ES2539480T3 - 3,4-disubstituted 1H-pyrazole compounds and their use as modulators of cyclin-dependent kinases (CDK) and glycogen synthase kinase-3 (GSK-3) - Google Patents

Abstract

The invention provides compounds of the formula (0) or salts or tautomers or N-oxides or solvates thereof for use in the prophylaxis or treatment of disease states and conditions such as cancers mediated by cyclin-dependent kinase and glycogen synthase kinase-3. In formula (0): X is a group R1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring; A is a bond, SO2, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; R1 is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO2; R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

Description

3,4-disubstituted 1H-pyrazole compounds and their use as modulators of cyclin-dependent kinases (CDK) and glycogen synthase kinase-3 (GSK-3)

This invention relates to pyrazole compounds that inhibit or modulate the activity of cyclin-dependent kinases (CDK) and glycogen synthase kinase-3 (GSK-3), to the use of the compounds in the treatment or prophylaxis of pathological conditions or mediated conditions by cyclin-dependent kinases and glycogen synthase kinase-3, and to new compounds that have inhibitory or modulating activity of cyclin-dependent kinases or glycogen synthase kinase-3. Pharmaceutical compositions containing the new compounds and chemical intermediates are also provided.

Background of the Invention

Protein kinases constitute a large family of structurally related enzymes that are responsible for controlling a wide variety of signal transduction processes in the cell (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA). Kinases can be classified into families by the phosphorylating substrates (for example, protein-tyrosine, protein-serine / threonine, lipids, etc.). Sequence residues have been identified that generally correspond to each of these kinase families (eg, Hanks, SK, Hunter, T., FASEB J., 9: 576-596 (1995); Knighton, et al., Science , 253: 407414 (1991); Hiles, et al., Cell, 70: 419-429 (1992); Kunz, et al., Cell, 73: 585-596 (1993); Garcia-Bustos, et al., EMBO J., 13: 2352-2361 (1994)).

Protein kinases can be characterized by their regulatory mechanisms. These mechanisms include, for example, autophosphorylation, transfosphorylation by other kinases, protein-protein interactions, protein-lipid interactions and protein-polynucleotide interactions. An individual protein kinase may be regulated by more than one mechanism.

The kinases regulate many different cellular processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular activation / inactivation switches that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. The appropriate protein kinase works in signaling pathways to activate or inactivate (either directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeleton protein, ion channel or pump or transcription factor. Uncontrolled signaling due to a defective control of protein phosphorylation has been implicated in several diseases, including, for example, inflammation, cancer, allergy / asthma, diseases and conditions of the immune system, diseases and conditions of the central nervous system and angiogenesis.

The eukaryotic cell division process can be broadly divided into a series of sequential phases called G1, S, G2 and M. It has been shown that the correct progression through the different phases of the cell cycle is critically dependent on spatial regulation and temporal of a family of proteins known as cyclin-dependent kinases (CDK) and a diverse set of their cognate protein equivalents called cyclines. CDKs are serine-threonine kinase proteins homologous to cdc2 (also known as CDK1) that are capable of using ATP as a substrate in the phosphorylation of various polypeptides in a sequence-dependent context. Cyclines are a family of proteins characterized by a region of homology,

which contains approximately 100 amino acids, called the "cyclin box" that is used in the binding to, and to define the selectivity for, CDK-specific equivalent proteins.

Modulation of expression levels, degradation rates, and activation levels of the different CDKs and cyclines throughout the cell cycle results in the cyclic formation of a series of CDK / cyclin complexes, in which the CDKs are enzymatically active. The formation of these complexes controls the passage through discrete cell cycle control points and thus allows the cell division process to continue. Failure to meet the pre-required biochemical criteria at a given cell cycle control point, that is, failure to form a required CDK / cyclin complex, can result in cell cycle stopping and / or cell apoptosis. Aberrant cell proliferation, as manifested in cancer, may frequently be due to the loss of proper control of the cell cycle. Inhibition of the enzymatic activity of the CDKs therefore provides a means by which the division of and / or eliminating abnormally dividing cells can be stopped. The diversity of CDK, and CDK complexes, and their critical roles in the mediation of the cell cycle, provides a broad spectrum of selected potential therapeutic targets based on a defined biochemical reasoning.

The progression of the G1 phase to the S phase of the cell cycle is mainly regulated by CDK2, CDK3, CDK4 and CDK6 by association with members of type D and E cyclines. Type D cyclines appear instrumental to allow passage beyond the restriction point of G1, while the CDK2 / cyclin complex

E is key to the transition from phase G1 to S. It is thought that subsequent progression through phase S and entry into G2 requires the CDK2 / cyclin A complex. Both mitosis and the transition from phase G2 to M that triggers them, they are regulated by complexes of CDK1 and type A and B cyclines.

During the G 1 phase the Retinoblastoma (Rb) protein, and related pocket proteins such as p130, are substrates for the CDK (2, 4, and 6) / cyclin complexes. Progression through G1 is facilitated in part by hyperphosphorylation, and therefore inactivation, of Rb and p130 by the CDK (4/6) / cyclin-D complexes. The hyperphosphorylation of Rb and p130 causes the release of transcription factors, such as E2F, and thus the expression of genes necessary for progression through G1 and for entry into the S phase, such as the cyclin gene

E. The expression of cyclin E facilitates the formation of the CDK2 / cyclin complex that amplifies, or maintains, E2F levels by additional phosphorylation of Rb. The CDK2 / cyclin E complex also phosphorylates other proteins necessary for DNA replication, such as NPAT, which has been implicated in histone biosynthesis. The progression in G1 and the G1 / S transition are also regulated by the Myc mitogen-stimulated pathway, which is fed into the CDK2 / cyclin E pathway. CDK2 is also connected to the p53-mediated DNA damage response pathway. p53 regulation of p21 levels. p21 is a CDK2 / cyclin E protein inhibitor and is thus capable of blocking, or delaying, the G1 / S transition. The CDK2 / cyclin E complex can thus represent a point at which the biochemical stimuli of the Rb, Myc and p53 pathways are integrated to some degree. CDK2 and / or the CDK2 / cyclin E complex therefore represent good targets for therapeutics designed to stop, or regain control of, the cell cycle in cells that divide aberrantly.

The exact role of CDK3 in the cell cycle is unclear. So far no cognate cyclin equivalent has been identified, but a dominant negative form of CDK3 delays cells in G1, thus suggesting that CDK3 has a role in regulating the G1 / S transition.

Although most CDKs have been implicated in the regulation of the cell cycle, there is evidence that certain members of the CDK family are involved in other biochemical processes. This is exemplified by CDK5 which is necessary for the correct neuronal development and which has also been implicated in the phosphorylation of several neuronal proteins such as Tau, NUDE-1, synapsin1, DARPP32 and the Munc18 / Syntaxin1A complex. Neural CDK5 is conventionally activated by binding to p35 / p39 proteins. The activity of CDK5 can be deregulated, however, by the union of p25, a truncated version of p35. The conversion of p35 to p25, and the subsequent deregulation of CDK5 activity, can be induced by ischemia, excitotoxicity and the βamiloid peptide. Consequently, p25 has been implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's, and is therefore interesting as a target for therapeutics directed against these diseases.

CDK7 is a nuclear protein that has CAK cdc2 activity and binds to cyclin H. CDK7 has been identified as a component of the TFIIH transcriptional complex that has C-terminal domain activity (CTD) of RNA polymerase II. This has been associated with the regulation of HIV-1 transcription through a biochemical route mediated by Tat. CDK8 binds to cyclin C and has been implicated in the phosphorylation of CTD of RNA polymerase II. Similarly, the CDK9 / cyclin-T1 complex (P-TEFb complex) has been implicated in the control of elongation of RNA polymerase II. PTEF-b is also required for activation of the transcription of the HIV-1 genome by the Tat viral transactivator through its interaction with the cyclin T1. CDK7, CDK8, CDK9 and the P-TEFb complex are therefore potential targets for anti-viral therapeutics.

At a molecular level, mediation of the activity of the CDK / cyclin complex requires a series of phosphorylation, or dephosphorylation, stimulators and inhibitors events. CDK phosphorylation is performed by a group of CDK activating kinases (CAK) and / or kinases such as wee1, Myt1 and Mik1. Dephosphorylation is performed by phosphatases such as cdc25 (a and c), pp2a, or KAP.

The activity of the CDK / cyclin complex can also be regulated by two families of endogenous cellular protein inhibitors: the Kip / Cip family, or the INK family. INK proteins specifically bind to CDK4 and CDK6. p 16ink4 (also known as MTS 1) is a potential tumor suppressor gene that is mutated, or deleted, in a large number of primary cancers. The Kip / Cip family contains proteins such as p21Cip1, Waf1, p27Kip1 and p57Kip2. As previously discussed, p21 is induced by p53 and is capable of inactivating the CDK2 / cyclin (E / A) and CDK4 / cyclin (D1 / D2 / D3) complexes. Atypically low levels of p27 expression have been observed in breast, colon and prostate cancers. In contrast, it has been shown that overexpression of cyclin E in solid tumors correlates with a poor prognosis of the patient. Overexpression of cyclin D1 has been associated with esophageal, breast, squamous and non-small cell lung carcinomas.

The main roles of the CDKs, and their associated proteins, in the coordination and direction of the cell cycle in proliferative cells have been previously underlined. Some of the biochemical routes in which CDKs play a key role have also been described. The development of monotherapies for the treatment of proliferative disorders, such as cancers, using therapeutics generically directed to the CDKs, or to specific CDKs, is therefore potentially highly desirable. CDK inhibitors could also possibly be used to treat other conditions such as viral infections, autoimmune diseases and neuro-degenerative diseases, among others. Therapeutics targeting CDK can also provide clinical benefits in the treatment of the previously described diseases when used in therapy.

combination with existing or new therapeutic agents. Anti-cancer therapies targeting CDKs could potentially have advantages over many current antitumor agents since they would not interact directly with DNA and should therefore reduce the risk of developing secondary tumors.

Glycogen synthase kinase-3 (GSK3) is a serine-threonine kinase that appears as two isoforms expressed ubiquitously in humans (GSK3α and GSK3β beta). GSK3 has been implicated as having roles in embryonic development, protein synthesis, cell proliferation, cell differentiation, microtubule dynamics, cell motility and cell apoptosis. As such GSK3 has been implicated in the progression of pathological conditions such as diabetes, cancer, Alzheimer's disease, stroke, epilepsy, motor neuron disease and / or head trauma. Phylogenetically, GSK3 is closely related to cyclin-dependent kinases (CDK).

The substrate consensus peptide sequence recognized by GSK3 is (Ser / Thr) -XXX- (pSer / pThr), in which X is any amino acid (at positions (n + 1), (n + 2), (n + 3)) and pSer and pThr are phospho-serine and phospho-threonine respectively (n + 4). GSK3 phosphorylates the first serine, or threonine, in position (n). Phospho-serine, or phosphotreonin, in position (n + 4) seems necessary to prime GSK3 to provide a maximum substrate replacement rate. Phosphorylation of GSK3α in Ser21, or GSK3β in Ser9, results in the inhibition of GSK3. Mutagenesis and peptide competition studies have resulted in the model that the phosphorylated N-terminal end of GSK3 is capable of competing with the phospho-peptide substrate (S / TXXXpS / pT) by an auto-inhibitory mechanism. There are also data that suggest that GSK3α and GSKβ may be subtly regulated by phosphorylation of tyrosines 279 and 216 respectively. Mutation of these residues to a Phe caused a reduction in kinase activity in vivo. The X-ray crystallographic structure of GSK3β has helped shed light on all aspects of GSK3 activation and regulation.

GSK3 is part of the insulin response pathway in mammals and is capable of phosphorylating, and thus inactivating, glycogen synthase. Upward regulation of glycogen synthase activity, and thus glycogen synthesis, by inhibiting GSK3, has thus been considered a potential means to combat type II, or non-insulin dependent diabetes mellitus (NIDDM) : a condition in which body tissues become resistant to insulin stimulation. The response to cellular insulin in liver tissues, adipose

or muscle, is triggered by the binding of insulin to an extracellular insulin receptor. This causes phosphorylation, and subsequent recruitment in the plasma membrane, of the insulin receptor substrate proteins (IRS). Additional phosphorylation of the IRS proteins initiates the recruitment of phosphoinositide-3 kinase (PI3K) into the plasma membrane in which it is capable of releasing the second phosphatidinylinosityl 3,4,5trisphosphate messenger (PIP3). This facilitates the co-localization of 3-phosphoinositide-dependent protein kinase 1 (PDK1) and protein kinase B (PKB or Akt) in the membrane, in which PDK1 activates PKB. PKB is capable of phosphorylating, and thus inhibiting, GSK3α and / or GSKβ by phosphorylation of Ser9, or ser21, respectively. The inhibition of GSK3 triggers the upward regulation of glycogen synthase activity. Therapeutic agents capable of inhibiting GSK3 may thus be able to induce cellular responses similar to those observed in insulin stimulation. An additional in vivo substrate of GSK3 is the starting factor for the synthesis of eukaryotic 2B proteins (eIF2B). eIF2B is inactivated by phosphorylation and is thus able to suppress protein biosynthesis.

Inhibition of GSK3, for example by inactivation of the "mammalian rapamycin target" (mTOR) protein, can thus regulate protein biosynthesis upwards. Finally, there is some evidence of the regulation of GSK3 activity by the pathogen of the mitogen-activated protein kinase (MAPK) by phosphorylation of GSK3 by kinases such as protein kinase 1 activated by the mitogen-activated protein kinase (MAPKAP- K1 or RSK). These data suggest that the activity of GSK3 can be modulated by mitogenic, insulin and / or amino acid stimuli.

It has also been shown that GSK3β is a key component in the Wnt vertebrate signaling path. This biochemical pathway has been shown to be critical for normal embryonic development and regulates cell proliferation in normal tissues. GSK3 is inhibited in response to Wnt stimuli. This may result in dephosphorylation of GSK3 substrates such as Axine, the colonic adenomatous polyposis gene product (APC) and βcatenin. Aberrant regulation of the Wnt route has been associated with many cancers. Mutations in APC, and / or β-catenin, are common in colorectal cancer and other tumors. It has also been shown that β-catenin is important in cell adhesion. Thus, GSK3 can also modulate cell adhesion processes to some degree. Apart from the biochemical routes already described, there are also data that involve GSK3 in the regulation of cell division by phosphorylation of cyclin-D1, in the phosphorylation of transcription factors such as c-Jun, CCAAT / α-enhancing protein junction ( C / EBPα), c-Myc and / or other substrates such as the Nuclear Factor of Activated T cells (NFATc), Heat Shock Factor-1 (HSF-1) and the binding protein of the c-AMP response element (CREB). GSK3 also seems to play a role, although tissue specific, in the regulation of cell apoptosis. The role of GSK3 in the modulation of cell apoptosis, through a proapoptotic mechanism, may have a particular relevance for medical conditions in which neuronal apoptosis can occur. Examples of these are head trauma, stroke, epilepsy, Alzheimer's and motor neuron diseases, progressive supranuclear paralysis, corticobasal degeneration, and Pick's disease. It has been shown in vitro that GSK3 is capable of hyper-phosphorylating the Tau microtubule associated protein. Tau hyperphosphorylation disrupts its normal binding to microtubules and can also lead to the formation of intracellular Tau filaments. It is believed that the progressive accumulation of these filaments leads to dysfunction and degeneration.

eventual neuronal The inhibition of Tau phosphorylation, by inhibition of GSK3, can thus provide a means to limit and / or prevent neurodegenerative effects.

Previous Technique

WO 02/34721 by Du Pont describes a class of indeno [1,2-c] pyrazol-4-ones as inhibitors of cyclin-dependent kinases.

WO 01/81348 from Bristol Myers Squibb describes the use of 5-thio-, sulfinyl- and sulfonylpyrazolo [3,4-b] -pyridines as cyclin-dependent kinase inhibitors.

WO 00/62778 also from Bristol Myers Squibb describes a class of protein tyrosine kinase inhibitors.

WO02 / 068406 from Amgen Inc. describes pyrazole compounds that inhibit protein kinases such as CDK-2 and CDK-5.

WO 01 / 72745A1 of Cyclacel describes 2-substituted 4-heteroaryl-pyrimidines and their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependent kinases (CDK) and therefore their use in the treatment of proliferative disorders such such as cancer, leukemia, psoriasis and the like.

WO 99/21845 by Agouron describes 4-aminothiazole derivatives to inhibit cyclin-dependent kinases (CDK), such as CDK1, CDK2, CDK4, and CDK6. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing said compounds and to methods for treating malignancies and other disorders by the administration of effective amounts of said compounds.

WO 01/53274 by Agouron describes as a CDK kinase inhibitor a class of compounds that may comprise an amide substituted benzene ring attached to an N-containing heterocyclic group.

WO 01/98290 (Pharmacia & Upjohn) describes a class of 3-aminocarbonyl-2-carboxamido thiophene derivatives as protein kinase inhibitors.

WO 01/53268 and WO 01/02369 of Agouron describe compounds that mediate or inhibit cell proliferation by inhibiting protein kinases such as cyclin-dependent kinase or tyrosine kinase. Agouron compounds have an aryl or heteroaryl ring attached directly or by a group CH = CH or CH = N to position 3 of an indazole ring.

WO 00/39108 and WO 02/00651 (both of Du Pont Pharmaceuticals) describe heterocyclic compounds that are inhibitors of trypsin-like serine protease enzymes, especially factor Xa and thrombin. The compounds are indicated to be useful as anticoagulants or for the prevention of thromboembolic disorders.

US 2002/0091116 (Zhu et al.), WO 01/19798 and WO 01/64642 each describe various groups of heterocyclic compounds as Factor Xa inhibitors. Some 1-substituted pyrazole carboxamides are described and exemplified.

US 6,127,382, WO 01/70668, WO 00/68191, WO 97/48672, WO 97/19052 and WO 97/19062 (all of Allergan) each describe compounds having retinoid-like activity for use in the treatment of several hyperproliferative diseases including cancers.

WO 02/070510 (Bayer) describes a class of amino-dicarboxylic acid compounds for use in the treatment of cardiovascular diseases. Although pyrazoles are semen generically, there are no specific examples of pyrazoles in this document.

WO 97/03071 (Knoll AG) describes a class of heterocyclyl-carboxamide derivatives for use in the treatment of disorders of the central nervous system. Pyrazoles are generally mentioned as examples of heterocyclic groups but specific pyrazole compounds are not described or exemplified.

WO 97/40017 (Novo Nordisk) describes compounds that are modulators of tyrosine protein phosphatases.

WO 03/020217 (Univ. Connecticut) describes a class of pyrazole 3-carboxamides as cannabinoid receptor modulators for treating neurological conditions. It is indicated (page 15) that the compounds can be used in cancer chemotherapy but it is not clear whether the compounds are active as anticancer agents or if they are administered for other purposes.

WO 01/58869 (Bristol Myers Squibb) describes cannabinoid receptor modulators that can be used inter alia to treat a variety of diseases. The main intended use is the treatment of respiratory diseases, although reference is made to cancer treatment.

WO 01/02385 (Aventis Crop Science) describes derivatives of 1- (quinoline-4-yl) -1H-pyrazole as fungicides. 1-unsubstituted pyrazoles are described as synthetic intermediates.

WO 2004/039795 (Fujisawa) describes amides containing a 1-substituted pyrazole group as inhibitors of apolipoprotein B secretion. The compounds are indicated to be useful in the treatment of conditions such as hyperlipidemia.

WO 2004/000318 (Cellular Genomics) describes several amino-substituted monocycles as kinase modulators. None of the exemplified compounds is pyrazole.

Summary of the Invention

The compounds of formula (II) have inhibitory or modulating activity of cyclin-dependent kinases, and are expected to be useful in the prevention or treatment of pathological conditions or conditions mediated by kinases.

Thus, for example, it is envisioned that the compounds of formula (II) will be useful for mitigating or reducing the incidence of cancer.

Accordingly, in a first aspect the invention provides a combination comprising:

(i)

compound of the formula (II):

or salts or tautomers or N-oxides or solvates thereof;

in which

Y is an alkylene chain or bond with a length of 1, 2 or 3 carbon atoms;

R1 is a carbocyclic or heterocyclic group having 3 to 12 ring members, in which the carbocyclic or heterocyclic groups are unsubstituted or substituted with one or more R10 substituent groups;

R2 is hydrogen or methyl;

R3 is selected from non-aromatic carbocyclic or heterocyclic groups having 3 to 12 ring members, in which the carbocyclic or heterocyclic groups are not substituted or substituted with one or more R10 substituent groups; Y

R10 is selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-hydrocarbonylamino C1-4, carbocyclic and heterocyclic groups having 3 to 12 ring members; a Ra-Rb group in which Ra is a bond, O, CO, X1C (X2), C (X2) X1, X1C (X2) X1, S, SO, SO2, NRc, SO2NRc or NRcSO2; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having 3 to 12 ring members, and a C1-8 alkyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-hydrocarbonylamino C1-4, carbocyclic and heterocyclic groups having 3 to 12 ring members;

Rc is selected from hydrogen and C1-4 hydrocarbyl; Y

X1 is O, S or NRc and X2 is = O, = S or = NRc;

and with the proviso that when the R10 substituent group comprises or includes a carbocyclic or heterocyclic group, said carbocyclic or heterocyclic group may not be substituted or may itself be substituted with one or more additional R10 substituent groups and in which (a) said additional R10 substituent groups include carbocyclic or heterocyclic groups, which are not themselves further substituted; or (b) said additional substituents do not include carbocyclic or heterocyclic groups but are nonetheless selected from the groups listed above in the definition of R10; Y

(ii) one or more additional therapeutic agents.

In a second aspect, the invention provides a compound of formula (II) as defined above for use in the treatment of a disease that is:

-

viral infections, for example herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevention of the development of AIDS in HIV-infected individuals; or -diabetes mellitus type II or non-insulin dependent; or - autoimmune diseases; or - head trauma; or -ict; or

-

epilepsy; or-neurodegenerative disorders, for example Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration or such as Alzheimer's, motor neuron disease, progressive supranuclear paralysis, corticobasal degeneration and Pick's disease; or

-

chronic inflammatory diseases, for example systemic lupus erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus; or

- cardiovascular diseases such as cardiac hypertrophy, restenosis, and atherosclerosis, or such as arrhythmia; or -glomerulonephritis; or -myelodysplastic syndrome; or -ischemic damage associated with heart attacks, stroke and reperfusion damage; or -hepatic diseases induced by toxins or related to alcohol; or -hematologic diseases, for example chronic anemia and aplastic anemia; or -degenerative diseases of the musculoskeletal system for example, osteoporosis and arthritis, or - aspirin sensitive rhinosinusitis; or -cystic fibrosis; or -multiple sclerosis; or -kidney diseases; or - cancer pain; or -Cancer, in particular RB + ve tumors. Any one or more of the following optional conditions, in any combination, may apply to

compounds of formula (II) and subgroups thereof: (a-i) R1 is different from a residue containing a purine nucleoside group. (a-ii) When Y-R3 is cycloalkyl, then R1 is different from a tetrahydronaphthalene, tetrahydroquinolinyl group,

tetrahydrochromanyl or substituted or unsubstituted tetrahydrothiochromanyl.

(a-iii) R3 is different from a moiety that contains a 1,2,8,8a-tetrahydro-7-methyl-cyclopropa [c] pyrrolo [3,2, e] indole-4 (5H) -one group. (a-iv) R1 (CO) NH is other than 4- (tert-butyloxycarbonylamino) -3-methylimidazol-2-ylcarbonylamino. (b-i) R3 is different from an azabicyclo group with bridge. (b-ii) When R1 or R3 contains a moiety in which a heterocyclic ring having a member in the S ring (= O) 2 is

fused with a carbocyclic ring, said carbocyclic ring is different from a benzene ring substituted or not

replaced. The reference in condition (a-i) to a purine nucleoside group refers to substituted and unsubstituted purine groups that have a monosaccharide group attached to them (for example, a pentose or hexose) or a derivative of a group monosaccharide, for example a monosaccharide deoxy group or a substituted group of monosaccharide.

The reference in condition (b-i) to a bridge azabicyclo group refers to bicycloalkane bridge systems in which one of the bicycloalkane carbon atoms has been replaced by a nitrogen atom. In bridge ring systems, two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992.

The invention also provides the use of a compound of the formula (II) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a pathological condition or condition mediated by a cyclin-dependent kinase.

Conditions (a-i) to (a-iv) and (b-i) to (b-ii) in formula (II) above, refer to the descriptions in the following documents of the prior art.

(a-i) WO 03/014137

(a-ii) WO 97/48672, WO 97/19052

(a-iii) US 5,502,068

(b-i) WO 03/040147

(b-ii) WO 00/59902

Any one or more of the above optional conditions, (ai) to (a-iv) and (bi) to (b-ii) in any combination, can also be applied to the compounds of formulas (IV), (IVa), ( Va), (Vb), (VIa), (VIb), and subgroups thereof as defined herein.

The invention also provides:

 The use of the combination as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a pathological condition or condition mediated by a cyclin-dependent kinase.

A combination as defined herein for use in the prophylaxis or treatment of a pathological condition or condition that is a proliferative disorder in which the proliferative disorder is a cancer. The invention also provides combinations of the invention for use in:

A method to mitigate or reduce the incidence of a disease or condition that comprises or arises from abnormal cell growth in a mammal, a method that comprises administering to the mammal a combination as defined herein in an amount effective to inhibit abnormal cell growth. .

 A method to mitigate or reduce the incidence of a pathological condition or condition mediated by a cyclin-dependent kinase or glycogen synthase kinase-3, a method comprising administering to a subject in need of a combination as defined herein.

 A method for the prophylaxis or treatment of a pathological condition or condition mediated by a cyclin dependent kinase, a method comprising administering to a subject in need of a combination as defined herein.

 A method of treating a disease or condition that comprises or arises from abnormal cell growth in a mammal, a method comprising administering to the mammal a combination as defined herein in an amount effective to inhibit abnormal cell growth.

A method for treating a disease or condition that comprises or arises from abnormal cell growth in a mammal, the method comprising administering to the mammal a combination as defined herein in an amount effective to inhibit a cyclin-dependent kinase (for example , CDK2).

 A method for inhibiting a cyclin-dependent kinase, a method comprising contacting the kinase with a kinase inhibitor combination as defined herein.

 A method of modulating a cellular process (eg, cell division) by inhibiting the activity of a cyclin dependent kinase using a combination as defined herein.

 A method for the treatment or prophylaxis of any one of the pathological conditions or conditions described herein, a method comprising administering to a patient (eg, a patient in need thereof) a combination (eg, a therapeutically effective amount ) as defined herein.

 A method to mitigate or reduce the incidence of a pathological condition or condition described herein, a method comprising administering to a patient (for example, a patient in need thereof) a combination as defined herein.

 A method for the diagnosis and treatment of a pathological condition or condition mediated by a cyclin dependent kinase, a method that comprises (II) screening a patient to determine if a disease or condition that the patient suffers or may suffer is one that would be susceptible to treatment with a combination that has activity against cyclin-dependent kinases; and (ii) when it is indicated that the disease or condition for which the patient is thus susceptible, subsequently administer to the patient a combination as defined herein.

The combinations of the invention are also considered to be inhibitors of glycogen synthase kinase-3 (GSK3) and, accordingly, the invention also provides methods and uses of kinase inhibitor or modulator combinations as defined herein but in which the kinase is glycogen synthase kinase-3.

In additional aspects, the invention provides:

 A pharmaceutical composition comprising a combination as defined herein and a pharmaceutically acceptable carrier.

 Combinations as defined herein for use in medicine.

 The use of a combination as defined herein, for the manufacture of a medicament for the prophylaxis or treatment of any of the pathological conditions or conditions described herein.

 The use of a combination as defined herein for the manufacture of a medicament for the treatment or prophylaxis of a pathological condition or condition in a patient who has been screened and determined to be suffering from or at risk of suffering, a disease or condition that would be susceptible to treatment with a compound that has activity against a cyclin-dependent kinase.

In each of the above uses, the methods and other aspects of the invention, as well as any aspects and embodiments of the invention as shown below, reference to compounds of the formulas (II), (IV), (IVa), ( Va), (Vb), (VIa) or (VIb) and subgroups thereof as defined herein include in their scope the salts or solvates or tautomers or N-oxides of the compounds.

General Preferences and Definitions

The following general preferences and definitions shall apply to each of the residues Y, R1 to R3 and any subdefinition, subgroup or realization thereof, unless the context indicates otherwise.

In this specification, references to formula (II) include formulas (IV), (IVa), (Va), (Vb), (VIa) or (VIb) and subgroups, examples or embodiments of formulas (IV) , (IVa), (Va), (Vb), (VIa) or (VIb) unless the context indicates otherwise.

Thus, for example, inter alia references to therapeutic uses, pharmaceutical formulations and processes to prepare the compounds, when referring to formula (II), should also be taken as referring to formulas (IV), (IVa), (Va), (Vb), (VIa) or (VIb) and subgroups, examples or embodiments of formulas (IV), (IVa), (Va), (Vb), (VIa) or (VIb).

Similarly, when preferences, embodiments and examples are provided for compounds of formula (II), they are also applicable to formulas (IV), (IVa), (Va), (Vb), (VIa) or (VIb ) and subgroups, examples or embodiments of formulas (IV), (IVa), (Va), (Vb), (VIa) or (VIb) unless the context requires otherwise.

References to "carbocyclic" and "heterocyclic" groups as used herein will include, not

If the context indicates otherwise, both aromatic and non-aromatic ring systems. Thus, for example, the term "carbocyclic and heterocyclic groups" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. In general, said groups may be monocyclic or bicyclic and may contain, for example, 3 to 12 members in the ring, more usually 5 to 10 members in the ring. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7, and 8 members in the ring, more usually 3 to 7, and preferably 5 or 6 members in the ring. Examples of bicyclic groups are those that contain 8, 9, 10, 11 and 12 members in the ring and more usually 9 or 10 members in the ring.

The carbocyclic or heterocyclic groups may be aryl or heteroaryl groups having 5 to 12 members in the ring, more usually 5 to 10 members in the ring. The term "aryl" as used herein

"Memo" refers to a carbocyclic group that has an aromatic character and the term "heteroaryl" is used herein to indicate a heterocyclic group that has an aromatic character. The terms "aryl" and

"Heteroaryl" encompasses polycyclic ring systems (eg, bicyclic) in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In said polycyclic systems, the group may be joined by the aromatic ring or by a non-aromatic ring. The aryl or heteroaryl groups may be monocyclic or bicyclic groups and may not be substituted or substituted with one or more substituents, for example one or more R10 groups as defined herein.

The term "non-aromatic group" encompasses unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms "unsaturated" and "partially saturated" refer to rings in which the ring structure or structures contain atoms that

they share more than one valence bond, that is, the ring contains at least one multiple bond, for example, a C = C, C≡C or N = C link. The term "fully saturated" refers to rings in which there are no multiple bonds between the atoms in the ring. Saturated carbocyclic groups include cycloalkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example cyclopentenyl, cycloheptenyl and cyclooctenyl. A further example of a cycloalkenyl group is cyclohexenyl.

Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve members in the ring and more usually five to ten members in the ring. The heteroaryl group may be, for example, a five-membered, six-membered monocyclic ring or a bicyclic structure formed from five-ring

or six fused members or two fused six-member rings or, as an additional example, two fused five-member rings. Each ring can contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl group contains at least one nitrogen atom in the ring. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole nitrogen or pyrrole. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any ring substituent amino group, will be less than five.

Examples of five-membered heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazol, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.

Examples of six-membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridacin, pyrimidine and triacin.

