Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4196—1,2,4-Triazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• 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, which are commonly overactive or overexpressed in cancerous tissue.
• the present compounds are selective inhibitors of ERK (extracellular-signal regulated kinase).
• the present invention further relates to methods for treating cancer or hyperproliferative diseases with compounds of the present invention.
• the processes involved in tumor growth, progression, and metastasis are mediated by signaling pathways that are activated in cancer cells.
• the ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface receptor tyrosine kinase ("RTK's"), such as ErbB family, PDGF, FGF, and VEGF receptor tyrosine kinase.
• RTK's ligand-bound cell surface receptor tyrosine kinase
• Activation of an RTK induces a cascade of phosphorylation events that begins with activation of Ras.
• Activation of Ras leads to the recruitment and activation of Raf, a serine-threonine kinase.
• Raf Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates ERKl/2.
• ERK 1/2 phosphorylates several downstream targets involved in a multitude of cellular events, including cytoskeletal changes and transcriptional activation.
• the ERK/MAPK pathway is one of the most important for cell proliferation, and it is believed that the ERK/MAPK pathway is frequently activated in many tumors.
• Ras genes which are upstream of ERKl/2, are mutated in several cancers, including colorectal, melanoma, breast and pancreatic tumors. The high Ras activity is accompanied by elevated ERK activity in many human tumors.
• BRAF a serine-threonine kinase of the Raf family
• ERKl/2 signaling pathway is an attractive pathway for anticancer therapies in a broad spectrum of human tumors.
• 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): pp. 699-713, and Sommer, Stephan and Frank Birklein. "Resolvins and inflammatory pain.” F1000 Medicine Reports. 3:19 (201 1)).
• 2013/020062 and WO 2013/130976 disclose ERK inhibitors.
• ERK2 activity would be useful for treating a broad spectrum of cancers, such as, for example, melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer, as well as a treatment for pain and inflammation, such as arthritis, low back pain, inflammatory bowel disease, and rheumatism. Such a contribution is provided herein.
• Raf/MEK/ERK pathway is an important signaling pathway, which is frequently overexpressed and/or overactive in many cancerous tissues. Design and development of new pharmaceutical compounds is essential.
• Another aspect provides a method for treating a hyperproliferative disorder by administering a therapeutically effective quantity 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, to a patient in need thereof.
• the compound can be administered alone or co-administered with at least one other anti-hyperproliferative or chemotherapeutic compound.
• Another aspect 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 attenuate or eliminate ERK kinase activity.
• Another aspect provides methods of treating or preventing a disease or disorder modulated by ERK, 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.
• diseases and disorders include, but are not limited to, hyperproliferative disorders, such as cancer.
• Another aspect provides methods of 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 additional compounds having anti-cancer properties.
• Another aspect provides a method of treating a hyperproliferative disease in a mammal comprising administering 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, to the mammal.
• Another aspect provides the use of a compound of Formula I, II, III, IV, V,
• Another aspect provides a compound of Formula I, II, III, IV, V, VI, VII,
• Another aspect provides a pharmaceutical composition
• a pharmaceutical composition 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 includes processes for preparing, methods of separation, and methods of purification of the compounds described herein.
• a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
• a compound refers to one or more compounds or at least one compound.
• the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
• the terms “comprise(s)” and “comprising” are to be interpreted as having an open- ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”.
• the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
• the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
• any variable e.g., R 1 , R 4a , Ar, X, or Het
• its definition on each occurrence is independent of its definition at every other occurrence.
• combinations of substituents and/or variables are permissible only if such compounds result in stable compounds.
• variable can be equal to any integer value of the numerical range, including the end-points of the range.
• variable can be equal to any real value of the numerical range, including the end-points of the range.
• a variable that is described as having values between 0 and 2 can be 0, 1 or 2 for variables that are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001 , or any other real value for variables that are inherently continuous.
• Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates.
• 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.
• the racemates of these isomers, the individual isomers and mixtures enriched in one enantiomer, as well as diastereomers when there are two chiral centers, and mixtures partially enriched with specific diastereomers are within the scope of the present invention.
• the present invention includes all the individual stereoisomers (e.g., enantiomers), racemic mixtures or partially resolved mixtures of the compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX or X and, where appropriate, the individual tautomeric forms thereof.
• 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 nontoxic salts.
• suitable acid addition salts are formed from acids that form nontoxic salts.
• salts of inorganic acids include the hydrochloride, hydrobromide, hydroiodide, chloride, bromide, iodide, sulfate, bisulfate, nitrate, phosphate, and hydrogen phosphate.
• salts of organic acids include acetate, fumarate, pamoate, aspartate, besylate, carbonate, bicarbonate, camsylate, D and L-lactate, D and L-tartrate, esylate, mesylate, malonate, orotate, gluceptate, methylsulfate, stearate, glucuronate, 2-napsylate, tosylate, hibenzate, nicotinate, isethionate, malate, maleate, citrate, gluconate, succinate, saccharate, benzoate, esylate, and pamoate salts.
• suitable salts see Berge, Stephen M, et al.
• alkylaryl haloalkylheteroaryl
• arylalkylheterocyclyl alkylcarbonyl
• alkoxyalkyl alkylcarbonyl
• phenylalkyl refers to an alkyl group having at least one phenyl substituent, and thus includes benzyl and phenylethyl.
• An "alkylaminoalkyl” is an alkyl group having at least one alkylamino substituent.
• “Hydroxyalkyl” includes 2-hydroxyethyl, 2-hydroxypropyl, l-(hydroxymethyl)-2- methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth. Accordingly, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups defined below.
• -(ar)alkyl refers to either an unsubstituted alkyl or an aralkyl group.
• (hetero)aryl or (het)aryl refers to a moiety that is either an aryl or a heteroaryl group.
• C1-C4 acyloxy-Q-Ca alkyl denotes a group of formula -(CH2) 1-2 OC(0)(CH 2 )o -3 H.
• C1-C4 acyloxy denotes the radical -OC(0)R, wherein R contains 1 to 4 carbon atoms (e.g., Q is formyl).
• alkyl includes linear or branched-chain radicals of carbon atoms.
• alkyl moieties have been abbreviated, for example, methyl (“Me”), ethyl (“Et”), propyl (“Pr”) and butyl (“Bu”), and further abbreviations are used to designate specific isomers of compounds, for example, 1 -propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1- butyl or n-butyl (“n-Bu”), 2-methyl-l -propyl or isobutyl (“i-Bu”), 1 -methylpropyl or s-butyl (“s-Bu”), 1,1-dimethylethyl or t-butyl (“t-Bu”) and the like.
• the abbreviations are sometimes used in conjunction with elemental abbreviations and chemical structures, for example, methanol (“MeOH”) or ethanol (“EtOH”).
• alkenyl and alkynyl also include linear or branched-chain radicals of carbon atoms.
• haloalkyl denotes an unbranched or branched chain alkyl group as defined above, wherein 1 , 2, 3 or more hydrogen atoms are substituted by a halogen.
• Examples are 1-fiuoromethyl, 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).
• heteroalkyl as used herein means an alkyl radical as defined herein, wherein one or two hydrogen atoms have been replaced with a substituent independently selected from the group consisting of -ORTM and -NR P R Y , with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom.
• R a is hydrogen or alkyl and R p and R Y are independently of each other hydrogen, acyl, alkyl, or R p and R T together with the nitrogen to which they are attached form a cyclic amine.
• Hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl moieties are subgenera encompassed by the term "heteroalkyl".
• Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-l -hydroxymethylethyl, 2,3- dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-l- methylpropyl, 2-aminoethyl, 3-methylaminopropyl, and the like.
• 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, with the proviso that the ring does not contain two adjacent O or S atoms. In certain instances, these terms may be specifically further limited, such as, five to six membered heteroaryl, wherein the heteroaryl contains one or two nitrogen heteroatoms. As well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some 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), pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiaziny
• these terms may be specifically further limited, such as, "five to six membered heterocyclyl” only including five and six membered rings.
• Heterocyclic groups may include, for example, oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahyrdothiopyranyl, piperidinyl, dioxanyl, oxathianyl, morpholinyl (morpholino), dithianyl, piperazinyl, azathianyl, oxepanyl, thiepanyl, azepanyl, dioxepanyl, oxathiepanyl, oxaazepanyl, dithiepanyl, thieazepanyl, diazepanyl, dihydrofuranyl, dihydropyranyl, pyranyl and tetra
• hydroxyalkyl and "alkoxyalkyl” as used herein denotes alkyl radical as herein defined, wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl or alkoxy groups respectively.
• a Ci-C 3 alkoxy-Ci-Q alkyl moiety refers to a C C 6 alkyl substituent in which one to three hydrogen atoms are replaced by a C C 3 alkoxy and the point of attachment of the alkoxy is the oxygen atom.
• a bond drawn into ring system indicates that the bond may be attached to any of the suitable ring atoms.
• Methods of this invention encompass methods of treating, preventing and/or managing various types of cancer and diseases and disorders associated with, or characterized by, undesired angiogenesis.
• treating refers to the administration of a compound of the invention or other additional active agent after the onset of symptoms of the particular disease or disorder.
• treatment also refer to therapeutic or palliative measures.
• Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
• Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
• Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder.
• the term "preventing” refers to the administration prior to the onset of symptoms, particularly to patients at risk of cancer, and other diseases and disorders associated with, or characterized by, undesired angiogenesis.
• prevention includes the inhibition of a symptom of the particular disease or disorder.
• Patients with familial history of cancer and diseases and disorders associated with, or characterized by, undesired angiogenesis are preferred candidates for preventive regimens.
• the term “managing” encompasses preventing the recurrence of the particular disease or disorder in a patient who had suffered from it, and/or lengthening the time a patient who had suffered from the disease or disorder remains in remission.
• phrases "therapeutically effective amount” or “effective amount” mean an amount of a compound described herein that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
• the amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
• 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, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
• squamous cell cancer e.g., epithelial squamous cell cancer
• lung cancer including small- cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or 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 carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, skin cancer, including melanoma, as well as head and neck cancer.
• NSCLC non-small cell lung cancer
• adenocarcinoma of the lung and squamous carcinoma of the lung cancer of the peritoneum, hepatocellular cancer
• a "chemotherapeutic agent” is a chemical compound useful in the treatment of cancer.
• chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafen
• dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), mo holino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, e
• chemotherapeutic agent also included in the definition of "chemotherapeutic agent” are: (i) anti- hormonal agents that act to regulate or inhibit hormone action on tumors such as anti- estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, keoxifene, LY 1 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA®
• phrases "pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
• phrases "pharmaceutically acceptable salt,” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein.
• the compounds described herein also include other salts of such compounds that are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds described herein and/or for separating enantiomers of compounds described herein.
• the term "mammal” means a warm-blooded animal that has or is 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.
• X ⁇ is selected from CH and N;
• X 2 is selected from CH and N;
• R 1 is selected from C1-C12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 7 cycloalkyl, phenyl, a 3 to 7 membered saturated or partially unsaturated heterocyclyl, a 5 to 6 membered heteroaryl, C 5 -C 14 bicyclic cycloalkyl, naphthyl, a 5 to 14 membered bicyclic saturated or partially unsaturated heterocycle, and a 9 to 10 membered bicyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyls, phenyl, heterocyclyls, heteroaryls and naphthyl are optionally substituted with one or more groups independently selected from halogen, OR a , NR b R c , oxo, oxide, CN, C 3 -C 6 cycloalkyl, cyclopropylmethyl,
• R 2 is selected from hydrogen, CrC 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, OR g , C 3 - C 7 cycloalkyl, phenyl, a 4 to 7 membered saturated or partially unsaturated heterocyclyl, a 5 to 6 membered heteroaryl, C 5 -Ci 4 bicyclic cycloalkyl, naphthyl, a 5 to 14 membered bicyclic saturated or partially unsaturated heterocyclyl, and a 9 to 10 membered bicyclic heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyls, phenyl, heterocyclyls, heteroaryls and naphthyl may be optionally substituted with one to eight groups selected from (a) halogen; (b) CN; (c) oxo; (d) OR j ; (e) SR k ; (f)
• bicyclic heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the bicyclic heterocyclyl may be optionally substituted with one to three groups selected from halogen and C C 3 alkyl optionally substituted with halogen; (q) a 9 to 10 membered bicyclic heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the bicyclic heterocyclyl may be optionally substituted with one to three groups selected from halogen and C C 3 alkyl optionally substituted with halogen; (q) a 9 to
• bicyclic heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the bicyclic heteroaryl is substituted with one to three groups selected from halogen and C!-C 3 alkyl optionally substituted with halogen; and (r) adamantanyl
• R 3 is selected from hydrogen and halogen
• R 4 is selected from hydrogen and halogen
• each R a , R b , R c and R d are independently selected from hydrogen and C ⁇ -C alkyl; each R J is independently selected from hydrogen, Q-C 4 alkyl, cyclopropyl and phenyl, wherein the alkyl and phenyl may be optionally substituted with one to three groups selected from halogen, OH, CN methyl and methoxy;
• each R k is independently selected from C1-C4 alkyl, C 5 cycloalkyl, phenyl and benzyl, wherein the phenyl may be optionally substituted with halogen;
• each R m and R n are independently selected from hydrogen, C C 2 alkyl and phenyl, wherein the alkyl may be substituted with oxo or phenyl substituted with halogen, and wherein the phenyl may be substituted with halogen;
• each R p is independently selected from halogen, OR 1 , cyclopropyl and Q-C3 alkyl optionally substituted with halogen;
• each R is independently selected from halogen, CN, OR", SR U , C 3 -C 6 cycloalkyl optionally substituted with halogen, Q-C3 alkoxy and Cj- alkyl optionally substituted with halogen; each R s is independently selected from halogen, CN, OR w , Q-C3 alkyl, C 3 -C 6 cycloalkyl, phenyl and benzyl, wherein the alkyl, cycloalkyl, phenyl and benzyl may be optionally substituted with one to three groups selected from halogen and methyl;
• each R l is independently selected from hydrogen and C1-C4 alkyl optionally substituted with halogen;
• each R u is independently selected from hydrogen and Q-C4 alkyl optionally substituted with halogen;
• each R w is independently selected from hydrogen and C ! -C 3 alkyl optionally substituted with halogen.
• One embodiment provides compounds of Formula I or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
• Xi is selected from CH and N;
• X 2 is selected from CH and N;
• R l is selected from (a) C 1 -C 6 alkyl optionally substituted with one or more groups independently selected from halogen, OR a , NR b R c , oxo, CN, C 3 -C 6 cycloalkyl and a 3 to 7 membered heterocycle; (b) C3-C7 cycloalkyl optionally substituted with one or more groups independently selected from halogen, OR a , CN and C C 3 alkyl optionally substituted with one or more groups independently selected from halogen and OR d ; (c) phenyl optionally substituted with one or more groups independently selected from halogen, OR a , CN, C 3 -C 6 cycloalkyl and C !
• -C 3 alkyl optionally substituted with one or more groups independently selected from halogen and OR d ;
• a 5 to 6 membered heteroaryl optionally substituted with one or more groups independently selected from halogen, OR e , oxide, CN, C 3 -C 6 cycloalkyl and C1-C3 alkyl optionally substituted with one or more groups independently selected from halogen, oxo and OR d ;
• a 7 to 10 membered bicyclic heterocycle optionally substituted with one or more groups independently selected from halogen, OR a , oxo, CN, C 3 -C 6 cycloalkyl and C C 3 alkyl optionally substituted with one or more groups independently selected from halogen and OR d ;
• R 2 is selected from (a) hydrogen; (b) C C 12 alkyl optionally substituted by one to eight R f groups; (c) C 2 -C 12 alkenyl optionally substituted by one to eight R f groups; (d) OR g ; (e) C 3 -C 7 cycloalkyl optionally substituted with one to six groups selected from halogen; OH; Ci-C 3 alkyl optionally substituted with halogen, OH or phenyl optionally substituted with halogen; alkyl), wherein the alkyl may be optionally substituted with halogen or OH; and phenyl optionally substituted with halogen; (f) phenyl optionally substituted with one to four groups selected from halogen, CrC 3 alkyl optionally substituted with halogen, OH or methoxy, and phenoxy optionally substituted with halogen, OH or methoxy; (g) 4 to 7 membered saturated or partially unsaturated heterocyclyl containing
• R 3 is selected from hydrogen and halogen
• R 4 is selected from hydrogen and halogen
• each R a , R b , R c , R d and R e are independently selected from hydrogen and Q-Q alkyl; each R f is independently selected from (a) halogen; (b) CN; (c) oxo; (d) OR j ; (e) SR k ; (f) S(0)R k ; (g) S(0) 2 R k ; (h) NR m R n ; (i) C 3 -C 6 cycloalkyl optionally substituted with one to three R p groups; (j) phenyl optionally substituted by one to four R q groups; (k) a 4 to 7 membered saturated or partially unsaturated heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the heterocyclyl may be optionally substituted with one to three groups selected from halogen, oxo and CrC 3 alkyl optionally substituted with halogen; (1) a 5 to 6 membered hetero
• R 8 is independently selected from hydrogen, Q-C4 alkyl, C 3 -C 6 cycloalkyl and phenyl, wherein the alkyl, cycloalkyl and phenyl may be optionally substituted with halogen; each R h is selected from halogen; OH; C C 3 alkyl optionally substituted with one to three groups selected from halogen, OH, CN, methoxy, oxo, cyclopropyl and phenyl optionally substituted by one to three groups selected from halogen, CN, methyl and methoxy; C1-C3 alkoxy optionally substituted by halogen or OH; oxo; phenyl optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; phenoxy wherein the phenoxy optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; and a 5 to 6 membered heteroary
• each R 1 is selected from halogen; OH; C 1 -C4 alkyl optionally substituted with one to three groups selected from halogen, OH, CN, methoxy, oxo, cyclopropyl and phenyl optionally substituted by one to three groups selected from halogen, CN, methyl and methoxy; Q-C3 alkoxy optionally substituted by halogen or OH; phenyl optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; benzyl optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; and a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted by one to four groups selected from halogen, OH, CN, methyl and methoxy;
• each R J is independently selected from hydrogen, CrC 4 alkyl, cyclopropyl and phenyl, wherein the alkyl and phenyl may be optionally substituted with halogen;
• each R k is independently selected from Cj-C 4 alkyl, C 5 cycloalkyl, phenyl and benzyl, wherein the phenyl may be optionally substituted with halogen;
• each R m and R" are independently selected from hydrogen, C C 2 alkyl and phenyl, wherein the alkyl may be substituted with oxo or phenyl substituted with halogen, and wherein the phenyl may be substituted with halogen;
• each R p is independently selected from halogen, OR', cyclopropyl and Cj-C? alkyl optionally substituted with halogen;
• each R l is independently selected from hydrogen and C]-C 4 alkyl optionally substituted with halogen;
• each R u is independently selected from hydrogen and C1-C4 alkyl optionally substituted with halogen; and each R w is independently selected from hydrogen and C1-C3 alkyl optionally substituted with halogen.
• R 1 is selected from (a) C -C alkyl optionally substituted with OH; (b) 5 to 6 membered heterocyclyl; and (c) 5 to 6 membered heteroaryl substituted with Q-C 3 alkyl;
• each R f is independently selected from (a) halogen; (b) CN; (c) oxo; (d) OR j ; (e) SR k ; (f) S(0)R k ; (g) S(0) 2 R k ; (h) NR m R n ; (i) C 3 -C 6 cycloalkyl optionally substituted with one or two R p groups; (j) phenyl optionally substituted by one to three R q groups; (k) a 4 to 7 membered saturated or partially unsaturated heterocyclyl containing one or two heteroatoms selected from N and O, wherein the heterocyclyl may be optionally substituted with one or two groups selected from oxo and C!-C 3 alkyl; (1) a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N and S, wherein the heteroaryl may be optionally substituted by one or two R s groups; (m) C 7 bicyclic cyclo
• R 8 is phenyl substituted with methoxy
• each R h is selected from Q-C3 alkyl optionally substituted with one to three groups selected from halogen, oxo, cyclopropyl and phenyl optionally substituted by two groups selected from halogen, CN and methoxy; oxo; phenyl optionally substituted with halogen; phenoxy optionally substituted with halogen; and a 6 membered heteroaryl containing one N heteroatom, wherein the heteroaryl is substituted by two groups selected from halogen and methoxy;
• each R 1 is selected from C1-C4 alkyl, phenyl, benzyl, and a 6 membered heteroaryl containing one N heteroatom, wherein the alkyl, phenyl and benzyl may be optionally substituted with halogen;
• each R* is independently selected from hydrogen, C C 4 alkyl, cyclopropyl and phenyl, wherein the alkyl and phenyl may be optionally substituted with halogen;
• each R k is independently selected from C 1 -C4 alkyl, C 5 cycloalkyl, phenyl and benzyl, wherein the phenyl may be optionally substituted with halogen;
• each R m and R n are independently selected from hydrogen, Cj-C 2 alkyl and phenyl, wherein the alkyl may be substituted with oxo or phenyl substituted with halogen, and wherein the phenyl may be substituted with halogen;
• each R p is independently selected from halogen, OR 1 , cyclopropyl and C ! -C 3 alkyl optionally substituted with halogen;
• each R q is independently selected from halogen, methyl, CN, CF 3 , methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio and C 3 -C 4 cycloalkyl;
• each R s is independently selected from halogen, OH, CN, methoxy, ethoxy, cyclopropyl, benzyl, Q-C3 alkyl optionally substituted with halogen, and phenyl optionally substituted with one or two groups selected from halogen and methyl;
• each R l is independently Q-C4 alkyl optionally substituted with halogen.
