TREATMENT OF SEPTICEMIA AND ARDS WITH ERK INHIBITORS

FIELD OF THE INVENTION

The invention relates to extracellular signal-regulated protein kinases 1 and 2 (ERKl/2) and associated diseases and disorders. More particularly, the invention relates to ERKl/2 inhibitors, compositions comprising an effective amount of an ERKl/2 inhibitor and methods for treating or preventing ERKl/2 associated diseases and disorders such as, for example, septicemia and acute respiratory distress syndrome (ARDS).

All publications, patents, patent applications, and other references cited in this application are incorporated herein by reference in their entirety for all purposes and to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention.

BACKGROUND OF THE INVENTION

Septicemia, also known as sepsis, is a leading cause of morbidity and mortality in the intensive care setting (1-3). The clinical course in septic patients is often complicated by dysfunction of multiple vital organs including the kidneys, lung, liver, and brain (4, 5). Acute kidney injury (AKI), for example, develops in up to 60% of patients diagnosed with sepsis or septic shock, and septic AKI is associated with an extremely high risk of mortality (-70%) (6-8). Acute lung injury (ALI), in turn, is one of the leading causes of death in sepsis with very few beneficial treatments available. Indeed, there is no cure for ALI; and the available treatments are just supportive to maintain adequate oxygenation and ventilation while minimizing secondary lung injury (77).

Clinical management of sepsis remains limited to non-specific supportive care aimed at maintaining organ homeostasis and preventing further infection (9). Although recent initiatives to implement early, goal-directed measures have shown modest benefits in septic patients, mortality resulting from this condition remains unacceptably high (10, 11). Thus, development of novel therapeutics that directly target organ injury and dysfunction remains a top priority in sepsis research. Organ insult in the setting of sepsis is initiated by activation of pattern recognition receptors (PRRs), including the Toll-like receptors (TLRs), by pathogen-associated molecular patterns (PAMPs) derived from the causative organism(s). Activation of TLRs expressed on immune cells (including dendritic cells, macrophages, neutrophils, and B lymphocytes), endothelial cells, and epithelial cells leads to an overwhelming systemic response characterized by production of acute phase cytokines (T F-a, IL-Ιβ, and IL-6), chemokines, and other proinflammatory mediators (12). Development of AKI involves combined local and peripheral effects of these factors, which ultimately contribute to microvascular dysfunction and direct tubular injury in the septic kidney (13). The mitogen-activated protein kinase (MAPK) family, including ERKl/2, TNKs, and p38 MAPKs are a major downstream target of TLRs and other PRRs responsible for induction of inflammatory signaling (14-16).

Hydrogen sulfide plays a role in many physiological and pathological processes, including an important role in the inflammatory response (A). The hyperactivity of cystathione gamma- lyase (CSE) in the liver overproduces endogenous hydrogen sulfide during polymicrobial sepsis (74). Hydrogen sulfide was found to contribute to the severity and inflammatory response in the CLP-induced mouse model of sepsis (B). The mechanism studies of hydrogen sulfide role in sepsis revealed an activation of ERK- FKB signaling pathway consistent with pathogen dissemination, but inhibition of hydrogen sulfide production did not completely block ERK activation, suggesting multiple mediators (74). Further, neurogenic inflammation in polymicrobial sepsis was also found to be regulated through the activation of the ERK- NFKB pathway by hydrogen sulfide (C).

ERKl/2 are serine/threonine kinases that regulate a variety of cellular processes including survival, differentiation, migration, proliferation, transcription, and metabolism via phosphorylation of a vast array of target proteins (17). Canonical ERKl/2 signaling is initiated by binding of growth factors (VEGF, IGF-1, EGF) to their respective receptor tyrosine kinases (RTKs) leading to downstream activation of the Ras/Raf/MEK/ERK pathway. However, more recent evidence indicates that other cellular signaling entities, including TLRs, also activate ERKl/2. TLR4 stimulation by lipopolysaccharide (LPS), a critical mediator of gram-negative sepsis, increases ERKl/2 activity in macrophages by engaging the tumor progression locus-2 (TPL-2)/mitogen activated protein kinase kinase- 1/2 (MEKl/2)/ERKl/2 cascade. ERKl/2 activation in this context plays a critical role in mediating the immune response to PAMPs by increasing transcription and translation of pro- inflammatory cytokines (TNF-a, IL-Ιβ) and chemokines (CXCL2) in multiple cell types (18- 22). Despite considerable evidence linking MEK/ERK signaling to innate immunity, studies investigating this pathway as a potential therapeutic target for prevention of unchecked inflammation and organ dysfunction in the setting of sepsis are lacking.

It was recently demonstrated that the FDA-approved MEK1/2 inhibitor trametinib (also known as GSK1120212 or JTP-74057) attenuates renal injury following systemic LPS exposure in mice (23). Pharmacological blockade of MEK/ERK signaling reversed endotoxin-induced increases in blood urea nitrogen (BUN) and mRNA expression of kidney injury molecule-1 (KIM-1), a marker of proximal tubule injury, at both 3 and 18 h time points. Restoration of renal function following trametinib administration was associated with decreased expression of TNF-a and IL-Ιβ transcripts in the renal cortex, further suggesting that MEK/ERK signaling may regulate organ-specific inflammatory responses in this model.

A subsequent study showed that trametinib significantly inhibits LPS-induced TNF-a production in mouse primary bone marrow-derived macrophages and human peripheral blood mononuclear cells (PBMCs) (24). In addition, MEK/ERK inhibition prevented mortality resulting from co-administration of LPS and the sensitizing agent D-galactosamine in mice in association with decreased levels of circulating TNF-a (24). Since trametinib has been safely used in the clinic, these findings suggest that targeted MEK/ERK inhibition may have translational potential as a novel therapy for sepsis-induced AKI and organ dysfunction in humans (25-27). It should be noted that clinical relevance of endotoxin models in rodents is limited due to a number of differences from human sepsis. Most importantly, systemic LPS exposure in mice leads to a massive, transient increase in serum pro-inflammatory cytokine levels (TNF-a, IL-Ιβ, IL-6) whereas elevations in these cytokines are more protracted and several orders of magnitude lower in septic humans (28). In addition, therapies that have shown promise in experimental endotoxin models including inhibitors of TNF-a and IL-1 have largely failed to improve mortality and other secondary outcome measures in clinical trials for sepsis likely due in part to the differences noted above.

A more recent study evaluated efficacy of the MEK/ERK inhibitor trametinib in a clinically relevant model of sepsis induced by cecal ligation and puncture (CLP) in mice. It was demonstrated that post-treatment with trametinib at 6 h following CLP attenuated the systemic inflammatory response and development of hypothermia. Trametinib administration also prevented development of AKI and multiple organ injury in CLP animals. In the kidney, MEK/ERK inhibition restored microvascular perfusion and reduced expression of tubular injury markers including kidney injury molecule-1 (KIM-1), neutrophil gelatinase- associated lipocalin (NGAL), and heme oxygenase-1 (HO-1) at the mRNA level (29-32). The renoprotective effects of trametinib were associated with decreased renal expression of pro-inflammatory cytokines including TNF-a and IL-Ιβ and a return of IL-6 to control levels. Taken together, our data provide evidence that the FDA-approved MEK/ERK inhibitor trametinib may be a viable drug to attenuate systemic inflammatory responses and organ injury in the setting of sepsis.

It is, thus, expected that ERK1/2 inhibition would be useful for the treatment of sepsis and ARDS. Consequently, there is a need for additional inhibitors of ERK1/2 for treating ERKl/2-associated diseases and disorders such as, for example, sepsis and ARDS.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, provided herein is a method of treating septicemia, comprising the step of administering a therapeutically effective amount of an ERK1/2 inhibitor, or a pharmaceutically acceptable salt or ester thereof, to a patient in need thereof.

In another embodiment, provided herein is a method of treating acute respiratory distress syndrome, comprising the step of administering a therapeutically effective amount of an ERK1/2 inhibitor, or a pharmaceutically acceptable salt or ester thereof, to a patient in need thereof.

BREIF DESCRIPTION OF DRAWINGS

Figure 1 shows LPS- induced activation of ERK and p90Rsk (a known Erk substrate) in Raw 264.7 cells.

Figure 2 shows quantitation of the results from Example 5. Each histogram represents the mean + SE of three independent experiments. Figure 3 shows the effect of the four AEZ ERK inhibitors as well as the VRT-252271 commercial ERK inhibitor on LPS-induced IL-6 production in Raw 264.7 cells.

DETAILED DESCRIPTION OF THE INVENTION

Based on emerging data, the inventors expect that inhibition of ERK1/2 would lead to a viable treatment of sepsis and ARDS. Sepsis is defined by the Surviving Sepsis Campaign Guidelines Committee in 2012 as the probable or documented presence of infection accompanied by systemic manifestations of infection (53). Severe sepsis is further defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion (53). Clinically, sepsis is associated with significant mortality and morbidity characterized by injury to multiple organ systems (4, 45, 51). Innate immune system activation in the setting of sepsis is largely mediated through activation of PRRs by microbial products collectively referred to as pathogen-associated molecular patterns (PAMPs). Stimulation of PRRs initiates signaling through a variety of downstream targets that act to promote the pro-inflammatory response including multiple MAPK signaling pathways involving MEK/ERK, J K, and p38 MAPKs (15, 16).

Although members of the JNK and p38 MAPK families have classically been implicated in the host response to infection, more recent evidence suggests that MEK/ERK signaling may control multiple aspects of the pro-inflammatory state associated with sepsis. Exposure of macrophages to lipopolysaccharide (LPS), a classical TLR4 agonist, has been shown to activate the MEK/ERK cascade in vitro (18, 24). MEK/ERK signaling is required for transcriptional up-regulation of TNF-a and IL-Ιβ in certain populations of LPS-treated macrophages (18, 24, 54). In addition, ERK activation in response to LPS in macrophages promotes nucleocytoplasmic transport and subsequent translation of TNF-a mRNA, indicating that the MEK/ERK signaling pathway may facilitate TNF-a biosynthesis by both transcriptional and post-transcriptional mechanisms (22). The molecular machinery necessary for stimulation of the MEK/ERK cascade in response to LPS includes TLR4 and its downstream effector TPL-2, a MAP kinase kinase kinase (MAP3K) that directly phosphorylates and activates MEK. Interestingly, TPL-2 is essential for endotoxin-induced TNF-a production in macrophages, and TPL-2-deficient mice are significantly protected against lethality following systemic administration of LPS and D-galactosamine (22). These data suggest that the MEK/ERK signaling pathway represents a novel and viable therapeutic target for the treatment of sepsis and sepsis-induced organ dysfunction. Unfortunately, studies that directly target MEK/ERK in animal models of sepsis are lacking.

The inventors recently used the potent and specific MEK1/2 inhibitor trametinib in a mouse model of endotoxin-induced AKI. Administration of trametinib (1 mg/kg, i.p.) inhibited LPS-induced phosphorylation of ERK1/2 in the renal cortex, indicating that in vivo administration of low dose trametinib is sufficient to block this signaling cascade in the LPS model (23). Trametinib pre-treatment at 1 h before systemic LPS exposure in mice attenuated early (< 3 h) development of renal dysfunction as measured by BUN. Preservation of renal function by MEK/ERK blockade was associated with reduced expression of KIM-1, a well-characterized marker of proximal tubule injury, and pro-inflammatory cytokines (TNF-a, IL-Ιβ) in the renal cortex of LPS-treated mice (23). A subsequent study demonstrated that MEK/ERK inhibition by trametinib also blocked TNF-a production in macrophage cell lines and isolated human PBMCs exposed to LPS in vitro (24). Trametinib treatment also prevented death of mice exposed to LPS and D-galactosamine in association with a reduction in circulating levels of TNF-a (24).

Trametinib is a highly potent allosteric inhibitor with IC ₅₀ values of 0.92 nM and 1.8 nM for MEKl and MEK2, respectively in an in vitro protein kinase assay (36). This compound also displays high specificity for MEK1/2, with no significant inhibitory activity seen on a panel of over 100 kinases including other members of the MAPK family (36). Trametinib has been safely and effectively used in humans and recently received FDA approval as a chemotherapeutic agent for use in BRAF-mutant melanoma (25-27). Thus, this drug has a number of favorable properties that make it an ideal candidate for clinical use in sepsis. However, the endotoxin models used to date to evaluate efficacy of trametinib suffer from a number of severe limitations. Both studies delivered this compound either before or concurrent with LPS administration, a scenario which would not be feasible in the clinical setting. In addition, neither study employed supportive measures commonly used in the intensive care unit such as fluid replacement, broad-spectrum antibiotics, and/or vasopressor agents (55). It should also be noted that the inflammatory response to LPS in mice is much more rapid and of a higher magnitude than that observed in septic humans (28). These fundamental differences likely explain why therapies developed using endotoxin models (such as anti-TNF-a agents) have largely failed to improve outcomes in septic patients (56). Thus, the inventors sought to determine the efficacy of trametinib in attenuating systemic inflammatory responses and organ injury in a more clinically relevant model of sepsis.

The inventors employed a well-established sepsis model induced by cecal ligation and puncture (CLP) in mice. CLP is widely considered the "gold standard" of sepsis models because it produces a much lower grade and sustained pro-inflammatory response when compared to LPS models (57). The model used here in 40-week-old mice also incorporates supportive measures including a broad-spectrum β-lactam antibiotic (imipenem/cilastatin) and fluids (0.9% saline, 40 ml/kg, s.c.) at 6 hours post-CLP to better mimic the basic clinical support of the elderly population, which is commonly affected by sepsis (2, 55). In addition, the inventors chose to delay trametinib administration until 6 h post-CLP, a time when organ injury and microvascular dysfunction is already established (33, 40, 45).

Delayed inhibition of MEK/ERK signaling attenuated CLP -induced increases in all proinflammatory cytokines measured including T F-a, IL-Ιβ, IL-6, and GM-CSF. Among these, the most significant inhibitory effect was observed on TNF-a. These findings are consistent with earlier studies demonstrating that MEK/ERK signaling is required for maximal induction of TNF-a synthesis in immune cells exposed to TLR agonists (15, 22, 24, 58, 59). Interestingly, serum levels of TNF-a, IL-Ιβ, and IL-6 may all serve as reliable predictors of mortality resulting from sepsis in the clinical setting, and IL-6 appears to be the single best predictor of poor outcomes in septic patients (60, 61). In addition, IL-6 has been validated as a marker of disease burden following CLP in mice (62). The observed decreases in circulating pro-inflammatory cytokines in CLP animals treated with trametinib likely indicate reduced disease severity. These findings suggest that MEK/ERK inhibition may prevent CLP-induced mortality, although the inventors did not assess this outcome. In support of this, trametinib also reversed development of hypothermia, a widely used indicator of physiologic dysfunction and impending death in septic mice (43, 44).

Based on the preceding, it is expected that an ERK1/2 inhibitor of the invention described below may reduce the systemic inflammatory response and partially attenuate AKI and other organ injury in a clinically relevant model of sepsis induced by CLP in mice. And given the favorable pharmacological properties of trametinib and its recent FDA approval, it is expected that ERK1/2 inhibition may represent a readily translatable approach to treat sepsis in subjects in need thereof. Definitions

The following definitions are used in connection with the ERK1/2 inhibitors:

The term "ERK1/2 inhibitor" includes any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs of the ERK1/2 inhibitors described herein.

The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

The term "and/or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

Unless otherwise specifically defined, the term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. The substituents can themselves be optionally substituted.

"C ₁ -C ₃ alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1-3 carbon atoms. Examples of a C ₁ -C ₃ alkyl group include, but are not limited to, methyl, ethyl, propyl and isopropyl.

"C ₁ -C ₄ alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1-4 carbon atoms. Examples of a C ₁ -C ₄ alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl.

"C ₁ -C5 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1-5 carbon atoms. Examples of a C ₁ -C5 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.

"Ci-C ₆ alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1-6 carbon atoms. Examples of a Ci-C ₆ alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl.

The terms "monocyclic or bicyclic aryl" or "monocyclic or bicyclic heteroaryl" as used herein include but are not limited to, indolyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, phthalazinyl, benzodioxyl, indolinyl, benzisobiazoline-l, l,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

The term "cycloalkyl" refers to a cyclic hydrocarbon containing 3-6 carbon atoms. Examples of a cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It is understood that any of the substitutable hydrogens on a cycloalkyl can be substituted with halogen, C1-C3 alkyl, hydroxyl, alkoxy and cyano groups.