A bicyclic heteroaryl group can be, for example, a group selected from:

a) a benzene ring fused with a 5 or 6 member ring containing 1, 2 or 3 heteroatoms in the ring;

b) a pyridine ring fused with a 5 or 6 member ring containing 1, 2 or 3 heteroatoms in the ring;

c) a pyrimidine ring fused with a 5 or 6 membered ring containing 1 or 2 heteroatoms in the ring;

d) a pyrrole ring fused with a 5 or 6 member ring containing 1, 2 or 3 heteroatoms in the ring;

e) a pyrazole ring fused with a 5 or 6 member ring containing 1 or 2 heteroatoms in the ring;

f) an imidazole ring fused with a 5 or 6 member ring containing 1 or 2 heteroatoms in the ring;

g) an oxazole ring fused with a 5 or 6 membered ring containing 1 or 2 heteroatoms in the ring;

h) an isoxazole ring fused with a 5 or 6 membered ring containing 1 or 2 heteroatoms in the ring;

i) a fused thiazole ring with a 5 or 6 member ring containing 1 or 2 heteroatoms in the ring;

j) an isothiazole ring fused with a 5 or 6 member ring containing 1 or 2 ring heteroatoms;

k) a thiophene ring fused with a 5 or 6 member ring containing 1, 2 or 3 heteroatoms in the ring;

l) a fused ring with a 5 or 6 member ring containing 1, 2 or 3 heteroatoms in the ring;

m) an oxazole ring fused with a 5 or 6 member ring containing 1 or 2 heteroatoms in the ring;

n) an isoxazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms in the ring;

o) a cyclohexyl ring fused with a 5 or 6-member ring containing 1, 2 or 3 heteroatoms in the ring; Y

p) a cyclopentyl ring fused with a 5 or 6 member ring containing 1, 2 or 3 heteroatoms in the ring.

Particular examples of bicyclic heteroaryl groups containing a five-membered ring fused with another five-membered ring include but are not limited to imidazothiazole (eg, imidazo [2,1-b] thiazole) and imidazoimidazole (eg, imidazo [ 1,2-a] imidazole).

Particular examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzothothiazole, isobenzofuran, indole, indole, isool indolicin, indoline, isoindoline, purine (for example, adenine, guanine), indazole, pyrazolopyrimidine (for example, pyrazolo [1,5a] pyrimidine), triazolopyrimidine (for example, [1,2,4] triazolo [1,5- a] pyrimidine), benzodioxol and pyrazolopyridine (for example, pyrazolo [1,5-a] pyridine).

Particular examples of bicyclic heteroaryl groups containing two fused six-membered ring include but are not limited to quinoline, isoquinoline, chromane, thiochroman, chromene, isochromen, chromane, isochroman, benzodioxane, quinolicin, benzoxacin, benzodiacin, pyridopyridine, quinoxaline groups, Quinazoline, cinnoline, phthalacin, naphthyridine and pteridine.

A subset of heteroaryl groups comprises pyridyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, triazolyl, tetrazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl , chromanyl, thiochromanyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzthiazolyl and benzisothiazole, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adenine, guanine), indazolyl, benzodioxolyl, chromenyl, isochromenyl, isochromanyl, benzodioxanyl, quinolizinyl , benzoxacinyl, benzodiacinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalacinyl, naphthyridinyl and pteridinyl.

Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiene, dihydrobenzofuran, 2,3-dihydro-benzo [1,4] dioxin, benzo [1,3] groups dioxol, 4,5,6,7-tetrahydrobenzofuran, indoline and indane.

Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl and tetrahydronaphthyl groups.

Examples of non-aromatic heterocyclic groups include unsubstituted or substituted heterocyclic groups (with one or more R10 groups) having 3 to 12 ring members, typically 4 to 12 ring members and more usually 5 to 10 members in the ring. the ring. Such groups may be monocyclic or bicyclic, for example, and typically have 1 to 5 heteroatoms as ring members (more usually 1,2,3 or 4 ring member heteroatoms) typically selected from nitrogen, oxygen and sulfur.

When sulfur is present, it can exist, when the nature of adjacent atoms and groups allows it, such as –S-, –S (O) -or –S (O) 2-.

Heterocyclic groups may contain, for example, cyclic ether moieties (for example, as in tetrahydrofuran and dioxane), cyclic thioether moieties (for example as in tetrahydrothiophene and dithian), cyclic amine moieties (for example, as in pyrrolidine), amide moieties cyclic (for example, as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ester moieties (for example, as in butyrolactone), cyclic sulfones (for example, as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (for example, morpholine and thiomorpholine and their S-oxide and S, S-dioxide). Additional examples of heterocyclic groups are those containing a cyclic urea moiety (for example, as in imidazolidin-2-one),

In a subset of heterocyclic groups, heterocyclic groups contain cyclic ether moieties (for example, as in tetrahydrofuran and dioxane), cyclic thioether moieties (for example, as in tetrahydrothiophene and dithian), cyclic amine moieties (for example as in pyrrolidine) , cyclic sulfones (for example, as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (for example, thiomorpholine).

Examples of non-aromatic monocyclic heterocyclic groups include 5, 6 and 7 membered heterocyclic monocyclic groups. Particular examples include morpholine, piperidine (for example, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (for example, 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran ( 2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g., 4-tetrahydropyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazoline, pyrazoline, 2-pyrazine, pyrazoline, pyrazoline and N-alkyl piperazines such as N-methyl piperazine. Additional examples include thiomorpholine and its S-oxide and S, S-dioxide (particularly thiomorpholine). More additional examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine.

A preferred subset of non-aromatic heterocyclic groups consists of saturated groups such as azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine S, S-dioxide, piperazine, N-alkyl piperazines, and N-alkyl piperidines.

Another subset of non-aromatic heterocyclic groups consists of pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine S, S-dioxide, piperazine and N-alkyl piperazines such as N-methyl piperazine.

A particular subset of heterocyclic groups consists of pyrrolidine, piperidine, morpholine and N-alkyl piperazines (for example, N-methyl piperazine), and optionally thiomorpholine.

Examples of non-aromatic carbocyclic groups include cycloalkane groups such as cyclohexyl and cyclopentyl, cycloalkenyl groups such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well as cyclohexadienyl, cyclooctatetraen, tetrahydronaphtenyl and decalinyl.

Preferred non-aromatic carbocyclic groups are monocyclic rings and most preferably saturated monocyclic rings.

Typical examples are saturated carbocyclic rings of three, four, five and six members, for example, optionally substituted cyclopentyl and cyclohexyl rings.

A subset of non-aromatic carbocyclic groups includes unsubstituted or substituted monocyclic groups (with one or more R10 groups) and particularly saturated monocyclic groups, for example, cycloalkyl groups. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; more typically cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclohexyl.

Additional examples of non-aromatic cyclic groups include bridge ring systems such as

bicycloalkanes and azabicycloalkanes although said bridge ring systems are generally less preferred. By "bridge ring systems" is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. The Examples of bridged ring systems include bicycles [2.2.1] heptane, azabicyclo [2.2.1] heptane, bicycles [2.2.2] octane, aza-bicycles [2.2.2] octane, bicycles [3.2.1] octane and aza-bike [3.2.1] octane. A particular example of a bridge ring system is the 1-aza-bicyclo [2.2.2] octan-3-yl group.

When reference is made herein to carbocyclic and heterocyclic groups, the carbocyclic or heterocyclic ring may, unless the context indicates otherwise, be unsubstituted or substituted with one or more R10 substituent groups selected from halogen, hydroxy, trifluoromethyl , cyano, nitro, carboxy, amino, mono or C1-4 dihydrocarbylamino, carbocyclic and heterocyclic groups having 3 to 12 ring members; a Ra-Rb group in which Ra is a bond, O, CO, X1C (X2), C (X2) X1, X1C (X2) X1, S, SO, SO2, NRc, SO2NRc or NRcSO2; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-hydrocarbonylamino C1-4, carbocyclic and heterocyclic groups having 3 to 12 ring members and in which one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRc, X1C (X2), C (X2) X1 or X1C (X2) X1;

Rc is selected from hydrogen and C1-4 hydrocarbyl; Y

X1 is O, S or NRc and X2 is = O, = S or = NRc.

When the R10 substituent group comprises or includes a carbocyclic or heterocyclic group, said carbocyclic or heterocyclic group may be unsubstituted or may itself be substituted with one or more additional R10 substituent groups. In a subgroup of compounds of the formula (II), said additional R10 substituent groups may include carbocyclic or heterocyclic groups, which are not typically themselves further substituted. In another subgroup of compounds of the formula (II), said additional substituents do not include carbocyclic or heterocyclic groups but are however selected from the groups listed above in the definition of R10.

The R10 substituents can be selected in a way that contains more than 20 different atoms of hydrogen, for example, no more than 15 different atoms of hydrogen, for example no more than 12, or 11, or 10, or 9, or 8, or 7, or 6, or 5 different atoms of hydrogen.

When the carbocyclic and heterocyclic groups have a pair of substituents on adjacent ring atoms, the two substituents may be joined to form a cyclic group. Thus, two adjacent R10 groups, together with the carbon atoms or heteroatoms to which they are attached can form a 5-membered heteroaryl ring or a 5 or 6-membered non-aromatic carbocyclic or heterocyclic ring, wherein said heteroaryl groups and Heterocyclics contain up to 3 heteroatoms as ring members selected from N, O and S. For example, an adjacent pair of substituents on adjacent carbon atoms of a ring may be linked by one or more heteroatoms and optionally substituted alkylene groups to form a group oxa-, dioxa-, aza-, diaza-u oxa-aza-cycloalkyl fused.

Examples of such attached substituent groups include:

Examples of halogen substituents include fluorine, chlorine, bromine and iodine. Particularly preferred are fluorine and chlorine.

In the definition of the compounds of the formula (II) above and as used hereafter, the term "hydrocarbyl" is a generic term that encompasses aliphatic, alicyclic and aromatic groups that have a fully nucleus. of carbon and consisting of carbon and hydrogen atoms, unless otherwise indicated.

In certain cases, as defined herein, one or more of the carbon atoms that make up the carbon core may be replaced by a specified atom or groups of atoms.

Examples of hydrocarbyl groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenyl alkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups. Such groups may be unsubstituted or, when indicated, substituted with one or more substituents as defined herein. The examples and preferences set forth below apply to each of the hydrocarbyl substituent groups or hydrocarbyl-containing substituent groups referred to in the different substituent definitions for the compounds of the formula (II) unless the context indicates otherwise.

Preferred non-aromatic hydrocarbyl groups are saturated groups such as alkyl and cycloalkyl groups.

Generally as an example, hydrocarbyl groups can have up to eight carbon atoms, unless the context requires otherwise. In the subset of hydrocarbyl groups having 1 to 8 carbon atoms, particular examples are C1-6 hydrocarbyl groups, such as C1-4 hydrocarbyl groups (eg, C1-3 hydrocarbyl groups or C1-2 hydrocarbyl groups), where Specific examples are any individual value or combination of values selected from C1, C2, C3, C4, C5, C6, C7 and C8 hydrocarbyl groups.

The term "alkyl" covers both straight chain and branched chain alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl butyl, 3-methyl butyl, and n-hexyl and its isomers. In the subset of alkyl groups having 1 to 8 carbon atoms, particular examples are C1-6 alkyl groups, such as C1-4 alkyl groups (for example, C1-3 alkyl groups or C1-2 alkyl groups).

Examples of cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. In the subset of cycloalkyl groups, the cycloalkyl group will have 3 to 8 carbon atoms, with particular examples being C3-6 cycloalkyl groups.

Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-1,4-dienyl, pentenyl, and hexenyl. In the subset of alkenyl groups, the alkenyl group will have from 2 to 8 carbon atoms, with particular examples being C2-6 alkenyl groups, such as C2-4 alkenyl groups.

Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. In the subset of cycloalkenyl groups, cycloalkenyl groups will have 3 to 8 carbon atoms, and particular examples are C3-6 cycloalkenyl groups.

Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl) groups. In the subset of alkynyl groups having 2 to 8 carbon atoms, particular examples are C2-6 alkynyl groups, such as C2-4 alkynyl groups.

Examples of carbocyclic aryl groups include substituted and unsubstituted phenyl groups.

Examples of cycloalkylalkyl, cycloalkenyl alkyl, carbocyclic aralkyl, aralkenyl and aralkynyl groups include phenethyl, benzyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl and cyclopenthenylmethyl groups.

When present, and when indicated, a hydrocarbyl group may be optionally substituted with one or more substituents selected from hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono or dihydrocarbylamino C1-4, and carbocyclic groups and monocyclic or bicyclic heterocyclics having 3 to 12 (typically 3 to 10 and more usually 5 to 10) members in the ring. Preferred substituents include halogen such as fluorine. Thus, for example, the substituted hydrocarbyl group may be a partially fluorinated group.

or perfluorinated such as difluoromethyl or trifluoromethyl. In one embodiment, preferred substituents include monocyclic carbocyclic and heterocyclic groups having 3-7 ring members, more usually 3, 4, 5 or 6 ring members.

When indicated, one or more carbon atoms of a hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRc, X1C (X2), C (X2) X1 or X1C (X2) X1 (or a subset of these ) wherein X1 and X2 are as defined hereinbefore, provided that at least one carbon atom of the hydrocarbyl group remains. For example, 1, 2, 3 or 4 carbon atoms of the hydrocarbyl group can be replaced by one of the atoms or groups listed and the atoms or groups they replace may be the same or different. In general, the number of linear or core carbon atoms replaced will correspond to the number of linear or core atoms in the group that replaces them. Examples of groups in which one or more carbon atoms of the hydrocarbyl group have been replaced by a replacement atom or group as defined above include ethers and thioethers (C replaced by O or S), amides, esters, thioamides and thioesters (CC replaced by X1C (X2) or C (X2) X1), sulfones and sulfoxides (C replaced by SO or SO2), amines (C replaced by NRc). Additional examples include ureas, carbonates and carbamates (C-C-C replaced by X1C (X2) X1).

When an amino group has two hydrocarbyl substituents, they can, together with the nitrogen atom to which they are attached, and optionally with another heteroatom such as nitrogen, sulfur or oxygen, join to form a ring structure of 4 to 7 members and the ring, more usually 5 to 6 members in the ring.

The term "aza-cycloalkyl" as used herein refers to a cycloalkyl group in which one of the ring member carbons has been replaced by a nitrogen atom. Thus, examples of aza-cycloalkyl groups include piperidine and pyrrolidine. The term "oxa-cycloalkyl" as used herein refers to a cycloalkyl group in which one of the ring member carbons has been replaced by an oxygen atom. Thus, examples of oxa-cycloalkyl groups include tetrahydrofuran and tetrahydropyran. From

in an analogous manner, the terms "diaza-cycloalkyl", "dioxa-cycloalkyl" and "aza-oxa-cycloalkyl" refer respectively to cycloalkyl groups in which two carbon members of the ring have been replaced by two nitrogen atoms, or by two oxygen atoms or a nitrogen atom and an oxygen atom.

The definition "Ra-Rb" as used herein, either with respect to the substituents present in a carbocyclic or heterocyclic moiety, or with respect to other substituents present in other locations in the compounds of the formula (II), includes inter alia the compounds in which Ra is selected from a bond, O, CO, OC (O), SC (O), NRcC (O), OC (S), SC (S), NRcC (S), OC ( NRc), SC (NRc), NRcC (NRc), C (O) O, C (O) S, C (O) NRc, C (S) O, C (S) S, C (S) NRc, C (NRc) O, C (NRc) S, C (NRc) NRc, OC (O) O, SC (O) O, NRcC (O) O, OC (S) O, SC (S) O, NRcC (S ) O, OC (NRc) O, SC (NRc) O, NRcC (NRc) O, OC (O) S, SC (O) S, NRcC (O) S, OC (S) S, SC (S) S , NRcC (S) S, OC (NRc) S, SC (NRc) S, NRcC (NRc) S, OC (O) NRc, SC (O) NRc, NRcC (O) NRc, OC (S) NRc, SC (S) NRc, NRcC (S) NRc, OC (NRc) NRc, SC (NRc) NRc, NRcC (NRcNRc, S, SO, SO2, NRc, SO2NRc and NRcSO2 in which Rc is as defined above in the Present memory.

The Rb moiety may be a hydrogen or it may be a group selected from carbocyclic and heterocyclic groups having 3 to 12 ring members (typically 3 to 10 and more usually 5 to 10), and a substituted C1-8 hydrocarbyl group optionally as defined hereinbefore. Examples of hydrocarbyl, carbocyclic and heterocyclic groups are as shown above.

When Ra is O and Rb is a C1-8 hydrocarbyl group, Ra and Rb together form a hydrocarbyloxy group. Preferred hydrocarbyloxy groups include saturated hydrocarbyloxy such as alkoxy (for example, C1-6 alkoxy, more commonly C1-4 alkoxy such as ethoxy and methoxy, particularly methoxy), cycloalkoxy (for example C3-6 cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy) and cycloalkyalkoxy (for example C3-6 cycloalkyl-C1-2 alkoxy such as cyclopropylmethoxy).

The hydrocarbyloxy groups may be substituted with several substituents as defined herein. For example, the alkoxy groups may be substituted with halogen (for example as in difluoromethoxy and trifluoromethoxy), hydroxy (for example, as in hydroxyethoxy), C1-2 alkoxy (for example as in methoxyethoxy), C1-2 hydroxyalkyl (as in hydroxyethoxyethoxy) or a cyclic group (for example, a cycloalkyl group or non-aromatic heterocyclic group as defined hereinbefore). Examples of alkoxy groups having a non-aromatic heterocyclic group as a substituent are those in which the heterocyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C1-4-alkyl piperazines, cycloalkyl-C3- 7

piperazines, tetrahydropyran or tetrahydrofuran and the alkoxy group is a C1-4 alkoxy group, more typically a C1-3 alkoxy group talcomomethoxy, ethoxypropoxy.

Alkoxy groups substituted with a monocyclic group such as pyrrolidine, piperidine, morpholine and piperazine and the N-substituted derivatives thereof such as N-benzyl, N-acyl C1-4 and N-alkoxycarbonyl C1-4. Particular examples include pyrrolidinoethoxy, piperidinoethoxy and piperacinoethoxy.

When Ra is a bond and Rb is a C1-8 hydrocarbyl group, examples of Ra-Rb hydrocarbyl groups are as defined hereinbefore. The hydrocarbyl groups may be saturated groups such as cycloalkyl and alkyl and particular examples of such groups include methyl, ethyl and cyclopropyl. The hydrocarbyl groups (for example, alkyl) may be substituted with various groups and atoms as defined herein. Examples of substituted alkyl groups include alkyl groups substituted with one or more halogen atoms such as fluorine and chlorine (including particular examples bromoethyl, chloroethyl and trifluoromethyl), or hydroxy (for example, hydroxymethyl and hydroxyethyl), C1-8 acyloxy ( for example, acetoxymethyl and benzyloxymethyl), amino and mono and dialkylamino (for example, aminoethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl and tert-butylaminomethyl), alkoxy (for example, C1-2 alkoxy such as methoxy-as in methoxyethyl), and groups cyclics such as cycloalkyl groups, aryl groups, heteroaryl groups and non-aromatic heterocyclic groups as defined hereinbefore).

Particular examples of alkyl groups substituted with a cyclic group are those in which the cyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, alkyl-C1-4-piperazines, cycloalkyl-C3-7-piperazines, tetrahydropyran or tetrahydrofuran and the alkyl group is a C1-4 alkyl group, more typically a C1-3 alkyl group such as methyl, ethyl or n-propyl. Specific examples of alkyl groups substituted with a cyclic group include pyrrolidinomethyl, pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, piperidinylmethyl, piperazinomethyl and N-substituted forms thereof as defined herein.

Particular examples of alkyl groups substituted with aryl groups and heteroaryl groups include benzyl and pyridylmethyl groups.

When Ra is SO2NRc, Rb can be, for example, hydrogen or an optionally substituted C1-8 hydrocarbyl group or a carbocyclic or heterocyclic group. Examples of Ra-Rb in which Ra is SO2NRc include aminosulfonyl, C1-4 alkylaminosulfonyl and di-alkylaminosulfonyl groups, and sulfonamides formed from a cyclic amino group such as piperidine, morpholine, pyrrolidine, or a piperazine N - optionally substituted such as N-methyl piperazine.

Examples of Ra-Rb groups in which Ra is SO2 include alkylsulfonyl, heteroarylsulfonyl and arylsulfonyl groups, particularly monocyclic aryl and heteroaryl sulfonyl groups. Particular examples include methylsulfonyl, phenylsulfonyl and toluenesulfonyl.

When Ra is NRc, Rb can be, for example, hydrogen or an optionally substituted C1-8 hydrocarbyl group or a carbocyclic or heterocyclic group. Examples of Ra-Rb in which Ra is NRc include amino, C1-4 alkylamino (for example, methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino), di-C1-4 alkylamino (for example, dimethylamino and diethylamino) and cycloalkylamino (for example, cyclopropylamino, cyclopentylamino and cyclohexylamino).

Realizations and Preferences for Specific Y, R1 aR3 and R10

R2

R2 is hydrogen or methyl, most preferably hydrogen.

R1

R1 is a carbocyclic or heterocyclic group having 3 to 12 ring members, in which the carbocyclic group

or heterocyclic is not substituted or is substituted with one or more R10 substituent groups, or a C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from halogen (eg, fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono or C1-4 di-hydrocarbylamino, and carbocyclic or heterocyclic groups having 3 to 12 ring members, in which the carbocyclic or heterocyclic group is not substituted or substituted with one

or more R10 substituent groups, and in which 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO2. Examples of carbocyclic or heterocyclic groups and hydrocarbyl groups and general preferences for such groups are as shown above in the General Preferences and Definitions section and as shown below.

In one embodiment, R1 is an aryl or heteroaryl group.

When R1 is a heteroaryl group, particular heteroaryl groups include monocyclic heteroaryl groups containing up to three heteroatoms as selected ring members of O, S and N, and heteroaryl groups

bicyclics containing up to 2 heteroatoms as selected ring members of O, S and N and in which both rings are aromatic.

Examples of such groups include furanyl (for example, 2-furanyl or 3-furanyl), indolyl (for example, 3-indolyl, 6-indolyl), 2,3-dihydro-benzo [1,4] dioxinyl (for example , 2,3-dihydro-benzo [1,4] dioxin-5-yl), pyrazolyl (for example, pyrazol-5-yl), pyrazolo [1,5-a] pyridinyl (for example, pyrazolo [1,5] -a] pyridine-3-yl), oxazolyl (for example), isoxazolyl (for example, isoxazol-4-yl), pyridyl (for example, 2-pyridyl, 3-pyridyl, 4-pyridyl), quinolinyl (for example , 2-quinolinyl), pyrrolyl (for example, 3-pyrrolyl), imidazolyl and thienyl (for example, 2-thienyl, 3-thienyl).

A subgroup of heteroaryl groups R 1 consists of furanyl (for example, 2-furanyl or 3-furanyl), indolyl, oxazolyl, isoxazolyl, pyridyl, quinolinyl, pyrrolyl, imidazolyl and thienyl.

A preferred subset of R 1 heteroaryl groups includes 2-furanyl, 3-furanyl, pyrrolyl, imidazolyl and thienyl.

Preferred aryl groups R1 are phenyl groups.

The R1 group may be an unsubstituted or substituted carbocyclic or heterocyclic group in which one or more substituents may be selected from the R10 group as defined hereinbefore. In one embodiment, the substituents on R1 may be selected from the group R10a consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, a Ra-Rb group in which Ra is a bond, O, CO, X3C (X4), C (X4) X3, X3C (X4) X3, S, SO, or SO2, and Rb is selected from hydrogen and a C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro , carboxy and non-aromatic monocyclic carbocyclic or heterocyclic groups having 3 to 6 ring members; wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, X3C (X4), C (X4) X3 or X3C (X4) X3; X3 is O or S; and X4 is = O or = S.

When the carbocyclic and heterocyclic groups have a pair of substituents on adjacent ring atoms, the two substituents may be joined to form a cyclic group. Thus, two adjacent R10 groups, together with the carbon atoms or heteroatoms to which they are attached can form a 5-membered heteroaryl ring or a 5 or 6-membered non-aromatic carbocyclic or heterocyclic ring, wherein said heteroaryl groups and Heterocyclics contain up to 3 heteroatoms as selected ring members of N, O and S. In particular, the two adjacent R10 groups, together with the carbon atoms or heteroatoms to which they are attached, can form a 6-membered non-aromatic heterocyclic ring , which contains up to 3, in particular 2, heteroatoms as ring members selected from N, O and S. More particularly, the two adjacent R10 groups can form a 6-membered non-aromatic heterocyclic ring, containing 2 heteroatoms as ring members selected from N, or O, such as dioxane, for example [1,4 dioxane]. In one embodiment, R1 is a carbocyclic group, for example, phenyl having a pair of substituents on adjacent ring atoms joined to form a cyclic group, for example to form 2,3-dihydro-benzo [1,4] dioxin.

More particularly, the substituents on R1 may be selected from halogen, hydroxy, trifluoromethyl, a Ra-Rb group in which Ra is a bond or O, and Rb is selected from hydrogen and a C1-4 hydrocarbyl group optionally substituted with one or more Selected substituents of hydroxyl, halogen (preferably fluorine) and saturated 5- and 6-membered carbocyclic and heterocyclic groups (for example, groups containing up to two heteroatoms selected from O, S and N, such as piperidine, pyrrolidino, morpholino, piperazine and N -methyl piperazino unsubstituted).

The R1 group may be substituted with more than one substituent. Thus, for example, there may be 1 or 2 or 3 or 4 substituents. In one embodiment, when R1 is a six-membered ring (for example, a carbocyclic ring such as a phenyl ring), there may be one, two or three substituents and these may be located at positions 2, 3, 4 or 6 of the ring. As an example, a phenyl group R 1 may be 2-monosubstituted, 3-monosubstituted, 2,6-substituted, 2,3-disubstituted, 2,4-disubstituted, 2,5-disubstituted, 2,3,6-trisubstituted or 2,4 , 6-trisubstituted. More particularly, a phenyl group R 1 may be monosubstituted at position 2 or substituted at positions 2 and 6 with substituents selected from fluorine, chlorine and Ra-Rb, in which Ra is O and Rb is C 1-4 alkyl (for example , methyl or ethyl). In one embodiment, fluorine is a preferred substituent. In another embodiment, preferred substituents are selected from fluorine, chlorine and methoxy.

Particular examples of non-aromatic R1 groups include unsubstituted or substituted monocyclic cycloalkyl groups (with one or more R10 groups). Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; more typically cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclohexyl.

Additional examples of non-aromatic R1 groups include unsubstituted or substituted heterocyclic groups (with one or more R10 groups) having 3 to 12 ring members, typically 4 to 12 ring members and more usually 5 to 10 members in the ring. the ring. Such groups may be monocyclic or bicyclic, for example, and typically have 1 to 5 heteroatoms as ring members (more usually 1,2,3 or 4 ring member heteroatoms) typically selected from nitrogen, oxygen and sulfur.

When sulfur is present, it can exist, when the nature of adjacent atoms and groups allows it, such as –S-, –S (O) -or –S (O) 2-.

Heterocyclic groups may contain, for example, cyclic ether moieties (for example, as in tetrahydrofuran and dioxane), cyclic thioether moieties (for example as in tetrahydrothiophene and dithian), cyclic amine moieties (for example, as in pyrrolidine), cyclic amides (for example, as in pyrrolidone), cyclic esters (for example, as in butyrolactone), thioamides and cyclic thioesters, cyclic sulfones (for example, as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (for example , morpholine and thiomorpholine and their S-oxide and S, S-dioxide).

In a subset of R1 heterocyclic groups, heterocyclic groups contain cyclic ether moieties (e.g., as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g., as in tetrahydrothiophene and dithian), cyclic amine moieties (e.g. as in pyrrolidine ), cyclic sulfones (for example, as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (for example, thiomorpholine).

Examples of non-aromatic monocyclic heterocyclic groups R1 include 5, 6 and 7 membered monocyclic heterocyclic groups such as morpholine, piperidine (for example, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (for example , 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrotiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran tetrahydropyran (e.g. ), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Additional examples include thiomorpholine and its S-oxide and S, S-dioxide (particularly thiomorpholine). Further examples include N-alkyl piperidines such as N-methyl piperidine.

A subgroup of R1 non-aromatic heterocyclic groups includes unsubstituted or substituted monocyclic heterocyclic groups of 5, 6 and 7 members (with one or more R10 groups) such as morpholine, piperidine (eg, 1-piperidinyl, 2-piperidinyl, 3- piperidinyl and 4-piperidinyl), pyrrolidine (for example, 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, piperazine, and N-alkyl piperazines such as N-methyl piperazine, in which a particular subset consists of pyrrolidine , piperidine, morpholine, thiomorpholine and N-methyl piperazine.

In general, preferred non-aromatic heterocyclic groups include pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine S, S-dioxide, piperazine, N-alkyl piperazines, and N-alkyl piperidines.

Another particular subset of heterocyclic groups consists of pyrrolidine, piperidine, morpholine and N-alkyl piperazines, and optionally N-methyl piperazine and thiomorpholine.

When R1 is a C1-8 hydrocarbyl group substituted with a carbocyclic or heterocyclic group, the carbocyclic and heterocyclic groups may be aromatic or non-aromatic and may be selected from the examples of such groups shown hereinbefore. The substituted hydrocarbyl group is typically a saturated C1-4 hydrocarbyl group such as an alkyl group, preferably a CH2 or CH2CH2 group. When the substituted hydrocarbyl group is a C2-4 hydrocarbyl group, one of the carbon atoms and their associated hydrogen atoms can be replaced by a sulfonyl group, for example as in the SO2CH2 moiety.

When the carbocyclic or heterocyclic group attached to the C1-8 hydrocarbyl group is aromatic, examples of such groups include monocyclic Aryan groups and monocyclic heteroaryl groups containing up to four heteroatoms as selected ring members of O, S and N, and bicyclic heteroaryl groups containing up to 2 heteroatoms as selected ring members of O, S and N and in which both rings are aromatic.

Examples of these groups are shown in the “General Preferences and Definitions” section above.

Particular examples of such groups include furanyl (for example, 2-furanyl or 3-furanyl), indolyl, oxazolyl, isoxazolyl, pyridyl, quinolinyl, pyrrolyl, imidazolyl and thienyl. Particular examples of aryl and heteroaryl groups as substituents for a C1-8 hydrocarbyl group include phenyl, imidazolyl, tetrazolyl, triazolyl, indolyl, 2-furanyl, 3-furanyl, pyrrolyl and thienyl. Such groups may be substituted with one or more R10 or R10a substituents as defined herein.

When R1 is a C1-8 hydrocarbyl group substituted with a carboxylic or heterocyclic aromatic heterocyclic group, the non-aromatic or heterocyclic group may be a group selected from the lists of said groups shown hereinbefore. For example, the non-aromatic group may be a monocyclic group that has 4 to 7 members in the ring, for example 5 to 7 members in the ring and typically contains 0 to 3, more typically 0, 1 or 2, heteroatoms such as Ring members selected from O, S and N. When the cyclic group is a carbocyclic group, it can be further selected from monocyclic groups having 3 members in the ring. Particular examples include monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and 5, 6 and 7 membered monocyclic heterocyclic groups such as morpholine, piperidine (eg, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (for example, 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, piperazine, and N-alkyl piperazines such as N-methyl

piperazine In general, preferred non-aromatic heterocyclic groups include pyrrolidine, piperidine, morpholine, thiomorpholine and N-methyl piperazine.

When R1 is an optionally substituted C1-8 hydrocarbyl group, the hydrocarbyl group may be as defined hereinbefore and preferably has a length of up to four 5 carbon atoms, more usually a length of up to three carbon atoms per example a length of one or two carbon atoms.

In one embodiment, the hydrocarbyl group is saturated and can be acyclic or cyclic, for example, acyclic. An acyclic saturated hydrocarbyl group (ie, an alkyl group) may be a straight or branched chain alkyl group.

Examples of straight chain R 1 alkyl groups include methyl, ethyl, propyl and butyl.

Examples of branched chain R 1 alkyl groups include isopropyl, isobutyl, tert-butyl and 2,2-dimethylpropyl.

In one embodiment, the hydrocarbyl group is a linear saturated group having 1-6 carbon atoms, more usually 1-4 carbon atoms, for example, 1-3 carbon atoms, for example, 1, 2 or 3 atoms carbon When the hydrocarbyl group is substituted, particular examples of said groups are substituted methyl and ethyl groups (for example, with a carbocyclic or heterocyclic group).

