from (S)(1-(5-fluoropyridinyl)ethylamino)(2- methoxypyridinylamino)pyrimidinecarboxamide (Preparation 5d) following the experimental procedure as described in Example 2.
LRMS (m/z): 370 .
EXAMPLE 7 (S)chloro(4-(1-(5-fluoropyridinyl)ethylamino)methylpyrimidin ylamino)pyridin-2(1H)-one Obtained as a brownish solid (98%) from (S)-N2-(5-chloromethoxypyridinyl)-N4-(1- (5-fluoropyridinyl)ethyl)methylpyrimidine-2,4-diamine ration 7) following the mental procedure as described in Example 2.
LRMS (m/z): 375 (M+1)+. 1H-NMR  (DMSO-d 6): 1.70 (d, 3H), 2.17 (s, 3H), 5.47 (t, 1H), 7.40 (d, 2H), 7.59 (dd, 2H), 7.78 (td, 1H), 7.98 (s, 1H), 8.08 (d, 1H), 8.57 (d, 1H), 8.67-8.81 (m, 1H), 9.48 (br s, 1H).
EXAMPLE 8 3-[(4-{[(1S)(5-fluoropyridinyl)ethyl]amino}methylpyrimidinyl)amino] (1H-pyrazolyl)pyridin-2(1H)-one Obtained as a white solid (7%) from (S)-N4-(1-(5-fluoropyridinyl)ethyl)-N2-(2- methoxy(1H-pyrazolyl)pyridinyl)methylpyrimidine-2,4-diamine (Preparation 9b) following the experimental procedure as described in Example 3 followed by cation of the crude product by e phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%).
LRMS (m/z): 407 (M+1)+. 1H-NMR  (CD 3OD): 1.63 (d, 3H), 2.10 (s, 3H), 4.63 (s, 1H), 5.47-5.67 (m, 1H), 7.18 (d, 1H), 7.40 (dd, 1H), 7.44-7.54 (m, 1H), 7.74 (s, 1H), 7.96 (s, 2H), 8.33 (s, 1H), 8.66 (d, 1H).
EXAMPLE 9 3-{[4-{[(1S)(5-Fluoropyridinyl)ethyl]amino}(4-hydroxypiperidinyl) dinyl]amino}pyridin-2(1H)-one Tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 4.82mL, 4.82 mmol) was added to a suspension of 3-[(4-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidinyl){[(1S)- 1-(5-fluoropyridinyl)ethyl]amino}pyrimidinyl)amino]pyridin-2(1H)-one (Preparation 10d, 520 mg, 0.96 mmol) in tetrahydrofuran (5 mL) and the mixture was stirred and heated to 70 ºC for 4 hours. After cooling to ambient temperature, the mixture was partitioned n water and ethyl acetate. The aqueous layer was washed with ethyl acetate (x3) and the combined c extract was washed with water, dried (Na2SO4) and the solvents were evaporated under reduced pressure. The residue was treated with diethyl ether and the solid that formed was filtered, washed with diethyl ether and purified by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (19 mg, 5%) as a yellow solid.
LRMS (m/z): 426 . 1H-NMR  (DMSO-d 6): 1.15 -1.36 (m, 2H), 1.46 (d, 3H), 1.66 (m, 2H), 3.63 (m, 1H), 4.07 (m, 2H), 4.99 (m, 1H), 5.45 (s, 1H), 6.17 (t, 1H), 6.63 (m, 1H), 6.86 (d, 1H), 7.42 (dd, 1H), 7.54-7.62 (m, 2H), 7.96 (dd, 1H), 8.44 (d, 1H).
EXAMPLE 10 3-[(5-fluoro{[(1S)(5-fluoropyridinyl)ethyl]amino}morpholin ylpyrimidinyl)amino]pyridin-2(1H)-one Trimethylsilyl chloride (0.147 mL, 1.16 mmol) and sodium iodide (174 mg, 1.16 mmol) were added to a stirred solution of (S)fluoro-N4-(1-(5-fluoropyridinyl)ethyl)-N2-(2- methoxypyridinyl)morpholinopyrimidine-2,4-diamine (Preparation 11c, 172 mg, 0.39 mmol) in acetonitrile (3 mL) and the mixture was stirred and heated at 80 ºC for 1 hour. After cooling to ambient temperature, the mixture was concentrated and treated with water. After stirring for 10 s, the precipitate was filtered, washed with water and dried to give 0.065 g of a brown solid. Concentrated aqueous sodium hydroxide solution was added to the aqueous phase until a basic pH was reached and the basic aqueous solution was then extracted with methylene chloride (X3). The combined organic extracts were dried (MgSO4) and the t was evaporated under reduced pressure to give an additional quantity of solid material (0.096 g). The combined solids were dissolved in ene de and washed with saturated aqueous potassium carbonate solution. The organic layer was separated, dried (MgSO4) and the sol vent was evaporated under reduced pressure to yield the title compound (0.134 g, 77%) as a brown solid.
LRMS (m/z): 430 (M+1)+. 1H-NMR  (CDCl 3): 1.57 (3H, d), 3.64 (4H, m), 3.78 (4H, m), 5.29 (1H, m), 5.63 (1H, br d), 6.89 (1H, dd), 7.32-7.37 (2H, m), 7.76 (1H, s), 8.18 (1H, dd), 8.44 (1H, d), 11.39 (1H, br s) EXAMPLE 11 3-[(6-{[(1S)(5-Fluoropyridinyl)ethyl]amino}pyrazinyl)amino]pyridin-2(1H)- A suspension of N-[(1S)(5-fluoropyridinyl)ethyl]-N'-(2-methoxypyridinyl) pyrazine-2,6-diamine ration 12b, 100 mg, 0.29 mmol) in 48% aqueous hydrogen bromide solution (1 mL) was d and heated at 100 ºC for 3 hours. After g to ambient temperature, the solvent was evaporated under reduced pressure. The residue was treated with acetonitrile and the solid that formed was filtered and dried to give the romide salt of the title compound (98 mg, 68%) as a yellow solid.
LRMS (m/z): 327 (M+1)+. 1H-NMR  (DMSO-d 6): 1.52 (d, 3H), 5.04 (m, 1H), 6.13 (m, 1H), 7.01 (d, 1H), 7.40 (s, 1H), 7.49 (m, 1H), 7.70 (m, 1H), 7.78 (s, 1H), 7.93 (d, 1H), 8.57 (d, 1H), 9.18 (s, 1H), 11.92 (br s, 1H) EXAMPLE 12 3-[(6-{[(1S)(5-fluoropyridinyl)ethyl]amino}pyridinyl)amino]pyridin-2(1H)- Obtained as a brown foam (96%) from (S)-N2-(1-(5-fluoropyridinyl)ethyl)-N6-(2- methoxypyridinyl)pyridine-2,6-diamine (Preparation 13b) following the experimental procedure as bed in Example 3.
LRMS (m/z): 326 (M+1)+. 1H-NMR  (CDCl 3): 1.58 (d, 3H), 4.93-5.04 (m, 1H), 5.08 (d, 1H), 5.85 (d, 1H), 6.09 (d, 1H), 6.23-6.30 (m, 1H), 6.85 (dd, 1H), 7.27-7.42 (m, 2H), 7.53 (s, 1H), 8.30 (dd, 1H), 8.44 (d, 1H), 11.17 (br s, 1H).
EXAMPLE 13 2-((1r, (5-Methyl(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino) cyclohexyl)acetonitrile Trimethylsilyl chloride (97 L, 0.77 mmol) and sodium iodide (115 mg, 0.77 mmol) were added to a on of 2-((1r, 4r)(2-(2-methoxypyridinylamino)methylpyrimidin- 4-ylamino)cyclohexyl)acetonitrile (Preparation 15b, 90 mg, 0.26 mmol) in acetonitrile (15 mL) and the mixture was stirred and heated at 80 ºC for 1 hour. After cooling to ambient temperature, water was added and the resulting suspension was stirred at ambient temperature for 20 min. The solid that formed was filtered, washed with acetonitrile and dried to give the title nd (45 mg, 52%) as a white solid.
LRMS (m/z): 339 (M+1)+. 1H-NMR  (DMSO-d 6): 1.21 (dd, 4H), 1.50 (dd, 4H), 1.67 (m, 1H), 1.80 -2.20 (m, 5H), 3.93 (m, 1H), 6.30 (m, 1H), 7.82 (s, 1H), 8.21 (m, 1H), 9.45 (s, 1H), 12.15 (bd, 1H).
EXAMPLE 14 3-({4-[(trans{[(3-hydroxypiperidinyl)sulfonyl]methyl}cyclohexyl)amino] pyrimidinyl}amino)pyridin-2(1H)-one Obtained as a solid (47%) from 1-(((1r,4r)(2-(2-methoxypyridinylamino)pyrimidin- 4-ylamino)cyclohexyl)methylsulfonyl)piperidinol (Preparation 18b) ing the experimental procedure as described in Example 2 followed by purification of the crude product by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%). 1H-NMR  (DMSO-d 6): 1.21-1.50 (m, 6H), 1.70-2.10 (m, 8H), 2.45-3.50 (m, 6H), 3.73 (m, 1H), 5.01 (d, 1H), 5.97 (d, 1H), 6.23 (m, 1H), 6.94 (d, 1H), 7.29 (s, 1H), 7.69 (s, 1H), 7.79 (m, 1H), 8.36 (d, 1H).
EXAMPLE 15 (R)Oxo(3-(2-(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino) piperidinyl)propanenitrile Triethylamine (33 µL, 0.24 mmol) and 3-[(2,5-dioxopyrrolidinyl)oxy]oxopropane nitrile (prepared as bed in BE875054(A1), 51 mg, 0.28 mmol) were added to a solution of (R)(4-(piperidinylamino)pyrimidinylamino)pyridin-2(1H)-one (Preparation 19c, 67 mg, 0.23 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at ambient temperature for 24 hours and solvent was evaporated. Water was added and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4), evaporated under reduced pressure and the residue was purified by reverse phase tography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (11 mg, 12%) as a solid.
LRMS (m/z): 354 (M+1)+. 1H-NMR  d 6): 1.55 (d, 1H), 1.74 (m, 1H), 1.95 (m, 1H), 2.13 -2.34 (m, 1H), 3.08 (m, 2H), 3.48-3.80 (m, 1H), 3.86 (m, 1H), 4.05 (d, 1H), 4.27 (m, 1H), 6.03 (d, 1H), 6.07-6.17 (m, 1H), 6.17-6.30 (m, 1H), 6.93 (br s, 1H), 7.22-7.47 (m, 1H), 7.73 (s, 1H), 7.83-7.95 (m, 1H), 8.32 (br s, 1H), 11.84 (br s, 1H).
EXAMPLE 16 (R)(3-(5-Methyl(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino) dinyl)oxopropanenitrile Obtained as a solid (15%) from (R)(5-methyl(piperidinylamino)pyrimidin ylamino)pyridin-2(1H)-one (Preparation 20c) following the experimental procedure as described in Example 5.
LRMS (m/z): 368 . 1H-NMR  (CDCl 3): 1.14-1.40 (m, 1H), 1.57-1.78 (m, 2H), 1.99 (br s, 3H), 2.59 (m, 2H), 3.10-3.33 (m, 1H), 3.42-3.69 (m, 2H), .35 (m, 2H), 4.55-5.01 (m, 1H), 6.11-6.41 (m, 1H), .01 (m, 1H), 7.70-7.92 (m, 1H), 8.08 (m, 2H), 8.30-8.53 (m, 1H), 11.18 (br s, 1H).
EXAMPLE 17 (R)(3-(5-Fluoro(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino) piperidinyl)oxopropanenitrile Obtained as a solid (45%) from (R)(5-fluoro(piperidinylamino)pyrimidin ylamino)pyridin-2(1H)-one (Preparation 22c) following the experimental procedure as described in Example 15.