The term "heterocycle" as used herein refers to a cyclic hydrocarbon containing 3-6 atoms wherein at least one of the atoms is an O, N, or S wherein a monocyclic heterocycle may contain up to two double bonds. Examples of heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane, and dioxane.

A "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus, and the terms "subject" and "patient" are used interchangeably herein.

The invention also includes pharmaceutical compositions comprising an effective amount of an ERK1/2 inhibitor and a pharmaceutically acceptable carrier. The invention includes an ERK1/2 inhibitor provided as a pharmaceutically acceptable prodrug, hydrate, salt, such as a pharmaceutically acceptable salt, enantiomers, stereoisomers, or mixtures thereof.

Representative "pharmaceutically acceptable salts" include, e.g., water-soluble and water- insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2- naphthoate, oleate, oxalate, palmitate, pamoate (l,l-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, subsalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

The term "carrier," as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.

The term "treating," with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder.

The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

The term "administer," "administering," or "administration" as used in this disclosure refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body. The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means {e.g., by hydrolysis) to an ERKl/2 inhibitor.

The term "optionally substituted," as used in this disclosure, means a suitable substituent can replace a hydrogen bound to a carbon, nitrogen, or oxygen. When a substituent is oxo {i.e., = O) then 2 hydrogens on the atom are replaced by a single O. Suitable substituents are selected from the following which include, but are not limited to, hydroxyl, halogen, perfluorinated Ci-C ₆ alkyl, amine, -C1-C12 alkyl, -C ₂ -C ₁₂ alkene, -C ₂ -C ₁₂ alkyne, -(C1-C3 alkyl)-(cycloalkyl), aryl, alkyl-aryl, -C(0)H, -C(0)OH, -C(0)alkyl, -C(0)-0-alkyl, -C(0) H(alkyl), benzyl, -C(0) H ₂ , -C(0)N(alkyl) ₂ , - HC(0)H, - HC(0)alkyl, - S0 ₂ (alkyl), -S0 ₂ H ₂ , -S0 ₂ H(alkyl), -S0 ₂ N(alkyl) ₂ , S, CN, and SCN. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable. Furthermore, combinations of substituents and/or variables within any of the Formulae represented herein are permissible only if such combinations result in stable compounds or useful synthetic intermediates wherein stable implies a reasonable pharmologically relevant half-life at physiological conditions.

Representative Compounds of the Invention

In one embodiment, an ERKl/2 inhibitor useful in the present invention is (S)-l-(l-(4-chloro- 3-fluorophenyl)-2-hydroxyethyl)-4-(2-((l -methyl- lH-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2(lH)-one (GDC-0994, purchased from Selleckchem Chemicals (Houston, TX)):

In another embodiment, an ERKl/2 inhibitor useful in the present invention is 4-(5-chloro-2- (isopropylamino)pyridin-4-yl)-N-((S)-l-(3-chlorophenyl)-2-hy droxyethyl)-lH-pyrrole-2- carboxamide (Ulixertinib (BVD-523, VRT752271), purchased from Selleckchem Chemicals (Houston, TX)):

In another embodiment, an ERKl/2 inhibitor useful in the present invention is 1-((R)-1- Methyl-4-phenyl-butyl)-3-[3-(l-propyl-lH-pyrazol-4-yl)-pyrid o[2,3-b]pyrazin-6-yl]-urea

In another embodiment, an ERKl/2 inhibitor useful in the present invention is

l-{3-[4-(2-Mo holin-4-yl-ethoxy)-phenyl]-pyrido[2,3-b]pyrazin-6-yl}-3-(4-p henyl-butyl)- urea

In another embodiment, an ERKl/2 inhibitor useful in the present invention is 1-((R)-1- Methyl-4-phenyl-butyl)-3-[3-(l-methyl-lH-pyrazol-4-yl)-pyrid o[2,3-b]pyrazin-6-yl]-urea

In another embodiment, an ERK1/2 inhibitor useful in the present invention is 1-((R)-1- Methyl-4-phenyl-butyl)-3-{3-[l-(2-morpholin-4-yl-ethyl)-lH-p yrazol-4-yl]-pyrido[2,3- b]pyrazin-6-yl}-urea

Other examples of useful ERK1/2 inhibitors of the present invention, and the methods of making them, are set forth in US Patent Nos. 7,276,507 and 8,791, 118, both of which are expressly incorporated herein by reference.

Accordingly in one aspect, the present invention provides ERK1/2 inhibitors according to Formula I of US Patent No. 7,276,507: wherein:

Rl and R2 are independently of one another:

(i) hydrogen,

(ii) hydroxyl,

(iii) halogen,

(iv) allyl, where the alkyl radical is saturated and may consist of 1 to 8 C atoms,

(v) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkylcycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, H-alkyl- H ₂ , H-alkyl-OH, N(alkyl) ₂ , HC(0)-alkyl, HC(0)-cycloalkyl, HC(0)-heterocyclyl, HC(0)-aryl, NHC(0)-heteroaiyl, HC(0)-alkyl-aiyl, NHC(O)- alkyl-heteroaryl, HS0 ₂ -alkyl, HS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, HS0 ₂ -aryl,

HS0 ₂ -heteroaryl, HS0 ₂ -alkyl-aiyl, HS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S- heteroaryl,OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl- cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, O—

(CH ₂ ) _n — O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(O)- heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ - alkylheteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ - alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkylheteroaiyl, C(O)— H ₂ , C(0) H-alkyl, C(0) H-cycloalkyl, C(0)NHheterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0)NH- alkyl-cycloalkyl, C(0) H-alkyl-heterocyclyl, C(0) H-alkyl-aryl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ H ₂ , SOZNH-alkyl, S0 ₂ NHaryl, S0 ₂ NH-heteroaryl, S0 ₂ NH-alkyl- aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, n is 1, 2 or 3, and the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl and alkyl-heteroaryl substituents may in turn themselves be substituted,

(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NHalkyl, NH-cycloalkyl, NH- heterocyclyl, NH-aryl, NH-heteroaryl, NHalkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkylheteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(O)- alkyl-aryl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ - heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-aiyl, O- heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(O)— H ₂ , C(0) Halkyl, C(0)NH-cycloalkyl, C(0) H-heterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0) H-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ 0- aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ Hheteroaiyl, S0 ₂ H-alkyl-aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ -aryl, S0 ₂ 0-alkylaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaiyl substituents, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaiyl substituents may in turn themselves be substituted,

(vii) OR5, where R5 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl substituents can, for their part, in turn be substituted,

(viii) SR6, where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl substituents can, for their part, in turn be substituted,

(ix) R7R8, where R7 and R8 are, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaiyl, alkylcyclyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl substituents can, for their part, in turn be substituted,

or R7 and R8 are together cycloalkyl or heterocyclyl, where the cycloalkyl and

heterocyclyl can, for their part, in turn be substituted;

R3 and R4 are, independently of each other, hydrogen or R9R10 with the proviso that, when R3= R9R10, R4=H and when R4= R9R10, R3=H, and R3 and R4 are not both H or R9R10 at the same time, where R9 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl substituents can, for their part, in turn be substituted, and RIO is: A, B, or C, where

(A) is:— C(Y)NR11R12, where Y is O, or S and Rl 1 and R12 are independently of one another

(i) hydrogen, (ii) unsubstituted or substituted alkyl, where the alkyl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkylcycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(O)- aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aiyl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaryl, NHS0 ₂ -alkyl- aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, Sheteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O- alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ - aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl- heteroaryl, C(O)— NH2, C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaiyl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ ,

C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S02NH-aryl, S0 ₂ NHheteroaiyl, S0 ₂ NH-alkyl-aryl, S0 ₃ H, S0 ₂ -alkyl, S0 ₂ 0- aryl, S0 ₂ 0-alkylaryl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(iii) unsubstituted or substituted cycloalkyl, where the cycloalkyl radical may have one or more identical or different F, CI, Br, I, NH ₂ , NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH- aryl, NH-heteroaryl, NH-alkyl-aryl, NHalkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aiyl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, NHS0 ₂ - aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl,— NHS0 ₂ -alkyl-heteroaiyl, OH, O-alkyl, O- cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(O)- alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl- aryl, OC(0)-alkyl-heteroaryl, OS03H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C02-aryl, C0 ₂ -heteroaryl, C0 ₂ - alkylcycloalkyl, C0 ₂ -alkylhetero-cyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NHaryl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaiyl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aryl, C(0)NH-alkyl- heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , alkyl or aryl substituents,

(iv) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may have one or more identical or different OH, O-alkyl, O-aiyl, H ₂ , Halkyl, H-aryl, alkyl, alkyl-aryl or aryl substituents,

(v) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F; CI, Br, I, CF ₃ , CN, H ₂ , H-alkyl, H-cycloalkyl, H-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkylcycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aiyl, NHC(O)- alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS02-heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaryl, NHS0 ₂ -alkyl-aiyl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S- cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O- heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-hetero-cyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, O— (CH ₂ ) _n — O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(O)- heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , OS0 ₂ -heterocyclyl, OS02-alkyl-aryl, OS02-alkyl-heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C02H, C0 ₂ - alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NHalkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH- alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aryl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH-heteroaryl, S0 ₂ NH-alkyl- aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkylaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and n is 1, 2 or 3,

(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH- heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkylheteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(O)- alkyl-aryl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ - heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-aiyl, O- heteroaryl, O-alkylcycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(O)- alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl- aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS02-heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C(O)- alkyl, C(0)-aryl, C(0)-heteroaryl, C02H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaiyl, C(O)— H ₂ , C(0) Halkyl, C(0) H-cycloalkyl, C(0)NH- heterocyclyl, C(0) H-aryl, C(0) H-heteroaiyl, C(0) H-alkyl-cycloalkyl, C(0)NH-alkyl- heterocyclyl, C(0) H-alkyl-aiyl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ ,

C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaiyl, S0 ₂ H-alkyl-aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(vii)— C(0)-R17, where R17 is alkyl, aryl, alkenyl, alkynyl or heteroaryl, and the alkyl, alkenyl, alkynyl and aryl substituents may in turn themselves be substituted,

(viii) or Rl 1 and R12 together are cycloalkyl or heterocyclyl

(ix) alkenyl or alkynyl radical, where the alkenyl or the alkynyl radical has 2 to 8 C atoms; (B) is— C(Y) R13R14, where Y is H and R13 and R14 are independently of one another

(i) hydrogen,

(ii) unsubstituted or substituted alkyl, where the alkyl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NHalkyl-heteroaryl, N(alkyl)2, NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, NHS02-aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ - heterocyclyl, C02-aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ - alkyl-aryl, C0 ₂ -alkylheteroaryl, C(O)— NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl,

C(0)NHheterocyclyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH-alkyl-cycloalkyl,

C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ ,SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ - aryl, S0 ₂ NH ₂ , SO3H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, (iii) unsubstituted or substituted cycloalkyl, where the cycloalkyl radical may have one or more identical or different F, CI, Br, I, H2, H-alkyl, Hcycloalkyl, H-heterocyclyl, NH- aryl, H-heteroaryl, H-alkyl-aryl, Halkyl-heteroaryl, N(alkyl) ₂ , HC(0)-alkyl, NHC(O)- cycloalkyl, HC(0)-heterocyclyl, HC(0)-aryl, HC(0)-heteroaryl, HS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, HS0 ₂ -aryl, HS0 ₂ -heteroaiyl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O- aryl, O-heteroaiyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(O)- heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ - heteroaryl, C(0)- H ₂ , C(0) H-alkyl, C(0) H-cycloalkyl, C(0) H-heterocyclyl, C(0)NH- aryl, C(O) NH-heteroaryl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , alkyl or aryl substituents,

(iv) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may have one or more identical or different OH, O-alkyl, O-aiyl, NH ₂ , NH-alkyl, NH-aryl, alkyl or aryl substituents,

(v) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHS0 ₂ -alkyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O- alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, 0-(CH ₂ ) _n O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS02-aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ - alkylcycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH- heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0)NHalkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ ,

C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NHaryl, S0 ₂ NH-heteroaryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and n is 1, 2 or 3,

(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NHalkyl, NH-cycloalkyl, NH- heterocyclyl, NH-aryl, NH-heteroaryl, NHalkyl-aryl, NH-alkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl; NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(O)- heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, N02, SH, S-alkyl, S-aryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, OC(0)-alkyl, OC(O)- cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C02H, C02-alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl- cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH- heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-hetero-cyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ ,

C(0)N(heteroaryl) ₂ , S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH- heteroaryl, SO ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(vii) or R13 and R14 together are cycloalkyl or heterocyclyl

(viii) alkenyl or alkynyl radical, where the alkenyl or the alkynyl radical has 2 to 8 C atoms; (C) is— C(NR15)R16 where R15 is H and R16 is

(i) unsubstituted or substituted alkyl, where the alkyl radical may have one or more identical or different F, CI, Br, I, CF ₃ , NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH- heteroaryl, NH-alkyl-aryl, NH-alkylheteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C0 ₂ H,C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ - heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ - alkyl-aryl, C0 ₂ -alkylheteroaryl,C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl,

C(0)NHheterocyelyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH-alkyl-cycloallcyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ - aryl, S0 ₂ NH ₂ , S0 ₃ H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(ii) unsubstituted or substituted cycloalkyl, where the cycloalkyl radical may have one or more identical or different F, CI, Br, I, NH ₂ , NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH- aryl, NH-heteroaryl, NH-alkyl-aryl, NHalkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O- aryl, O-heteroaiyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(O)- heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ - heteroaryl, C(0)-NH2, C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH- aryl, C(0)NH-heteroaryl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl)2, alkyl or aryl substituents,

(iii) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may have one or more identical or different OH, O-alkyl, O-aiyl, NH ₂ , NH-alkyl, NH-aryl, alkyl or aryl substituents,

(iv) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH- heteroaryl, NH-alkyl-cycloalkyl, NH-alkylheterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH2, NHalkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(O)- heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -aryl, NHS0 ₂ - heteroaryl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, Daryl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl- heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, O— (CH ₂ ) _n — O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl OS0 ₂ - cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl- cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(O)— NH ₂ , C(0)NHalkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH- heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ ,

C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NHheteroaryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0 -heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and is 1, 2 or 3,

(v) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH- aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O- heterocyclyl, O-aiyl, O-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ - heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ - alkyl-aryl, C0 ₂ -alkyl-heteroaiyl, C(O)— H ₂ , C(0) Halkyl, C(0) H-cycloalkyl, C(0)NH- heterocyclyl, C(0) H-aryl, C(0) H-heteroaiyl, C(0) H-alkyl-cycloalkyl, C(0)NH-alkyl- heterocyclyl, C(0) H-alkyl-aiyl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ ,

C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0- heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents

(vi) alkenyl or alkynyl radical, where the alkenyl or the alkynyl radical has 2 to 8 C atoms; and physiologically tolerable salts, hydrates thereof, and where the compound of the general Formula I and the physiologically tolerable salts and hydrates thereof are present in the form of their racemates, in the form of their pure enantiomers and/or diastereomers or in the form of their tautomers or in the form of mixtures of these enantiomers and/or diastereomers.