A C1-8 R1 hydrocarbyl group may be optionally substituted with one or more substituents selected from halogen (eg, fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-hydrocarbonylamino C1-4, and carbocyclic groups or heterocyclics having 3 to 12 ring members and in which 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO2. Particular substituents for the hydrocarbyl group include hydroxy, chlorine, fluorine (for example, as in

Trifluoromethyl), methoxy, ethoxy, amino, methylamino and dimethylamino, hydroxy and fluorine being the preferred substituents.

Particular R1-CO groups are the groups shown in Table 1 below.

In Table 1, the point of attachment of the group to the nitrogen atom of the pyrazol-4-amino group is represented by the terminal single bond that extends from the carbonyl group. Thus, as an illustration, the group B in the table is the trifluoroacetyl group, the group D in the table is the phenylacetyl group and the group I in the table is the group

3- (4-chlorophenyl) propionyl.

Table 1 - Examples of the R1-CO group

CH3-C (= O) -A

CF3-C (= O) -B

A subgroup of R1-CO groups consists of groups A to BF in Table 1 above. Another subgroup of R1-CO groups consists of groups A to BS in Table 1 above. A preferred group of R1-CO groups consists of groups J, AB, AH, AJ, AL, AS, AX, AY, AZ, BA, BB, BD, BH,

BL, BQ, BS and BAI

Another set of preferred R1-CO groups consists of groups J, AB, AH, AJ, AL, AS, AX, AY, AZ, BA, BB, BD, BH, BL, BQ and BS. The most preferred R1-CO-groups are AJ, AX, BQ, BS and BAI. A particularly preferred subset of R1-CO-groups consists of AJ, BQ and BS. Another particularly preferred subset of R1-CO-groups consists of AJ and BQ. When R1 is a phenyl ring having a substituent at position 4, the substituent at position 4 is

preferably different from a phenyl group having an SO2NH2 or SO2Me group in the ortho position. In a general embodiment, R 1 may be different from a tetrahydroquinoline, chromane, chromene, thiochroman group, substituted or unsubstituted thiochromen, dihydro-naphthalene or tetrahydronaphthalene. More particularly, R1 can be

other than a tetrahydroquinoline, chromane, chromene, thiochroman, thiochromen, dihydro-naphthalene or substituted or unsubstituted tetrahydronaphthalene bound by its aromatic ring to the A-NR4- moiety. In another general embodiment, when R1 is a substituted or unsubstituted phenyl group, the Y-R3 moiety may be different

of unsubstituted C5-10 cycloalkyl. When R1 is an optionally substituted hydrocarbyl group and the hydrocarbyl group comprises or contains a group

substituted or unsubstituted alkene, it is preferred that the carbon-carbon double bond of the alkene group is not attached directly to group A. When R1 is an optionally substituted hydrocarbyl group, the hydrocarbyl group may be different from a group

alkene

Y

In the compounds of the formula (II), Y is an alkylene chain or bond with a length of 1, 2 or 3 carbon atoms.

The term "alkylene" has its usual meaning and refers to a divalent saturated acyclic hydrocarbon chain. The hydrocarbon chain can be branched or unbranched. When an alkylene chain is branched, it may have one or more side chains of methyl groups. Examples of alkylene groups include -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, CH (CH3) -, -C (CH3) 2-, –CH2 – CH (CH3) -, -CH2- C (CH3) 2-and –CH (CH3) –CH (CH3) -.

In one embodiment, Y is a link.

In another embodiment, Y is an alkylene chain.

When Y is an alkylene chain, it is preferably not branched and more particularly contains 1 or 2 carbon atoms, preferably 1 carbon atom. Thus, the preferred Y groups are -CH2-and -CH2-CH2-, with a most preferred group being (CH2) -.

When Y is a branched chain, it preferably has no more than two methyl side chains. For example, it can have a single methyl side chain. In one embodiment, Y is a group -CH (Me) -.

In a subset of compounds, Y is a bond, CH2, CH2CH2 or CH2CH (CH3).

R3

The R3 group is selected from non-aromatic carbocyclic and heterocyclic groups having 3 to 12 ring members.

In another subgroup of compounds, Y is a bond or an alkylene chain (for example, a group - (CH2) -) and R3 is a non-aromatic carbocyclic or heterocyclic group.

In an additional subgroup of compounds, Y is a bond and R3 is a non-aromatic carbocyclic or heterocyclic group.

In a more additional subgroup of compounds, Y is an alkylene chain (for example, a group - (CH2) -) and R3 is a non-aromatic carbocyclic or heterocyclic group.

The carbocyclic and heterocyclic R3 groups may be non-aromatic carbocyclic or non-aromatic heterocyclic and examples of such groups are as shown in detail above in the General Preferences and Definitions section and as shown below.

Examples of non-aromatic R3 groups include cycloalkyl, oxa-cycloalkyl, aza-cycloalkyl, diazacycloalkyl, dioxa-cycloalkyl and aza-oxa-cycloalkyl groups optionally substituted (with R10 or R10a). Additional examples include C7-10 aza-bicycloalkyl groups such as 1-aza-bicyclo [2.2.2] octan-3-yl.

Particular examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran, morpholine, tetrahydrofuran, piperidine, and unsubstituted or substituted pyrrolidine groups.

A subset of non-aromatic R3 groups consists of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran, tetrahydrofuran, piperidine and pyrrolidine groups.

Preferred non-aromatic R3 groups include unsubstituted or substituted cyclopentyl, cyclohexyl, tetrahydropyran, tetrahydrofuran, piperidine and pyrrolidine groups.

The non-aromatic groups may not be substituted or be substituted with one or more R10 or R10a groups as defined hereinbefore.

Particular substituents for R3 are selected from the R10a group consisting of halogen; hydroxy; monocyclic carbocyclic and heterocyclic groups having 3 to 6 ring members and containing up to 2 heteroatoms as selected ring members of O, N and S; and a Ra-Rben group which Ra is a bond, O, CO, CO2, SO2, NH, SO2NH or NHSO2; and Rb is selected from hydrogen, a carbocyclic or heterocyclic group with 3-6 ring members and containing up to 2 heteroatoms as ring members selected from O, N and S; and a C1-6 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, carboxy, amino, mono or di-hydrocarbonylamino C1-4, a carbocyclic or heterocyclic group with 3-6 ring members and which contains up to 2 heteroatoms as selected ring members of O, N and S; and in which one or two carbon atoms of the C1-6 hydrocarbyl group may optionally be replaced by O, S, SO, SO2 or NH.

In one embodiment, preferred R10a substituent groups in R3 include halogen, a Ra-Rb group in which Ra is a bond, O, CO, C (X2) X1, and Rb is selected from hydrogen, heterocyclic groups having 3- 7 ring members and a C1-4 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy, carboxy, amino, mono or C1-4 dihydrocarbylamino, and heterocyclic groups having 3-7 members in the ring.

Particularly preferred R10a substituent groups in R3 include halogen, especially fluorine, C1-3 alkoxy such as comomethoxy, optionally substituted C1-3 hydrocarbyl with fluorine, hydroxy (for example, hydroxymethyl), C1-2 alkoxy or a saturated 5- or 6-membered heterocyclic ring such as piperidine, morpholino , piperacino and N-methylpiperacino.

In another embodiment, the substituents for R3 are selected from:

Halogen (for example, fluorine and chlorine)

 C1-4 alkoxy (eg, methoxy and ethoxy) optionally substituted with one or substituents selected from halogen, hydroxy, C1-2 alkoxy and saturated five and six membered heterocyclic rings containing 1 or 2 heteroatoms selected from O, N and S, the heterocyclic rings being optionally further substituted with one or more C1-4 groups (eg, methyl) and in which S, when present, may be present as S, SO or SO2;

 C1-4 alkyl optionally substituted with one or substituents selected from halogen, hydroxy, C1-4 alkoxy, amino, C1-4 alkylsulfonylamino, 3 to 6 membered cycloalkyl groups (eg, cyclopropyl), phenyl (optionally substituted with one or more substituents selected from halogen, methyl, methoxy and amino) and saturated five and six membered heterocyclic rings containing 1 or 2 heteroatoms selected from O, N and S, the heterocyclic rings being optionally substituted in addition to one or more C1-4 groups ( for example, methyl) and in which S, when present, may be present as S, SO or SO2;

Hydroxy;

 amino, C 1-4 alkylamino, C 1-4 alkylamino, benzyloxycarbonylamino and C 1-4 alkoxycarbonylamino;

 carboxy and C1-4 alkoxycarbonyl;

 C1-4 alkylaminosulfonyl and C1-4 alkylsulfonylamino;

C 1-4 alkylsulfonyl;

 an O-Hets or NH-Hets group in which Hets is a saturated five or six membered heterocyclic ring containing 1 or 2 heteroatoms selected from O, N and S, the heterocyclic rings being optionally further substituted with one or more groups C1-4 (for example, methyl) and in which S, when present, may be present as S, SO or SO2;

5  saturated five- and six-membered heterocyclic rings containing 1 or 2 heteroatoms selected from O, N and S, the heterocyclic rings being further optionally substituted with one or more C1-4 groups (eg, methyl) and in which the S, when present, may be present as S, SO or SO2;

Oxo; Y

 six-membered aryl and heteroaryl rings containing up to two nitrogen as ring members and which are optionally substituted with one or substituents selected from halogen, methyl and methoxy.

In a further embodiment, R3 is selected from:

 C3-C7 cycloalkyl groups optionally substituted with 1-4 (for example, 1-2, for example 1) R10 or R10a substituents;

5-membered saturated heterocyclic rings containing 1 heteroatom in the selected ring

15 of O, N and S and which are optionally substituted with an oxo group and / or with 1-4 (for example, 1-2, for example, 1) R10 or R10a substituents;

 saturated six-membered heterocyclic rings containing 1 or 2 ring heteroatoms selected from O, N and S and which are optionally substituted with an oxo group and / or with 1-4 (for example, 1-2, for example, 1) R10 or R10a substituents;

• Mono-azabicycloalkyl and diazabicycloalkyl groups each having 7 to 9 ring members and which are optionally substituted with 1-4 (for example, 1-2, for example, 1) R10 or R10a substituents.

Specific examples of the Y-R3 group are shown in Table 2. In Table 2, the point of attachment of the group to the nitrogen atom of the pyrazol-3-carboxamide group is represented by the terminal single bond extending from the group .

Table 2 - Examples of Group Y-R3

H CH

A subset of groups selected from table 2 consists of CA to EU groups.

Another subset of groups selected from Table 2 consists of the CA to CV groups.

Preferred groups selected from Table 2 include the CL, CM, ES, ET and FC groups.

Particularly preferred groups selected from Table 2 include the CL, CM and ES groups, and most preferably CL and CM.

When R3 is an aza-cycloalkyl group, the nitrogen atom of the aza-cycloalkyl group is preferably not substituted with an alkylene chain attached to a 2,3-dihydro-benzo [1,4] dioxin or tetrahydronaphthalene group.

In another general embodiment, R3 is distinct from a moiety containing a five-membered heteroaryl ring directly linked by a single bond to a monocyclic or bicyclic aryl group or R3 is different from a moiety containing a bis heteroaryl group comprising two heteroaryl rings of five members joined together by a single link.

In a further general embodiment, R1 is distinct from a moiety containing a five-membered heteroaryl ring directly linked by a single bond to a monocyclic or bicyclic aryl group or R1 is different from a moiety containing a bis heteroaryl group comprising two rings five-member heteroaryl joined together by a single bond.

In another general embodiment, R1- (CO) -NH is distinct from an optionally substituted nicotinoyl-amino or benzoyl-amino group when Y-R3 is an optionally substituted alkyl, cycloalkyl, or optionally substituted phenylalkyl group.

In one embodiment, Y-R3 may be different from a cycloalkyl group substituted at position 1 with a hydrocarbon chain simultaneously presenting an oxy substituent such as hydroxy, an aryl substituent and a diazol or triazole substituent.

Preferably, R1 or R3 are each distinct from a moiety containing a substituted phenyl group having thio and / or oxy substituents such as hydroxy, alkoxy and alkylthiotanto in the 3 as 4 position of the phenyl ring.

The Y-R3 group preferably does not include a benzo-fused lactam group having an unsubstituted or substituted imidazole group attached thereto.

The group Y-R3 preferably does not include the moiety -CH = C (CO2Rq) -S-in which Rq is hydrogen or alkyl.

In another general embodiment, neither R1 nor R3 contain a moiety in which a five-membered nitrogen-containing heteroaryl group is attached directly or via an alkylene, oxa-alkylene, thia-alkylene or aza-alkylene group to an unsubstituted pyridyl group or to a substituted aryl, heteroaryl or piperidine ring, each of said rings having a substituent selected from cyano attached thereto, and substituted or unsubstituted amino, aminoalkyl, amidine, guanidine, and carbamoyl groups.

In a further general embodiment, R1 and R3 are each distinct from an unsaturated nitrogen-containing heterocyclic group or a benzofuran or benzothiophene group in which said nitrogen-containing heterocyclic group, nitrogen-containing heteroaryl group, benzofuran or bicyclic benzothiophene group are linked directly by a single bond to a substituted pyridyl ofenyl group.

In another general embodiment, neither R1 nor R3 contain a moiety in which a five-membered nitrogen-containing heteroaryl group is attached directly or via an alkylene, oxa-alkylene, thia-alkylene or aza-alkylene group to an aryl, heteroaryl group or substituted piperidine or an unsubstituted pyridyl group.

In general, it is preferred that the compounds of the invention, when they contain a carboxylic acid group, contain no more than one of said groups.

Particular and Preferred Subgroups of the formulas (II)

The compounds of formula (II) are represented by the formula (II):

or salts or tautomers or N-oxides or solvates thereof;

wherein R1, R2, R3 and Y are each independently selected from R1, R2, R3 and Y as defined herein.

In formula (II), it is preferred that R2 is hydrogen or C1-4 alkyl (for example, C1-3 alkyl), and more preferably R2 is hydrogen.

In a subset of compounds of the formula (II), R1 is:

(i)

phenyl optionally substituted with one or more substituents (eg, 1, 2 or 3) selected from fluorine; chlorine; hydroxy; 5 and 6-membered saturated heterocyclic groups containing 1 or 2 heteroatoms selected from O, N and S, the heterocyclic groups being optionally substituted with one or more C1-4 alkyl groups; C1-4 hydrocarbyloxy; and C1-4 hydrocarbyl; wherein the C1-4 hydrocarbyl and C1-4 hydrocarbyloxy groups are optionally substituted with one or more substituents chosen from hydroxy, fluorine, C1-2 alkoxy, amino, mono and di-C1-4 alkylamino, phenyl, halophenyl, carbocyclic groups saturated ones having 3 to 7 members in the ring (more preferably 4, 5 or 6 members in the ring, for example, 5 or 6 members in the ring) or saturated heterocyclic groups of 5 or 6 members in the ring and containing up to 2 heteroatoms selected from O, S and N; or 2,3-dihydro-benzo [1,4] dioxin; or

(ii)

a monocyclic heteroaryl group containing one or two heteroatoms selected from O, S and N; or a bicyclic heteroaryl group containing a single heteroatom selected from O, S and N; each of the monocyclic and bicyclic heteroaryl groups being optionally substituted with one or more fluorine selected substituents; chlorine; C1-3 hydrocarbyloxy; and C1-3 hydrocarbyl optionally substituted with hydroxy, fluorine, methoxy or a saturated five or six membered carbocyclic or heterocyclic group containing up to two heteroatoms selected from O, S and N; or

(iii) a substituted or unsubstituted cycloalkyl group having 3 to 6 members in the ring; or

(iv) a C1-4 hydrocarbyl group optionally substituted with one or more fluorine selected substituents; hydroxy; C1-4 hydrocarbyloxy; Not me; mono or di-hydrocarbonylamino C1-4; and carbocyclic or heterocyclic groups having 3 to 12 ring members and in which one of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, NH, SO and SO2.

In group (i), a subgroup of the R1 groups consists of phenyl optionally substituted with one or more fluorine selected substituents; chlorine; hydroxy; C1-3 hydrocarbyloxy; and C1-3 hydrocarbyl in which the C1-3 hydrocarbyl group is optionally substituted with one or more substituents chosen from hydroxy, fluorine, C1-2 alkoxy, amino, mono and di-C1-4 alkylamino, saturated carbocyclic groups having 3 to 7 members in the ring (more preferably 4, 5 or 6 members in the ring, for example, 5 or 6 members in the ring) or saturated heterocyclic groups of 5 or 6 members in the ring and containing up to 2 heteroatoms selected from 0, S and N.

In another subgroup of compounds of the formula (II), R1 is selected from (i) and (iii) above and additionally from a subset (aii) in which the subset (aii) consists of 2-furanyl, 3-furanyl, imidazolyl, 2-pyridyl, indolyl, 2-thienyl and 3-thienyl, each optionally substituted with one or more substituents selected from fluorine, chlorine, C1-3 hydrocarbyloxy, and C1-3 hydrocarbyl optionally substituted with hydroxy, ometoxy fluorine.

In the group of compounds defined by formula (II), in which R1 is (i) an optionally substituted phenyl group, it can be, for example, an unsubstituted phenyl group or a 2-mono-substituted, 3-mono-substituted phenyl group, 2 , 3 disubstituted, 2.5 disubstituted or 2.6 disubstituted or 2,3-dihydro-benzo [1,4] dioxin, wherein the substituents are selected from halogen; hydroxyl; C1-3 alkoxy; and C1-3 alkyl groups in which the C1-3 alkyl group is optionally substituted with hydroxy, fluorine, C1-2 alkoxy, amino, mono and di-C1-4 alkylamino, or saturated carbocyclic groups having 3 to 6 members in the ring and / or saturated heterocyclic groups of 5 or 6 members in the ring and containing 1 or 2 heteroatoms selected from N and O.

In one embodiment, R 1 is selected from unsubstituted phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 2- (2- (pyrrolidin-1-yl) ethoxy) -phenyl, 3-fluorophenyl, 3 -methoxyphenyl, 2,6-difluorophenyl, 2-fluoro-6-hydroxyphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-6-methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2 , 6-dichlorophenyl and 2-chloro-6-fluorophenyl and is also optionally selected from 5-fluoro-2-methoxyphenyl.

In another embodiment, R 1 is selected from unsubstituted phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 2- (2- (pyrrolidin-1-yl) ethoxy) -phenyl, 3-fluorophenyl, 3 -methoxyphenyl, 2,6-difluorophenyl, 2-fluoro-6-hydroxyphenyl, 2-fluoro-3-methoxyphenyl and 2-fluoro-5-methoxyphenyl.

Particular R1 groups are 2,6-difluorophenyl, 2-fluoro-6-methoxyphenyl and 2,6-dichlorophenyl.

A particularly preferred R1 group is 2,6-difluorophenyl.

Another particularly preferred R1 group is 2,6-dichlorophenyl.

When R1 is (ii) a monocyclic heteroaryl group containing one or two heteroatoms selected from O, S and N

or a bicyclic heteroaryl group containing a single heteroatom, examples of monocyclic and bicyclic heteroaryl groups include furanyl groups (e.g., 2-furanyl and 3-furanyl), imidazolyl, pyridyl (e.g., 2-pyridyl), indolyl, thienyl (for example, 2-thienyl and 3-thienyl). Optional substituents for such groups may include chloro, fluorine, methyl, methoxy, hydroxymethyl, methoxymethyl, morpholinomethyl, piperazinomethyl, N-methylpiperazinomethyl and piperidinylmethyl groups. Particular examples of groups (ii) include unsubstituted 2-furanyl, 3-methyl-2-furanyl, unsubstituted 4- (1 H) -imidazolyl, 5- (1 H) unsubstituted imidazolyl, unsubstituted 3-furanyl, Unsubstituted 3-thienyl, 2-methyl-3-thienyl and unsubstituted 3-pyrrolyl and additional examples include 4-methoxy3-thienyl, 5- (1-pyrrolidinyl) methyl-2-furyl and 5- (4-morpholino) groups ) methyl-2-furyl.

When R1 is (iii) an optionally substituted cycloalkyl group, it can be for example a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. When the cycloalkyl group is substituted, preferred substituents include methyl, fluorine and hydroxyl. Particular examples of cycloalkyl groups include 1-methylcyclopropyl, 1-hydroxycyclopropyl, and unsubstituted cyclohexyl, cyclopentyl and cyclobutyl.

In the context of formula (II) and group R1, examples of optionally substituted hydrocarbyl groups are optionally substituted methyl, ethyl and propyl groups in which one of the carbon atoms of the hydrocarbyl group is optionally replaced by O, NH, SO or SO2. Particular examples of such groups include methyl, ethyl, trifluoromethyl, methyl and ethyl substituted with a carbocyclic or heterocyclic group having 3 to 12 ring members, sulfonylmethyl substituted with a carbocyclic or heterocyclic group having 3 to 12 members in the ring, hydroxymethyl, hydroxyethyl, 3-hydroxy-2-propyl, propyl, isopropyl, butyl and tertiary butyl. Examples of hydrocarbyl groups and carbocyclic and heterocyclic groups are as shown above in the general definitions of such groups. Particular carbocyclic and heterocyclic groups include phenyl, indolyl, tetrazolyl, triazolyl, piperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, unsubstituted or substituted imidazolyl in which the optional substituents can be selected from the R10 group, and subgroups thereof, as defined In the present memory.

In another subgroup of compounds of the formula (II), R1 is a C1-4 hydrocarbyl group optionally substituted with one or more substituents selected from fluorine, hydroxy, C1-4 hydrocarbyloxy, amino, mono or C1-4 dihydrocarbylamino and groups carbocyclic or heterocyclic having 3 to 12 ring members and in which 1 of the carbon atoms of the hydrocarbyl group can optionally be replaced by an atom or group selected from O, NH, SO and SO2.

In one embodiment, R1 is a group R1a- (V) n-in which:

n is 0 or 1;

V is selected from CH2, CH2CH2 and SO2CH2; Y

R1a is a carbocyclic or heterocyclic group selected from phenyl;

five-membered heteroaryl rings having up to 4 heteroatoms as ring members selected from N, O and S;

six-membered heteroaryl rings containing one or two nitrogens as ring members;

saturated, non-aromatic, five or six membered heterocyclic rings containing one or two ring member heteroatoms selected from N, O, S and SO2;

C3-6 cycloalkyl groups; indole; and quinoline;

wherein each of the carbocyclic and heterocyclic groups R1a may be optionally substituted with one or more substituents selected from non-aromatic saturated carbocyclic and heterocyclic groups of five or six members containing up to two heteroatoms as selected ring members of N, O, S and SO2; hydroxy; Not me; oxo; C1-4 mono-alkylamino; di-C1-4 alkylamino; fluorine; chlorine; nitro; C1-4 alkyl - (O) q-wherein q is 0 or 1 and the C1-4 alkyl moiety is optionally substituted with fluorine, hydroxy, C1-2 alkoxy or a saturated, non-aromatic carbocyclic or heterocyclic group of five or six members containing up to two heteroatoms as selected ring members of N, O, S and SO2; phenyl and C1-2 alkylene dioxy.

Specific examples of the R1-CO-groups in formula (II) have been shown in Table 1 above.

A preferred subgroup of R1-CO groups consists of groups J, AB, AH, AJ, AL, AS, AX, AY, AZ, BA, BB, BD, BH, BL, BQ and BS.

Another subgroup of groups R1-CO consists of groups A to BF.

An additional subgroup of groups R1-CO consists of groups A to BS.

Particularly preferred groups are groups AJ, BQ and BS in Table 1, for example, the subset consisting of AJ and BQ.

Another subgroup of compounds of the formula (II) can be represented by the formula (IV):

or salts or tautomers or N-oxides or solvates thereof; wherein R1 and R2 are as defined herein; an optional second bond may be present between carbon atoms numbered 1 and 2; one of U and T is

selects from CH2, CHR13, CR11R13, NR14, N (O) R15, O and S (O) t; and the other of U and T is selected from NR14, O, CH2,

CHR11, C (R11) 2, and C = O; r is 0, 1, 2, 3 or 4; t is 0, 1 or 2; R11 is selected from hydrogen, halogen (particularly fluorine), C1-3 alkyl (e.g., methyl) and C1-3 alkoxy (by example, methoxy);

R13 is selected from hydrogen, NHR14, NOH, NOR14 and Ra-Rb; R14 is selected from hydrogen and Rd-Rb; Rd is selected from a link, CO, C (X2) X1, SO2 and SO2NRc; Ra, Rb and Rc are as defined hereinbefore; Y R15 is selected from saturated C1-4 hydrocarbyl optionally substituted with hydroxy, C1-2 alkoxy, halogen or a

5 or 6 membered monocyclic carbocyclic or heterocyclic group, with the proviso that U and T cannot be O

simultaneously. Examples of, and preferences, for groups R1 and R2 are as shown above for compounds of the formula (II) unless the context indicates otherwise.

In formula (IV), r can be 0, 1, 2, 3 or 4. In one embodiment, r is 0. In another embodiment, r is 2, and in one

further embodiment r is 4. In formula (IV), a preferred subset of compounds is the set of compounds in which there is only one single bond between carbon atoms numbered 1 and 2.

However, in another subset of compounds, there is a double bond between carbon atoms numbered 1 and

2.

Another subset of compounds is characterized by a gem substitution in carbon 2 (when there is a single bond between carbon atoms with numbers 1 and 2) and / or carbon 6. Preferred gem substituents include difluoro and dimethyl.

An additional subset of compounds is characterized by the presence of an alkoxy group, for example a methoxy group in the numbered carbon atom 3, that is, in an α position with respect to the T group.

In formula (IV) they are compounds in which, for example R3 is selected from any of the following ring systems:

Preferred ring systems include G1 and G3. A preferred subgroup of compounds in formula (IV) can be represented by formula (IVa):

5 or salts or tautomers or N-oxides or solvates thereof; wherein R1 and R2 are as defined hereinbefore; one of U and T is selected from CH2, CHR13, CR11R13, NR14, N (O) R15, O and S (O) t; and the other of U and T is selected from

CH2, CHR11, C (R11) 2, and C = O; r is 0, 1 or 2; t is 0, 1 or 2;

R11 is selected from hydrogen and C1-3 alkyl; R13 is selected from hydrogen and Ra-Rb;

R14 is selected from hydrogen and Rd-Rb;

Rd is selected from a link, CO, C (X2) X1, SO2 and SO2NRc;

Ra, Rb and Rc are as defined hereinbefore; Y

R15 is selected from saturated C1-4 hydrocarbyl optionally substituted with hydroxy, C1-2 alkoxy, halogen or a

15 carbocyclic or heterocyclic or cyclic hetero group of 5 or 6 members.

Examples of, and preferences, for groups R1 and R2 are as shown above for

compounds of the formula (II) unless the context indicates otherwise.

In formula (IVa), T is preferably selected from CH2, CHR13, CR11R13, NR14, N (O) R15, O and S (O) t; and U is preferably selected from CH2, CHR11, C (R11) 2, and C = O.

In the definitions for substituents R11 and R14, Rb is preferably selected from hydrogen; monocyclic carbocyclic and heterocyclic groups having 3 to 7 ring members; and C1-4 hydrocarbyl (more preferably saturated acyclic C1-4 groups) optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, amino, mono or C1-4 dihydrocarbylamino, and monocyclic carbocyclic and heterocyclic groups having 3 to 7 ring members (more preferably 3 to 6 ring members) and in which one or more carbon atoms of the C1-4 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRc, X1C ( X2), C (X2) X1; Rc is selected from hydrogen and C1-4 hydrocarbyl; and X1 is O, S or NRc and X2 is = O, = S or = NRc.

R11 is preferably selected from hydrogen and methyl and most preferably is hydrogen.

R13

it is preferably selected from hydrogen; hydroxy; halogen; cyano; Not me; C1-4 saturated monohydrocarbonyl; saturated C1-4 dihydrocarbonylamino; monocyclic carbocyclic and heterocyclic groups of 5 or 6 members; saturated C1-4 hydrocarbyl optionally substituted with hydroxy, C1-2 alkoxy, halogen or a carbocyclic or heterocyclic monocyclic group of 5 or 6 members.

Particular examples of R13 are hydrogen, hydroxy, amino, C1-2 alkylamino (for example, methylamino), C1-4 alkyl (for example, methyl, ethyl, propyl and butyl), C1-2 alkoxy (for example, methoxy) , C1-2 alkylsulfonamido (for example, methanesulfonamido), hydroxy C1-2 alkyl (for example, hydroxymethyl), C1-2 alkoxy-C1-2 alkyl (for example, methoxymethyl and methoxyethyl), carboxy, C1-4 alkoxycarbonyl ( for example, ethoxycarbonyl) and amino-C1-2 alkyl (for example, aminomethyl).

Particular examples of R14 are hydrogen; C1-4 alkyl optionally substituted with fluorine or a saturated five or six membered heterocyclic group (for example, a group selected from (i) methyl, ethyl, n-propyl, i-propyl, butyl, 2,2,2-trifluoroethyl and tetrahydrofuranylmethyl; and / or (ii) 2-fluoroethyl and 2,2-difluoroethyl); cyclopropylmethyl; substituted or unsubstituted pyridyl-C1-2 alkyl (for example, 2-pyridylmethyl); substituted or unsubstituted phenyl-C1-2 alkyl (eg, benzyl); C1-4 alkoxycarbonyl (for example, ethoxycarbonyl and t-butyloxycarbonyl); substituted and unsubstituted C1-2 alkoxycarbionyl (eg, benzyloxycarbonyl); substituted and unsubstituted 5- and 6-membered heteroaryl groups such as pyridyl (for example, 2-pyridyl and 6-chloro-2-pyridyl) and pyrimidinyl (for example, 2-pyrimidinyl); C1-2 alkoxy-C1-2 alkyl (for example, methoxymethyl and methoxyethyl); C 1-4 alkylsulfonyl (for example, methanesulfonyl).

Preferred compounds include those in which (i) U is CHR13 (more preferably CH2) and T is NR14, and (ii) T is CHR13 (more preferably CH2) and U is NR14.

A particular preferred subgroup of compounds of the formula (IV) can be represented by the formula (Va):

or salts or tautomers or N-oxides or solvates thereof;

wherein R14a is selected from hydrogen, C1-4 alkyl optionally substituted with fluorine (eg, methyl, ethyl, n-propyl, i-propyl, butyl and 2,2,2-trifluoroethyl), cyclopropylmethyl, phenyl-alkyl- C1-2 (for example, benzyl), C1-4 alkoxycarbonyl (for example, ethoxycarbonyl and t-butyloxycarbonyl), phenyl-C1-2 alkoxycarbonyl (for example, benzyloxycarbonyl), C1-2alkoxy-C1-2-alkyl for example, methoxymethyl and methoxyethyl), and C 1-4 alkylsulfonyl (for example, methanesulfonyl), wherein the phenyl moieties when present are optionally substituted with one to three substituents selected from fluorine, chlorine, C 1-4 alkoxy optionally substituted with fluorine or C1-2 alkoxy, and C1-4 alkyl optionally substituted with fluorine or C1-2 alkoxy;

w is 0, 1, 2 or 3;

R2 is hydrogen or methyl, most preferably hydrogen;

R11 and r are as defined hereinbefore; Y

R19 is selected from fluorine; chlorine; C1-4 alkoxy optionally substituted with fluorine or C1-2 alkoxy; and C1-4 alkyl optionally substituted with fluorine or C1-2 alkoxy.

Another particular preferred subgroup of compounds of the formula (IV) can be represented by the formula (Vb):

5 or salts or tautomers or N-oxides or solvates thereof;

wherein R14a is selected from hydrogen, C1-4 alkyl optionally substituted with fluorine (eg, methyl, ethyl, n-propyl, i-propyl, butyl and 2,2,2-trifluoroethyl), cyclopropylmethyl, phenyl-alkyl- C1-2 (for example, benzyl), C1-4 alkoxycarbonyl (for example, ethoxycarbonyl and t-butyloxycarbonyl), phenyl-C1-2 alkoxycarbonyl (for example, benzyloxycarbonyl), C1-2alkoxy-C1-2-alkyl for example, methoxymethyl and methoxyethyl), and C 1-4 alkylsulfonyl (by

10 example, methanesulfonyl), in which the phenyl moieties when present are optionally substituted with one to three substituents selected from fluorine, chlorine, C1-4 alkoxy optionally substituted with fluorine or C1-2 alkoxy, and C1-4 alkyl optionally substituted with fluorine or C1-2 alkoxy;

w is 0, 1, 2 or 3;

R2 is hydrogen or methyl, most preferably hydrogen;

R11 and r are as defined hereinbefore; Y

R19 is selected from fluorine; chlorine; C1-4 alkoxy optionally substituted with fluorine or C1-2 alkoxy; and C1-4 alkyl optionally substituted with fluorine or C1-2 alkoxy.