LRMS (m/z): 372 . 1H-NMR  (CDCl 3): 1.59 -1.98 (m, 2H), 3.17-3.33 (m, 1H), 3.33-3.42 (m, 1H), 3.46-3.63 (m, 2H), 3.90 (d, 1H), 4.04 (d, 1H), 4.13-4.22 (m, 1H), 4.27 (d, 1H), 4.91 (m, 1H), 6.31-6.47 (m, 1H), 6.98 (dd, 1H), 7.86 (d, 1H), 7.91 (d, 1H), 8.00 (s, 1H), 8.11 (s, 1H), 8.50 (d, 1H).
EXAMPLE 18 (R)(4-(1-(4H-1,2,4-Triazolyl)piperidinylamino)fluoropyrimidinylamino) pyridin-2(1H)-one A mixture of (R)(5-fluoro(piperidinylamino)pyrimidinylamino)pyridin-2(1H)- one (Preparation 22c, 50 mg, 0.16 mmol) and o-4H-1,2,4-triazole (prepared as described in J. Med. Chem. 2004, 47(19), 4645, 12.2 mg, 0.08 mmol) was stirred and heated overnight at 150 ºC. The reaction mixture was cooled to ambient ature and diluted with methanol. Diethyl ether was then added and the itate that formed was filtered. The filtrate was concentrated under reduced pressure and the resulting semisolid was suspended in diethyl ether and filtered to yield the title compound (12 mg, 40%) as a yellow solid.
LRMS (m/z): 372 (M+1)+. 1H-NMR  (DMSO-d 6): 1.61 (m, 2H), 1.73-1.86 (m, 1H), 1.88-2.06 (m, 2H), 2.83 (m, 4H), 3.09 (m, 1H), 3.23 (m, 1H), 3.80 (m, 2H), 4.07 (br s, 3H), 4.30 (br s, 1H), 6.07 (t, 2H), 6.27 (t, 1H), 6.85-7.05 (m, 2H), 7.36-7.68 (m, 3H), 7.73-7.89 (m, 2H), 8.03 (d, 1H), 8.10-8.35 (m, 3H), 8.78 (br s, 1H), 11.87 (br s, 2H), 12.57 (br s, 1H),13.05 (br s, 1H).
EXAMPLE 19 (R)(3-(2-(5-Chlorooxo-1,2-dihydropyridinylamino)methylpyrimidin ylamino)piperidinyl)oxopropanenitrile Obtained as a solid (8%) from (R)chloro(5-methyl(piperidin ylamino)pyrimidinylamino)pyridin-2(1H)-one (Preparation 23b) following the experimental procedure as described in Example 15.
LRMS (m/z): 402 (M+1)+. 1H-NMR  (DMSO-d 6): 1.67 (t, 2H), 1.78 -1.90 (m, 1H), 2.02 (s, 3H), .78 (m, 1H), 3.04 (dd, 1H), 3.68-3.85 (m, 1H), 3.95-4.20 (m, 2H), 4.32 (d, 1H), 4.50 (d, 1H), 6.71 (dd, 1H), 7.19 (d, 1H), 7.77 (s, 1H), 7.87 (d, 1H), 8.23 (s, 1H), 8.38 (d, 1H), 12.21 (br s, 1H).
EXAMPLE 20 3-[(3R)({5-fluoromorpholinyl[(2-oxo-1,2-dihydropyridinyl)amino] pyrimidinyl}amino)piperidinyl]oxopropanenitrile Obtained as a brown solid (34%) from (R)(5-fluoromorpholino(piperidin o)pyrimidinylamino)pyridin-2(1H)-one (Preparation 24c) following the experimental ure as described in Example 15 ed by purification of the crude product by flash chromatography (0-100% ethyl acetate in hexanes then 0-20% methanol in ethyl acetate).
LRMS (m/z): 457 (M+1)+. 1H-NMR  (CD 3OD): 1.25-1.29 (m, 1H), 1.64-1.71 (m, 2H), 1,87 (m, 1H), 2.09- 2.16 (m, 2H), 2.75-2.82 (m, 1H); 2.91-2.99 (m, 1H), 3.05-3.20 (m, 1H), 3.59- 3.61 (m, 4H), 3.77 (m, 4H), 3.84-3.92 (m, 1H), 4.21 (d, 1H), 4.62 (s, 2H), 6.37- 6.46 (m, 1H), 6.92-6.98 (m, 1H), 8.37-8.43 (m, 1H).
EXAMPLE 21 3-[(3R)({5-methylmorpholinyl[(2-oxo-1,2-dihydropyridinyl)amino] pyrimidinyl}amino)piperidinyl]oxopropanenitrile e salt Obtained as a yellow solid (17%) from (R)(5-methylmorpholino(piperidinyl amino)pyrimidinylamino)-pyridin-2(1H)-one (Preparation 26b) following the experimental procedure as described in Example 15 followed by purification of the crude product by reverse phase chromatography (C-18 silica from Waters, acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%).
LRMS (m/z): 453 (M+1)+. 1H-NMR  (CDCl 3): 1.60 -1.68 (m, 1H), 1.74-1.81 (m, 1H), 1.86 (s, 3H), 1.97- 2.06 (m, 1H), 3.13 (m, 1H) 3.18 (t, 4H), 3.42 (s, 1H), 3.48 (s, 1H), 3.78 (t, 4H), 3.97 (m, 1H), 4.03 (m, 1H), 4.18 (d, 1H), 6.25-6.31 (m, 1H), 6.92 (dd, 1H), 7.78 (s, 1H), 8.39 (dd, 1H).
EXAMPLE 22 3-[(3R)({5-methylmorpholinyl[(2-oxo-1,2-dihydropyridinyl)amino] pyrimidinyl}amino)piperidinyl]oxopropanenitrile Obtained as a green solid (70%) from (R)(5-methylmorpholino(piperidinyl amino)pyrimidinylamino)pyridin-2(1H)-one (Preparation 27b) ing the experimental procedure as described in Example 15 followed by purification of the crude product by flash chromatography (0-20% methanol in dichloromethane).
LRMS (m/z): 453 (M+1)+. 1H-NMR  (CDCl 3): 1.55-1.85 (4H, m), 2.11 (3H, s), 3.15-3.25 (4H, m), 3.35 (2H, d), 3.55 (2H, m), 3.80-3.95 (6H, m), 4.67 (1H, br d), 6.38 (1H, dt), 6.95 (1H, m), 7.73 (1H, s), 8.53 (1H, br dd), 10.88 (1H, br s).
E 23 3-[(3R)({4-[(5-chlorooxo-1,2-dihydropyridinyl)amino]methyl morpholinylpyrimidinyl}amino)piperidinyl]oxopropanenitrile Obtained as a white solid (54%) from (R)chloro(5-methylmorpholino idinylamino)pyrimidinylamino)pyridin-2(1H)-one (Preparation 28b) ing the experimental procedure as bed in Example 15.
LRMS (m/z): 487/489 (M+1)+. 1H-NMR  (DMSO-d 6): 1.53 (2H, m), 1.77 (2H, m), 1.97 (3H, s), 2.42-2.54 (4H, m), 3.05-3.17 (4H, m), 3.60-3.77 (6H, m), 4.04 (1H, m), 6.75 (1H, br dd), 7.15 (1H, br dd), 7.75 (1H, s), 8.53 (1H, br s), 12.25 (1H, br s) Following a similar procedure to that described above, the following compounds were obtained: EXAMPLE 24 3-[(3R)({5-chloro[(2-oxo-1,2-dihydropyridinyl)amino]pyrimidinyl}amino) piperidinyl]oxopropanenitrile EXAMPLE 25 3-[(4-{[(1S)(5-Fluoropyridinyl)ethyl]amino}pyrimidinyl)methyl]pyridin- 2(1H)-one E 26 3-(5-{6-{[(1S)(5-Fluoropyridinyl)ethyl]amino}[(2-oxo-1,2-dihydropyridin yl)amino]pyrimidinyl}-1,3-thiazolyl)benzoic acid PHARMACOLOGICAL ACTIVITY In vitro JAK kinase Assays Compounds were screened for their ability to inhibit JAK1, JAK2 and JAK3 using the assays as indicated below.
The catalytic domains of human JAK1 (aa 850-1154), JAK2 (aa 826-1132), JAK3 (aa 795-1124) and Tyk2 (aa 87) were expressed as N-terminal GST-fusion ns using a baculovirus expression system and were purchased from Carna Biosciences.
The enzymatic activity was assayed using as substrate a biotinylated peptide, poly (GT)-Biotin (CisBio). The peptide concentration in the reactions was 60 nM for JAK1, nM for JAK2, 140 nM for JAK3 and 50 nM for Tyk2. The degree of orylation was detected by TR-FRET (time-resolved fluorescence energy transfer).
IC50s of compounds were measured for each kinase in a reaction e containing the enzyme, ATP and the peptide in 8 mM MOPS (pH 7.0), 10 mM MgCl2, 0.05% ptoethanol , 0.45 mg/ml BSA. The ATP concentration in the reactions was 3 µM for JAK1, 0.2 µM for JAK2, 0.6 µM for JAK3 and 1.8 µM for Tyk2. The enzymatic reactions took place for 30 minutes at room temperature. Then, the reactions were stopped with 20 µL of quench detection buffer (50 mM HEPES, 0.5 M KF, EDTA 0.25 M, 0.1% (w/v) BSA, pH 7.5) containing 0.115 µg/mL of anti-phosphoTyr (PT66)- Cryptate (CisBio) and a le tration of SA-XL665 (CisBio) to keep the SA-B ratio constant. Incubate for 3 h and read on Victor 2V spectrofluorometer (PerkinElmer) set to read fluorescence resonance energy transfer.
Some of the acronyms used above have the following meaning: AA: aminoacids GST: glutathione-S-transferase MOPS: 3-(N-morpholino)propane sulfonic acid BSA: bovine serum albumin ATP: adenosine tri-phosphate EDTA: ethylenediaminetetraacetic acid HEPES: 4-(2-hydroxyethyl)piperazineethanesulfonic acid SA-XL665: Streptavidin (biotin-binding tetrameric protein ed from Streptomyces avidinii) XL665 Table 1 depicts IC50 values for n exemplary compounds described in the invention. In Table 1, “A” represents an IC50 value of less than 0.1 µM (100 nM), “B” represents an IC50 value in the range of 0.1 µM (100 nM) to 1 µM (1000 nM), and C represents an IC50 value higher than 1 µM (1000 nM).
Table 1 Example No. IC50 JAK3 IC50 JAK2 IC50 JAK1 (µM) (µM) (µM) 4 A A A A A A 6 A A B 7 A A A 11 A A A 12 A A B 13 A A A 14 B A C 17 A A A 18 A A B A A A 22 A A A It can be seen from Table 1 that the compounds of formula (I) are potent inhibitors of JAK1, JAK2 and JAK3 kinases. Preferred pyridin-2(1H)-one derivatives of the ion possess an IC50 value for the inhibition of JAK1, JAK2 and JAK3 kinases (determined as defined above) of less than 1 µM (1000 nM), preferably of less than 0.5 µM (500 nM), more ably of less than 0.2 µM (200 nM) for each Janus Kinase.
The invention is also directed to a compound of the invention as bed herein for use in the treatment of the human or animal body by therapy. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze , spray drying, or ative drying. ave or radio ncy drying may be used for this purpose.
Combinations The pyridin-2(1H)-one derivatives defined herein may also be combined with other active compounds in the treatment of a pathological condition or disease susceptible to ration by inhibition of Janus Kinases.
The combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of myeloproliferative disorders (such as polycythemia vera, essential thrombocythemia or mielofibrosis), leukemia, lymphoid malignancies and solid tumors; bone marrow and organ lant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein the ogical condition or disease is selected from rheumatoid arthritis, multiple sclerosis, matory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis, such as (a) ofolate reductase inhibitors, such as Methotrexate or CH-1504; (b) Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide, or the compounds described in the International Patent Application Nos. WO2008/077639 and WO2009/021696; (c) Immunomodulators such as amer acetate (Copaxone), imod or Imiquimod; (d) Inhibitors of DNA synthesis and repair, such as Mitoxantrone or Cladribine; (e) Immunosuppressants, such as Imuran (azathioprine) or Purinethol (6-mercaptopurine or 6-MP); (f) Anti-alpha 4 integrin antibodies, such as Natalizumab (Tysabri); (g) Alpha 4 integrin antagonists such as R-1295 , TBC-4746, CDP-323, ELND-002, Firategrast or TMC-2003; (h) Corticoids and glucocorticoids such as prednisone or methylprednisolone, fluticasone, mometasone, budesonide, ciclesonide or beta-metasone; (i) c acid esters, such as BG-12; (j) Anti-tumor is -alpha (Anti-TNF-alpha), such as Infliximab, Adalimumab, or Certolizumab pegol; (k) Soluble Tumor necrosis factor-alpha (TNF- alpha) receptors such as Etanercept; (l) Anti-CD20 (lymphocyte protein) monoclonal antibodies such as mab, Ocrelizumab Ofatumumab or TRU-015; (m) Anti-CD52 (lymphocyte n) onal antibodies such as alemtuzumab; (n) Anti-CD25 (lymphocyte n) such as daclizumab; (o) Anti-CD88 (lymphocyte n), such as eculizumab or pexilizumab; (p) Anti-Interleukin 6 or (IL-6R), such as tocilizumab; (q) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL-23R), such as ustekinumab; (r) Calcineurin inhibitors such as cyclosporine A or tacrolimus; (s) e-monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, ribavirin, mizoribine or mycophenolic acid; (t) Cannabinoid receptor agonists such as Sativex; (u) Chemokine CCR1 antagonists such as MLN-3897 or PS-031291; (v) Chemokine CCR2 antagonists such as INCB-8696; (w) Necrosis factor-kappaB (NF-kappaB or NFKB) Activation tors such as Sulfasalazine, Iguratimod or MLN- 0415; (x) Adenosine A2A ts, such as ATL-313, ATL-146e, CGS-21680, Regadenoson or UK-432,097; (y) Sphingosine-1 (S1P) phosphate receptor agonists such as fingolimod, BAF-312, or ACT128800; (z) Sphingosine-1 (S1P) liase inhibitors such as LX2931; (aa) Spleen tyrosine kinase (Syk) inhibitors, such as R-112; (bb) n Kinase Inhibitors (PKC) inhibitors, such as NVP-AEB071; (cc) Anti-cholinergic agents such as tiotropium or aclidinium; (dd) Beta adrenergic agonists such as formoterol, indacaterol or abediterol (LAS100977); (ee) Compounds having tional Muscarinic Antagonist-Beta2 Agonist activity (MABAs); (ff) Histamine 1 (H1) or antagonists, such as azelastine or ebastine; (gg) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors, such as OC-459, AZD-1981, ACT-129968, QAV-680; (hh) n D derivatives like calcipotriol (Daivonex); (ii) Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclooxygenase-2 (COX-2) inhibitors such as aceclofenac, diclofenac, ibuprofen, naproxen, apricoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, lumiracoxib, parecoxib sodium, rofecoxib, coxib-1 or valdecoxib; (jj) Anti-allergic agents; (kk) Anti-viral agents; (ll) Phosphodiestearase (PDE) III inhibitors; (mm) Phosphosdiesterase (PDE) IV inhibitors such as roflumilast or GRC-4039; (nn) Dual Phosphodiestearase (PDE) III/IV inhibitors; (oo) Xanthine derivatives, such as theophylline or theobromine; (pp) p38 n-Activated Protein Kinase (p38 MAPK) Inhibitors such as ARRY-797; (qq) Mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, such as ARRY-142886 or ARRY-438162; (rr) Phosphoinositide 3-Kinases (PI3Ks) inhibitors; (ss) Interferons comprising Interferon beta 1a such as Avonex from Biogen Idec, ex from CinnaGen and Rebif from EMD Serono, and Interferon beta 1b such as ron from Schering and Betaseron from Berlex; and (tt) Interferon alpha such as Sumiferon MP.
Specific examples of le corticoids and glucocorticoids that can be combined with the JAK inhibitors of the present invention are prednisolone, methylprednisolone, dexamethasone, dexamethasone cipecilate, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone ionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, prednisolone aceponate, dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, butixocort propionate, RPR-106541, deprodone propionate, fluticasone propionate, asone furoate, halobetasol propionate, loteprednol ate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, solone sodium phosphate and hydrocortisone probutate.
Specific examples of le Syk kinase inhibitors that can be combined with the JAK inhibitors of the t ion are fosfamatinib (from Rigel), R-348 (from Rigel), R- 343 (from Rigel), R-112 (from Rigel), piceatannol, 2-(2-Aminoethylamino)[3- (trifluoromethyl)phenylamino] pyrimidinecarboxamide, R-091 (from Rigel), 6-[5- Fluoro(3,4,5-trimethoxyphenylamino)pyrimidinylamino]-2,2-dimethyl-3,4-dihydro- 2H-pyrido[3,2-b][1,4]oxazinone benzenesulfonate (R-406 from Rigel), 1-(2,4,6- roxyphenyl)(4-methoxyphenyl)ethanone, N-[4-[6-(Cyclobutylamino)-9H- purinylamino]phenyl]-N-methylacetamide (QAB-205 from Novartis), 2-[7-(3,4- Dimethoxyphenyl)imidazo[1,2-c]pyrimidinylamino]pyridinecarboxamide dihydrochloride (BAY3606 from Bayer) and AVE-0950 (from -Aventis).
Specific examples of suitable M3 antagonists (anticholinergics) that can be combined with the JAK inhibitors of the present invention are pium salts, oxitropium salts, flutropium salts, opium salts, glycopyrronium salts, trospium salts, zamifenacin, revatropate, espatropate, darotropium bromide, CI-923, 695, BEA-2108, 3-[2- Hydroxy-2,2-bis(2-thienyl)acetoxy](3-phenoxypropyl)azoniabicyclo[2.2.2]octane salts (in particular aclidinium salts, more preferably aclidinium bromide), 1-(2- Phenylethyl)(9H-xanthenylcarbonyloxy)azoniabicyclo[2.2.2]octane salts, 2-oxo- 1,2,3,4-tetrahydroquinazolinecarboxylic acid endomethylazabicyclo[3.2.1]oct yl ester salts (DAU-5884), 3-(4-Benzylpiperazinyl)cyclobutylhydroxy phenylpropanone 4695), N-[1-(6-Aminopyridinylmethyl)piperidinyl]- 3,3-difluoro-1(R)-cyclopentyl]hydroxyphenylacetamide (J-104135), 2(R)- Cyclopentylhydroxy-N-[1-[4(S)-methylhexyl]piperidinyl]phenylacetamide (J- 106366), 2(R)-Cyclopentylhydroxy-N-[1-(4-methylpentenyl)piperidyl] phenylacetamide (J-104129), 2-Aminoethyl)piperidinyl]-2(R)-[3,3- difluorocyclopent-1(R)-yl]hydroxyphenylethanone (Banyu-280634), N-[N-[2-[N- [1-(Cyclohexylmethyl)piperidin-3(R)-ylmethyl]carbamoyl]ethyl]carbamoylmethyl]-3,3,3- triphenylpropionamide (Banyu CPTP), 2(R)-Cyclopentylhydroxyphenylacetic acid 4-(3-azabicyclo[3.1.0]hexyl)butynyl ester (Ranbaxy ), 3(R)-[4,4-Bis(4- fluorophenyl)oxoimidazolidinyl]methyl[2-oxo(3-thienyl)ethyl]pyrrolidinium iodide, N-[1-(3-Hydroxybenzyl)methylpiperidinium-3(S)-yl]-N-[N-[4- (isopropoxycarbonyl)phenyl]carbamoyl]-L-tyrosinamide trifluoroacetate, UCB-101333, s OrM3, 7-endo-(2-hydroxy-2,2-diphenylacetoxy)-9,9-dimethyloxa azoniatricyclo[3.3.1.0(2,4)]nonane salts, 3(R)-[4,4-Bis(4-fluorophenyl) oxoimidazolidinyl]methyl(2-phenylethyl)pyrrolidinium iodide, trans[2- [Hydroxy-2,2-(dithienyl)acetoxy]methyl(2-phenoxyethyl)piperidinium bromide from Novartis (412682), 7-(2,2-diphenylpropionyloxy)-7,9,9-trimethyloxa azoniatricyclo[3.3.1.0*2,4*]nonane salts, 7-hydroxy-7,9,9-trimethyloxa azoniatricyclo[3.3.1.0*2,4*]nonane 9-methyl-9H-fluorenecarboxylic acid ester salts, all of them optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally in the form of their pharmacologically-compatible acid addition salts. Among the salts chlorides, bromides, s and methanesulphonates are preferred.
Specific examples of suitable beta rgic agonists (2-agonists) that can be ed with the JAK tors of the present invention are are terbutaline sulphate, eformoterol te, formoterol fumarate, bambuterol, ibuterol, isoprenaline hydrochloride, dopexamine, metaprotenerol, tulobuterol, procaterol hydrochloride, sibenadet hydrochloride, mabuterol hydrochloride, albuterol sulphate, salbutamol sulphate, amol, salmeterol xinafoate, carmoterol hydrochloride, (R)-albuterol hydrochloride, Levalbuterol hydrochloride; Levosalbutamol hydrochloride; (-)- Salbutamol hydrochloride, formoterol, (R,R)-Formoterol tartrate; Arformoterol tartrate, sulfonterol, Bedoradrine sulphate, Indacaterol, Trantinterol hydrochloride, Milveterol hydrochloride, Olodaterol, fenoterol hydrobromide, rimoterol romide, erol hydrochloride, Vilanterol broxaterol, pirbuterol hydrochloride, bitolterol mesylate, clenbuterol hydrochloride, AZD-3199, GSK-159802; GSK-597901, GSK-678007, GSK- 961081; 4-[2-[3-(1H-Benzimidazolyl)-1,1-dimethylpropylamino]hydroxyethyl](4- methoxybenzylamino)phenol, 1-[2Hhydroxyoxo-4H-1,4-benzoxazinyl][3-(4- N,N-dimethylaminophenyl)methylpropylamino]ethanol, 1-[2Hhydroxyoxo- 4H-1,4-benzoxazinyl][3-(4-domethoxyphenyl)methylpropylamino]ethanol, 1- [2Hhydroxyoxo-4H-1,4-benzoxazinyl][3-(4-n-butyloxyhenyl)methyl propylamino]ethanol, KUL-1248, HOKU-81, SM-110444, 02B, abediterol (LAS 100977) and compounds described in PCT patent applications Nos. , A1, , WO 2008095720, and WO 2010/072354.
Specific examples of suitable Phosphosdiesterase IV (PDE IV) inhibitors that can be ed with the JAK tors of the present invention are benafentrine dimaleate, ate, denbufylline, rolipram, cipamfylline, zardaverine, arofylline, filaminast, tipelukast, tofimilast, piclamilast, tolafentrine, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilomilast, oglemilast, apremilast, tetomilast, nast, (R)-(+) [2-(3-Cyclopentyloxymethoxyphenyl)phenylethyl]pyridine 40), N-(3,5- Dichloropyridinyl)[1-(4-fluorobenzyl)hydroxy-1H-indolyl]oxoacetamide (GSK-842470), 9-(2-Fluorobenzyl)-N6-methyl(trifluoromethyl)adenine (NCS-613), N- (3,5-Dichloropyridinyl)methoxyquinolinecarboxamide 8), 3-[3- (Cyclopentyloxy)methoxybenzyl](ethylamino)isopropyl-3H-purine hydrochloride 94A), 6-[3-(N,N-Dimethylcarbamoyl)phenylsulfonyl](3-methoxyphenylamino)- 8-methylquinolinecarboxamide hloride (GSK-256066), 4-[6,7-Diethoxy-2,3- bis(hydroxymethyl)naphthalenyl](2-methoxyethyl)pyridin-2(1H)-one (T-440), (-)- trans[3'-[3-(N-Cyclopropylcarbamoyl)oxo-1,4-dihydro-1,8-naphthyridinyl] fluorobiphenylyl]cyclopropanecarboxylic acid, MK-0873, CDC-801, UK-500001, BLX-914, 2-carbomethoxycyano(3-cyclopropylmethoxy difluroromethoxyphenyl)cyclohexan1-one, cis [4-cyano(3-cyclopropylmethoxy romethoxyphenyl)cyclohexanol, 5(S)-[3-(Cyclopentyloxy)methoxyphenyl]- 3(S)-(3-methylbenzyl)piperidinone (IPL-455903), ONO-6126 (Eur Respir J 2003, 22(Suppl. 45): Abst 2557) and the compounds claimed in the PCT patent applications number WO 03/097613, , , , WO 2005/123692, and .