The following non-limiting compound examples serve to illustrate further embodiments of the ERK1/2 inhibitors of formula I of US Patent No. 7,276,507: l-allyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;

l-allyl-3-(3 -naphthalen-2-ylpyrido[2,3-b]pyrazin-6-yl)thiourea;

l-allyl-3-[3-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl]t hiourea;

l-allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]t hiourea hydrochloride;

l-(2-methylallyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)th iourea;

l-(2-methylallyl)-3-(3-naphthalen-2-ylpyrido[2,3-b]pyrazi n-6-yl)thiourea;

l-[3-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl)-3-(2-met hylallyl)thiourea;

l-(3-naphthalen-2-ylpyrido [2,3-b]pymzin-6-yl)-3-(4-nitrophenyl)thiourea;

l-[3-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(4-nit rophenyl)thiourea;

l-tert-butyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thioure a;

l-cyclopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiour ea;

l-methyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;

l-benzyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;

l-(4-fluorophenyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)t hiourea; l-cyclohexyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;

l-isopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea ;

l-furan-2-ylmethyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)t hiourea;

l-methyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-6-yl]th iourea;

l-[3-(4-hydroxyphenyl)pyrido[2,3-]pyrazin-6-yl]-3-methylt hiourea;

l-allyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-6-yl]thi ourea;

ethyl 4-[6-(3-allylthiourea)pyrido[2,3-b]pyrazin-3-yl]benzoate;

l-allyl-3-[3-(3-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]t hiourea;

l-allyl-3-(3-benzo[l,3]dioxol-5-ylpyrido[2,3-b]pyrazin-6- yl)thiourea;

l-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-prop-2 -ynylthiourea;

l-allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]t hiourea;

l-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(prope nyl)thiourea;

l-ally3-[2,3-bis(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-y l]thiourea;

l-[2,3-bis(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-( propenyl)thiourea;

l-allyl-3-[2-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]t hiourea;

l-allyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-7-yl]thi ourea;

l-cyclopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea;

l-allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]u rea;

l-(3-phenylpyrido[2,3-b]pyrazin-6-yl)-3-p-tolylurea;

l-(4-chloro-3-trifluoromethylphenyl)-3-(3-phenylpyrido[2, 3-b]pyrazin-6-yl-)urea; l-(2-morpholin-4-ylethyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6- yl)urea;

l-phenethyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea;

l-(2,3-dipyridin-2-ylpyrido[2,3-b)pyrazin-6-yl)-3-ethylur ea; and

l-(2,3-dimethylpyrido[2,3-b]pyrazin-6-yl)-3-ethylurea.

In another embodiment, the present invention provides ERKl/2 inhibitors according to Formula I of US Patent No. 8,791 , 118 : wherein:

X is O;

Rl :

(I) substituted aryl, wherein the aryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, H ₂ , H-alkyl, H-cycloalkyl, H-heterocyclyl, H-aryl, H-heteroaryl, H-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, H-alkyl-aryl, H-alkyl- heteroaryl, H-alkyl- H ₂ , H-alkyl-OH, N(alkyl) ₂ , HC(0)-alkyl, HC(0)-cycloalkyl, HC(0)-heterocyclyl, HC(0)-aryl, NHC(0)-heteroaiyl, HC(0)-alkyl-aryl, NHC(O)- alkyl-heteroaryl, HS0 ₂ -alkyl, HS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, HS0 ₂ -aryl,

HS0 ₂ -heteroaryl, HS0 ₂ -alkyl-aiyl, HS0 ₂ -alkyl-heteroaryl, N0 ₂ , SH, S-alkyl, S-aryl, S- heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl- cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, 0-(CH ₂ ) _n -0, 0-(-CH ₂ -CH ₂ -0-)n-CH ₂ -CH ₂ -OH, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OC(0)- H- Alkyl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ - heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, 0-C0 ₂ -alkyl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ - aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ - alkyl-heteroaryl, C(0)- H ₂ , C(0) H-alkyl, C(0) H-cycloalkyl, C(0) H-heterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0) H-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0) H-alkyl-aryl, C(0) H-alkyl-heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ ,

C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -heterocyclyl; S0 ₂ -aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaryl, S0 ₂ H-alkyl-aryl, S0 ₃ H, S0 ₂ 0- alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, n can have the value 0, 1, 2 or 3 and the alkyl-, cycloalkyl-, heterocyclyl-, aryl-, heteroaryl-, alkyl - cycloalkyl-, alkyl-heterocyclyl-, alkyl-aryl- and alkyl-heteroaryl substituents for their part can in turn be substituted,

(II) unsubstituted or substituted heteroaryl, wherein the heteroaryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, H ₂ , H-alkyl, H-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkyl -heteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(O)- alkyl-aryl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ - heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-aiyl, O- heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl,

OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH-heteroaiyl, S0 ₂ NH-alkyl-aryl, S03H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, alkyl- heteroaryl, aryl or heteroaryl, and the alkyl-, cycloalkyl-, heterocyclyl-, alkyl-heterocyclyl, alkyl-aryl, alkyl-cycloalkyl, alkyl-heteroaryl, aryl- and heteroaryl substituents for their part can in turn be substituted, and R2:

(I) unsubstituted or substituted alkyl-aryl wherein the alkyl-aryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH- heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkyl -heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(O)- heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aryl, NHC(0)-alkyl- heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalky), NHS0 ₂ -heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ - heteroaryl, HS0 ₂ -alkyl-aryl, HS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S- heterocyclyl, S-aryl, S-heteroaryl, =0, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O- aryl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl- heteroaryl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(O)- heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl- heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ - cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl- heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0) H-alkyl, C(0)NH- cycloalkyl, C(0) H-heterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0)NH-alkyl- cycloalkyl, C(0) H-alkyl-heterocyclyl, C(0) H-alkyl-aryl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaryl, S0 ₂ NH-alkyl- aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,

(II) unsubstituted or substituted alkyl-heteroaryl wherein the alkyl-heteroaryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl- heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aiyl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, NHS0 ₂ - aryl, NHS0 ₂ -heteroaryl, NHS0 ₂ -alkyl-aiyl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S- cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O- heterocyclyl, 0-aryl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O- alkyl-heteroaryl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(O)- heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl- heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ - cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl- heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH- cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH-alkyl- cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aryl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaryl, S0 ₂ NH-alkyl- aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

its physiologically tolerated salts, in the form of its racemates, in the form of its pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers or in the form of its tautomers.

The following non-limiting compound examples serve to illustrate further embodiments of the ERK1/2 inhibitors of formula I of US Patent No. 8,791,118:

l-[3-(4-{2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethoxy]-phenyl)- pyrido[2,3-b]pyrazin-6-yl]-3-(4 phenyl-butyl)-urea -[3-(3,5-Dimethyl-lH-pyrazol-4-yl)-pyrido[2,3-b]pyrazin-6-yl ]-3-(4-phenyl-butyl)-urea

-(4-Phenyl-butyl)-3-[3-(2,3,4-trimethoxy-phenyl)-pyrido[2,3- b]pyrazin-6-yl]-urea

- 3-(4-Methyl-piperazin-l-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4- phenyl-butyl)-urea

-[3-(3H-Benzoimidazol-5-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4- phenyl-butyl)-

l-[3-(3-Amino-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-phe nyl-butyl)-urea

-(4-Phenyl-butyl)-3-(3-piperazin-l-yl-pyrido[2,3-b]pyrazin-6 -yl)-urea; hydrochloride

,CI

H'

l-[3-(l-Methyl-lH-pyrazol-4-yl)-pyrido[2,3-b]pyrazin-6-yl ]-3-(4-p-tolyl-butyl)-urea

l-[3-(3,4-Dimethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3- ((R)-l-methyl-4-phenyl-butyl)

l-[4-(4-Fluoro-phenyl)-butyl]-3-[3-(l-methyl-lH-pyrazol-4 -yl)-pyrido[2,3-b]pyrazin

l-(4-Methyl-4-phenyl-pentyl)-3-[3-(l-propyl-lH-pyrazol-4- yl)-pyrido[2,3-b]pyrazin-6-yl]- urea

-[3-(2,4-Dimethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-p henyl-butyl)-urea

-[3-(2-Ethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-phenyl -butyl)-urea

-[3-(3,5-Dichloro-4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-y l]-3-(4-phenyl-butyl)-urea

-[3-(3-Hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-pheny l-butyl)-urea

l-(4-Phenyl-butyl)-3-[3-(2H-pyrazol-3-yl)-pyrido[2,3-b]py razin-6-yl]-urea

-[3-(4-Hydroxy-2-methyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3 -(4-phenyl-butyl)-urea

Acetic acid 4-{6-[3-(4-phenyl-butyl)-ureido]-pyrido[2,3-b]pyrazin-3-yl}- phenyl ester

-[3-(l-Ethyl-lH-pyrazol-4-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-( 4-phenylbutyl)-urea

l-[3-(3-Bromo-4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl ]-3-(4-phenyl-butyl)-urea

-(4-Phenyl-butyl)-3-(3-pyridin-3-yl-pyrido[2,3-b]pyrazin-6-y l)-urea

l-[3-(l-Methyl-lH-pyrazol-4-yl)-pyrido[2,3-b]pyrazin-6-yl ]-3-(l,2,3,4-tetrahydro-

l-[3-(2,3-Dimethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3- ((R)-l-methyl-4-phenyl-butyl)- urea

l-[3-(5-Methyl-l-phenyl-lH-pyrazol-4-yl)-pyrido[2,3-b]pyr azin-6-yl]-3-(4-phenyl-butyl)

l-[3-(l-Butyl-lH-pyrazol-4-yl)-pyrido[2,3-b]pyrazin-6-yl] -3-(4-phenyl-butyl)-urea

l-[4-(4-Methoxy-phenyl)-butyl]-3-[3-(l-methyl-lH-pyrazol-4-y l)-pyrido[2,3-b]pyrazin-6- yl]-urea

-(4-Phenyl-butyl)-3-[3-(piperidin-4-ylamino)-pyrido[2,3-b]py razin-6-yl]-urea

- 4-Phenyl-butyl)-3-{3-[(pyridin-4-ylmethyl)-amino]-pyrido[2,3 -b]pyrazin-6-yl}-urea

-[3-(4-Methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-pheny l-butyl)-urea

- 4-Phenyl-butyl)- -(3-propylamino-pyrido[2,3-b]pyrazin-6-yl)-urea

-(4-Phenyl-butyl)-3-(3-o-tolyl-pyrido[2,3-b]pyrazin-6-yl)-ur ea

3-{6-[3-(4-Phenyl-butyl)-ureido]-pyrido[2,3-b]pyrazin-3-yl}- benzoic acid ethyl ester

Ethyl-carbamic acid 4-{6-[3-(4-phenyl-butyl)-ureido]-pyrido[2,3-b]pyrazin-3-yl}- phenyl ester

-[3-(4-Amino-3-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3- (4-phenyl-butyl)-urea

-[3-(2-Methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-pheny l-butyl)-urea

l-((R)-l-Methyl-4-phenyl-butyl)-3-[3-(2,3,4-trimethoxy-ph enyl)-pyrido[2,3-b]pyrazin-6-yl]- urea

l-(l-Methyl-4-phenyl-butyl)-3-[3-(l-propyl-lH-pyrazol-4-y l)-pyrido[2,3-b]pyrazin-6-yl]- urea

l-{3-[l-(2-Mo holin-4-yl-ethyl)-lH-pyrazol-4-yl]-pyrido[2,3-b]pyrazin-6-yl }-3-(4-phenyl- butyl)-urea

-[3-(2-Ethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-((R)-l-me thyl-4-phenyl-butyl)-urea

l-[3-(3-Chloro-4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-y l]-3-((R)-l-methyl-4-phenyl- butyl)-urea

-[3-(2-Amino-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-phenyl- butyl)-urea

l-(4-Oxo-4-phenyl-butyl)-3-[3-(l-propyl-lH-pyrazol-4-yl)- pyrido[2,3-b]pyrazin-6-yl]-urea

Carbonic acid ethyl ester 4-{6-[3-(4-phenyl-butyl)-ureido]-pyrido[2,3-b]pyrazin-3-yl}- phenyl ester l-[3-(2-Hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-phen yl-butyl)-urea

2,2-Dimethyl-propionic acid 4-{6-[3-(4-phenyl-butyl)-ureido]-pyrido[2,3-b]pyrazin-3-yl}- phenyl ester

-[3-(4-Methylsulfanyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-( 4-phenyl-butyl)-urea

-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-phenyl-butyl)-urea

l-{3-[(S)-l-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-pyrido[2 ,3-b]pyrazin-6-yl}-3-(4- phenyl-butyl)-urea

l-[3-(3-Hydroxy-4,5-dimethoxy-phenylamino)-pyrido[2,3-b]p yrazin-6-yl]-3-(4-phenyl- butyl)-urea

l-{3-[l-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-pyrido[2, 3-b]pyrazin-6-yl}-3-(4-phenyl- butyl)-urea

-[3-(4-Fluoro-2-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3 -(4-phenyl-butyl)-urea

l-{3-[4-Methoxy-3-(morpholine-4-sulfonyl)-phenyl]-pyrido[ 2,3-b]pyrazin-6-yl}-3-(4- phenyl-butyl)-urea

l-[3-(2-Methoxy-pyridin-3-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-( 4-phenyl-butyl)-urea

l-[3-(4-Hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-((R) -l-methyl-4-phenyl-butyl)-urea

l-[3-(3-Hydroxy-4-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6- yl]-3-((R)-l-methyl-4-phenyl- butyl)-urea

1 -(3 -Furan-3 -yl-pyrido[2,3-b]pyrazin-6-yl)-3-((R)-l-methyl-4-phenyl-buty l)-urea

l-((R)-l-Methyl-4-phenyl-butyl)-3-(3-pyridin-3-yl-pyrido[ 2,3-b]pyrazin-6-yl)-urea

-[3-(3-Hydroxy-4-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]- 3-(4-phenyl-butyl)-urea

1 -(3 -Furan-3 -yl-pyrido[2,3 -b]pyrazin-6-yl)-3 -(4-phenyl-butyl)-urea

l-((R)-l-Methyl-4-phenyl-butyl)-3-[3-(4-methyl-piperazin- l-yl)-pyrido[2,3-b]pyrazin-6-yl]- urea

-((R)- 1 -Methyl-4-phenyl-butyl)-3 -(3 -piperidin- 1 -yl-pyrido[2,3-b]pyrazin-6-yl)-urea

l-[3-(l-Methyl-l H-pyrazol-4-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-phenyl-butyl )-urea

l-[3-(4-Hydroxymethyl-2-methoxy-phenyl)-pyrido[2,3-b]pyra zin-6-yl]-3-((R)-l-methyl-4- phenyl-butyl)-urea

l- R)-l-Methyl-4-phenyl-butyl)-3- -pyridin-4-yl-pyrido[2,3-b]pyrazin-6-yl)-urea

l-[3-(3-Hydroxymethyl-2-methoxy-phenyl)-pyrido[2,3-b]pyrazin -6-yl]-3-((R)-l-methyl-4- phenyl-butyl)-urea

l-(4-Phenyl-butyl)-3-[3-(lH-pyrazol-4-yl)-pyrido[2,3-b]py razin-6-yl]-urea

l-[3-(4-Hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-p henyl-butyl)-urea

l-[3-(2-Methoxy-pyridin-3-yl)-pyrido[2,3-b]pyrazin-6-yl]- 3-((R)-l-methyl-4-phenyl-butyl)- urea

l-{3-[l-(3-Hydroxy-propyl)-lH-pyrazol-4-yl]-pyrido[2,3-b] pyrazin-6-yl}-3-(4-phenyl- butyl)-urea

l-{3 1-(2,2-Difluoro-ethyl)-lH-pyrrol-3-yl]-pyrido[2,3-b]pyrazin- 6-yl}-3-(4-phenyl-butyl)- urea

l-(l-Methyl-4-phenyl-butyl)-3-[3-(l-methyl-lH-pyrazol-4-y l)-pyrido[2,3-b]pyrazin-6-yl]- urea

Phosphoric acid mono-(4-{6-[3-(4-phenyl-butyl)-ureido]-pyrido[2,3-b]pyrazin- 3-yl}-phenyl) ester

l-((R)-l-Methyl-4-phenyl-butyl)-3-(3-mo holin-4-yl-pyrido[2,3-b]pyrazin-6-yl)-urea

l-[3-(4-Hydroxymethyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]- 3-((R)-l-methyl-4-phenyl-butyl)- urea

l-((R).l-Methyl-4-phenyl-butyl)-3-{3-[l-(2-morpholin-4-yl -ethyl)-lH-pyrazol-4-yl]- pyrido[2,3-b]pyrazin-6-yl}-urea

l-(4-Methyl-4-phenyl-pentyl)-3-[3-(l-methyl-lH-pyrazol-4-yl) -pyrido[2,3-b]pyrazin-6-yl]- urea

l-((R)-l-Methyl-4-phenyl-butyl)-3-[3-(l-propyl-lH-pyrazol -4-yl)-pyrido[2,3-b]pyrazin-6- yl]-urea

