HK1223877B - Serine/threonine kinase inhibitors - Google Patents

Description

Serine/threonine kinase inhibitors

Technical Field

The present invention relates to compounds that inhibit serine/threonine kinases and are useful for treating hyperproliferative and neoplastic diseases by inhibiting signal transduction pathways that are typically overactivated or overexpressed in cancerous tissues. The compounds of the present invention are selective inhibitors of ERK (extracellular signal-regulated kinase). The present invention also relates to methods for treating cancer or hyperproliferative diseases with the compounds of the present invention.

Background Art

The processes involved in tumor growth, progression and metastasis are mediated by signal transduction pathways activated in cancer cells. The ERK pathway plays a major role in regulating mammalian cell growth by taking over extracellular signals from ligand-bound cell surface receptor tyrosine kinases ("RTKs") (such as ErbB family, PDGF, FGF and VEGF receptor tyrosine kinases). The activation of RTKs can induce a cascade of phosphorylation events that begins with the activation of Ras. The activation of Ras can lead to the recruitment and activation of Raf (a serine-threonine kinase). The activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates ERK1/2. When activated, ERK1/2 phosphorylates several downstream targets involved in numerous cellular events (including cytoskeleton changes and transcriptional activation). The ERK/MAPK pathway is a path that is most important to cell proliferation, and it is believed that the ERK/MAPK pathway is often activated in many tumors. The Ras gene upstream of ERK1/2 is mutated in several cancers including colorectal tumors, melanomas, breast tumors, and pancreatic tumors. In many human tumors, high Ras activity is accompanied by elevated ERK activity. In addition, mutations in BRAF, a serine-threonine kinase of the Raf family, are associated with increased kinase activity. Mutations in BRAF have been identified in melanoma (60%), thyroid cancer (greater than 40%), and colorectal cancer. These observations indicate that the ERK1/2 signaling pathway is an attractive pathway for anticancer therapy in a broad spectrum of human tumors (M. Hohno and J. Pouyssegur, Prog. in Cell Cycle Res. 2003 5:219).

The ERK pathway has also been cited as a promising therapeutic target for the treatment of pain and inflammation (Ma, Weiya and Remi Quirion. “The ERK/MAPK pathway, as a target for the treatment of neuropathic pain.” Expert Opin. Ther. Targets. 9(4) (2005): 699-713; and Sommer, Claudia and Frank Birklein. “Resolvins and inflammatory pain.” F1000 Medicine Reports. 3:19 (2011)).

International Patent Application Publications WO 2012/118850, WO 2013/020062, and WO 2013/130976 disclose ERK inhibitors.

Therefore, small molecule inhibitors of ERK activity (i.e., ERK1 and/or ERK2 activity) will be useful in treating a wide spectrum of cancers, such as, for example, melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer; and in treating pain and inflammation, such as arthritis, lower back pain, inflammatory bowel disease, and rheumatism. This effect is provided herein.

Summary of the Invention

There is a continuing need for new and novel therapeutic agents that can be used for cancer and hyperproliferative conditions. The Raf/MEK/ERK pathway is an important signaling pathway that is often overexpressed and/or overactivated in many cancerous tissues. The design and development of new drug compounds is essential.

More specifically, one aspect provides a compound of formula I:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X ₁ , X ₂ , R ¹ , R ² , R ³ and R ⁴ are as defined herein.

In another aspect, provided is a compound of Formula II, III, IV, V, VI, VII, VIII, IX, or X, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Another aspect provides a method for treating a hyperproliferative disorder by administering to a patient in need thereof a therapeutically effective amount of a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. The compound can be administered alone or in combination with at least one other anti-hyperproliferative or chemotherapeutic compound.

In another aspect, a method of inhibiting ERK protein kinase activity in a cell is provided, comprising treating the cell with a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in an amount effective to reduce or eliminate ERK kinase activity.

In another aspect, a method for treating or preventing a disease or condition regulated by ERK is provided, comprising administering to a mammal in need thereof an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. Examples of such diseases and conditions include, but are not limited to, hyperproliferative conditions such as cancer.

Another aspect provides a method for treating or preventing cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more other compounds having anti-cancer properties.

Another aspect provides a method of treating a hyperproliferative disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another aspect provides the use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a hyperproliferative disease.

In another aspect, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, is provided for use in treating a hyperproliferative disease.

In another aspect, a pharmaceutical composition is provided comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

Another aspect provides intermediates for preparing compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, or X. Certain compounds of the formula are useful as intermediates for making other compounds of the formula.

Another aspect includes methods for preparing, isolating, and purifying the compounds described herein.

DETAILED DESCRIPTION

With reference now to certain embodiments in detail, the example of the embodiment is illustrated with accompanying structure and formula. Although the embodiments of enumeration will be described, it should be understood that they are not intended to limit the present invention to those embodiments. On the contrary, the present invention is intended to encompass all substitutes, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize that many methods and materials that can be used to implement the present invention are similar or equivalent to the methods and materials described herein. The present invention is by no means limited to the methods and materials. If one or more incorporated documents and similar materials are different or conflict with the present application (including but not limited to defined terms, term usage, described technology, etc.), then the present application shall prevail.

definition

As used herein, the phrases "a" or "an" entity refer to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. Thus, the terms "a," "one or more," and "at least one" are used interchangeably herein.

The phrase "as defined herein" refers to the broadest definition provided in the detailed description of the invention or the broadest claim for each group. In all other embodiments provided below, substituents that may be present in each embodiment and are not explicitly defined retain the broadest definition provided in the detailed description of the invention.

As used in this specification, the terms "comprise(s)/comprising" should be interpreted as having a beginning meaning, whether in a transitional phrase or in the body of the claims. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a method, the term "comprise" means that the method includes at least the recited steps, but may include other steps. When used in the context of a compound or composition, the term "comprise" means that the compound or composition includes at least the recited features or components, but may also include other features or components. In addition, the words "include/including/includes" when used in this specification and the following claims are intended to specify the presence of the stated features, integers, components or steps, but they do not exclude the presence or addition of one or more other features, integers, components, steps or groups thereof.

The term "independently" is used herein to indicate that a variable is applied in any instance without regard to the presence or absence of that variable having the same or different definition within the same compound. Thus, in a compound in which R" appears twice and is defined as "independently carbon or nitrogen," both R"s may be carbon, both R"s may be nitrogen, or one R" may be carbon and the other R" may be nitrogen.

When any variable (e.g., R ¹ , R ^4a , Ar, X ₁ or Het) occurs more than one time in any moiety or formula depicting and describing compounds employed or claimed in the present invention, its definition on each occurrence is independent of its definition at every other occurrence. Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted" means that the optionally substituted moiety may incorporate hydrogen or a substituent.

The term "about" is used herein to mean approximately, roughly, roughly, or about. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values recited. Generally, the term "about" is used herein to modify a numerical value by a variance of 20% above and below the stated value.

As used herein, the description of the numerical range of a variable is intended to express that the present invention can be implemented when the variable is equal to any value within that range. Therefore, for inherent discrete variables, the variable can be equal to any integer value of the numerical range, including the endpoints of the range. Similarly, for inherent continuous variables, the variable can be equal to any real value of the numerical range, including the endpoints of the range. For example, a variable described as having a value between 0 and 2 can be 0, 1 or 2 for inherent discrete variables, and can be 0.0, 0.1, 0.01, 0.001 or any other real value for inherent continuous variables.

Certain compounds of formula I, II, III, IV, V, VI, VII, VIII, IX or X may exhibit tautomerism. Tautomeric compounds may exist in two or more mutually convertible forms. Prototropic tautomers are caused by the migration of covalently bonded hydrogen atoms between two atoms. Tautomers typically exist in equilibrium, and attempts to separate individual tautomers typically produce mixtures whose chemical and physical properties are consistent with those of the compound. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones (such as acetaldehyde), the keto form predominates; whereas in phenols, the enol form predominates. Common prototropic tautomers include keto/enolamide/imidic acid and amidine tautomers. The latter two are particularly common in heteroaryls and heterocycles, and the present invention encompasses all tautomeric forms of compounds.

The skilled artisan will appreciate that some of the compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX or X may contain one or more chiral centers and therefore exist in two or more stereoisomeric forms. Racemates of these isomers, individual isomers, and mixtures enriched in one enantiomer, as well as diastereomers when two chiral centers are present, and mixtures partially enriched in a specific diastereomer are within the scope of the present invention. The present invention includes all individual stereoisomers (e.g., enantiomers), racemic mixtures, or partially resolved mixtures of compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX or X and, where appropriate, their individual tautomeric forms.

The compounds of formula I, II, III, IV, V, VI, VII, VIII, IX or X may contain a basic center, and suitable acid addition salts are formed from acids that form non-toxic salts. Examples of salts with inorganic acids include hydrochlorides, hydrobromides, hydroiodides, chlorides, bromides, iodides, sulfates, bisulfates, nitrates, phosphates and hydrogenphosphates. Examples of salts of organic acids include acetate, fumarate, pamoate, aspartate, benzenesulfonate, carbonate, bicarbonate, camsylate, D- and L-lactate, D- and L-tartrate, ethanesulfonate, methanesulfonate, malonate, orotate, glucoheptonate, methylsulfate, stearate, glucuronate, 2-naphthalenesulfonate, toluenesulfonate, hibenzate, nicotinate, isethionate, malate, maleate, citrate, gluconate, succinate, sucrose, benzoate, ethanesulfonate, and pamoate. For reviews of suitable salts, see Berge, Stephen M. et al. "Pharmaceutical salts." J. Pharm. Sci. Vol. 66, No. 1 (1977): 1-19; and Paulekuhn, G. Steffen et al. "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database." J. Med. Chem. Vol. 50, No. 26 (2007): 6665-6672.

Unless otherwise defined, the technical and scientific terms used herein have the meanings commonly understood by those skilled in the art. Reference is made herein to various methods and materials known to those skilled in the art. Standard reference works setting forth the general principles of pharmacology include Hardman, Joel Griffith et al., Goodman &Gilman's The Pharmacological Basis of Therapeutics. New York: McGraw-Hill Professional, 2001. The starting materials and reagents used to prepare these compounds are generally available from commercial suppliers such as Sigma-Aldrich (St. Louis, MO), or are prepared by methods known to those skilled in the art following the procedures described in the references. Unless otherwise indicated, the substances, reagents, etc. mentioned in the following description and examples are available from commercial sources. General synthetic procedures are described in monographs such as Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis. Vols. 1-23, New York: Wiley 1967-2006 editions (also available through the Wiley website); LaRock, Richard C., Comprehensive Organic Transformations: A Guide to Functional Group Preparations. New York: Wiley-VCH, 1999; B. Trost and I. Fleming, eds. Comprehensive Organic Synthesis. Vols. 1-9, Oxford: Pergamon 1991; A. R. Katritzky and C. W. Rees, eds. Comprehensive Heterocyclic Chemistry. Oxford: Pergamon 1984; A. R. Katritzky and C. W. Rees, eds. Comprehensive Heterocyclic Chemistry II. Oxford: Pergamon 1996; and Paquette, Leo A., ed. Organic Reactions. Vols. 1-40, New York: Wiley & Sons 1991; and will be familiar to those skilled in the art.

The definitions described herein can be appended to form chemically related combinations, such as "heteroalkylaryl", "haloalkylheteroaryl", "arylalkylheterocyclyl", "alkylcarbonyl", "alkoxyalkyl", etc. When the term "alkyl" is used as a suffix after another term, as in "phenylalkyl" or "hydroxyalkyl", this means an alkyl group as defined above that is substituted with at least one substituent selected from another specifically named group. Thus, for example, "phenylalkyl" refers to an alkyl group having at least one phenyl substituent and thus includes benzyl and phenylethyl. "Alkylaminoalkyl" is an alkyl group having at least one alkylamino substituent. "Hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, etc. Thus, as used herein, the term "hydroxyalkyl" is used to define a subset of heteroalkyl groups defined below. The term -(ar)alkyl refers to an unsubstituted alkyl or aralkyl group. The term (hetero)aryl refers to a moiety that is an aryl or heteroaryl group.

As used herein, the term "C ₁ -C ₄ acyloxy-C ₁ -C ₂ alkyl" refers to a radical of the formula -(CH ₂ ) _1-2 OC(O)(CH ₂ ) _0-3 H. As used herein, the term "C ₁ -C ₄ acyloxy" refers to a radical -OC(O)R, wherein R contains 1 to 4 carbon atoms (e.g., C ₁ is formyl).

The term "alkyl" includes straight or branched chain groups of carbon atoms. Some alkyl moieties have been abbreviated, such as methyl ("Me"), ethyl ("Et"), propyl ("Pr"), and butyl ("Bu"), and other abbreviations are used to designate specific isomers of a compound, such as 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), and the like. Abbreviations are sometimes used in conjunction with element abbreviations and chemical structures, such as methanol ("MeOH") or ethanol ("EtOH").

Other abbreviations used throughout the application may include, for example, benzyl ("Bn"), phenyl ("Ph"), and acetate ("Ac").

The terms "alkenyl" and "alkynyl" also include straight or branched chain groups of carbon atoms.

As used herein, the term "haloalkyl" refers to an unbranched or branched chain alkyl group as defined above, wherein 1, 2, 3 or more hydrogen atoms are replaced by halogen. Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1-fluoroethyl, 1-chloroethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-dichloroethyl, 3-bromopropyl, 2,2,2-trifluoroethyl, 2-chloro-3-fluoropropyl and 1,1,2,2,2-pentafluoroethyl (perfluoroethyl).

As used herein, the term "heteroalkyl" means an alkyl group as defined herein, wherein one or two hydrogen atoms are independently selected from the substituent replacement of the group consisting of -OR ^α and -NR ^β R ^γ , provided that the point of attachment of the heteroalkyl group is realized by a carbon atom. ^{R α} is hydrogen or alkyl, and R ^β and R ^γ are hydrogen, acyl, alkyl, or R ^β and R ^γ form a cyclic amine together with the nitrogen to which they are connected. Hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl moieties are subgenuses encompassed by the term "heteroalkyl". Representative examples include but are not limited to 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-methylaminopropyl etc.

The term "heteroaryl" includes five to six-membered monocyclic and nine to ten-membered bicyclic aromatic rings containing one, two, three, or four heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, provided that the ring does not contain two adjacent O or S atoms. In some cases, these terms can be further specifically defined, such as five to six-membered heteroaryl, wherein the heteroaryl contains one or two nitrogen heteroatoms. As is well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counterparts. Therefore, for the purposes of the present invention, heteroaryl groups only need to have a certain degree of aromatic character.

Heteroaryl groups may include, for example, pyrrolyl, thiophenyl (thienyl), furanyl (furyl), imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, Oxamethazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolopyridinyl, imidazopyridinyl, pyrazolopyridine, isoindolyl, indazolyl, purinyl, indolinyl, pyrrolopyridazinyl, imidazopyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyrimidopyrimidinyl, and pyrazinopyrazinyl.

The terms "heterocycle", "heterocyclic" and "heterocyclyl" include three to seven membered monocyclic saturated or partially unsaturated rings containing one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, S(=O) and S(=O) ₂ , provided that the ring does not contain two adjacent O or S atoms. In some cases, these terms can be further specifically defined, such as "five to six membered heterocyclyl" which only includes five and six membered rings. Bicyclic heterocyclic groups include five to fourteen membered bicyclic saturated or partially unsaturated rings containing one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, S(=O) and S(=O) _2. In some cases, these terms can be further specifically defined, such as "seven to ten membered heterocyclyl" which only includes seven to ten membered bicyclic rings.

Heterocyclic groups can include, for example, oxirane, thiol, aziridine, oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrophenylthio, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, dioxanyl, oxathianyl, morpholinyl (morpholino), dithianyl, piperazinyl, azathianyl, oxepanyl, thiepanyl, azepanyl, dioxepanyl, oxathianyl, oxazepanyl, dithianyl, thiazepanyl, diazepanyl, dihydrofuranyl, dihydropyranyl, pyranyl and tetrahydropyridinyl. Additional examples of 5- and 6-membered ring systems discussed above can be found in U.S. Pat. No. 4,278,793.

As used herein, the terms "hydroxyalkyl" and "alkoxyalkyl" refer to an alkyl group as defined herein in which one to three hydrogen atoms on different carbon atoms are replaced by hydroxy or alkoxy groups, respectively. _{A C1} - _C3alkoxy - _C1 - _C6alkyl moiety refers to a _C1 - _C6alkyl substituent in which one to three hydrogen atoms are replaced by _C1 - _C3alkoxy groups, and the point of attachment of the alkoxy groups is an oxygen atom.

A bond introduced into a ring system (as opposed to being attached at a specific vertex) indicates that the bond may be attached to any suitable ring atom.

The methods of the present invention encompass methods for treating, preventing, and/or managing various types of cancer, as well as diseases and conditions associated with or characterized by unwanted angiogenesis. As used herein, unless otherwise specified, the terms "treating" and "treat" refer to the administration of a compound of the present invention or other additional active agent after the onset of symptoms of a particular disease or condition. The terms "treat" and "treatment" also refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction in disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean prolonging survival compared to the expected survival if not receiving treatment. Those in need of treatment include those already suffering from the condition or disorder, as well as those predisposed to developing the condition or disorder. As used herein, unless otherwise specified, the term "preventing" refers to administration prior to the onset of symptoms, particularly to patients at risk for cancer and other diseases and conditions associated with or characterized by unwanted angiogenesis. The term "prevent" includes suppressing the symptoms of a particular disease or condition. Patients with a family history of cancer and diseases and conditions associated with or characterized by undesirable angiogenesis are preferred candidates for preventive regimens. As used herein and unless otherwise indicated, the term "manage" encompasses preventing the recurrence of a particular disease or condition in a patient already suffering from the disease or condition and/or prolonging the time a patient already suffering from the disease or condition remains in remission.