Examples of suitable Phosphoinositide 3-Kinases (PI3Ks) inhibitors that can be combined with the JAK inhibitors of the present invention are 2-Methyl[4-[3-methyl- 2-oxo(3-quinolinyl)-2,3-dihydro-1H-imidazo[4,5-c]quinolinyl]phenyl]propanenitrile (BEZ-235 from Novartis), CAL-101 (from Calistoga Pharmaceuticals) and N-Ethyl-N'-[3- (3,4,5-trimethoxyphenylamino)pyrido[2,3-b]pyrazinyl]thiourea (AEZS-126 from Aeterna Zentaris).
The compounds of formula (I) and the combinations of the invention may be used in the treatment of myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; -mediated diseases and matory diseases, wherein the use of a JAK inhibitor is expected to have a beneficial effect, for example rheumatoid arthritis, le sclerosis, matory bowel disease (such as ulcerative colitis or Crohn’s disease), dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
The active nds in the combination product may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential stration by the same or a different route.
It is contemplated that all active agents would be administered at the same time, or very close in time. Alternatively, one or two actives could be administered in the morning and the other (s) later in the day. Or in another scenario, one or two actives could be administered twice daily and the other (s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately. Preferably at least two, and more preferably all, of the actives would be administered together at the same time.
Preferably, at least two, and more preferably all actives would be administered as an admixture.
The invention is also directed to a combination product of the compounds of the invention together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the ogical condition or disease is selected from roliferative disorders, leukemia, id malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated es and inflammatory es, more in particular wherein the pathological condition or disease is ed from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic is, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
The invention also encompasses the use of a combination of the compounds of the invention together with one or more other therapeutic agents for the manufacture of a formulation or medicament for treating these diseases.
Also described is a method of ent of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological ion or e is selected from myeloproliferative ers, leukemia, id ancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein the pathological condition or disease is selected from toid tis, multiple sclerosis, matory bowel disease, dry eye, uveitis, allergic ctivitis, allergic rhinitis, , chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis; comprising administering a therapeutically effective amount of a ation of the compounds of the invention together with one or more other therapeutic agents.
The active compounds in the combinations of the invention may be administered by any suitable route, depending on the nature of the disorder to be treated, e.g. orally (as syrups, s, capsules, lozenges, lled-release preparations, fast-dissolving preparations, etc); topically (as creams, ointments, lotions, nasal sprays or aerosols, etc); by injection (subcutaneous, ermic, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, a solution, a dispersion, etc).
The active compounds in the combination, i.e. the pyridin-2(1H)-one derivatives of the invention, and the other optional active compounds may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or tial administration by the same or a different route.
Also described is a kit of parts comprising a pyridin-2(1H)-one derivative of the invention together with instructions for simultaneous, concurrent, separate or sequential use in combination with another active compound useful in the treatment of myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular useful in the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
Also described is a package comprising a pyridin-2(1H)-one derivative of the invention and another active compound useful in the treatment of myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular useful in the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis. ceutical Compositions Pharmaceutical compositions ing to the present invention comprise the compounds of the invention in association with a pharmaceutically acceptable diluent or r.
As used herein, the term pharmaceutical composition refers to a e of one or more of the compounds described herein, or logically/pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers, deuterated derivatives thereof or gs f, with other chemical components, such as logically/pharmaceutically acceptable rs and excipients. The purpose of a ceutical composition is to tate administration of a compound to an organism.
As used herein, a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
The invention further provides pharmaceutical compositions comprising the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other eutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), such as the ones previously described.
The invention is also directed to pharmaceutical compositions of the invention for use in the ent of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular n the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid ; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in ular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sis, inflammatory bowel disease, dry eye, s, allergic conjunctivitis, allergic rhinitis, asthma, c obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis. The invention also encompasses the use of a pharmaceutical composition of the invention for the manufacture of a medicament for treating these diseases.
Also described is a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the ogical condition or disease is ed from myeloproliferative disorders, leukemia, id malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory es, more in ular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis, comprising administering a therapeutically effective amount of a pharmaceutical ition of the invention.
The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a nd of formula (I) or a pharmaceutically able salt thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ient may comprise 0.001% to 99% by weight, preferably 0.01% to 90% by weight, of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application.
Preferably the compositions are made up in a form suitable for oral, inhalation, topical, nasal, rectal, percutaneous or injectable administration.
Pharmaceutical itions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art.
Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of cy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.
The pharmaceutically acceptable excipients which are admixed with the active compound or salts of such compound, to form the compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions. Examples, without limitation, of ents include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
Additional suitable carriers for formulations of the compounds of the present invention can be found in Remington: The Science and Practice of cy, 21st Edition, cott Williams & Wilkins, Philadelphia, Pa., 2001. i) Oral Administration The compounds of the invention may be administered orally (peroral administration; per os (latin)). Oral administration e swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal ation (hepatic first pass metabolism) and finally enters the intestinal (GI) tract.
Compositions for oral administration may take the form of tablets, retard s, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, solutions, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art. The active ingredient may also be presented as a bolus, ary or paste.
Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, talc, gelatine, acacia, stearic acid, starch, lactose and e.
A tablet may be made by compression or ng, ally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert t, lubricating, surface active or dispersing agent.
Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to e slow or controlled e of the active ingredient therein.
For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl ose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, atinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized , hydroxypropyl cellulose and hydroxypropyl cellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate ate. Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as n dioxide and talc. When present, surface active agents are lly in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl te. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other tional ingredients include anti-oxidants, nts, flavoring agents, preservatives and taste- masking agents.
Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% , from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% egrant, and from about 0.25 wt% to about 10 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may include one or more layers and may be coated or ed; or encapsulated.
The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1 ", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., 1980.
Where the composition is in the form of a capsule, any routine encapsulation is le, for example using the aforementioned rs in a hard gelatine capsule.
Where the composition is in the form of a soft gelatine capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example s gums, celluloses, silicates or oils, and are incorporated in a soft gelatine capsule.
Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified e formulations include d-, sustained-, pulsed-, controlled-, targeted and programmed release.
Suitable modified release formulations are described in U.S. Patent No. 6,106,864.
Details of other le release logies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, ceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their ties.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard es and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an ble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. ii) Oral mucosal administration The nds of the invention can also be administered via the oral mucosal. Within the oral mucosal cavity, delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosal nes lining the floor of the mouth, (b) buccal ry, which is drug stration through the mucosal membranes lining the cheeks (buccal mucosa), and (c) local delivery, which is drug delivery into the oral cavity.
Pharmaceutical ts to be administered via the oral mucosal can be designed using mucoadhesive, quick dissolve tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive (bioadhesive) polymers (such as hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl ose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol, polyisobutylene or polyisoprene); and oral mucosal permeation enhancers (such as butanol, c acid, propranolol, sodium lauryl te and others) iii) Inhaled administration The compounds of the invention can also be administered by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with olipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for e, chitosan or cyclodextrin.
Dry powder itions for topical ry to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base er substance) such as lactose or starch. Use of lactose is preferred. Each capsule or cartridge may generally contain between 0.001-50 mg, more preferably 0.01-5 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof. Alternatively, the active ingredient (s) may be presented without ents.
Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi- dose delivery, the formulation can be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multiple unit dose and (c) multi dose devices.
For rs of the first type, single doses have been weighed by the manufacturer into small containers, which are mostly hard gelatine capsules. A capsule has to be taken from a separate box or container and inserted into a receptacle area of the inhaler.
Next, the capsule has to be opened or perforated with pins or cutting blades in order to allow part of the inspiratory air stream to pass through the capsule for powder entrainment or to discharge the powder from the capsule through these perforations by means of centrifugal force during inhalation. After tion, the emptied capsule has to be removed from the inhaler again. Mostly, disassembling of the inhaler is necessary for inserting and removing the capsule, which is an operation that can be ult and burdensome for some patients.
Other cks related to the use of hard gelatine capsules for inhalation powders are (a) poor protection against re uptake from the ambient air, (b) problems with opening or ation after the capsules have been exposed previously to e relative humidity, which causes fragmentation or indenture, and (c) le inhalation of capsule fragments. er, for a number of capsule inhalers, incomplete expulsion has been reported (e. g. n et al, 1997).
Some capsule inhalers have a magazine from which individual capsules can be transferred to a receiving chamber, in which perforation and emptying takes place, as described in WO 92/03175. Other capsule inhalers have revolving magazines with capsule chambers that can be brought in line with the air conduit for dose discharge (e. g. WO91/02558 and GB 4). They comprise the type of multiple unit dose inhalers together with blister inhalers, which have a limited number of unit doses in supply on a disk or on a strip.
Blister inhalers provide better moisture protection of the medicament than capsule inhalers. Access to the powder is ed by perforating the cover as well as the blister foil, or by peeling off the cover foil. When a blister strip is used instead of a disk, the number of doses can be increased, but it is inconvenient for the patient to replace an empty strip. Therefore, such s are often disposable with the incorporated dose system, including the technique used to transport the strip and open the blister pockets.
Multi-dose rs do not contain pre-measured quantities of the powder formulation.
They consist of a vely large container and a dose measuring ple that has to be operated by the patient. The container bears multiple doses that are isolated individually from the bulk of powder by volumetric displacement. Various dose measuring principles exist, including rotatable membranes (Ex. EP0069715) or disks (Ex. GB 2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinders (Ex.
EP 4; GB 2165159 and WO 92/09322) and rotatable frustums (Ex. WO 92/00771), all having cavities which have to be filled with powder from the container.
Other multi dose s have measuring slides (Ex. US 5201308 and WO 97/00703) or measuring rs with a local or ferential recess to ce a certain volume of powder from the container to a delivery r or an air conduit (Ex. EP 0505321, WO 92/04068 and WO 92/04928), or measuring slides such as the Genuair® rly known as Novolizer SD2FL), which is described the following patent applications Nos: WO97/000703, WO03/000325 and WO2006/008027.
Reproducible dose measuring is one of the major concerns for multi dose inhaler devices.
The powder formulation has to exhibit good and stable flow properties, because filling of the dose measuring cups or cavities is mostly under the influence of the force of gravity.
For reloaded single dose and multiple unit dose inhalers, the dose measuring accuracy and reproducibility can be guaranteed by the manufacturer. Multi dose inhalers on the other hand, can contain a much higher number of doses, whereas the number of handlings to prime a dose is generally lower.
Because the inspiratory air stream in multi-dose devices is often straight across the dose measuring cavity, and because the massive and rigid dose measuring systems of multi dose inhalers can not be agitated by this inspiratory air stream, the powder mass is simply entrained from the cavity and little de-agglomeration is obtained during discharge.
Consequently, te disintegration means are ary. However in practice, they are not always part of the inhaler design. Because of the high number of doses in multidose devices, powder adhesion onto the inner walls of the air conduits and the deagglomeration means must be minimized and/or regular cleaning of these parts must be possible, without affecting the residual doses in the device. Some multi dose inhalers have disposable drug containers that can be replaced after the prescribed number of doses has been taken (Ex. WO 97/000703). For such semi-permanent multi dose inhalers with disposable drug containers, the requirements to prevent drug accumulation are even stricter.