-((R)-l-Methyl-4-phenyl-butyl)-3-[3-(lH-pyrazol-4-yl)-pyrido [2,3-b]pyrazin-6-yl]-urea

-(4-Phenyl-butyl)-3-(3-pyrrolidin-l-yl-pyrido[2,3-b]pyrazin- 6-yl)-urea

l-((R)-l-Methyl-4-phenyl-butyl)-3-(3-pyrrolidin-l-yl-pyri do[2,3-b]pyrazin-6-yl)-urea

-[3-(3-Fluoro-4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3 -(4-phenyl-butyl)-urea

l-[3-(3-Hydroxymethyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]- 3-(4-phenyl-butyl)-urea

l-(3-Morpholin-4-yl-pyrido[2,3-b]pyrazin-6-yl)-3-(4-pheny l-butyl)-urea

l-[3-(3,5-Dimethyl-lH-pyrazol-4-yl)-pyrido[2,3-b]pyrazin- 6-yl]-3-((R)-l-methyl-4-phenyl- butyl)-urea

l-[3- 3,4-Dimethoxy-phenyl)-pyrido[2, -b]pyrazin-6-yl]-3-(4-phenyl-butyl)-urea

l-[3-(2-Methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-((R) -l-methyl-4-phenyl-butyl)-urea

l-((R)-l-Methyl-4-phenyl-butyl)-3-[3-(l-methyl-lH-pyrazol -4-yl)-pyrido[2,3-b]pyrazin-6- -urea

l-[3-(3-Hydroxymethyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-( (R)-l-methyl-4-phenyl-butyl)

-[3-(4-Hydroxymethyl-pheny -pyrido[2,3-b]pyrazin-6-yl]-3-(4-phenyl-butyl)-urea

l-[3-(2,4-Dimethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3- ((R)-l-methyl-4-phenyl-butyl)

-(4-Phenyl-butyl)-3-(3-pyridin-4-yl-pyrido[2,3-b]pyrazin-6-y l)-urea

l-[3-(3-Fluoro-4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-y l]-3-((R)-l-methyl-4-phenyl- butyl)-urea

l-[3-(3-Chloro-4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-y l]-3-(4-phenyl-butyl)-urea

l-[3-(4-{2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethoxy}-phenyl)-pyr ido[2,3-b]pyrazin-6-yl]-3- - 1 -methyl-4-phenyl-butyl)-urea

l-{3-[l-(2-Hydroxy-ethyl)-lH-pyrazol-4-yl]-pyrido[2,3-b]pyra zin-6-yl]-3-(4-phenyl-butyl)- urea

(S)-2-Amino-3-(4-{6-[3-((R)-l-methyl-4-phenyl-butyl)-ureido] -pyrido[2,3-b]pyrazin-3-yl}- phenyl)-propionic acid; hydrochloride

-{6-[3-((R)-l-Methyl-4-phenyl-butyl)-ureido]-pyrido[2,3-b]py razin-3-yl}-benzoic acid

-{6-[3-(4-Phenyl-butyl)-ureido]-pyrido[2,3-b]pyrazin-3-yl}-b enzoic acid

l-{3-[4-(2-Methoxy-ethoxy)-phenyl]-pyrido[2,3-b]pyrazin-6 -yl]-3-(4-phenyl-butyl)-urea

rac l-{3-[4-(2-Hydroxy-propoxy)-phenyl]-pyrido[2,3-b]pyrazin-6-y l}-3-(4-phenyl-butyl)- urea

l-(3-{4-[2-(2-Hydroxy-ethoxy)-ethoxy]-phenyl}-pyrido[2,3- b]pyrazin-6-yl)-3-(4-phenyl- butyl)-urea

l-{3-[4-(2-Mo holin-4-yl-ethoxy)-phenyl]-pyrido[2,3-b]pyrazin-6-yl]-3-(4-p henyl-butyl)- urea ^'

l-[3-(3-Methoxymethyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-( (R)-l-methyl-4-phenyl- butyl)-urea

l-{3-[3-(2-Methoxy-ethoxymethyl)-phenyl]-pyrido[2,3-b]pyr azin-6-yl}-3-((R)-l-methyl-4- phenyl -butyl)-urea

l-{3-[3-(2-Dimethylamino-ethoxymethyl)-phenyl]-pyrido[2,3 -b]pyrazin-6-yl}-3-((R)-l-

Methanesulfonic acid 3-{6-[3-((R)-l-methyl-4-phenyl-butyl)-ureido]-pyrido[2,3-b]p yrazin- 3yl } -benzyl ester

l-((R)-l-Methyl-4-phenyl-butyl)-3-13-[3-(2-mo holin-4yl-ethoxymethyl)phenyl]py b]pyrazin-6-yl }-urea

Ethyl-carbamic acid 3-{6-[3-((R)-l-methyl-4-phenyl-butyl)-ureido]-pyrido[2,3-b]p yrazin-3- -benzyl ester

Methods for using ERKl/2 inhibitors

In another aspect, methods of treating a disease associated with high ERKl/2 expression is provided, which comprises administering to a subject in need thereof, a therapeutically- effective amount of an ERKl/2 inhibitor. In one embodiment, the disease associated with high ERKl/2 expression is sepsis.

The invention also includes pharmaceutical compositions useful for treating or preventing an ERKl/2 associated disease, or for inhibiting an ERKl/2 associated disease, or more than one of these activities. The compositions can be suitable for internal use and comprise an effective amount of an ERKl/2 inhibitor and a pharmaceutically acceptable carrier.

The ERKl/2 inhibitors can each be administered in amounts that are sufficient to treat or prevent sepsis. Administration of the ERKl/2 inhibitors can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral (intravenous), intramuscular, intrathecal, intra- vitreal, transdermal, subcutaneous, vaginal, buccal, rectal, topical administration modes or as a drug-eluting stent.

Depending on the intended mode of administration, the compositions can be in solid, semisolid or liquid dosage form, such as, by way of non-limiting examples, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (non- limiting examples include bolus and infusion), intraperitoneal, intrathecal, intra-vitreal injection, subcutaneous or intramuscular form, all using forms well known to those skilled in the pharmaceutical arts.

Non-limiting illustrative pharmaceutical compositions are tablets and gelatin capsules comprising an ERK1/2 inhibitor and a pharmaceutically acceptable carrier, such as: a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the ERK1/2 inhibitor is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the ERKl/2 inhibitors. The ERK1/2 inhibitors can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

In further embodiments, the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations

The ERK1/2 inhibitors can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in United States Patent No. 5,262,564, the contents of which are herein incorporated by reference in their entirety.

ERK1/2 inhibitors can also be delivered by the use of monoclonal antibodies as individual carriers to which the ERK1/2 inhibitors are coupled. The ERK1/2 inhibitors can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the ERK1/2 inhibitors can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, ERK1/2 inhibitors are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1 % to about 80 %, from about 5 % to about 60 %, or from about 1 % to about 20 % of the ERKl/2 inhibitor by weight or volume.

A "therapeutically effective amount" when used in connection with an ERKl/2 inhibitor is an amount effective for treating or preventing an ERKl/2-associated disease or disorder. The dosage regimen utilizing the ERKl/2 inhibitor is selected in accordance with a variety of factors including type, species, age, weight, sex, race, diet, concomitant medications, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular ERKl/2 inhibitor employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Therapeutically effective amounts of the present invention, when used for the indicated effects, range from about 0.1 mg to about 5000 mg of the active ingredient per unit dose which could be administered. In one embodiment, the compositions are in the form of a tablet that can be scored. Appropriate dosages of the ERKl/2 inhibitors can be determined as set forth in Goodman, L. S.; Gilman, A. The Pharmacological Basis of Therapeutics, 5th ed.; MacMillan: New York, 1975, pp. 201-226, the contents of which are hereby incorporated by reference.

ERKl/2 inhibitors can also be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, ERKl/2 inhibitors can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen. Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of the ERKl/2 inhibitor ranges from about 0.1 % to about 15 %, w/w or w/v.

The ERKl/2 inhibitors can also each be administered in amounts that are sufficient to treat or prevent ERKl/2-associated diseases. These diseases include, but are not limited to, cardiovascular and cerebrovascular diseases, autoimmune diseases, inflammatory disorders, fibrotic diseases, metabolic disorders, and oncologic diseases either individually or in combination with one or more agents and or methods for treating and preventing these ERKl/2-associated diseases.

EXAMPLES

The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.

The methodologies described herein and below are designed to (1) quantitate and describe the nature of the physical interaction between ERKl/2 and candidate compounds, (2) determine the biological consequence resulting from the interaction of ERKl/2 with the candidate compound, (3) evaluate the impact of the candidate compound in animal models of ERKl/2 mediated disease.

It is to be understood that any embodiments listed in the Examples section are embodiments of the ERKl/2 inhibitors and, as such, are suitable for use in the methods and compositions described above.

Example 1

LPS Model of Sepsis-Induced AKI

Six- to 8-week-old male C57BL/6 mice are acquired from the National Institutes of Health National Cancer Institute/Charles River Laboratories (Frederick, MD). Mice are given an intraperitoneal injection of 0.5, 2, or 10 mg/kg lipopolysaccharide (LPS) derived from Escherichia coli serotype 0111 :B4 (Sigma-Aldrich, St. Louis, MO). Control mice received an intraperitoneal injection of an equal volume of 0.9% normal saline. Mice are euthanized by isoflurane asphyxiation and cervical dislocation at 1, 3, and 18 hours after LPS exposure, and kidneys and serum are collected for molecular analysis. For experiments using TLR4- deficient animals, TLR4 knockout (TLR4KO) mice are generated by crossing C57BL/10ScN mice with the tlr4LPs-d mutation onto the C57BL/6 background for at least five generations (Ellett et al., 2009). All studies areconducted in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animal use is approved by the Institutional Animal Care and Use Committee at the Medical University of South Carolina.

To determine the role of MEK/ERK signaling in LPS-induced AKI, mice receive an injection of a representative ERKl/2 of the invention (1 mg/kg i.p.) or vehicle control (dimethylsulfoxide i.p.) 1 hour before administration of LPS. To assess the effects of TNF-a on regulation of MB in this model, rat anti-TNF-a neutralizing antibody (clone MP6-XT22) and the appropriate rat IgGl K isotype control antibody (done RTK2071) are purchased from BioLegend (San Diego, CA). Mice are randomly assigned to one of three groups: 1) control, 2) LPS + isotype control antibody (25 mg/kg), and 3) LPS + anti-TNF-a neutralizing antibody (25 mg/kg). Isotype control antibody and anti-TNF-a neutralizing antibody are administered intravenously 1 hour before LPS via tail vein injection. Control mice received an intravenous injection of vehicle control (phosphatebuffered saline).

Recombinant mouse TNF-a is obtained from BioLegend to evaluate whether TNF-a alone reproduced LPS-mediated changes in renal function and/or MB. Wild-type C57BL/6 male mice (6 to 8 weeks of age) are treated intravenously with either vehicle control (diluent), 20 μg/kg recombinant murine TNF-a, or 50 μg/kg TNF-a via tail vein injection. Animals are euthanized at 18 hours after TNF-a administration, and kidneys and serum are collected for analysis.

Blood Urea Nitrogen Measurement. Blood urea nitrogen (BUN) is determined using the QuantiChrom Urea Assay kit (BioAssay Systems, Hayward, CA) based on the manufacturer's directions. All values are expressed as BUN concentration in milligrams per deciliter.

Quantitative Real-Time Polymerase Chain Reaction Analysis of mRNA Expression. Total RNA is isolated from renal cortical tissue with TRIzol reagent (Life Technologies, Grand Island, NY). The iScript Advanced cDNA Synthesis Kit for quantitative realtime polymerase chain reaction (qRT-PCR) (Bio-Rad Laboratories, Hercules, CA) is used to produce a cDNA library from 1 pg total RNA according to the manufacturer's protocol. qRT-PCR is performed with the generated cDNA using the S so Advanced Universal SYBR Green Supermix reagent (Bio-Rad Laboratories). The relative mRNA expression of all genes is determined by the 2- AAG method, and 18S ribosomal RNA (18S rRNA) is used as a reference gene for normalization as previously described elsewhere (Wills et al., 2012).

Analysis of Mitochondrial DNA Content. Mitochondrial DNA content is determined by qRT- PCR analysis. Total DNA is isolated from the renal cortex using the DNeasy Blood and Tissue Kit (Qiagen, Valencia, CA) as described in the manufacturer's protocol. Extracted DNA is quantified, and 5 ng is used for PCR. Relative mitochondrial DNA content is assessed by the mitochondrial-encoded NADH dehydrogenase 1 [NADH dehydrogenase subunit 1 (NDl)] and is normalized to nuclear-encoded j 3 -actin. Primer sequences for NDl and P-actin are NDl sense: 5'-TAGAACGCAAAATCTTAGGG-3'; NDl antisense: 5'- TGCTAGTGTGAGTGATAGGG-3'; P-actin sense: 5 ' -GGGATGTTTGCTC CAAC

CAA-3 ' ; and P- actin antisense: 5' -GCGCTTTTGACTCAGGATTTAA-3' .

Immunoblot Analysis. Protein is extracted from renal cortex using radioimmunoprecipitation assay buffer (50 mM Tris-HCl, 150 mM NaCl, 0.1% SDS, 0.5% sodium deoxycholate, 1% Triton X-100, pH 7.4) with protease inhibitor cocktail (1 : 100), 1 mM sodium fluoride, and 1 mM sodium orthovanadate (Sigma-Aldrich). Total protein amount is determined by BCA protein assay. Equal protein quantities (50-100 pg) are loaded onto 4-15% SDS-PAGE gels (Bio-Rad Laboratories). Proteins are resolved by gel electrophoresis and transferred onto nitrocellulose membranes (Life Technologies). Membranes are blocked in 2.5% bovine serum albumin and incubated overnight with primary antibody at 4°C. Primary antibodies used in these studies include neutrophil gelatinase-associated lipocalin (NGALYlipocalin-2 (1 : 1000), phospho— tumor progression locus 2 (phospho-TPL2) (1 :500), total TPL2 (1 : 1000; all from Abeam, Cambridge, MA), phospho-ERKl/2 (1 : 1000), total ERK1/2 (1 : 1000; both from Cell Signaling Technology, Danvers, MA), kidney injury molecule-1 (KIM-1) (1 : 1000; R&D systems, Minneapolis, MN), PGC-1 (1 : 100; Cayman Chemical, Ann Arbor, MI), and P- actin (1 : 1000; Santa Cruz Biotechnology, Dallas, TX). Membranes are incubated with the appropriate horseradish peroxidase— conjugated secondary antibody before visualization using enhanced chemiluminescence (Thermo Scientific, Waltham, MA) and the GE ImageQuant LAS4000 (GE Life Sciences, Pittsburgh, PA). Optical density is determined using the National Institutes of Health ImageJ software (version 1.46). Example 2

In Vitro Study

Cell Culture

The RAW 264.7 mouse macrophage cell line, purchased from the China Cell Line Bank ( Beij ing, China ), is cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 3 niM glutamine, antibiotics (100 U/ml penici llin and 100 U/ml streptomycin ), 10 % heat-inactivated fetal bovine serum, at 7 °C under a humidified atmosphere of 5 % C02. In all experiments, macrophages are incubated in the presence or absence of various concentrations of representative ERK 1 /2 inhibitors of the invention which were always added 1 h prior to LPS (1 Lig ml ) stimulation.

Cell Viability Assay

Representativ e ERK 1/2 inhibitors of the invention are solubilized in DM SO (less than 0. 1 % of total volume of cells) and diluted in DMEM prior to treatment. MTT assay is established to evaluate cell viability. Firstly, cells are seeded onto 96-well plates at a density of 2 105 cells/ml and cultured in a 37 °C, 5 % C02 incubator for 1 h. After that, a representative ERK 1/2 inhibitor of the invention (0-300 ^ig/ml) is added into the wells to pretreat cells and incubated for 1 h. Then the LPS groups are stimulated with LPS (1 g/ml).

After 18 h, 20 ul of MTT (5 mg/ml ) is added to each well, and incubation was continued for 4 h. The supernatant is removed and the formation of formazan is resolved with 150 μΐ/well of DM SO. The optical density i s measured at a wavelength of 570 nm using a microplate reader (TEC AN, Austria). Concentrations are determined for three wel ls of each sample, and each experiment is done in triplicate. Cytokine assay (T F-a and IL-6).