The phrase "therapeutically effective amount" or "effective amount" means an amount of a compound described herein that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition, or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound that will correspond to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the characteristics (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by abnormal or unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma); lung cancer, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma, and lung squamous carcinoma; peritoneal cancer; hepatocellular carcinoma; gastric/stomach cancer, including gastrointestinal cancer; pancreatic cancer; glioblastoma; cervical cancer; ovarian cancer; liver cancer; bladder cancer; hepatoma; breast cancer; colon cancer; rectal cancer; colorectal cancer; endometrial or uterine cancer; salivary gland cancer; kidney/renal cancer; prostate cancer; vulvar cancer; thyroid cancer; hepatic carcinoma; anal cancer; penile cancer; skin cancer, including melanoma; and head and neck cancer.

A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (Genentech/OSI Pharm.); bortezomib (Millennium Pharm.); fulvestrant (AstraZeneca); sunitinib (Pfizer/Sugen); letrozole (Novartis); imatinib mesylate (Novartis); finasulan (Novartis); oxaliplatin (Sanofi); 5-FU (5-fluorouracil); leucovorin; rapamycin (Sirolimus, Wyeth); lapatinib (GSK572016, GlaxoSmithKline); lonafamib (SCH 66336); sorafenib (Bayer Labs); gefitinib (AstraZeneca); AG1478, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; polyacetyl groups; ns) (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including its synthetic analogues , KW-2189, and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novemb ichin), phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma and calicheamicin omega (Angew Chem. Intl. Ed. Engl. 1994) 33:183-186); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromoproteins (enediyne antibiotic chromophores), aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzophilin, inophilin), chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolinyl-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins (such as mitomycin C), mycophenolic acid acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimethoprim-sulfamethoxazole, quinolones, quinolones, dapoxetine ... trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate propionate, epitiostanol, mepitiostane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; polysaccharide complex (JHS) Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A) A) and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL) and (docetaxel/doxetaxel; Sanofi-Aventis; chloranmbucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide. etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); a retinoid, such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

Also included within the definition of "chemotherapeutic agent" are: (i) antihormonal agents used to modulate or inhibit the effects of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene citrate; (ii) aromatase inhibitors that inhibit the aromatase enzyme that regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate, and dapoxetine. acetate), (exemestane; Pfizer), formestanie, fadrozole, (vorozole), (letrozole; Novartis), and (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabine (a 1,3-dioxolane nucleoside cytosine analogs); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation (such as, for example, PKC-α, Raf and H-Ras); (vii) ribozymes, such as VEGF expression inhibitors (for example) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, for example, and rIL-2; topoisomerase 1 inhibitors, such as rmRH; (ix) anti-angiogenic agents, such as bevacizumab (Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above.

The phrase "pharmaceutically acceptable" indicates that the substance or composition is chemically and/or toxicologically compatible with the other ingredients comprising the formulation, and/or the mammal to be treated therewith.

As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound described herein.

The compounds described herein also include other salts of the compounds, which are not necessarily pharmaceutically acceptable salts and which may be useful as intermediates in preparing and/or purifying the compounds described herein and/or for separating enantiomers of the compounds described herein.

The term "mammal" means a warm-blooded animal having or at risk of developing a disease described herein, and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.

ERK compounds

Provided herein are compounds and pharmaceutical formulations thereof that are potentially useful in treating diseases, conditions, and/or disorders modulated by ERK.

One embodiment provides a compound of formula I:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

_X is selected from CH and N;

_X2 is selected from CH and N;

^R1 is selected _{from C1-C12 alkyl} , C2- _{C12 alkenyl} , _C2 - _C12 alkynyl, C3 _{-C7 cycloalkyl} , phenyl, 3 to 7 membered saturated or partially unsaturated heterocyclyl, 5 to 6 membered heteroaryl, _C5 - _C14 bicyclic cycloalkyl, naphthyl, 5 to 14 membered bicyclic saturated or partially unsaturated heterocycle and 9 to 10 membered bicyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl and naphthyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen, ^ORa , ^NRbRc , ^oxo , oxide, CN, _C3 -C6 cycloalkyl, cyclopropylmethyl, 3 to ₇ membered heterocycle, _C1 - _C6 haloalkyl, _C1 - _C3 hydroxyalkyl, C1- _C4 acyloxy- _C1 - _C2 alkyl, phenyl and optionally substituted with one or more _groups independently selected from the group consisting of oxo and ORa, ^d is a C ₁ -C ₆ alkyl group substituted by a group;

^R2 is selected from hydrogen, _C1 - _C12 alkyl, _C2 - _C12 alkenyl, _C2 - _C12 alkynyl, _C3 - _C7 cycloalkyl, 3 to 7 membered saturated or partially unsaturated heterocyclyl, phenyl, 5 to 6 membered heteroaryl, _C5 - _C14 bicyclic cycloalkyl, naphthyl, 5 to 14 membered bicyclic saturated or partially unsaturated heterocyclyl and 9 to 10 membered bicyclic heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl and naphthyl may be optionally substituted with one or more groups independently selected from the group consisting of halogen; hydroxy; _C1 - _C6 alkyl optionally substituted with one or more groups independently selected from the group consisting of halogen, _C1 - _C3 alkoxy, or phenyl optionally substituted with two groups selected from the group consisting of halogen and _C1 - _C3 alkoxy; _C1 - _C6 alkoxy optionally substituted with one or more groups selected from the group consisting ^of halogen: ^NRkRm C ₃ -C ₆ cycloalkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, and phenyl optionally substituted by C ₁ -C ₃ alkoxy, wherein the alkyl, alkoxy, and phenyl may be optionally substituted by halogen; 4 to 6 membered heterocyclyl optionally substituted by one or more groups independently selected from the group consisting of halogen, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl optionally substituted by halogen, -C(═O)O(C ₁ -C ₆ alkyl), and phenyl; phenyl optionally substituted by one or more groups independently selected from the group consisting of halogen, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy, wherein the alkyl and alkoxy may be optionally substituted by halogen; 5 to 6 membered heteroaryl optionally substituted by one or more groups independently selected from the group consisting of halogen, C ₁ -C ₃ alkyl, C ₁ -C _3- membered alkoxy and 5- to 6-membered heteroaryl, wherein the alkyl and alkoxy groups may be optionally substituted with halogen;

^R3 is selected from hydrogen and halogen;

R ⁴ is selected from hydrogen and halogen;

each of ^Ra , ^Rb , ^Rc , and ^Rd is independently selected from hydrogen, _C1 - _C6 alkyl, and _C1 - _C6 haloalkyl; and

Each of R ^k and R ^m is independently selected from hydrogen, C ₁ -C ₃ alkyl, and C ₁ -C ₆ haloalkyl.

One embodiment provides compounds of Formula I and stereoisomers and pharmaceutically acceptable salts thereof, wherein:

_X is selected from CH and N;

_X2 is selected from CH and N;

R ¹ is selected from (a) C ₁ -C ₆ alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^a , NR ^b R ^c , oxo, CN, C ₃ -C ₆ cycloalkyl and 3 to 7 membered heterocyclic ring; (b) C ₃ -C ₇ cycloalkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^a , CN and C 1 -C 3 alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen and OR ^d ; (c) phenyl optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^a , CN, C ₃ -C ₆ cycloalkyl and C _{1 -C 3} alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen and OR ^d ; (d) 3 to 7 membered saturated or partially unsaturated heterocyclic ring optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^a , oxo, CN, C ₃ -C ₆ cycloalkyl and C _{1 -C 3} alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen and OR d (e) 5- to 6- ^membered heteroaryl optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^e , oxide, CN, C ₃ -C 6 cycloalkyl, and C ₁ -C ₃ alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, OR a , oxo, CN, C 3 -C ₆ cycloalkyl, and C _{1 -C 3} alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^a , oxo, CN, C 3 -C 6 cycloalkyl, and C 1 -C 3 alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen and OR d; and (f) 7- to 10-membered bicyclic heterocycle optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^a , oxo, CN, C ₃ -C ₆ cycloalkyl, and C ₁ -C ₃ alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen and OR ^d ;

R ² is selected from (a) C ₁ -C ₁₀ alkyl optionally substituted with one to four R ^f groups; (b) C _{3 -C 6} cycloalkyl optionally substituted with halogen, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy; (c) 4 to 6 membered heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the heterocyclyl may be optionally substituted with one to four R ^g groups; (d) phenyl optionally substituted with one to four groups selected from the following: halogen, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy; (e) 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted with one to four groups selected from the following: halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy and 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S; (f) optionally substituted with halogen, C ₁ -C ₃ alkyl and C (g) a 9- to 10-membered bicyclic heterocyclyl group containing one to three heteroatoms selected from N, O and S, _{wherein the heterocyclyl group may be optionally substituted with halogen, C 1 -C 3 alkyl and} C ₁ -C ₃ alkoxy _;

^R3 is selected from hydrogen and halogen;

R ⁴ is selected from hydrogen and halogen;

each of ^Ra , ^Rb , ^Rc , ^Rd and ^Re is independently selected from hydrogen and _C1 - _C6 alkyl;

each ^Rf is selected from (a) halogen; (b) hydroxy; (c) _C1 - _C3 ^alkoxy ; (d) ^NRkRm ; (e) _C3 - _C6 cycloalkyl optionally substituted with one or more ^Rh groups; (f) 4- to 6-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S, wherein the heterocyclyl may be optionally substituted with one or more groups selected from halogen, _C1 - _C3 alkoxy, _C1 - _C3 alkyl optionally substituted with halogen, -C(=O)O( _C1 - _C6 alkyl), and phenyl; (g) phenyl optionally substituted with one or more ^Rj groups; and (h) 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, wherein the heteroaryl may be optionally substituted with one or more ^Rj groups;

Each ^Rg is selected from (a) halogen; (b) _C1 - _C3 alkyl optionally substituted with halogen, _C1 - _C3 alkoxy or phenyl optionally substituted with two groups selected from halogen and _C1 - _C3 alkoxy; (c) _C1 - _C3 alkoxy optionally substituted with halogen; (d) phenyl optionally substituted with halogen or _C1 - _C3 alkoxy; and (e) 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted with one or two groups selected from halogen and _{C1-C3 alkoxy} ;

each R ^h is selected from halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, and phenyl optionally substituted with C ₁ -C ₃ alkoxy, wherein the alkyl, alkoxy, and phenyl groups may be optionally substituted with halogen;

each R ^j is selected from halogen, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy, wherein the alkyl and alkoxy groups may be optionally substituted with halogen; and

Each of ^Rk and ^Rm is independently selected from hydrogen and _C1 - _C3 alkyl.

In certain embodiments of Formula I:

_X is selected from CH and N;

_X2 is selected from CH and N;

R ¹ is selected from (a) C ₁ -C ₅ alkyl optionally substituted by one or two groups selected from the following: OH, cyclopropyl, oxetanyl and morpholino; (b) C ₃ -C ₄ cycloalkyl; (c) 4 to 6 membered heterocyclyl containing one O heteroatom optionally substituted by halogen or methyl; and (d) 5 membered heteroaryl containing two to four heteroatoms selected from N and S substituted by one to three groups selected from the following: methyl and cyclopropyl;

R ² is selected from (a) C ₁ -C ₆ alkyl optionally substituted with one or two R ^f groups; (b) C ₃ -C ₆ cycloalkyl optionally substituted with one or two halogens; (c) 4 to 6 membered heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the heterocyclyl may be optionally substituted with one to three R ^g groups; (d) 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted with one or two groups selected from the following: C _{1 -C 3} alkyl and 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S; and (e) C ₈ -C ₁₀ bicyclic cycloalkyl optionally substituted with halogens;

^R3 and ^R4 are hydrogen;

each ^Rf is independently selected from (a) halogen; (b) hydroxy; (c) _C1 - _C3 alkoxy; (d) ^NRkRm ; (e) _C3 - _C6 ^cycloalkyl optionally substituted with one or two ^Rh groups; (f) 4- to 6-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S, wherein the heterocyclyl may be optionally substituted with a group selected from the following: _C1 - _C3 alkyl optionally substituted with halogen, -C(=O)O( _C1 - _C6 alkyl), and phenyl; (g) phenyl optionally substituted with one or two ^Rj groups; and (h) 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, wherein the heteroaryl may be optionally substituted with one or two ^Rj groups;

Each ^Rg is selected from (a) halogen; (b) _C1 - _C3 alkyl optionally substituted by phenyl, said phenyl optionally substituted by two groups selected from halogen and _C1 - _C3 alkoxy; (c) _C1 - _C3 alkoxy; (d) phenyl optionally substituted by halogen; and (e) 5- to 6-membered heteroaryl containing one N heteroatom optionally substituted by one or two groups selected from halogen and _C1 - _C3 alkoxy;

each R ^h is selected from halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, and phenyl optionally substituted with: C ₁ -C ₃ alkoxy optionally substituted with halogen;

each R ^j is selected from halogen, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy, wherein the alkyl and alkoxy groups may be optionally substituted with halogen; and

Each of R ^k and R ^m is independently C ₁ -C ₃ alkyl.

In certain embodiments, _Xi is CH (the compound has the structure of Formula II). In certain embodiments, _Xi is N (the compound has the structure of Formula III).

In certain embodiments, X ₂ is CH (the compound has the structure of Formula IV). In certain embodiments, X ₂ is N (the compound has the structure of Formula V).

In certain embodiments, X ₁ is CH and X ₂ is CH (the compound has the structure of Formula VI). In certain embodiments, X ₁ is CH and X ₂ is N (the compound has the structure of Formula VII). In certain embodiments, X ₁ is N and X ₂ is CH (the compound has the structure of Formula VIII). In certain embodiments, X ₁ is N and X ₂ is N (the compound has the structure of Formula IX).

In certain embodiments, _Xi is CH and _X2 is CH; _Xi is CH and _X2 is N; or _Xi is N and _X2 is CH.

International Patent Application Publications WO 2012/118850 (Formula I -NH-R ^b ), WO 2013/020062 (Formula I -NH-R ² ), and WO 2013/130976 (-NH-R ¹ ) disclose amines at the -NH-R ¹ position that can be used in the present application for Formula I, II, III, IV, V, VI, VII, VIII, IX, or X.

In certain embodiments, R ¹ is selected from (a) C _{1 -C 6 alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, OR a , NR b R c , oxo, CN, C 3 -C 6 cycloalkyl, and 3 to 7 membered heterocyclic ring; (b) C 3 -C 7} ^{cycloalkyl optionally substituted} _{by one} or more groups independently selected from the group consisting of halogen, OR ^a , CN, and C _{1 -C 3} alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen and OR ^d ; (c) phenyl optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^a , CN, C ₃ -C ₆ cycloalkyl, and C ₁ -C ₃ alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen and OR ^d ; (d) 3 to 7 membered saturated or partially unsaturated heterocyclic ring optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^a , oxo, CN, C ₃ -C ₆ cycloalkyl, and C 1 -C ₃ alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen and OR d. (e) 5- to 6- ^membered heteroaryl optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^e , oxide, CN, C ₃ -C 6 cycloalkyl, and C ₁ -C ₃ alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, OR a , oxo, CN, C 3 -C ₆ cycloalkyl, and C ₁ -C ₃ alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen and OR ^d ; and (f) 7- to 10-membered bicyclic heterocycle optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^a , oxo, CN, C ₃ -C ₆ cycloalkyl, and C ₁ -C ₃ alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen and OR ^d ; wherein each of ^Ra , R ^b , R ^c , R ^d , and ^Re is independently selected from hydrogen and _Ci -C ₆ alkyl.

In certain embodiments, R ¹ is selected from (a) C ₁ -C ₆ alkyl optionally substituted with one or more groups independently selected from the group consisting of halogen, OR ^a , NR ^b R ^c , oxo, CN, C ₃ -C ₆ cycloalkyl, and a 3- to 7-membered heterocycle, wherein the heterocycle contains one, two, or three heteroatoms selected from the group consisting of O, N, S, S(═O), and S(═O) ₂ , (b) C ₃ -C ₇ cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of halogen, OR ^a , CN, and C ₁ -C ₃ alkyl optionally substituted with one or more groups independently selected from the group consisting of halogen and OR ^d , (c) phenyl optionally substituted with one or more groups independently selected from the group consisting of halogen, OR ^a , CN, C ₃ -C ₆ cycloalkyl, and C ₁ -C 3 alkyl optionally substituted with one or more groups independently selected from the group consisting of halogen and OR ^d (d) a _3- to 7-membered saturated or partially unsaturated heterocyclic ring optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^a , oxo, CN, C ₃ -C ₆ cycloalkyl, and C ₁ -C ₃ alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen and OR ^d , wherein the heterocyclic ring contains one, two or three heteroatoms selected from the group consisting of O, N, S, S(═O) and S(═O) ₂ , (e) a 5- to 6-membered heteroaryl optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^e , oxide, CN, C ₃ -C ₆ cycloalkyl, and C _{1 -C 3} alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, oxo, and OR ^d , wherein the heteroaryl contains one, two, three or four heteroatoms selected from the group consisting of O, N and S, and (f) a 7- to 10-membered bicyclic heterocyclic ring optionally substituted by one or more groups independently selected from the group consisting of halogen, OR ^a , oxo, CN, C ₃ -C ₆ cycloalkyl and C ₁ -C ₃ alkyl optionally substituted by one or more groups independently selected from halogen and OR ^d , wherein the heterocycle contains one, two or three heteroatoms selected from the group consisting of O, N, S, S(═O) and S(═O) ₂ ; wherein each ^Ra , ^Rb , ^Rc , ^Rd and ^Re are independently selected from hydrogen and C ₁ -C ₆ alkyl.