Apart from applications through dry powder rs the compositions of the invention can be administered in aerosols which operate via propellant gases or by means of ed atomisers, via which solutions of pharmacologically-active substances can be sprayed under high re so that a mist of inhalable particles results. The advantage of these atomisers is that the use of propellant gases can be completely dispensed with. Such atomiser is the Respimat® which is described, for example, in PCT Patent Applications Nos. W0 91/14468 and WO 87, reference here is being made to the contents thereof.
Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous ons or suspensions or as aerosols delivered from rised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for tion can be either a suspension or a on and generally contain the active ient (s) and a suitable lant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e. g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1,1, 1, 2-tetrafluoroethane, 1,1, 1,2, 3,3, 3- heptafluoro-n-propane or a mixture thereof. Carbon dioxide or other suitable gas may also be used as propellant.
The aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants (eg. oleic acid or lecithin) and cosolvens (eg. ethanol). Pressurised formulations will generally be retained in a canister (eg. an ium canister) closed with a valve (eg. a metering valve) and fitted into an actuator provided with a mouthpiece.
Medicaments for administration by inhalation desirably have a lled particle size.
The optimum particle size for inhalation into the bronchial system is usually 1-10 m, preferably 2-5 m. Particles having a size above 20 m are generally too large when inhaled to reach the small airways. To achieve these particle sizes the les of the active ingredient as produced may be size reduced by conventional means eg by micronisation. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline.
Achieving high dose reproducibility with micronised powders is difficult e of their poor flowability and extreme agglomeration tendency. To e the efficiency of dry powder compositions, the particles should be large while in the inhaler, but small when discharged into the respiratory tract. Thus, an excipient such as lactose or glucose is generally employed. The particle size of the excipient will usually be much greater than the inhaled medicament within the present invention. When the excipient is lactose it will typically be present as milled lactose, preferably crystalline alpha lactose drate. rized aerosol compositions will generally be filled into canisters fitted with a valve, especially a metering valve. Canisters may optionally be coated with a plastics al e. g. a fluorocarbon polymer as described in W096/32150. ers will be fitted into an actuator adapted for buccal delivery. iv) Nasal mucosal administration The compounds of the invention may also be administered via the nasal mucosal.
Typical compositions for nasal mucosa administration are typically applied by a metering, ing spray pump and are in the form of a solution or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents. v) Parenteral Administration The compounds of the invention may also be administered ly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral stration include intravenous, rterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) ors, needle-free injectors and infusion techniques.
Parenteral formulations are typically s ons which may n excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non- aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed e. Thus compounds of the invention may be formulated as a solid, semi-solid, or ropic liquid for administration as an implanted depot providing modified e of the active compound. Examples of such formulations e drug-coated stents and PGLA microspheres. vi) Topical Administration The compounds of the invention may also be administered topically to the skin or mucosa, that is, ly or transdermally. Typical ations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin s, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers e alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, horesis, sonophoresis and microneedle or needle-free ion.
Formulations for topical administration may be ated to be immediate and/or ed release. ed release formulations e delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. vii) Rectal/lntravaginal Administration Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional itory base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or ed release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. viii) Ocular Administration Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable {e.g. absorbable gel sponges, en) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or lar systems, such as es or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
Formulations for ocular/aural administration may be ated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. ix) Other Technologies Compounds of the ion may be combined with soluble macromolecular entities, such as cyclodextrin and suitable tives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
The amount of the active compound administered will be dependent on the t being treated, the severity of the disorder or ion, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is lly in the range of 0.01-3000 mg, more preferably 0.5-1000 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt f per day. Daily dosage may be administered in one or more treatments, ably from 1 to 4 treatments, per day.
Preferably, the the pharmaceutical compositions of the ion are made up in a form suitable for oral, inhalation or topical administration, being particularly red oral or inhalation administration.
The pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
Preferably the composition is in unit dosage form, for example a tablet, e or metered aerosol dose, so that the patient may administer a single dose.
The amount of each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disorder or disease being treated.
The following preparations forms are cited as formulation examples: Formulation Examples Formulation Example 1 (Oral suspension) Ingredient Amount Active nd 3 mg Citric acid 0,5 g Sodium chloride 2,0 g Methyl paraben 0,1 g Granulated sugar 25 g Sorbitol (70% solution) 11 g Veegum K 1,0 g Flavoring 0,02 g Dye 0,5 mg Distilled water q.s. to 100 mL Formulation Example 2 (Hard gelatine e for oral administration) ient Amount Active Compound 1 mg Lactose 150 mg Magnesium stearate 3 mg Formulation Example 3 (Gelatin cartridge for inhalation) Ingredient Amount Active Compound nized) 0,2 mg Lactose 25 mg Formulation e 4 (Formulation for inhalation with a DPI) Ingredient Amount Active Compound (micronized) 15 mg Lactose 3000 mg Formulation Example 5 (Formulation for a MDI) Ingredient Amount Active nd (micronized) 10 g 1,1,1,2,3,3,3-heptafluoro-n-propane q.s. to 200 mL Modifications, which do not affect, alter, change or modify the essential aspects of the compounds, combinations or pharmaceutical compositions described, are included within the scope of the present invention.

Claims (6)

Claims
1. A compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or N- oxide, or stereoisomer or deuterated tive f: NH Y O R2 R4)m W N A D Formula (I) 10 wherein, m is 0, 1, 2 or 3; X and Y each independently represent a nitrogen atom or a -CR6 group, wherein at 15 least one of X and Y represents a -CR6 group; A and B each ndently represent a nitrogen atom or a -CR7 group, wherein at least one of A and B represents a -CR7 group; 20 D represents a nitrogen atom or a -CR5 group, wherein when one of A and B represents a nitrogen atom, D represents a -CR5 group; W represents a linker selected from a -NR8- group, a -(CR9R10)- group, -O- or -S-; 25 R1 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, or a 5- to 14- membered heterocyclyl group containing at least one atom selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a 5 halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkylsulfonyl group, a C3- C7 cycloalkyl group, a phenyl group, a l group, a pyrimidinyl group or a piperidyl group; 10 R2 and R7 each independently represent a en atom, a n atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 14- membered 15 heterocyclyl group containing at least one heteroatom selected from O, S and N, or a bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or cyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the lkyl, cycloalkenyl, aryl, aryl, and heterocyclyl groups, 20 and the bicyclyl group which is a clic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group are unsubstituted or substituted by one or more substituents selected from a halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a 25 monocyclic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N; a 5- to 14- membered heterocyclyl group containing at least one heteroatom ed from O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; 30 a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -(CH2)n’-C(O)-(CH2)n- 2 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a -(CH2)n’-S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2; said monocyclic or ic C6-C14 aryl group being unsubstituted or further substituted by one or more carboxyl 35 groups; R3 and R4 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a 5 pyrimidinyl group or a piperidyl group; R5 and R6 each independently represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a 10 monocyclic or bicyclic C6-C14 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 14- membered heterocyclyl group containing at least one atom selected from O, S and N, a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 15 group; a -C(O)-(CH2)n-NR11R12 group; a -S(O)2(CH2)nR11 group; a (CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a 20 halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl, a phenyl group, a l group, a dinyl group, a piperidyl group or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0, 1 or 2; 25 R8, R9 and R10 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a dyl group; R11, R12 and R13 each independently represent a hydrogen atom; a C1-C4 haloalkyl group; a C1-C4 yalkyl group; a 5-to 9- membered heterocyclyl group contaning one, two or three heteroatoms selected from O, S and N, which heterocyclyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom, 35 a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group or a C1-C4 hydroxyalkyl group; or linear or ed C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by one or more tuents selected from a C1-C4 alkoxy group, a cyano group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a dinyl group or a piperidyl group; wherein the compound of formula (I) is other than: 5 a) 3-[[5-Chloro[[2,5-dimethyl(piperidinyl)phenyl]amino]pyrimidin yl]amino]pyridin-2(1H)-one; and b) 2-[7-[[5-Chloro[(2-oxo-1,2-dihydropyridinyl)amino]pyrimidinyl]amino] methoxy-1,2,4,5-tetrahydrobenzo[d]azepinyl]-N,N-dimethylacetamide. 10 2. A compound according to claim 1, wherein m, X, Y, W, A, B, D and R1 to R13 are as defined in claim 1; and wherein when D represents a nitrogen atom, A and B represent a -CR7 group, m is 0, R2 is other than a substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepine group or a phenyl group substituted by a piperidinyl group. 3. A compound according to claim 1 or claim 2 of formula (I’): NH Y O R2 (R3-C-R4)m W N B R5 20 Formula (I’) m is 0 or an integer from 1 to 3; X and Y each independently represent a nitrogen atom or a -CR6 group, wherein at least one of X and Y represents a -CR6 group; A and B each independently represent a nitrogen atom or a -CR7 group, wherein at least one of A and B represents a -CR7 group; W represents a linker selected from a -NR8- group, a -(CR9R10)- group, -O- or -S-; R1 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkoxy group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S 10 and N, or a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the lkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 15 haloalkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 alkylsulfonyl group, a C3- C7 lkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group; R2 and R7 each independently represent a hydrogen atom, a n atom, a cyano 20 group, a linear or ed C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14- membered heteroaryl group ning at least one heteroatom selected from O, S and N, a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, or a 25 bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group, said heteroaryl or heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl , and the bicyclyl group which is a monocyclic C6-C9 aryl or 5- to 9- membered 30 heteroaryl group fused to a 5- to 9- membered cycloalkyl or heterocyclyl group are unsubstituted or substituted by one or more tuents selected from a halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a C1-C4 kyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a monocyclic or bicyclic C6-C14 aryl group; a 5- to 14- ed heteroaryl group 35 containing at least one heteroatom selected from O, S and N; a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; a 1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a (CH2)n-R11 group; a -C(O)-(CH2)n-NR11R12 group; a -S(O)2(CH2)nR11 group; a -S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein 5 each n is 0, 1 or 2; said monocyclic or bicyclic C6-C14 aryl group being unsubstituted or further substituted by one or more carboxyl groups. R3 and R4 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C6 alkyl group, which alkyl group is 10 unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a dyl group; R5 and R6 each ndently represent a hydrogen atom, a halogen atom, a cyano 15 group, a linear or branched C1-C6 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkenyl group, a monocyclic or bicyclic C6-C14 aryl group, a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N, a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, 20 a -(CH2)nOR11 group; a -NR11R12 group; a (O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -C(O)-(CH2)n-NR11R12 group; a -S(O)2(CH2)nR11 group; a -S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; 25 wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more tuents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group or 30 a -C(O)-(CH2)n-NR11R12 group; wherein n is 0, 1 or 2; R8, R9 and R10 each independently represent a hydrogen atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a linear or ed C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 35 alkoxy group, a cyano group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group; R11, R12 and R13 each independently represent a en atom, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by one or more substituents selected from a C1-C4 alkoxy group, a cyano group, a C3-C7 cycloalkyl group, a phenyl group, a l group, 5 a pyrimidinyl group or a piperidyl group. 