In formulas (Va) and (Vb), when w is 1, 2 or 3, it is preferred that the phenyl ring be 2-monosubstituted, 3-monosubstituted, 2,6-disubstituted, 2,3-disubstituted, 2,4 -disubstituted, 2,5-disubstituted, 2,3,6-trisubstituted or

20 2,4,6-trisubstituted. Most preferably, the phenyl ring is disubstituted at positions 2 and 6 with substituents selected from fluorine, chlorine and methoxy.

R11 is preferably hydrogen (or r is 0).

R14a is most preferably omethyl hydrogen.

A preferred subgroup of compounds of the formula (Va) can be represented by the formula (VIa):

or salts or tautomers or N-oxides or solvates thereof; wherein R20 is selected from hydrogen and methyl; R21 is selected fluorine and chlorine; Y R22 is selected from fluorine, chlorine and methoxy; or

one of R21 and R22 is hydrogen and the other is selected from chlorine, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy and benzyloxy.

Another preferred subgroup of compounds of the formula (Va) can be represented by the formula (VIb):

or salts or tautomers or N-oxides or solvates thereof; wherein R20 is selected from hydrogen and methyl; R21a is selected from fluorine and chlorine; Y R22a is selected from fluorine, chlorine and methoxy. Particular compounds in the formula (VIb) include: 4- (2,6-Difluoro-benzoylamino) -1 H -pyrazol-3-carboxylic acid piperidine-4-ylamide; 4- (2,6-Difluoro-benzoylamino) -1 H -pyrazol-3-carboxylic acid (1-methyl-piperidin-4-yl) -amide; 4- (2,6-Dichloro-benzoylamino) -1 H-pyrazol-3-carboxylic acid piperidine-4-ylamide; Y 4- (2-Fluoro-6-methoxy-benzoylamino) -1 H-pyrazol-3-carboxylic acid piperidine-4-ylamide;

or salts or tautomers or N-oxides or solvates thereof.

For the avoidance of doubt, it should be understood that each general and specific preference, embodiment and example of groups R1 can be combined with each preference, embodiment and general and specific example of groups R2 and / or R3 and / or R4 and / or R10 and / or Y and / or Rg and / or subgroups thereof as defined herein and that all such combinations are encompassed by this application.

The various functional groups and substituents that form the compounds of the formula (II) are typically chosen such that the molecular weight of the compound of the formula (II) does not exceed 1,000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the pesomolecular is less than 525 and, for example, is 500 or less.

The particular compounds of formula (II) are as illustrated in the examples below.

Salts, Solvates, Tautomers, Isomers, N-Oxides, Esters, Prodrugs and Isotopes

Unless otherwise specified, a reference to a particular compound also includes the ionic forms, salts, solvates and protections thereof, for example, as discussed below.

Many compounds of the formula (II) may exist in the form of salts, for example, acid addition salts or, in certain cases, salts of organic and inorganic bases such as carboxylate, sulphonate and phosphate salts. All these salts are within the scope of this invention, and references to the compounds of the formula (II) include the salt forms of the compounds. As in the preceding sections of this application, all references to formula (II) should be taken to also refer to formulas (IV), (IVa), (Va), (Vb), (VIa) or (VIb) and subgroups of these unless the context indicates otherwise.

Salt forms can be selected and prepared according to the methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Cover Hard, 388 pages, August 2002.

Acid addition salts can be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic acids (eg, L-ascorbic), L-aspartic,

benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+) - (1S) -campho-10sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2 -disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactharic, gentisic, glucoheptonic, D-gluconic, glucuronic (for example, D-glucuronic), glutamic (for example, L-glutamic), α-oxoglutaric, glycolic, hippuric , hydrobromic, hydrochloric, iohydric, isethionic, (+) - L-lactic, (±) -DL-lactic, lactobionic, maleic, malic, (-) - L-malic, malonic, (±) -DL-mandelic, methanesulfonic , naphthalen-2-sulfonic, naphthalen-1,5-disulfonic, 1-hydroxy-2naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic , sebacic, stearic, succinic, sulfuric, tannic, (+) - L-tartaric, thiocyanic, p-toluenesulfonic, undecyl unique and valeric, as well as acylated amino acids and cation exchange resins.

A particular group of salts consists of salts formed from hydrochloric, iohydric, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, valhenesulfonic, , acetic, propanoic, butanoic, malonic, glucuronic and lactobionic.

A preferred group of salts consists of salts formed from hydrochloric, acetic, adipic, L-aspartic and DL-lactic acids.

Particularly preferred salts are hydrochloride salts.

For example, if the compound is anionic, or has a functional group that can be anionic (for example, -COOH can be -COO-), a salt with a suitable cation can be formed. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K +, alkaline earth cations such as Ca2 + and Mg2 +, and other cations such as Al3 +. Examples of suitable organic cations include, but are not limited to, ammonium ion (ie, NH4 +) and substituted ammonium ions (eg, NH3R +, NH2R2 +, NHR3 +, NR4 +). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine An example of a common quaternary ammonium ion is N (CH3) 4+.

When the compounds of the formula (II) contain an amine function, they can form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to those skilled in the art. Said quaternary ammonium compounds are within the scope of formula (II).

The salt forms of the compounds of formula (II) are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, p. 1-19. However, salts that are not pharmaceutically acceptable can also be prepared as intermediate forms that can be converted into pharmaceutically acceptable salts. Said non-pharmaceutically acceptable salts, which may be useful, for example, in the purification or separation of the compounds of formula (II), also form part of the invention.

Compounds of the formula (II) containing an amine function can also form N-oxides. A reference herein to a compound of the formula (II) containing an amine function also includes the N-oxide.

When a compound contains several amine functions, one or more of a nitrogen atom can be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

The N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (for example, a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, the N-oxides can be prepared by the LW Deady process (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

The compounds of the formula (II) may exist in several different geometric and tautomeric isomeric forms and references to the compounds of the formula (II) include all of these forms. For the avoidance of doubt, when a compound may exist in one of several geometric or tautomeric isomeric forms and only one is specifically described or shown, all others are however encompassed by formula (II).

For example, in the compounds of the formula (II) the pyrazole group can take any of the following two tautomeric forms A and B (in which X represents R1 (CO) NH). For simplicity, the general formula (II) illustrates form A but the formula should be taken as encompassing both tautomeric forms.

Other examples of tautomeric forms include, for example, the keto-, enol-, and enolate forms, as, for example, in the following tautomeric couples: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitrous / oxime, thioketone / enothiol, and nitro / aci-nitro.

When the compounds of the formula (II) contain one or more chiral centers, and may exist in the form of two

or more optical isomers, references to the compounds of the formula (II) include all the optical isomeric forms thereof (for example enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (for example, racemic mixtures) or two or more optical isomers, unless the context requires otherwise.

Optical isomers can be characterized and identified by their optical activity (ie, as + and - or dyl isomers) or can be characterized in terms of their absolute stoichiometry using the "RyS" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.

Optical isomers can be separated by various techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to those skilled in the art.

When the compounds of the formula (II) exist as two or more optical isomeric forms, an enantiomer in a pair of enantiomers may have advantages over the other enantiomer, for example, in terms of biological activity. Thus, under certain circumstances, it may be desirable to use only one of an enantiomer pair or only one of a plurality of diastereoisomers as a therapeutic agent. Accordingly, the invention provides compositions containing a compound of the formula (II) having one or more chiral centers, in which at least 55% (for example, at least 60%, 65%, 70%, 75 %, 80%, 85%, 90% or 95%) of the compound of the formula (II) is present as a single optical isomer (for example, enantiomer or diastereoisomer). In a general embodiment, 99% or more (for example, substantially all) of the total amount of the compound of the formula (II) may be present as a single optical isomer (for example, enantiomer or diastereoisomer).

Compounds of formula (II) include compounds with one or more isotopic substitutions, and a reference to a particular element includes in its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope 1H, 2H (D), and 3H (T). Similarly, references to carbon and oxygen usually include respectively 12C, 13C and 14C and 16O and 18O.

Isotopes can be radioactive or non-radioactive. In one embodiment of the invention, the compounds do not contain radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.

Esters such as carboxylic acid esters and acyloxy esters of the compounds of formula (II) having a carboxylic acid group or a hydroxyl group are also encompassed by Formula (II). Examples of esters are compounds containing the group -C (= O) OR, in which R is an ester substituent, for example a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group , preferably a C1-7 alkyl group. Particular examples of ester groups include, but are not limited to, –C (= O) OCH3, –C (= O) OCH2CH3, –C (= O) OC (CH3) 3, and –C (= O) OPh . Examples of acyloxy (reverse ester) groups are represented by -OC (= O) R, wherein R is an acyloxy substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or an aryl group C5-20, preferably a C1-7 alkyl group. Particular examples of acyloxy groups include, but are not limited to, -OC (= O) CH3 (acetoxy), -OC (= O) CH2CH3, -OC (= O) C (CH3) 3, -OC (= O ) Ph, and –OC (= O) CH2Ph.

Any polymorphic forms of the compounds, solvates (for example, hydrates) and complexes (for example, inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes) of the compounds are also encompassed in formula (II).

For example, some prodrugs are esters of the active compound (for example, a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C (= O) OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid (-C (= O) OH) groups in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound. , followed by check out if required.

Examples of such metabolically labile esters include those of the formula -C (= O) OR in which R is:

C1-7 alkyl

(for example, –Me, –Et, –nPr, –iPr, –nBu, –sBu, –iBu, –tBu); C1-7 aminoalkyl (for example, aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl); Y acyloxy-C1-7 alkyl (for example, acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1- (1-Methoxy-1-methyl) ethylcarbonyloxyethyl; 1- (benzoyloxy) ethyl; isopropoxycarbonyloxymethyl; 1-isopropoxycarbonyloxyethyl; cyclohexylcarbonyloxymethyl; 1-cyclohexylcarbonyloxyethyl; cyclohexyloxycarbonyloxymethyl; 1-cyclohexyloxycarbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; 1- (4-tetrahydropyranyloxy) carbonyloxyethyl; (4-tetrahydropyranyl) carbonyloxymethyl; Y 1- (4-tetrahydropyranyl) carbonyloxyethyl). Also, some prodrugs are enzymatically activated to yield the active compound, or a compound that,

after additional chemical reaction, the active compound yields (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or another glycoside conjugate, or it may be an amino acid ester derivative.

Biological Activity

The compounds of the formulas (II), (IV), (IVa), (Va), (Vb), (VIa) or (VIb) and subgroups thereof are inhibitors of cyclin-dependent kinases and, in particular, of cyclin dependent kinases selected from CDK1, CDK2, CDK3, CDK4, CDK5 and CDK6.

Preferred compounds are compounds that inhibit one or more CDK kinases selected from CDK1, CDK2, CDK4 and CDK5, for example CDK1 and / or CDK2.

The compounds of formula (II) are also considered as glycogen synthase kinase-3 inhibitors (GSK3).

As a consequence of their activity in the modulation or inhibition of CDK kinases and glycogen synthase kinase, they are expected to be useful by providing a means to stop, or regain control of, the cell cycle in abnormally dividing cells. It is anticipated, therefore, that the compounds will prove useful for treating or

prevent proliferative disorders such as cancers. It is also anticipated that the compounds of formula (II) will be useful for treating conditions such as viral infections, diabetes mellitus type II or non-insulin dependent, autoimmune diseases, head trauma, stroke, epilepsy, neurodegenerative diseases such as Alzheimer's , motor neuron disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease, for example. A subset of pathological conditions and conditions in which the compounds of formula (II) are expected to be useful consist of viral infections, autoimmune diseases and neurodegenerative diseases.

CDKs play a role in cell cycle regulation, apoptosis, transcription, differentiation and CNS function. Therefore, CDK inhibitors could be useful in the treatment of diseases in which there is a proliferation, apoptosis or differentiation disorder such as cancer. In particular, RB + vo tumors may be particularly sensitive to CDK inhibitors. RB-vo tumors may also be sensitive to CDK inhibitors.

Examples of cancers that can be inhibited include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (for example, colorectal carcinomas such as adenocarcinoma of the colon and adenoma of the colon), kidney, epidermis, liver, lung, for example adenocarcinoma, small cell lung cancer and non-small cell carcinomas of the lung, esophagus, gallbladder, ovary, pancreas, for example, exocrine pancreatic carcinoma, stomach, cervix, thyroid, prostate, or skin , for example, squamous cell carcinoma; a hematopoietic tumor of the lymphoid lineage, for example, leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair cell lymphoma or Burkett lymphoma; a hematopoietic tumor of the myeloid lineage, for example, acute and chronic myelogenous leukemias, myelodysplastic syndrome or promyelocytic leukemia; follicular thyroid cancer; a tumor of mesenchymal origin, for example fibrosarcoma or habdomiosarcoma, a tumor of the central or peripheral nervous system, for example, astrocytoma, neuroblastoma, glioma or schwanoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentoso; keratoctantoma; follicular thyroid cancer; or Kaposi's sarcoma.

The cancers can be cancers that are sensitive to the inhibition of any one or more cyclin dependent kinases selected from CDK1, CDK2, CDK3, CDK4, CDK5 and CDK6, for example, one or more CDK kinases selected from CDK1, CDK2, CDK4 and CDK5, for example, CDK1 and / or CDK2.

Whether a particular cancer is one that is sensitive or not to inhibition by a cyclin-dependent kinase can be determined by a cell growth assay as shown in Example 250 below or by a method as shown in the section entitled "Methods of Diagnosis".

It is also known that CDKs play a role in apoptosis, proliferation, differentiation and transcription and, therefore, CDK inhibitors may also be useful in the treatment of the following diseases other than cancer; viral infections, for example herpes virus, smallpox virus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevention of the development of AIDS in HIV-infected individuals; chronic inflammatory diseases, for example, systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus; cardiovascular diseases, for example, cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, for example, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndromes, ischemic damage associated with myocardial infarction, stroke and reperfusion damage, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver diseases, hematological diseases, for example, chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosism, kidney diseases and cancer pain.

It has also been discovered that some cyclin-dependent kinase inhibitors can be used in combination with other anticancer agents. For example, the cyclin-dependent kinase inhibitor flavopyridol has been used with other anticancer agents in combination therapy.

Thus, in the pharmaceutical compositions, the uses or methods of this invention to treat a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth in one embodiment is a cancer.

A group of cancers includes human breast cancers (eg, primary breast tumors, negative ganglion breast cancer, invasive ductal breast adenocarcinomas, non-endometrioid breast cancers); and lymphomas of the mantle cells. In addition, other cancers are colorectal and endometrial cancers.

Another subset of cancers includes breast cancer, ovarian cancer, colon cancer, prostate cancer, esophageal cancer, squamous cancer and non-small cell carcinomas of the lung.

The activity of the compounds of formula (II) as inhibitors of cyclin-dependent kinases and glycogen synthase kinase-3 can be measured using the tests shown in the examples below and the

Activity level presented by a given compound can be defined in terms of the IC50 value. Preferred compounds of the present invention are compounds having an IC50 value of less than 1 micromol, more preferably less than 0.1 micromol.

Methods for the Preparation of Compounds of Formula (II)

The compounds of the formula (II) and the various subgroups thereof can be prepared according to synthetic methods well known to those skilled in the art. Unless otherwise indicated, R1, R2, R3, and Y are as defined hereinbefore.

In this section, as in all other sections of this application, references to formula (II) should be taken to also refer to formulas (IV), (IVa), (Va), (Vb), (VIa) or (VIb) and subgroups of these unless the context indicates otherwise.

The compounds of the formula (II) can be prepared by reacting a carboxylic acid of the formula R1-CO2H or an activated derivative thereof with an appropriately substituted 4-amino-pyrazole as shown in Scheme 1.

The starting material for the synthetic route shown in Scheme 1 is 4-nitro-pyrazol-3-carboxylic acid (X) which can be obtained commercially or can be prepared by nitration of the corresponding unsubstituted 4-pyrazole carboxy compound.

The 4-nitro-pyrazole carboxylic acid (X), or a reactive derivative thereof, is reacted with the H2N-Y-R3 amine to provide 4-nitro-amide (XI). The coupling reaction between the carboxylic acid (X) and the amine is preferably carried out in the presence of a reagent of the type commonly used in the formation of peptide bonds. Examples of such reagents include 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al, J. Amer.

Chem Soc. 1955, 77, 1067), 1-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide (referred to herein as EDC or EDAC but also known in the art as EDCI and WSCDI) (Sheehan et al, J. Org. Chem., 1961, 26, 2525), uronium-based coupling agents such as O- (7-azabenzotriazol-1-yl) hexafluorophosphate)

N, N, N ', N'-tetramethyluronium (HATU) and phosphonium-based coupling agents such as 1-benzo-triazolyloxytris- (pyrrolidine) phosphonium hexafluorophosphate (PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205). Carbodiimide-based coupling agents are advantageously used in combination with 1-hydroxy-7-azabenzotriazole (HOAt) (LA Carpino, J. Amer. Chem. Soc., 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt) ( Konig et al, Chem. Ber., 103, 708, 2024-2034). Preferred coupling agents include EDC (EDAC) and DCC in combination with HOAt or HOBt.

The coupling reaction is typically carried out in a non-aqueous, non-protic solvent, such as acetonitrile, dioxane, dimethylsulfoxide, dichloromethane, dimethylformamide or N-methylpyrrolidine, or in an aqueous solvent optionally together with one or more miscible co-solvents. The reaction can be carried out at room temperature or, when the reactants are less reactive (for example, in the case of electron-poor anilines that have electron acceptor groups such as sulfonamide groups) at an appropriate elevated temperature. The

The reaction can be carried out in the presence of a base that does not interfere, for example, a tertiary amine such as triethylamine or N, N-diisopropylethylamine.

Alternatively, a reactive carboxylic acid derivative, for example, an anhydride or acid chloride can be used. Reaction with a reactive derivative such as an anhydride is typically achieved by stirring the amine and the anhydride at room temperature in the presence of a basetal such as pyridine.

The amines of the formula H2N-Y-R3 can be obtained from commercial sources or can be prepared by any of a large number of standard synthetic methods well known to those skilled in the art, see for example Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, 1992, and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8), 1995, and see also the methods described in the experimental section a continuation.

Nitro-pyrazole amide (XI) is reduced to provide the corresponding 4-amino compound of the formula (XII). The reduction can be carried out by standard methods such as catalytic hydrogenation, for example, in the presence of palladium on carbon in a polar solvent such as ethanol or dimethylformamide at room temperature. Alternatively, the reduction can be effected using a reducing agent such as tin (II) chloride in ethanol, typically with heating, for example up to the reflux temperature of the solvent.

The 4-amino-pyrazole compound (XII) is reacted with a carboxylic acid of the formula R1-CO2H, or a reactive derivative thereof, using the methods and conditions described above for the formation of the amide (XI), to provide a compound of the formula (II).

The carboxylic acids of the formula R1-CO2H can be obtained commercially or can be synthesized according to methods well known to those skilled in the art, see for example Advanced Organic Chemistry and Organic Syntheses, the details of which have been provided above.

In an alternative synthetic route, the compounds of the formula (II) can be prepared by reacting a compound of the formula (XIII) (in which X represents R1 (CO) NH) with a compound of the formula R3-Y-NH2 . The reaction can be performed using the amide coupling conditions described above.

Once formed, a compound of the formula (II) can be transformed into another compound of the formula (II) using standard chemistry procedures well known in the art. For examples of interconversions of functional groups, see for example, Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2), and Organic Syntheses, Volumes 1- 8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8), 1995.

The starting materials for the synthetic routes shown in the above Schemes, for example, the pyrazoles of formula (X), can be obtained commercially or can be prepared by methods known to those skilled in the art. They can be obtained using known methods, for example, from ketones, such as in a process described in EP308020 (Merck), or the methods discussed by Schmidt in Helv. Chim. Acta., 1956, 39, 986-991 and Helv. Chim. Minutes., 1958, 41, 306-309. Alternatively, they can be obtained by conversion of a commercially available pyrazole, for example, those containing halogen, nitro, ester or amide functionalities in pyrazoles containing the desired functionality by standard methods known to one skilled in the art. For example, in 3-carboxy-4-nitropyrazole, the nitro group can be reduced to an amine by standard methods. The 4-nitropyrazol-3-carboxylic acid (XII) can be obtained commercially or can be prepared by nitration of the corresponding unsubstituted 4-pyrazole carboxy compound and the pyrazoles containing a halogen can be used in coupling reactions with tin or palladium chemistry.

Protective Groups

In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from taking place at an undesirable location in the molecule. Examples of protective groups, and methods to protect and unprotect functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

A hydroxy group can be protected, for example, as an ether (-OR) or an ester (-OC (= O) R), for example, as: a t-butyl ether; a tetrahydropyranyl ether (THP); a benzyl ether, benzidrile (diphenylmethyl), or trityl (triphenylmethyl); a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC (= O) CH3, -OAc).

An aldehyde or ketone group can be protected, for example, as an acetal (R-CH (OR) 2) or ketal (R2C (OR) 2), respectively, in which the carbonyl group (> C = O) becomes a diester (> C (OR) 2), by reaction, for example, with a primary alcohol. The aldehyde or ketone group is easily regenerated by hydrolysis using a large excess of water in the presence of acid.

An amine group can be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz or NH-Z); as a t-butoxy amide (-NHCO-OC (CH3) 3, -NH-Boc); a 2-biphenyl-2-propoxy (-NHCO-OC (CH3) 2C6H4C6H5, -NH-Bpoc) amide, such as a 9-fluorenylmethoxy (-NH-Fmoc) amide, such as a 6-nitroveratriloxy (-NH) amide -Nvoc), as a 2-trimethylsilylethyloxy (-NH-Teoc) amide, as a 2,2,2-trichloroethyloxy (-NH-Troc) amide, as an allyloxy (-NH-Alloc) amide, or as an amide of 2 (-phenylsulfonyl) ethyloxy (-NH-Psec).

For example, in Scheme 1 above, when the R3 moiety in the H2N-Y-R3 amine contains a second amino group, such as a cyclic amino group (for example, a piperidine or pyrrolidine group), the second amino group can be protected by a protecting group as defined hereinbefore, the tert-butyloxycarbonyl group (Boc) being a preferred group. When a subsequent modification of the second amino group is not required, the protecting group can be carried through the sequence of reactions to provide a protected form of a compound of the formula (II) that can be deprotected by standard methods (eg, treatment with acid in the case of the Boc group) to provide the compound of formula (II).

Other protecting groups for amines, such as cyclic amines and heterocyclic N-H groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.

A carboxylic acid group can be protected as an ester for example, such as: a C1-7 alkyl ester (for example a methyl ester; a t-butyl ester); a C1-7 haloalkyl ester (for example, a C1-7 trihaloalkyl ester); a trialkylsilyl C1-7-C1-7 alkyl ester; or a C5-20 aryl ester-C1-7 alkyl (for example, a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide. A thiol group may be protected, for example, as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC (= O) CH3).

Isolation and purification of the compounds of formula (II)

The compounds of formula (II) can be isolated and purified according to standard techniques well known to those skilled in the art. One technique with a particular utility in the purification of the compounds is preparative liquid chromatography using too many spectrometry as a means to detect purified compounds leaving the chromatography column.

Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein. The methods for liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide a better separation of the raw materials and an improved detection of the samples by MS. Optimization of the preparative LC gradient method will involve varying the columns, volatile eluents and modifiers and gradients. The methods are well known in the art to optimize preparative LC-MS methods and use them to purify compounds. Such methods are described in Rosentreter U, Huber U .; Optimal fraction collecting in preparative LC / MS; J Comb Chem .; 2004; 6 (2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem .; 2003; 5 (3); 322-9.

An example of such a system for purifying compounds by preparative LC-MS is described below in the Examples section of this application (under the heading "LC-MS Mass Directed Purification System"). However, it will be appreciated that alternative systems and methods to those described could be used. In particular, methods based on preparative normal phase LC could be used instead of the reverse phase methods described herein. Most preparative LC-MS systems use reverse phase LC and volatile acid modifiers, since the strategy is very effective for the purification of small molecules and because eluents are compatible with mass spectrometry with positive ionic electrospray. The use of other chromatographic solutions, for example, normal phase LC, alternatively buffered mobile phase, basic modifiers etc. as highlighted in the analytical methods described below could alternatively be used to purify the compounds.

Pharmaceutical Formulations

Although it is possible to administer the active compound alone, it is preferable to present it as a pharmaceutical composition (eg, formulation) comprising at least one active compound of the invention together with one

or more vehicles, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, pharmaceutically acceptable lubricants or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.

Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods for preparing a pharmaceutical composition comprising mixing at least one active compound, as defined above, together with one or more carriers, excipients, buffers, adjuvants. , pharmaceutically acceptable stabilizers or other materials, as described herein.

The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of the responsible medical criteria, suitable for use in contact with the tissues of a subject (for example, a human being) without toxicity, irritation, excessive allergic response or other problem or complication, according to a benefit / risk ratio

reasonable. Each vehicle, excipient, etc. It must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

Accordingly, in a further aspect, the invention provides compounds of the formula (II) and subgroups thereof such as formulas (IV), (IVa), (Va), (Vb), (VIa), or ( VIb) and subgroups thereof as defined herein in the form of pharmaceutical compositions.

The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. When the compositions are intended to be for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct administration to a target organ or tissue by injection, infusion or other means of administration.

In a preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for administration iv, for example by injection or infusion.

In another preferred embodiment, the pharmaceutical composition is in a form suitable for subcutaneous administration (s.c.).

Dosage dosage forms suitable for oral administration include tablets, capsules, oblong tablets, pills, pills, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and mouth patches.

Pharmaceutical compositions containing the compounds of formula (II) can be formulated according to known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

Thus, the tablet compositions may contain a unit dosage of the active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, for example; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as demaiz starch. The tablets may also contain standard ingredients such as agglutination and granulating agents such as polyvinylpyrrolidone, disintegrants (for example, swellable crosslinked polymers such as cross-linked carboxymethyl cellulose), lubricating agents (for example, stearates), preservatives (for example, parabens), antioxidants (for example, BHT), buffering agents (for example, phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and a detailed discussion is not necessary here.

The capsule formulations may be of the hard gelatin or soft gelatin variety and may contain the active component in solid, semi-solid or liquid form. The gelatin capsules may be formed of animal or synthetic gelatin or plant-derived equivalents thereof.

Solid dosage forms (e.g., tablets, capsules etc.) may be coated or uncoated, but typically have a coating, for example, a protective film coating (e.g., a wax or varnish) or a coating that controls the Liberation. The coating (for example, a polymer of the Eudragit ™ type) can be designed to release the active component at a desired location in the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions in the gastrointestinal tract, thereby selectively releasing the compound in the stomach or in the ileum or in the duodenum.

Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising an agent that controls the release, for example an agent that delays the release that can be adapted to selectively release the compound under different acidity conditions or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or the coating that delays the release may be in the form of an erodible polymer (eg, a maleic anhydride polymer) that erodes substantially continuously as the dosage form passes through the gastrointestinal tract. As an additional alternative, the active compound can be formulated in an administration system that provides osmotic control of the release of the compound. Osmotic release formulations and other delayed release or sustained release formulations can be prepared according to methods well known to those skilled in Latin America.

Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (eg, intraocular inserts). Said compositions may be formulated according to known methods.

Compositions for parenteral administration are typically presented as sterile aqueous or oleaginous solutions or fine suspensions, or they can be provided in the form of finely divided sterile powder to prepare extemporaneously with sterile water for injection.

Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories that may be formed, for example, by a moldable or ceruginous shaped material containing the active compound.

Compositions for administration by inhalation may be in the form of inhalable powder compositions or liquid or powder sprayers and may be administered as standard using devices for inhaling dust or aerosol dispensing devices. Such devices are well known. For administration by inhalation, powder formulations typically comprise the active compound together with a solid powder diluent such as lactose.

The compounds of formula (II) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation directed for oral administration may contain from 0.1 milligrams to 2 grams of active ingredient, more usually from 10 milligrams to 1 gram, for example, 50 milligrams to 500 milligrams.

The active compound will be administered to a patient in need (for example, a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

Treatment Methods

Compounds of the formula (II) and subgroups thereof such as formulas (IV), (IVa), (Va), (Vb), (VIa), or (VIb) and subgroups thereof are defined as defined herein they will be useful in the prophylaxis or treatment of a range of pathological conditions or conditions mediated by cyclin-dependent kinases. Examples of such disease states and conditions have been shown above.

The compounds are generally administered to a subject in need of such administration, for example a human or animal patient, preferably a human being.

The compounds will typically be administered in amounts that are therapeutically or prophylactically useful and that are generally not toxic. However, in certain situations (for example, in the case of life-threatening diseases), the benefits of administering a compound of the formula (II) may outweigh the disadvantages of any effectotoxic or side effects, in which case it may be considered desirable to administer the compounds in amounts that are associated with a degree of toxicity.

The compounds may be administered for a prolonged time to maintain the beneficial therapeutic effects or may be administered only for a short period. Alternatively, they can be administered in a pulsatile or continuous manner.

A typical daily dose of the compound may be in the range of 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of body weight and more usually 10 nanograms to 15 milligrams per kilogram (for example, 10 nanograms to 10 milligrams) per kilogram of body weight although higher or lower doses may be administered when required. Finally, the amount of the compound administered and the type of composition used will be consistent with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

The compounds of the formula (II) may be administered as the sole therapeutic agent or may be administered in combination therapy with one or more additional compounds for the treatment of a particular pathological condition, for example, a neoplastic disease such as a cancer as it has been defined above herein. Examples of other therapeutic agents that can be administered together with (either simultaneously or at different time intervals) the compounds of the formula (II) include, but are not limited to, topoisomerase inhibitors, alkylating agents, antimetabolites, DNA binders and inhibitors of

microtubules (tubulin-directed agents), such as cisplatin, cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5FU, taxanes, mitomycin C, or radiation therapy. Alternatively, the compounds of the formula (II) can be administered in a combination therapy with monoclonal antibodies or signal transduction inhibitors. In the case of CDK inhibitors combined with other therapies, the two or more treatments can be provided in dose schedules that vary individually and by different routes.

When the compound of the formula (II) is administered in combination therapy with one, two, three four or more additional therapeutic agents (preferably, one or two, more preferably one), the compounds can be administered simultaneously or sequentially. When administered sequentially, they can be administered at spaced intervals (for example, over a period of 5-10 minutes) or at larger intervals (for example, separated 1, 2, 3, 4 or more hours, or even separated by longer periods when required), the precise dosing regimen being consistent with the properties of the therapeutic agent (s).

The compounds of formula (II) can also be co-administered with non-chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy; Surgery and controlled diets.

For use in combination therapy with another chemotherapeutic agent, the compound of the formula (II) and one, two, three, four or more additional therapeutic agents may be formulated, for example, together in a dosage form containing two, three, Four or more therapeutic agents. In an alternative, individual therapeutic agents can be formulated separately and presented together in the form of a kit, optionally with instructions for use.

A person skilled in the art will know through his general knowledge the dosage regimens and combination therapies that should be used.

Diagnostic Methods

Prior to the administration of a compound of the formula (II), a patient can be screened to determine if a disease or condition that the patient suffers or may suffer from is one that would be susceptible to treatment with a compound that has activity against cyclin-dependent kinases.