In certain embodiments, ^R is selected from (a) _C1 - _C6 alkyl optionally substituted with one to six groups independently selected from halogen, ^ORa , ^NRbRc , ^C3 - _C6 cycloalkyl, and a 3- to ₇ -membered heterocyclic ring, wherein the heterocyclic ring contains one, two, or three heteroatoms selected from the group consisting of O, N, S, S(=O), and S(=O) ₂ , (b) C3- _C7 cycloalkyl optionally substituted with one to _four groups independently selected from halogen and ^ORa , (c) phenyl optionally substituted with one to four groups independently selected from halogen and _C1 - _C3 alkyl, (d) a 3- to 7-membered saturated or partially unsaturated heterocyclic ring optionally substituted with one to four groups independently selected from halogen, oxo, ^ORa, and C1- _C3 alkyl optionally substituted with ^ORd , wherein the heterocyclic ring contains one, two, or _three heteroatoms selected from the group consisting of O, N, S, S(=O), and S(=O)2. (e) a 5- to 6-membered heteroaryl optionally substituted by one to _four groups independently selected from the group consisting of halogen, CN, OR ^e , C ₃ -C ₆ cycloalkyl, oxide, and C ₁ -C ₃ alkyl optionally substituted by one to three groups independently selected from the group consisting of hydroxy, methoxy, oxo, and halogen, wherein the heteroaryl contains one, two, three, or four heteroatoms selected from the group consisting of O, N, and S, and (f) a 7- to 10-membered bicyclic heterocycle optionally substituted by one or two groups selected from the group consisting of C ₁ -C ₃ alkyl and oxo, wherein the heterocycle contains one, two, or three heteroatoms selected from the group consisting of O, N, S, S(═O), and S(═O) ₂ ; wherein each of ^Ra , ^Rb , ^Rc , ^Rd , and ^Re is independently selected from hydrogen and C ₁ -C ₆ alkyl.

In certain embodiments, R ¹ is selected from optionally substituted C ₁ -C ₁₀ alkyl; optionally substituted aryl or aryl-C ₁ -C ₆ alkyl; optionally substituted heteroaryl or heteroaryl-C ₁ -C ₆ alkyl, wherein the heteroaryl is selected from the group consisting of isoxazole, pyridinyl, pyridone, pyrimidinyl, pyrazinyl, pyrazole, thiazolyl, triazolyl, N C ₁ -C ₆ alkyl-pyrazolyl, N-benzylpyrazolyl, N C ₁ -C ₆ alkyltriazolyl and 2-oxo-tetrahydroquinolin-6-yl; heterocyclyl or heterocyclyl-C ₁ -C ₆ alkyl, wherein the heterocyclyl is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, morpholinyl, N C ₁ -C ₆ alkyl-piperidinyl and N C ₁ -C ₆ alkyl-2-oxo-pyrrolidinyl; and C ₃ -C ₇ cycloalkyl or C ₃ -C wherein the alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted by OH, oxo (except not on an aromatic ring), halogen, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C _{1 -C 6} alkoxy, benzyl, phenyl, C _{3 -C 7} cycloalkyl, 3 to ₆ membered heterocyclyl or 5 to 6 membered heteroaryl, wherein the phenyl, cycloalkyl, heterocyclyl and heteroaryl are optionally substituted by halogen or C ₁ -C ₄ alkyl.

In certain embodiments, R ¹ is in the (S) configuration. In certain embodiments, R ¹ is in the (R) configuration.

In certain embodiments, ^R is selected from methyl, ethyl, isopropyl, tert-butyl, isobutyl, 2-hydroxyethyl, 1-hydroxymethylpropyl, 2-hydroxy-1-methyl-ethyl (or 1-hydroxypropan-2-yl), 2-methoxy-1-methyl-ethyl, 2-hydroxypropyl, 2-hydroxy-1-hydroxymethyl-ethyl, 1-hydroxy-2,2-dimethylpropan-3-yl, 2-hydroxy-2-methylpropan-1-yl, 1,2-dihydroxypropan-3-yl, acetyl, 2,2,2-trifluoro-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxymethyl-ethyl, 2-fluoro-1-methyl-ethyl, 2-fluoro-1-fluoromethyl-ethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, 2-morpholin-4-yl-ethyl, 2,2-difluoro-1-methyl-ethyl, oxetane Alkyl-3-ylmethyl, 2-methyl-1-morpholinopropan-2-yl, 4-fluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 2-o-tolyl, 4-fluoro-2-methylphenyl, 2-chlorophenyl, 2-chloro-4-fluorophenyl, 4-fluoro-2-trifluoromethylphenyl, 4-cyano-2-fluorophenyl, pyrimidin-5-yl, 4-methylpyrimidin-5-yl, 2-methylpyrimidin-4 -yl, 6-methylpyrimidin-4-yl, 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl, 3,5-dimethylisoxazol-4-yl, 2-methylpyridin-4-yl, 4-chloropyridin-2-yl, 2-methylpyridin-3-yl, 2-methylpyridin-4-yl, 2-ethoxypyridin-4-yl, 2-cyclopropylpyridin-4-yl, 1-methyl-1H-pyrazol-4-yl, 1- Ethyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 2-ethyl-2H-pyrazol-3-yl, 1-benzyl-1H-pyrazol-4-yl, 2-methyl-2H-pyrazol-3-yl, 2-isopropyl-2H-pyrazol-3-yl, 1-methyl-1H-pyrazol-5-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1,3,5-trimethyl-1 H-pyrazol-4-yl, 3-cyclopropyl-1-methyl-1H-pyrazol-5-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 4-methylthiazol-2-yl, 1-methyl-1H-[1,2,4]triazol-3-yl, 2-methyl-2H-1,2,3-triazol-4-yl, 1-methyl-1H-1,2,4-triazol-5-yl, 5-chloropyrazin-2 -yl, 1-methyl-1H-tetrazol-5-yl, 2-methyl-2H-tetrazol-5-yl, 5-methyl-1,3,4-thiadiazol-2-yl, oxetane-3-yl, 3-methyloxetane-3-yl, tetrahydropyran-4-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyran-3-yl, 2-methyl-tetrahydropyran-4-yl, 2,2-dimethyl-tetrahydropyran- In another embodiment, R is selected from the group consisting of (S)-2-hydroxy- ^1- methyl-ethyl, (S)-1-hydroxymethyl-propyl, (1S,3S)-3-hydroxycyclopentyl and tetrahydropyran-4-yl. In another embodiment, R ¹ is selected from (S) -2-hydroxy-1-methyl-ethyl, (S) -1-hydroxymethyl-propyl, (1S, 3S) -3-hydroxycyclopentyl, tetrahydropyran-4-yl, isopropyl, 1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 2-methyl-2H-1,2,3-triazol-4-yl and 1-methyl-1H-1,2,4-triazol-5-yl. In certain embodiments, R ¹ is selected from 1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, tetrahydro-2H-pyran-4-yl, (S) -2-hydroxy-1-methyl-ethyl, (S) -1-hydroxymethyl-propyl and (1S, 3S) -3-hydroxycyclopentyl.

In certain embodiments, R ¹ is selected from methyl, ethyl, isopropyl, tert-butyl, isobutyl, 2-hydroxyethyl, 1-hydroxymethylpropyl, 2-hydroxy-1-methyl-ethyl (or 1-hydroxypropan-2-yl), 2-methoxy-1-methyl-ethyl, 2-hydroxypropyl, 2-hydroxy-1-hydroxymethyl-ethyl, acetyl, 2,2,2-trifluoro-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxymethyl-ethyl, 2-fluoro-1-methyl-ethyl, 2-fluoro-1-fluoromethyl-ethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, 2-morpholin-4-yl-ethyl, 2,2-difluoro- 1-methyl-ethyl, 4-fluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 2-o-tolyl, 4-fluoro-2-methylphenyl, 2-chlorophenyl, 2-chloro-4-fluorophenyl, 4-fluoro-2-trifluoromethylphenyl, 4-cyano-2-fluorophenyl, pyrimidin-5-yl, 4-methylpyrimidin-5-yl, 2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl, 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl, 3,5-dimethylisoxazol-4-yl, 2-methylpyridin-4-yl, 4-chloropyridin-2-yl, 2-methylpyridin-3-yl, 2-methylpyridin-4-yl yl, 2-ethoxypyridin-4-yl, 2-cyclopropylpyridin-4-yl, 1-methyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 2-ethyl-2H-pyrazol-3-yl, 1-benzyl-1H-pyrazol-4-yl, 2-methyl-2H-pyrazol-3-yl, 2-isopropyl-2H-pyrazol-3-yl, 1-methyl-1H-pyrazol-5-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 4-methylthiazol-2-yl, 1-methyl-1H-[1,2,4]triazol-3-yl, 2-methyl-2 H-1,2,3-triazol-4-yl, 5-chloropyrazin-2-yl, tetrahydropyran-4-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyran-3-yl, 2-methyl-tetrahydropyran-4-yl, 2,2-dimethyl-tetrahydropyran-4-yl, 2-hydroxymethyltetrahydropyran-4-yl, 3-fluorotetrahydropyran-4-yl, 1-methylpiperidin-4-yl, 1-methyl-5-oxo-pyrrolidin-3-yl, tetrahydrofuran-3-yl, cyclopentyl, 3-hydroxycyclopentyl, 3,3-difluorocyclopentyl, 4-hydroxycyclohexyl, 3,3-difluorocyclobutyl, 3-hydroxycyclobutyl and 4,4-difluorocyclohexyl. In another embodiment, R ¹ is selected from (S)-2-hydroxy-1-methyl-ethyl, (S)-1-hydroxymethyl-propyl, (1S,3S)-3-hydroxycyclopentyl and tetrahydropyran-4-yl. In another embodiment, R ¹ is selected from (S)-2-hydroxy-1-methyl-ethyl, (S)-1-hydroxymethyl-propyl, (1S,3S)-3-hydroxycyclopentyl, tetrahydropyran-4-yl, isopropyl, 1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl and 1-methyl-1H-1,2,4-triazol-5-yl. In certain embodiments, R ¹ is selected from 1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, tetrahydro-2H-pyran-4-yl, (S)-2-hydroxy-1-methyl-ethyl, (S)-1-hydroxymethyl-propyl, and (1S,3S)-3-hydroxycyclopentyl.

In certain embodiments, ^R1 is selected from the group consisting of: (a) _C1 - _C10 alkyl; (b) _C1 - _C6 haloalkyl; (c) heterocyclyl or heterocyclyl- _C1 - _C6 alkyl, wherein the heterocyclyl or heterocyclyl- _C1 - _C6 alkyl is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, piperidinyl, N- _C1 - _C6 alkyl-piperidinyl and N- _C1 - _C6 alkyl-2-oxo-pyrrolidinyl, and wherein the heterocyclyl or heterocyclyl- _C1 - _C6 alkyl is optionally substituted with 1 to 3 groups independently selected from the group consisting of: _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C4 acyloxy- _C1 - _C2 alkyl, halogen, hydroxy, phenyl, _C1 - _C3 hydroxyalkyl and oxo; (d) _C3 - _C7 cycloalkyl or _C3 -C ₍₇ ) cycloalkyl-C ₁ -C ₆ alkyl, wherein the cycloalkyl is optionally substituted with hydroxy or halo; and (e) C ₁ -C ₆ heteroalkyl.

In certain embodiments, ^R1 is selected from the group consisting of: (a) _C1 - _C10 alkyl; (b) _C1 - _C6 haloalkyl; (c) heterocyclyl or heterocyclyl- _C1 - _C6 alkyl, wherein the heterocyclyl or heterocyclyl- _C1 - _C6 alkyl is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, piperidinyl, N- _C1 - _C6 alkyl-piperidinyl and N- _C1 - _C6 alkyl-2-oxo-pyrrolidinyl, and wherein the heterocyclyl or heterocyclyl- _C1 - _C6 alkyl is optionally substituted with 1 to 3 groups independently selected from the group consisting of: _C1 - _C6 alkyl, _C1 - _C4 acyloxy- _C1 - _C2 alkyl, halogen and _C1 - _C3 hydroxyalkyl; (d) _C3 - _C7 cycloalkyl or _C3 - _C7 cycloalkyl- _C1 -C (e) C 1 -C ₆ alkyl, wherein the cycloalkyl group is optionally substituted with hydroxy or halo; and (e) C ₁ -C ₆ heteroalkyl.

In certain embodiments, each ^Ra is independently selected from hydrogen and C ₁ -C ₆ alkyl. In certain embodiments, each ^Ra is independently selected from hydrogen and C ₁ -C ₃ alkyl. In certain embodiments, each ^Ra is independently selected from hydrogen and methyl.

In certain embodiments, each R ^b and R ^c is independently selected from hydrogen and C ₁ -C ₆ alkyl. In certain embodiments, each R ^b and R ^c is independently selected from hydrogen and C ₁ -C ₃ alkyl. In certain embodiments, each R ^b and R ^c is independently selected from hydrogen and methyl.

In certain embodiments, each R ^d is independently selected from hydrogen and C ₁ -C ₆ alkyl. In certain embodiments, each R ^d is independently selected from hydrogen and C ₁ -C ₃ alkyl. In certain embodiments, each R ^d is independently selected from hydrogen and methyl.

In certain embodiments, each ^Re is independently selected from hydrogen and C ₁ -C ₆ alkyl. In certain embodiments, each ^Re is independently selected from hydrogen and C ₁ -C ₃ alkyl. In certain embodiments, each ^Re is independently selected from methyl and ethyl.

In certain embodiments, R ¹ is selected from 1-hydroxypropan-2-yl, isopropyl, 1-hydroxybutan-2-yl, 1-cyclopropylethyl, 1-hydroxy-3-methoxypropan-2-yl, 1,3-difluoropropan-2-yl, 1-cyclopropyl-2-hydroxyethyl, oxetan-3-ylmethyl, 4-methoxybutan-2-yl, 4,4,4-trifluoro-1-hydroxybutan-2-yl, 1-aminopropan-2-yl, 1-hydroxy-2,2-dimethylpropan-3-yl, 2-hydroxy-2-methylpropan-1-yl, 1,2-dihydroxypropan-3-yl, 3- Hydroxycyclopentyl, 3,3-difluorocyclobutyl, 3-hydroxycyclobutyl, cyclopropylmethyl, 2-methyl-1-morpholinopropan-2-yl, 2-chloro-4-fluorophenyl, 4-fluoro-2-methylphenyl, tetrahydropyran-4-yl, 3-fluorotetrahydropyran-4-yl, tetrahydrodioxothiopyran-4-yl, 1,1-dioxotetrahydrothiophen-3-yl, oxetan-3-yl, 3-methyloxetan-3-yl, tetrahydrofuran-3-yl, 2,2-dimethyltetrahydropyran-4-yl, 2-methyltetrahydropyran-4-yl yl, pyrrolidin-3-yl, azetidin-3-yl, piperidin-3-yl, 2-(hydroxymethyl)tetrahydropyran-4-yl, 6-oxo-1,6-dihydropyridin-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl, 6-methoxypyrimidin-4-yl, 2-methylpyridin-4-yl, 1,3-dimethylpyrazol-4-yl, 2-methoxypyridin-4-yl, 1-methylpyrazol-3-yl, 6-methoxypyridin-3-yl, 2-ethylpyrimidin-4-yl , 6-methylpyridin-2-yl, 2-cyclopropylpyrimidin-4-yl, 5-fluoro-6-methylpyridin-2-yl, 5-cyclopropyl-1-methylpyrazol-4-yl, 5-bromo-2-methylpyridin-4-yl, 1,5-dimethylpyrazol-4-yl, 1,3-dimethylpyrazol-5-yl, 4-(2-hydroxypropyl-2-yl)pyridin-2-yl, 1-ethyl-3-methylpyrazol-4-yl, 5-ethoxy-2-methylpyridin-4-yl, 1-isopropylpyrazol-4-yl, 4-methylimidazol-5-yl, 1- Methylimidazol-5-yl, 1-ethylpyrazol-4-yl, 2-(2-hydroxypropyl-2-yl)pyridin-4-yl, 1-methyl-4-cyanopyrazol-5-yl, 3-methylpyridin-4-yl, 1-ethyl-3-methylpyrazol-5-yl, 1-methylpyrazol-5-yl, 1,4-dimethylpyrazol-5-yl, 1-ethylpyrazol-5-yl, 3-isopropyl-1-methylpyrazol-5-yl, 3-methylpyrazol-4-yl, 3-ethyl-1-methylpyrazol-4-yl, 1,3,5-trimethylpyrazol-4 -yl, 3,5-dimethylpyrazol-4-yl, 2-cyclopropyl-5-methoxypyridin-4-yl, 5-ethyl-1-methylpyrazol-4-yl, 4-(2-methoxypyridine 1-oxide), 5-methoxy-2-methylpyridin-4-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 3-ethyl-1-methylpyrazol-5-yl, 1-(2-hydroxyethyl)-3-methylpyrazol-4-yl, 1-(2-hydroxyethyl)-5-methylpyrazol-4-yl, 1-methyl-3-(trifluoromethyl)pyrazol-2-yl )pyrazol-4-yl, 1-methyl-3-(trifluoromethyl)pyrazol-5-yl, 1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-4-yl, 1-methyl-1,2,4-triazol-5-yl, 2-methylpyridin-4-yl, 1-(2-hydroxyethyl)pyrazol-5-yl, methyl 4-picolinate, 4-pyridinic acid, 1-cyclopropyl-5-methylpyrazol-4-yl, 1-cyclopropyl-3-methylpyrazol-4-yl, 2,3-dimethylpyridin-4-yl, 2, 5-dimethylpyridin-4-yl, 1,3,4-oxadiazol-2-yl, 3-methylpyridazin-4-yl, pyridazin-4-yl, tetrazol-5-yl, 1-methyltetrazol-5-yl, 3-cyclopropyl-1-methylpyrazol-5-yl, 2-methyltetrazol-5-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 2-methyl-2,4,5,6-tetrahydrocyclopentapyrazol-3-yl, 3-oxo-2-oxabicyclo[2.2.1]hept-5-yl and 2-oxabicyclo[2.2.1]hept-5-yl.