4. A compound according to any one of the preceding claims, wherein W represents a linker selected from a -NR8- group or a -(CR9R10)- group wherein R8, R9 and R10 are as defined in claim 1. 5. A compound according to any one of the ing claims wherein W represents a – NR8- group wherein R8 is as defined in claim 1. 6. A compound according to any one of the preceding claims, wherein R1 represents a 15 hydrogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1- C4 yalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group. 7. A compound according to any one of the preceding claims, wherein R1 represents a 20 hydrogen atom, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 yalkyl group, a C3-C7 cycloalkyl group, a phenyl group or a pyridyl group. 8. A compound according to any one of the preceding claims, wherein R1 represents a hydrogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 kyl group or a C1- 25 C3 hydroxyalkyl group. 9. A nd according to any one of the preceding claims,wherein R1 represents a hydrogen atom. 10. A compound according to any one of claims 1, 2, and 4 to 9, n R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 yalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, 35 S and N, a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or tuted by one or more substituents selected from a halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a 5 clic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group ning at least one heteroatom selected from O, S and N; a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a (O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; 10 a -C(O)-(CH2)1CN group; a (CH2)n-R11 group; a-(CH2)n’-C(O)-(CH2)n- NR11R12 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a -(CH2)n’-S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2; and wherein R11, R12 and R13 are as defined in claim 1 and said monocyclic or bicyclic C6-C14 aryl group is unsubstituted or 15 further substituted by one or more carboxyl groups. 11. A compound according to claim 3, wherein R2 represents a linear or branched C1- C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a clic or ic C6-C10 aryl group, a 5- to 7- membered heteroaryl group 20 containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a 25 halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a monocyclic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group containing at least one heteroatom ed from O, S and N; a 5- to 14- membered heterocyclyl group ning at least one heteroatom selected from 30 O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -C(O)-(CH2)n-NR11R12 group; a -S(O)2(CH2)nR11 group; a -S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; n 35 each n is 0, 1 or 2; and wherein R11, R12 and R13 are as defined in claim 1 and said monocyclic or bicyclic C6-C14 aryl group is unsubstituted or further substituted by one or more carboxyl groups. 12. A compound according to any one of the preceding claims, wherein R3 and R4 each independently represent a hydrogen atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group. 13. A compound according to any one of the preceding claims, n R3 and R4 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group. 10 14. A compound ing to any one of the preceding claims, wherein R3 and R4 each independently represent a hydrogen atom or a methyl group. 15. A compound according to any one of the preceding claims, wherein R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, 15 a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a (CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; n 20 each n is 0, 1 or 2; and wherein R11, R12 and R13 each independently represent a hydrogen atom or a linear or ed C1-C3 alkyl group. 16. A compound according to any one of the preceding claims, wherein R6 represents a en atom, a n atom, a cyano group, a linear or branched C1-C4 alkyl group, 25 a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three atoms selected from O, S and N, or a 5- to 7- membered heterocyclyl group containing one, two or three atoms selected from O, S and N, 30 wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, or 35 a -C(O)-(CH2)n-NR11R12 group; wherein n is 0, 1 or 2; and wherein R11 and R12 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group. 17. A compound according to any one of the preceding claims, wherein R7 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a 5 monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group ning one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered heterocyclyl group containing one, two or three atoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are 10 unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C7 lkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a dinyl group, a piperidyl group, a -(CH2)1-3CN group, 15 a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; and wherein R11, 20 R12 and R13 each independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group. 18. A compound according to any one of the preceding claims, n R8 represents a hydrogen atom or a linear or branched C1-C6 alkyl group, which alkyl group is 25 unsubstituted or substituted by a C1-C2 alkoxy group. 19. A nd according to any one of the preceding claims, wherein R8 represents a hydrogen atom or a linear or branched C1-C3 alkyl group. 30 20. A compound according to any one of the preceding claims, n R8 represents a hydrogen atom. 21. A compound according to claim 1, wherein: 35 m is 0, 1 or 2; X is a en atom and Y is a -CR6 group; or Y is a nitrogen atom and X is a -CR6 group; or both X and Y are a -CR6 group; A is a nitrogen atom, B is a -CR7 group and D is a -CR5 group; or B is a nitrogen atom, 5 A is a -CR7 group and D is a -CR5 group; or both A and B are a -CR7 group and D is nitrogen atom or a -CR5 group; W represents a linker selected from a -NR8- group or a -(CR9R10)- group; 10 R1 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 lkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group; R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 15 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- ed heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups 20 are unsubstituted or substituted by one or more substituents selected from a halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a monocyclic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group containing at least one atom selected from O, S and N; a 5- to 14- 25 membered heterocyclyl group containing at least one heteroatom selected from O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a (CH2)n-R11 group; a-(CH2)n’-C(O)-(CH2)n- NR11R12 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a -(CH2)n’-S(O)2(CH2)nNR11R12 30 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2 and said monocyclic or ic C6-C14 aryl group is unsubstituted or further substituted by one or more carboxyl groups. R3 and R4 each independently ent a hydrogen atom or a linear or branched C1-C6 35 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 yalkyl group, a C3-C7 cycloalkyl group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, 5 a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R6 represents a en atom, a halogen atom, a cyano group, a linear or branched 10 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or ic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, 15 wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one, two or three substituents selected from a n atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl, a phenyl group, a l group, a pyrimidinyl group, a piperidyl group, or 20 a -C(O)-(CH2)n-NR11R12 group; wherein n is 0, 1 or 2 R7 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 yalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered 25 heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one, two or three substituents ed from a 30 halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)1-3CN group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, 35 a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a (CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a (CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R8 ents a hydrogen atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; R9 and R10 each independently represent a en atom or a linear or branched C1- C3 alkyl group; R11, R12 and R13 each independently represent a hydrogen atom, a linear or branched 10 C1-C3 alkyl group, or a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, which cyclyl group is unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group or a C1- C4 hydroxyalkyl group. 22. A compound according to claim 21, wherein: m is 0, 1 or 2; 20 both X and Y represents a -CR6 group; A is a nitrogen atom, B is a -CR7 group and D is a -CR5 group; or B is a nitrogen atom, A is a -CR7 group and D is a -CR5 group; or both A and B are a -CR7 group and D is nitrogen atom or a -CR5 group; W represents a linker selected from a -NR8- group or a -(CR9R10)- group; R1 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 lkyl group, a phenyl group, 30 a pyridyl group, a pyrimidinyl group or a piperidyl group; R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 yalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms 35 selected from O, S and N, a 5- to 7- membered cyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, aryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 hydroxyalkyl group; a C3-C7 cycloalkyl group; a 5 monocyclic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N; a 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; 10 a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a-(CH2)n’-C(O)-(CH2)n- NR11R12 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a -(CH2)n’-S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2 and said monocyclic or bicyclic C6-C14 aryl group is tituted or further substituted by one or more carboxyl groups; R3 and R4 each independently represent a en atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched 20 C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 yalkyl group, a C3-C7 lkyl group, a -(CH2)nOR11 group, a 12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or 25 a -NR11S(O)2(CH2)nNR12R13 group; n each n is 0, 1 or 2; R6 represents a hydrogen atom, a n atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered 30 heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one, two or three tuents selected from a 35 halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, or a (CH2)n-NR11R12 group; wherein n is 0, 1 or 2 R7 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 kyl group, a C1-C4 yalkyl group, a C3-C7 5 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group ning one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and cyclyl groups are 10 unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a yl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)1-3CN group, 15 a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R8 represents a hydrogen atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; R9 and R10 each ndently represent a hydrogen atom or a linear or branched C1- 25 C3 alkyl group; R11, R12 and R13 each independently represent a en atom, a linear or branched C1-C3 alkyl group, or a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, which heterocyclyl group is unsubstituted 30 or substituted by one, two or three substituents selected from a halogen atom, a hydroxyl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group or a C1- C4 hydroxyalkyl group. 