• X ⁇ is CH (such compounds have the structure of
• X 2 is CH (such compounds have the structure of
• X 2 is N (such compounds have the structure of Formula V).
• X ⁇ is CH and X 2 is CH (such compounds have the structure of Formula VI).
• X] is CH and X 2 is N (such compounds have the structure of Formula VII).
• X] is N and X 2 is CH (such compounds have the structure of Formula VIII).
• Xi is N and X 2 is N (such compounds have the structure of Formula IX).
• Xi is CH and X 2 is CH; Xi is CH and X 2 is N; or Xi is N and X 2 is CH.
• Formula I) and WO 2013/020062 disclose amines that may be used in the instant application at the R 1 position of Formula I, II, III, IV, V, VI, VII, VIII, IX or X.
• R 1 is selected from (a) Q-Q alkyl optionally substituted with one or more groups independently selected from halogen, OR a , NR b R c , oxo, CN, C 3 -C 6 cycloalkyl and a 3 to 7 membered heterocycle; (b) C 3 -C 7 cycloalkyl optionally substituted with one or more groups independently selected from halogen, OR a , CN and Q- C 3 alkyl optionally substituted with one or more groups independently selected from halogen and OR d ; (c) phenyl optionally substituted with one or more groups independently selected from halogen, OR a , CN, C 3 -C 6 cycloalkyl and Q-C3 alkyl optionally substituted with one or more groups independently selected from halogen and OR d ; (d) a 3 to 7 membered saturated or partially unsaturated heterocyclyl optionally substituted with one or more groups independently selected from halogen and OR
• R a , R b , R c , R d and R e are independently selected from hydrogen and C[-C alkyl.
• R 1 is selected from optionally substituted Q-Cio alkyl; optionally substituted aryl or aryl-Q-C f s alkyl; optionally substituted heteroaryl or heteroaryl-Q-Ce alkyl, wherein said heteroaryl is selected from the group consisting of isoxazole, pyridinyl, pyridone, pyrimidinyl, pyrazinyl, pyrazole, thiazolyl, triazolyl, N-C ⁇ -C(, alkyl-pyrazolyl, N-benzylpyrazolyl, alkyl triazolyl and 2-oxo-tetrahydroquinolin-6- yl; heterocyclyl or heterocyclyl-C 1 -C 6 alkyl, wherein said heterocyclyl is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidin
• R 1 is in the (5) configuration. In certain embodiments,
• R 1 is in the (R) configuration.
• 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-l -methyl-ethyl, 2-hydroxypropyl, 2-hydroxy-l- hydroxymethyl-ethyl, acetyl, 2,2,2-trifluoro-l -methyl-ethyl, 2,2,2-trifluoro-l-hydroxymethyl- ethyl, 2-fluoro-l -methyl-ethyl, 2-fluoro-l-fluoromethyl-ethyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoropropyl, cyclopropylmethyl, 2-mo holin-4-yl-ethyl, 2,2-difluoro-l -methyl
• R 1 is selected from (S)-2-hydroxy-l -methyl- ethyl, (5)-l -hydroxymethyl-propyl, (lS ⁇ S ⁇ -hydroxycyclopentyl and tetrahydropyran-4-yl.
• R 1 is selected from (S)-2-hydroxy-l -methyl-ethyl, (S)- ⁇ - hydroxymethyl-propyl, (lS,3iS)-3-hydroxycyclopentyl, tetrahydropyran-4-yl, isopropyl, 1- methyl-lH-pyrazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, 2-methyl-2H-l ,2,3-triazol-4-yl and 1- methyl-lH-l ,2,4-triazol-5-yl.
• R 1 is selected from 1-methyl-lH- pyrazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, tetrahydro-2H-pyran-4-yl, (5)-2-hydroxy-l -methyl- ethyl, (S)- 1-hydroxymethyl -propyl and (l.S,35)-3-hydroxycyclopentyl.
• R 1 is selected from methyl, ethyl, isopropyl, tert- butyl, isobutyl, 2-hydroxyethyl, 1-hydroxymethylpropyl, 2-hydroxy-l -methyl-ethyl (or 1- hydroxypropan-2-yl), 2-methoxy-l -methyl-ethyl, 2-hydroxypropyl, 2-hydroxy-l- hydroxymethyl-ethyl, acetyl, 2,2,2-trifluoro-l -methyl-ethyl, 2,2,2-trifluoro-l-hydroxymethyl- ethyl, 2-f uoro-l -methyl-ethyl, 2-fluoro-l-fluoromethyl-ethyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoropropyl, cyclopropylmethyl, 2-mo holin-4-yl-ethyl, 2,2-difluoro-l -methyl-e
• R 1 is selected from (S)-2 -hydroxy- 1 -methyl-ethyl, (S)-l- hydroxymethyl-propyl, (15,35 -3-hydroxycyclopentyl and tetrahydropyran-4-yl.
• R 1 is selected from (S)-2-hydroxy-l -methyl-ethyl, (5)- 1 -hydroxymethyl -propyl, (lS,3iS)-3-hydroxycyclopentyl, tetrahydropyran-4-yl, isopropyl, 1 -methyl- lH-pyrazol-5-yl, 1- methyl-lH-pyrazol-4-yl, 2-methyl-2H-l ,2,3-triazol-4-yl and l-methyl-lH-l ,2,4-triazol-5-yl.
• R 1 is selected from 1 -methyl- lH-pyrazol-5-yl, 1 -methyl- lH-pyrazol- 4-yl, tetrahydro-2H-pyran-4-yl, (S)-2-hydroxy-l -methyl-ethyl, (5 -l-hydroxymethyl-propyl and (15",3iS -3-hydroxycyclopentyl.
• R 1 is selected from the group consisting of (a) Q-Qo alkyl; (b) C C 6 haloalkyl; (c) heterocyclyl or heterocyclyl-C 1 -C 6 alkyl, wherein said heterocycle or heterocyclyl-C ! -C 6 alkyl is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, piperidinyl, N-Ci-C(, alkyl-piperidinyl and N- C !
• heterocycle or heterocyclyl-Q-Ce alkyl is optionally substituted by 1 to 3 groups independently selected from C C 6 alkyl, Ci-C 6 haloalkyl, C C 4 acyloxy-C 1 -C 2 alkyl, halogen, hydroxyl, phenyl, Ci-C 3 hydroxyalkyl and oxo; (d) C 3 -C 7 cycloalkyl or C 3 -C cycloalkyl-d-Ce alkyl, wherein said cycloalkyl is optionally substituted by hydroxyl or halo; and (e) Q-Q heteroalkyl.
• R 1 is selected from the group consisting of (a) C!-C 10 alkyl; (b) Q-C 6 haloalkyl; (c) heterocyclyl or heterocyclyl-Ci-Ce alkyl, wherein said heterocycle or heterocyclyl-C!-C 6 alkyl is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, piperidinyl, N-d-C 6 alkyl-piperidinyl and N- C!-C alkyl-2-oxo-pyrrolidinyl, and wherein said heterocycle or heterocyclyl-C!-C 6 alkyl is optionally substituted by 1 to 3 groups independently selected from C ⁇ -Ce alkyl, Q-Q acyloxy-Ci-C 2 alkyl, halogen, and CrC 3 hydroxyalkyl; (d) C 3 -C 7 cycloalky
• each R a is independently selected from hydrogen and
• each R a is independently selected from hydrogen and C1-C3 alkyl. In certain embodiments, each R a is independently selected from hydrogen and methyl.
• each R b and R c are independently selected from hydrogen and Cj-C 6 alkyl. In certain embodiments, each R b and R c are independently selected from hydrogen and Q-C 3 alkyl. In certain embodiments, each R b and R c are independently selected from hydrogen and methyl.
• each R d is independently selected from hydrogen and
• each R d is independently selected from hydrogen and C C 3 alkyl. In certain embodiments, each R d is selected from hydrogen and methyl.
• each R e is independently selected from hydrogen and
• each R e is independently selected from hydrogen and C ! -C 3 alkyl. In certain embodiments, each R e is independently selected from methyl and ethyl.
• R 1 is selected from l-hydroxypropan-2-yl, isopropyl,
• R 1 is selected from l-hydroxypropan-2-yl, isopropyl,
• R 1 is selected from the group consisting of (a) Q-Qo alkyl; (b) Q-C6 haloalkyl; (c) heterocyclyl or heterocyclyl-C ! -C 6 alkyl, wherein said heterocycle or heterocyclyl-Q-Ce alkyl is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl and oxetanyl and wherein said heterocycle is optionally substituted by Ci-C 6 alkyl, halogen, C[-C 3 hydroxyalkyl or Q-Q acyloxy-Cj-C 2 alkyl; (d) C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-C!-C alkyl, wherein said cycloalkyl is optionally substituted by hydroxyl; and (e) C C6 heteroalkyl.