RAW 264.7 cells are plated onto 24-well plates (4x 105 cells/well), and incubated in DMEM for 1 h prior (25, 50, and 100 μ§/ηι1) pretreatment with a representativ e ERK 1/2 inhibitor of the invention. One hour after treatment with a representative ERK 1/2 inhibitor of the invention, LPS (1 pg/ml ) is added to stimulated inflammatory reaction. Cell -free supematants are collected after 12-h incubation, and cytokines are assayed by ELISA kit (R&DS systems) according to manufacturer's instructions (Bio Legend, Inc, Cam i no Santa Fe, Suite E, San Diego, CA, USA). Example 3

Mouse Model

Mouse Cecal Ligation and Puncture Model of Sepsis

Male C57BL/6 mice aged 40 weeks are obtained from Harlan Laboratories (Indianapolis, IN). Cecal ligation and puncture are performed as previously described (33, 34). 1.5 cm of the cecum is mobilized and ligated with a 4-0 silk suture under isoflurane anesthesia after midline laparotomy. The mobilized cecum is then punctured with a 21 -gauge needle and gently pressed to produce a ~1 mm column of fecal material from each puncture site. Sham animals undergo midline laparotomy followed by isolation of the cecum, but the cecum is not ligated or punctured. All mice receive buprenorphine (0.05 mg/kg, s.c.) at the time of surgery. At 6 h post-CLP mice receive a second dose of buprenorphine and imipenem/cilastatin (14 mg/kg, s.c.) in 1.5 ml of warm saline for fluid support (40 ml/kg). Mice are euthanized 18 h after CLP and kidneys and serum are collected for analysis. Core body temperature is measured using a rectal temperature probe. All experiments are carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

Administration of ERK1/2 Inhibitor

A representative ERK1/2 inhibitor of the invention is formulated in vehicle solution containing 1% DMSO in Neobee M-5 (Spectrum Chemical, New Brunswick, NJ). Mice are treated with 1 mg/kg of the inhibitor or an equal volume of vehicle solution via intraperitoneal (i.p.) injection at 6 h after CLP.

Determination of Circulating Cytokine Levels

Measurement of serum levels of TNF-a, IL-Ιβ, IL-6 and GM-CSF are performed using the Inflammatory Cytokine Mouse Magnetic 4-Plex Panel for the Luminex platform (Life Technologies, Grand Island, NY). Detection of cytokines are performed using a Bio-Rad Bio- Plex 200 system (Bio-Rad Laboratories, Hercules, CA) and quantified using a standard curve and protein standards supplied in the kit. For values that fell below the lower limit of detection of the assay in sham animals, values are recorded as the lower limit (TNF-a - 22.4 pg/ml; IL-Ιβ - 28.1 pg/ml; IL-6 - 9.8 pg/ml; GM-CSF - 16.06 pg/ml).

Intravital Microscopy and Assessment of Peritubular Capillary Perfusion

To assess changes in renal microcirculation after CLP, intravital video microscopy is performed as previously described (34, 40). Mice are anesthetized with isoflurane and FITC- labeled dextran (2 μιηοΐ/kg in 3 ml/kg normal saline) is injected via the penile vein to visualize microvascular flow. After 10 minutes, the left kidney is exposed by a flank incision and placed on a glass stage above an inverted Zeiss Axiovert 200M fluorescent microscope with an Axiocam HSm camera (Zeiss, Jena, Germany). Ten second videos are acquired at -30 frames per second from five randomly selected, non-overlapping fields for each animal. Core body temperature is maintained at 35-37°C with a heating lamp. Roughly 150 capillaries from each animal are selected for analysis and categorized into three categories based on the degree of perfusion as follows: "continuous flow" where red blood cell movement is uninterrupted throughout the video; "intermittent flow" where red blood cell movement stops or reverses during the course of the video; or "no flow" where no red blood cell movement is observed throughout the video. Data are shown as percentage (mean ± S.E.M.) of vessels in each category.

Serum Chemistries

Blood urea nitrogen (BUN) is measured using the QuantiChrom Urea Assay kit as directed by the manufacturer (BioAssay Systems, Hayward, CA). Serum creatinine (SCr) is assessed using the Creatinine Enzymatic Reagent Set based on the provided protocol (Pointe Scientific, Canton, MI). Alanine aminotransferase (ALT), creatine kinase (CK), and lactate dehydrogenase (LDH) are measured using standard biochemical assay kits from BioVision (Milpitas, CA) as directed.

Quantitative Real-Time PCR Analysis of Gene Expression

Total RNA is extracted from renal cortex tissue samples using the TRIzol reagent (Life Technologies). One microgram of total RNA is reversed transcribed into a cDNA library using the iScript Advanced cDNA Synthesis Kit for quantitative real-time polymerase chain reaction (qRT-PCR) based on the manufacturer's protocol (Bio-Rad). qRT-PCR is then performed with the synthesized cDNA using S so Advanced Universal SYBR Green Supermix (Bio-Rad). Relative mRNA content for all genes of interest is calculated by the 2 ^"AACt method as previously described using β-actin as a reference for normalization (41). Primer sequences used for qRT-PCR were the same as previously reported (23, 42).

Immunoblot Analysis

Protein is isolated from the renal cortex in radioimmunoprecipitation assay (RIP A) buffer (50 mM Tris-HCl, 150 mM NaCl, 0.1% SDS, 0.5% sodium deoxycholate, 1% Triton X-100, pH 7.4) containing protease inhibitor cocktail (1 : 100), 1 mM sodium fluoride, and 1 mM sodium orthovanadate (Sigma-Aldrich, St. Louis, MO). Protein quantification is performed using the BCA protein assay. Equal quantities of protein are loaded onto 4-15% SDS-PAGE gels (Bio- Rad) and resolved by gel electrophoresis. Primary antibodies used for this study included phospho-ERKl/2 (Thr202/Tyr204, 1 : 1000) and total ERK1/2 (1 : 1000, Cell Signaling Technology, Danvers, MA), and β-Actin (1 : 1000, Santa Cruz Biotechnology, Dallas TX). Proteins of interest are imaged using enhanced chemiluminescence (ECL) reagents and the GE ImageQuant LAS4000 digital imaging system (GE Life Sciences, Pittsburgh, PA). Optical densitometry is performed using NIH ImageJ software (version 1.46).

Example 4

Determination of Lung Vascular Leak and Acute Lung Injury

A representative ERK1/2 inhibitor of the invention is formulated in vehicle solution containing 1% DMSO in Neobee M-5 (Spectrum Chemical, New Brunswick, NJ). Mice are treated with 2 mg/kg of the inhibitor or an equal volume of vehicle solution via intravenous (i.v.) injection.

To assess survival, CD1 mice will be subjected to CLP or Sham procedure, and one i.v. dose of either dosing vehicle or erk inhibitor 6 hours post-surgery. Pain management techniques are used, and all animals are monitored daily for mortality, signs of pain and distress for up to 7 days.

To assess the changes in lung vascular leak and acute lung injury after CLP, the following experimental techniques are used: histology, Evan's Blue dye assay measurement, lung water calculation, bronchoalveolar lavage fluid protein measurement, bronchoalveolar lavage cell count measurement and bronchoalveolar lavage inflammatory cytokine measurement.

For histologic analysis, sections of lungs are fixed in 10% formalin for at least 24 hours. Fixed lung is sectioned and stained with hematoxylin and eosin and viewed under light microscopy. Features indicative of acute lung injury are assessed for and include: 1) accumulation of neutrophils in the alveolar or interstitial spaces, 2) formation of hyaline membranes, 3) proteinaceous material in the alveolar space, and 4) alveolar wall thickening. Experimental animals are injected with Evan's Blue dye (30mg/kg, i.v.) 40 minutes before sacrifice. At the time of sacrifice, the lungs are perfused via the pulmonary artery with phosphate-buffered saline. Sections of lung are weighed and homogenized in formamide and then incubated at 60° C for 16 hours. The homogenized tissue is then centrifuged at 10,000g for 10 minutes and the concentration of Evan's Blue dye that is extracted to formamide is measured with spectrophotometry at 620nm and quantified against a standard curve. Dye amounts are expressed as micrograms of dye per milligram of tissue weight.

In a separate experimental group, whole lungs are excised at the time of sacrifice, weighed, and then dried for 48 hours at 70° C. Dried lungs are re-weighed and the lung water content is calculated as: (wet weight - dry weight)/(wet weight) x 100.

In a separate experimental group, animals are sacrificed and their thorax is opened to expose the trachea. The trachea is cannulated with a 20 gauge angiocatheter and lavaged with cold phosphate-buffered saline (0.75ml) using a 1ml syringe. A total of four consecutive lavages are performed. Collected lavage fluid is centrifuged at 600g for 5 min to pellet cells. The supernatant is separated into aliquots and stored at -80° C. The cell pellet is resuspended in 500ul lx RBC lysis buffer and centrifuged at 3000 rpm for 5 min. Cells are then resuspended in 500ul of phosphate-buffered saline and white blood cells are quantified using a hemacytometer. Commercially available Differential-Quick kits are used to determine the proportion of different cell types following the manufacturer's instructions. Stored lavage supernatants are thawed and protein concentrations are measured using the DC protein assay following the manufacturer's instructions and compared to a standard curve. Inflammatory cytokine levels including interleukin-6, interleukin-ΐβ, tumor necrosis factor-a, interleukin-8 are also measured in the lavage supernatants using commercially available ELISA kits. Examples 5 and 6

The compounds used in these examples were:

AEZS-134:

l-((R)-l-Methyl-4-phenyl-butyl)-3-[3-(l-propyl-lH-pyrazol -4-yl)-pyrido[2,3-b]pyrazin-6- yl -urea

AEZS-140:

l-{3-[4-(2-Mo holin-4-yl-ethoxy)-phenyl]-pyrido[2,3-b]pyrazin-6-yl}-3-(4-p henyl-butyl)- urea

AEZS-141:

l-((R)-l-Methyl-4-phenyl-butyl)-3-[3-(l-methyl-lH-pyrazol -4-yl)-pyrido[2,3-b]pyrazin-6- yl]-urea

AEZS-142:

1 -((R)- 1 -Methyl-4-phenyl-butyl)-3 -{ 3 -[ 1 -(2-morpholin-4-yl-ethyl)- lH-pyrazol-4-yl]- p rido[2,3-b]pyrazin-6-yl}-urea

GDC-0994:

; and

Ulixertinib BVD-523, VRT752271 :

All of the data was derived in Raw 264.7 cells, a murine macrophage-like cell line which is routinely used for studies of innate immunity. When stimulated with bacterial lipopolysaccharide (LPS), the cells produce a number of inflammatory molecules as part of the innate immune response. IL-6 is one of these inflammatory cytokines, and plays a key role in the response to bacterial infections. One of the hallmarks of LPS stimulation is a rapid induction of ERK activation. In these studies, LPS-induced activation of ERK was assessed, measured by western immunoblot of the activation -specific phosphorylation of ERK, and activation of a known substrate of ERK kinase, p90 RSK, again by western blot of the activation-specific phosphorylation of p90 Rsk. In addition, the inventors measured LPS- induced IL-6 production in cells. The inventors measured the ability of the AEZ ERK inhibitors, 134, 140, 141, and 142; 2 commercial ERK inhibitors, VRT-752271 (BVD-523, ulixertinib) and GDC-0994; and a MEK inhibitor (MEK is the enzyme which phosphorylates and activates ERK), GSK1120212 (trametinib) to inhibit LPS-mediated ERK and p90 phosphorylation, and the AEZ compounds well as one commercial ERK inhibitor, VRT- 752271 to inhibit LPS-induced IL-6 production.

Example 5

In this experiment, sub-confluent Raw264.7 cells were seeded into a 12-well tissue culture plate and incubated in a humidified 5% C02 incubator at 37 °C for 48 hours. The cells were then incubated with compound in DMSO or DMSO alone for 1 hour at a final concentration of 1 mM. The total DMSO concentration in the media was 1%. After one hour, the cells were stimulated with 30 ng/ml LPS in media or media alone for an additional 45 minutes. After incubation with LPS, the media was removed, and the cells were lysed in laemli sample buffer. Cell lysates were sonicated, boiled and loaded on a 4-12% Tris-glycine gradient gel, transferred to nitrocellulose, and immunoblotted with either a phospho-ERK or phoshpo-p90 RSK antibody. As shown in Figure 1, LPS induced a strong activation of pERK (mean response 4.84-fold increase over non-stimulated + 0.62 SE; n=4) and an increase in p90 RSK phosphorylation (mean phosphorylation 2.7 fold + 0.45 SE; n=4). All compounds tested were able to inhibit p90 RSK phosphorylation, as expected. However, ERK phosphorylation was largely unaffected, except by GSK 1120212, which inhibited both basal (non-stimulated) and LPS-induced ERK activation, consistent with its inhibition of MEK. No inhibition of total ERK or total p90 Rsk expression by any of the compounds was observed (data not shown). Figure 2 is the quantitation of these results. Each histogram represents the mean + SE of three independent experiments.

Example 6

In this experiment, Raw 264.7 cells were seeded in a 24-well plate at either 0.1 X 10 ⁶ cells per well (for 24-hour experiments) or 0.2 XI 0 ⁶ cells per well (for 6-hour experiments). Cells were allowed to grow for 16 hours in a humidified 5% C02 incubator at 37 °C, then were treated with 1 mM of compound in DMSO or DMSO alone (final DMSO concentration was 1%). After 1 hour incubation, cells were stimulated with 15 ng/ml LPS in media or media alone and incubated for either 6- or 24-hours at 37 °C. Cell supernatants were collected, spun down at 10,000 rpm for 5 min to pellet any cell debris, and the supernatants were assayed for murine IL-6 using a commercial sandwich ELISA kit (BioLegend). Figure 3 shows the effect of the four AEZS ERK inhibitors as well at the VRT-252271 commercial ERK inhibitor on LPS-induced IL-6 production in Raw 264.7 cells. No detectable IL-6 levels were observed in cells not stimulated with LPS. Three of the AEZS compounds showed reduced LPS-induced IL-6 production at 6 hrs (134, 142, and 141), as did VRT-752271. However, the inventors were not able to detect inhibition by AEZS-140 at that time point. By 24 hrs, 134 and 142 show sustained inhibition of LPS-induced IL-6 levels, and inhibitory activity was also observed with AEZS 140. However, compound AEZS 141 and VRT-752271 did not show sustained inhibition of IL-6 production at 24-hours. This histogram represents the mean + SE from 3 independent experiments.

The above Examples show that that Erk inhibitors block LPS-mediated activation of known ERK substrate p90 Rsk, and were able to block LPS-induced production of IL-6. Two of the AEZS compounds, AEZS-134 and AEZS 142 provided very good results in the cell based assays. Thus, the Examples show that the compounds herein are useful for the treatment of sepsis and ARDS.

The invention will be further described, without limitation, by the following numbered paragraphs:

1. A method of treating septicemia, comprising the step of administering a

therapeutically effective amount of an ERK 1/2 inhibitor, or a pharmaceutically acceptable salt or ester thereof, to a patient in need thereof.