23. A compound according to claim 22, wherein: m is 0 or 1; both X and Y represents a -CR6 group; A is a nitrogen atom, B is a -CR7 group and D is a -CR5 group; or B is a nitrogen atom, A is a -CR7 group and D is a -CR5 group; or both A and B are a -CR7 group and D is 5 nitrogen atom or a -CR5 group; W represents a linker selected from a -NR8- group or a -(CR9R10)- group; R1 represents a hydrogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 10 haloalkyl group or a C1-C3 hydroxyalkyl group; R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 kyl group, a C1-C4 yalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a triazolyl group, a thiazolyl group, a pyrrolidinyl group or a piperidyl 15 group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, pyrrolidinyl or piperidyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl 20 group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a triazolyl group, a thiazolyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a (O)-(CH2)n-NR12R13 group, a (CH2)1CN group, a -C(O)-(CH2)n-R11 group, a-(CH2)n’-C(O)-(CH2)n- 25 NR11R12 group; a -(CH2)n’-S(O)2(CH2)nR11 group; a -(CH2)n’-S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n’ and n are 0, 1 or 2; R3 and R4 each independently ent a hydrogen atom or a linear or branched C1-C3 30 alkyl group; R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)1-3CN group, a nOR11 group, a -NR11R12 group, 35 a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R6 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 5 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, a pyrrolidinyl group, a piperidyl group, a tetrahydropyranyl group or a morpholinyl group; R7 ents a hydrogen atom, a halogen atom, a cyano group, a linear or branched 10 C1-C3 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a triazolyl group, a thiazolyl group, a pyrrolidinyl group, a piperidyl group, a tetrahydropyranyl group or a morpholinyl group; n the lkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, 15 pyrrolidinyl, piperidyl, tetrahydropyranyl or morpholinyl groups are unsubstituted or substituted by one, two or three substituents selected from a n atom, a linear or branched C1-C6 alkyl group, a C1-C4 kyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a triazolyl group, a thiazolyl 20 group, a pyrimidinyl group, a piperidyl group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a (CH2)1CN group, a -C(O)-(CH2)n-R12 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR12 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or 25 a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R8 represents a en atom or a linear or branched C1-C3 alkyl group; R9 and R10 each independently represent a hydrogen atom or a linear or branched C1- 30 C3 alkyl group; R11, R12 and R13 each independently ent a hydrogen atom or a linear or branched C1-C3 alkyl group, or a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, which heterocyclyl group is unsubstituted 35 or substituted by one, two or three substituents selected from a halogen atom, a yl group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group or a C1- C4 hydroxyalkyl group. 24. A compound according to any one of claims 21 to 23, wherein W represents a -NR8- group. 5 25. A nd according to claim 1, wherein: m is 0 or 1; both X and Y represents a -CR6 group; A is a en atom, B is a -CR7 group and D is a -CR5 group; or B is a en atom, A is a -CR7 group and D is a -CR5 group; or both A and B are a -CR7 group and D is nitrogen atom or a -CR5 group; 15 W represents a -NH- group or a -CH2- group; R1 represents a en atom; R2 represents a cyclohexyl group, a pyridyl group or a piperidyl group, 20 wherein the cyclohexyl, pyridyl and piperidyl and groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a triazolyl group, a -(CH2)1-3CN group, -C(O)-(CH2)1CN group or a -(CH2)-S(O)2- pyrimidinyl group, which pyrimidinyl is unsubstituted or substituted by one, two or three hydroxyl groups; R3 and R4 each independently ent a hydrogen atom or a methyl group; R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a linear or ed C1-C3 alkyl group, a -OCH3 group or a -C(O)-(CH2)n-NR11R12 group; wherein n is 0 or 1; 30 and wherein R11 and R12 independently represent a hydrogen atom or a linear or branched C1-C3 alkyl group; R6 represents a hydrogen atom, a halogen atom or a pyrazolyl group; 35 R7 represents a hydrogen atom, piperidyl group, a thiazolyl group or a morpholinyl group; wherein the piperidyl, thiazolyl and morpholinyl groups are unsubstituted or substituted by one or two substituents selected from a yl group or a benzoic acid. 5 26. A compound according to claim 25, wherein W represents a –NH- group. 27. A compound according to claim 3, n: m is 0, 1 or 2; X is a nitrogen atom and Y is a -CR6 group; or Y is a en atom and X is a -CR6 group; or both X and Y are a -CR6 group; A is a nitrogen atom and B is a -CR7 group; or B is a nitrogen atom and A is a -CR7 15 group; or both A and B are a -CR7 group; W represents a linker selected from a -NR8- group or a -(CR9R10)- group; R1 represents a hydrogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 20 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group or a piperidyl group; R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 lkyl group, a monocyclic or bicyclic C6-C10 aryl group, 25 a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are unsubstituted or substituted by one or more substituents ed from a 30 halogen atom; a cyano group; a linear or branched C1-C6 alkyl group; a C1-C4 haloalkyl group; a C1-C4 yalkyl group; a C3-C7 lkyl group; a monocyclic or bicyclic C6-C14 aryl group; a 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N; a 5- to 14- ed heterocyclyl group containing at least one heteroatom selected from 35 O, S and N; a -(CH2)1-3CN group; a -(CH2)nOR11 group; a -NR11R12 group; a -NR11C(O)-(CH2)n-R12 group; a -NR11C(O)-(CH2)n-NR12R13 group; a -C(O)-(CH2)1CN group; a -C(O)-(CH2)n-R11 group; a -C(O)-(CH2)n-NR11R12 group; a -S(O)2(CH2)nR11 group; a -S(O)2(CH2)nNR11R12 group; a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; n each n is 0, 1 or 2 and said clic or bicyclic C6-C14 aryl group is 5 unsubstituted or further substituted by one or more carboxyl groups. R3 and R4 each independently represent a hydrogen atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; 10 R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)nOR11 group, a -NR11R12 group, a (O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a (CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, 15 a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R6 represents a hydrogen atom, a halogen atom, a cyano group, a linear or ed C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 20 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a 5- to 7- membered heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are 25 tituted or substituted by one, two or three substituents ed from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl, a phenyl group, a pyridyl group, a pyrimidinyl group, a piperidyl group, or a (CH2)n-NR11R12 group; wherein n is 0, 1 or 2 R7 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a monocyclic or bicyclic C6-C10 aryl group, a 5- to 7- membered heteroaryl group containing one, two or three heteroatoms selected from O, S and N, a 35 5- to 7- ed heterocyclyl group containing one, two or three heteroatoms selected from O, S and N, wherein the cycloalkyl, aryl, aryl and heterocyclyl groups are unsubstituted or substituted by one, two or three substituents selected from a n atom, a cyano group, a linear or ed C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl 5 group, a phenyl group substituted by a carboxyl group, a l group, a pyrimidinyl group, a piperidyl group, a -(CH2)1-3CN group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 10 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R8 represents a hydrogen atom or a linear or branched C1-C6 alkyl group, which alkyl group is unsubstituted or substituted by a C1-C2 alkoxy group; R9 and R10 each independently represent a hydrogen atom or a linear or branched C1- C3 alkyl group; R11, R12 and R13 each independently represent a hydrogen atom or a linear or branched 20 C1-C3 alkyl group. 28. A compound according to claim 27, wherein: m is 0 or 1; both X and Y ents a -CR6 group; A is a nitrogen atom and B is a -CR7 group; or B is a nitrogen atom and A is a -CR7 group; or both A and B are a -CR7 group; W represents a linker selected from a -NR8- group or a -(CR9R10)- group; R1 represents a hydrogen atom, a linear or branched C1-C3 alkyl group, a C1-C3 kyl group or a C1-C3 hydroxyalkyl group; R2 represents a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a triazolyl group, a thiazolyl group, a idinyl group or a piperidyl group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, triazolyl, lyl, pyrrolidinyl or piperidyl groups are unsubstituted or substituted by one, two or 5 three substituents selected from a halogen atom, a cyano group, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a pyridyl group, a triazolyl group, a thiazolyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)nOR11 group, a -NR11R12 group, 10 a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a (CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R3 and R4 each independently represent a hydrogen atom or a linear or ed C1-C3 alkyl group; R5 represents a hydrogen atom, a halogen atom, a cyano group, a linear or branched 20 C1-C3 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a -(CH2)1-3CN group, a -(CH2)nOR11 group, a -NR11R12 group, a -NR11C(O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, a -C(O)-(CH2)n-R11 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR11 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or 25 a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R6 ents a hydrogen atom, a n atom, a cyano group, a linear or branched C1-C3 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a dinyl group, a pyrrolidinyl 30 group, a piperidyl group, a tetrahydropyranyl group or a morpholinyl group; R7 represents a hydrogen atom, a halogen atom, a cyano group, a linear or ed C1-C3 alkyl group, a C1-C4 haloalkyl group, a C1-C4 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a pyridyl group, a pyrimidinyl group, a triazolyl group, 35 a thiazolyl group, a pyrrolidinyl group, a piperidyl group, a tetrahydropyranyl group or a morpholinyl group; wherein the cycloalkyl, phenyl, pyridyl, pyrimidinyl, lyl, thiazolyl, pyrrolidinyl, dyl, tetrahydropyranyl or morpholinyl groups are tituted or substituted by one, two or three substituents selected from a halogen atom, a linear or branched C1-C6 alkyl group, a C1-C4 haloalkyl group, a C1-C4 5 hydroxyalkyl group, a C3-C7 cycloalkyl group, a phenyl group, a phenyl group substituted by a carboxyl group, a l group, a triazolyl group, a thiazolyl group, a pyrimidinyl group, a piperidyl group, a -(CH2)nOR11 group, a -NR11R12 group, a (O)-(CH2)n-R12 group, a -NR11C(O)-(CH2)n-NR12R13 group, a -C(O)-(CH2)1CN group, 10 a -C(O)-(CH2)n-R12 group, a -C(O)-(CH2)n-NR11R12 group, a -S(O)2(CH2)nR12 group, a -S(O)2(CH2)nNR11R12 group, a -NR11S(O)2(CH2)nR12 group or a -NR11S(O)2(CH2)nNR12R13 group; wherein each n is 0, 1 or 2; R8 represents a hydrogen atom or a linear or branched C1-C3 alkyl group; R9 and R10 each independently ent a hydrogen atom or a linear or branched C1- C3 alkyl group; R11, R12 and R13 each independently ent a hydrogen atom or a linear or branched 20 C1-C3 alkyl group. 29. A compound according to claim 3, wherein: m is 0 or 1; both X and Y represents a -CR6 group; A is a nitrogen atom and B is a -CR7 group; or B is a nitrogen atom and A is a -CR7 group; or both A and B are a -CR7 group; W represents a -NH- group or a -CH2- group; R1 represents a hydrogen atom; 35 R2 represents a cyclohexyl group, a pyridyl group or a piperidyl group, wherein the cyclohexyl, pyridyl and piperidyl groups are unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a lyl group, a -(CH2)1-3CN group or -C(O)-(CH2)1CN group; R3 and R4 each independently represent a hydrogen atom or a methyl group; 5 R5 represents a hydrogen atom, a halogen atom, a linear or branched C1-C3 alkyl group or a (CH2)n-NR11R12 group; wherein n is 0 or 1; and wherein R11 and R12 independently represent a en atom or a linear or branched C1-C3 alkyl group; R6 represents a hydrogen atom or a halogen atom; R7 represents a hydrogen atom, piperidyl group, a thiazolyl group or a morpholinyl group; wherein the piperidyl, thiazolyl and morpholinyl groups are unsubstituted or substituted by one or two tuents selected from a hydroxy group or a 15 benzoic acid. 30. A compound according to claim 1 which is one of: (S)(4-(1-(5-fluoropyridinyl)ethylamino)pyrimidinylamino)pyridin-2(1H)-one; (S)(4-(1-(5-fluoropyridinyl)ethylamino)methylpyrimidinylamino)pyridin-2(1H)- 20 one; (S)(5-chloro(1-(5-fluoropyridinyl)ethylamino)pyrimidinylamino)pyridin-2(1H)- one; (S)(4-(1-(5-fluoropyridinyl)ethylamino)methoxypyrimidinylamino)pyridin- 2(1H)-one; 25 (S)(4-(1-(5-fluoropyridinyl)ethylamino)hydroxypyrimidinylamino)pyridin- 2(1H)-one; (S)(1-(5-fluoropyridinyl)ethylamino)(2-oxo-1,2-dihydropyridin ylamino)pyrimidinecarboxamide; (S)chloro(4-(1-(5-fluoropyridinyl)ethylamino)methylpyrimidin 30 ylamino)pyridin-2(1H)-one; (S)(4-(1-(5-fluoropyridinyl)ethylamino)methylpyrimidinylamino)(1H- pyrazolyl)pyridin-2(1H)-one; (S)(4-(1-(5-fluoropyridinyl)ethylamino)(4-hydroxypiperidinyl)pyrimidin ylamino)pyridin-2(1H)-one; 35 (S)(5-fluoro(1-(5-fluoropyridinyl)ethylamino)morpholinopyrimidin o)pyridin-2(1H)-one; (S)(6-(1-(5-fluoropyridinyl)ethylamino)pyrazinylamino)pyridin-2(1H)-one; (S)(6-(1-(5-fluoropyridinyl)ethylamino)pyridinylamino)pyridin-2(1H)-one;