• R 1 is selected from the group consisting of (a) tetrahydropyranyl; (b) tetrahydrofuranyl; (c) oxetanyl; (d) 2-hydroxy-l-methyl-ethan-l-yl; (e) 2,2,2-trifluoro-l-methyl-ethan-l-yl; (f) 1-cyclopropyl-ethan-l-yl; (g) 2-methoxyethyl; (h) 3- fluoropropyl; (i) cyclopropylmethyl; (j) oxetanylmethyl; (k) 4-hydroxycyclohexyl; and (1) pyrazolyl;
• said (1) pyrazolyl moiety is optionally substituted with one to three groups independently selected from C ! -C 6 alkyl, Q-C6 haloalkyl and halogen.
• R 1 is selected from the group consisting of 1- hydroxypropan-2-yl, isopropyl, 1-cyclopropylethyl, cyclopropylmethyl, 4- hydroxycyclohexyl, l ,l ,l-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, oxetany-3-ylmethyl, 2- methoxyethyl, 1 -methyl- lH-pyrazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, 2-methylpyrazol-3-yl, 2,5-di
• R 1 is selected from (a) C C6 alkyl optionally substituted with ⁇ ; (b) 5 to 6 membered heterocyclyl; and (c) 5 to 6 membered heteroaryl substituted with Q-C3 alkyl.
• R 1 is selected from Q-C6 alkyl optionally substituted with ⁇ , 5 to 6 membered heterocyclyl containing one O heteroatom, and 5 to 6 membered heteroaryl containing two or three N heteroatoms, wherein the heteroaryl is substituted with C C 3 alkyl.
• R 1 is selected from Q- alkyl optionally substituted with ⁇ , 5 to 6 membered heterocyclyl selected from tetrahydropyranyl, and 5 to 6 membered heteroaryl selected from pyrazolyl and triazolyl, wherein the heteroaryl is substituted with Q-C3 alkyl.
• R 1 is selected from isopropyl, l-hydroxypropan-2-yl, 1 -methyl- lH-pyrazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, tetrahydro-2H-pyran-4-yl, 2-methyl-2H-l ,2,3-triazol-4-yl and l-methyl-lH-l ,2,4-triazol-5-yl.
• R 1 is selected from 1 -methyl- lH-pyrazol-5-yl, 1 -methyl- lH-pyrazol- 4-yl and tetrahydro-2H-pyran-4-yl.
• R is selected from (a) hydrogen; (b) C ! -C 6 alkyl optionally substituted by one to seven R groups; (c) C 4 -C 5 alkenyl substituted with phenyl; (d) OR g ; (e) C 3 -C 6 cycloalkyl optionally substituted with one to four groups selected from C - C 3 alkyl optionally substituted with halogen, OH or phenyl; alkyl); and phenyl substituted with halogen; (f) phenyl optionally substituted with halogen or phenoxy substituted with halogen or methoxy; (g) a 5 to 6 membered saturated or partially unsaturated heterocyclyl containing one or two heteroatoms selected from N and O, wherein the heterocyclyl may be optionally substituted with one to three R h groups; (h) a 5 membered heteroaryl containing two heteroatoms selected from N and O, wherein the heteroaryl
• R is selected from hydrogen, methyl, ethyl, 2- methylbutyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 3-methylpentyl, 2- methylpentyl, isopentyl, neopentyl, isobutyl, 3,3-dimethylbutyl, butyl, propyl, trifluoromethyl, 4-methylpentyl, 3-methylbutan-2-yl, 2-fluorobutyl, 4,4,4-trifluoro-2- methylbutyl, 3,3,3-trifluoro-2-methylpropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2- fiuoro-2-methylpropyl, 3,3,3-trifluoro-2-(trifluoromethyl)propyl, 1,1-difluoropropyl, 3- fluoro-3-methylbutyl, 2,2-
• R is hydrogen
• R is Ci-C 12 alkyl optionally substituted by one to f * * 2 *
• R is Ci-C 12 alkyl optionally substituted by one to f 2 2 seven R groups. In certain embodiments, R is C C 12 alkyl. In certain embodiments, R is
• Ci-Cio alkyl optionally substituted by one to eight R groups.
• R is
• R is C C 10 alkyl. In certain embodiments, R is C -Cs alkyl optionally substituted by one to eight f 9 f
• R is Q-Cs alkyl optionally substituted by one to seven R groups. In certain embodiments, R is C C alkyl. In certain embodiments, R is C C6 alkyl optionally substituted by one to eight R groups. In certain embodiments, R is Q-Q alkyl f 2
• R is Q-C6 alkyl
• each R is independently selected from (a) halogen
• bicyclic heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the bicyclic heterocyclyl may be optionally substituted with one to three groups selected from halogen and Q-C3 alkyl optionally substituted with halogen; (o) a 9 to 10 membered bicyclic heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the bicyclic heterocyclyl may be optionally substituted with one to three groups selected from halogen and Q-C3 alkyl optionally substituted with halogen; (o) a 9 to
• bicyclic heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the bicyclic heteroaryl is substituted with one to three groups selected from halogen and C ! -C 3 alkyl optionally substituted with halogen; and (p) adamantanyl.
• each R is independently selected from (a) halogen
• each R J is independently selected from hydrogen, Ci-
• each R k is independently selected from C 1 -C 4 alkyl
• each R m and R n are independently selected from hydrogen, C ! -C 2 alkyl and phenyl, wherein the alkyl may be substituted with oxo or phenyl substituted with halogen, and wherein the phenyl may be substituted with halogen.
• each R p is independently selected from halogen, OR 1 , cyclopropyl and C ⁇ -Ci alkyl optionally substituted with halogen.
• each R l is independently selected from hydrogen and
• each R l is independently C!-C 4 alkyl optionally substituted with halogen.
• each R q is independently selected from halogen, CN,
• each R q is independently selected from halogen, CN, OR", SR U , C 3 -C 6 cycloalkyl, and Q-C3 alkyl optionally substituted with halogen.
• each R q is independently selected from halogen, CN, OR", SR U , C 3 -C 4 cycloalkyl optionally substituted with halogen, and C 1 -C3 alkyl optionally substituted with halogen.
• each R q is independently selected from halogen, CN, OR", SR U , C 3 -C 4 cycloalkyl, and C!-C 3 alkyl optionally substituted with halogen.
• each R q is independently selected from halogen, methyl, CN, CF 3 , methoxy, ethoxy, difluoromethoxy, trifiuoromethoxy, methylthio and C 3 -C 4 cycloalkyl.
• each R u is independently selected from hydrogen and
• each R u is independently selected from hydrogen and C C 3 alkyl optionally substituted with halogen. In certain embodiments, each R u is independently selected from hydrogen and C C 2 alkyl optionally substituted with halogen. In certain embodiments, each R u is independently Q-C2 alkyl optionally substituted with halogen.
• each R s is independently selected from halogen, CN, OR , Q-C3 alkyl, C 3 -C cycloalkyl, phenyl and benzyl, wherein the alkyl, cycloalkyl, phenyl and benzyl may be optionally substituted with one to three groups selected from halogen and methyl.
• each R s is independently selected from halogen, CN, OR w , Q-C3 alkyl, C 3 -C 6 cycloalkyl, benzyl and phenyl optionally substituted with one to three groups selected from halogen and methyl.
• each R s is independently selected from halogen, CN, OR w , C C 3 alkyl, cyclopropyl, benzyl and phenyl optionally substituted with one or two groups selected from halogen and methyl.
• each R s is independently selected from halogen, OH, CN, methoxy, ethoxy, cyclopropyl, benzyl, C 1 -C3 alkyl optionally substituted with halogen, and phenyl optionally substituted with one or two groups selected from halogen and methyl.
• each R w is independently selected from hydrogen and C!-C 3 alkyl optionally substituted with halogen. In certain embodiments, each R w is independently selected from hydrogen and Q-C3 alkyl.
• R is selected from methyl, ethyl, 2-methylbutyl, 2,3- dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 3-methylpentyl, 2-methylpentyl, isopentyl, neopentyl, isobutyl, 3,3-dimethylbutyl, butyl, propyl, trifiuoromethyl, 4-methylpentyl, 3- methylbutan-2-yl, 2-fluorobutyl, 4,4,4-trifluoro-2-methylbutyl, 3,3,3-trifluoro-2- methylpropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2-fluoro-2-methylpropyl, 3,3,3- trifluoro-2-(trifluoromethyl)propyl, 1,1-difluoropropyl, 3-fluoro-3-methylbutyl, 2,2- difluor
• R is a C 2 -C 12 alkenyl optionally substituted by one to f 2
• R is a C 2 -C 12 alkenyl optionally substituted by one to three R groups. In certain embodiments, R is a C 2 -C 10 alkenyl optionally substituted by
• R is a C 2 -C 10 alkenyl optionally substituted
• R is a C 2 -C 8 alkenyl optionally
• R is a C 2 -C 8 alkenyl optionally substituted by one to three R groups. In certain embodiments, R is a C 2 -C 6 alkenyl optionally substituted by one to eight R groups. In certain embodiments, R is a C 2 - C alkenyl optionally substituted by one to three R groups.
• R is a C 2 -C 6 alkenyl optionally substituted by one to three groups selected from halogen; CN; SR h ; S(0)R h ; S(0) 2 R h ; NR'R"; C 3 -C 6 cycloalkyl optionally substituted with one to three R k groups; phenyl optionally substituted by one to four R m groups; a 4 to 7 membered saturated or partially unsaturated heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the heterocyclyl may be optionally substituted with one to three groups selected from halogen, oxo and Cj-Cj alkyl optionally substituted with halogen; and a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted by one to three R" groups.
• R is a C 2 -C 6 alkenyl optionally substituted by one to three groups selected from halogen; CN; SR h ; S(0)R h ; S(0) 2 R h ; N ⁇ R J ; C 3 -C 6 cycloalkyl; phenyl; a 4 to 7 membered saturated or partially unsaturated heterocyclyl containing one to three heteroatoms selected from N, O and S; and a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S.
• R 2 is a C 2 -C 6 alkenyl optionally substituted by one to three groups selected from halogen; CN; NR'R*; C3-C6 cycloalkyl; phenyl; a 4 to 7 membered saturated or partially unsaturated heterocyclyl containing one to three heteroatoms selected from N, O and S; and a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S.
• R is a C 2 -C 6 alkenyl optionally substituted by phenyl.
• R is a C 4 -C 5 alkenyl optionally substituted with phenyl.