For example, a biological sample taken from a patient can be analyzed to determine if a condition or disease, such as cancer, that the patient suffers or may suffer from is one that is characterized by a genetic abnormality or abnormal protein expression that results in overactivation. of CDK or sensitization of a route to normal CDK activity. Examples of such abnormalities that result in activation or sensitization of the CDK2 signal include upregulation of cyclin E, (Harwell RM, Mull BB, Porter DC, Keyomarsi K .; J Biol Chem. 2004 Mar 26; 279 (13 ): 12695-705) or the loss of p21 or p27, or the presence of variants of CDC4 (Rajagopalan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B, Lengauer C .; Nature. 2004 Mar 4; 428 (6978): 77-81). The term upward regulation includes high expression or overexpression, including gene amplification (ie, multiple copies of genes) and expression increased by a transcriptional effect and hyperactivity and activation, including activation by mutations. Thus, the patient can undergo a diagnostic test to detect a characteristic marker of upward regulation of cyclin E, or loss of p21 or p27,

or presence of CDC4 variants. The term diagnosis includes screening. By marker we include genetic markers including, for example, the measurement of DNA composition to identify CDC4 mutations. The term "marker" also includes markers that are characteristic of the upward regulation of cyclin E, including enzymatic activity, enzyme levels, enzyme status (eg, phosphorylated or not) and mRNA levels of the above-mentioned proteins.

Tumors with upregulation of cyclin E, or loss of p21 or p27 may be particularly sensitive to CDK inhibitors. Tumors may preferably be screened for upward regulation of cyclin E, or loss of p21 or p27 before treatment. Thus, the patient can undergo a diagnostic test to detect a characteristic marker of upward regulation of cyclin E, or loss of p21 or p27. Diagnostic assays are typically performed on a selected biological sample of tumor biopsy samples, blood samples (isolation and enrichment of disseminated tumor cells), stool biopsies, sputum, chromosomal analysis, pleural fluid, peritoneal fluid, or urine.

It has been found, Rajagopalan et al (Nature. 2004 Mar 4; 428 (6978): 77-81), that there were mutations present in CDC4 (also known as Fbw7 or Archipelago) in colorectal cancers and human endometrial cancers (Spruck et al, Cancer Res. 2002 Aug 15; 62 (16): 4535-9). The identification of individuals carrying a mutation in CDC4 may mean that the patient would be particularly suitable for treatment with a CDK inhibitor. Tumors may preferably be screened for the presence of a variant of CDC4 before treatment. The screening process will typically involve direct sequencing, oligonucleotide microarray analysis or a specific mutant antibody.

The methods of identification and analysis of mutations and the upward regulation of proteins are known to one skilled in the art. Screening methods could include, but are not limited to, standard methods such as polymerase chain reaction with reverse transcriptase (RT-PCR) or in-situ hybridization.

In RT-PCR screening, the level of mRNA in the tumor is evaluated by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR. Methods for PCR amplification, primer selection and conditions for amplification are known to one skilled in the art. Nucleic acid manipulations and PCR are performed by standard methods, as described for example in Ausubel, F.M. et al., eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis, M.A. et-al., eds. PCR Protocols: a guide to methods and applications, 1990, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., 2001, 3rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, a commercially available kit for RT-PCR (eg, Roche Molecular Biochemicals), or the methodology as shown in United States patents 4,666,828; 4,683,202; 4,801,531; 5,192,659, 5,272,057, 5,882,864, and 6,218,529.

An example of an in situ hybridization technique to assess mRNA expression would be fluorescence in situ hybridization (FISH) (see, Angerer, 1987 Meth. Enzymol., 152: 649).

Generally, in situ hybridization comprises the following main steps: (1) fixation of the tissue to be analyzed; (2) sample prehybridization treatment to increase accessibility of the target nucleic acid and to reduce non-specific binding; (3) hybridization of the mixture of nucleic acids to the nucleic acid in the structure

or biological tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound in hybridization, and (5) detection of hybridized nucleic acid fragments. The probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are long enough, for example, from about 50, 100, or 200 nucleotides to about 1,000 or more nucleotides, to allow specific hybridization with the target nucleic acid (s) under astringent conditions. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed .; ISBN: 1-59259-760-2; March 2004, p. 077-088; Series: Methods in Molecular Medicine.

Alternatively, protein products expressed from mRNAs can be tested by immunohistochemistry of tumor samples, solid phase immunoassay with microtiter plates, Western blotting, SDS-two-dimensional polyacrylamide gel electrophoresis, ELISA, flow cytometry and other methods known in the technique for the detection of specific proteins. Detection methods will include the use of site specific antibodies. The person skilled in the art will recognize that all these well-known techniques for the detection of upward regulation of cyclin E, or loss of p21 or p27, or detection of CDC4 variants could be applied in the present case.

Therefore, all of these techniques could also be used to identify tumors particularly suitable for treatment with CDK inhibitors. Patients with mantle cell lymphoma (MCL) could be selected for treatment with a CDK inhibitor using the diagnostic assays presented herein. MCL is a distinct clinicopathological entity of non-Hodgkin lymphoma, characterized by the proliferation of small to medium-sized lymphocytes with co-expression of CD5 and CD20, an aggressive and incurable clinical course and translocation t (11; 14) (q13; q32) frequent. Overexpression of cyclin D1 mRNA, found in mantle cell lymphoma (MCL), is a critical diagnostic marker. Yatabe et al (Blood. 2000 Apr 1; 95 (7): 2253-61) have proposed that positivity in cyclin D1 should be included as one of the standard criteria for MCL, and that innovative therapies for this incurable disease should be explored. based on the new criteria. Jones et al (J Mol Diagn. 2004 May; 6 (2): 84-9) have developed a quantitative, real-time reverse transcription PCR assay for the expression of cyclin D1 (CCND1) to aid in the diagnosis of mantle cell lymphoma (MCL). Howe et al (Clin Chem. 2004 Jan; 50 (1): 80-7) have used quantitative real-time RT-PCR to evaluate the expression of cyclin D1 mRNA and found that quantitative RT-PCR for mRNA expression for cyclin D1 normalized for CD19 mRNA can be used in the diagnosis of MCL in blood, marrow and tissue. Alternatively, breast cancer patients could be selected for treatment with a CDK inhibitor using the diagnostic assays presented above. Tumor cells commonly overexpress cyclin E and cyclin E has been shown to be overexpressed in breast cancer (Harwell et al, Cancer Res, 2000, 60, 481-489). Therefore, breast cancer can be treated in particular with a CDK inhibitor.

Antifungal Use

In a further aspect, the invention provides the use of the compounds of the formulas (II), (IV), (IVa), (Va), (Vb), (VIa) or (VIb) and subgroups thereof as defined in this memory as antifungal agents.

The compounds can be used in animal medicine (for example, in the treatment of mammals such as humans) or in the treatment of plants (for example, in agriculture and horticulture), or as general antifungal agents, for example, as preservatives and disinfectants

In one embodiment, the invention provides a compound of the formula (II) and subgroups thereof such as formulas (IV), (IVa), (Va), (Vb), (VIa) or (VIb) and subgroups thereof as defined herein for use in the prophylaxis or treatment of a fungal infection in a mammal such as a human being.

The use of a compound of the formula (II) and subgroups thereof such as formulas (IV), (IVa), (Va), (Vb), (VIa), (VIb) and subgroups thereof such as It is defined herein for the manufacture of a medicament for use in the prophylaxis or treatment of a fungal infection in a mammal such as a human being.

For example, the compounds of formula (II) can be administered to human patients suffering from, or at risk of infection by, topical fungal infections caused among other organisms by, Candida species, Trichophyton, Microsporum or Epidermophyton, or mucosal infections caused by Candida albicans (for example, thrush and vaginal candidiasis). The compounds of formula (II) can also be administered for the treatment or prophylaxis of systemic fungal infections caused, for example, by Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, Coccidiodies, Paracoccidioides, Histoplasma or Blastomyces.

In another aspect, the invention provides an antifungal composition for agricultural use (including horticultural), which comprises a compound of formula (II) and subgroups thereof such as formulas (IV), (V) and (VI) as described. defined hereinbefore together with an agriculturally acceptable diluent or vehicle.

The invention further provides a method of treating an animal (including a mammal such as a human being), plant or seed having a fungal infection, which comprises treating said animal, plant or seed, or the locus of said plant or seed. , with an effective amount of a compound of the formula (II) and subgroups thereof such as formulas (IV), (V) and (VI) as defined hereinbefore.

The invention also provides a method of treating a fungal infection in a plant or seed that comprises treating the plant or seed with an antifungal effective amount of a fungicidal composition as defined hereinbefore.

Differential screening assays can be used to select those compounds of the present invention with specificity for non-human CDK enzymes. Compounds that act specifically on CDK enzymes of eukaryotic pathogens can be used as anti-fungal or anti-parasitic agents. Candida CDK kinase inhibitors, CKSI, can be used in the treatment of candidiasis. Antifungal agents may be used against infections of the type defined hereinbefore, or opportunistic infections that commonly occur in weakened and immunosuppressed patients such as patients with leukemia and lymphomas, people who are receiving immunosuppressive therapy and patients with predisposing conditions. such as diabetes mellitus or AIDS, as well as for non-immunosuppressed patients.

The assays described in the art can be used to screen for agents that may be useful to inhibit at least one fungus involved in mycoses such as candidiasis, aspergillosis, mucormycosis, blastomycosis, geotrichosis, cryptococcosis, chromoblastomycosis, coccidiodomycosis, conidiosporosis, histoplasmosis, histoplasmosis, histoplasmosis, histoplasmosis, histoplasmosis, histoplasmosis, histoplasmosis, histoplasmosis, histoplasmosis, Rhinosporidosis, nocaidiosis, para-actinomycosis, penicilliosis, monoliasis, or sporotrichosis. Differential screening assays can be used to identify anti-fungal agents that may have therapeutic value in the treatment of aspergillosis using cloned yeast CDK genes such as Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, or Aspergillus terreus, or When the fungal infection is mucormycosis, the CDK assay can be derived from yeasts such as Rhizopus arrhizus, Rhizopus oryzae, Absidia corymbifera, Absidia ramosa, or Mucorpusillus. Sources of other CDK enzymes include the pathogen Pneumocystis carinii.

As an example, the in vitro evaluation of the antifungal activity of the compounds can be performed by determining the minimum inhibitory concentration (M.I.C.) which is the concentration of the test compounds, in a suitable medium, at which the growth of the particular microorganism does not occur. In practice, a series of agar plates, each having the test compound incorporated at a particular concentration, is inoculated with a standard culture, for example, of Candida albicans and each plate is incubated for an appropriate period at 370C. Plates are examined for the presence or absence of fungus growth and the M.I.C. value is indicated. appropriate.

The in vivo evaluation of the compounds can be performed at a series of dose levels by intraperitoneal or intravenous injection or by oral administration, to mice that have been inoculated with a fungus, for example, a strain of Candida albicans or Aspergillus flavus. The activity of the compounds can be evaluated based on the survival of a treated group of mice after the death of an untreated group of mice. The activity can be measured in terms of the dose level at which the compound provides 50% protection against the lethal effect of the infection (DP50).

For antifungal use in humans, the compounds may be administered alone or in admixture with a pharmaceutical carrier selected according to the intended route of administration and standard pharmaceutical practice. Thus, for example, they can be administered orally, parenterally, intravenously, intramuscularly or subcutaneously by

formulations described above in the section entitled "Pharmaceutical Formulations".

For oral and parenteral administration to human patients, the daily dosage level of the antifungal compounds of formula (II) may be 0.01 to 10 mg / kg (in divided doses), depending inter alia on the potency.

of the compounds when administered well by oral or parenteral route. The tablets or capsules of the compounds may contain, for example, 5 mg. 0.5 g of the active compound for single administration or two or more at a time as appropriate. The doctor in any event will determine the actual dosage (effective amount) that will be the most appropriate for an individual patient and will vary with the age, weight and response of the particular patient.

Alternatively, the antifungal compounds may be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or fine powder. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, in a concentration between 1 and 10%, into an ointment consisting of a white wax base

or white soft paraffin together with stabilizers and preservatives as required.

In addition to the therapeutic uses described above, the anti-fungal agents developed with said differential screening assays can be used, for example, as preservatives in food products, food supplement to stimulate weight gain in cattle or in disinfectant formulations for treatment. of non-living matter, for example, to decontaminate equipment and hospital rooms. Similarly, comparing each other of the inhibition of a mammalian CDK and an insect CDK, such as the Drosophilia CDK5 gene (Hellmich et al. (1994) FEBS Lett 356: 317-21), will allow selection between the compounds herein of inhibitors that discriminate between human / mammalian and insect enzymes. Accordingly, the present application describes the use and formulations of the compounds of formula (II) in insecticides, such as for use in handling insects such as fruit flies.

In yet another embodiment, some of the subject CDK inhibitors can be selected based on the inhibitory specificity for plant CDKs relative to the mammalian enzyme. For example, a plant CDK can be arranged in a differential screen with one or more human enzymes to select those compounds with a greater selectivity to inhibit the plant enzyme. Thus, the present invention specifically contemplates formulations of the object CDK inhibitors for agricultural applications, such as in the form of a scrubber or the like.

For agricultural and horticultural purposes, the compounds of formula (II) may be used in the form of a composition formulated as appropriate for the particular use and intended purpose. Thus, the compounds can be applied in the form of fine powders, or granules, seed fertilizers, aqueous solutions, dispersions or emulsions, disinfectant baths, sprayers, aerosols or fumes. The compositions can also be supplied in the form of dispersible powders, granules or grains, or concentrates for dilution before use. Such compositions may contain conventional carriers, diluents or adjuvants as are known and acceptable in agriculture and horticulture and are manufactured according to conventional procedures. The compositions may also incorporate other active ingredients, for example, compounds having herbicidal or insecticidal activity or an additional fungicide. The compounds and compositions can be applied in various ways, for example, they can be applied directly to the leaves of plants, stems, branches, seeds or roots or to the soil or other growth medium and can be used not only to eradicate the disease, but also prophylactically to protect plants or seeds from attack. As an example, the compositions may contain 0.01 to 1% by weight of the active ingredient. For use in the field, the probable application rates of the active ingredient can be 50 to 5,000 g / hectare.

The invention also contemplates the use of the compounds of the formula (II) and subgroups thereof such as formulas (IV), (IVa), (Va), (Vb), (VIa) or (VIb) and subgroups thereof as defined herein in the control of wood decay fungi and in the treatment of soil in which plants grow, wetlands for seeds or water for infusion. Also contemplated by the invention is the use of the compounds of the formula (II) and subgroups thereof such as formulas (IV), (IVa), (Va), (Vb), (VIa), or (VIb) and Subgroups of these as defined herein to protect stored grains and other plant loci from fungal infestation.

EXAMPLES

The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples.

In the examples, the prepared compounds were characterized by liquid chromatography and mass spectroscopy (LC-MS) using the system and operating conditions shown below. When chlorine is present and a single mass is indicated, the mass indicated for the compound is for 35Cl. The two systems were equipped with identical chromatography columns and adjusted to operate under the same operating conditions. The operating conditions used are also described below. In the examples, retention times are provided in minutes.

Platform system

System:

Waters 2790 / LC Platform

Spec Detector Mas:

Micromass LC Platform

PDA Detector:

Waters 996 PDA

Analytical Conditions:

Eluent A: 5% CH3CN in 95% H2O (0.1% Formic Acid) Eluent B: CH3CN (0.1% Formic Acid) Gradient: 10-95% eluent B Flow rate: 1.2 ml / min Column: Synergi 4µm Max-RP C12, 80A, 50 x 4.6 mm (Phenomenex)

MS Conditions:

Capillary voltage: 3.5 kV Cone voltage: 30 V Source temperature: 1200C

FractionLynx system

System: Waters FractionLynx (dual analytical / prep) Spec Mass Detector: Waters-Micromass ZQ PDA Detector: Waters 2996 PDA

Analytical Conditions:

Eluent A: H2O (0.1% Formic Acid) Eluent B: CH3CN (0.1% Formic Acid) Gradient: 5-95% eluent B Flow rate: 1.5 ml / min Column: Synergi 4µm Max-RP C12, 80A, 50 x 4.6 mm (Phenomenex)

MS Conditions:

Capillary voltage: 3.5 kV Cone voltage: 30 V Source temperature: 1200C Desolvation temperature: 3000C

LC-MS Analytical System

Several systems were used, as described below, and these were equipped with adjusted to operate under very similar operating conditions. The operating conditions used are also described below.

HPLC System: Waters 2795 Spec Detector More: Micromass LC Platform PDA Detector: Waters 2996 PDA

Acid Analytical Conditions:

Eluent A: H2O (0.1% Formic Acid)

Eluent B: CH3CN (0.1% Formic Acid)

Gradient: 5-95% eluent B for 3.5 minutes

Flow rate: 0.8 ml / min

Column: PhenomenexSynergi4µMAX-RP80A, 2,0x50mm

Basic Analytical Conditions:

Eluent A: H2O (10mM buffer NH4HCO3 adjusted to pH = 9.5 with NH4OH)

Eluent B: CH3CN

5 Gradient: 05-95% eluent for 3.5 minutes

Flow rate: 0.8 ml / min

Column: Thermo Hypersil-Keystone BetaBasic-18 5µm 2.1 x 50 mm

or

Column: PhenomenexLunaC18 (2) 5µm2,0x50mm 10 Polar Analytical Conditions:

Eluent A: H2O (0.1% Formic Acid)

Eluent B: CH3CN (0.1% Formic Acid)

Gradient: 00-50% eluent for 3 minutes

Flow rate: 0.8 ml / min 15 Column: ThermoHypersil-KeystoneHyPurityAquastar, 5µ, 2,1x50mm

or

Column: PhenomenexSynergi4µMAX-RP80A, 2,0x50mm

Long Analytical Conditions:

Eluent A: H2O (0.1% Formic Acid) 20 Eluent B: CH3CN (0.1% Formic Acid)

Gradient: 05-95% eluent for 15 minutes

Flow rate: 0.4 ml / min

Column: PhenomenexSynergi4µMAX-RP80A, 2,0x150mm

ConditionsMS: 25 Capillary voltage: 3.6 kV

Cone voltage: 30 V

Source Temperature: 1200C

Scan Interval: 165-700 amu

Ionization Mode: Positive Electro Spray or 30 Negative Electro Spray or

ElectroPulverización Positive and Negative

LC-MS Mass Directed Purification System

The following preparative chromatography systems can be used to purify the compounds of formula (II).

 Hardware:

FractionlynxWater System: 2767 Dual Autosampler / Fraction Collector 2525 CFO preparatory pump (fluidic column organizer) for the selection of the RMA column (reactive manager Waters) as a compensating pump Mass SpectrometerWaters ZQ Photo Detector Series DiodesWaters 2996

 Software: Masslynx 4.0

 Columns:

one.

Low pH chromatography: Phenomenex Synergy MAX-RP, 10µ, 150 x 15mm (alternatively the same type of column with dimensions 100 x 21.2mm was used).

2.

High pH chromatography: Phenomenex Luna C18 (2), 10 µ, 100 x 21.2 mm (alternatively Thermo Hypersil Keystone BetaBasic C 18, 5 µ, 100 x 21.2mm was used)

 Eluents:

one.

Low pH chromatography: Solvent A: H20 + 0.1% Formic Acid, pH 1.5 Solvent B: CH3CN + 0.1% Formic Acid

2.

High pH chromatography: Solvent A: H20 + 10mM NH4HCO3 + NH4OH, pH 9.5 Solvent B: CH3CN

3.

Compensatory solvent: MeOH + 0.1% formic acid (for both types of chromatography)

 Methods:

Before using preparative chromatography to isolate and purify the product compounds, analytical LC-MS (see above) can first be used to determine the most appropriate conditions for preparative chromatography. A typical routine is to perform an analytical LC-MS using the type of chromatography (low or high pH) most suitable for the structure of the compound. Once the analytical trace shows a good chromatography, a suitable preparative method of the same type can be chosen. The typical operating condition for low and high pH chromatography methods are:

Flow rate: 24 ml / min

Gradient: Generally all gradients have an initial stage of 0.4 min with 95% A + 5% B. Then, according to the analytical trace a gradient of 3.6 min is chosen in order to achieve a good separation (for example , from 5% to 50% B for compounds that are retained soon; from 35% to 80% B for compounds that are retained immediately and so on)

Wash: A 1 minute wash stage is performed at the end of the gradient

Rebalanced: A 2.1 minute rebalancing stage is performed to prepare the system for the next operation

Compensatory flow rate: 1ml / min

 Solvent:

All compounds were usually dissolved in 100% MeOH or 100% DMSO

 Operating conditions of MS:

Capillary voltage: 3.2 kV

5 Cone voltage: 25 V

Source Temperature: 1200C

Multiplier: 500 V

Scan Interval: 125-800 amu

Ionization Mode: Positive Electrospray 10 Starting materials for each of the Examples are commercially available unless

Specify something else.

* = comparative example EXAMPLE 1 * 4-amino-1H-pyrazol-3-carboxylic acid phenylamide

15 1A. 4-nitro-1H-pyrazol-3-carboxylic acid phenylamide

4-Nitropyrazol-3-carboxylic acid (2.5 g; 15.9 mmol) was added to a stirred solution of aniline (1.6 ml; 17.5 mmol), EDC (3.7 g; 19.1 mmol ), and HOBt (2.6 g; 19.1 mmol) in N, N-dimethylformamide (DMF) (25 ml) and stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the

The residue was triturated with ethyl acetate / saturated NaHCO3 solution. The resulting solid was collected by filtration, washed with water and diethyl ether and dried in vacuo to provide 2.85 g of the title compound (sodium salt) as a yellow / brown solid. (LC / MS: Rt 2.78, [M + H] + 232.95).

1 B. 4-amino-1H-pyrazol-3-carboxylic acid phenylamide

25 4-Nitro-1 H -pyrazol-3-carboxylic acid phenylamide (100 mg; 0.43 mmol) was dissolved in ethanol (5 mL), treated with tin (II) chloride dihydrate (500 mg; 2.15 mmoles) and heated to reflux all night. The reaction mixture was cooled and evaporated. The residue was partitioned between ethyl acetate and concentrated saline solution and the ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated. The crude product was purified by flash column chromatography eluting with 1: 1 ethyl acetate / petroleum ether and 5% methanol / dichloromethane. Evaporation of

30 fractions containing the product followed by preparative LC / MS provided 15 mg of the product as an off-white solid. (LC / MS: Rt 1.40, [M + H] + 202.95).

EXAMPLE 2 * (4-Acetylamino-1 H -pyrazol-3-carboxylic acid 4-Fluoro-phenyl) -amide 2A. 4-Nitro-1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

5 4-Nitropyrazol-3-carboxylic acid (10 g; 63.66 mmol) was added to a stirred solution of 4-fluoroaniline (6.7 ml; 70 mmol), EDC (14.6 g; 76.4 mmol) , and HOBt (10.3 g; 76.4 mmol) in DMF (25 ml) and stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue was triturated with ethyl acetate / saturated concentrated saline. The resulting yellow solid was collected by filtration, washed with 2M hydrochloric acid and dried in vacuo to provide 15.5 g of the title compound. (LC / MS: Rt 2.92

10 [M + H] + 250.89).

2B. 4-Amino-1 H -pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

4-Nitro-1H-pyrazol-3-carboxylic acid (4-fluorophenyl) -amide (15 g) was dissolved in 200 ml of ethanol, treated with 1.5 g of 10% palladium on carbon under a nitrogen atmosphere and hydrogenated at temperature and pressure

15 atmosphere all night. The catalyst was removed by filtration through Celite and the filtrate was evaporated. The crude product was dissolved in acetone / water (100 ml: 100 ml) and after slowly evaporating the acetone, the product was collected by filtration as a solid crystalline brown (8.1 g). (LC / MS: Rt 1.58, [M + H] + 220.95).

2 C. 4-Acetylamino-1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

20 4-Amino-1 H -pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide (500 mg; 2.27 mmol) was dissolved in 5 ml of pyridine, treated with acetic anhydride (240 µl, 2 , 5 mmol) and stirred at room temperature overnight. The solvent was removed by evaporation and dichloromethane (20 ml) and 2M hydrochloric acid (20 ml) were added. The undissolved solid was collected by filtration, washed with more dichloromethane and water and dried in vacuo. The product was isolated as an off-white solid (275 mg). (LC / MS: Rt 2.96, [M + H] + 262.91).

EXAMPLE 3 * 4- (2,2,2-Trifluoro-acetylamino) -1 H -pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

4-Amino-1 H -pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide (Example 2B) (500 mg; 2.27 mmol) was dissolved in

5 5ml of pyridine, treated with anhydrofluoroacetic acid (320 µl, 2.5 mmol) and temperature was added overnight. The solvent was removed by evaporation, the residue was partitioned between ethyl acetate (50 ml) and 2M hydrochloric acid (50 ml), and the ethyl acetate layer was separated, washed with concentrated saline (50 ml), dried (MgSO4), filtered and evaporated to provide 560 mg of product as a brown solid. (LC / MS: [M + H] + 317).

10 EXAMPLE 4 *

4 - [(5-Oxo-pyrrolidine-2-carbonyl) -amino] -1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

To a stirred solution of 4-amino-1 H -pyrazol-3-carboxylic acid (4-fluorophenyl) -amide (Example 2B) (50 mg; 0.23 mmol), EDAC (52 mg; 0.27 mmol) and HOBt (37 mg; 0.27 mmol) in 5 ml of DMF 2-oxoproline was added

15 (33 mg; 0.25 mmol), and the mixture was left at room temperature overnight. The reaction mixture was evaporated and the residue was purified by preparative LC / MS to provide 24 mg of the product as a white solid. (LC / MS: Rt 2.27 [M + H] + 332).

EXAMPLE 5 *

4-Phenylacetylamino-1 H -pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The reaction was carried out in a manner analogous to Example 4 but using phenylacetic acid (34 mg; 0.23 mmol) as the starting material. The title compound (14 mg) was isolated as a white solid. (LC / MS: Rt 3.24 [M + H] + 339).

EXAMPLE 6 * 4- (2-1H-indole-3-yl-acetylamino) -1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The reaction was performed in a manner analogous to Example 4 but using indole-3-acetic acid (44 mg; 0.23 mmol) as the starting material. The title product (14 mg) was isolated as a white solid. (LC / MS: Rt 3.05 [M + H] + 378).

EXAMPLE 7 * 4- (2-Benzenesulfonyl-acetylamino) -1H-pyrazol-3-carboxylic acid 4-fluoro-phenyl) -amide

The reaction was carried out in a manner analogous to Example 4 but using 2- (phenylsulfonyl) acetic acid (50 mg; 0.23 mmol) as the starting material. The title compound (29 mg) was isolated as a white solid. (LC / MS: Rt 3.00 [M + H] + 403).

EXAMPLE 8 * 4- [2- (5-Amino-tetrazol-1-yl) -acetylamino] -1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The reaction was performed in a manner analogous to Example 4 but 5-aminotetrazol-1-acetic acid (36 mg; 0.23 mmol) was used as the starting material. The title compound (23 mg) was isolated as a white solid. (LC / MS: Rt 2.37 [M + H] + 346).

EXAMPLE 9 * 20 N- [3- (4-Fluoro-phenylcarbamoyl) -1H-pyrazol-4-yl] -6-hydroxy-nicotinamide

The reaction was carried out in a manner analogous to Example 4 but using 6-hydroxynicotinic acid (38 mg; 0.23 mmol) as the starting material. The title compound (17 mg) was isolated as a white solid. (LC / MS: Rt 2.32 [M + H] + 342).

EXAMPLE 10 * 4- [3- (4-Chloro-phenyl) -propionylamino] -1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The reaction was carried out in a manner analogous to Example 4 but using 3- (4-chlorophenyl) propionic acid (46 mg; 0.23 mmol) as the starting material. The title compound (40 mg) was isolated as a white solid. (LC / MS: Rt 3.60 [M + H] + 388).

10 EXAMPLE 11 *

4- (3-4H- [1,2,4] triazol-3-yl-propionylamino] -1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The reaction was carried out in a manner analogous to Example 4 but using 3-triazol-3-yl propionic acid (36 mg; 0.23 mmol) as the starting material. The title compound (18 mg) was isolated as a white solid. (LC / MS: Rt 15 2.39 [M + H] + 344).

EXAMPLE 12 * 4- [2- (1-Methyl-1 H -indol-3-yl) -acetylamino] -1 H -pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The reaction was carried out in a manner analogous to Example 4 but using N-methyl indole-3-acetic acid (48 mg; 20 0.23 mmol) as the starting material. The title compound (20 mg) was isolated as a white solid. (LC / MS: Rt 3.34 [M + H] + 392).

EXAMPLE 13 * 4 - [(1-Hydroxy-cyclopropanecarbonyl) -amino] -1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The reaction was carried out in a manner analogous to Example 4 but using 1-hydroxycyclopropane carboxylic acid (26 mg; 0.23 mmol) as the starting material. The title compound (24 mg) was isolated as a white solid. (LC / MS: Rt 2.55 [M + H] + 305).

EXAMPLE 14 * 1-Acetyl-piperidine-4-carboxylic acid [3- (4-Fluoro-phenylcarbamoyl) -1H-pyrazol-4-yl] -amide

The reaction was carried out in a manner analogous to Example 4 but using N-acetylpiperidine acetic acid (43 mg; 0.23 mmol) as the starting material. The title compound (19 mg) was isolated as a white solid. (LC / MS: Rt 2.49 [M + H] + 374).

EXAMPLE 15 * 4- [3- (4-Methyl-piperazin-1-yl) -propionylamino] -1 H -pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The reaction was carried out in a manner analogous to Example 4 but using 4-N-methylpiperazine-1-N-propionic acid (31 mg; 0.23 mmol) as the starting material. The title compound (19 mg) was isolated as a white solid. (LC / MS: Rt 1.77 [M + H] + 375).

EXAMPLE 16 * 20 (4-Fluorophenyl) -amide 4- (2-1H-imidazol-4-yl-acetylamino) -1H-pyrazole-3-carboxylic acid

The reaction was performed in a manner analogous to Example 4 but using imidazol-4-acetic acid (32 mg; 0.23 mmol) as the starting material. The title compound (35 mg) was isolated as a white solid. (LC / MS: Rt 1.82 [M + H] + 329).

EXAMPLE 17 * 4- (3-Morpholin-4-yl-propionylamino) -1 H -pyrazol-3-carboxylic acid (4-fluorophenyl) -amide

The reaction was performed in a manner analogous to Example 4 but using 3-morpholin-4-yl propionic acid (40 mg; 0.23 mmol) as the starting material. The title compound (15 mg) was isolated as a white solid. (LC / MS: Rt 1.84 [M + H] + 362).

10 EXAMPLE 18 *

4- (3-Piperidin-1-yl-propionylamino) -1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The reaction was carried out in a manner analogous to Example 4 but using 3-piperidine-4-yl propionic acid (39 mg; 0.23 mmol) as the starting material. The title compound (19 mg) was isolated as a white solid. (LC / MS: 15 Rt 1.92 [M + H] + 360).

EXAMPLE 19 * 4-Cyclohexylamino-1 H -pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

To a solution of (4-fluoro-phenyl) -amide of 4-amino-1 H -pyrazol-3-carboxylic acid (200 mg; 1 mmol) and

Cyclohexanone (107 mg; 1.1 mmol) in dichloromethane (10 ml) 3Å molecular sieves (1 g) and sodium triacetoxyborohydride (315 mg; 1.5 mmol) were added, and the mixture was stirred at room temperature for weekend. The reaction mixture was filtered through Celite®, diluted with ethyl acetate, washed with concentrated saline, dried (MgSO4) and evaporated to provide 48 mg of the product as a gray gum. (LC / MS: Rt 2.95, [M + H] +285).

EXAMPLE 20 * 4-Isopropylamino-1 H -pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The title compound was prepared in a manner analogous to Example 19, but using acetone instead of cyclohexanone. (LC / MS: Rt 2.08, [M + H] + 245).

EXAMPLE 21 * 4- (2-Hydroxy-1-methyl-ethylamino) -1H-pyrazol-3-carboxylic acid (4-fluorophenyl) -amide

The compound was prepared in a manner analogous to Example 19, but using hydroxyacetone instead of cyclohexanone. 1HRMN (400MHz, D6-DMSO): 9.9 (1H, br s), 7.8 (2H, dd), 7.3 (1H, s), 7.15 (2H, t), 5.15 ( 1H, d), 4.7 (1H, br s), 3.4 (2H, m), 3.2 (1H, m), 1.1 (3H, d).