In certain embodiments, R ¹ is selected from 1-hydroxypropan-2-yl, isopropyl, 1-hydroxybutan-2-yl, 1-cyclopropylethyl, 1-hydroxy-3-methoxypropan-2-yl, 1,3-difluoropropan-2-yl, 1-cyclopropyl-2-hydroxyethyl, oxetan-3-ylmethyl, 4-methoxybutan-2-yl, 4,4,4-trifluoro-1-hydroxybutan-2-yl, 1-aminopropan-2-yl, 1-hydroxy-2,2-dimethylpropan-3-yl, 2-hydroxy-2-methylpropan-1-yl, 1,2-dihydroxypropan-3-yl, 3-Hydroxycyclopentyl, 3,3-difluorocyclobutyl, 3-hydroxycyclobutyl, cyclopropylmethyl, 2-methyl-1-morpholinopropan-2-yl, 2-chloro-4-fluorophenyl, 4-fluoro-2-methylphenyl, tetrahydropyran-4-yl, 3-fluorotetrahydropyran-4-yl, tetrahydrodioxothiopyran-4-yl, 1,1-dioxotetrahydrothiophen-3-yl, oxetan-3-yl, 3-methyloxetan-3-yl, tetrahydrofuran-3-yl, 2,2-dimethyltetrahydropyran-4-yl, 2-methyltetrahydropyran-4-yl, pyrimidine-4-yl, pyrrolidin-3-yl, azetidin-3-yl, piperidin-3-yl, 2-(hydroxymethyl)tetrahydropyran-4-yl, 6-oxo-1,6-dihydropyridin-3-yl, 1-methylpyrazol-4-yl, 2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl, 6-methoxypyrimidin-4-yl, 2-methylpyridin-4-yl, 1,3-dimethylpyrazol-4-yl, 2-methoxypyridin-4-yl, 1-methylpyrazol-3-yl, 6-methoxypyridin-3-yl, 2-ethyl Pyrimidin-4-yl, 6-methylpyridin-2-yl, 2-cyclopropylpyrimidin-4-yl, 5-fluoro-6-methylpyridin-2-yl, 5-cyclopropyl-1-methylpyrazol-4-yl, 5-bromo-2-methylpyridin-4-yl, 1,5-dimethylpyrazol-4-yl, 1,3-dimethylpyrazol-5-yl, 4-(2-hydroxypropyl-2-yl)pyridin-2-yl, 1-ethyl-3-methylpyrazol-4-yl, 5-ethoxy-2-methylpyridin-4-yl, 1-isopropylpyrazol-4-yl, 4-methyl Imidazol-5-yl, 1-methylimidazol-5-yl, 1-ethylpyrazol-4-yl, 2-(2-hydroxypropyl-2-yl)pyridin-4-yl, 1-methyl-4-cyanopyrazol-5-yl, 3-methylpyridin-4-yl, 1-ethyl-3-methylpyrazol-5-yl, 1-methylpyrazol-5-yl, 1,4-dimethylpyrazol-5-yl, 1-ethylpyrazol-5-yl, 3-isopropyl-1-methylpyrazol-5-yl, 3-methylpyrazol-4-yl, 3-ethyl-1-methylpyrazol-4-yl, 1, 3,5-trimethylpyrazol-4-yl, 3,5-dimethylpyrazol-4-yl, 2-cyclopropyl-5-methoxypyridin-4-yl, 5-ethyl-1-methylpyrazol-4-yl, 4-(2-methoxypyridine 1-oxide), 5-methoxy-2-methylpyridin-4-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 3-ethyl-1-methylpyrazol-5-yl, 1-(2-hydroxyethyl)-3-methylpyrazol-4-yl, 1-(2-hydroxyethyl)-5-methylpyrazol-4-yl , 1-methyl-3-(trifluoromethyl)pyrazol-4-yl, 1-methyl-3-(trifluoromethyl)pyrazol-5-yl, 1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-4-yl, 2-methylpyridin-4-yl, 1-(2-hydroxyethyl)pyrazol-5-yl, methyl 4-picolinate, 4-pyridinic acid, 1-cyclopropyl-5-methylpyrazol-4-yl, 1-cyclopropyl-3-methylpyrazol-4-yl, 2,3-dimethylpyridin-4-yl, 2,5-dimethylpyridin-4-yl, methylpyridin-4-yl, 1,3,4-oxadiazol-2-yl, 3-methylpyridazin-4-yl, pyridazin-4-yl, tetrazol-5-yl, 1-methyltetrazol-5-yl, 3-cyclopropyl-1-methylpyrazol-5-yl, 2-methyltetrazol-5-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 2-methyl-2,4,5,6-tetrahydrocyclopentapyrazol-3-yl, 3-oxo-2-oxabicyclo[2.2.1]hept-5-yl and 2-oxabicyclo[2.2.1]hept-5-yl.

In certain embodiments, R ¹ is selected from the group consisting of: (a) C ₁ -C ₁₀ alkyl; (b) C ₁ -C ₆ haloalkyl; (c) heterocyclyl or heterocyclyl-C ₁ -C ₆ alkyl, wherein the heterocycle or heterocyclyl-C ₁ -C ₆ alkyl is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl and oxetanyl, and wherein the heterocycle is optionally substituted with C ₁ -C ₆ alkyl, halogen, C ₁ -C ₃ hydroxyalkyl or C ₁ -C ₄ acyloxy-C ₁ -C ₂ alkyl; (d) C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ cycloalkyl-C ₁ -C ₆ alkyl, wherein the cycloalkyl is optionally substituted with hydroxy; and (e) C ₁ -C ₆ heteroalkyl.

In certain embodiments, R ¹ is selected from the group consisting of: (a) tetrahydropyranyl; (b) tetrahydrofuranyl; (c) oxetanyl; (d) 2-hydroxy-1-methyl-1-yl; (e) 2,2,2-trifluoro-1-methyl-1-yl; (f) 1-cyclopropyl-1-yl; (g) 2-methoxyethyl; (h) 3-fluoropropyl; (i) cyclopropylmethyl; (j) oxetanylmethyl; (k) 4-hydroxycyclohexyl; and (l) pyrazolyl;

wherein the (a) tetrahydropyranyl, (b) tetrahydrofuranyl and (c) oxetanyl are optionally substituted with one to three groups independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₄ acyloxy-C ₁ -C ₂ alkyl, C ₁ -C ₃ hydroxyalkyl and halogen; and

wherein the (1) pyrazolyl moiety is optionally substituted with one to three groups independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and halogen.

In certain embodiments, R ¹ is selected from the group consisting of: 1-hydroxypropan-2-yl, isopropyl, 1-cyclopropylethyl, cyclopropylmethyl, 4-hydroxycyclohexyl, 1,1,1-trifluoropropan-2-yl, 3-fluoropropyl, tetrahydro-2H-pyran-4-yl, 3-fluorotetrahydropyran-4-yl, 2-(hydroxymethyl)tetrahydropyran-4-yl, (4-tetrahydro-2H-pyran-2-yl)methyl acetate, tetrahydrofuran-3-yl, 3-methyl 1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 2-methylpyrazol-3-yl, 2,5-dimethylpyrazol-3-yl, 1,3-dimethylpyrazol-4-yl, 2-methyl-2H-1,2,3-triazol-4-yl and 1-methyl-1H-1,2,4-triazol-5-yl.

In certain embodiments, R ¹ is selected from the group consisting of: 1-hydroxypropan-2-yl, isopropyl, 1-cyclopropylethyl, cyclopropylmethyl, 4-hydroxycyclohexyl, 1,1,1-trifluoropropan-2-yl, 3-fluoropropyl, tetrahydro-2H-pyran-4-yl, 3-fluorotetrahydropyran-4-yl, 2-(hydroxymethyl)tetrahydropyran-4-yl, (4-tetrahydro-2H-pyran-2-yl)methyl acetate, tetrahydrofuran-3-yl, 3-methyloxetan-3-yl, oxetan-3-ylmethyl, 2-methoxyethyl, 1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 2-methylpyrazol-3-yl, 2,5-dimethylpyrazol-3-yl, 1,3-dimethylpyrazol-4-yl and 2-methyl-2H-1,2,3-triazol-4-yl.

In certain embodiments, R ¹ is selected from (a) C ₁ -C _{6 alkyl optionally substituted with one to three groups selected from halogen, OH, cyclopropyl, and a 4- to 6-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S; (b) C 3 -C 6 cycloalkyl optionally} substituted with one to three groups selected from halogen, OH, and C ₁ -C ₃ alkyl; (c) a 4- to 6-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S optionally substituted with one to three groups selected from halogen, OH, and C ₁ -C ₃ alkyl; and (d) a 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S optionally substituted with one to three groups selected from halogen, OH, C ₁ -C ₃ alkyl, and cyclopropyl. In certain embodiments, R ¹ is selected from (a) C ₁ -C _{6 alkyl optionally substituted with one or two groups selected from halogen, OH, cyclopropyl, and a 4- to 6-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S; (b) C 3 -C 6 cycloalkyl optionally} substituted with one or two groups selected from halogen, OH, and methyl; (c) a 4- to 6-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S optionally substituted with one or two groups selected from halogen, OH, and methyl; and (d) a 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S optionally substituted with one to three groups selected from halogen, OH, methyl, and cyclopropyl.

In certain embodiments, R ¹ is selected from (a) C ₁ -C ₆ alkyl optionally substituted with one or two groups selected from OH, cyclopropyl, oxetanyl, and morpholino; (b) C ₃ -C ₆ cycloalkyl; (c) 4- to 6-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S optionally substituted with halogen or methyl; and (d) 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S optionally substituted with one to three groups selected from methyl and cyclopropyl. In certain embodiments, R ¹ is selected from (a) C ₁ -C ₅ alkyl optionally substituted with one or two groups selected from OH, cyclopropyl, oxetanyl, and morpholino; (b) C ₃ -C ₄ cycloalkyl; (c) 4 to 6 membered heterocyclyl containing one O heteroatom optionally substituted with halogen or methyl; and (d) 5 membered heteroaryl containing two to four heteroatoms selected from N and S substituted with one to three groups selected from methyl and cyclopropyl.

In certain embodiments, R ¹ is selected from isopropyl, 1-hydroxy-2,2-dimethylpropan-3-yl, 2-hydroxy-2-methylpropan-1-yl, 1-hydroxypropan-2-yl, 1,2-dihydroxypropan-3-yl, cyclopropylmethyl, oxetan-3-ylmethyl, 2-methyl-1-morpholinopropan-2-yl, cyclopropyl, cyclobutyl, oxetan-3-yl, 3-methyloxetan-3-yl, tetrahydro-2H-pyran-4-yl, 3-fluorotetrahydro-2H-pyran-4-yl, (3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl, (3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl, 1-methyl-1H-pyrazol-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, 3-cyclopropyl-1-methyl-1H-pyrazol-5-yl, 2-methyl-2H-1,2,3-triazol-4-yl, 1-methyl-1H-tetrazol-5-yl, 2-methyl-2H-tetrazol-5-yl and 5-methyl-1,3,4-thiadiazol-2-yl.

In certain embodiments, ^R2 is selected from (a) _C1 - _C10 alkyl optionally substituted with one to four ^Rf groups; (b) C3-C6 cycloalkyl optionally substituted with halogen, _C1 - _C3 alkyl, and _C1 - _C3 alkoxy; (c) _4- to ₆ -membered heterocyclyl containing one to three heteroatoms selected from N, O, and S, wherein the heterocyclyl may be optionally substituted with one to four ^Rg groups; (d) phenyl optionally substituted with one to four groups selected from halogen, _C1 - _C3 alkyl, and _C1 - _C3 alkoxy; (e) 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, wherein the heteroaryl may be optionally substituted with one to four groups selected from halogen, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, and 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S; (f) optionally substituted with halogen, _C1 -C and (g) a 9- to 10 _- membered bicyclic heterocyclyl containing one to three heteroatoms selected from N, O and S, _{wherein the heterocyclyl may be optionally substituted by halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy} .

In certain embodiments, R ² is selected from (a) C ₁ -C ₆ alkyl optionally substituted with one or two R ^f groups; (b) C ₃ -C ₆ cycloalkyl optionally substituted with one or two halogens; (c) a 4- to 6-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S, wherein the heterocyclyl may be optionally substituted with one to three R ^g groups; (d) a 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, wherein the heteroaryl may be optionally substituted with one or two groups selected from the following: C _{1 -C 3} alkyl and a 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S; and (e) a C ₈ -C ₁₀ bicyclic cycloalkyl optionally substituted with halogen.

In certain embodiments, R ² is selected from (a) C ₁ -C ₆ alkyl optionally substituted with one or two R ^f groups; (b) C ₃ -C ₆ cycloalkyl optionally substituted with one or two halogens; (c) a 4- to 6-membered heterocyclyl containing one N heteroatom, wherein the heterocyclyl may be optionally substituted with one to three R ^g groups; (d) a 5- to 6-membered heteroaryl containing two N heteroatoms, wherein the heteroaryl may be optionally substituted with one or two groups selected from methyl and a 5- to 6-membered heteroaryl containing one N heteroatom; and (e) a C ₈ -C ₁₀ bicyclic cycloalkyl optionally substituted with halogen.

In certain embodiments, each ^Rf is selected from (a) halogen; (b) hydroxy; (c) _C1 - _C3 alkoxy; (d) ^NRkRm ; (e) _C3 - _{C6 cycloalkyl optionally substituted with one or more Rh groups; (f) 4- to 6-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S, wherein the heterocyclyl may be optionally substituted with one or more groups selected from halogen, C1-C3} ^{alkoxy ,} _{C1 - C3 alkyl} optionally substituted with halogen, -C(=O)O( _C1 - _C6 alkyl), and phenyl; (g) phenyl optionally substituted with one or more ^Rj groups; and (h) 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, wherein the heteroaryl may be optionally substituted with one or more ^Rj groups.

In certain embodiments, each ^Rf is selected from (a) halogen; (b) hydroxy; (c) _C1 - _C3 alkoxy; (d) ^NRkRm ; (e) _C3 - _{C6 cycloalkyl optionally substituted with one or two Rh groups; (f) 4- to 6-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with a group selected from the following: C1-C3} ^{alkyl optionally} _{substituted with} halogen, -C(═O)O( _C1 - _C6 alkyl), and phenyl; (g) phenyl optionally substituted with one or two ^Rj groups; and (h) 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or two ^Rj groups.

In certain embodiments, each ^Rf is selected from (a) halogen; (b) hydroxy; (c) _C1 - _C3 alkoxy; (d) dimethylamino; (e) _C3 - _C5 cycloalkyl optionally substituted with one or two ^Rh groups; (f) 4- to 6-membered heterocyclyl containing one heteroatom selected from N and O, wherein the heterocyclyl is optionally substituted with a group selected from the following: C1- _C3 alkyl optionally substituted with halogen, -C( ₌ O)O( _C1 - _C6 alkyl) and phenyl; (g) phenyl substituted with one or two ^Rj groups; and (h) 5- to 6-membered heteroaryl containing one to three N heteroatoms, wherein the heteroaryl is optionally substituted with one or two ^Rj groups.

In certain embodiments, each ^Rf is selected from F, hydroxy, methoxy, ethoxy, isopropoxy, dimethylamino, cyclopentyl, 4,4-difluorocyclohexyl, 3,3-difluorocyclobutyl, 1-(ethoxymethyl)cyclopropyl, 1-(4-(trifluoromethoxy)phenyl)cyclopropyl, 1-methylcyclobutyl, 1-methylazetidin-3-yl, oxetan-3-yl, azetidin-3-yl, 1-(tert-butoxycarbonyl)azetidin-3-yl, 1-(2,2,2-trifluoroethyl)azetidin-3-yl, 4-phenylpiperidin-4-yl, pyrrolidin-1-yl, tetrahydro-2H-pyran-2-yl, 2-chlorophenyl, 2-(trifluoromethyl)phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-(difluoromethoxy)phenyl, 4-methoxyphenyl, 2 ,3-difluorophenyl, 2,4-difluorophenyl, 3-fluoro-4-methoxyphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 1H-pyrazol-1-yl, 4-chloro-1H-pyrazol-1-yl, 4-methyl-1H-pyrazol-1-yl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl , 1-methyl-1H-imidazol-2-yl, 1-methyl-1H-1,2,3-triazol-5-yl, 3-methoxypyridin-2-yl, 3,5-difluoropyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 6-methylpyridin-2-yl, 2-methylpyridin-3-yl, 2-methoxypyridin-3-yl, 2-chloropyridin-3-yl and 6-methylpyridin-3-yl.