2. The method according to paragraph 1, wherein the ERK1/2 inhibitor is a compound of formula:

wherein:

Rl and R2 are independently of one another:

(i) hydrogen,

(ii) hydroxyl, (iii) halogen,

(iv) allyl, where the alkyl radical is saturated and may consist of 1 to 8 C atoms,

(v) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, H ₂ , H-alkyl, H-cycloalkyl, H-heterocyclyl, NH-aryl, H-heteroaryl, H-alkylcycloalkyl, H-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, H-alkyl- H ₂ , H-alkyl-OH, N(alkyl) ₂ , HC(0)-alkyl, HC(0)-cycloalkyl, HC(0)-heterocyclyl, HC(0)-aryl, NHC(0)-heteroaiyl, HC(0)-alkyl-aiyl, NHC(O)- alkyl-heteroaryl, HS0 ₂ -alkyl, HS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, HS0 ₂ -aryl,

HS0 ₂ -heteroaryl, HS0 ₂ -alkyl-aiyl, HS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S- heteroaryl,OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl- cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, O—

(CH ₂ ) _n — O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(O)- heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ - alkylheteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ - alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkylheteroaryl, C(O)— NH ₂ , C(0) H-alkyl, C(0) H-cycloalkyl, C(0)NHheterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0)NH- alkyl-cycloalkyl, C(0) H-alkyl-heterocyclyl, C(0) H-alkyl-aryl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ H ₂ , SOZNH-alkyl, S0 ₂ NHaryl, S0 ₂ NH-heteroaryl, S0 ₂ NH-alkyl- aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, n is 1, 2 or 3, and the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl and alkyl-heteroaryl substituents may in turn themselves be substituted,

(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NHalkyl, NH-cycloalkyl, NH- heterocyclyl, NH-aryl, NH-heteroaryl, NHalkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkylheteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(O)- alkyl-aryl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ - heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-aiyl, O- heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl,

OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(O)— H ₂ , C(0) Halkyl, C(0)NH-cycloalkyl, C(0) H-heterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0) H-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ 0- aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ Hheteroaiyl, S0 ₂ H-alkyl-aiyl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ -aryl, S0 ₂ 0-alkylaryl, alkyl, cycloalkyl, heterocyclyl, aiyl or heteroaiyl substituents, and the alkyl, cycloalkyl, heterocyclyl, aiyl and heteroaiyl substituents may in turn themselves be substituted,

(vii) OR5, where R5 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aiyl, heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aiyl, heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl substituents can, for their part, in turn be substituted,

(viii) SR6, where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aiyl, heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aiyl and heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl substituents can, for their part, in turn be substituted,

(ix) R7R8, where R7 and R8 are, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aiyl, heteroaiyl, alkylcyclyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aiyl and heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl substituents can, for their part, in turn be substituted,

or R7 and R8 are together cycloalkyl or heterocyclyl, where the cycloalkyl and

heterocyclyl can, for their part, in turn be substituted;

R3 and R4 are, independently of each other, hydrogen or R9R10 with the proviso that, when R3= R9R10, R4=H and when R4= R9R10, R3=H, and R3 and R4 are not both H or R9R10 at the same time, where R9 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aiyl, heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaiyl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aiyl and heteroaiyl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl substituents can, for their part, in turn be substituted, and RIO is: A, B, or C, where

(A) is:— C(Y)NR11R12, where Y is O, or S and Rl 1 and R12 are independently of one another

(i) hydrogen,

(ii) unsubstituted or substituted alkyl, where the alkyl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkylcycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(O)- aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aiyl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaryl, NHS0 ₂ -alkyl- aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, Sheteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O- alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ - aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl- heteroaryl, C(O)— NH2, C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaiyl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ ,

C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S02NH-aryl, S0 ₂ NHheteroaiyl, S0 ₂ NH-alkyl-aryl, S0 ₃ H, S0 ₂ -alkyl, S0 ₂ 0- aryl, S0 ₂ 0-alkylaryl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(iii) unsubstituted or substituted cycloalkyl, where the cycloalkyl radical may have one or more identical or different F, CI, Br, I, NH ₂ , NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH- aryl, NH-heteroaryl, NH-alkyl-aryl, NHalkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aiyl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, NHS0 ₂ - aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl,— NHS0 ₂ -alkyl-heteroaiyl, OH, O-alkyl, O- cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(O)- alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl- aryl, OC(0)-alkyl-heteroaryl, OS03H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C02-aryl, C0 ₂ -heteroaryl, C0 ₂ - alkylcycloalkyl, C0 ₂ -alkylhetero-cyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)- H ₂ , C(0) Haryl, C(0)NH-cycloalkyl, C(0) H-heterocyclyl, C(0) H-aryl, C(0) H-heteroaiyl, C(0) H-alkyl-cycloalkyl, C(0) H-alkyl-heterocyclyl, C(0) H-alkyl-aryl, C(0)NH-alkyl- heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , alkyl or aryl substituents,

(iv) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may have one or more identical or different OH, O-alkyl, O-aiyl, H ₂ , Halkyl, H-aryl, alkyl, alkyl-aryl or aryl substituents,

(v) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F; CI, Br, I, CF ₃ , CN, H ₂ , H-alkyl, H-cycloalkyl, H-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkylcycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aiyl, NHC(O)- alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS02-heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaryl, NHS0 ₂ -alkyl-aiyl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S- cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O- heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-hetero-cyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, O— (CH ₂ ) _n — O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(O)- heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , OS0 ₂ -heterocyclyl, OS02-alkyl-aryl, OS02-alkyl-heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C02H, C0 ₂ - alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NHalkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH- alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aryl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH-heteroaryl, S0 ₂ NH-alkyl- aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkylaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and n is 1, 2 or 3,

(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH- heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkylheteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(O)- alkyl-aryl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ - heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-aiyl, O- heteroaryl, O-alkylcycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(O)- alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl- aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS02-heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C(O)- alkyl, C(0)-aryl, C(0)-heteroaryl, C02H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(O)— NH ₂ , C(0)NHalkyl, C(0)NH-cycloalkyl, C(0)NH- heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaiyl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl- heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ ,

C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH-heteroaiyl, S0 ₂ NH-alkyl-aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(vii)— C(0)-R17, where R17 is alkyl, aryl, alkenyl, alkynyl or heteroaryl, and the alkyl, alkenyl, alkynyl and aryl substituents may in turn themselves be substituted,

(viii) or Rl 1 and R12 together are cycloalkyl or heterocyclyl

(ix) alkenyl or alkynyl radical, where the alkenyl or the alkynyl radical has 2 to 8 C atoms; (B) is— C(Y)NR13R14, where Y is NH and R13 and R14 are independently of one another

(i) hydrogen,

(ii) unsubstituted or substituted alkyl, where the alkyl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NHalkyl-heteroaryl, N(alkyl)2, NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, NHS02-aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ - heterocyclyl, C02-aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ - alkyl-aryl, C0 ₂ -alkylheteroaryl, C(O)— H ₂ , C(0) H-alkyl, C(0) H-cycloalkyl,

C(0) Hheterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0) H-alkyl-cycloalkyl,

C(0) H-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ ,SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ - aryl, S0 ₂ H ₂ , SO ₃ H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(iii) unsubstituted or substituted cycloalkyl, where the cycloalkyl radical may have one or more identical or different F, CI, Br, I, H2, H-alkyl, Hcycloalkyl, H-heterocyclyl, NH- aryl, H-heteroaryl, H-alkyl-aryl, Halkyl-heteroaryl, N(alkyl) ₂ , HC(0)-alkyl, NHC(O)- cycloalkyl, HC(0)-heterocyclyl, HC(0)-aryl, HC(0)-heteroaryl, HS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, HS0 ₂ -aryl, HS0 ₂ -heteroaiyl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O- aryl, O-heteroaiyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(O)- heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ - heteroaryl, C(0)- H ₂ , C(0) H-alkyl, C(0) H-cycloalkyl, C(0) H-heterocyclyl, C(0)NH- aryl, C(O) NH-heteroaryl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , alkyl or aryl substituents,

(iv) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may have one or more identical or different OH, O-alkyl, O-aiyl, NH ₂ , NH-alkyl, NH-aryl, alkyl or aryl substituents,

(v) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHS0 ₂ -alkyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O- alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, 0-(CH ₂ ) _n O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS02-aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ - alkylcycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH- heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0)NHalkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ Haryl, S0 ₂ H-heteroaryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and n is 1, 2 or 3,

(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , Halkyl, NH-cycloalkyl, NH- heterocyclyl, NH-aryl, NH-heteroaryl, NHalkyl-aryl, NH-alkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl; NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(O)- heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, N02, SH, S-alkyl, S-aryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, OC(0)-alkyl, OC(O)- cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C02H, C02-alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl- cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH- heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-hetero-cyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ ,

C(0)N(heteroaryl) ₂ , S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH- heteroaryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(vii) or R13 and R14 together are cycloalkyl or heterocyclyl

(viii) alkenyl or alkynyl radical, where the alkenyl or the alkynyl radical has 2 to 8 C atoms; (C) is— C(NR15)R16 where R15 is H and R16 is

(i) unsubstituted or substituted alkyl, where the alkyl radical may have one or more identical or different F, CI, Br, I, CF ₃ , NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH- heteroaryl, NH-alkyl-aryl, NH-alkylheteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C0 ₂ H,C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ - heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ - alkyl-aryl, C0 ₂ -alkylheteroaryl,C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl,

C(0)NHheterocyelyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH-alkyl-cycloallcyl, C(0) H-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ - aryl, S0 ₂ H ₂ , SO ₃ H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(ii) unsubstituted or substituted cycloalkyl, where the cycloalkyl radical may have one or more identical or different F, CI, Br, I, H ₂ , NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH- aryl, NH-heteroaryl, NH-alkyl-aryl, NHalkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O- aryl, O-heteroaiyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(O)- heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ - heteroaryl, C(0)-NH2, C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH- aryl, C(0)NH-heteroaryl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl)2, alkyl or aryl substituents,

(iii) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may have one or more identical or different OH, O-alkyl, O-aiyl, NH ₂ , NH-alkyl, NH-aryl, alkyl or aryl substituents,

(iv) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH- heteroaryl, NH-alkyl-cycloalkyl, NH-alkylheterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH2, NHalkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(O)- heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -aryl, NHS0 ₂ - heteroaryl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, Daryl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl- heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, O— (CH ₂ ) _n — O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl OS0 ₂ - cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl- cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(O)— NH ₂ , C(0)NHalkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH- heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ ,

C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ H-aryl, S0 ₂ Hheteroaryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0 -heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and is 1, 2 or 3,

(v) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , H ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH- aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O- heterocyclyl, O-aiyl, O-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ - heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ - alkyl-aryl, C0 ₂ -alkyl-heteroaiyl, C(O)— NH ₂ , C(0)NHalkyl, C(0)NH-cycloalkyl, C(0)NH- heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaiyl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl- heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ ,

C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH-heteroaryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0- heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents

(vi) alkenyl or alkynyl radical, where the alkenyl or the alkynyl radical has 2 to 8 C atoms; pharmaceutically acceptable salt or ester thereof.

3. The method according to paragraph 1, wherein the ERK1/2 inhibitor is a compound of formula:

wherein:

X is O;

Rl : (I) substituted aryl, wherein the aryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, H ₂ , H-alkyl, H-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aiyl, NHC(O)- alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaryl, NHS0 ₂ -alkyl-aiyl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S- heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl- cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, 0-(CH ₂ ) _n -0, 0-(-CH ₂ -CH ₂ -0-)n-CH ₂ -CH ₂ -OH, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OC(0)-NH- Alkyl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ - heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, 0-C0 ₂ -alkyl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ - aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ - alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaiyl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ ,

C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -heterocyclyl; S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH-heteroaiyl, S0 ₂ NH-alkyl-aryl, S0 ₃ H, S0 ₂ 0- alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, n can have the value 0, 1, 2 or 3 and the alkyl-, cycloalkyl-, heterocyclyl-, aryl-, heteroaryl-, alkyl- cycloalkyl-, alkyl-heterocyclyl-, alkyl-aryl- and alkyl-heteroaryl substituents for their part can in turn be substituted,

(II) unsubstituted or substituted heteroaryl, wherein the heteroaryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(O)- alkyl-aryl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ - heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-aiyl, O- heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl,

OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)- H ₂ , C(0) H-alkyl, C(0) H-cycloalkyl, C(0) H-heterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0) H-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaiyl, S0 ₂ H-alkyl-aryl, S03H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, alkyl- heteroaryl, aryl or heteroaryl, and the alkyl-, cycloalkyl-, heterocyclyl-, alkyl-heterocyclyl, alkyl-aryl, alkyl-cycloalkyl, alkyl-heteroaryl, aryl- and heteroaryl substituents for their part can in turn be substituted; and R2:

(I) unsubstituted or substituted alkyl-aryl wherein the alkyl-aryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, H ₂ , H-alkyl, H-cycloalkyl, NH- heterocyclyl, H-aryl, H-heteroaryl, NH-alkyl-cycloalkyl, H-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkyl -heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(O)- heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aryl, NHC(0)-alkyl- heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalky), NHS0 ₂ -heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ - heteroaryl, NHS0 ₂ -alkyl-aiyl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S- heterocyclyl, S-aryl, S-heteroaryl, =0, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O- aryl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl- heteroaryl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(O)- heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl- heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ - cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl- heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH- cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH-alkyl- cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aryl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaryl, S0 ₂ H-alkyl- aryl, SO ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,

(II) unsubstituted or substituted alkyl-heteroaryl wherein the alkyl-heteroaryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, NH ₂ , H-alkyl, H-cycloalkyl, H-heterocyclyl, H-aryl, H-heteroaryl, NH-alkyl-cycloalkyl, H-alkyl- heterocyclyl, H-alkyl-aryl, H-alkyl-heteroaryl, N(alkyl) ₂ , HC(0)-alkyl, HC(O)- cycloalkyl, HC(0)-heterocyclyl, HC(0)-aryl, HC(0)-heteroaiyl, HC(0)-alkyl-aiyl, HC(0)-alkyl-heteroaryl, HS0 ₂ -alkyl, HS0 ₂ -cycloalkyl, HS0 ₂ -heterocyclyl, HS0 ₂ - aryl, HS0 ₂ -heteroaryl, HS0 ₂ -alkyl-aiyl, HS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S- cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O- heterocyclyl, 0-aryl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O- alkyl-heteroaryl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(O)- heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl- heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ - cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl- heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0) H-alkyl, C(0) H- cycloalkyl, C(0) H-heterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0) H-alkyl- cycloalkyl, C(0) H-alkyl-heterocyclyl, C(0) H-alkyl-aryl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaryl, S0 ₂ H-alkyl- aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

pharmaceutically acceptable salt or ester thereof.

4. The method according to paragraph 1, wherein the ERK1/2 inhibitor is: (S)-l-(l-(4- chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((l-methyl-lH-py razol-5-yl)amino)pyrimidin- 4-yl)pyridin-2(lH)-one; or

4-(5-chloro-2-(isopropylamino)pyridin-4-yl)-N-((S)-l-(3-c hlorophenyl)-2-hydroxyethyl)-lH- py rrol e-2-carb oxami de, pharmaceutically acceptable salt or ester thereof.

5. The method according to paragraph 1, wherein the ERK1/2 inhibitor is: l-((R)-l-Methyl-4-phenyl-butyl)-3-[3-(l-propyl-lH-pyrazol-4- yl)-pyrido[2,3-b]pyrazin-6- yl]-urea; l-{3-[4-(2-Mo holin-4-yl-ethoxy)-phenyl]-pyrido[2,3-b]pyrazin-6-yl}-3-(4-p henyl-butyl)- urea; l-((R)-l-Methyl-4-phenyl-butyl)-3-[3-(l-methyl-lH-pyrazol-4- yl)-pyrido[2,3-b]pyrazin-6- yl]-urea; or

1 -((R)- 1 -Methyl-4-phenyl-butyl)-3 -{ 3 -[ 1 -(2-morpholin-4-yl-ethyl)- lH-pyrazol-4-yl]- pyrido[2,3-b]pyrazin-6-yl}-urea, pharmaceutically acceptable salt or ester thereof.

6. A method of treating acute respiratory distress syndrome, comprising the step of administering a therapeutically effective amount of an ERK1/2 inhibitor, or a

pharmaceutically acceptable salt or ester thereof, to a patient in need thereof.