EXAMPLE 22 * 4- (1-Ethyl-propylamino) -1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The compound was prepared in a manner analogous to Example 19, but using 3-pentanone instead of cyclohexanone. 1HRMN (400MHz, D6-DMSO): 12.85 (1h, br s), 9.9 (1H, br s), 7.8 (2H, br t), 7.3 (1H, s), 7, 15 (2H, t), 5.0 (1H, d), 2.9 (1H, br m), 1.5 (4H, m), 3.2 (1H, m), 0.9 (6H, t).

EXAMPLE 23 * 4- (3-Chloro-pyrazin-2-ylamino) -1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

A mixture of 4-amino-1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide (50 mg; 0.23 mmol) and 2,3-dichloropyrazine (140 mg; 0.92 mmol) is heated at 1500C (50W) for 20 minutes in a CEM Discover ™ microwave synthesizer. The crude reaction mixture was purified by flash column chromatography eluting with ethyl acetate / hexane (1: 3 and 1: 2). Fractions containing the product were combined and evaporated to provide 15 mg of the title compound as a white solid. (LC / MS: Rt 4.06 M + H] + 332).

EXAMPLE 24 *

4- (Piracin-2-ylamino) -1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The compound was prepared in a manner analogous to Example 23, but using 2-chloropyrazine instead of 2,3-dichloropyrazine. (LC / MS: Rt3,28 [M + H] +299).

EXAMPLE 25 * Synthesis of 4- (2-Methoxy-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl) -amide

2-Methoxy-benzoic acid (38 mg, 0.25 mmol) was added to a solution of (4-fluoro-phenyl) -amide of the acid

4-amino-1 H -pyrazol-3-carboxylic acid (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol), and HOBt (37 mg, 0.27 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The residue was purified by preparative LC / MS and, after evaporating the fractions containing the product, yielded the product as a pinkish solid (12mg, 15%). (LC / MS: Rt 4.00, [M + H] + 354.67).

EXAMPLE 26 *

Synthesis of 4-Benzoylamino-1 H -pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 25 using benzoic acid (31 mg, 0.25 mmol) as the starting acid. The product was isolated as a solder (26 mg, 35%). (LC / MS: Rt 3.96, [M + H] +324.65).

EXAMPLE 27 * 25 Synthesis of 4- (Cyclohexanecarbonyl-amino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 25 using cyclohexanecarboxylic acid (32 mg, 0.25 mmol) as the starting acid. The product was isolated as a pink solid (28 mg, 37%). (LC / MS: Rt 4.16, [M + H] + 330.70).

EXAMPLE 28 * Synthesis of 4 - [(1-Methyl-cyclopropanecarbonyl) -amino] -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 25 using 1-methyl-cyclopropanecarboxylic acid (25 mg, 0.25 mmol) as the starting acid. The product was isolated as a pink solid (24 mg, 35%). (LC / MS: Rt 3.72, [M + H] + 302.68).

10 EXAMPLE 29 *

Synthesis of 4- (2-Hydroxy-acetylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that in Example 25 using hydroxy-acetic acid (19 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (26 mg, 41%). (LC / MS: Rt 2.65, 15 [M + H] + 278.61).

EXAMPLE 30 * Synthesis of 4- (2,2-dimethyl-propionylamino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 25 using 2,2-dimethyl-propionic acid (26 mg, 0.25 mmol) as the starting acid. The product was isolated as a pink solid (21 mg, 30%). (LC / MS: Rt 3.83, [M + H] + 304.68).

EXAMPLE 31 * Synthesis of 4- (3-hydroxy-propionylamino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 25 using 3-hydroxy-propionic acid (75.1 mg, 0.25 mmol) as the starting acid. The product was isolated as a beige solid (5 mg, 8%). (LC / MS: Rt 2.58, [M + H] + 292.65).

EXAMPLE 32 *

Synthesis of 4- (2-Fluoro-benzoylamino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

2-Fluorobenzoic acid (36 mg, 0.25 mmol) was added to a 4-amino acid (4-fluoro-phenyl) -amide solution

1 H -pyrazol-3-carboxylic acid (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol), and HOBt (37 mg, 0.27 mmol) in DMSO (1ml). The reaction mixture was stirred at room temperature for 24 hours and purified by preparative LC / MS. Evaporation of the fractions containing the product yielded the product as a white solid (15 mg, 19%). (LC / MS: Rt 3.91, [M + H] +. 342.66).

EXAMPLE 33. *

Synthesis of 4- (3-Fluoro-benzoylamino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 3-fluorobenzoic acid (36 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (19 mg, 24%). (LC / MS: Rt 4.03, [M + H] + 342.67).

15 EXAMPLE 34 *

Synthesis of 4- (3-Methoxy-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 3-methoxy-benzoic acid (39 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (20 mg, 25%). (LC / MS: Rt 3.97, 20 [M + H] + 354.68).

EXAMPLE 35 * Synthesis of 4- (2-Nitro-benzoylamino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 2-nitrobenzoic acid (43 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (17 mg, 20%). (LC / MS: Rt 3.67, [M + H] + 369.66).

EXAMPLE 36 *

Synthesis of 4- (4-Nitro-benzoylamino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 4-nitrobenzoic acid (43 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (15 mg, 18%). (LC / MS: Rt 3.98, [M + H] + 369.63).

EXAMPLE 37 * Synthesis of 4 - [(3-methyl-furan-2-carbonyl) -amino] -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 3-methyl-2-furoic acid (32 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (15 mg, 20%). (LC / MS: Rt3.86, [M + H] + 328.68).

EXAMPLE 38 * Synthesis of 4 - [(furan-2-carbonyl) -amino] -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 2-furoic acid (29 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (18mg, 25%). (LC / MS: Rt 3.56, [M + H] + 314.64).

EXAMPLE 39 * Synthesis of 4 - [(3 H -imidazol-4-carbonyl) -amino] -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 1H-imidazol-4-carboxylic acid (29 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (16 mg, 22%). (LC / MS: Rt 2.59, [M + H] + 314.65).

EXAMPLE 40 *

Synthesis of 4- (4-Fluoro-benzoylamino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 4-fluorobenzoic acid (36 mg, 0.25 mmol) as the starting acid. The product was isolated as a cream-colored solid (23 mg, 29%). (LC / MS: Rt 4.00, [M + H] + 342.67).

EXAMPLE 41 * Synthesis of 4- (2,6-Difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 2,6-difluorobenzoic acid (40 mg, 0.25 mmol) as the starting acid. The product was isolated as a cream-colored solid (25 mg, 30%). (LC / MS: Rt 3.76, [M + H] + 360.66).

EXAMPLE 42 * Synthesis of 4- (3-Nitro-benzoylamino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 3-nitrobenzoic acid (43 mg, 0.25 mmol) as the starting acid. The product was isolated as a cream-colored solid (15 mg, 18%). (LC / MS: Rt 3.94, [M + H] + 369.65).

EXAMPLE 43 * 20 Synthesis of 1H-indole-3-carboxylic acid [3- (4-Fluoro-phenylcarbamoyl) -1H-pyrazol-4-yl] -amide

The experiment was performed in a manner analogous to that of Example 32 using indole-3-carboxylic acid (41 mg, 0.25 mmol) as the starting acid. The product was isolated as a red solid (14 mg, 17%). (LC / MS: Rt 3.60, [M + H] + 363.66).

EXAMPLE 44 *

Synthesis of 4- (4-Hydroxymethyl-benzoylamino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 4-hydroxymethylbenzoic acid (39 mg, 0.25 mmol) as the starting acid. The product was isolated as a white solid (19 mg, 23%). (LC / MS: Rt 3.12, [M + H] + 354.68).

EXAMPLE 45 * Synthesis of 4- (3-methyl-benzoylamino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 3-methylbenzoic acid (35 mg, 0.25 mmol) as the starting acid. The product was isolated as an off-white solid (21 mg, 27%). (LC / MS: Rt 4.13, [M + H] + 338.71).

EXAMPLE 46 * Synthesis of 4- (2-methyl-benzoylamino) -1 H -pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 2-methylbenzoic acid (35 mg, 0.25 mmol) as the starting acid. The product was isolated as an off-white solid (20 mg, 26%). (LC / MS: Rt 4.05, [M + H] + 338.69).

EXAMPLE 47 * 20 Synthesis of 4- (4-Methyl-benzoylamino) -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 32 using 4-methylbenzoic acid (35 mg, 0.25 mmol) as the starting acid. The product was isolated as an off-white solid (19 mg, 24%). (LC / MS: Rt 4.16, [M + H] + 338.70).

EXAMPLE 48 *

Synthesis of 4 - [(2-methyl-thiophene-3-carbonyl) -amino] -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

2-Methyl-3-thiophenecarboxylic acid (36 mg, 0.25 mmol) was added to a solution of (4-fluoro-phenyl) -amide of the

5-Amino-1 H -pyrazol-3-carboxylic acid (Example 2B) (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol), and HOBt (37 mg, 0.27 mmol) in DMSO (1ml). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was added dropwise to water (30 ml) and the resulting solid was collected by filtration, washed and dried by aspiration. The title compound was obtained as a beige solid (15 mg, 19%). (LC / MS: Rt 4.08, [M + H] + 344.67).

10 EXAMPLE 49 *

Synthesis of quinoline-2-carboxylic acid [3- (4-Fluoro-phenylcarbamoyl) -1 H -pyrazol-4-yl] -amide

The experiment was carried out in a manner analogous to that of Example 48 using quinadic acid (44mg, 0.25 mmol) as the starting acid. The product was isolated as a solid vessel (16 mg, 19%). (LC / MS: Rt 4.29, [M + H] + 375.66). EXAMPLE 50 * Synthesis of 4 - [(Thiophene-3-carbonyl) -amino] -1H-pyrazole-3-carboxylic acid (4-Fluoro-phenyl) -amide

The experiment was performed in a manner analogous to that of Example 48 using thiophene-3-carboxylic acid (33 mg, 0.25 mmol) as the starting acid. The product was isolated as a beige solid (15 mg, 20%). (LC / MS: Rt 3.77, 20 [M + H] + 330.61).

EXAMPLE 51 * Synthesis of 4- (2-Fluoro-3-methoxy-benzoylamino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

4-Amino-1-Hirozol-3-carboxylic acid (4-fluoro-phenyl) -amide (Example 2B) (0.055 g, 0, was stirred 2-Fluoro-3-methoxybenzoic acid (0.047 g, 0.28 mmol) 25 mmol), EDC (0.58 g, 0.30 mmol) and HOBt (0.041 g, 0.30 mmol) at room temperature in DMSO (1.25 ml) for 5 hours. The reaction mixture was poured into water (30 ml) and the resulting solid was collected by filtration and dried in a vacuum oven to provide the title compound as a gray solid (0.058 g, 63%). (LC / MS: Rt 3.99, [MH] + 372.98).

EXAMPLE 52 *

Synthesis of 4- [2- (2-Pyrrolidin-1-yl-ethoxy) -benzoylamino] -1H-pyrazol-3-carboxylic acid 4-Fluorophenylamide

52A 2- (2-Pyrrolidin-1-yl-ethoxy) -benzoic acid methyl ester

10 Diisopropylazodicarboxylate (0.404 g, 2 mmol) was added dropwise to a solution of triphenylphosphine (0.524 g, 2 mmol) in THF (10 ml). Methyl salicylate (0.304 g, 2 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 1 hour. 1,2-Hydroxyethyl pyrrolidine (0.230 g, 2 mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for an additional 1.5 hours. The resulting solution was reduced in vacuo and subjected to flash column chromatography, eluting with hexane: ethyl acetate.

15 (5: 1, 1: 1) and ethyl acetate: methanol (4: 1) to provide the product as a light yellow oil (0.104 g, 21%). (LC / MS: Rt 0.69, 1.62, [MH] + 250.02).

52B 4- [2- (2-Pyrrolidin-1-yl-ethoxy) -benzoylamino] -1H-pyrazol-3-carboxylic acid 4-fluorophenylamide

The 2- (2-pyrrolidin-1-yl-ethoxy) -benzoic acid methyl ester (0.104 g, 0.42 mmol) was treated with 2M aqueous NaOH

20 (20 ml) and water (20 ml). The reaction mixture was stirred at room temperature for 20 hours, reduced in vacuo and an azeotrope formed with toluene (3 x 5 ml). Water (50 ml) was added and the mixture was brought to pH 5 using 1M aqueous HCl. The resulting solution was reduced in vacuo and an azeotrope was formed with toluene (3 x 5 ml) to provide a white solid, which was combined with (4-amino-1 H -pyrazol-3 acid 4-fluoro-phenyl) -amide. -carboxylic (Example 2B) (0.055 g, 0.25 mmol), EDC (0.058 g, 0.3 mmol) and HOBt (0.041g, 0.3 mmol) and stirred at room temperature

25 in DMSO (3 ml) for 20 hours. The reaction mixture was poured into water (30 ml) and the resulting solid was collected by filtration and dried in a vacuum oven to provide the title compound as a gray solid (0.015 g, 14%). (LC / MS: Rt 2.18, [MH] + 438.06).

EXAMPLE 53

Synthesis of 4- (2,6-Difluoro-benzoylamino) -1H-pyrazol-3-carboxylic acid (1-methyl-piperidin-4-yl) -amide

A mixture of 4- (2,6-difluoro-benzoylamino) -1 H -pyrazol-3-carboxylic acid (134 mg, 0.50 mmol), 4-amino-N-methylpiperidine (50.0 µl, 0.45 mmol), EDAC (104 mg, 0.54 mmol) and HOBt (73.0 mg, 0.54 mmol) in DMF (3 ml) was stirred at room temperature for 16 hours. The mixture was reduced in vacuo, the residue was taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and concentrated saline. The organic part was dried (MgSO4) and reduced in vacuo to provide 4- (2,6-difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid (1-methyl-piperidin-4-yl) -amide as a solid white (113 mg, 69%). (LC / MS: Rt 2.52, [M + H] + 364.19).

EXAMPLE 54 *

Synthesis of 4- (Cyclohexyl-methyl-amino) -1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

This compound was prepared in a manner analogous to the compound of Example 19 by successive reductive alkylations using first place cyclohexane and then formaldehyde. (LC / MS: Rt2.77 [MH] +316.71).

EXAMPLE 55 * 4- (Pyridin-2-ylamino) -1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The title compound was prepared in a manner analogous to the compound of Example 23. (LC / MS: Rt 2.07 15 [MH] +298.03).

EXAMPLES 56 - 81

Following the procedures described in the previous examples or methods analogous to these, or by performing chemical transformations using the compounds described in the previous examples and synthetic methods well known to those skilled in the art, the compounds shown in Table 3 were prepared. .

Table 3

Example No.

Structure Prepared using a method analogous to Example No Differences with the Example? LCMS

56 *

4 Rt 3.20 min [M + H] +406.07

57 *

4 Then removal of the t-Boc protective group with TFA as described in Example 82 Rt 2.35 min m / z 343.72

58 *

4 DMSO was used instead of DMF as solvent Rt 3.51 min m / z 314.62

59 *

4 DMSO was used instead of DMF as solvent Rt 3.79 min m / z 363.67

60 *

48 Purified by column chromatography using EtOAC eluent: Petroleum ether Rt 3.68 min m / z 384.69

Example No.

Structure Prepared using a method analogous to Example No Differences with the Example? LCMS

61 *

48 Purified by column chromatography using EtOAC eluent: Petroleum ether Rt 3.61 min m / z 326.10

62 *

48 Purified by column chromatography using EtOAC eluent: Petroleum ether Rt 3.51 min m / z 387.11

63 *

48 Rt 3.11 min m / z 313.65

64 *

48 Purified by column chromatography using EtOAC eluent: Petroleum ether Rt 2.20 min m / z 455.19

65

53 Rt 3.95 min m / z 349.09

Example No.

Structure Prepared using a method analogous to Example No Differences with the Example? LCMS

66

48 Purified by column chromatography using EtOAC eluent: Petroleum ether Rt 2.39 min m / z 351.07

67

48 Purified by column chromatography using EtOAC eluent: Petroleum ether Rt 2.83 min m / z 365.13

68 *

Elimination of the PMB group of the compound of Example 62 using TFA-anisole Rt 2.10 min m / z 266.97

69

48 DMF was used instead of DMSO as solvent Rt 3.22 min m / z 363.10

70 *

48 Rt 4.48 min m / z 358.96

71 *

48 Rt 3.93 min m / z 340.96

Example No.

Structure Prepared using a method analogous to Example No Differences with the Example? LCMS

72 *

48 Rt 4.11 min m / z 373.01

73 *

48 DMF was used instead of DMSO as solvent Rt 2.56 min m / z 373.05

74 *

Obtained by oxidation and reductive amination of Example 73 Rt 1.99 min m / z 442.09

75

53 Purified by column chromatography using eluent DCM: MeOH (1: 0 to 19: 1) Rt 3.65 min m / z 335.03

76

25 Purified by column chromatography. Then, removal of the t-Boc protecting group with ethyl acetate / saturated HCl Rt 1.57 min m / z 350.10

77

53 Rt 5.05 min m / z 405.14

Example No.

Structure Prepared using a method analogous to Example No Differences with the Example? LCMS

78 *

53 Rt 2.87 min m / z 416.07

79

53 Purified by column chromatography using EtOAC eluent: Petroleum ether (1: 1) Rt 3.41 min m / z 321.03

80 *

2A, 2B and 53 Commercially available 5-methylpyrazol-1H-3 carboxylic acid used as a starting material. Purified by column chromatography using eluent EtOAC: Hexane (1: 3 to 1: 1) Rt 3.42 min m / z 375.05

81 *

2 C Purified by column chromatography using eluent EtOAC: Hexane (1: 1 to 1: 0) Rt 2.37 min m / z 277.04

EXAMPLE 82 * 4 - [(4-Amino-1-methyl-1 H -imidazol-2-carbonyl) -amino] -1 H -pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

Trifluoroacetic acid (200 µl) was added to a stirred suspension of {2- [3- (4-fluorophenylcarbamoyl) -1H-pyrazol-4-ylcarbamoyl] -1-methyl-1H-imidazol-4- tert-butyl ester il} -carbamic (30 mg) in dichloromethane (5 ml), and stirred at room temperature for 2 hours. The solvent was evaporated and evaporated again with toluene (2 x 10 ml). The residue was triturated with diethyl ether and the resulting solid was collected by filtration. The solid washed with

5 diethyl ether and dried in vacuo to provide 15 mg of 4 - [(4-amino-1-methyl-1Himidazol-2-carbonyl) -amino] -1H-pyrazole (4-fluoro-phenyl) -amide 3-carboxylic as an off-white solid. (LC / MS: [M + H] + 343.72).

EXAMPLE 83

Synthesis of 4 - {[4- (2,6-Difluoro-benzoylamino) -1 H -pyrazol-3-carbonyl] -amino} -cyclohexanecarboxylic acid

83A. 4 - {[4- (2,6-Difluoro-benzoylamino) -1H-pyrazol-3-carbonyl] -amino} 10 cyclohexanecarboxylic acid ethyl ester

Thionyl chloride (0.32 ml, 4.40 mmol) was slowly added to a mixture of 4-aminocyclohexanecarboxylic acid (572 mg, 4.00 mmol) in EtOH (10 ml) and stirred at room temperature for 16 hours. The mixture was reduced in vacuo, an azeotrope was formed with toluene, to provide the ethyl ester

15 corresponding (650 mg) as a clear solid.

A mixture of the ethyl ester (103 mg, 0.60 mmol), 4- (2,6-difluoro-benzoylamino) -1 H -pyrazol-3-carboxylic acid (134 mg, 0.50 mmol), EDC (115 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) in DMF (5 ml) was stirred at room temperature for 16 hours. The mixture was reduced in vacuo, the residue was taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and concentrated saline. The organic part

20 was dried (MgSO4) and reduced in vacuo to provide 4 - {[4- (2,6-difluoro-benzoylamino) -1-Hirozol-3-carbonyl] -amino} -cyclohexanecarboxylic acid ethyl ester (112 mg).

83B. 4 - {[4- (2,6-Difluoro-benzoylamino) -1 H -pyrazol-3-carbonyl] -amino} -cyclohexanecarboxylic acid

A mixture of the ester (45 mg) (of 83A) in MeOH (2.5 ml) and aqueous 2M NaOH (2.5 ml) was stirred at temperature

25 room for 16 hours. Volatiles were removed in vacuo, water (10 ml) was added and the mixture was brought to pH 5 using aqueous 1M HCl. The precipitate formed was collected by filtration and purified by column chromatography using EtOAc / MeOH (1: 0 -9: 1) to provide 4 - {[4- (2,6-difluoro-benzoylamino) -1H-pyrazole- 3-carbonyl] amino} -cyclohexanecarboxylic acid (11 mg) as a white solid and mixture of cis- / trans isomers. (LC / MS: Rt 2.78 and 2.96, [M + H] + 393.09).

EXAMPLES 84-152

General Procedure A Preparation of the Pyrazole Carboxylic Acid Amide

A mixture of the appropriate benzoylamino-1H-pyrazol-3-carboxylic acid (0.50 mmol), EDAC (104 mg, 0.54 mmol), HOBt (73.0 mg, 0.54 mmol) and the corresponding amine ( 0.45 mmol) in DMF (3 ml) was stirred at room temperature for 16 hours. The mixture was reduced in vacuo, the residue was taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and concentrated saline. The organic part was dried (MgSO4) and reduced in vacuo to provide the desired product.

10 General Procedure B

Preparation of Amino-Pyrazole Amide

To a stirred solution of the appropriate 4-amino-1 H -pyrazol-3-carboxylic acid amide (0.23 mmol), EDAC (52 mg; 0.27 mmol) and HOBt (37 mg; 0.27 mmol) in 5 ml of N, N-dimethylformamide carboxylic acid was added

15 (0.25 mmol), and the mixture was left at room temperature overnight. The reaction mixture was evaporated and the residue was purified by preparative LC / MS to provide the product. General Procedure C Deprotection of the Nitrogen from the Piperidine Ring by Elimination of the tert-Butoxycarbonyl Group

A product of Procedure A or Procedure B containing a piperidine group having a group

Protective N-tert-butoxycarbonyl (t-Boc) (40 mg) was treated with ethyl acetate / saturated HCl, and stirred at room temperature for 1 hour. A solid precipitated from the reaction mixture, which was collected by filtration, washed with ether and dried to provide 25 mg of product (LC / MS: [M + H] +364). Procedure L Preparation of Amina Starting Materials

The following method was used to prepare the following amines: 4-thiomorpholine-4-yl-cyclohexylamine; 4- (1,1-dioxo-thiomorpholine-4-yl) -cyclohexylamine; N- (tetrahydro-pyran-4-yl) -cyclohexane-1,4-diamine; 4- (4-methyl-piperazin-1-yl) -cyclohexylamine; 1'-methyl- [1,4 '] bipiperidinyl-4-ylamine; Y

4-morpholin-4-yl-cyclohexylamine.

A solution of N-4-Boc-aminocyclohexanone (0.5 g, 2.3 mmol) in THF (10 mL) was treated with the appropriate amine, for example, thiomorpholine (0.236 g, 2.3 mmol), and triacetoxyborohydride sodium (0.715 g, 2.76 mmol) and acid

5 acetic (0.182 ml). The reaction was stirred overnight at room temperature, diluted with CH2Cl2 and washed with saturated sodium carbonate. The organic layer was dried over MgSO4 and evaporated to provide a white solid that was used without further purification in the next step. The white solid was treated with saturated HCl / EtOAc, stirred at a temperature for 1 hour, evaporated to dryness and evaporated again with toluene. The resulting amines were isolated as the hydrochloride salt. (LC / MS: Rt 1.75, [M + H] + 201).

10 Following General Procedures A, B, C and L, modified when indicated, the compounds shown in Table 4 were prepared.

Table 4

Example No.

Preparation method LCMS

84

Procedure A [M + H] + 380 Rt 1.42

85

Procedure A [M + H] + 426 Rt 1.93

86

Procedure A [M + H] + 440 Rt 1.87

87

Procedure A [M + H] + 406 Rt 2.78

Example No.

Preparation method LCMS

88

Procedure A [M + H] + 406 Rt 2.55

89 *

A DMSO procedure instead of DMF [M + H] + 358 Rt 1.98

90 *

A DMSO procedure instead of DMF [M + H] + 357 Rt 3.37

91 *

A DMSO procedure instead of DMF [M + H] + 391 Rt 3.16

92 *

A DMSO procedure instead of DMF [M + H] + 375 Rt 3.02

93 *

A DMSO procedure instead of DMF [M + H] + 425 Rt 3.27

Example No.

Preparation method LCMS

94 *

A DMSO procedure instead of DMF [M + H] + 393 Rt 3.01

95

A DMSO procedure instead of DMF [M + H] + 365 Rt 2.22

96 *

A DMSO procedure instead of DMF [M + H] +387 Rt 3.05

97

A DMSO procedure instead of DMF [M + H] + 464 Rt 3.17

98

Procedure C using the product of Example 97 as starting material [M + H] + 364 Rt 1.76

Example No.

Preparation method LCMS

99 *

A DMSO procedure instead of DMF [M + H] + 389 Rt 2.36

100

A DMSO procedure instead of DMF [M + H] + 351 Rt 2.55

101 *

A DMSO procedure instead of DMF [M + H] + 362 Rt 2.63

102

Procedure A DMSO instead of DMF Starting amine prepared according to Procedure L [M + H] + 364 Rt 1.75

103 *

A DMSO procedure instead of DMF [M + H] + 358 Rt 3.2

Example No.

Preparation method LCMS

104 *

A DMSO procedure instead of DMF [M + H] + 358 Rt 1.77

105 *

A DMSO procedure instead of DMF [M + H] +344 Rt 2.71

106

A DMSO procedure instead of DMF [M + H] + 392 Rt 2.57

107 *

A DMSO procedure instead of DMF [M + H] + 347 Rt 2.8

108 *

A DMSO procedure instead of DMF [M + H] + 371 Rt 3.1

Example No.

Preparation method LCMS

109

Procedure A Et3N 1 equiv., DMSO instead of DMF [M + H] + 404 Rt 2.7

110 *

Procedure A Et3N 2 equiv., HOAt instead of HOBt, DMSO instead of DMF [M + H] + 428 Rt 2.63

111

Procedure A followed by Procedure C Et3N 2 equiv., HOAt instead of HOBt, DMSO instead of DMF [M + H] + 364 Rt 1.75

112

Procedure A Et3N 2 equiv., HOAt instead of HOBt, DMSO instead of DMF [M + H] + 427 Rt 2.71

113

Procedure A HOAt instead of HOBt, DMSO instead of DMF [M + H] +363 Rt 3.34

Example No.

Preparation method LCMS

114

Procedure A Et3N 2 equiv., HOAt instead of HOBt, DMSO instead of DMF [M + H] + 432 Rt 2.63

115

Procedure A [M + H] + 461 Rt 3.3

116

Chiral Procedure A DMSO instead of DMF, Et3N 2 equiv Starting amine prepared according to Procedure L [M + H] + 448 Rt 1.87

117

Chiral Procedure A DMSO instead of DMF, Et3N 2 equiv Starting amine prepared according to Procedure L [M + H] + 447 Rt 1.65

Example No.

Preparation method LCMS

118

Chiral Procedure A DMSO instead of DMF, Et3N 2 equiv Starting amine prepared according to Procedure L [M + H] + 447 Rt 1.72

119

Procedure B [M + H] + 462 Rt 2.97

120

Procedure A N-ethylmorpholine (NEM) 2 equiv [M + H] + 379 Rt 2.45

121

Procedure A HOAt instead of HOBt, Et3N 2 equiv Starting amine prepared according to Procedure L [M + H] + 450 Rt 1.97

Example No.

Preparation method LCMS

122

Procedure B [M + H] + 387 Rt 3.83

123

Procedure B [M + H] + 417 Rt 3.65

124

Chiral Procedure A HOAt instead of HOBt, Et3N 2 equiv [M + H] + 392 Rt 1.85

125

Procedure A HOAt instead of HOBt, Et3N 2 equiv [M + H] + 408 Rt 1.82

126

Procedure B [M + H] + 403 Rt 4.02

Example No.

Preparation method LCMS

127

Procedure B [M + H] + 369 Rt 3.78

128

Procedure B [M + H] + 435 Rt 3.83

129

Procedure B [M + H] + 405 Rt 3.96

130

A HOAt procedure instead of HOBt [M + H] + 512 Rt 3.1

Example No.

Preparation method LCMS

131

A HOAt procedure instead of HOBt, [M + H] + 428 Rt 2.45

132

Procedure A HOAt instead of HOBt, Et3N 2 equiv. Cis and trans isomers separated after the amide coupling step Starting amine prepared according to Procedure L [M + H] +482 Rt 1.96

133

Procedure A HOAt instead of HOBt, DMSO instead of DMF [M + H] + 434 Rt 2.3

134

Procedure B [M + H] + 442 Rt 2.39

135

Procedure B [M + H] + 458 Rt 2.26

Example No.

Preparation method LCMS

136

Procedure B HOAt instead of HOBt, [M + H] + 468 Rt 3.07

137

Chiral Procedure A Et3N 2 equiv., HOAt instead of HOBt, [M + H] + 379 Rt 2.6

138

Procedure B [M + H] + 472 Rt 2.40

139

Procedure A Et3N 2 equiv., HOAt instead of HOBt, DMSO instead of DMF [M + H] +364 Rt 2.1

140

Procedure B followed by Procedure C [M + H] + 314 Rt 1.78

Example No.

Preparation method LCMS

141

Procedure B followed by Procedure C [M + H] + 332 Rt 1.89

142

Procedure B followed by Procedure C [M + H] + 362 Rt 1.78

143

Procedure B followed by Procedure C [M + H] + 348 Rt 2.01

144

Procedure B followed by Procedure C [M + H] + 350 Rt 1.97

145

Procedure B followed by Procedure C [M + H] + 380 Rt 2.01

Example No.

Preparation method LCMS

146

Procedure B followed by Procedure C [M + H] + 395 Rt 1.94

147

Procedure B followed by Procedure C [M + H] + 396 Rt 2.11

148

Procedure B followed by Procedure C HOAt instead of HOBt [M + H] + 368 Rt 1.76

149

Procedure B followed by Procedure C [M + H] + 366 Rt 1.78

150

Procedure B followed by Procedure C [M + H] + 383 Rt 1.87

Stage D (i):

A mixture of 4-nitro-3-pyrazolcarboxylic acid (4.98 g, 31.7 mmol), trans 4-aminocyclohexanol (3.65 g, 31.7 mmol), EDAC (6.68 g, 34.8 mmol ) and HOBt (4.7 g, 34.8 mmol) in DMF (120 ml) was stirred at room temperature for 16 hours. The mixture was reduced in vacuo, the residue was taken up in CH2Cl2 and washed successively

10 with 5% citric acid, saturated aqueous sodium bicarbonate, water and concentrated saline. It was found that the product was mainly in the citric acid wash, which was basified and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated to provide a white solid, which was triturated with CHCl3 to provide 1.95 g of 4-nitro-1H-pyrazol-3-carboxylic acid 4-hydroxy-cyclohexylamide. (LC / MS: Rt 1.62, [M + H] + 255).

Stage D (ii):

Introduction of the Tetrahydro-piran-2-ilo Protective Group

A solution of 4-nitro-1H-pyrazol-3-carboxylic acid 4-hydroxy-cyclohexylamide (1.95 g; 7.67 mmol) in a mixture of THF (50 ml) and chloroform (100 ml), was treated with 3,4-dihydro-2H-pyran (1.54 ml, 15.34 mmol) and ptoluenesulfonic acid monohydrate (100 mg). The reaction mixture was stirred at room temperature overnight and excess pyranus (0.9 ml) was added in total to bring the reaction to completion. The reaction mixture was diluted with CH2Cl2 and washed successively with saturated aqueous sodium bicarbonate, water and concentrated saline. The resulting solution was reduced in vacuo and subjected to Biotage column chromatography, eluting with hexane (2 column lengths) followed by 30% ethyl acetate: hexane (10 column lengths), 70% ethyl acetate: hexane (10 column lengths) to provide 1.25 g of 4-nitro-1- (tetrahydro-pyran-2-yl-1H-pyrazol-3) [4- (tetrahydro-pyran-2-yloxy) -cyclohexyl] -amide -carboxylic. (LC / MS: Rt 2.97, [M + H] +423).