In certain embodiments, each ^Rk and ^Rm is independently selected from hydrogen and _C1 - _C3 alkyl. In certain embodiments, each ^Rk and ^Rm is independently _C1 - _C3 alkyl. In certain embodiments, each ^Rk and ^Rm is methyl.

In certain embodiments, each R ^h is selected from halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, and phenyl optionally substituted with C ₁ -C ₃ alkoxy, wherein the alkyl, alkoxy, and phenyl groups are optionally substituted with halogen. In certain embodiments, each R ^h is selected from halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, and phenyl optionally substituted with C ₁ -C ₃ alkoxy groups optionally substituted with halogen. In certain embodiments, each R ^h is selected from F, methyl, ethoxymethyl, and 4-(trifluoromethoxy)phenyl.

In certain embodiments, each ^Rj is selected from halogen, _C1 - _C3 alkyl, and _C1 - _C3 alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with halogen. In certain embodiments, each ^Rj is selected from halogen, methyl, trifluoromethyl, methoxy, and difluoromethoxy. In certain embodiments, each ^Rj is selected from halogen, trifluoromethyl, methoxy, and difluoromethoxy. In certain embodiments, each ^Rj is selected from halogen, methyl, trifluoromethyl, and methoxy.

In certain embodiments, each ^Rg is selected from (a) halogen; (b) _C1 - _C3 alkyl optionally substituted with halogen, _C1 - _C3 alkoxy, or phenyl optionally substituted with two groups selected from halogen and _C1 - _C3 alkoxy; (c) C1- _C3 alkoxy optionally substituted with halogen; (d) phenyl optionally substituted with halogen or _C1 - _C3 alkoxy; and (e) 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, wherein the heteroaryl may be optionally substituted with one or two groups selected from halogen _{and C1} - _C3 alkoxy. In certain embodiments, each ^Rg is selected from (a) halogen; (b) _C1 - _C3 alkyl optionally substituted with phenyl, the phenyl being optionally substituted with two groups selected from halogen and _C1 - _C3 alkoxy; (c) _C1 - _C3 alkoxy; (d) phenyl optionally substituted with halogen; and (e) 5- to 6-membered heteroaryl containing one N heteroatom optionally substituted with one or two groups selected from halogen and _C1 - _C3 alkoxy. In certain embodiments, each ^Rg is selected from F, methyl, ethyl, isopropyl, 2-fluoro-6-methoxybenzyl, 2-methoxyethyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, and 5-fluoro-2-methoxypyridin-3-yl.

In certain embodiments, ^R is selected from 2-methylbutyl, 2-ethylbutyl, isobutyl, 2,2-difluoropropyl, 2,2-difluoroethyl, 3-fluoropropyl, 3-hydroxybutyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 2-methoxy-2-methylpropyl, 3-methoxy-2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl, 3-isopropoxypropyl, cyclopentylmethyl, (3,3-difluorocyclobutyl)methyl, (1-(ethoxymethyl)cyclopropyl)methyl, (1-(4-(trifluoromethoxy)phenyl)cyclopropyl)methyl, (1-methylcyclobutyl)methyl, (1-methylazetidin-3-yl)methyl )methyl, oxetan-3-ylmethyl, azetidin-3-ylmethyl, (1-(tert-butoxycarbonyl)azetidin-3-yl)methyl, (1-(2,2,2-trifluoroethyl)azetidin-3-yl)methyl, (4-phenylpiperidin-4-yl)methyl, (tetrahydro-2H-pyran-2-yl)methyl, 2,3-difluorobenzyl, 3-fluoro-4-methoxybenzyl, 4-(difluoromethoxy)benzyl, 4-chlorobenzyl, 4-methoxybenzyl, 3-fluorobenzyl, 4-chloro-3-fluorobenzyl, 4-fluorobenzyl, 3-chlorobenzyl, 3-chloro-4-fluorobenzyl, 2-(trifluorobenzyl)methyl methyl)benzyl, 2,4-difluorobenzyl, 4-chlorophenethyl, 2-chlorophenethyl, 3-chlorophenethyl, 1-(4-chloro-3-fluorophenyl)-2-(dimethylamino)ethyl, 1-(4-chloro-3-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl, 2-hydroxy-1-(4-chloro-3-fluorophenyl)ethyl, (S)-2-hydroxy-1-(4-chloro-3-fluorophenyl)ethyl, (R)-2-hydroxy-1-(4-chloro-3-fluorophenyl)ethyl, 2-hydroxy-1-(3-fluoro-4-methoxyphenyl)ethyl, (S)-2-hydroxy-1-(3-fluoro-4-methoxyphenyl)ethyl , 2-(4-chloro-1H-pyrazol-1-yl)ethyl, (1-methyl-1H-pyrazol-3-yl)methyl, (1-methyl-1H-pyrazol-5-yl)methyl, (6-(trifluoromethyl)pyridin-2-yl)methyl, (2-methylpyridin-3-yl)methyl, (2-methoxypyridin-3-yl)methyl, (6-methylpyridin-3-yl)methyl, (6-methylpyridin-2-yl)methyl, (2-chloropyridin-3-yl)methyl, (3-methoxypyridin-2-yl)methyl, (3,5-difluoropyridin-2-yl)methyl, 2-(4-methyl-1H-pyrazol-1-yl)ethyl, 2-(1H- pyrazol-1-yl)ethyl, (3-fluoro-4-methoxyphenyl)(1-methyl-1H-pyrazol-4-yl)methyl, (3-fluoro-4-methoxyphenyl)(1-methyl-1H-1,2,3-triazol-5-yl)methyl, (3-fluoro-4-methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methyl, 4,4-difluorocyclohexyl, piperidin-4-yl, 1-methylazetidin-3-yl, 1-(2-fluoro-6-methoxybenzyl)azetidin-3-yl, 4-(3-fluorophenyl)piperidin-3-yl, 4-(4-fluorophenyl)piperidin-3-yl, 4-(2,4-difluorophenyl) )-1-methylpyrrolidin-3-yl, (3S,4R)-4-(2,4-difluorophenyl)-1-methylpyrrolidin-3-yl, 4-(3,4-difluorophenyl)-1-methylpyrrolidin-3-yl, (3S,4R)-4-(3,4-difluorophenyl)-1-methylpyrrolidin-3-yl, 4-(3,5-difluorophenyl)-1-methylpyrrolidin-3-yl, (3S,4R)-4-(3,5-difluorophenyl)-1-methylpyrrolidin-3-yl, 4-(3,4-difluorophenyl)-1-ethylpyrrolidin-3-yl, (3S,4R)-4-(3,4-difluorophenyl)-1-ethyl Pyrrolidin-3-yl, 4-(3,4-difluorophenyl)pyrrolidin-3-yl, (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-yl, 5,5-difluoropiperidin-3-yl, 4-(3,5-difluorophenyl)-1-isopropylpyrrolidin-3-yl, (3S,4R)-4-(3,5-difluorophenyl)-1-isopropylpyrrolidin-3-yl, 1-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-3-yl, 4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl, (3R,4S)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl 1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl, (R)-1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl, 1-(5,5-difluoro-1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl, (R)-1-(5,5-difluoro-1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl, 3-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl and 5-chloro-2,3-dihydro-1H-inden-1-yl.

In certain embodiments, R ² is C ₁ -C ₁₀ alkyl optionally substituted with one to four R ^f groups. In certain embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one to four R ^f groups. In certain embodiments, R ² is C ₁ -C ₁₀ alkyl optionally substituted with one or two R ^f groups. In certain embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or two R ^f groups. In certain embodiments, R ² is C ₁ -C ₆ alkyl.

In certain embodiments, R ² is —CH ₂ R ^f (the compound has the structure of Formula X).

In certain embodiments, ^R is selected from hydrogen and halogen. In certain embodiments, ^R is hydrogen. In certain embodiments, R is halogen. In certain embodiments, ^R is selected ^from hydrogen, fluorine, and chlorine. In certain embodiments, ^R is selected from hydrogen and fluorine. In certain embodiments, ^R is fluorine.

In certain embodiments, ^R4 is selected from hydrogen and halogen. In certain embodiments, ^R4 is hydrogen. In certain embodiments, ^R4 is halogen. In certain embodiments, ^R4 is selected from hydrogen, fluorine, and chlorine. In certain embodiments, ^R4 is selected from hydrogen and fluorine. In certain embodiments, ^R4 is fluorine.

In certain embodiments, ^R3 and ^R4 are selected from hydrogen and halogen. In certain embodiments, ^R3 and ^R4 are selected from hydrogen, fluorine, and chlorine. In certain embodiments, ^R3 and ^R4 are selected from hydrogen and fluorine. In certain embodiments, ^R3 and ^R4 are hydrogen. In certain embodiments, ^R3 is hydrogen; and ^R4 is selected from hydrogen and halogen. In certain embodiments, ^R3 is hydrogen; and ^R4 is selected from hydrogen, fluorine, and chlorine. In certain embodiments, ^R3 is hydrogen; and ^R4 is selected from hydrogen and fluorine. In certain embodiments, ^R3 is selected from hydrogen and halogen; and ^R4 is hydrogen. In certain embodiments, ^R3 is selected from hydrogen, fluorine, and chlorine; and ^R4 is hydrogen. In certain embodiments, ^R3 is selected from hydrogen and fluorine; and ^R4 is hydrogen. In certain embodiments, ^R3 is hydrogen and ^R4 is selected from hydrogen and halogen, or ^R3 is selected from hydrogen and halogen, and ^R4 is hydrogen. In certain embodiments, R ³ is hydrogen and R ⁴ is selected from hydrogen, fluorine and chlorine, or R ³ is selected from hydrogen, fluorine and chlorine, and R ⁴ is hydrogen. In certain embodiments, R ³ is hydrogen and R ⁴ is selected from hydrogen and fluorine, or R ³ is selected from hydrogen and fluorine, and R ⁴ is hydrogen.

In certain embodiments, compounds of Examples 1 to 126 are provided.

In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, or X is provided.

It will be appreciated that certain compounds described herein may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds described herein, including but not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof (such as racemic mixtures), form part of the compounds of the present invention.

In the structures shown herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as compounds described herein. When stereochemistry is specified by a solid wedge or dashed line representing a specific configuration, then that stereoisomer is so specified and identified.

It will also be appreciated that certain compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX or X may be useful as intermediates for other compounds of Formula I, II, III, IV, V, VI, VII, VII, IX or X.

It is further understood that the compounds described herein can exist in unsolvated as well as solubilized forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the compounds include both solubilized and unsolvated forms.

Synthesis of compounds

The compounds described herein can be synthesized by synthetic routes including methods analogous to those well known in the chemical arts, particularly in view of the description contained herein. Starting materials are generally available from commercial sources such as Sigma-Aldrich (St. Louis, MO), Alfa Aesar (Ward Hill, MA), or TCI (Portland, OR), or are readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis . Vols. 1-23, New York: Wiley 1967-2006 editions (also available through the Wiley website); or Beilsteins Handbuch der organischen Chemie , 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available through the Beilstein online database)).

For illustrative purposes, processes 1-3 show general methods for preparing compounds described herein and key intermediates. For a more detailed description of individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic pathways can be used to synthesize compounds. Although specific starting materials and reagents are depicted in the processes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many compounds prepared by the following methods can be further modified using conventional chemistry well known to those skilled in the art in view of the present disclosure.

Scheme 1 shows a general scheme for the synthesis of compound 6, wherein X ₁ , R ¹ and R ² are as defined herein. Compound 2, wherein Z ₂ is Cl or F, and Z ₃ is Cl or Br, can be prepared starting from compound 1, wherein Z ₁ is Cl, Br, I, such as 4-chloro-1-fluoro-2-nitrobenzene. Palladium-mediated coupling reaction of compound 1 with a heteroaromatic boronic acid ester or boronic acid, such as the Suzuki reaction, will provide compound 2. Compound 2 can then be reacted with an appropriate amine under Buchwald reaction conditions to provide compound 3. Compound 3 can be subjected to a SnAr reaction with an amine in the presence of a base such as Cs ₂ CO ₃ , K ₂ CO ₃ , NaH in a polar solvent such as DMF, DMSO, THF, etc. to provide compound 4. Reaction of compound 4 with a reducing agent such as Zn:NH ₄ Cl, Pd:H ₂ , SnCl ₂ will provide the diamine derivative 5 , which can be treated with NaNO ₂ in the presence of an acid such as acetic acid, HCl, etc. to provide the benzotriazole analog 6 .

Scheme 2 depicts an alternative route to obtain benzotriazole analogs 6, wherein X ₁ , R ¹ , and R ² are as defined herein. According to this method, compound 2, wherein Z ₂ is as defined above, can be subjected to a SnAr reaction with a suitable amine in the presence of a base to produce compound 7, wherein Z ₃ is as defined above. Reduction of the nitro group in compound 7 can be carried out according to the method described in Scheme 1 for the synthesis of compound 5. The resulting diamine compound 8 can be converted to benzotriazole 9 according to the method described in Scheme 1 for the preparation of compound 6. Buchwald-type coupling of compound 9 with amines such as alkylamines, heteroarylamines, cyclic alkylamines, etc., provides the final benzotriazole analogs 6.

Scheme 3 shows a general scheme for the synthesis of benzotriazole analogs 15, wherein ^R and ^R are as defined herein. According to this method, 2,4-dihalogeno-substituted pyridine analogs 10, wherein _Z is as defined above, can be subjected to a SnAr reaction with an amine in the presence of a base such as _KCO , _CsCO , NaH _, etc. to provide compound 11. Compound 11 can be subjected to a Pd-mediated coupling reaction, such as the Suzuki reaction, as described for the synthesis of compound 2 in Scheme 1 to provide compound 12, wherein _Z is as defined above. Compound 12 can then be subjected to a second SnAr reaction with an amine in the presence of a base to produce compound 13. Reduction of the nitro group of compound 13 with a reducing agent such as Zn: _NHCl , SnCl _{, etc.} , followed by treatment with _NaNO in the presence of an acid such as HCl, acetic acid, etc., will provide benzotriazole analogs 15.

When preparing compound of formula I, it is necessary to protect the distal functional group (such as primary amine or secondary amine etc.) of intermediate. The need for such protection will vary depending on the property of the distal functional group and the conditions of the preparation method. Suitable amino protecting groups (NH-Pg) include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (" Boc "), benzyloxycarbonyl (" CBz ") and 9-fluorenylmethyleneoxycarbonyl (" Fmoc "). The need for such protection is easy to be determined by those skilled in the art. For a general description of protecting groups and their use, see Greene's Protective Groups in Organic Synthesis .New York:Wiley Interscience, 2006, etc., such as TW Greene.

Separation method

It may be advantageous to separate the reaction products from each other and/or from the starting materials. The desired products of each step or series of steps are separated and/or purified (hereinafter referred to as separation) to the desired degree of homogeneity by techniques common in the art. Typically, the separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reverse phase and normal phase; size exclusion; ion exchange; high pressure, medium pressure, and low pressure liquid chromatography methods and apparatus; small scale analysis; simulated moving bed (SMB) and preparative thin or thick layer chromatography and small scale thin layer and flash chromatography techniques. One skilled in the art will apply the technique most likely to achieve the desired separation.

Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

A single stereoisomer (e.g., an enantiomer) substantially free of its stereoisomers can be obtained by resolving the racemic mixture using a method such as the formation of diastereomers using an optically active resolving agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds . New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr. 113(3) (1975): pp. 283-302). Racemic mixtures of chiral compounds described herein can be separated and isolated by any suitable method, including: (1) forming ionic diastereomeric salts with chiral compounds and separating by fractional crystallization or other methods, (2) forming diastereomeric compounds with chiral derivatizing agents, separating the diastereomers, and converting them to the pure stereoisomers, and (3) separating the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., ed. Drug Stereochemistry: Analytical Methods and Pharmacology . New York: Marcel Dekker, Inc., 1993.

Under method (1), diastereomeric salts can be formed by reacting an enantiomerically pure chiral base (such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), etc.) with an asymmetric compound carrying an acidic functional group (such as a carboxylic acid and a sulfonic acid). Diastereomeric salts can be induced to separate by fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds, the addition of a chiral carboxylic acid or sulfonic acid (such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid) can lead to the formation of diastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds . New York: John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing agent (such as a menthyl derivative), followed by separation of the diastereomers and hydrolysis to produce the pure or enriched enantiomer. One method for determining optical purity involves preparing a chiral ester of the racemic mixture, such as a menthyl ester (e.g., (-) menthyl chloroformate) or mosheryl acetate α-methoxy-α-(trifluoromethyl)phenyl ester (Jacob III, Peyton. "Resolution of (±)-5-Bromonornicotine. Synthesis of (R)- and (S)-Nornicotine of High Enantiomeric Purity." J. Org. Chem . Vol. 47, No. 21 (1982): pp. 4165-4167), and analyzing the ¹ H NMR spectrum for the presence of two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal and reverse phase chromatography following the method for separating atropisomeric naphthyl-isoquinolines (WO 96/15111).