• R is selected from 3-methyl-l-phenylbut-l-en-l-yl and but-l-en-l-yl.
• R 2 is selected from (Z)-3 -methyl- 1-phenylbut-l -en- 1-yl and (E)-but-l-en-l-yl.
• R 2 is OR g .
• R 8 is independently selected from hydrogen, C1-C4 alkyl, C 3 -C 6 cycloalkyl and phenyl, wherein the alkyl, cycloalkyl and phenyl may be optionally substituted with halogen.
• R 8 is independently selected from hydrogen, Q-C4 alkyl, cyclopropyl and phenyl, wherein the alkyl and phenyl may be optionally substituted with halogen.
• R 8 is phenyl optionally substituted with methoxy.
• R 8 is phenyl substituted with methoxy.
• R 2 is 4-methoxyphenoxy.
• R 2 is selected from 2-(2-fluoropropan-2-yl)cyclopropyl, cyclohexyl, 2,2-dimethylcyclopropyl, 2- (ethoxycarbonyl)cyclopropyl, 2-(2-hydroxypropan-2-yl)cyclopropyl, 2-
• R is phenyl optionally substituted with one to four groups selected from halogen, C1-C3 alkyl optionally substituted with halogen, OH or methoxy, and phenoxy optionally substituted with halogen, OH or methoxy.
• R 2 is phenyl optionally substituted with halogen or phenoxy substituted with halogen or methoxy.
• R 2 is selected from phenyl, 2-chlorophenyl, 2- fluorophenyl, 2-(4-methoxyphenoxy)phenyl, 3-chlorophenyl, 3 -fluorophenyl, 4- chlorophenyl, 2-chloro-4-fluorophenyl and 2-(4-fluorophenoxy)phenyl.
• R is a 4 to 7 membered saturated or partially unsaturated heterocyclyl containing one to three heteroatoms selected from N, O and S, wherein the heterocyclyl may be optionally substituted with one to four R h groups.
• R 2 is a 4 to 7 membered saturated or partially unsaturated heterocyclyl containing one or two heteroatoms selected from N and O, wherein the heterocyclyl may be optionally substituted with one to four R h groups.
• R 2 is a 4 to 7 membered saturated or partially unsaturated heterocyclyl containing one or two heteroatoms selected from N and O, wherein the heterocyclyl may be optionally substituted with one to h * 2
• R is a 5 to 6 membered saturated or partially unsaturated heterocyclyl containing one or two heteroatoms selected from N and O, wherein the heterocyclyl may be optionally substituted with one to four R h groups. In certain embodiments, R is a 5 to 6 membered saturated or partially unsaturated heterocyclyl containing one or two heteroatoms selected from N and O, wherein the heterocyclyl may be optionally substituted with one to three R h groups.
• each R h is selected from halogen; OH; C C 3 alkyl optionally substituted with one to three groups selected from halogen, OH, CN, methoxy, oxo, cyclopropyl and phenyl optionally substituted by one to three groups selected from halogen, CN, methyl and methoxy; C C 3 alkoxy optionally substituted by halogen or OH; oxo; phenyl optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; phenoxy wherein the phenoxy optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; and a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted by one to four groups selected from halogen, OH, CN, methyl and methoxy.
• each R h is selected from C ! -C 3 alkyl optionally substituted with one to three groups selected from halogen, oxo, cyclopropyl and phenyl optionally substituted by two groups selected from halogen, CN and methoxy; oxo; phenyl optionally substituted with halogen; phenoxy optionally substituted with halogen; and a 6 membered heteroaryl containing one N heteroatom, wherein the heteroaryl is may be optionally substituted by two groups selected from halogen and methoxy.
• each R h is selected from Cj-C 3 alkyl optionally substituted with one to three groups selected from halogen, oxo, cyclopropyl and phenyl optionally substituted by two groups selected from halogen, CN and methoxy; oxo; phenyl optionally substituted with halogen; phenoxy optionally substituted with halogen; and a 6 membered heteroaryl containing one N heteroatom, wherein the heteroaryl is substituted by two groups selected from halogen and methoxy.
• R is selected from 4-(2-fluoro-6- methoxybenzyl)morpholin-2-yl, l-(2-fluoro-6-methoxybenzyl)piperidin-3-yl, 5-(2,6- difluorophenoxy)-l-methylpiperidin-3-yl, (5-chloro-2-fluorobenzyl)piperidin-3-yl, piperdin- 3-yl, ((5-fluoro-2-methoxypyridin-3-yl)methyl)piperidin-3-yl, 1 -(5-cyano-2- fluorobenzyl)piperidin-3-yl, 1 -methyl-5-oxo-3-phenylpyrrolidin-2-yl, 4-
• R is 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 to four R 1 groups.
• R 2 is a 5 to 6 membered heteroaryl containing one or two heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted with one to four R 1 groups.
• R 2 is a 5 to 6 membered heteroaryl containing one or two heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted with one to three R l groups.
• R 2 is a 5 membered heteroaryl containing two heteroatoms selected from N and O, wherein the heteroaryl may be optionally substituted with one to three R 1 groups. In certain embodiments, R 2 is a 5 membered heteroaryl containing two heteroatoms selected from N and O, wherein the heteroaryl is substituted with one to three R 1 groups.
• each R 1 is selected from halogen; OH; Cj-C 4 alkyl optionally substituted with one to three groups selected from halogen, OH, CN, methoxy, oxo, cyclopropyl and phenyl optionally substituted by one to three groups selected from halogen, CN, methyl and methoxy; C C 3 alkoxy optionally substituted by halogen or OH; phenyl optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; benzyl optionally substituted with one to three groups selected from halogen, OH, CN, methyl and methoxy; and a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S, wherein the heteroaryl may be optionally substituted by one to four groups selected from halogen, OH, CN, methyl and methoxy.
• each R 1 is selected from halogen; CrC 4 alkyl; phenyl; benzyl; and a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S; wherein the alkyl, phenyl, benzyl and heteroaryl may be optionally substituted with halogen.
• each R 1 is selected from halogen; C C 4 alkyl; phenyl; benzyl; and a 5 to 6 membered heteroaryl containing one to four heteroatoms selected from N, O and S; wherein the alkyl, phenyl and benzyl may be optionally substituted with halogen.
• each R' is selected from halogen; C1-C4 alkyl; phenyl; benzyl; and a 5 to 6 membered heteroaryl containing one N heteroatom; wherein the alkyl, phenyl, benzyl and heteroaryl may be optionally substituted with halogen.
• each R 1 is selected from C 1 -C4 alkyl, phenyl, benzyl, and a 6 membered heteroaryl containing one N heteroatom, wherein the alkyl, phenyl and benzyl may be optionally substituted with halogen.
• R is selected from 1 -phenyl- lH-pyrazol-5-yl, 1 - methyl-3-(pyridin-3-yl)-lH-pyrazol-4-yl, 3 -phenyl- lH-pyrazol-4-yl, 3-isopropyl-l -methyl- lH-pyrazol-4-yl, 3-methyl-5-phenylisoxazol-4-yl, 3-isobutyl-l -methyl- lH-pyrazol-4-yl, 5- isobutyl- 1 -methyl- 1 H-pyrazol-4-yl, 5 -isopropyl- 1 -methyl- 1 H-pyrazol-4-yl, 1 -(3 - fluorophenyl)- lH-pyrazol-5-yl, l -(3-fluorophenyl)-5-methyl-lH-pyrazol-3-yl, l -(3-(3-fluoropheny
• R is 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 with one to four R h groups.
• R 2 is 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 with one to three R h groups.
• R is 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 with one to three groups selected from halogen, methyl and methoxy.
• R is a 9 to 10 membered bicyclic heterocyclyl containing one O heteroatom, wherein the heterocyclyl may be optionally substituted with
• R is a 9 to 10 membered bicyclic heterocyclyl containing one O heteroatom, wherein the heterocyclyl may be optionally substituted with one to three R groups.
• R is a 9 to 10 membered bicyclic heterocyclyl containing one O heteroatom, wherein the heterocyclyl may be optionally substituted with one to three groups selected from halogen, methyl and methoxy.
• R is a 10 membered bicyclic heterocyclyl containing one O heteroatom, wherein the heterocyclyl may be optionally substituted with one to three R h groups.
• R is a 10 membered bicyclic heterocyclyl containing one O heteroatom, wherein the heterocyclyl may be optionally substituted with one to three groups selected from halogen, methyl and methoxy.
• R is a 10 membered bicyclic heterocyclyl containing one O heteroatom.
• R is isochroman-l-yl.
• R is -CH 2 R (such compounds have the structure of Formula X).
• R is selected from hydrogen and halogen. In certain embodiments, R is hydrogen. In certain embodiments, R is halogen. In certain embodiments, R 3 is selected from hydrogen, fluorine and chlorine. In certain embodiments, R is selected from hydrogen and fluorine. In certain embodiments, R is fluorine.
• R 4 is selected from hydrogen and halogen. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is selected from hydrogen, fluorine and chlorine. In certain embodiments, R 4 is selected from hydrogen and fluorine. In certain embodiments, R 4 is fluorine.
• R 3 and R 4 are selected from hydrogen and halogen. In certain embodiments, R 3 and R 4 are selected from hydrogen, fluorine and chlorine. In certain embodiments, R 3 and R 4 are selected from hydrogen and fluorine. In certain embodiments, R 3 and R 4 are hydrogen. In certain embodiments, R 3 is hydrogen; and R 4 is selected from hydrogen and halogen. In certain embodiments, R 3 is hydrogen; and R 4 is selected from hydrogen, fluorine and chlorine. In certain embodiments, R 3 is hydrogen; and R 4 is selected from hydrogen and fluorine. In certain embodiments, R is selected from hydrogen and halogen; and R 4 is hydrogen. In certain embodiments, R 3 is selected from hydrogen, fluorine and chlorine; and R 4 is hydrogen. In certain embodiments, R 3 is selected from hydrogen, fluorine and chlorine; and R 4 is hydrogen.
• R 3 is selected from hydrogen and fluorine; and R 4 is hydrogen. In certain embodiments, R 3 is hydrogen and R 4 is selected from hydrogen and halogen, or R 3 is selected from hydrogen and halogen and R 4 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 is selected from hydrogen and fluorine, or R 3 is selected from hydrogen and fluorine and R 4 is hydrogen.