7. The method according to paragraph 6, wherein the ERKl/2 inhibitor is a compound of formula:

wherein:

Rl and R2 are independently of one another:

(i) hydrogen,

(ii) hydroxyl,

(iii) halogen,

(iv) allyl, where the alkyl radical is saturated and may consist of 1 to 8 C atoms,

(v) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkylcycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, HC(0)-heterocyclyl, HC(0)-aryl, NHC(0)-heteroaiyl, HC(0)-alkyl-aiyl, NHC(O)- alkyl-heteroaryl, HS0 ₂ -alkyl, HS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, HS0 ₂ -aryl,

HS0 ₂ -heteroaryl, HS0 ₂ -alkyl-aiyl, HS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S- heteroaryl,OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl- cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, O—

(CH ₂ ) _n — O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(O)- heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ - alkylheteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ - alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkylheteroaiyl, C(O)— H ₂ , C(0) H-alkyl, C(0) H-cycloalkyl, C(0)NHheterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0) H- alkyl-cycloalkyl, C(0) H-alkyl-heterocyclyl, C(0) H-alkyl-aryl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ H ₂ , SOZNH-alkyl, S0 ₂ NHaryl, S0 ₂ NH-heteroaryl, S0 ₂ NH-alkyl- aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, n is 1, 2 or 3, and the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl and alkyl-heteroaryl substituents may in turn themselves be substituted,

(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NHalkyl, NH-cycloalkyl, NH- heterocyclyl, NH-aryl, NH-heteroaryl, NHalkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkylheteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(O)- alkyl-aryl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ - heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-aiyl, O- heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(O)— NH ₂ , C(0)NHalkyl, C(0)NH-cycloalkyl, C(0) H-heterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0) H-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ 0- aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ Hheteroaiyl, S0 ₂ H-alkyl-aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ -aryl, S0 ₂ 0-alkylaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituents may in turn themselves be substituted,

(vii) OR5, where R5 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl substituents can, for their part, in turn be substituted,

(viii) SR6, where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl substituents can, for their part, in turn be substituted,

(ix) R7R8, where R7 and R8 are, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcyclyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl substituents can, for their part, in turn be substituted,

or R7 and R8 are together cycloalkyl or heterocyclyl, where the cycloalkyl and

heterocyclyl can, for their part, in turn be substituted;

R3 and R4 are, independently of each other, hydrogen or R9R10 with the proviso that, when R3= R9R10, R4=H and when R4= R9R10, R3=H, and R3 and R4 are not both H or R9R10 at the same time, where R9 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl substituents can, for their part, in turn be substituted, and RIO is: A, B, or C, where

(A) is:— C(Y)NR11R12, where Y is O, or S and Rl 1 and R12 are independently of one another

(i) hydrogen,

(ii) unsubstituted or substituted alkyl, where the alkyl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkylcycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(O)- aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aiyl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaryl, NHS0 ₂ -alkyl- aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, Sheteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O- alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ - aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl- heteroaryl, C(O)— NH2, C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaiyl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ ,

C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S02NH-aryl, S0 ₂ NHheteroaiyl, S0 ₂ NH-alkyl-aryl, S0 ₃ H, S0 ₂ -alkyl, S0 ₂ 0- aryl, S0 ₂ 0-alkylaryl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(iii) unsubstituted or substituted cycloalkyl, where the cycloalkyl radical may have one or more identical or different F, CI, Br, I, NH ₂ , NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH- aryl, NH-heteroaryl, NH-alkyl-aryl, NHalkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aiyl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, NHS0 ₂ - aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl,— NHS0 ₂ -alkyl-heteroaiyl, OH, O-alkyl, O- cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(O)- alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl- aryl, OC(0)-alkyl-heteroaryl, OS03H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C02-aryl, C0 ₂ -heteroaryl, C0 ₂ - alkylcycloalkyl, C0 ₂ -alkylhetero-cyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NHaryl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaiyl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aryl, C(0)NH-alkyl- heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , alkyl or aryl substituents, (iv) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may have one or more identical or different OH, O-alkyl, O-aiyl, H ₂ , Halkyl, H-aryl, alkyl, alkyl-aryl or aryl substituents,

(v) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F; CI, Br, I, CF ₃ , CN, H ₂ , H-alkyl, H-cycloalkyl, H-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkylcycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aiyl, NHC(O)- alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS02-heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaryl, NHS0 ₂ -alkyl-aiyl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S- cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O- heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-hetero-cyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, O— (CH ₂ ) _n — O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(O)- heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , OS0 ₂ -heterocyclyl, OS02-alkyl-aryl, OS02-alkyl-heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C02H, C0 ₂ - alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NHalkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH- alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aryl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH-heteroaryl, S0 ₂ NH-alkyl- aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkylaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and n is 1, 2 or 3,

(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH- heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkylheteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(O)- alkyl-aryl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ - heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-aiyl, O- heteroaryl, O-alkylcycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(O)- alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl- aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS02-heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C(O)- alkyl, C(0)-aryl, C(0)-heteroaryl, C02H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaiyl, C(0)— NH ₂ , C(0)NHalkyl, C(0)NH-cycloalkyl, C(0)NH- heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaiyl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl- heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ ,

C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH-heteroaiyl, S0 ₂ NH-alkyl-aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(vii)— C(0)-R17, where R17 is alkyl, aryl, alkenyl, alkynyl or heteroaryl, and the alkyl, alkenyl, alkynyl and aryl substituents may in turn themselves be substituted,

(viii) or Rl 1 and R12 together are cycloalkyl or heterocyclyl

(ix) alkenyl or alkynyl radical, where the alkenyl or the alkynyl radical has 2 to 8 C atoms; (B) is— C(Y)NR13R14, where Y is NH and R13 and R14 are independently of one another

(i) hydrogen,

(ii) unsubstituted or substituted alkyl, where the alkyl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NHalkyl-heteroaryl, N(alkyl)2, NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, NHS02-aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ - heterocyclyl, C02-aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ - alkyl-aryl, C0 ₂ -alkylheteroaryl, C(O)— NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl,

C(0)NHheterocyclyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH-alkyl-cycloalkyl,

C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ ,SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ - aryl, S0 ₂ NH ₂ , S0 ₃ H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(iii) unsubstituted or substituted cycloalkyl, where the cycloalkyl radical may have one or more identical or different F, CI, Br, I, NH2, NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH- aryl, H-heteroaryl, H-alkyl-aryl, Halkyl-heteroaryl, N(alkyl) ₂ , HC(0)-alkyl, NHC(O)- cycloalkyl, HC(0)-heterocyclyl, HC(0)-aryl, HC(0)-heteroaryl, HS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, HS0 ₂ -aryl, HS0 ₂ -heteroaiyl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O- aryl, O-heteroaiyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(O)- heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ - heteroaryl, C(0)- H ₂ , C(0) H-alkyl, C(0) H-cycloalkyl, C(0) H-heterocyclyl, C(0)NH- aryl, C(O) NH-heteroaryl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , alkyl or aryl substituents,

(iv) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may have one or more identical or different OH, O-alkyl, O-aiyl, NH ₂ , NH-alkyl, NH-aryl, alkyl or aryl substituents,

(v) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl- heteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHS0 ₂ -alkyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O- alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, 0-(CH ₂ ) _n O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS02-aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ - alkylcycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH- heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0)NHalkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ ,

C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NHaryl, S0 ₂ NH-heteroaryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and n is 1, 2 or 3,

(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NHalkyl, NH-cycloalkyl, NH- heterocyclyl, NH-aryl, NH-heteroaryl, NHalkyl-aryl, NH-alkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl; NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(O)- heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, N02, SH, S-alkyl, S-aryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, OC(0)-alkyl, OC(O)- cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C02H, C02-alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl- cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH- heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-hetero-cyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ ,

C(0)N(heteroaryl) ₂ , S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH- heteroaryl, SO ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(vii) or R13 and R14 together are cycloalkyl or heterocyclyl

(viii) alkenyl or alkynyl radical, where the alkenyl or the alkynyl radical has 2 to 8 C atoms; (C) is— C(NR15)R16 where R15 is H and R16 is

(i) unsubstituted or substituted alkyl, where the alkyl radical may have one or more identical or different F, CI, Br, I, CF ₃ , NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH- heteroaryl, NH-alkyl-aryl, NH-alkylheteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C0 ₂ H,C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ - heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ - alkyl-aryl, C0 ₂ -alkylheteroaryl,C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl,

C(0)NHheterocyelyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH-alkyl-cycloallcyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ - aryl, S0 ₂ NH ₂ , S0 ₃ H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(ii) unsubstituted or substituted cycloalkyl, where the cycloalkyl radical may have one or more identical or different F, CI, Br, I, NH ₂ , NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH- aryl, NH-heteroaryl, NH-alkyl-aryl, NHalkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - cycloalkyl, HS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O- aryl, O-heteroaiyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(O)- heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ - heteroaryl, C(0)- H2, C(0) H-alkyl, C(0) H-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH- aryl, C(0)NH-heteroaryl, C(0) H-alkyl-aiyl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl)2, alkyl or aryl substituents,

(iii) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may have one or more identical or different OH, O-alkyl, O-aiyl, H ₂ , H-alkyl, H-aryl, alkyl or aryl substituents,

(iv) unsubstituted or substituted aryl, where the aryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , H ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH- heteroaryl, NH-alkyl-cycloalkyl, NH-alkylheterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH2, NHalkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(O)- heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -aryl, NHS0 ₂ - heteroaryl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, Daryl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl- heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, O-alkyl-OH, O— (CH ₂ ) _n — O, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl OS0 ₂ - cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl- cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(O)— NH ₂ , C(0)NHalkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH- heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaryl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ ,

C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NHheteroaryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0 -heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and is 1, 2 or 3,

(v) unsubstituted or substituted heteroaryl, where the heteroaryl radical may have one or more identical or different F, CI, Br, I, CF ₃ , NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH- aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ - aryl, NHS0 ₂ -heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O- heterocyclyl, O-aiyl, O-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ - heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkylheterocyclyl, C0 ₂ - alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(O)— H ₂ , C(0) Halkyl, C(0) H-cycloalkyl, C(0) H- heterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0) H-alkyl-cycloalkyl, C(0)NH-alkyl- heterocyclyl, C(0) H-alkyl-aryl, C(0) H-alkyl-heteroaryl, C(0)N(alkyl) ₂ ,

C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0- heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents

(vi) alkenyl or alkynyl radical, where the alkenyl or the alkynyl radical has 2 to 8 C atoms; or a pharmaceutically acceptable salt or ester thereof.

8. The method according to paragraph 6, wherein the ERK1/2 inhibitor is a compound of formula:

wherein:

X is O:

Rl :

(I) substituted aryl, wherein the aryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, H ₂ , H-alkyl, H-cycloalkyl, H-heterocyclyl, H-aryl, H-heteroaryl, H-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, H-alkyl-aryl, H-alkyl- heteroaryl, H-alkyl- H ₂ , H-alkyl-OH, N(alkyl) ₂ , HC(0)-alkyl, HC(0)-cycloalkyl, HC(0)-heterocyclyl, HC(0)-aryl, NHC(0)-heteroaiyl, HC(0)-alkyl-aiyl, NHC(O)- alkyl-heteroaryl, HS0 ₂ -alkyl, HS0 ₂ -cycloalkyl, NHS0 ₂ -heterocyclyl, HS0 ₂ -aryl, HS0 ₂ -heteroaryl, HS0 ₂ -alkyl-aiyl, HS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S- heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aiyl, O-heteroaiyl, O-alkyl- cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, 0-alkyl-heteroaryl, O-alkyl-OH, 0-(CH ₂ ) _n -0, 0-(-CH ₂ -CH ₂ -0-)n-CH ₂ -CH ₂ -OH, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OC(0)-NH- Alkyl, OSO ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ - heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, 0-C0 ₂ -alkyl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ - aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ - alkyl-heteroaryl, C(0)- H ₂ , C(0) H-alkyl, C(0) H-cycloalkyl, C(0) H-heterocyclyl, C(0) H-aryl, C(0) H-heteroaiyl, C(0) H-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0) H-alkyl-aiyl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ ,

C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -heterocyclyl; S0 ₂ -aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaiyl, S0 ₂ H-alkyl-aiyl, S0 ₃ H, S0 ₂ 0- alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, n can have the value 0, 1, 2 or 3 and the alkyl-, cycloalkyl-, heterocyclyl-, aryl-, heteroaryl-, alkyl- cycloalkyl-, alkyl-heterocyclyl-, alkyl-aryl- and alkyl-heteroaryl substituents for their part can in turn be substituted,

(II) unsubstituted or substituted heteroaryl, wherein the heteroaryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, H ₂ , H-alkyl, H-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkyl -heteroaryl, NH-alkyl-NH ₂ , NH-alkyl-OH, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(0)-heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(O)- alkyl-aryl, NHC(0)-alkyl-heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalkyl, NHS0 ₂ - heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ -heteroaiyl, NHS0 ₂ -alkyl-aryl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-aiyl, O- heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl-heteroaiyl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(0)-heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ -cycloalkyl, OS0 ₂ - heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl-heteroaryl,

OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ -cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl-heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH-cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH-alkyl-cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aiyl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaiyl, S0 ₂ H-alkyl-aryl, S03H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, alkyl- heteroaryl, aryl or heteroaryl, and the alkyl-, cycloalkyl-, heterocyclyl-, alkyl-heterocyclyl, alkyl-aryl, alkyl-cycloalkyl, alkyl-heteroaryl, aryl- and heteroaryl substituents for their part can in turn be substituted; and R2:

(I) unsubstituted or substituted alkyl-aryl wherein the alkyl-aryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, H ₂ , H-alkyl, H-cycloalkyl, NH- heterocyclyl, H-aryl, H-heteroaryl, NH-alkyl-cycloalkyl, H-alkyl-heterocyclyl, NH- alkyl-aryl, NH-alkyl -heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(0)-cycloalkyl, NHC(O)- heterocyclyl, NHC(0)-aryl, NHC(0)-heteroaiyl, NHC(0)-alkyl-aryl, NHC(0)-alkyl- heteroaryl, NHS0 ₂ -alkyl, NHS0 ₂ -cycloalky), NHS0 ₂ -heterocyclyl, NHS0 ₂ -aryl, NHS0 ₂ - heteroaryl, NHS0 ₂ -alkyl-aiyl, NHS0 ₂ -alkyl-heteroaiyl, N0 ₂ , SH, S-alkyl, S-cycloalkyl, S- heterocyclyl, S-aryl, S-heteroaryl, =0, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O-heterocyclyl, O- aryl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O-alkyl- heteroaryl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(O)- heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl- heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ - cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl- heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0)NH-alkyl, C(0)NH- cycloalkyl, C(0)NH-heterocyclyl, C(0)NH-aryl, C(0)NH-heteroaryl, C(0)NH-alkyl- cycloalkyl, C(0)NH-alkyl-heterocyclyl, C(0)NH-alkyl-aryl, C(0)NH-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ NH ₂ , S0 ₂ NH-alkyl, S0 ₂ NH-aryl, S0 ₂ NH-heteroaryl, S0 ₂ NH-alkyl- aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,

(II) unsubstituted or substituted alkyl-heteroaryl wherein the alkyl-heteroaryl group can be substituted with one or more, the same or different F, CI, Br, I, CF ₃ , CN, NH ₂ , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl- heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl) ₂ , NHC(0)-alkyl, NHC(O)- cycloalkyl, HC(0)-heterocyclyl, HC(0)-aryl, HC(0)-heteroaryl, HC(0)-alkyl-aryl, HC(0)-alkyl-heteroaryl, HS0 ₂ -alkyl, HS0 ₂ -cycloalkyl, HS0 ₂ -heterocyclyl, HS0 ₂ - aryl, HS0 ₂ -heteroaryl, HS0 ₂ -alkyl-aryl, HS0 ₂ -alkyl-heteroaryl, N0 ₂ , SH, S-alkyl, S- cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF ₃ , O-alkyl, O-cycloalkyl, O- heterocyclyl, O-aryl, O-heteroaiyl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aiyl, O- alkyl-heteroaryl, OC(0)-alkyl, OC(0)-cycloalkyl, OC(0)-heterocyclyl, OC(0)-aryl, OC(O)- heteroaryl, OC(0)-alkyl-aryl, OC(0)-alkyl-heteroaryl, OS0 ₃ H, OS0 ₂ -alkyl, OS0 ₂ - cycloalkyl, OS0 ₂ -heterocyclyl, OS0 ₂ -aryl, OS0 ₂ -heteroaryl, OS0 ₂ -alkyl-aryl, OS0 ₂ -alkyl- heteroaryl, OP(0)(OH) ₂ , C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 ₂ H, C0 ₂ -alkyl, C0 ₂ - cycloalkyl, C0 ₂ -heterocyclyl, C0 ₂ -aryl, C0 ₂ -heteroaryl, C0 ₂ -alkyl-cycloalkyl, C0 ₂ -alkyl- heterocyclyl, C0 ₂ -alkyl-aryl, C0 ₂ -alkyl-heteroaryl, C(0)-NH ₂ , C(0) H-alkyl, C(0) H- cycloalkyl, C(0) H-heterocyclyl, C(0) H-aryl, C(0) H-heteroaryl, C(0) H-alkyl- cycloalkyl, C(0) H-alkyl-heterocyclyl, C(0) H-alkyl-aryl, C(0) H-alkyl-heteroaiyl, C(0)N(alkyl) ₂ , C(0)N(cycloalkyl) ₂ , C(0)N(aryl) ₂ , C(0)N(heteroaryl) ₂ , SO-alkyl, SO-aryl, S0 ₂ -alkyl, S0 ₂ -aryl, S0 ₂ H ₂ , S0 ₂ H-alkyl, S0 ₂ H-aryl, S0 ₂ H-heteroaryl, S0 ₂ H-alkyl- aryl, S0 ₃ H, S0 ₂ 0-alkyl, S0 ₂ 0-aryl, S0 ₂ 0-alkyl-aryl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

or a pharmaceutically acceptable salt or ester thereof.