By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Lough, WJ, ed. Chiral Liquid Chromatography . New York: Chapman and Hall, 1989; Okamoto, Yoshio et al. "Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase." J. of Chromatogr . Vol. 513 (1990): pp. 375-378). The enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

Biological assessment

It is possible to determine the ERK activity of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, or X by a number of direct and indirect detection methods. An ERK inhibition assay (Biological Example 1) was performed for certain exemplary compounds described herein. The range of ERK binding activity was less than 1 nM (nanomolar) to about 10 μM (micromolar). A cell-based functional assay (Biological Example 2) was used to determine the effect of ERK inhibitors on downstream signaling by measuring phosphorylation of p90RSK.

Administration and drug formulation

The compounds described herein can be administered by any suitable route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.

The compound can be administered in any suitable form of administration, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. The composition may contain conventional components of pharmaceutical preparations, such as diluents, carriers, pH regulators, sweeteners, bulking agents, and other active agents. If parenteral administration is desired, the composition will be sterile and in the form of a solution or suspension suitable for injection or infusion.

A typical formulation is prepared by mixing a compound described herein with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems . Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy . Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients . Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromas, flavorings, diluents and other known additives to provide an elegant appearance of the drug (i.e., a compound described herein or a pharmaceutical composition thereof) or to facilitate the manufacture of a pharmaceutical product (i.e., a medicament).

One embodiment includes a pharmaceutical composition comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a stereoisomer or pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Methods of treatment using the compounds of the invention

Also provided are methods of treating or preventing a disease or condition by administering one or more compounds described herein, or stereoisomers or pharmaceutically acceptable salts thereof. In one embodiment, provided is a method of treating a hyperproliferative disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment provides a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment provides a method of treating or preventing pain in a mammal in need of such treatment, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment provides a method of treating or preventing an inflammatory disorder in a mammal in need of such treatment, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment provides a method of inhibiting ERK protein kinase activity in a cell, comprising treating the cell with a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment provides a method of inhibiting ERK protein kinase activity in a cell, comprising treating the cell with a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in an amount effective to reduce or eliminate ERK kinase activity.

Another embodiment provides a method of inhibiting ERK protein kinase activity in a patient in need thereof, comprising the step of administering to the patient a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment provides a method of treating or ameliorating the severity of a hyperproliferative disorder in a patient in need thereof, comprising administering to the patient a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment provides a method of treating or ameliorating the severity of a hyperproliferative disorder in a patient in need thereof, comprising co-administering to the patient a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and at least one other chemotherapeutic agent for treating or ameliorating the hyperproliferative disorder.

Another embodiment provides a method of treating or ameliorating the severity of pain in a patient in need thereof, comprising administering to the patient a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment provides a method of treating or ameliorating the severity of an inflammatory disorder in a patient in need thereof, comprising administering to the patient a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

In another embodiment, a method of treating or preventing a disease or condition regulated by ERK comprises administering to a mammal in need of such treatment an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. Examples of such diseases and conditions include, but are not limited to, hyperproliferative diseases (such as cancer) and pain or inflammatory diseases.

Another embodiment provides the use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a hyperproliferative disease. Another embodiment provides the use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

Another embodiment provides the use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating pain.

Another embodiment provides the use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an inflammatory disease.

Another embodiment provides the use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for treating a hyperproliferative disease. Another embodiment provides the use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for treating cancer.

Another embodiment provides the use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for treating pain.

Another embodiment provides the use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for treating an inflammatory disease.

In certain embodiments, the hyperproliferative disease is cancer. In certain embodiments, the cancer can be selected from breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, myeloid disorders, lymphoid disorders, hairy cell cancer, buccal and pharyngeal (oral) cancer, lip cancer, tongue cancer, mouth cancer, pharyngeal cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain and central nervous system cancer, Hodgkin's cancer and leukemia. In certain embodiments, the cancerous condition is melanoma. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is thyroid cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is acute myeloid leukemia. In certain embodiments, the cancer is chronic myelomonocytic leukemia. In certain embodiments, the cancer is chronic myeloid leukemia. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is myeloid leukemia.

In certain embodiments, the inflammatory disorder may be selected from arthritis, lower back pain, inflammatory bowel disease, and rheumatic disease.

Combination therapy

The compounds described herein and their stereoisomers, tautomers and pharmaceutically acceptable salts can be used for treatment alone or in combination with other therapeutic agents. The compounds described herein can be used in combination with one or more other drugs (e.g., anti-hyperproliferative (or anti-cancer) agents that act by acting on different target proteins). The second compound of the pharmaceutical combination formulation or dosing regimen preferably has an activity complementary to that of the compound described herein so that they do not adversely affect each other. The molecules are suitable for being present in the combination in an amount effective for the intended purpose. The compounds can be administered together or separately in the form of a single pharmaceutical composition, and when administered separately, this can occur simultaneously or sequentially in any order. The sequential administration can be close in time or distant in time.

Example

The following examples are included for illustrative purposes. However, it should be understood that these examples do not limit the present invention and are intended only to illustrate a method of implementing the present invention. Those skilled in the art will recognize that the chemical reactions described can be easily adapted to prepare many other compounds described herein, and alternative methods for preparing compounds are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds can be successfully carried out by modifications that are obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art that are different from the reagents described, and/or by making conventional modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered to be applicable to the preparation of other compounds described herein.

In the following examples, unless otherwise indicated, all temperatures are set forth in degrees Celsius. Unless otherwise indicated, reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification.

The reactions described below were generally carried out in anhydrous solvents under positive nitrogen or argon pressure or with a drying tube (unless otherwise stated), and the reaction flasks were generally equipped with rubber septa to allow the introduction of substrates and reagents by syringe. Glassware was oven dried and/or heat dried.

Column chromatography was performed on a Biotage system (manufacturer: Dyax Corporation) with silica gel columns or on silica SepPak cartridges (Waters) (unless otherwise stated). ^{1H-NMR spectra were recorded on a Varian instrument operating at 400 MHz. 1H} -NMR spectra were obtained _as solutions of _{CDCl3 ,} CD3OD, D2O, ₍ CD3 ₎ 2SO, ( _{CD3 ) 2CO} , C6D6, and CD3CN (reported in ppm) using tetramethylsilane (0.00 ppm) or residual solvent ( _CDCl3 : 7.26 _ppm ; _CD3OD : 3.31 ppm; D2O: _4.79 ppm; ( _{CD3 )} 2SO: _2.50 ppm; ( _CD3 )2CO: _2.05 ppm; _C6D6 : _{7.16 ppm} ; _CD3CN : ^1.94 ppm) as reference standards. When reporting peak multiplicities, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double of doublets), dt (double of triplets). Coupling constants are reported in Hertz (Hz) when given.

Biological Example 1

ERK-2 enzymatic assay

Compounds were tested in an enzymatic assay using human ERK-2 (mitogen-activated kinase 1), recombinantly expressed in E. coli as an N-terminal 6-His fusion protein corresponding to aa 8-360. The substrate used was the fluorescent Omnia peptide S/T17 (Invitrogen, Carlsbad, CA; Catalog No. KNZ1171C). Test compounds were diluted in dimethyl sulfoxide (DMSO) at 100x final concentration in a 3-fold serial dilution. In addition to the compounds, the assay contained 50 mM HEPES (pH 7.3), 10 mM MgCl2, 1 mM DTT, 0.005% Triton-X100, 5 nM ERK-2 enzyme, 6.25 μM S/T17 peptide substrate, and 25 μM ATP (corresponding to the observed _Km ) in a total reaction volume of 25 μL. The assay was performed in white 384-well polypropylene plates (Nunc, Inc of Naperville, IL; catalog number 267462) at ambient temperature, and data were collected every 50 seconds for approximately 30 minutes on an Envision plate reader (PerkinElmer, Inc. of Waltham, MA) (excitation 340 nm/emission 495 nm). The data collected from each well were fitted to a straight line, and the resulting rate was used to calculate the percentage of control. The percentage of control was plotted against compound concentration, and _IC50 values were determined using a four-parameter fit. Table 1 contains representative data for the embodiments disclosed herein. The reported IC50s in Table 1 may be from a single assay or an average of multiple assays. Examples _1-126 were tested in the above assays and found to have an _IC50 of less than 1 μM. Examples 1-21, 23-34, 36-60, 62-80, 82-83, 86-126 were tested in the above assays and found to have an _IC50 of less than 100 nM. Many examples (100 out of 126) were tested in the above assay and found to have an _IC50 of less than 10 nM.

Biological Example 2

Cellular P90RSK (Ser380) phosphorylation assay

Inhibition of PMA-stimulated P90RSK (Ser380) phosphorylation was determined by an in vitro cellular mechanistic assay consisting of incubating cells with compounds for 1.5 hours and quantifying the fluorescent pP90RSK (Ser380) signal on fixed cells and normalizing to the GAPDH signal.

HepG2 cells were obtained from ATCC and grown in DMEM supplemented with 10% fetal bovine serum. Cells were seeded at 35,000 cells/well in 96-well plates and allowed to adhere overnight at 37°C/5% _CO2 . Diluted compounds were then added at a final concentration of 0.5% DMSO. After incubation for 1.5 hours with the compounds, cells were stimulated with phorbol 12-myristate 13-acetate ("PMA") at a final concentration of 100 ng/mL; PMA stimulation was incubated for 30 minutes at 37°C/5% _CO2 . After 30 minutes of PMA stimulation, cells were washed with phosphate-buffered saline ("PBS") and fixed in PBS containing 3.7% formaldehyde for 15-20 minutes at room temperature. This was followed by another wash in PBS and then permeabilization in 100% MeOH for 10-15 minutes at room temperature. After permeabilization, cells were washed in PBS/0.05% Tween-20 and then blocked in Odyssey blocking buffer (LI-COR Biosciences) for at least 1 hour. Antibodies against phosphorylated p90RSK (Ser380) (Cell Signaling #9335, rabbit monoclonal) and GAPDH (Fitzgerald 10R-G109a, mouse monoclonal) were added to the cells and incubated overnight at 4°C. pP90RSK (Ser380) antibodies were used at a dilution of 1:250; GAPDH antibodies were used at a dilution of 1:10,000. After washing with PBS/0.05% Tween-20, the cells were incubated with fluorescently labeled secondary antibodies (anti-rabbit Alexa Flour680, Invitrogen catalog number A21109; anti-mouse IRDye800CW, Rockland Inc. catalog number 610-131-121) for 1 hour. Both secondary antibodies were used at a dilution of 1:1000. The cells were then washed and fluorescence was analyzed at two wavelengths using the Odyssey infrared imaging system (LI-COR Biosciences). The phosphorylated P90RSK (Ser380) signal was normalized relative to the GAPDH signal. Table 1 contains representative data for the embodiments disclosed herein. The reported IC ₅₀ in Table 1 may be from a single assay or an average of multiple assays.

Table 1 contains the examples tested in the above assay:

Table 1

Example 1

4-(1-(2,3-difluorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazole- 5-aminobenzoyl)pyrimidin-2-amine

Step 1: A resealable glass pressure tube was charged with 2,4-dichloropyrimidine (5.0 g, 33.56 mmol), (4-fluoro-3-nitrophenyl)boronic acid (6.83 g, 36.9 mmol), _PdCl2 (dppf) _-CH2Cl2 adduct (1.37 _g , 1.68 mmol), 20% _{aqueous Na2CO3} (16.78 mL, 33.56 mmol), and 1,4-dioxane (67 mL, 33.56 mmol). The mixture was sparged with _N2 for 5 minutes. The tube was sealed with a cap under _N2 , stirred at 90°C for 5 hours, and allowed to cool to room temperature. A precipitate formed with cooling. The mixture was poured into water (50 mL) and extracted into EtOAc, DCM, and 5% MeOH:DCM. However, the solid did not dissolve in the solvents used. Therefore, the mixture was filtered (suction filtration) to isolate the solid. The collected filtrate is transferred to a separatory funnel. Each phase is separated, and the organic layer is concentrated in vacuo without _MgSO4 drying. The obtained residue is merged with the solid filtered above. It is then dissolved in hot THF:EtOAc (1:1, 500 mL) and washed with water (1X 50 mL). The organic layer is separated, dried ( _MgSO4 ), filtered and concentrated in vacuo. The solid residue obtained from hot _CH3CN crystallization is to provide 2-chloro-4-(4-fluoro-3-nitrophenyl)pyrimidine (7.9 g, 92.8% yield) as a solid. ¹ HNMR (400MHz, CDCl ₃ )δ8.816-8.743(m,1H),8.759(dd,J1＝5.086Hz,J2＝1.174Hz,1H),8.468-8.431(m,1H),7.70(dd,J1＝5.478Hz,J2＝1.174Hz,1H),7.50-7.456(m,1H).

Step 2: A suspension of 2-chloro-4-(4-fluoro-3-nitrophenyl)pyrimidine (5 g, 19.7 mmol), 1-methyl-1H-pyrazol-5-amine (1.91 g, 19.7 mmol), _Pd2 (dba) ₃ (0.903 g, 0.986 mmol), _Xantphos (1.71 g, 2.96 mmol), _K3PO4 (8.37 g, 39.4 mmol) in dioxane (98.6 mL, 19.7 mmol) was degassed with nitrogen for 5 minutes and then heated in a sealed tube at 120°C for 24 hours. The reaction mixture was filtered and the solid washed with ethyl acetate. The filtrate was concentrated and purified by flash chromatography eluting with a DCM:MeOH gradient 0-10% to provide 4-(4-fluoro-3-nitrophenyl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (5.14 g, 83% yield) as a solid. LCMS (APCI negative) m/z 313 (M-1).

Step ₃ : A solution of 4-(4-fluoro-3-nitrophenyl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (100 mg, 0.318 mmol) in DMSO (1.6 mL, 0.318 mmol) was treated with (2,3-difluorophenyl)methanamine (68.3 mg, 0.477 mmol) and potassium carbonate (66 mg, 0.477 mmol) under N2. The resulting mixture was stirred at room temperature for 30 minutes. LCMS showed that the reaction was complete. The mixture was poured into water (15 mL) and the formed precipitate was filtered and washed with additional water. The collected solid was evaporated from _CH3CN and dried under high vacuum to provide 4-(4-((2,3-difluorobenzyl)amino)-3-nitrophenyl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (140 mg, 90.5% yield) as a solid. LCMS (APCI+) m/z 438 (M+1). This material was used in the next reaction without purification.

[0146] Step 4: A solution of crude 4-(4-((2,3-difluorobenzyl)amino)-3-nitrophenyl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (149 mg, 0.307 mmol) in a mixture of THF (10 mL) and saturated aqueous _NH4Cl (10 mL) was treated with zinc dust (<10 μm, 98+%; 133 mg, 1.99 mmol) at 0°C with rapid stirring. Upon completion of the Zn addition, the ice bath was removed and the mixture was stirred at ambient temperature for 30 minutes. The reaction went to completion (LCMS data). The mixture was diluted with EtOAc (60 mL), and the organic layer was separated, dried (MgSO ₄ ), filtered, and concentrated in vacuo to afford crude N 1-(2,3-difluorobenzyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)benzene-1,2-diamine as a solid. (APCI+) m/z 408 (M+1). This was used directly in the next reaction.

[0266] Step 5: To a stirred solution of crude Nl-(2,3-difluorobenzyl)-4-(2-((l-methyl-lH-pyrazol-5-yl)amino)pyrimidin-4-yl)benzene-l, _2- diamine (233 mg, 0.572 mmol) in 4:1 DCM:concentrated HCl (10 mL) at 0°C was added NaNO2 (39.5 mg, 0.572 mmol). After 10 minutes, the ice bath was removed and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc (50 mL), transferred to a separatory funnel, and washed sequentially with 1 N NaOH and brine (10 mL). The organic layer was dried ( _MgSO4 ), filtered, and concentrated in vacuo. The obtained residue was purified by C-18 flash chromatography (Biotage 25M+) on a Biotage SP1 apparatus eluting with a gradient of 5-90% _CH3CN :water (25CV) to afford 4-(1-(2,3-difluorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (26.42 mg, 11% yield) as a solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.52 (s, 1H), 8.85 (s, 1H), 8.56 (d, J = 5.075 Hz, 1H), 8.34 (dd, J1 = 1.171 Hz, J2 = 8.98 Hz, 1H), 8.013 (d, J = 5.47 Hz, 1H), 7.48-7.40 (m, 1H), 7.37 (d, J = 1.952 Hz, 1H), 7.25-7.17 (m, 2H), 6.32 (d, J = 1.562 Hz, 1H), 6.14 (s, 2H), 3.70 (s, 3H). LCMS (APCI+) m/z 419.1 (M+1). Analytical HPLC 96 area % (220 nm) and 98 area % (254 nM), retention time 3.475 minutes.

Example 2

4-(1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H- Pyrazol-4-yl)pyrimidin-2-amine

Step 1: A suspension of 2-chloro- _4- (4-fluoro-3-nitrophenyl)pyrimidine (1 g, 3.94 mmol) in DMSO (39 mL, 3.94 mmol) was treated sequentially with (3-fluoro-4-methoxyphenyl)methanamine (0.583 mL, 3.94 mmol) and K ₂ CO ₃ (0.55 g, 3.94 mmol) at ambient temperature under N 2 atmosphere. After 1 hour, the mixture was poured into water (300 mL), and the formed precipitate was filtered and washed with additional water. The collected solid was evaporated from CH ₃ CN, and the obtained residue was triturated with CH ₃ CN to provide (about 95% pure according to NMR) 4-(2-chloropyrimidin-4-yl)-N-(3-fluoro-4-methoxybenzyl)-2-nitroaniline (1.55 g, 96.1% yield) as a solid. LCMS (APCI+) m/z 389.1 (M+1).