• a compound of Formula I, II, HI, IV, V, VI, VII, VIII, IX or X is provided.
• Compounds described herein may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
• the 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., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, New York: Wiley 1967-2006 ed. (also available via the Wiley InterScience® website), or Beilsteins Handbuch der organischen Chemie. 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).
• Schemes 1-4 show general methods for preparing the compounds described herein, as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are depicted in the Schemes 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 of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
• Scheme 1 shows a general scheme for the synthesis of compound 5, wherein Xi, X 2 and R 1 are as defined herein.
• the synthesis can be started either from compound 1, wherein X is CI or Br, 4-halo substituted 2-fluro pyridine analog or from the commercially available (2-fluoropyridin-4-yl)boronic acid.
• (2-Fluoropyridin-4-yl)boronic acid can be prepared according to the methods described in the literature (WO 03/000689; Bouillon, Alexandre, et al. "Synthesis of novel halopyridinylboronic acids and esters. Part 3: 2, or 3- Halopyridin-4-yl-boronic acids and esters.” Tetrahedron.
• Compound 2 may be subjected to a Pd mediated coupling reaction, such as Suzuki reaction, with a 2,6-dichloropyrimidine analog to provide compound 3.
• a Pd mediated coupling reaction such as Suzuki reaction
• the reaction of compound 3 with an appropriate amine under Buchwald reaction condition can provide the intermediate 4.
• S AT reaction of compound 4 with hydrazine or hydrazine monohydrate will furnish the advanced intermediate 5.
• Scheme 2 shows a general scheme for the synthesis of compound 7, wherein
• X X 2 , R and R are as defined herein.
• the hydrazine intermediate 5 may be reacted with a suitable acid (alkyl, substituted alkyl, aryl, heteroaryl, etc.) in the presence of trichloroacetonitrile, Ph 3 P and an organic base, such as Et 3 N or Hunig's base, as shown in Scheme 2, to provide the triazolopyridine analog 7.
• a suitable acid alkyl, substituted alkyl, aryl, heteroaryl, etc.
• Ph 3 P trichloroacetonitrile
• an organic base such as Et 3 N or Hunig's base
• the first step is to carry out a standard coupling reaction of compound 5 with a suitable acid in the presence of a coupling agent, such as l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (“EDC”), ⁇ , -carbonyldiimidazole (“CDI”), etc., and a base, such as Et 3 N, Hunig's, N-methyl morpholine, to provide the amide intermediate 6.
• EDC l-ethyl-3-(3- dimethylaminopropyl)carbodiimide
• CDI ⁇ , -carbonyldiimidazole
• Base such as Et 3 N, Hunig's, N-methyl morpholine
• Scheme 3 shows a general scheme for the synthesis of compound 5, wherein Xi, X 2 , and R 1 are as defined herein.
• a 4-halo-2-fluoropyridine analogue 8 where X is Br or CI, may be subjected to S Ar reaction with an appropriate amine in the presence of a base (NaH, K 2 C0 3 , Cs 2 C0 3 , etc.) to prepare compound 9.
• Compound 9 may then be subjected to a Pd mediated coupling reaction (such as Suzuki) with a 2-fluoropyridyl boronate or boronic acid 2 to provide compound 4.
• Compound 4 may be treated with hydrazine to provide compound 5 as described in Scheme 1.
• a subsequent coupling reaction of compound 5 with an acid, and the cyclization of the amide intermediate 6 can be achieved as described for the synthesis of compound 7 in Scheme 2.
• Compound 13 may be either purchased from a vendor or it can be prepared according to the methods described in the literature (Step 1 : US 2006/0287323; Step 2: Coelho, Alberto, et al. "Pyridazine derivatives. Part 39: Reactivity of 5-iodopyridazine-3(2H)-ones in palladium- catalysed reactions.” Tetrahedron. 60(52) (2004): pp. 12177-12190).
• Compound 13 or the N- protected analogue 14 (which may be prepared by the reaction of compound 13 with p- methoxybenzyl ether-Br in the presence of a base, such as K 2 C0 3 , Cs 2 C03, etc.) may be subjected to a Pd mediated coupling reaction with a pyrimidine stannate derivative to prepare compound 15.
• Compound 15 may be treated with a strong acid, such as H 2 S0 4 , trifluoroacetic acid (“TFA”) or combination of TFA: concentrated H 2 S0 4 ) to achieve the deprotection of the /?-methoxybenzyl ether (“PMB”) group and to obtain pyridazinone 16.
• a strong acid such as H 2 S0 4 , trifluoroacetic acid (“TFA”) or combination of TFA: concentrated H 2 S0 4
• hydrazine intermediate 18 may be subjected to a coupling reaction with an appropriate acid chloride in the presence of a base, such as Et 3 N, Hunig's, etc.) to make the amide analogue 19.
• a base such as Et 3 N, Hunig's, etc.
• the hydrazine intermediate 18 may be subjected to a coupling reaction with an appropriate acid in the presence of a coupling reagent, such as EDC, to prepare compound 19.
• the ring closure of compound 19 may be achieved by heating it in a suitable solvent with or without an acid, such as acetic acid.
• Oxidation of the SMe group in compound 20 with an oxidating agent such as meta-chloroperoxybenzoic acid (“w-CPBA”), followed by the SNAR reaction of the resulting sulfone 21 may give rise to the fully elaborated [l,2,4]triazolo[4,3- 6]pyridazine analogue 22.
• an oxidating agent such as meta-chloroperoxybenzoic acid (“w-CPBA”
• Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc”), benzyloxycarbonyl ("CBz”) and 9- fluorenylmethyleneoxycarbonyl ("Fmoc”).
• Boc trifluoroacetyl
• CBz benzyloxycarbonyl
• Fmoc 9- fluorenylmethyleneoxycarbonyl
• reaction products from one another and/or from starting materials.
• the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
• separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
• Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (“SMB”) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
• SMB simulated moving bed
• Diastereomeric mixtures can be separated into their individual diastereomers on the basis of 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., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
• an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
• Enantiomers can also be separated by use of a chiral high-performance liquid chromatography (“HPLC”) column.
• HPLC high-performance liquid chromatography
• a single stereoisomer e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al. "Chromatographic resolution of enantiomers: Selective review.” J. Chromatogr. 113(3) (1975): pp. 283-302).
• Racemic mixtures of chiral compounds described herein may be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of 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.
• diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, oc-methyl- ⁇ -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
• the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
• 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 asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.
• a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloro formate in the presence of base, or Mosher ester, oc-methoxy-a- (trifluoromethyl)phenyl acetate (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.
• chiral esters such as a menthyl ester, e.g., (-) menthyl chloro formate in the presence of base, or Mosher ester, oc-methoxy-a- (trifluoromethyl)phenyl acetate (Jacob III, Peyton. "Resolution of ( ⁇ )-5-Bromonornicotine. Synthesis of (R)
• Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/1511 1).
• a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Lough, W.J., Ed. Chiral Liquid Chromato graphy. 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).
• 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.
• the compounds described herein may be administered by any convenient 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 compounds may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
• Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.
• a typical formulation is prepared by mixing a compound described herein and a carrier or excipient.
• Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., 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 formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug ⁇ i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product ⁇ i.e., 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.
• a further 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, together with a pharmaceutically acceptable carrier or excipient.
• a method of treating a hyperproliferative disease in a mammal comprising administering a therapeutically effective amount of the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX or X, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, to the mammal is provided.
• Another embodiment provides a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said 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 said 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 said 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 attenuate 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 said 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 said 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 coadministering to said 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, with at least one other chemotherapeutic agent used to treat or ameliorate 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 said 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 said 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.
• a method of treating or preventing a disease or disorder modulated by ERK 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.
• diseases and disorders 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 the treatment of 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 the treatment of 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 the treatment of 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 the treatment of 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 use in the treatment of hyperproliferative 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, for use in the treatment of 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 use in the treatment of 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 use in the treatment of inflammatory diseases.
• the hyperproliferative disease is cancer.
• the cancer may be selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rect
• the cancer disorder 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 myelogenous leukemia. In certain embodiments, the cancer is chronic myelomonocytic leukemia. In certain embodiments, the cancer is chronic myelogenous leukemia. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is myeloid leukemia.
• the inflammatory disorder may be selected from arthritis, low back pain, inflammatory bowel disease, and rheumatism.
• the compounds described herein and stereoisomers, tautomers and pharmaceutically acceptable salts thereof may be employed alone or in combination with other therapeutic agents for treatment.
• the compounds described herein may be used in combination with one or more additional drugs, for example an anti-hyperproliferative (or anti-cancer) agent that works through action on a different target protein.
• the second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound described herein, such that they do not adversely affect each other.
• Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
• the compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
• ⁇ -NMR spectra were obtained as CDC1 3 , CD 3 OD, D 2 0, (CD 3 ) 2 SO, (CD 3 ) 2 CO, C 6 D 6 , CD 3 CN solutions (reported in ppm), using tetramefhylsilane (0.00 ppm) or residual solvent (CDC1 3 : 7.26 ppm; CD 3 OD: 3.31 ppm; D 2 0: 4.79 ppm; (CD 3 ) 2 SO: 2.50 ppm; (CD 3 ) 2 CO: 2.05 ppm; C 6 D : 7.16 ppm; CD 3 CN: 1.94 ppm) as the reference standard.
• the assay contained 50 mM HEPES [pH 7.3], 10 mM MgC12, 1 mM DTT, 0.005% Triton-XlOO, 5 nM ERK-2 enzyme, 6.25 ⁇ S/T17 peptide substrate and 25 ⁇ ATP (corresponding to the observed K m ) for a total reaction volume of 25 ⁇ ,.
• the assay was run at ambient temperature in a white 384-well polypropylene plate (Nunc, Inc of Naperville, IL; Cat. 267462) collecting data every 50 seconds for approximately 30 minutes on an Envision plate reader (PerkinElmer, Inc. of Waltham, MA); Excitation 340 nm/Emission 495 nm.