Stage D (iii):

A 4-nitro-1- (tetrahydro-pyran-2-yl) -1 H -pyrazol-3-carboxylic acid [4- (tetrahydro-pyran-2-yloxy) -cyclohexyl] -amide solution (0.3 g; 0 , 71 mmol) in methanol (25ml), treated with 10% palladium on carbon (30mg) and hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration and washed three times with methanol. The filtrate was evaporated to provide 0.264 g of the required product. (LC / MS: Rt 2.39, [M + H] + 393).

General Procedure E

Procedure to Remove a Tetrahydropyran-2-yl Protective Group

To a 4- (2-methoxy-benzoylamino) -1- (tetrahydropyran-2-yl-1H-pyrazol-3-carboxylic acid) [4- (tetrahydro-pyran-2-yloxy) -cyclohexyl] -amide suspension ( 0.125 g, 0.23 mmol) in EtOH (10 ml) was added p-toluene sulfonic acid hydrate (90 mg, 0.46 mmol) The reaction mixture was heated at 700 ° C for 30 minutes The reaction was diluted with EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and concentrated saline solution.The resulting solution was reduced in vacuo to provide a white solid, containing traces of p-toluene sulfonic acid hydrate.The solid was collected in EtOAc and washed with 1M NaOH and concentrated saline solution. The resulting solution was reduced in vacuo and triturated with ether / hexane to provide 10 mg of the required product. (LC / MS: Rt 2.29, [M + H] +359)

General Procedure F

Preparation of a urea from an amide of 4-Amino-pyrazol-3-carboxylic acid

To a 4-amino-1- (tetrahydro-pyran-2-yl-1H-pyrazol-3-carboxylic acid [4-tetrahydro-pyran-2-yloxy-cyclohexyl] -amide solution (80 mg, 0.2 mmol) in toluene (2 ml) phenyl isocyanate (929 mg, 0.24 mmol) was added.The reaction mixture was heated at 700 ° C. for 1 hour The reaction was diluted with EtOAc and washed successively with water and concentrated saline. The resulting solution was reduced in vacuo to provide yellow oil, which was used without further purification (LC / MS: Rt 2.28, [M + H] + 344).

General Procedure G

Conversion of a 4-Amino-pyrazole group into a 4- (Morpholine-4-carbonylamino) -Pyrazole group

To a 4-amino-1- (tetrahydro-pyran-2-yl-1H-pyrazol-3-carboxylic acid [4- (tetrahydro-pyran-2-yloxy) -cyclohexyl] -amide solution (0.1 g, 0.255 mmoles) in CH2Cl2 (5 ml) at -100C a 20% phosgene solution in toluene was added dropwise.The reaction mixture was stirred at -100C for 15 minutes and morpholine (0.765 mmol) was added. the reaction mixture was heated to room temperature for 1 hour and stirred at room temperature overnight The reaction was diluted with CH2Cl2 and washed successively with saturated sodium bicarbonate and concentrated saline solution.The resulting solution was reduced in vacuo to provide a yellow oil that was used without further purification (LC / MS: Rt 1.68, [M + H] +338).

General Procedure H

N-Oxide Preparation

To a suspension of the compound of Example 53 (7.7 mg, 0.02 mmol) in CH2Cl2 (0.5 ml) was added metachloroperbenzoic acid (MCPBA) (3.6 mg, 0.02 mmol). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was purified by preparative LC / MS to provide 3 mg of the required product. (LC / MS: Rt 1.83, [M + H] + 380)

General Procedure I Elimination of a Benzyloxycarbonyl Protective Group

A solution of the compound of Example 130 (0.2 g; 0.39 mmol) in EtOAc (40 ml), was treated with 10% palladium on carbon (20 mg) and hydrogenated at room temperature and pressure for 3 hours. The catalyst was removed

5 by filtration and washed three times with EtOAc. The filtrate was evaporated and the residue was chromatographed using 10% MeOH-CH2Cl2 and 20% MeOH-CH2Cl2 to provide 80 mg of the required product. (LC / MS: Rt 1.88, [M + H] +378).

General Procedure J Mesylation of an Amine

To a solution of the compound of Example 163 (20 mg, 0.05 mmol) in CH3CN (3 ml) was added methanesulfonyl chloride (0.0045 ml, 0.058 mmol) followed by Hunig's Base (0.018 ml, 0 , 1 mmol). The reaction mixture was stirred at room temperature for 2 hours and evaporated. The residue was purified by preparative LC / MS to provide 8 mg of the product required. (LC / MS: Rt 2.54, [M + H] + 456).

Following Procedures A to L, the compounds shown in Table 5 were prepared.

15 Table 5

Example No.

Preparation method LCMS

153

Procedure D followed by B then E HOAt instead of HOBt, CH2Cl2 instead of DMF [M + H] + 359 Rt 2.29

154

Procedure D followed by B then E HOAt instead of HOBt, CH2Cl2 instead of DMF [M + H] + 377 Rt 2.22

155

Procedure D followed by B then E HOAt instead of HOBt, CH2Cl2 instead of DMF [M + H] + 381 Rt 2.34

156

Procedure D followed by F then E [M + H] +344 Rt 2.28

Example No.

Preparation method LCMS

157

Procedure D followed by F then E [M + H] + 358 Rt 2.22

158

Procedure D followed by B then E HOAt instead of HOBt, CH2Cl2 instead of DMF [M + H] +365 Rt 2.21

159

Procedure D followed by B then E HOAt instead of HOBt, CH2Cl2 instead of DMF [M + H] + 387 Rt 2.29

160

Procedure D followed by F then E [M + H] + 380 Rt 2.17

161

Procedure D followed by G then E [M + H] + 338 Rt 1.68

Example No.

Preparation method LCMS

162

Procedure H [M + H] + 380 Rt 1.83

163

Procedure A (HOAt instead of HOBt) to provide the compound of Example 130 followed by Procedure I. [M + H] + 378 Rt 1.78

164

Procedures A (HOAt instead of HOBt) and I to provide the compound of Example 163 followed by Procedure J [M + H] +456 Rt 2.54

General Procedure M Formation of the 4-amide pyrazole group

5 4-Nitropyrazol-3-carboxylic acid (7.3 g; 15.9 mmol) was added to a stirred solution of 4-amino-1-Bocpiperidine (10.2 mg; 51 mmol), EDC (10.7 g ; 55.8 mmol), and HOAt (55.8 g; 19.1 mmol) in DMF (100 ml) and stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue was triturated with water (250ml). The resulting cream solid was collected by filtration, washed with water and dried in vacuo to provide 13.05 g of 4 - [(4-nitro-1 H -pyrazol-3-carbonyl) -amino] tert-butyl ester]

10 piperidine-1-carboxylic acid (LC / MS: Rt2.50, [M + H] + 340).

4 - [(Nitro-1 H -pyrazol-3-carbonyl) -amino] -piperidine-1-carboxylic acid tert-butyl ester (13.05 g) was dissolved in ethanol / DMF (300 ml / 75 ml), He treated with 10% palladium on carbon (500 mg) and hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration through Celite and the filtrate was evaporated and evaporated again with toluene. The crude material was purified by flash column chromatography eluting with EtOAc and 2%

15 MeOH / EtOAc and 5% MeOH / EtOAc. The fractions containing the product were combined and evaporated to provide 8.78 g of 4 - [(4-amino-1 H -pyrazol-3-carbonyl) -amino] -piperidine-1-carboxylic acid tert-butyl ester as a brown foam (LC / MS: Rt 1.91, [M + H] + 310).

To a stirred solution of 4 - [(amino-1 H -pyrazol-3-carbonyl) -amino] -piperidine-1-carboxylic acid tert-butyl ester (200 mg; 0.65 mmol), EDAC (150 mg; 0.78 mmol) and HOBt (105 mg; 0.78 mmol) in 5 ml of N, N-dimethylformamide the corresponding carboxylic acid (0.25 mmol) was added, and the mixture was left at room temperature overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and the product was collected by filtration and dried in vacuo. The Boc protected compound was dissolved in saturated HCl / EtOAc stirred at room temperature for 3 hours. The product was collected by filtration, washed with diethyl ether and dried in vacuo.

General Procedure N

Preparation of 1-tert-Butyl-piperidin-4-ylamine

Stage N (i)

To a solution of 1-ethyl-4-oxopiperidine (25 g, 0.197 mol) in acetone (250 ml) at RT in a water bath was added methyl iodide (15.5 ml, 0.25 mol) at such a rate To keep the temperature below 300C. The mixture was filtered and the precipitate was washed with acetone and dried to yield 1-ethyl-1-methyl-4-oxopiperidinium iodide (45 g) (LC / MS: Rt 0.38, [M + H] + 143 ).

Stage N (ii)

To a solution of t-butylamine (78.2 ml, 0.74 mol) in toluene (400 ml) was added a solution of 1-ethyl-1-methyl-4-oxopiperidinium iodide (40g, 0.148 mol) and bicarbonate of sodium (1,245 g, 0.014 mol) in water (60 ml). The reaction mixture was heated at 780C for 6 hours and allowed to cool to room temperature. The layers were separated and the aqueous layer was washed with EtOAc. The organics were combined and washed with concentrated saline, dried (MgSO4), filtered and reduced in vacuo to yield 1-tert-butyl-4-oxopiperidine (14g) (LC / MS: Rt 0.39, [ M + H] + 156).

Stage N (iii)

A solution of 1-tert-butyl-4-oxopiperidine (3.6g, 23.1), benzylamine (5.1ml, 46.8mmol), acetic acid (1.5ml) and sodium triacetoxyborohydride (7.38 g, 34.8 mmol) was stirred at room temperature for 2 days. The reaction mixture was reduced in vacuo and the residue was partitioned between aqueous K2CO3 and EtOAc. The organic part was dried (Na2SO4), filtered and reduced in vacuo. The residue was chromatographed using CH2Cl2 / MeOH / NH4OH (87/12/1) as the eluent to yield N-benzyl-1-tert-butylpiperidine-4-amine (1.5g) (LC / MS: Rt 0, 45, [M + H] + 247).

Stage N (iv)

A solution of N-benzyl-1-tert-butylpiperidin-4-amine (1.56 g) and 10% palladium on carbon (2 g) in MeOH (250 ml) was hydrogenated on a Parr shaker at 50 psi for 16 hours . The solution was filtered and the reaction mixture was reduced in vacuo, to yield 1-tert-butylpiperidin-4-amine (0.64 g) (LC / MS: Rt 02.31, not [M + H] +).

EXAMPLE 165 *

Synthesis of 4- (2,6-Difluoro-benzoylamino) -1-pyrazol-3-carboxylic acid [5-fluoro-2- (1-methyl-piperidin-4-yloxy) -phenyl] -amide

165A. Synthesis of 4-nitro-1H-pyrazol-3-carboxylic acid ethyl ester

Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolcarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at room temperature and The mixture was stirred for 48 h. The mixture was reduced in vacuo and dried by azeotrope with toluene to yield 4-nitro-1 H -pyrazol-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96%). (1 H NMR (400 MHz, DMSO-d6) δ 14.4 (s, 1 H), 9.0 (s, 1 H), 4.4 (q, 2 H), 1.3 (t, 3 H)).

165B. Synthesis of 4-amino-1H-pyrazol-3-carboxylic acid ethyl ester

A mixture of 4-nitro-1 H -pyrazol-3-carboxylic acid ethyl ester (6.40 g, 34.6 mmol) and 10% Pd / C (650 mg) in EtOH (150 ml) was stirred under an atmosphere of hydrogen for 20 h. The mixture was filtered through a pad

10 from Celite, was reduced in vacuo and dried by azeotrope with toluene to yield 4-amino1H-pyrazol-3-carboxylic acid ethyl ester as a pink solid (5.28 g, 98%). (1 H NMR (400 MHz, DMSO-d6) δ 12.7 (s, 1 H), 7.1 (s, 1 H), 4.8 (s, 2 H), 4.3 (q, 2 H), 1 , 3 (t, 3H)).

165C. Synthesis of 4- (2,6-Difluoro-benzoylamino) -1H-pyrazol-3-carboxylic acid ethyl ester

A mixture of 2,6-difluorobenzoic acid (6.32 g, 40.0 mmol), 4-amino-1 H -pyrazol-3 carboxylic acid ethyl ester (5.96 g, 38.4 mmol), EDC (8 , 83 g, 46.1 mmol) and HOBt (6.23 g, 46.1 mmol) in DMF (100 ml) was stirred at room temperature for 6 h. The mixture was reduced in vacuo, water was added and the solid formed was collected by filtration and dried in air to provide 4- (2,6-difluoro-benzoylamino) -1Hpyrazol-3-carboxylic acid ethyl ester as the main component. of a mixture (15.3 g). (LC / MS: Rt 3.11, [M + H] + 295.99).

20 165D. Synthesis of 4- (2,6-Difluoro-benzoylamino) -1H-pyrazol-3-carboxylic acid

A mixture of 4- (2,6-difluoro-benzoylamino) -1 H -pyrazol-3-carboxylic acid ethyl ester (10.2 g) in aqueous 2M NaOH / MeOH (1: 1, 250 ml) was stirred at room temperature for 14 h. Volatiles were removed in vacuo, water (300 ml) was added and the mixture was brought to pH 5 using aqueous 1M HCl. The resulting precipitate is

25 collected by filtration and dried by azeotrope with toluene to yield 4- (2,6-difluoro-benzoylamino) -1-Hirozol-3-carboxylic acid as a pink solid (5.70 g). (LC / MS: Rt 2.33, [M + H] +267.96).

165E. Synthesis of 5-fluoro-2- (1-methyl-piperidin-4-yloxy) -phenylamine

3,4-Dinitrofluorobenzene (1.86 g, 10 mmol) and 4-hydroxy-1-methylpiperidine (1.38 g, 12 mmol) were dissolved in THF (20 ml) and stirred at room temperature while adding hydride. sodium (60% dispersion in mineral oil, 0.40 g, 10 mmol) in several small parts. The reaction mixture was stirred for one hour and reduced in vacuo, partitioned between ethyl acetate and water, and the organic phase was washed with concentrated saline, dried (MgSO4) and reduced in vacuo. The resulting residue was subjected to column chromatography and eluted with 5% MeOH / DCM to provide a yellow solid (1.76 g, 2: 1 ratio of 4- (3,4-dinitro-phenoxy) -1-methyl- piperidine and 4- (4-fluoro-2-nitro-phenoxy) -1-methyl-piperidine).

A sample of the product mixture obtained (0.562 g) was dissolved in DMF (10 ml) under a nitrogen atmosphere. Palladium on carbon (10%, 0.056 g) was added and the reaction mixture was stirred under a hydrogen atmosphere for 40 hours. The solids were removed by filtration and the filtrate was reduced in vacuo, collected in ethyl acetate, washed (saturated aqueous ammonium chloride solution, and saturated aqueous concentrated saline), dried (MgSO4) and reduced in vacuo. to provide 5-fluoro-2- (1-methyl-piperidin-4-yloxy) -phenylamine) as a brown oil (0.049 g, 7%). (1H NMR (400 MHz, MeOD-d4) δ 6.6 (m, 2H), 6.4 (m, 1H), 4.3 (m, 1H), 2.7 (m, 2H), 2, 3 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H)).

165F. Synthesis of 4- (2,6-Difluoro-benzoylamino) -1-pyrazol-3-carboxylic acid [5-fluoro-2- (1-methyl-piperidin-4-yloxy) -phenyl] -amide

5-Fluoro-2- (1-methyl-piperidin-4-yloxy) -phenylamine) (0.049 g, 0.22 mmol) was combined with 4- (2,6-difluorobenzoylamino) -1 H -pyrazol-3-carboxylic acid (0.053 g, 0.20 mmol), EDC (0.048 g, 0.25 mmol), HOBt (0.034 g, 0.25 mmol) and DMF (1 ml) and the resulting reaction mixture was stirred at room temperature for 18 hours . The reaction mixture was reduced in vacuo and purified by preparative LC / MS to provide 4- (2,6-Difluoro-) 4-fluoro-2- (1-methylpiperidin-4-yloxy) -phenyl] -amide benzoylamino) -1 H -pyrazol-3-carboxylic acid as a beige solid. (0.010 g, 11%) (LC / MS: Rt2.19, [M + H] + 474.27).

EXAMPLE 166 *

Synthesis of 4- (2,6-Difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid [5-fluoro-2- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -amide

3,4-Dinitrofluorobenzene (0.93 g, 5 mmol) and 1- (2-hydroxyethylpyrrolidine) (0.69 g, 6 mmol) were dissolved in THF (10 ml) and stirred at room temperature while sodium hydride was added (60% dispersion in mineral oil, 0.24 g, 6 mmol) in several small parts. The reaction mixture was stirred for 5 hours, diluted with ethyl acetate and the combined organics washed with water and concentrated saline, dried (MgSO4) and reduced in vacuo. The resulting residue was subjected to column chromatography, eluting with 5% MeOH / DCM to provide an orange oil (0.94 g, 1: 1 ratio of 1- [2- (3,4-dinitro-phenoxy) -ethyl] -pyrrolidine and 1- [2- (4-Fluoro-2-nitro-phenoxy) -ethyl] -pyrrolidine.

A sample of the product mixture obtained (0.281 g) was dissolved in DMF (5 ml) under a nitrogen atmosphere. Palladium on carbon (10%, 0.028 g) was added and the reaction mixture was stirred under a hydrogen atmosphere for 20 hours. The solids were removed by filtration and the filtrate was reduced in vacuo and combined with 4- (2,6-difluoro-benzoylamino) -1 H -pyrazol-3-carboxylic acid (0.134 g, 0.50 mmol), EDC (0.116 g, 0.60 mmol), HOBt (0.081 g, 0.60 mmol) and DMF (2.5 ml) and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was reduced in vacuo and the residue was partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate solution (50 ml). The organic layer was washed with concentrated saline, dried (MgSO4) and reduced in vacuo to provide intermediate amides. Acetic acid (10 ml) was added to the crude amide and the mixture was heated at reflux for 3 hours and reduced in vacuo. 4- (2,6-Difluoro-benzoylamino) -1 H -pyrazol-3-carboxylic acid [5-fluoro-2- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -amide was isolated from the residue by LC / Preparative MS as an off-white solid (0.040 g, 5.6%). (LC / MS: Rt 2.38, [M + H] + 474.33).

Following the procedures described above, the compounds shown in Table 6 were prepared.

Table 6

Example No.

Structure Method Differences LCMS

171 *

Procedure D followed by G then E [M + H] + 365 Rt 0.34

172

B Purified by column chromatography (pet.-EtOAc ether (1: 1)) [M + H] +414.13 Rt3.05

173

B Purified by column chromatography (pet.-EtOAc ether (1: 1)) [M + H] +432.12 Rt3.12

174

B Purified by column chromatography (pet.-EtOAc ether (1: 1)) [M + H] +448.06 Rt3.33

175

B Purified by column chromatography (pet.-EtOAc ether (1: 1)) [M + H] +450.08 Rt3.29

176

B Purified by column chromatography (pet.-EtOAc ether (1: 1)) [M + H] +480.05 Rt3.18

Example No.

Structure Method Differences LCMS

177

A Starting amine prepared according to Procedure L HOAt instead of HOBt DMSO as solvent instead of DMF Et3N 2 eq Purified by HPLC and formation of the HCl salt [M + H] + 447 Rt 2.01

178

B [M + H] +343.05 Rt3.38 (polar method)

179

A Butylpiperidine-4-amine prepared by Procedure N HOAt instead of HOBt Purified by crushing with MeOH [M + H] + 406 Rt 1.85

180

B [M + H] +371.09 Rt3.27 (polar method)

181

B [M + H] +306.06 Rt1.53

182

B [M + H] +403.98 Rt2.78

183

B [M + H] +345.05 Rt3.03

Example No.

Structure Method Differences LCMS

184 *

B [M + H] +280.05 Rt 3.75 (basic method)

185

TO HOAt instead of HOBt followed by EtOAc / HCl deprotection [M + H] + 336 Rt 1.67

186

TO [M + H] +380.05 Rt1.78

187

TO [M + H] +396.02 Rt1.86

188

TO [M + H] +386.10 Rt1.88

189

TO [M + Hr 342.10 Rt 1.95

Example No.

Structure Method Differences LCMS

208

TO Coupling using (S) -3-amino-1-N-BOCpiperidine. Deprotection as the procedure M. Purified using column chromatography (CH2Cl2-MeOHAcOH-H2O (90: 18: 3: 2)) [M + H] +382.02 Rt1.82

209

TO [M + H] +440.22 Rt1.92

210

TO [M + H] + 411.20 Rt 2.97

211

TO Purified by LCMS prep. after treatment [M + H] +362.11 Rt1.91

212

TO Purified by LCMS prep. after treatment [M + H] +396.08 Rt2.06

213

TO Purified by LCMS prep. after treatment [M + H] +396.06 Rt2.04

EXAMPLE 224 * 4- (4-Methyl-piperazin-1-yl) -1 H -pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

5 Bis (2-Chloroethyl) methylamine hydrochloride (97mg; 0.5 mmol) was added to a stirred solution of 4-amino-1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) amide (100mg; 0, 45 mmol), tetrabutylammonium iodide (20 mg; 0.045 mmol) and diisopropylethylamine (200ul) 1.13 mmol) in DMF (5ml), and the resulting mixture was heated at 2000C (100W) for 30 minutes in a CEM Discover ™ microwave synthesizer. The DMF was removed in vacuo, purified by flash column chromatography, eluting with dichloromethane / methanol / acetic acid / water (90: 18: 3: 2).

The fractions containing the product were combined and evaporated, treated with HCl in ethyl acetate and evaporated again with toluene (2x20ml) to provide an off-white solid (27mg). (LC / MS: Rt 1.64, [M + H] + 378).

EXAMPLE 225 * 4-Morpholin-4-yl-1 H -pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

The compound was prepared in a manner analogous to Example 224, but using bis (2-chloroethyl) ether instead of bis (2-chloroethyl) methylamine hydrochloride.

(LC / MS: Rt 2.48 [M + H] + 291).

EXAMPLE 226 * 4- (2,4-Dichloro-phenyl) -1 H -pyrazol-3-carboxylic acid 4- (4-methyl-piperazin-1-yl) -benzylamide

10 226A. Preparation of 4- (2,4-dichloro-phenyl) -1 H -pyrazol-3-carboxylic acid

A solution of 4- (2,4-dichloro-phenyl) -1 H -pyrazol-3-carboxylic acid ethyl ester (205 mg; 0.72 mmol) and lithium hydroxide monohydrate (125 mg; 2.9 mmol) in 1: 1 THF / water (10 ml) was heated at 600C overnight. THF was removed by evaporation, the aqueous phase was acidified with 1M hydrochloric acid and extracted with ethyl acetate (20 ml). The ethyl acetate layer was dried (MgSO4), filtered and evaporated to provide 200 mg of acid.

4- (2,4-Dichloro-phenyl) -1 H -pyrazol-3-carboxylic acid. (LC / MS: [M + H] +256.85).

226B. Preparation of 4- (2,4-Dichloro-phenyl) -1 H -pyrazol-3-carboxylic acid 4- (4-methyl-piperazin-1-yl) -benzylamide

A solution of 4- (2,4-dichloro-phenyl) -1 H -pyrazol-3-carboxylic acid (70 mg; 0.27 mmol), 4- (4-methyl-piperazin-1-yl) benzylamine (62 mg ; 0.3 mmol), EDAC (63 mg; 0.33 mmol) and HOBt (45 mg; 0.33 mmol) in 5 ml of DMF are

20 stirred at room temperature for 48 hours. The reaction was evaporated and the residue was partitioned between ethyl acetate and concentrated saline. The ethyl acetate layer was separated, dried (MgSO4), filtered, evaporated and dried further in vacuo to provide 34 mg of 4- (4-methyl-piperazin-1-yl) -benzylamide of the acid 4- (2,4-Dichloro-phenyl) 1 H -pyrazol-3-carboxylic. (LC / MS: Rt 2.42 [M + H] +444).

EXAMPLE 227 *

4- (2,4-Dichloro-phenyl) -1 H -pyrazol-3-carboxylic acid 4-Methylsulfamoylmethyl-benzylamide

The title compound was prepared in a manner analogous to Example 226, but using (4-aminomethyl-phenyl) -N-methylmethanesulfonamide as the starting material. 6 mg of product was isolated as a white solid. (LC / MS: Rt 3.56 [M + H] +440).

EXAMPLE 228 * 4-Phenyl-1H-pyrazol-3-carboxylic acid amide

228A. 2-Benzylidene-but-3-ino nitrile

To a solution of benzaldehyde (2 g; 18.9 mmol), and malononitrile (1.37 g; 20.7 mmol) in ethanol (40 ml), 5 drops of piperidine were added and the mixture was heated at reflux overnight. . The reaction was cooled, evaporated and purified by flash column chromatography eluting with 1: 9 ethyl acetate / hexane and the fractions containing the product were combined and evaporated to provide 930 mg of 2-benzylidene-but- nitrile. 3-ino.

228B. 4-phenyl-5-trimethylsilanyl-1H-pyrazol-3-carbonitrile

N-Butyl lithium (2.7 M solution in heptane) (3.3 ml, 9 mmol) was added dropwise to a stirred solution of trimethylsilyl diazomethane (2 M solution in diethyl ether) (4.5 ml, 9 mmol ) in anhydrous THF (10 ml) at -780C under a nitrogen atmosphere and stirred for a further 30 minutes. To this a solution of 2-benzylidene-but-3-ino nitrile (920 mg; 6 mmol) in anhydrous THF (5 ml) was added dropwise, the mixture was stirred for 30 minutes at -780C and allowed to It will gradually warm up to room temperature overnight. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with saturated ammonium chloride solution followed by concentrated saline. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated. The crude product was purified by flash column chromatography eluting with 1: 8 and 1: 4 ethyl acetate / hexane and the fractions containing the product were combined and evaporated to provide 1.0 g of 4-phenyl-5-trimethylsilanyl. -1H-pyrazole-3carbonitrile.

228C. 4-Phenyl-1H-pyrazol-3-carboxylic acid amide

4-Phenyl-5-trimethylsilanyl-1H-pyrazol-3-carbonitrile (500 mg; 2.1 mmol) was dissolved in 1 ml of ethanol, treated with potassium hydroxide (600 mg) in water (3 ml) and heated at 1500C (100W) for 30 minutes and 1700C (100W) for 20 minutes in a CEM Discover ™ microwave synthesizer. The reaction mixture was acidified to pH1 with concentrated hydrochloric acid, diluted with water (40 ml) and extracted with ethyl acetate (2 x 40 ml). The combined ethyl acetate layers were separated, dried (MgSO4), filtered and evaporated to provide a 3: 1 mixture of 4-phenyl-1H-pyrazol-3-carboxylic acid and 4-phenyl-1H acid amide. -pyrazol-3-carboxylic. A 50 mg batch of the crude material was purified by flash column chromatography eluting with 5% methanol / dichloromethane, and the fractions containing the product were combined and evaporated to provide 15 mg of 4-phenyl-1H-pyrazole acid amide. -3-carboxylic as a white solid. (LC / MS: Rt 2.15 [M + H] + 188).

EXAMPLE 229 *

4-Phenyl-1H-pyrazol-3-carboxylic acid phenylamide

A solution of 4-phenyl-1H-pyrazol-3-carboxylic acid (75 mg; 0.4 mmol) (prepared according to Example 228C), aniline (45 µl; 0.48 mmol), EDAC (92 mg; 0, 48 mmol) and HOBt (65 mg; 0.48 mmol) in 5 ml of DMF was stirred at room temperature overnight. The reaction was evaporated and purified by flash column chromatography eluting with 1: 3 and 1: 2 ethyl acetate / hexane. Fractions containing the product were combined and evaporated to provide 30 mg of 4-phenyl-1 H -pyrazol-3-carboxylic acid phenylamide as a white solid. (LC / MS: Rt 3.12 [M + H] +264).

EXAMPLE 230 * 4-Phenyl-1H-pyrazol-3-carboxylic acid 4- (4-Methyl-piperazin-1-yl) -benzylamide

The compound was prepared in a manner analogous to Example 229, but using 4- (4-methyl-piperazin-1-yl) -benzylamine as the starting material. 6mg of product was isolated as a white solid. (LC / MS: Rt 2.05 [M + H] + 376).

EXAMPLE 231 * 4-Phenyl-1H-pyrazol-3-carboxylic acid (6-methoxy-pyridin-3-yl) amide

The compound was prepared in a manner analogous to Example 230, but using 3-amino-6-methoxypyridine as the fragment amine. 100 mg of solid-solid product were isolated (LC / MS: Rt3.17 [M + H] +295).

EXAMPLE 232 * 4- (3-Benzyloxy-phenyl) -1H-pyrazol-3-carboxylic acid 4- (4-methyl-piperazin-1-yl) -benzylamide

The compound was prepared in a manner analogous to Example 226. The product was isolated as a white solid. 15 (LC / MS: Rt 2.65 [M + H] +482).

EXAMPLE 233 * 4- (3-Hydroxy-phenyl) -1H-pyrazol-3-carboxylic acid 4- (4-methyl-piperazin-1-yl) -benzylamide

A 4- (3-benzyloxy-phenyl) -1 H -pyrazol-3-carboxylic acid 4- (4-methyl-piperazin-1-yl) -benzylamide solution

20 (25 mg; 0.05 mmol) in methanol (5 ml), treated with 10% palladium on carbon (10 mg) and hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration through Celite and the filtrate was evaporated. Purification by preparative LC / MS provided 8 mg of the required product as a cream solid. (LC / MS: Rt 1.67 [M + H] +392).

EXAMPLE 234 * 4- (5-Methyl-3 H -imidazol-4-yl) -1 H -pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

The compound was prepared in a manner analogous to Example 226, but using 4-methyl-5-formylimidazole as the starting material in the condensation step. The product (6 mg) was isolated as a white solid. (LC / MS: Rt 2.00 [M + H] + 286).

EXAMPLE 235 * 4- (2,5-Dimethyl-pyrrol-1-yl) -1 H -pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide

A mixture of 4-amino-1H-pyrazol-3-carboxylic acid (4-fluoro-phenyl) -amide (100 mg) and Montmorillonite KSF clay (100 mg) in acetonylacetone (1 ml) was heated to 1200C (50 W ) for 15 minutes in a CEM discover microwave synthesizer. The reaction mixture was diluted with 5% methanol / dichloromethane, filtered and evaporated. The crude product was purified by flash column chromatography eluting with 1: 2 ethyl acetate / hexane and the fractions containing the product were combined and evaporated to provide 65 mg of the target molecule as a light brown solid. (LC / MS: Rt 3.75 [M + H] + 299).

EXAMPLE 236 *

4- (3-Hydroxymethyl-phenyl) -1H-pyrazol-3-carboxylic acid phenylamide

236A. 4-iodo-1H-pyrazol-3-carboxylic acid phenylamide

An aqueous solution of sodium nitrite (760 mg) in 2 ml of water was added dropwise to a stirred suspension of 4-amino-1 H -pyrazol-3-carboxylic acid phenylamide (2 g; 10 mmol) in hydrochloric acid concentrate (20 ml) at 00C and stirred at 00C for an additional 60 minutes. The reaction mixture was diluted with acetone (10 ml), treated with depotassium iodide (1.8 g) and decorative iodide (II) (2.1 g) and seated at room temperature for 90 minutes. The reaction mixture was diluted with concentrated saline and ethyl acetate and washed with saturated sodium thiosulfate solution. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated to provide 680 mg of 4-iodo-1 H -pyrazol-3-carboxylic acid phenylamide.