[0146] Step 2: A solution of 4-(2-chloropyrimidin-4-yl)-N-(3-fluoro-4-methoxybenzyl)-2-nitroaniline (1.5 g, 3.86 mmol) in a mixture of THF (80 mL) and saturated aqueous NH4Cl (40 mL) was treated as described in Example 1, Step 4, with zinc dust (<10 μm, ₉₈ +%; 1.29 g, 19.3 mmol) at 0°C to afford crude 4-(2-chloropyrimidin-4-yl)-N1-(3-fluoro-4-methoxybenzyl)benzene-1,2-diamine (1.48 g, 3.30 mmol, 85.5% yield) as a solid. LCMS (APCI+) m/z 359 (M+1).

Step 3: To a stirred solution of approximately 80% pure 4-(2-chloropyrimidin-4-yl)-N1-(3-fluoro-4-methoxybenzyl)benzene-1,2-diamine (1.48 g, 3.3 mmol) in DCM:acetic acid (4:1, 60 mL) was added _NaNO2 (0.228 g, 3.30 mmol) at ambient temperature. Shortly after the addition of _NaNO2 , vigorous gas evolution and a slightly exothermic reaction were observed. Therefore, the mixture was placed in an ice bath. After 5 minutes, the ice bath was removed and the mixture was stirred at room temperature. After 10 minutes, the reaction turned to completion (LCMS data). The mixture was diluted with additional DCM (150 mL), transferred to a separatory funnel, and washed sequentially with 1N NaOH and brine (50 mL). The organic layer was dried ( _MgSO4 ), filtered, and concentrated in vacuo. The isolated crude material was purified by flash silica gel chromatography on a Biotage SP1 apparatus (Ready Sep 80 g) eluting with a 0-7% MeOH:DCM gradient (12 CV). The isolated product crystallized from EtOAc to provide 5-(2-chloropyrimidin-4-yl)-1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazole (1.1 g, 90% yield) as a solid. LCMS (APCI+) m/z 370 (M+1).

Step 4: A resealable glass pressure tube was charged with a mixture of 5-(2-chloropyrimidin-4-yl)-1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazole (40 mg, 0.11 mmol), 1-methyl-1H-pyrazol-4-amine (21 mg, 0.22 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (9.4 mg, 0.019 mmol), _Pd2dba3 ( ₅ mg, 0.005 mmol), _{powdered K3PO4} (68.9 mg, 0.32 mmol), and 1,4-dioxane (216 μL, 0.11 mmol). The mixture was sparged with _N2 for 3 minutes. The tube was sealed with a cap and stirred at 85°C for 15 hours. The mixture was diluted with dioxane (3 mL) and filtered through a 45 μM filter. The collected filtrate was concentrated, and the resulting residue was purified by C-18 flash chromatography (Biotage 12M+) on a Biotage SP1 apparatus using a 5-90% CH ₃ CN:water gradient. The isolated product was crystallized from MeOH to provide 4-(1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (8 mg, 17.2% yield) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 (s, 1H), 8.47 (d, J = 5.478 Hz, 1H), 8.18 (d, J = 8.216 Hz, 1H), 7.88 (s, 1H), 7.57 (s, 1H), 7.45 (d, J = 8.99 Hz, 1H), 7.154 (d, J = 5.09 Hz, 1H), 7.06 (d, J = 5.86 Hz, 1H), 7.04 (s, 1H), 6.95-6.89 (m, 2H), 5.81 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H). LCMS (APCI+) m/z 431 (M+1), analytical HPLC: area % 99% (220 nm), retention time 3.447 min.

Example 3

4-(1-(4-chlorophenethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl) Pyrimidine-2-amine

[0266] Step 1: A mixture of 4-(4-fluoro-3-nitrophenyl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (100 mg, 0.318 mmol) and _K2CO3 (88 mg, 0.636 mmol) in DMSO (2 mL) was treated with 2-( ₄ -chlorophenyl) _ethanamine (90 μL, 0.636 mmol) at ambient temperature. After 3 hours, the reaction mixture was diluted with DCM and washed with water. The layers were separated and the organics were dried (MgSO4), filtered and concentrated in vacuo to afford 4-(4-((4-chlorophenethyl)amino)-3-nitrophenyl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (140 mg, 97.8% yield). The material was carried forward directly to the next step. LCMS (APCI+) m/z 450.1 (M+1), retention time 3.128 minutes.

Step 2: 4-(4-((4-chlorophenethyl)amino)-3-nitrophenyl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (140 mg, 0.311 mmol) and Zn powder (61 mg, 0.934 mmol) were treated according to the method described in Example 1, Step 4 to provide N1-(4-chlorophenethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)benzene-1,2-diamine (130 mg, 99.5% yield).

Step 3: N1-(4-chlorophenethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)benzene-1,2-diamine (110 mg, 0.262 mmol) and NaNO2 (18 mg. 0.262 mmol) were treated according to the method described in Example ₂ , Step 3 to provide 4-(1-(4-chlorophenethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (3 mg, 3%). ¹ HNMR (CD ₃ OD)δ8.74(s,1H),8.51(d,J＝5.47Hz,1H),8.24(d,J＝8.58Hz,1H),7.62-7.60(m,2H),7.53(d,J＝5.47Hz,1H),7.17(d,J＝8 .20Hz, 2H), 7.04 (d, J = 8.20Hz, 2H), 6.52 (d, J = 1.95Hz, 1H), 4.99 (t, J = 6.64Hz, 2H), 3.83 (s, 3H), 3.33 (t, J = 6.64Hz, 2H). LCMS(APCI+)m/z 431.1(M+1).

Example 4

4-(1-(2-(4-chloro-1H-pyrazol-1-yl)ethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl -1H-pyrazol-5-yl)pyrimidin-2-amine

Step 1: A solution of 4-(4-fluoro-3-nitrophenyl)-N-(1-methyl-1H-pyrazol- _5- yl)pyrimidin-2-amine (100 mg, 0.318 mmol) in _DMSO (1.5 mL, 0.318 mmol) was treated with 2-(4-chloro-1H-pyrazol-1-yl) _ethanamine (93 mg, 0.636 mmol) and K2CO3 (88 mg, 0.636 mmol) under N2. The mixture was stirred at room temperature overnight. The mixture was poured into ice water (25 mL) and extracted with EtOAc (2X). The organic extracts were combined, dried ( _MgSO4 ), filtered, concentrated and dried in vacuo to provide crude 4-(4-((2-(4-chloro-1H-pyrazol-1-yl)ethyl)amino)-3-nitrophenyl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine. LCMS (APCI+) m/z 440.2 (M+1).

Step 2: Crude 4-(4-((2-(4-chloro-1H-pyrazol-1-yl)ethyl)amino)-3-nitrophenyl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (140 mg, 0.318 mmol) and zinc dust (<10 μm, 98+%; 104 mg, 1.59 mmol) were treated according to the synthesis described for Example 1, Step 4 to provide crude N1-(2-(4-chloro-1H-pyrazol-1-yl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)benzene-1,2-diamine. LCMS (APCI+) m/z 410.2 (M+1).

Step 3: To a stirred solution of crude N1-(2-(4-chloro-1H-pyrazol-1-yl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)benzene-1,2-diamine (130 mg, 0.317 mmol) in 4:1 DCM:acetic acid (10 mL) was added _NaNO2 (21.9 mg, 0.317 mmol) at ambient temperature, and the mixture was stirred at room temperature. After 1 hour, the reaction mixture was diluted with additional DCM (30 mL), transferred to a separatory funnel, and washed sequentially with 1N NaOH and brine (10 mL). The organic layer was dried ( _MgSO4 ), filtered, and concentrated in vacuo. The isolated crude material was purified by flash chromatography on a Biotage SP1 apparatus (Ready Sep 40 g) eluting with a gradient of 1-12% MeOH:DCM (25 CV) to afford 4-(1-(2-(4-chloro-1H-pyrazol-1-yl)ethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.667 (s, 1H), 8.49-8.48 (m, 1H), 8.079-8.048 (m, 1H), 7.565-7.517 (m, 1H), 7.29-7.27 (m, 2H), 7.10 (d, J=9.37 Hz, 1H), 6.885-6.862 (m, 1H), 6.384 (s, 1H), 5.987 (s, 1H), 5.15-5.116 (m, 2H), 4.79-4.71 (m, 2H), 3.834 (s, 3H). LCMS (APCI+) m/z 421.2 (M+1), retention time 1.271 minutes.

Example 5

4-(3-(3-fluoro-4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(1-methyl -1H-pyrazol-5-yl)pyrimidin-2-amine

Step 1: To a stirred solution of 5-bromo-N-[(3-fluoro-4-methoxy-phenyl)methyl]-3-nitro-pyridin-2-amine (1.02 g, 2.86 mmol) and ethanol (50 mL) was added ammonium chloride (5.0 equiv, 14.3 mmol, 0.77 g) and water (20 mL). The mixture was heated to 90° C. Zinc (2.81 g, 43.0 mmol) was added and stirred for 1 hour. The reaction was cooled and filtered through a bed of Celite®, washing with ethyl acetate. The mixture was further diluted with EtOAc and washed sequentially with saturated NaHCO ₃ (aq.), water, and brine. The product was dried over Na ₂ SO ₄ and evaporated to afford an oil (0.83 g). MS 326.1.

Step 2: 5-Bromo-N2-[(3-fluoro-4-methoxy-phenyl)methyl]pyridine-2,3-diamine (0.83 g, 2.58 mmol) was suspended in glacial acetic acid (7.69 g, 128 mmol). The suspension was cooled in an ice bath (0°C) followed by the slow addition of sodium nitrite (212 mg, 3.07 mmol) dissolved in water (2 mL). Sulfuric acid (0.5 mL) was added and the mixture was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 30 minutes. The mixture was slowly added to 1N NaOH (aq.) in ice. Additional sodium hydroxide was added until the pH reached 4. The mixture was diluted _{with CH2Cl2} and the phases were separated. The aqueous phase was extracted three times with _CH2Cl2 . The combined organic phases were washed with saturated _NaHCO3 (aq _. ) and brine, _dried over _Na2SO4 and evaporated. Purification by CombiFlash (12 g silica column - 0-100% ethyl acetate:heptane) provided a solid (0.5 g).MS 339.0.

Step 3: A microwave vial was charged with 6-bromo-3-[(3-fluoro-4-methoxy-phenyl)methyl]triazolo[4,5-b]pyridine (198 mg, 0.587 mmol), 1,4-dioxane (5 mL), potassium acetate hydrate (173 mg, 1.76 mmol), bis(pinacolato)diboron (298 mg, 1.17 mmol), and [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (21.5 mg, 0.029 mmol, 21.5 mg). The mixture was heated in a microwave at 120°C for 20 minutes. The mixture was diluted with EtOAc and filtered through Celite®. The mixture was washed sequentially with saturated _NaHCO3 (aq.) and brine. The product was dried _{over Na2SO4} , evaporated, and purified by CombiFlash (12 g column; 0-100% EtOAc:heptane) to afford a solid (177 mg).MS=303.

[0266] Step 4: A microwave vial was charged with (3-(3-fluoro-4-methoxybenzyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl]boronic acid (166 mg, 0.55 mmol), 1,4-dioxane (4 mL), 4-iodo-2-methylsulfanyl-pyrimidine (139 mg, 0.55 mmol), 1 _{N Na2CO3} (aq., 1.1 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (40 mg, 0.055 mmol). The mixture was purged with nitrogen and then heated in a microwave at 120°C for 30 min. The mixture was diluted with EtOAc and filtered through Celite®. The organic phase was washed sequentially with saturated _NaHCO3 (aq.) and brine. The product was purified by _{Na2SO The product} was dried, evaporated, and purified by CombiFlash (4 g column; 0-100% EtOAc:heptane) to give 3-(3-fluoro-4-methoxybenzyl)-6-(2-(methylthio)pyrimidin-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine (64 mg) as a solid. MS=383.

Step 5: 3-(3-Fluoro-4-methoxybenzyl)-6-(2-(methylthio)pyrimidin-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine (64 mg, 0.167 mmol) was dissolved in CH ₂ Cl ₂ (4 mL). The mixture was cooled to 0° C., and then 3-chloroperbenzoic acid (285 mg, 1.65 mmol) was slowly added portionwise over 2 minutes. The mixture was stirred at room temperature overnight. The mixture was quenched with saturated NaHSO ₃ (aq.) and diluted with CH ₂ Cl ₂ (10 mL). The mixture was stirred for 5 minutes, and the phases were separated. The organic phase was washed sequentially with saturated NaHCO ₃ (aq.) and brine. The product was dried over Na ₂ SO ₄ and evaporated to give 3-(3-fluoro-4-methoxybenzyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine as an oil. MS=415.

Step 6: A flask was charged with 3-(3-fluoro-4-methoxybenzyl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine (61 mg, 0.147 mmol), DMF (4.0 mL, 51.5 mmol), and 2-methylpyrazol-3-amine (21.4 mg, 0.221 mmol). The mixture was purged with nitrogen and cooled in an ice bath (0°C). Sodium hydride (11.8 mg, 0.294 mmol) was added, and the mixture was stirred at room temperature. After 30 minutes, the mixture was cooled to 0°C, quenched with water, and diluted with EtOAc. The mixture was washed sequentially with saturated _NaHCO3 (aq.) and brine. The product was dried _{over Na2SO4} , evaporated, and purified by HPLC to afford 4-(3-(3-fluoro-4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (14.8 mg). MS = 432.2.

The following compounds in Table 2 were prepared according to the above procedures using appropriate starting materials and intermediates.

Table 2

It should be understood that the embodiments listed are not intended to limit the present invention to those embodiments. On the contrary, the present invention is intended to encompass all alternatives, modifications and equivalents that may be included in the scope of the present invention as defined by the claims. Therefore, the above description is considered to be merely illustrative of the principles of the present invention.

Claims (46)