2-((1r,4r)(5-methyl(2-oxo-1,2-dihydropyridinylamino)pyrimidin ylamino)cyclohexyl)acetonitrile; 3-(4-((1r,4r)((3-hydroxypiperidinylsulfonyl)methyl)cyclohexylamino)pyrimidin 5 ylamino)pyridin-2(1H)-one; (R)oxo(3-(2-(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino)piperidin yl)propanenitrile; (R)(3-(5-methyl(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino)piperidin- 1-yl)oxopropanenitrile; 10 (3-(5-fluoro(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino)piperidin- 1-yl)oxopropanenitrile; (R)(4-(1-(4H-1,2,4-triazolyl)piperidinylamino)fluoropyrimidin ylamino)pyridin-2(1H)-one; (R)(3-(2-(5-chlorooxo-1,2-dihydropyridinylamino)methylpyrimidin 15 o)piperidinyl)oxopropanenitrile; (R)(3-(5-fluoromorpholino(2-oxo-1,2-dihydropyridinylamino)pyrimidin ylamino)piperidinyl)oxopropanenitrile; (R)(3-(5-methylmorpholino(2-oxo-1,2-dihydropyridinylamino)pyrimidin ylamino)piperidinyl)oxopropanenitrile; 20 (R)(3-(5-methylmorpholino(2-oxo-1,2-dihydropyridinylamino)pyrimidin ylamino)piperidinyl)oxopropanenitrile; (R)(3-(4-(5-chlorooxo-1,2-dihydropyridinylamino)methyl morpholinopyrimidinylamino)piperidinyl)oxopropanenitrile; (R)(3-(5-chloro(2-oxo-1,2-dihydropyridinylamino)pyrimidinylamino)piperidin- 25 1-yl)oxopropanenitrile;
3-[(
4-{[(1S)(
5-Fluoropyridinyl)ethyl]amino}pyrimidinyl)methyl]pyridin-2(1H)-one; (S)(5-(
6-(1-(5-fluoropyridinyl)ethylamino)(2-oxo-1,2-dihydropyridin ylamino)pyrimidinyl)thiazolyl)benzoic acid; 30 or a pharmaceutically acceptable salt, or e, or N-oxide, or stereoisomer or deuterated derivative thereof. 31. A compound as defined in any one of claims 1 to 30, for use in the treatment of the human or animal body by therapy. 32. A nd as defined in any one of claims 1 to 30, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Janus Kinases. 5 33. A compound for use according to claim 32, wherein the pathological condition or disease is selected from roliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases. 10 34. A compound for use according to claim 32 or 33, wherein the pathological ion or disease is selected from rheumatoid arthritis, multiple sclerosis, matory bowel disease, dry eye, s, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis. 15 35. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 30 in association with a pharmaceutically acceptable diluent or carrier. 36. Use of a compound as d in any one of claims 1 to 30, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in any 20 one of claims 32 to 34. 37. A combination product comprising (i) a compound as defined in any one of claims 1 to 30; and (ii) another compound selected from: 25 a) Dyhydrofolate reductase tors; b) Dihydroorotate dehydrogenase (DHODH) inhibitors; c) Immunomodulators; d) Inhibitors of DNA synthesis and repair; e) Immunosuppressants; 30 f) Anti-alpha 4 integrin antibodies; g) Alpha 4 in antagonists; h) Corticoids and orticoids; i) Fumaric acid esters; j) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) antibodies; 35 k) Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors; l) Anti-CD20 (lymphocyte protein) monoclonal antibodies; m) Anti-CD52 (lymphocyte protein) onal antibodies; n) Anti-CD25 (lymphocyte protein) monoclonal antibodies; o) Anti-CD88 (lymphocyte n) monoclonal antibodies; p) Anti-Interleukin 6 Receptor (IL-6R) monoclonal antibodies; q) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 or (IL- 5 23R) monoclonal antibodies; r) Calcineurin inhibitors; s) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors; t) Cannabinoid receptor agonists; u) Chemokine CCR1 antagonists; 10 v) Chemokine CCR2 antagonists; w) Necrosis factor-kappaB (NF-kappaB or NFKB) Activation Inhibitors; x) ine A2A agonists; y) Sphingosine-1 (S1P) phosphate receptor agonists; z) osine-1 (S1P) liase inhibitors; 15 aa) Spleen tyrosine kinase (Syk) inhibitors; bb) n Kinase Inhibitors (PKC) inhibitors; cc) Anti-cholinergic agents; dd) Beta adrenergic agonists; ee) Compounds having bifunctional Muscarinic Antagonist-Beta2 20 Agonist activity (MABAs); ff) ine 1 (H1) or antagonists; gg) Chemoattractant receptor homologous molecule expressed on TH2 cells ) inhibitors; hh) Vitamin D derivatives; 25 ii) Anti-inflammatory agents; jj) Anti-allergic agents; kk) Anti-viral agents; ll) Phosphodiestearase (PDE) III inhibitors; mm) Phosphosdiesterase (PDE) IV tors; 30 nn) Dual Phosphodiestearase (PDE) III/IV inhibitors; oo) Xanthine derivatives; pp) p38 Mitogen-Activated Protein Kinase (p38 MAPK) Inhibitors; qq) Mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor; 35 rr) Phosphoinositide 3-Kinases ) inhibitors; ss) Interferons; and tt) Interferon alpha. 38. A combination t as defined in claim 37, wherein: a) the dyhydrofolate reductase inhibitor is methotrexate, or CH-1504; 5 b) the DHODH inhibitors are ed from leflunomide and teriflunomide; c) the immunomodulators are selected from Glatiramer acetate, Laquinimod and Imiquimod; d) the inhibitors of DNA sis and repair are selected from 10 Mitoxantrone and Cladribine; e) the immunosuppressants are selected from azathioprine or 6- mercaptopurine; f) the anti-alpha 4 integrin antibody is Natalizumab; g) the alpha 4 integrin antagonists are selected from R-1295, TB- 15 4746, CDP-323, ELND-002 and Firategrast; h) the corticoids and glucocorticoids are selected from prednisone; methylprednisolone, fluticasone, mometasone, budesonide, ciclesonide and beta-metasone, i) the fumaric acid esters is dimethyl te; 20 j) the NF alpha antibodies are ed from Infliximab; Adalimumab, and Certolizumab pegol; k) the soluble TNF alpha receptors is Etanercept; l) the anti-CD20 monoclonal antibodies are selected from Rituximab; Ocrelizumab, Ofatumumab; and TRU-015; 25 m) the D52 monoclonal antibody is alemtuzumab; n) the anti-CD25 monoclonal antibody is daclizumab; o) the anti-CD88 monoclonal antibodies are selected from eculizumab and pexilizumab; p) the nterlukin 6 receptor monoclonal antibody is tocilizumab; q) the anti-IL12R /IL23R onal dy is ustekinumab; r) the calcineurin inhibitors are selected from porine A and tacrolimus; s) the IMPDH inhibitors are selected from mycophenolate mophetyl, 5 rin, mizoribine and mycophenolic acid; t) the cannabinoid receptor agonists is Nabiximols; u) the chemokine CCR1 antagonists are selected from MLN-3897 and PS-031291; v) the ine CCR2 antagonist is INCB-8696; 10 w) the NF-kappaB activation inhibitor is selected from Sulfasalazine, Iguratimod and MLN-0415; x) the adenosine A2A agonists are selected from 3, ATL-146e, CGS-21680, Regadenoson and UK-432,097; y) the S1P receptor agonists are selected from fingolimod BAF-312, 15 or ACT12880; z) the S1P liase inhibitor is LX2931; aa) the syk inhibitor is R-112; bb) the PKC inhibitor is NVP-AEB071; cc) the anti-cholinergic agent is selected from tiotropium and aclidinium; 20 dd) the beta adrenergic agonist is selected from formoterol, indacaterol and abediterol; ee) the H1 receptor antagonists are ed from azelastine or ebastine; ff) the CRTH2 inhibitors are selected from OC-459, AZD-1981, ACT- 25 129968 and QAV-680; gg) the vitamin D derivative is calcipotriol; hh) the anti-inflammatory agents are selected from eroidal antiinflammatory drugs (NSAIDs) or selective cyclooxygenase-2 (COX- 2) inhibitors; ii) the Phosphosdiesterase IV inhibitors is roflumilast or 39; 5 jj) the xanthine derivatives are selected from theophylline and theobromine; kk) the p38 MAPK inhibitor is ARRY-797; ll) the MEK inhibitor is ARRY-142886 or ARRY-438162; mm) the interferons are selected from Interferon beta 1a and Interferon 10 beta 1b; and nn) the eron alpha is Sumiferon MP. 39. The combination product of claim 38, wherein the COX-2 inhibitors are selected from aceclofenac, diclofenac, ibuprofen, naproxen, apricoxib, celecoxib, cimicoxib, 15 xib, oxib, lumiracoxib, parecoxib sodium, rofecoxib, selenocoxib-1 and valdecoxib. 40. A combination product according to any one of claims 37 to 39 which is for simultaneous, separate or sequential use in the treatment of the human or animal 20 body. 41. Use of (i) a compound as defined in any one of claims 1 to 30, and (ii) another compound ed from: a) Dyhydrofolate reductase tors; 25 b) Dihydroorotate dehydrogenase (DHODH) inhibitors; c) Immunomodulators; d) Inhibitors of DNA synthesis and repair; e) Immunosuppressants; f) lpha 4 integrin dies; g) Alpha 4 integrin antagonists; h) Corticoids and glucocorticoids; i) Fumaric acid ; 5 j) Anti-tumor necrosis factor-alpha TNF-alpha) antibodies; k) Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors; l) Anti-CD20 (lymphocyte protein) monoclonal antibodies; m) Anti-CD52 (lymphocyte protein) monoclonal antibodies; n) Anti-CD25 (lymphocyte protein) monoclonal antibodies; 10 o) Anti-CD88 (lymphocyte protein) monoclonal antibodies; p) Anti-Interleukin 6 Receptor (IL-6R) monoclonal antibodies; q) Anti-Interleukin 12 Receptor (IL-12R) / Interleukin 23 Receptor (IL- 23R) monoclonal antibodies; r) eurin inhibitors; 15 s) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors; t) Cannabinoid receptor agonists; u) Chemokine CCR1 antagonists; v) ine CCR2 antagonists; w) Necrosis factor-kappaB (NF-kappaB or NFKB) Activation Inhibitors; 20 x) Adenosine A2A agonists; y) Sphingosine-1 (S1P) phosphate receptor agonists; z) Sphingosine-1 (S1P) liase tors; aa) Spleen tyrosine kinase (Syk) inhibitors; bb) Protein Kinase Inhibitors (PKC) inhibitors; cc) Anti-cholinergic ; dd) Beta adrenergic agonists; ee) Compounds having bifunctional Muscarinic Antagonist-Beta2 5 Agonist activity (MABAs); ff) Histamine 1 (H1) receptor antagonists; gg) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) inhibitors; hh) n D tives; 10 ii) Anti-inflammatory agents;, jj) Anti-allergic agents; kk) Anti-viral agents; ll) Phosphodiestearase (PDE) III inhibitors; mm) Phosphosdiesterase (PDE) IV inhibitors; 15 nn) Dual odiestearase (PDE) III/IV inhibitors; oo) Xanthine derivatives; pp) p38 Mitogen-Activated Protein Kinase (p38 MAPK) Inhibitors; qq) Mitogen-activated extracellular signal ted kinase kinase (MEK) inhibitor; 20 rr) Phosphoinositide 3-Kinases (PI3Ks) inhibitors; ss) Interferons tt) Interferon alpha; in the manufacture of a medicament for simultaneously, separately or sequentially treating a disease or condition of the human or animal body. 42. The use of claim 41 wherein: 5 a) the ofolate reductase inhibitor is methotrexate, or CH-1504; b) the DHODH inhibitors are selected from leflunomide and teriflunomide; c) the immunomodulators are selected from Glatiramer acetate, Laquinimod and Imiquimod; 10 d) the inhibitors of DNA synthesis and repair are selected from Mitoxantrone and Cladribine; e) the immunosuppressants are selected from azathioprine or 6- mercaptopurine; f) the lpha 4 integrin dy is Natalizumab; 15 g) the alpha 4 integrin antagonists are ed from R-1295, TB- 4746, CDP-323, ELND-002 and Firategrast; h) the oids and glucocorticoids are selected from sone; methylprednisolone, fluticasone, mometasone, budesonide, ciclesonide and beta-metasone, 20 i) the fumaric acid esters is dimethyl fumarate; j) the anti-TNF alpha antibodies are selected from Infliximab; Adalimumab, and Certolizumab pegol; k) the soluble TNF alpha receptors is Etanercept; l) the anti-CD20 monoclonal antibodies are ed from Rituximab; 25 Ocrelizumab, Ofatumumab; and TRU-015; m) the D52 monoclonal antibody is alemtuzumab; n) the anti-CD25 monoclonal antibody is daclizumab; o) the D88 monoclonal antibodies are selected from eculizumab and pexilizumab; p) the anti-interlukin 6 receptor monoclonal antibody is tocilizumab; q) the anti-IL12R /IL23R monoclonal antibody is ustekinumab; 5 r) the calcineurin inhibitors are selected from cyclosporine A and tacrolimus; s) the IMPDH inhibitors are selected from mycophenolate mophetyl, ribavirin, mizoribine and mycophenolic acid; t) the cannabinoid receptor agonists is Nabiximols; 10 u) the chemokine CCR1 antagonists are selected from MLN-3897 and PS-031291; v) the chemokine CCR2 antagonist is 696; w) the NF-kappaB activation inhibitor is selected from Sulfasalazine, Iguratimod and MLN-0415; 15 x) the adenosine A2A ts are selected from ATL-313, ATL-146e, CGS-21680, Regadenoson and UK-432,097; y) the S1P receptor agonists are selected from fingolimod 2, or ACT12880; z) the S1P liase tor is LX2931; 20 aa) the syk inhibitor is R-112; bb) the PKC tor is NVP-AEB071; cc) the anti-cholinergic agent is selected from tiotropium and aclidinium; dd) the beta adrenergic t is selected from formoterol, indacaterol 25 and abediterol; ee) the H1 receptor antagonists are selected from azelastine or ebastine; ff) the CRTH2 inhibitors are selected from OC-459, 81, ACT- 129968 and QAV-680; gg) the vitamin D derivative is calcipotriol; hh) the anti-inflammatory agents are selected from non-steroidal anti- 5 inflammatory drugs s) or ive cyclooxygenase-2 (COX- 2) inhibitors; ii) the Phosphosdiesterase IV inhibitors is roflumilast or GRC-4039; jj) the xanthine derivatives are selected from theophylline and theobromine; 10 kk) the p38 MAPK inhibitor is ARRY-797; ll) the MEK inhibitor is ARRY-142886 or ARRY-438162; mm) the interferons are selected from Interferon beta 1a and Interferon beta 1b; and nn) the Interferon alpha is Sumiferon MP. 43. The use of claim 42, wherein the COX-2 inhibitors are selected from aceclofenac, diclofenac, ibuprofen, naproxen, apricoxib, celecoxib, cimicoxib, deracoxib, oxib, lumiracoxib, parecoxib sodium, rofecoxib, selenocoxib-1 and valdecoxib. 20 44. A compound of formula (I) or a pharmaceutically acceptable salt, or solvate, or N - oxide, or stereoisomer f, as claimed in any one of claims 1 to 34, substantially as herein bed with reference to any example f. 45. A pharmaceutical composition as claimed in claim 35, substantially as herein 25 described with reference to any example thereof. 46. A use as claimed in any one of claims 36 and 41 to 43, substantially as herein described with reference to any example thereof. 47. A ation product as claimed in any one of claims 37 to 39, substantially as 5 herein described with reference to any example thereof.
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US201161556948P 2011-11-08 2011-11-08
US61/556,948 2011-11-08
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