236B. 4-Iodo-1- (4-methoxy-benzyl) -1H-pyrazol-3-carboxylic acid phenylamide

A solution of 4-iodo-1H-pyrazol-3-carboxylic acid phenylamide (670 mg; 2.14 mmol) in acetonitrile (10 ml) was treated with potassium carbonate (360 mg; 2.57 mmol)) followed by chloride of 4-methoxybenzyl (320 µl; 2.35 mmol). The mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and concentrated saline; The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated. The crude material was purified by flash column chromatography eluting with

1: 3 ethyl acetate / hexane and the fractions containing the product were combined and evaporated to provide 660 mg of 4-iodo-1- (4-methoxy-benzyl) -1H-pyrazole-3-carboxylic acid phenylamide.

236C. 4- (3-Hydroxymethyl-phenyl) -1- (4-methoxy-benzyl) -1H-pyrazol-3-carboxylic acid phenylamide

A mixture of 4-iodo-1- (4-methoxy-benzyl) -1 H -pyrazol-3-carboxylic acid phenylamide (50 mg; 0.11 mmol), bis (tri-tert-butylphosphine) palladium (12 mg) , potassium carbonate (100 mg; 0.66 mmol) and 3- (hydroxymethyl) benzene boronic acid (21mg; 0.14 mmol) in ethanol / toluene / water (4 ml: 1 ml: 1 ml) was heated to 1200C ( 50 W) for 15 minutes in a CEM Discover microwave synthesizer. The reaction was evaporated and the residue was partitioned between ethyl acetate and concentrated saline. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated and the crude material was purified by flash column chromatography eluting with 1: 2 and 2: 1 ethyl acetate / hexane. Fractions containing the product were combined and evaporated to provide 60 mg of 4- (3-hydroxymethyl-phenyl) -1- (4-methoxy-benzyl) -1 H -pyrazol-3-carboxylic acid phenylamide.

236D. 4- (3-Hydroxymethyl-phenyl) -1H-pyrazol-3-carboxylic acid phenylamide

A mixture of 4- (3-hydroxymethyl-phenyl) -1- (4-methoxy-benzyl) -1H-pyrazol-3-carboxylic acid (20 mg) and anisole (20 µl) in trifluoroacetic acid (1 ml) heated at 1200C (50 W) for 15 minutes in a CEM Discover microwave synthesizer. The reaction was evaporated and purified by flash column chromatography eluting with

2: 1 ethyl acetate / hexane. Fractions containing the product were combined and evaporated to provide 5mg of product. (LC / MS: Rt 2.55 [M + H] + 294).

EXAMPLE 237

Preparation of 4- (2,6-Dichloro-benzoylamino) -1H-pyrazole-3-carboxylic acid piperidine-4-ylamide hydrochloride

237A. 4- (2,6-Dichloro-benzoylamino) -1H-pyrazol-3-carboxylic acid

2,6-Dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was carefully added to a solution of 4-amino-1H-pyrazol-3-carboxylic acid methyl ester (prepared analogously to 165B) ( 5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxane (50 ml) and stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate was treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 500 ° C for 4 hours and evaporated. 100 ml of water was added to the residue and acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and dried by aspiration to provide 10.05 g of 4- (2,6-dichloro-benzoylamino) -1 H -pyrazol-3-carboxylic acid as a solid. light violet.

237B. 4 - {[4- (2,6-Dichloro-benzoylamino) -1 H -pyrazol-3-carbonyl] -amino} -piperidine-1-carboxylic acid tert-butyl ester

A mixture of 4- (2,6-dichloro-benzoylamino) -1 H -pyrazol-3-carboxylic acid (6.5 g, 21.6 mmol), 4-amino-1-BOCpiperidine (4.76 g, 23, 8 mmol), EDC (5.0 g, 25.9 mmol) and HOBt (3.5 g, 25.9 mmol) in DMF (75 mL) was stirred at room temperature for 20 hours. The reaction mixture was reduced in vacuo and the residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The organic layer was washed with saturated saline, dried (MgSO4) and reduced in vacuo. The residue was taken up in 5% MeOH-DCM

(~ 30 ml). The insoluble material was collected by filtration and washed with DCM and dried in vacuo to provide 4 - {[4- (2,6-dichloro-benzoylamino) -1 H -pyrazol-3-carbonyl] tert-butyl ester - amino} -piperidine-1-carboxylic acid (5.38 g) as a white solid. The filtrate was reduced in vacuo and the residue was purified by column chromatography using a 1: 2 gradient elution EtOAc / hexane to EtOAc to provide more tert-butyl ester of 4 - {[4- (2,6-dichloro-benzoylamino) acid -1 H -pyrazol-3-carbonyl] -amino} -piperidine-1-carboxylic acid (2.54 g) as a white solid.

237C. 4- (2,6-Dichloro-benzoylamino) -1H-pyrazol-3-carboxylic acid piperidine-4-ylamide

A solution of 4 - {[4- (2,6-dichloro-benzoylamino) -1 H -pyrazol-3-carbonyl] -amino} piperidine-1-carboxylic acid tert-butyl ester (7.9 g) in MeOH ( 50 mL) and EtOAc (50ml) was treated with HCl-EtOAc sat. (40 mL) and stirred at

t.a. all night. The product did not crystallize due to the presence of methanol and therefore the reaction mixture was evaporated and the residue was triturated with EtOAc. The resulting off-white solid was collected by filtration, washed with EtOAc and dried by aspiration in the sinter to provide 6.3g of 4- (2,6-dichlorobenzoylamino) -1H-pyrazole-3- acid piperidin-4-ylamide carboxylic as the hydrochloride salt. (LC / MS: Rt 5.89, [M + H] + 382/384).

EXAMPLE 238 *

4-Methanesulfonylamino-1H-pyrazol-3-carboxylic acid (4-Fluoro-phenyl) -amide

A solution of (4-fluorophenyl) -amide of 4-amino-1H-pyrazol-3-carboxylic acid (50mg) (Example 2B) and anhydride

5 methanesulfonic acid (45mg) in pyridine (1ml) was stirred at room temperature overnight, evaporated and purified by flash column chromatography eluting with 2: 1 EtOAc / hexane. Evaporation of the fractions containing the product provided 20mg of the title compound. (LC / MS: Rt 2.87; [M + H +] 299).

EXAMPLES 239 TO 245

The compounds of Examples 239 to 245 were prepared using the methods described above or methods very analogous to them.

EXAMPLE 239 4- (2,6-Difluoro-benzoylamino) -1H-pyrazole-3-carboxylic acid [1- (2-Fluoro-ethyl) -piperidin-4-yl] -amide

EXAMPLE 240 * 4- (2,6-Dichloro-benzoylamino) -1H-pyrazol-3-carboxylic acid (6-chloro-pyridin-3-yl) -amide

EXAMPLE 242 * 4- (2,6-Dichloro-benzoylamino) -1H-pyrazol-3-carboxylic acid (6-methoxy-pyridin-3-yl) -amide

EXAMPLE 245 4- [3- (4-Methyl-piperazin-1-yl) -benzoylamino] -1H-pyrazol-3-carboxylic acid cyclohexylamide

BIOLOGICAL ACTIVITY

EXAMPLE 246

15 Measurement of Inhibitory Activity (IC50) of CDK2 Kinase

Compounds of formula (II) were tested for kinase inhibitory activity using the following protocol or the activated kinase protocol CDK2 / cyclin A described in Example 241.

1.7 µl of active CDK2 / CyclinA (Upstate Biotechnology, 10U / µl) are diluted in assay buffer (250 µl of 10X concentration of assay buffer (200mM MOPS pH 7.2, 250mM β-glycerophosphate, 50mM EDTA, 150mM 20 MgCl2), 11.27µl10mMATP, 2.5µl1MDTT, 25µl100mMortovanadatodesodium, 708.53µlH2O), and mix10µl with 10 µl of histone substrate mixture (60 µl of bovine histone H1 (Upstate Biotechnology, 5 mg / mlO), 940 µL, 940 µCi γ33P-ATP) and was added to 96-well plates together with 5 µl of the different dilutions of the compound

test in DMSO (up to 2.5%). The reaction was allowed to proceed for 5 hours before stopping it with an excess of ortho-phosphoric acid (30 µl at 2%).

Γ33P-ATP that remains unincorporated in histone H1 is separated from phosphorylated histone H1 in a Millipore MAPH filter plate. The MAPH plate wells are moistened with 0.5% orthophosphoric acid and the reaction results are filtered with a Millipore vacuum filtration unit through the wells. After filtration, the residue is washed twice with 200 µl of 0.5% orthophosphoric acid. Once the filters have dried, 25 µl Microscint 20 scintillation liquid is added and counted in a Packard Topcount for 30 seconds.

The% inhibition of CDK2 activity is calculated and represented in order to determine the concentration of test compound required to inhibit 50% of the activity of CDK2 (IC50).

By the protocol shown above, it was found that the compounds of Examples 2C through 87, 89-92, 94, 96-101, 104-105, 165, 166, 224, 225, 227, 229, 231, 233, 234 and 236 each have IC50 values less than 20 µM or provide at least 50% inhibition of CDK2 activity at a concentration of 10 µM. The compounds of Examples 88, 93, 226, 228, 230 and 235 each have IC50 values of less than 750 µM.

EXAMPLE 247

CDK Selectivity Assays

The compounds of formula (II) are tested for kinase inhibitory activity against several different kinases using the general protocol described in Example 239, peromodified as shown below.

The kinases are diluted to a 10x working stock preparation in 20 mM MOPS pH 7.0, 1 mM EDTA, 0.1% γ-mercaptoethanol, 0.01% Brij-35, 5% glycerol, 1 mg / ml BSA. One unit is equal to the incorporation of 1 nmol of phosphate per minute in 0.1 mg / ml of histone H1, or peptide substrate of CDK7 at 300C with a final ATP concentration of 100 µM.

The substrate for all CDK assays (except CDK7) is histone H1, diluted to a 10X working stock preparation in 20 mM MOPS pH 7.4 before use. The substrate for CDK7 is a specific peptide obtained from diluted Upstate until a 10X working mother preparation in deionized water.

Test Procedure for CDK1 / cyclinB, CDK2 / cyclinA, CDK2 / cyclinE, CDK3 / cyclinE, CDK5 / p35, CDK6 / cyclinD3:

In a final reaction volume of 25 µl, the enzyme (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.1 mg / ml histone H1, 10 mM MgAcetate and [γ -33P-ATP] (specific activity approx 500 cpm / pmol, concentration as required). The reaction is initiated by the addition of Mg2 + [γ-33P-ATP]. After incubating for 40 minutes at room temperature, the reaction is stopped by the addition of 5 µl of a 3% phosphoric acid solution. 10 ml of the reaction is deposited on a P30 filter mesh and washed 3 times for 5 minutes in 75 mM phosphoric acid and once in methanol before drying and counting.

Enelensayo CDK3 / cyclin E, the compound of Example 150 had an IC50 of less than 20 µM.

Enelensayo CDK5 / p35, the compounds of the Examples41 and 150 had an IC50 of less than 20 µM.

Enelensayo CDK6 / cyclin D3, the compound of Example 150 had an IC50 of less than 20 µM.

Test Procedure for CDK7 / cyclin H / MAT1

In a final reaction volume of 25 µl, the enzyme (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 500 µM peptide, 10 mM MgAcetate and [γ-33P-ATP ] (specific activity approx 500 cpm / pmol, concentration as required). The reaction is initiated by the addition of Mg2 + [γ-33P-ATP]. After incubating for 40 minutes at room temperature, the reaction is stopped by the addition of 5 µl of a 3% phosphoric acid solution. 10 ml of the reaction is deposited on a P30 filter mesh and washed 3 times for 5 minutes in 75 mM phosphoric acid and once in methanol before drying and counting.

EXAMPLE 248

A. Measurement of the Inhibitory Activity Test (IC50) of Activated CDK2 Kinase / CyclinA

The compounds of formula (II) were tested for kinase inhibitory activity using the following protocol.

Activated CDK2 / CyclinA (Brown et al, Nat. Cell Biol., 1, p 438-443, 1999; Lowe, ED, et al Biochemistry, 41, p 15625-15634, 2002) is diluted to 125 pM in assay buffer 2.5X concentration (50 mM MOPS pH 7.2, 62.5 mM β-glycerophosphate, 12.5 mM EDTA, 37.5 mM MgCl2, 112.5 mM ATP, 2.5 mM DTT, 2.5 mM Sodium orthovanadate, 0.25 mg / ml bovine serum albumin), and mix 10 µl with 10 µl histone substrate mixture (60 µl bovine histone H1 (Upstate Biotechnology, 5 mg / ml), 940 µl H2O, 35 µCi γ33P-ATP) and added to 96 plates

wells together with 5 µl of several dilutions of the test compound in DMSO (up to 2.5%). Allow the reaction to proceed for 2 to 4 hours before stopping it with an excess of ortho-phosphoric acid (5 µl at 2%).

Γ33P-ATP that remains unincorporated in histone H1 is separated from phosphorylated histone H1 in a Millipore MAPH filter plate. The MAPH plate wells are moistened with 0.5% orthophosphoric acid and the reaction results are filtered with a Millipore vacuum filtration unit through the wells. After filtration, the residue is washed twice with 200 µl of 0.5% orthophosphoric acid. Once the filters have dried, 20 µl of Microscint 20 scintillation liquid is added and counted in a Packard Topcount for 30 seconds.

The% inhibition of CDK2 activity is calculated and represented in order to determine the concentration of test compound required to inhibit 50% of the activity of CDK2 (IC50).

By the above protocol, it was found that the compounds of Examples 95, 96, 99-104, 106-121, 123-125, 130-137, 139, 142-145, 147-150, 152-156, 158-160 , 162-164, 167–173, 177-179, 181-182, 184-190, 194, 196–204, 208–213 and 215 have IC50 values of less than 20 µM. The compounds of Examples 122, 126-129, 140, 141, 146, 157 and 161 each have IC50 values of less than 750 µM and most have IC50 values of less than 100 µM.

B. Test CDK1 / CiclinaB.

The CDK1 / CiclinaB assay is identical to that of the previous CDK2 / CiclinaA except that CDK1 / CiclinaB (Upstate Discovery) is used and the enzyme is diluted to 6.25 nM.

In the CDK1 assay performed as described above or by the protocol shown in Example 240, it was found that the compounds of Examples 2C, 41, 48, 53, 64, 65, 66, 73, 76, 77, 91 , 95, 102, 106, 117, 123, 125, 133, 137, 142, 150, 152, 154, 167, 186, 187, 189, 190, 193, 194, 196, 199, 202-204, 207, 208 -213, 215 and 218-223 have IC50 values less than 20 µM, and the compounds of Examples 188 and 206 were found to have IC50 values less than 100 µM.

EXAMPLE 249

Test Procedure for CDK4

Assays for CDK4 inhibitory activity were performed by Proqinase GmbH, Freiburg, Germany, using its patented 33PanQinase® Activity Test. The tests were performed in 96-well FlashPlates ™ (PerkinElmer). In each case, the reaction mixture (final volume 50 µl) is composed of; 20 µl of assay buffer (60mM final composition HEPES-NaOH, pH 7.5, 3 mM MgCl2, 3 µM Na-orthovanadate, 1.2mM DTT, 50 µg / ml PEG2000, 5 µl ATP solution (1 µM final concentration [γ-33P] -ATP (approx 5x105 cpm per well)), 5 µl of test compound (in 10% DMSO), 10 µl substrate / 10 µl enzyme solution (premixed) Final amounts of enzyme and substrate were as follows.

Kinase

Kinase ng / 50 µl Substratum Substrate ng / 50µl

CDK4 / CicD1

fifty Poly (Ala, Glu, Lys, Tyr) 6: 2: 5: 1 500

The reaction mixture was incubated at 300C for 80 minutes. The reaction was stopped with 50 µl of 2% H3PO4, the plates were aspirated and washed twice with 200 µl 0.9% NaCl. The incorporation of 33P was determined with a microplate scintillation counter. The background values were subtracted from the data before calculating the residual activities for each well. IC50s were calculated using Prism 3.03.

The compound of Example 150 has an IC50 demenes of 5 µM in this assay.

EXAMPLE 250

Anti-proliferative Activity

The anti-proliferative activities of the compounds of formula (II) are determined by measuring the ability of the compounds to inhibit cell growth in several cell lines. Cell growth inhibition is measured using the Alamar Blue assay (Nociari, M. M, Shalev, A., Benias, P., Russo, C. Journal of Immunological Methods 1998, 213, 157-167). The method is based on the ability of viable cells to reduce resazurin to its fluorescent resorufin product. For each proliferation assay, the cells are plated in 96-well plates and allowed to recover for 16 hours before the addition of the inhibitor compounds for an additional 72 hours. At the end of the incubation period, 10% (v / v) Alamar Blue is added and incubated for an additional 6 hours before the determination of the fluorescent product at 535nM ex / 590nM em. In the case of the non-proliferative cell assay, the cells are kept in confluence for 96 hours before the addition of the inhibitor compounds for an additional 72 hours. The number of viable cells is determined by the Alamar Blue assay as above. All cell lines are obtained from ECACC (European Collection of cell Cultures).

In the assays against the human colon carcinoma cell line HCT 116 (ECACC No. 91091005), the compounds of Examples 10, 25-27, 41, 44, 46, 48, 50, 52, 53, 60, 62 , 64-67, 69, 73-77, 79, 80, 83A, 86, 90-93, 95-98, 100-104, 106, 107, 109-121, 123-125, 131-134, 136-143 , 147-155, 158, 159, 162-164, 166, 167, 178, 179, 185-190, 192-205, 207-215 and 218-223 have IC50 values of less than 20 µM and the compounds of Examples 2C, 3,29,38,39,49,51,85,89,99,108,135,160,182,183,206 and 216 have values of IC50 of less than 100 µM.

EXAMPLE 251

Measurement of inhibitory activity against glycogen synthase kinase-3 (GSK-3)

The activities of the compounds of formula (II) as GSK-3 inhibitors were determined using Protocol A or Protocol B below.

Protocol A

GSK3-β (Upstate Discovery) is diluted to 7.5 nM in 25 mM MOPS, pH 7.00, 25 mg / ml BSA, 0.0025% Brij-35RTM, 1.25% glycerol, 0.5 mM EDTA, 25 mM MgCl2, 0.025% β-mercaptoethanol, 37.5 mM ATP and mix 10 µl with 10 µl of substrate mixture. The substrate mixture is 12.5 µM phospho-glycogen synthase peptide-2 (Upstate Discovery) in 1 ml of water with 35 µCi γ33P-ATP. The enzyme and the substrate are added to 96-well plates together with 5 µl of various dilutions of the test compound in DMSO (up to 2.5%). The reaction is allowed to proceed for 3 hours before stopping it with an excess of ortho-phosphoric acid (5 µl at 2%). The filtration procedure is as for the previous Activated CDK2 / CyclinA assay.

Protocol B

GSK3β (human) is diluted to a 10x working stock preparation in 50mM Tris pH 7.5, 0.1mM EGTA, 0.1mM sodium vanadate, 0.1% β-mercaptoethanol, 1mg / ml BSA. One unit is equal to the incorporation of 1nmol of phosphate per minute to the phospho-glycogen synthase peptide 2 per minute.

In a final reaction volume of 25 µl, GSK3β (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 20 µM YRRAAVPPSPSLSRHSSPHQS (p) EDEEE (phosphorus GS2 peptide), 10 mM MgAcetate and [γ-33P-ATP] (specific activity approx 500 cpm / pmol, concentration as required). The reaction is initiated by the addition of Mg2 + [γ-33P-ATP]. After incubating for 40 minutes at room temperature, the reaction is stopped by the addition of 5 µl of a 3% phosphoric acid solution. 10 µl of the reaction is deposited on a P30 filter mesh and washed 3 times for 5 minutes in 50mM phosphoric acid and once in methanol before drying and counting.

From the results of the GSK3-B tests performed using either of the two protocols shown above, it was found that the compounds of Examples 2C, 26, 48, 53, 65, 76, 77, 84, 86, 95, 102, 106, 119, 122, 123, 126, 127, 128, 129, 131, 134, 135, 138, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150 and 151 each have values of IC50 at least 10 µM .

PHARMACEUTICAL FORMULATIONS

EXAMPLE 252

(i) Formulation in Tablets

A tablet composition containing a compound of the formula (II) is prepared by mixing 50mg of the compound with 197mg of lactose (BP) as a diluent and 3mg of magnesium stearate as a lubricant and compressed to form a tablet in a known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100mg of a compound of formula (II) with 100mg of lactose and using the resulting mixture to fill standard opaque hard gelatin capsules.

(iii) Injectable Formulation I

A parenteral composition for injection administration can be prepared by dissolving a compound of the formula (II) (for example, in a salt form) in water containing 10% propylene glycol to provide a concentration of active compound of 1.5% in weight. The solution is sterilized by filtration, used to fill a blister and sealed.

(iv) Injectable Formulation II

A parenteral composition for injection is prepared by dissolving in water a compound of the formula (II) (for example, in salt form) (2 mg / ml) and mannitol (50 mg / ml), sterilizing the solution by filtration and using it to fill vials or ampoules of 1 ml that can be sealed.

(iv) Formulation for Subcutaneous Injection

A composition for subcutaneous administration is prepared by mixing a compound of the formula (II) with pharmaceutical grade corn oil to provide a concentration of 5 mg / ml. The composition is sterilized and used to fill a suitable container.

EXAMPLE 253

Determination of Antifungal Activity

The antifungal activity of the compounds of the formula (II) is determined using the following protocol.

The compounds are tested against a panel of fungi including Candida parpsilosis, Candida tropicalis, Candida albicans-ATCC 36082 and Cryptococcus neoformans. The test organisms are maintained in inclined means of Sabourahd Dextrose Agar at 40C. Singlet suspensions of each organism are prepared by growing the yeast overnight at 270C in a rotating drum in nitrogen-based (YNB) broth with amino acids (Difco, Detroit, Mich.), PH 7.0 with 0.05 acid Propanesulfonic morpholine (MOPS). The suspension is centrifuged and washed twice with 0.85% NaCl before sonicating the washed cell suspension for 4 seconds (Branson sonicator, model 350, Danbury, Conn.). The singlet blastospores are counted in a hemocytometer and adjusted to the desired concentration in 0.85% NaCl.

The activity of the test compounds is determined using a modification of a broth demilrodilution technique. The test compounds are diluted in DMSO at a rate of 1.0 mg / ml and diluted to 64 µg / ml in YNB broth, pH 7.0 with MOPS (Fluconazole is used as a control) to provide a working solution of each compound Using a 96-well plate, wells 1 and 3 to 12 are prepared with YNB broth, ten-fold dilutions of the compound's solution are prepared in wells 2 to 11 (concentration ranges are 64 to 0.125 µg / ml) . Well 1 serves as a sterility control and blank for spectrophotometric tests. Well 12 serves as a growth control. Microtiter plates are inoculated with 10 µl in each of wells 2 to 11 (the final inoculum size is 104 organisms / ml). The inoculated plates are incubated for 48 hours at 350C. MIC values are determined spectrophotometrically by measuring absorbance at 420 nm (Automatic Microplate Reader, DuPont Instruments, Wilmington, Del.) After stirring the plates for 2 minutes with a vortex mixer (Vorte-Genie 2 Mixer, Scientific Industries, Inc ., Bolemia, NY). The MIC endpoint is defined as the lowest drug concentration that exhibits a reduction of approximately 50% (or more) of growth compared to the control well. With the turbidity test it is defined as the lowest drug concentration at which turbidity in the well is <50% of the control

(IC50). Minimum Cytolytic Concentrations (MCC) are determined by subculturing all wells of the 96-well plate in a Sabourahd Dextrose Agar plate (SDA), incubating for 1 to 2 days at 350C and checking viability.

EXAMPLE 254

Protocol for the Biological Evaluation of Fungal Infection Control of Complete Plants in vivo

The compounds of the formula (II) are dissolved in acetone, with subsequent serial dilutions in acetone to obtain a range of desired concentrations. The final treatment volumes are obtained by adding 9 volumes of 0.05% aqueous Tween-20 ™ or 0.01% Triton X-100 ™, depending on the pathogen.

The compositions are used to test the activity of the compounds of formula (II) against tomato blight (Phytophthora infestans) using the following protocol. Tomatoes (Rutgers cultivated variety) are grown from seeds in a potted soil-based potting mix until the seedlings have a height of 10-20 cm. Plants are sprayed to drain with the test compound at a rate of 100 ppm. After 24 hours, the test plants are inoculated by spraying with a suspension of aqueous sporangia of Phytophthora infestans, and stored in a dew chamber overnight. The plants are transferred to the greenhouse until the disease develops in the untreated control plants.

Similar protocols are also used to test the activity of compounds of formula (II) to combat Brown Wheat Rust (Puccinia), Dusty Wheat Mildiú (Ervsiphe vraminis), Wheat (Monon cultivated variety), Wheat Leaf Spot (Septoria tritici), and Stain of Wheat Gluma (Leptosphaeria nodorum).

Claims (13)

1. A combination comprising:

(i)

a compound of the formula (II):

or salts or tautomers or N-oxides or solvates thereof;

in which Y is an alkylene chain or bond with a length of 1, 2 or 3 carbon atoms; R1 is a carbocyclic or heterocyclic group having 3 to 12 ring members, in which the carbocyclic or heterocyclic groups are unsubstituted or substituted with one or more R10 substituent groups; R2 is hydrogen or methyl; R3 is selected from non-aromatic carbocyclic and heterocyclic groups having 3 to 12 ring members, in which the carbocyclic or heterocyclic groups are not substituted or substituted with one or more R10 substituent groups; Y R10 is selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-hydrocarbonylamino C1-4, carbocyclic and heterocyclic groups having 3 to 12 ring members; a Ra-Rb group in which Ra is a bond, O, CO, X1C (X2), C (X2) X1, X1C (X2) X1, S, SO, SO2, NRc, SO2NRc or NRcSO2; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having 3 to 12 ring members, and a C1-8 alkyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-hydrocarbonylamino C1-4, carbocyclic and heterocyclic groups having 3 to 12 ring members; Rc is selected from hydrogen and C1-4 hydrocarbyl; Y X1 is O, S or NRc and X2 is = O, = S or = NRc; and with the proviso that when the R10 substituent group comprises or includes a carbocyclic or heterocyclic group, said carbocyclic or heterocyclic group may not be substituted or may itself be substituted with one or more additional R10 substituent groups and in which (a) said additional R10 substituent groups include carbocyclic or heterocyclic groups, which are not themselves further substituted; or (b) said additional substituents do not include carbocyclic or heterocyclic groups but are nonetheless selected from the groups listed above in the definition of R10; Y (ii) one or more additional therapeutic agents.

2.

A combination according to claim 1 wherein R2 is hydrogen.

3.

A combination according to any one of the preceding claims wherein R1 is an unsubstituted or substituted monocyclic carbocyclic or heterocyclic group in which the carbocyclic and heterocyclic groups are substituted with one or more R10 or R10a substituent groups; wherein R10 is as defined in claim 1 and R10a is selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, a Ra-Rb group in which Ra is a bond, O, CO, X3C (X4 ), C (X4) X3, X3C (X4) X3, S, SO, or SO2, and Rb is selected from hydrogen and a C1-8 alkyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano , nitro, carboxy and non-aromatic monocyclic carbocyclic or heterocyclic groups having 3 to 6 ring members.

Four.

A combination according to claim 1 wherein the compound of formula (II) has the formula (IV):

or salts or tautomers or N-oxides or solvates thereof; wherein R1 and R2 are as defined in any one of the preceding claims; an optional second bond may be present between carbon atoms numbered 1 and 2; One of U and T is selected from CH2, CHR13, CR11R13, NR14, N (O) R15, O and S (O) t; and the other of U and T is selected from NR14, O, CH2, CHR11, C (R11) 2, and C = O; r is 0, 1, 2, 3 or 4; t is 0, 1 or 2; R11 is selected from hydrogen, halogen, C1-3 alkyl and C1-3 alkoxy; R13 is selected from hydrogen, NHR14, NOH, NOR14 and Ra-Rb; R14 is selected from hydrogen and Rd-Rb; 10 Rd is selected from a link, CO, C (X2) X1, SO2 and SO2NRc; Ra, Rb and Rc are as defined in any one of the preceding claims; and R15 is selected from saturated C1-4 hydrocarbyl optionally substituted with hydroxy, C1-2 alkoxy, halogen or a 5 or 6 membered monocyclic carbocyclic or heterocyclic group, with the proviso that U and T cannot be O simultaneously. A combination according to claim 4 wherein the compound of formula (II) has the formula (Va): or salts or tautomers or N-oxides or solvates thereof; wherein R14a is selected from hydrogen, C1-4 alkyl optionally substituted with fluorine, cyclopropylmethyl, phenyl-C1-2 alkyl, C1-4 alkoxycarbonyl, phenyl-C1-2 alkoxycarbonyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 alkylsulfonyl, in which When phenyl moieties are present, they are optionally substituted with one to three substituents selected from fluorine, chlorine, C1-4 alkoxy optionally substituted with fluorine or C1-2 alkoxy, and C1-4 alkyl optionally substituted with fluorine or C1-2 alkoxy; w is 0, 1, 2 or 3; R2 is hydrogen or methyl; R11 and r are as defined in any one of claims 17 to 19; Y R19 is selected from fluorine; chlorine; C1-4 alkoxy optionally substituted with fluorine or C1-2 alkoxy; and C1-4 alkyl optionally substituted with fluorine or C1-2 alkoxy. 6. A combination according to claim 1 wherein the compound of formula (II) has the formula (VIb): or salts or tautomers or N-oxides or solvates thereof; wherein R20 is selected from hydrogen and methyl; R21a is selected from fluorine and chlorine; Y R22a is selected from fluorine, chlorine and methoxy.

7.

A combination according to claim 6 wherein the compound of formula (II) is 4- (2,6-dichloro-benzoylamino) -1 H -pyrazol-3-carboxylic acid piperidin-4-ylamide or a salt thereof.

8.

A combination according to any of the preceding claims wherein the one or more additional therapeutic agents are selected from anti-cancer agents including: -topoisomerase inhibitors -alkylating agents -antimetabolites -DNA-binding ligands -microtubule inhibitors (latubulin-directed agents) -monoclonal antibodies

-inhibitors of signal transduction -radiotherapy.

9.

A combination according to any one of the preceding claims wherein the one or more additional therapeutic agents are selected from anticancer agents including cisplatin, cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5FU, taxanes, and mitomycin C.

10.

A combination according to any one of the preceding claims wherein the compound of formula (II) and the one or more additional therapeutic agents are administered either simultaneously or sequentially.

eleven.

A combination according to any one of the preceding claims wherein the compound of formula (II) and one, two, three, four or more additional therapeutic agents are formulated together in a dosage form containing two, three, four or more therapeutic agents.

12.

A combination according to any of the preceding claims for use in medicine, for example for the treatment of cancer.

13.

A pharmaceutical composition (eg formulation) comprising at least one compound of formula (II) as defined in any one of claims 1 to 7 together with one or more vehicles, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, pharmaceutically acceptable lubricants, and other additional therapeutic or prophylactic agents.

14.

A compound of formula (II) as defined in any one of claims 1 to 7 for use in the

treatment of a disease that is: - viral infections, for example herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevention of the development of AIDS in HIV-infected individuals; or

-

Type II or non-insulin dependent diabetes mellitus; or - autoimmune diseases; or - head trauma; or -ict; or -epilepsy; or-neurodegenerative disorders, for example Alzheimer's disease, AIDS-related dementia,

5 Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration or such as Alzheimer's disease, motor neuron disease, progressive supranuclear paralysis, corticobasal degeneration and Pick's disease; or

-

chronic inflammatory diseases, for example systemic lupus erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus; 10 or - cardiovascular diseases such as cardiac hypertrophy, restenosis, and atherosclerosis, or such as arrhythmia; or -glomerulonephritis; or - myelodysplastic syndrome; or -ischemic damage associated with heart attacks, stroke and reperfusion damage; or 15 -induced hepatic diseases related to alcohol-related toxins; or -hematological diseases, for example, chronic anemia and aplastic anemia; or - degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, or aspirin-sensitive rhinosinusitis; or cystic fibrosis; or 20 -sclerosism multiple, or-kidney diseases; or - cancer pain; or - cancer, in particular RB + ve tumors.