1. A compound of formula I: or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: _X is selected from CH and N; _X2 is selected from CH and N; R ¹ is selected from (a) C ₁ -C ₅ alkyl optionally substituted by one or two groups selected from the group consisting of OH, cyclopropyl, oxetanyl and morpholino; (b) C ₃ -C ₄ cycloalkyl; (c) 4 to 6 membered heterocyclyl containing one O heteroatom optionally substituted by halogen or methyl; and (d) 5 membered heteroaryl containing two to four heteroatoms selected from N and S substituted by one to three groups selected from the group consisting of methyl and cyclopropyl; R ² is selected from (a) C ₁ -C ₆ alkyl optionally substituted with one or two R ^f groups; (b) C ₃ -C ₆ cycloalkyl optionally substituted with one or two halogens; (c) 4 to 6 membered heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the heterocyclyl may be optionally substituted with one to three R ^g groups; (d) 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted with one or two groups selected from the following: C ₁ -C ₃ alkyl and 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S; and (e) C ₈ -C ₁₀ bicyclic cycloalkyl optionally substituted with halogens; ^R3 and ^R4 are hydrogen; each ^Rf is independently selected from (a) halogen; (b) hydroxy; (c) _C1 - _C3 alkoxy; (d) ^NRkRm ; (e) _C3 - _C6 ^cycloalkyl optionally substituted with one or two ^Rh groups; (f) 4- to 6-membered heterocyclyl containing one to three heteroatoms selected from N, O, and S, wherein the heterocyclyl may be optionally substituted with a group selected from the following: _C1 - _C3 alkyl optionally substituted with halogen, -C(=O)O( _C1 - _C6 alkyl), and phenyl; (g) phenyl optionally substituted with one or two ^Rj groups; and (h) 5- to 6-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, wherein the heteroaryl may be optionally substituted with one or two ^Rj groups; Each ^Rg is selected from (a) halogen; (b) _C1 - _C3 alkyl optionally substituted by phenyl, said phenyl optionally substituted by two groups selected from halogen and _C1 - _C3 alkoxy; (c) _C1 - _C3 alkoxy; (d) phenyl optionally substituted by halogen; and (e) 5- to 6-membered heteroaryl containing one N heteroatom optionally substituted by one or two groups selected from halogen and _C1 - _C3 alkoxy; each R ^h is selected from halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, and phenyl optionally substituted with: C ₁ -C ₃ alkoxy optionally substituted with halogen; each R ^j is selected from halogen, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy, wherein the alkyl and alkoxy groups may be optionally substituted with halogen; and Each of R ^k and R ^m is independently C ₁ -C ₃ alkyl. 2. The compound of claim 1, wherein _X1 is CH and _X2 is CH; _X1 is CH and _X2 is N; or _X1 is N and _X2 is CH. 3. The compound of claim 1, wherein the compound has the structure of Formula VI: 4. The compound of claim 1, wherein the compound has the structure of Formula VII: 5. The compound of claim 1, wherein the compound has the structure of Formula VIII: 6. The compound of claim 1, wherein the compound has the structure of Formula IX: 7. The compound of claim 1, wherein R ¹ is selected from isopropyl, 1-hydroxy-2,2-dimethylpropan-3-yl, 2-hydroxy-2-methylpropan-1-yl, 1-hydroxypropan-2-yl, 1,2-dihydroxypropan-3-yl, cyclopropylmethyl, oxetan-3-ylmethyl, 2-methyl-1-morpholinopropan-2-yl, cyclopropyl, cyclobutyl, oxetan-3-yl, 3-methyloxetan-3-yl, tetrahydro-2H-pyran-4-yl, 3-fluorotetrahydro-2H-pyran-4-yl, 1-methyl-1H-pyrazol-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, 3-cyclopropyl-1-methyl-1H-pyrazol-5-yl, 2-methyl-2H-1,2,3-triazol-4-yl, 1-methyl-1H-tetrazol-5-yl, 2-methyl-2H-tetrazol-5-yl and 5-methyl-1,3,4-thiadiazol-2-yl. 8. The compound of claim 7, wherein R ¹ is (3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl or (3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl. 9. The compound of claim 1 , wherein ^R is selected from the group consisting of 2-methylbutyl, 2-ethylbutyl, isobutyl, 2,2-difluoropropyl, 2,2-difluoroethyl, 3-fluoropropyl, 3-hydroxybutyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 2-methoxy-2-methylpropyl, 3-methoxy-2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl, 3-isopropoxypropyl, cyclopentylmethyl, (3,3-difluorocyclobutyl)methyl, (1-(ethoxymethyl)cyclopropyl)methyl, (1-(4-(trifluoromethoxy)phenyl)cyclopropyl)methyl, (1-methylcyclobutyl)methyl, (1-methylazetidin-3-yl)methyl, oxetan-3-ylmethyl, azetidin-3-ylmethyl, (1-(tert-butoxycarbonyl)azetidin-3-yl)methyl, (1-(2,2,2-trifluoroethyl)azetidin-3-yl)methyl, (4-phenylpiperidin-4-yl)methyl, (tetrahydro-2H-pyran-2-yl)methyl, 2, 3-difluorobenzyl, 3-fluoro-4-methoxybenzyl, 4-(difluoromethoxy)benzyl, 4-chlorobenzyl, 4-methoxybenzyl, 3-fluorobenzyl, 4-chloro-3-fluorobenzyl, 4-fluorobenzyl, 3-chlorobenzyl, 3-chloro-4-fluorobenzyl, 2-(trifluoromethyl)benzyl, 2,4-difluorobenzyl, 4-chlorophenethyl, 2-chlorophenethyl, 3-chlorophenethyl, 1-(4-chloro-3-fluorophenyl)-2-(dimethylamino)ethyl, 1 -(4-chloro-3-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl, 2-hydroxy-1-(4-chloro-3-fluorophenyl)ethyl, 2-hydroxy-1-(3-fluoro-4-methoxyphenyl)ethyl, 2-(4-chloro-1H-pyrazol-1-yl)ethyl, (1-methyl-1H-pyrazol-3-yl)methyl, (1-methyl-1H-pyrazol-5-yl)methyl, (6-(trifluoromethyl)pyridin-2-yl)methyl, (2-methylpyridin-3-yl)methyl, (2-methoxypyridin-3-yl)methyl, (6-methylpyridin-3-yl)methyl, (6-methylpyridin-2-yl)methyl, (2-chloropyridin-3-yl)methyl, (3-methoxypyridin-2-yl)methyl, (3,5-difluoropyridin-2-yl)methyl, 2-(4-methyl-1H-pyrazol-1-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl, (3-fluoro-4-methoxyphenyl)(1-methyl-1H-pyrazol-4-yl)methyl, ( 3-fluoro-4-methoxyphenyl)(1-methyl-1H-1,2,3-triazol-5-yl)methyl, (3-fluoro-4-methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methyl, 4,4-difluorocyclohexyl, (4,4-difluorocyclohexyl)cyclohexyl, piperidin-4-yl, 1-methylazetidin-3-yl, 1-(2-fluoro-6-methoxybenzyl)azetidin-3-yl, 4-(3-fluorophenyl)piperidin-3-yl, 4-(4-fluoro 4-(2,4-difluorophenyl)-1-methylpyrrolidin-3-yl, 4-(3,4-difluorophenyl)-1-methylpyrrolidin-3-yl, 4-(3,5-difluorophenyl)-1-methylpyrrolidin-3-yl, 4-(3,4-difluorophenyl)-1-ethylpyrrolidin-3-yl, 4-(3,4-difluorophenyl)pyrrolidin-3-yl, 5,5-difluoropiperidin-3-yl, 4-(3,5-difluorophenyl)-1-isopropylpyrrolidin-3-yl. 1-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-3-yl, 4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl, 1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl, 1-(5,5-difluoro-1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl, 3-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl and 5-chloro-2,3-dihydro-1H-inden-1-yl. 10. The compound of claim 9, wherein ^R2 is (S)-2-hydroxy-1-(4-chloro-3-fluorophenyl)ethyl or (R)-2-hydroxy-1-(4-chloro-3-fluorophenyl)ethyl. 11. The compound of claim 9, wherein ^R2 is (S)-2-hydroxy-1-(3-fluoro-4-methoxyphenyl)ethyl. 12. The compound of claim 9, wherein ^R2 is (3S,4R)-4-(2,4-difluorophenyl)-1-methylpyrrolidin-3-yl. 13. The compound of claim 9, wherein ^R2 is (3S,4R)-4-(3,4-difluorophenyl)-1-methylpyrrolidin-3-yl. 14. The compound of claim 9, wherein ^R2 is (3S,4R)-4-(3,5-difluorophenyl)-1-methylpyrrolidin-3-yl. 15. The compound of claim 9, wherein ^R2 is (3S,4R)-4-(3,4-difluorophenyl)-1-ethylpyrrolidin-3-yl. 16. The compound of claim 9, wherein ^R2 is (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-yl. 17. The compound of claim 9, wherein ^R2 is (3S,4R)-4-(3,5-difluorophenyl)-1-isopropylpyrrolidin-3-yl. 18. The compound of claim 9, wherein ^R2 is (3R,4S)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl or (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl. 19. The compound of claim 9, wherein ^R2 is (R)-1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl. 20. The compound of claim 9, wherein R2 is (R) ^-1- (5,5-difluoro-1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl. 21. The compound of claim 1, wherein ^R2 is _C1 - _C6 alkyl optionally substituted with one or two ^Rf groups. 22. The compound of claim 1, wherein the compound has the structure of Formula X: 23. The compound of claim 1, wherein ^R2 is _C1 - _C6 alkyl. 24. The compound of claim 1, wherein the compound is: 4-(1-(2,3-Difluorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (1); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (2); 4-(1-(4-chlorophenethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (3); 4-(1-(2-(4-chloro-1H-pyrazol-1-yl)ethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (4); 4-(3-(3-Fluoro-4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (5); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (6); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (7); N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-(1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (8); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(2-methyl-2H-1,2,3-triazol-4-yl)pyrimidin-2-amine (9); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(oxetan-3-yl)pyrimidin-2-amine (10); N-(4-(1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-yl)-5-methyl-1,3,4-thiadiazol-2-amine (11); N-cyclobutyl-4-(1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (12); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-isopropylpyrimidin-2-amine (13); N-(cyclopropylmethyl)-4-(1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (14); N-cyclopropyl-4-(1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (15); 3-((4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-yl)amino)-2,2-dimethylpropan-1-ol (16); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(oxetan-3-ylmethyl)pyrimidin-2-amine (17); 1-((4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-yl)amino)-2-methylpropan-2-ol (18); (S)-2-((4-(1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-yl)amino)propan-1-ol (19); (R)-3-((4-(1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-yl)amino)propane-1,2-diol (20); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(3-methyloxetan-3-yl)pyrimidin-2-amine (21); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (22); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(2-methyl-1-morpholinopropan-2-yl)pyrimidin-2-amine (23); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-tetrazol-5-yl)pyrimidin-2-amine (24); N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-4-(1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (25); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(2-methyl-2H-tetrazol-5-yl)pyrimidin-2-amine (26); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-(2-methylbutyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (27); 4-(1-(2-ethylbutyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (28); 4-(1-(Cyclopentylmethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (29); 4-(1-(2-methoxypropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (30); 4-(1-(2,2-difluoropropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (31); 4-(1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (32); 4-(1-((4,4-difluorocyclohexyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (33); 4-(1-((3,3-difluorocyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (34); 4-(1-(4,4-difluorocyclohexyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (35); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((1-methylazetidin-3-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (36); 4-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (37); 4-(1-Isobutyl-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (38); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (39); 4-(1-(3-Fluoropropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (40); 4-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-1-yl)butan-2-ol (41); 4-(1-(3-methoxypropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (42); 4-(1-(3-ethoxypropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (43); 4-(1-(2-methoxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (44); 4-(1-((1-(ethoxymethyl)cyclopropyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (45); 4-(1-(3-methoxy-2,2-dimethylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (46); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((1-(4-(trifluoromethoxy)phenyl)cyclopropyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (47); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((1-methylcyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (48); 4-(1-(2-chlorophenethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (49); 4-(1-(3-chlorophenethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (50); 4-(1-(4-(difluoromethoxy)benzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (51); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (52); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((2-methylpyridin-3-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (53); 4-(1-((2-methoxypyridin-3-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (54); 4-(1-(4-Chlorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (55); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((2-methylpyridin-3-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyridin-2-amine (56); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((6-methylpyridin-3-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (57); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((6-methylpyridin-2-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (58); 4-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (59); 2-Methyl-1-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-1-yl)propan-2-ol (60); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-(oxetan-3-ylmethyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (61); 4-(1-(azetidin-3-ylmethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (62); tert-Butyl 3-((5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-1-yl)methyl)azetidine-1-carboxylate (63); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (64); 4-(1-(4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (65); 4-(1-((2-chloropyridin-3-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (66); 4-(1-((2-methoxypyridin-3-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (67); 4-(1-((3-methoxypyridin-2-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (68); 4-(1-((3,5-difluoropyridin-2-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (69); (S)-4-(1-((3-Fluoro-4-methoxyphenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (70); (S)-4-(1-((3-Fluoro-4-methoxyphenyl)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (71); (S)-4-(1-((3-fluoro-4-methoxyphenyl)(1-methyl-1H-imidazol-2-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (72); 4-(1-((3S,4R)-4-(2,4-difluorophenyl)-1-methylpyrrolidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (73); 4-(1-((3S,4R)-4-(2,4-difluorophenyl)-1-methylpyrrolidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (74); 4-(1-((3S,4R)-4-(3,4-difluorophenyl)-1-methylpyrrolidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (75); 4-(1-((3S,4R)-4-(3,5-difluorophenyl)-1-methylpyrrolidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (76); 4-(1-((3S,4R)-4-(3,4-difluorophenyl)-1-ethylpyrrolidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (77); 4-(1-((3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (78); (R)-4-(1-(5,5-difluoropiperidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (79); 4-(1-((3S,4R)-4-(3,5-difluorophenyl)-1-isopropylpyrrolidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (80); (S)-4-(1-(1-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (81); 4-(1-(3-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (82); 4-(1-((3R,4S)-4-(4-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (83); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((4-phenylpiperidin-4-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (84); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-(piperidin-4-yl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (85); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-(1-methylazetidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (86); 4-(1-((3S,4R)-4-(4-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (87); 4-(1-(1-(2-Fluoro-6-methoxybenzyl)azetidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (88); 4-(1-(4-(3-Fluorophenyl)piperidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (89); 4-(1-(4-(4-Fluorophenyl)piperidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (90); 4-(1-(1-(4-chloro-3-fluorophenyl)-2-(dimethylamino)ethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (91); 4-(1-(1-(4-chloro-3-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (92); (S)-2-(4-chloro-3-fluorophenyl)-2-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-1-yl)ethanol (93); (R)-2-(4-chloro-3-fluorophenyl)-2-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-1-yl)ethanol (94); (S)-2-(3-Fluoro-4-methoxyphenyl)-2-(5-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-1-yl)ethanol (95); N-(1-methyl-1H-pyrazol-4-yl)-4-(1-(2-methylbutyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (96); 4-(1-Isobutyl-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (97); (2S)-2-((4-(1-(2-methylbutyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-yl)amino)propan-1-ol (98); 4-(1-Isobutyl-1H-benzo[d][1,2,3]triazol-5-yl)-N-(2-methyl-2H-1,2,3-triazol-4-yl)pyrimidin-2-amine (99); N-(2-methyl-2H-1,2,3-triazol-4-yl)-4-(1-(2-methylbutyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (100); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (101); 4-(1-(3-Isopropoxypropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (102); 4-(1-(2-(4-methyl-1H-pyrazol-1-yl)ethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (103); 4-(1-(2-(1H-pyrazol-1-yl)ethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (104); (R)-4-(1-(1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (105); (R)-4-(1-(5,5-difluoro-1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (106); 4-(1-(3-Fluorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (107); 4-(1-(4-chloro-3-fluorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (108); 4-(1-(4-chloro-3-fluorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (109); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (110); 4-(1-(4-Fluorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (111); 4-(1-(4-chlorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (112); 4-(1-(3-Fluoro-4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (113); 4-(3-Isobutyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (114); 4-(3-(3-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (115); 4-(3-(4-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (116); 4-(1-(3-chlorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (117); 4-(3-(3-chlorophenethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (118); 4-(3-(4-chloro-3-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (119); 4-(1-(3-Fluorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (120); 4-(3-(3-chloro-4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (121); N-(1-methyl-1H-pyrazol-5-yl)-4-(1-(2-(trifluoromethyl)benzyl)-1H-benzo[d][1,2,3]triazol-5-yl)pyrimidin-2-amine (122); 4-(1-(2,4-Difluorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (123); 4-(3-(3-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (124); 4-(1-(3-chloro-4-fluorobenzyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (125); or 4-(3-((2-methoxypyridin-3-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (126); or a pharmaceutically acceptable salt thereof. 25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24. 26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 and at least one pharmaceutically acceptable carrier, excipient or diluent. 27. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 24 for use in the treatment of a hyperproliferative disease. 28. Use of a compound as claimed in any one of claims 1 to 24 for the manufacture of a medicament for the treatment of a hyperproliferative disease. 29. A compound as claimed in any one of claims 1 to 24 for use as a medicament. 30. A compound as claimed in any one of claims 1 to 24 for use in therapy. 31. Use of a compound as claimed in any one of claims 1 to 24 in the preparation of a medicament for the treatment of a hyperproliferative disease. 32. The method of claim 31 , wherein the hyperproliferative disease is selected from the group consisting of adenoma, bladder cancer, brain cancer, breast cancer, colon cancer, epidermal cancer, follicular cancer, genitourinary tract cancer, glioblastoma, Hodgkin's disease, head and neck cancer, hepatoma, keratoacanthoma, renal cancer, large cell carcinoma, leukemia, lung adenocarcinoma, lung cancer, lymphoid disorders, melanoma and non-melanoma skin cancer, myelodysplastic syndrome, neuroblastoma, non-Hodgkin's lymphoma, ovarian cancer, papillary carcinoma, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, small cell carcinoma, testicular cancer, teratoma, thyroid cancer, and anaplastic carcinoma. 33. The use of claim 31, wherein the hyperproliferative disease is selected from the group consisting of melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer. 34. The use of claim 31, wherein the hyperproliferative disease is selected from the group consisting of acute myeloid leukemia, chronic myelomonocytic leukemia, chronic myelogenous leukemia, multiple myeloma, and myeloid leukemia. 35. Use of the compound according to claims 1 to 24 in the preparation of a medicament for inhibiting ERK protein kinase activity in cells. 36. Use of a compound as claimed in claims 1 to 24 for the preparation of a medicament for inhibiting ERK protein kinase activity in a patient in need thereof. 37. Use of a compound as claimed in claims 1 to 24 in the preparation of a medicament for treating or ameliorating the severity of a hyperproliferative disease in a patient in need thereof. 38. The method of claim 37, wherein the hyperproliferative disease is selected from the group consisting of adenoma, bladder cancer, brain cancer, breast cancer, colon cancer, epidermal cancer, follicular cancer, genitourinary tract cancer, glioblastoma, Hodgkin's disease, head and neck cancer, hepatoma, keratoacanthoma, renal cancer, large cell carcinoma, leukemia, lung adenocarcinoma, lung cancer, lymphoid disorders, melanoma and non-melanoma skin cancer, myelodysplastic syndrome, neuroblastoma, non-Hodgkin's lymphoma, ovarian cancer, papillary carcinoma, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, small cell carcinoma, testicular cancer, teratoma, thyroid cancer, and anaplastic carcinoma. 39. The use of claim 37, wherein the hyperproliferative disease is selected from the group consisting of melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer. 40. The use of claim 37, wherein the hyperproliferative disease is selected from the group consisting of acute myeloid leukemia, chronic myelomonocytic leukemia, chronic myelogenous leukemia, multiple myeloma, and myeloid leukemia. 41. The use of any one of claims 37 to 40, wherein the compound of any one of claims 1 to 24 is co-administered with at least one other chemotherapeutic agent for the treatment or amelioration of a hyperproliferative disease. 42. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 24 for use in the treatment of an inflammatory disease. 43. Use of a compound as claimed in any one of claims 1 to 24 for the manufacture of a medicament for the treatment of an inflammatory disease. 44. A compound as claimed in any one of claims 1 to 24 for use in the treatment of an inflammatory disease. 45. Use of a compound as claimed in claims 1 to 24 in the preparation of a medicament for treating or ameliorating the severity of an inflammatory disorder in a patient in need thereof. 46. The composition, use or compound of any one of claims 42 to 45, wherein the inflammatory disorder is selected from arthritis, low back pain, inflammatory bowel disease and rheumatism.