9. The method according to paragraph 6, wherein the ERK1/2 inhibitor is:

(S)-l-(l-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-( (l-methyl-lH-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin-2(lH)-one; or

4-(5-chloro-2-(isopropylamino)pyridin-4-yl)-N-((S)-l-(3-c hlorophenyl)-2-hydroxyethyl)-lH- py rrol e-2-carb oxami de, or a pharmaceutically acceptable salt or ester thereof.

10. The method according to paragraph 6, wherein the ERK1/2 inhibitor is: l-((R)-l-Methyl-4-phenyl-butyl)-3-[3-(l-propyl-lH-pyrazol-4- yl)-pyrido[2,3-b]pyrazin-6- yl]-urea; l-{3-[4-(2-Mo holin-4-yl-ethoxy)-phenyl]-pyrido[2,3-b]pyrazin-6-yl}-3-(4-p henyl-butyl)- urea; l-((R)-l-Methyl-4-phenyl-butyl)-3-[3-(l-methyl-lH-pyrazol-4- yl)-pyrido[2,3-b]pyrazin-6- yl]-urea; or 1 -((R)- 1 -Methyl-4-phenyl-butyl)-3 -{ 3 -[ 1 -(2-morpholin-4-yl-ethyl)- lH-pyrazol-4-yl]- pyrido[2,3-b]pyrazin-6-yl}-urea, or a pharmaceutically acceptable salt or ester thereof.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

References:

A. Madhav Bhatia, Review Article: Role of Hydrogen Sulfide in the Pathology of Inflammation, Scientifica, 2012, 159680.

B. Huili Zhang, Liang Zhi, Phlip K. Moore, Madhav Bhatia Role of hydrogen sulfide in cecal ligation and puncture-induced sepsis in the mouse, Am J Physiol Lung Cell Mol Physiol 290: L1193-L1201, 2006.

C. Ang SF, Moochhala SM, MacAry PA, Bhatia M (2011) Hydrogen Sulfide and Neurogenic Inflammation in Polymicrobial Sepsis: Involvement of Substance P and ERK- NF-KB Signaling. PLOS ONE 6(9): e24535.

1. Adhikari NK, Fowler RA, Bhagwanjee S, et al. Critical care and the global burden of critical illness in adults. Lancet 2010;376(9749): 1339-1346.

2. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Critical care medicine 2001;29(7): 1303-1310.

3. Lever A, Mackenzie I. Sepsis: definition, epidemiology, and diagnosis. Bmj 2007;335(7625):879-883. 4. Singh S, Evans TW. Organ dysfunction during sepsis. Intensive care medicine 2006;32(3):349-360.

5. Sonneville R, Verdonk F, Rauturier C, et al. Understanding brain dysfunction in sepsis. Annals of intensive care 2013;3(1): 15.

6. Suh SH, Kim CS, Choi JS, et al. Acute kidney injury in patients with sepsis and septic shock: risk factors and clinical outcomes. Yonsei medical journal 2013;54(4):965-972.

7. Plataki M, Kashani K, Cabello-Garza J, et al. Predictors of acute kidney injury in septic shock patients: an observational cohort study. Clinical journal of the American Society ofNephrology : CJASN 2011;6(7): 1744-1751.

8. Schrier RW, Wang W. Acute renal failure and sepsis. The New England journal of medicine 2004;351(2): 159-169.

9. Claessens YE, Dhainaut JF. Diagnosis and treatment of severe sepsis. Critical care 2007; 11 Suppl 5:S2.

10. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. The New England journal of medicine 2001;345(19): 1368- 1377.

11. Levy MM, Rhodes A, Phillips GS, et al. Surviving sepsis campaign: association between performance metrics and outcomes in a 7.5-year study. Critical care medicine 2015;43(1):3-12.

12. Zhang B, Ramesh G, Uematsu S, et al. TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. Journal of the American Society of Nephrology : JASN 2008; 19(5):923-932.

13. Gomez H, Ince C, De Backer D, et al. A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock 2014;41(1):3-11.

14. Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Annual review of immunology 2002;20:55-72. 15. Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity. Nature reviews Immunology 2013;13(9):679-692.

16. Jiang R, Ye J, Zhu B, et al. Roles of TLR3 and RIG-I in mediating the inflammatory response in mouse microglia following Japanese encephalitis virus infection. Journal of immunology research 2014;2014:787023.

17. Roskoski R, Jr. ERKl/2 MAP kinases: structure, function, and regulation. Pharmacological research : the official journal of the Italian Pharmacological Society 2012;66(2): 105-143.

18. Reimann T, Buscher D, Hipskind RA, et al. Lipopolysaccharide induces activation of the Raf-l/MAP kinase pathway. A putative role for Raf-1 in the induction of the IL-1 beta and the TNF-alpha genes. Journal of immunology 1994; 153(12):5740-5749.

19. Geppert TD, Whitehurst CE, Thompson P, et al. Lipopolysaccharide signals activation of tumor necrosis factor biosynthesis through the ras/raf-l/MEK/MAPK pathway. Molecular medicine 1994; 1(1):93-103.

20. Schaefer L, Babelova A, Kiss E, et al. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. The Journal of clinical investigation 2005; 115(8):2223-2233.

21. Luan H, Zhang Q, Wang L, et al. OM85-BV induced the productions of IL-lbeta, IL- 6, and TNF-alpha via TLR4- and TLR2-mediated ERKl/2/NF-kappaB pathway in RAW264.7 cells. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2014;34(7):526-536.

22. Dumitru CD, Ceci JD, Tsatsanis C, et al. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 2000; 103(7): 1071-1083.

23. Smith JA, Stations LJ, Collier JB, et al. Suppression of mitochondrial biogenesis through toll-like receptor 4-dependent mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling in endotoxin-induced acute kidney injury. The Journal of pharmacology and experimental therapeutics 2015;352(2):346-357. 24. Shi-Lin D, Yuan X, Zhan S, et al. Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (T F)-alpha production and endotoxin shock. Biochemical and biophysical research communications 2015 ;458(3): 667- 673.

25. Johnson AS, Crandall H, Dahlman K, et al. Preliminary Results from a Prospective Trial of Preoperative Combined BRAF and MEK-Targeted Therapy in Advanced BRAF Mutation-Positive Melanoma. Journal of the American College of Surgeons 2015;220(4):581-593 e581.

26. Schadendorf D, Amonkar MM, Stroyakovskiy D, et al. Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. European j ournal of cancer 2015;51(7):833-840.

27. Coupe N, Corrie P, Hategan M, et al. PACMEL: a phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel. European journal of cancer 2015;51(3):359-366.

28. Remick DG, Ward PA. Evaluation of endotoxin models for the study of sepsis. Shock 2005;24 Suppl 1 :7-11.

29. Zager RA, Johnson AC, Becker K. Plasma and urinary heme oxygenase- 1 in AKI. Journal of the American Society of Nephrology : JASN 2012;23(6): 1048-1057.

30. Mishra J, Ma Q, Prada A, et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. Journal of the American Society of Nephrology : JASN 2003; 14(10):2534-2543.

31. Ichimura T, Bonventre JV, Bailly V, et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up- regulated in renal cells after injury. The Journal of biological chemistry 1998;273(7):4135- 4142.

32. Adler M, Ramm S, Hafner M, et al. A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. Journal of the American Society of Nephrology : JASN 2015. 33. Miyaji T, Hu X, Yuen PS, et al. Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice. Kidney international 2003;64(5): 1620-1631.

34. Wang Z, Sims CR, Patil K, et al. Pharmacologic targeting of sphingosine-1- phosphate receptor 1 improves the renal microcirculation during sepsis in the mouse. The Journal of pharmacology and experimental therapeutics 2015;352(l):61-66.

35. Hippalgaonkar K, Majumdar S, Kansara V. Injectable lipid emulsions-advancements, opportunities and challenges. AAPS PharmSciTech 2010; 11 (4): 1526- 1540.

36. Yamaguchi T, Kakefuda R, Tajima N, et al. Antitumor activities of JTP-74057 (GSKl 120212), a novel MEKl/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. International journal of oncology 2011;39(1):23-31.

37. Yamaguchi T, Kakefuda R, Tanimoto A, et al. Suppressive effect of an orally active MEKl/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide. Inflammation research : official journal of the European Histamine Research Society [et al] 2012;61(5):445-454.

38. Schadendorf D, Amonkar MM, Stroyakovskiy D, et al. Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. European journal of cancer 2015.

39. Blumenschein G, Jr., Smit EF, Planchard D, et al. A randomized phase 2 study of the MEK1/MEK2 inhibitor trametinib (GSKl 120212) compared with docetaxel in KRAS-mutant advanced non-small cell lung cancer (NSCLC). Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2015.

40. Wang Z, Holthoff JH, Seely KA, et al. Development of oxidative stress in the peritubular capillary microenvironment mediates sepsis-induced renal microcirculatory failure and acute kidney injury. The American journal of pathology 2012;180(2):505-516.

41. Wills LP, Trager RE, Beeson GC, et al. The beta2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis. The Journal of pharmacology and experimental therapeutics 2012;342(1): 106-118. 42. Stations LJ, Whitaker RM, Schnellmann RG. Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis. Toxicology letters 2014;224(3):326- 332.

43. Ebong SJ, Goyert SM, Nemzek JA, et al. Critical role of CD 14 for production of proinflammatory cytokines and cytokine inhibitors during sepsis with failure to alter morbidity or mortality. Infection and immunity 2001;69(4):2099-2106.

44. Herzig DS, Driver BR, Fang G, et al. Regulation of lymphocyte trafficking by CXC chemokine receptor 3 during septic shock. American journal of respiratory and critical care medicine 2012; 185(3):291-300.

45. Dear JW, Yasuda H, Hu X, et al. Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis. Kidney international 2006;69(5):832-836.

46. Cunningham PN, Dyanov HM, Park P, et al. Acute renal failure in endotoxemia is caused by T F acting directly on T F receptor- 1 in kidney. Journal of immunology 2002; 168(l l):5817-5823.

47. Wang Z, Herzog C, Kaushal GP, et al. Actinonin, a meprin A inhibitor, protects the renal microcirculation during sepsis. Shock 2011;35(2): 141-147.

48. Verma SK, Molitoris BA. Renal Endothelial Injury and Microvascular Dysfunction in Acute Kidney Injury. Seminars in nephrology 2015;35(1):96-107.

49. Lush CW, Kvietys PR. Microvascular dysfunction in sepsis. Microcirculation 2000;7(2):83-101.

50. Lee WL, Slutsky AS. Sepsis and endothelial permeability. The New England journal of medicine 2010;363(7):689-691.

51. Vincent JL, De Backer D. Microvascular dysfunction as a cause of organ dysfunction in severe sepsis. Critical care 2005;9 Suppl 4:S9-12.

52. Nath KA, Balla G, Vercellotti GM, et al. Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. The Journal of clinical investigation 1992;90(l):267-270. 53. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Critical care medicine 2013;41(2):580-637.

54. Means TK, Pavlovich RP, Roca D, et al. Activation of TNF-alpha transcription utilizes distinct MAP kinase pathways in different macrophage populations. Journal of leukocyte biology 2000;67(6):885-893.

55. Doi K, Leelahavanichkul A, Yuen PS, et al. Animal models of sepsis and sepsis- induced kidney injury. The Journal of clinical investigation 2009; 119(10):2868-2878.

56. Dyson A, Singer M. Animal models of sepsis: why does preclinical efficacy fail to translate to the clinical setting? Critical care medicine 2009;37(1 Suppl):S30-37.

57. Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. Nature reviews Drug discovery 2005;4(10):854-865.

58. Cho MK, Jang YP, Kim YC, et al. Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan, inhibits MAP kinases and AP-1 activation via potent MKK inhibition: the role in TNF-alpha inhibition. International immunopharmacology 2004;4(10- 11): 1419-1429.

59. Guha M, O'Connell MA, Pawlinski R, et al. Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression. Blood 2001;98(5): 1429-1439.

60. Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Annals of internal medicine 1993; 119(8):771- 778.

61. Hack CE, De Groot ER, Felt-Bersma RJ, et al. Increased plasma levels of interleukin- 6 in sepsis. Blood 1989;74(5): 1704-1710.

62. Remick DG, Bolgos G, Copeland S, et al. Role of interleukin-6 in mortality from and physiologic response to sepsis. Infection and immunity 2005;73(5):2751-2757. 63. Xu C, Chang A, Hack BK, et al. TNF-mediated damage to glomerular endothelium is an important determinant of acute kidney injury in sepsis. Kidney international 2014;85(1):72-81.

64. Nesseler N, Launey Y, Aninat C, et al. Clinical review: The liver in sepsis. Critical care 2012; 16(5):235.

65. Ware LB. Pathophysiology of acute lung injury and the acute respiratory distress syndrome. Seminars in respiratory and critical care medicine 2006;27(4):337-349.

66. Beier K, Eppanapally S, Bazick HS, et al. Elevation of blood urea nitrogen is predictive of long-term mortality in critically ill patients independent of "normal" creatinine. Critical care medicine 2011;39(2):305-313.

67. Wu L, Gokden N, Mayeux PR. Evidence for the role of reactive nitrogen species in polymicrobial sepsis-induced renal peritubular capillary dysfunction and tubular injury. Journal of the American Society of Nephrology : JASN 2007; 18(6): 1807-1815.

68. Wu L, Tiwari MM, Messer KJ, et al. Peritubular capillary dysfunction and renal tubular epithelial cell stress following lipopolysaccharide administration in mice. American journal of physiology Renal physiology 2007;292(l):F261-268.

69. Holthoff JH, Wang Z, Patil NK, et al. Rolipram improves renal perfusion and function during sepsis in the mouse. The Journal of pharmacology and experimental therapeutics 2013;347(2):357-364.

70. Holthoff JH, Wang Z, Seely KA, et al. Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury. Kidney international 2012;81(4):370-378.

71. Nwariaku FE, Rothenbach P, Liu Z, et al. Rho inhibition decreases TNF-induced endothelial MAPK activation and monolayer permeability. Journal of applied physiology 2003;95(5): 1889-1895.

72. Varma S, Breslin JW, Lai BK, et al. p42/44MAPK regulates baseline permeability and cGMP -induced hyperpermeability in endothelial cells. Microvascular research 2002;63(2): 172-178. 73. Zou L, Feng Y, Li Y, et al. Complement factor B is the downstream effector of TLRs and plays an important role in a mouse model of severe sepsis. Journal of immunology 2013; 191(l l):5625-5635.

74. Zhang H, Moochhala SM, Bhatia M. Endogenous hydrogen sulfide regulates inflammatory response by activating the ERK pathway in polymicrobial sepsis. Journal of immunology 2008; 181(6):4320-4331.

75. Ramesh G, Reeves WB. Salicylate reduces cisplatin nephrotoxicity by inhibition of tumor necrosis factor-alpha. Kidney international 2004;65(2):490-499.

76. Chen YY, Yeh CH, So EC, et al. Anticancer drug 2-methoxyestradiol protects against renal ischemia/reperfusion injury by reducing inflammatory cytokines expression. BioMed research international 2014;2014:431524.

77. Varisco, Brian Michael, The Pharmacology of Acute Lung Injury in Sepsis.

Advances in Pharmacological Sciences 2011, doi: 10.1155/2011/254619.