• Table 1 contains representative data for Examples disclosed herein. The reported IC 50 in Table 1 may be from a single assay or the mean of multiple assays. Examples 1-570 were tested in the above assay and were found to have an IC 50 of less than 1 ⁇ . Examples 1-130, 133-135, 137-210, 212-386, 388-418, 420-51 1, 513-562 and 564-570 (562 out of 570 examples) were tested in the above assay and were found to have an IC50 of less than 100 nM. Many of the Examples (507 out of 570) were tested in the above assay and were found to have an IC 0 of less than 10 nM.
• HepG2 cells were obtained from ATCC (Manassas, Virginia) and grown in DMEM supplemented with 10% fetal bovine serum. Cells were plated in 96- well plates at 35,000 cells/well and allowed to attach overnight at 37°C/5% C0 2 . Diluted compounds were then added at a final concentration of 0.5% DMSO. After 1.5 hours compound incubation, cells were stimulated with the addition of phorbol 12-myristate 13 -acetate (“PMA”) at a final concentration of 100 ng/mL; the PMA stimulation was a 30-minute incubation at 37°C/5% C0 2 .
• PMA phorbol 12-myristate 13 -acetate
• pP90RSK(Ser380) antibody was used at a 1 :250 dilution; GAPDH was used at a 1 :10,000 dilution. After washing with PBS/0.05% Tween-20, the cells were incubated with fluorescently-labeled secondary antibodies (Anti-rabbit- Alexa Flour680, Invitrogen Cat#A21 109; Anti-mouse- IRDye800CW, Rockland Inc. Cat#610-131-121) for 1 hour. Both secondary antibodies were used at a 1 : 1000 dilution. Cells were then washed and analyzed for fluorescence at both wavelengths using the Odyssey Infrared Imaging System (LI-COR Biosciences). Phosphorylated P90RSK(Ser380) signal was normalized to GAPDH signal. Table 1 contains representative data for Examples disclosed herein. The reported IC 50 in Table 1 may be from a single assay or the mean of multiple assays.
• Table 1 contains Examples tested in the above assays:
• Example 402 0.6 27.4
• Example 403 0.9 18.6
• Example 493 0.8 116.7
• Example 411 11 606.7
• Step 1 To a solution of anhydrous toluene and tetrahydrofuran (“THF”) (4:1, 250 mL) were added 4-bromo-2-fluoropyridine 1 (30.0 g, 0.17 mol) and triisopropyl borate (38.4 g, 0.20 mol). The mixture was cooled to -78 °C under a nitrogen atmosphere. Then, n- butyllithium (80 mL, 0.20 mol) (2.5 M in hexanes) was added dropwise over 30 minutes, followed by stirring at the same temperature for an additional 30 minutes. The mixture was finally warmed up to -20 °C over 1 hour.
• THF tetrahydrofuran
• TLC Thin layer chromatography
• PE petroleum ether
• EtOAc ethyl acetate
• the reaction mixture was acidified to a pH of 2 with 3N HCl (50 mL) and then stirred at room temperature for 15 minutes.
• the mixture was partitioned between EtOAc (150 mL) and water (150 mL).
• the organic layer was isolated, washed with water, brine, dried over anhydrous MgS0 4 , then filtered and evaporated to provide (2-fluoropyridin-4-yl)boronic acid (22.0 g, 91%) as a solid.
• Step 4 To isopropanol (50 mL) was added 4-(2-fluoropyridin-4-yl)-N-(l - methyl-lH-pyrazol-5-yl)pyrimidin-2-amine (14.5 g, 53.7 mmol) and hydrazine hydrate (9.47 g, 161.1 mmol, 85%). The mixture was heated at 100 °C with stirring for 6 hours. LC/MS indicated that the starting material was consumed. The mixture was cooled to room temperature, then concentrated to give a solid residue that was triturated with cold water (50 mL) and dichloromethane (50 mL).
• Step 1 Lithium aluminum hydride (5.46 mL, 5.46 mmol) was slowly added to methyl l-(trifluoromethyl)cyclobutanecarboxylate (0.829 g, 4.55 mmol) in THF (5 mL, 4.55 mmol) at 0 °C. This was then stirred for 2 hours at room temperature. The mixture was quenched at 0 °C with water (1 mL), then 2N NaOH (1 mL), and then water (1 mL) again. The mixture was stirred for 5 minutes at room temperature and then filtered. The filtrate was concentrated down to give (l-(trifluoromethyl)cyclobutyl)methanol (0.70 g, 4.54 mmol, 99.8% yield).
• Step 2 A mixture of (l-(trifluoromethyl)cyclobutyl)methanol (0.70 g, 4.54 mmol), methanesulfonic anhydride (0.949 g, 5.45 mmol) and triethylamine (“TEA") (d. 0.726) (0.950 mL, 6.81 mmol) in dichloromethane (“DCM”) (9.08 mL, 4.54 mmol) was stirred at room temperature for 4 hours. The mixture was worked up with saturated Na 2 C0 3 and DCM to give (l-(trifluoromethyl)cyclobutyl)methyl methanesulfonate (0.851 g, 3.66 mmol, 80.7% yield).
• TEA triethylamine
• Step 4 A mixture of 2-(l-(trifluoromethyl)cyclobutyl)acetonitrile (0.315 g, 1.93 mmol) in NaOH (3 mL, 18.0 mmol) and EtOH (6 mL, 1.93 mmol) was heated to reflux overnight. The mixture was worked up with 2 N HCl and DCM. The organics were extracted twice with DCM, washed with brine and dried with Na 2 S0 4 . This was then concentrated down to give 2-(l-(trifluoromethyl)cyclobutyl)acetic acid (0.169 g, 0.928 mmol, 48.1% yield). ⁇ NMR (400 MHz, CDC1 3 ) 2.50 (s, 2H), 1.99 (m, 6H).
• Step 1 (Z)-Ethyl 3-(methylamino)but-2-enoate (0.500 g, 3.49 mmol) and 3- fluorobenzonitrile (4.23 g, 34.9 mmol) were placed in dimethylacetamide (“DMA”) (2 mL) and heated at 120 °C overnight, cooled to room temperature, filtered through Celite®, worked up with water and EtOAc and then purified by column chromatography using 500:10 DCM:MeOH to give ethyl 3-(3-fluorophenyl)-l,5-dimethyl-lH-pyrazole-4-carboxylate (0.66 g, 72.06% yield).
• DMA dimethylacetamide
• Step 2 Ethyl 3-(3-fluorophenyl)-l ,5-dimethyl-lH-pyrazole-4-carboxylate (0.50 g, 1.9 mmol) was placed in 3: 1 THF:water. LiOH (5.7 mL, 5.7 mmol) was then added, and the mixture was stirred for 24 hours at room temperature. The mixture was adjusted to pH 3 with 1M HCl, and extracted with EtOAc to give 3-(3-fluorophenyl)-l ,5-dimethyl-lH- pyrazole-4-carboxylic acid (0.4 g, 90% yield). Exam le D
• a glass sealable pressure tube was charged with ethyl 3,3-difluorobutanoate (100 mg, 0.657 mmol) and a mixture of concentrated HCLglacial acetic acid (2 mL, 1 : 1). The tube was capped with a Teflon cap and heated to 80 °C for 18 hours. The mixture was allowed to cool to room temperature and then to 0 °C. The reaction mixture was transferred to a separatory funnel, diluted with 5% MeOH:DCM (25 mL) and washed with water (2 X 10 mL).
• Step 1 Ethyl 4,4,5,5, 5-pentafluoro-3-hydroxypentanoate was prepared as described in Jagodzinska, Monika, et al. "Studies on a three-step preparation of ⁇ -fluoroalkyl acrylates from fluoroacetic esters.” Tetrahedron. Vol. 63, No. 9 (2007): pp. 2042-2046.
• Step 2 A sealable glass pressure tube was charged with a solution of crude ethyl 4,4,5,5,5-pentafluoro-3-hydroxypentanoate (400 mg, 1.69 mmol) in a mixture of acetic acid and concentrated HC1 (1 :1, 4 mL). The tube was capped with a Teflon screw cap, and the mixture was heated at 80 °C overnight. The mixture was cooled to 0 °C, diluted with EtOAc (50 mL) and washed with water (4 X). The organic layer was separated, dried (MgS0 4 ), filtered and concentrated in vacuo to provide the crude as an oil.
• Step 1 A solution of ethyl 2-(triphenylphosphoranylidene)acetate (15 g, 44 mmol) in dichloromethane (26 mL, 40 mmol) was cooled to 0 °C and treated with 1,1,1- trifluorobutan-2-one (5 g, 40 mmol). The mixture was stirred at 0 °C for 15 minutes. The reaction mixture was concentrated in vacuo (water bath below 10 °C and vacuum at 170 Torr). With concentration Ph 3 PO started to precipitate out. The solids were filtered off washing with Et 2 0. The filtrate collected was treated with Et 2 0 (20 mL), and the solids formed were decanted off.
• Step 2 To a suspension of 10% palladium on activated carbon (wet) (1.1 g, 1.0 mmol) in EtOH (20 mL) under N 2 was added a solution of E and Z isomers of ethyl 3- (trifluoromethyl)pent-2-enoate in MeOH (10 mL). The mixture was purged under N 2 (3 cycles) and back filled with H 2 . The mixture was then stirred under H 2 balloon for 8 hours. The mixture was filtered through a Celite® pad, and the Celite® cake was washed well with additional EtOH. The filtrate collected was treated with lithium hydroxide hydrate (1.1 g, 25 mmol) in water (5 mL). The mixture was stirred at ambient temperature for 4 hours.
• Li hydroxide hydrate 1.1 g, 25 mmol
• Step 1 Methyl 2-(4,4-difluorocyclohexyl)acetate was prepared according to a method described in U.S. Pat. Appl. Publ. 2008/0019978. A solution of methyl 2-(4- oxocyclohexyl)acetate (500 mg, 2.94 mmol) in dichloromethane (14688 ⁇ , 2.94 mmol) at ambient temperature was treated with diethylamino sulfurtrifluoride (“DAST”) (1 164 ⁇ , 8.81 mmol). The resulting mixture was stirred at ambient temperature for one overnight. The mixture was diluted with DCM (20 mL) and poured into ice water (10 mL).
• DAST diethylamino sulfurtrifluoride
• Step 2 2-(4,4-Difluorocyclohexyl)acetic acid was prepared from methyl 2- (4,4-difluorocyclohexyl)acetate (520 mg, 2.71 mmol) according to the method described for the preparation of the same compound in U.S. Pat. Appl. Publ. 2008/0019978.
• LCMS (APCI) m/z 177 (M-l).
• the reaction mixture was concentrated in vacuo, and the residue was dissolved in MeOH:THF (1 :1, 5 mL) and treated with 2 M sodium hydroxide (1585 ⁇ , 3.17 mmol). The mixture was stirred at room temperature for one overnight. The mixture was concentrated in vacuo, and the residue obtained was dissolved in water (20 mL) and 1 N NaOH (5 mL). The basic aqueous layer was washed with EtOAc (3 X). The aqueous layer was made acidic (pH 2, with 2 N HCl) and extracted into 5% MeOH:DCM (3 X).
• Step 1 To a suspension of sodium hydride 60% in mineral oil (3.14 g, 78.5 mmol) in dry tetrahydrofuran (143 mL, 71.3 mmol) at 0 °C was added dropwise (over 20 minutes) ethyl 2-(diethoxyphosphoryl)acetate (15.7 mL, 78.5 mmol) maintaining internal temperature below 10 °C. Vigorous gas evolution was observed during the addition. The resulting mixture was stirred at 0 °C for 30 minutes and treated dropwise with cyclopropanecarbaldehyde (5.0 g, 71.3 mmol). The mixture was stirred at room temperature for 1 overnight.
• Step 2 A sealable glass pressure tube was charged with a solution of (E)-ethyl 3-cyclopropylacrylate (1.0 g, 7.13 mmol) in methanol (7.13 mL, 7.13 mmol) and trimethylphosphine (0.369 mL, 3.57 mmol).
• the reaction vessel was capped with a Teflon screw cap, and the reaction mixture was heated to 45 °C for 2 days.
• Step 3 A solution of methyl 3-cyclopropyl-3-methoxypropanoate (254 mg, 1.61 mmol) in methanol (1606 ⁇ , 1.61 mmol) and tetrahydrofuran (6422 ⁇ , 1.61 mmol) was treated with a solution of lithium hydroxide hydrate (135 mg, 3.21 mmol) in water (0.5 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (10 mL) and adjusted to pH 14 with 1 N NaOH. The basic aqueous layer was washed with EtOAc to remove organic impurities.
• Step 1 A solution of benzyl 2-(triphenylphosphoranylidene)acetate (19.2 g, 46.8 mmol) in dichloromethane (28.4 mL, 42.5 mmol) was cooled to 0 °C and treated with l,3-difluoropropan-2-one (4 g, 42.5 mmol). The mixture was stirred at 0 °C and allowed to warm to ambient temperature slowly overnight. The reaction mixture was directly subjected to fractional distillation to remove DCM (oil bath 30 °C, pressure at 300-170 Torr). The pot containing the product and Ph 3 PO was cooled to 0 °C, and the solid formed was filtered off.
• DCM oil bath 30 °C, pressure at 300-170 Torr
• Step 2 To a suspension of Wilkinson's catalyst (4 mg, 0.00432 mmol) in EtOH (50 mL) under N 2 was added a solution of benzyl 4-fluoro-3-(fluoromethyl)but-2- enoate (200 mg, 0.884 mmol) in EtOH (10 mL). The mixture was purged under N 2 (3 cycles) and back filled with H 2 (3 cycles). Then the reaction mixture was stirred at ambient temperature under an H 2 balloon. After 4 hours, the mixture was charged with additional catalyst (10 mg, 0.012 equivalents, 0.011 mmol) and stirred under H 2 overnight.
• Step 3 To a suspension of 10% palladium on activated charcoal (wet) (12 mg, 0.012 mmol) in ethanol (4644 ⁇ , 0.23 mmol) under N 2 was added a solution of benzyl 4- fluoro-3-(fluoromethyl)butanoate (53 mg, 0.23 mmol) in EtOH (2 mL). The reaction vessel was purged under N 2 (2 cycles) and back filled with H 2 (3 cycles). The mixture was then stirred under H 2 balloon for 1 hour.
• Step 1 5-Amino-l -methyl- lH-pyrazole (6.25 g, 64.4 mmol) was dissolved in THF (120 ml) and treated with sodium hydride (3.51 g, 87.8 mmol). The reaction was heated to 35 °C for 30 minutes and then treated with a dimethylformamide (“DMF") solution (24 mL) of 4-bromo-2-fluoropyridine (10.3 g, 58.5 mmol). The reaction was heated to 50 °C and stirred for 1 hour. The reaction was allowed to cool and treated with water, and the organics were concentrated. The residue was diluted with ethyl acetate and washed with water and brine.
• DMF dimethylformamide
• Step 2 4-Bromo-N-(l -methyl- lH-pyrazol-5-yl)pyridin-2-amine (6.91 g, 27.3 mmol) was dissolved in 4:1 acetonitrile ("ACN"):water (55 mL) and treated with 2- fluoropyridyl-4-boronic acid (4.04 g, 28.7 mmol) and potassium carbonate (11.3 g, 81.9 mmol). The reaction mixture was degassed with argon and treated with 1,1'- bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (2.25 g, 2.73 mmol).
• the reaction was purged with argon for an additional 5 minutes, sealed, and heated to 90 °C. The reaction was allowed to heat at this temperature for 16 hours. The reaction was cooled to ambient temperature, filtered and concentrated. The reaction was diluted with ethyl acetate and washed with water and brine. The organics were dried over sodium sulfate, filtered and concentrated. The material was purified on silica gel eluting with 30-100% acetonerhexanes to afford 2'-fluoro-N-(l-methyl-lH-pyrazol-5-yl)-[4,4'-bipyridin]- 2-amine (3.1 g, 1 1.51 mmol, 42.2% yield).
• Step 3 2'-Fluoro-N-(l-methyl-lH-pyrazol-5-yl)-[4,4'-bipyridin]-2-amine (3.1 g, 11.5 mmol) was dissolved in ethanol (23 mL) and treated with hydrazine (3.61 mL, 115 mmol). The reaction was heated to 80 °C and stirred for 16 hours. The reaction was allowed to cool to ambient temperature and then concentrated.
• Step 1 To a solution of 4-bromo-2-fluoropyridine (5.0 g, 28.4 mmol) in DMSO (56.8 mL, 28.4 mmol) was sequentially added tetrahydro-2H-pyran-4-amine (3.30 g, 32.7 mmol) and cesium carbonate (18.5 g, 56.8 mmol). The mixture was then stirred at 80 °C for 4 hours and cooled to ambient temperature. The mixture was then poured into water and extracted into EtOAc (200 mL). The combined organics were washed with half saturated brine (50 mL), dried (MgS0 4 ), filtered and concentrated in vacuo.
• Step 2 A mixture of 4-bromo-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (294 mg, 1.14 mmol), (2,3-difluoropyridin-4-yl)boronic acid (200 mg, 1.26 mmol), PdCl 2 (dppf)*dcm (47 mg, 0.057 mmol) and Na 2 CO s 20% aqueous (1.15 mL, 2.29 mmol) in dioxane (5.7 mL, 1.14 mmol) was heated to 90 °C with stirring for 18 hours and allowed to cool to room temperature.
• Step 3 To a solution of 2',3 , -difluoro-N-(tetrahydro-2H-pyran-4-yl)-[4,4'- bipyridin]-2-amine (50 mg, 0.17 mmol) in 2-butanol (1.7 mL, 0.17 mmol) was added hydrazine (17 mg, 0.51 mmol). The mixture was stirred at 50 °C. After 30 minutes, additional hydrazine (17 mg, 0.51 mmol) was added, and the mixture was stirred at 60 °C. After 1 hour, the mixture was cooled to ambient temperature and partitioned between 5% MeOH: DCM and half saturated NaHC0 3 .
• Step 1 2-Benzyl-4,5-dichloropyridazin-3(2H)-one (41 g, 63.9% yield) was prepared from 4,5-dichloropyridazin-3(2H)-one (41.5 g, 252 mmol) and (bromomethyl)benzene (43.0 g, 252 mmol) as described for the synthesis of the same compound in US 2006/0287323.
• Step 2 2-Benzyl-5-iodopyridazin-3(2H)-one was prepared according to the method described in Coelho, supra. A solution of 2-benzyl-4,5-dichloropyridazin-3(2H)-one (30 g, 118 mmol) in 57% hydrogen iodide (155 mL, 1 176 mmol) was heated at reflux for 24 hours and allowed to cool to room temperature. The mixture was diluted with DCM (6 X 100 mL) and poured into ice water (200 mL), and solid Na 2 S 2 0 3 was added with stirring. The layers were separated, and the aqueous phase was extracted with DCM until there was no product left in the aqueous phase.
• Step 3 A mixture of 2-benzyl-5-iodopyridazin-3(2H)-one (28 g, 90 mmol) and AICI 3 (60 g, 449 mmol) in dry toluene (748 mL, 90 mmol) were processed according to the method described in Coelho, supra, to provide 5-iodopyridazin-3(2H)-one (12 g, 60% yield) as a solid.
• Step 4 To a solution of 5-iodopyridazin-3(2H)-one (5 g, 23 mmol) in NJV- dimethylformamide (45 mL, 23 mmol) was sequentially added l-(bromomethyl)-4- methoxybenzene (4.5 g, 23 mmol) and K 2 C0 3 (3.4 g, 25 mmol). The mixture was stirred at ambient temperature under N 2 atmosphere. After 48 hours, additional 1 -(bromomethyl)-4- methoxybenzene (450 mg, 0.1 equivalent) was added, and the mixture was stirred at ambient temperature for 4 more hours.
• l-(bromomethyl)-4- methoxybenzene 4.5 g, 23 mmol
• K 2 C0 3 3.4 g, 25 mmol
• Step 5 A resealable glass pressure tube was charged with a suspension of 5- iodo-2-(4-methoxybenzyl)pyridazin-3(2H)-one (2.78 g, 8.13 mmol), 4- (dibutyl(propyl)stannyl)-2-(methylthio)pyrimidine (3.26 g, 8.13 mmol), Cu(I)I (0.155 g, 0.813 mmol) and PdCl 2 (PPh 3 ) 2 (0.570 g, 0.813 mmol) in l-methylpyrrolidin-2-one ("NMP") (16.3 mL, 8.13 mmol).
• NMP l-methylpyrrolidin-2-one
• the mixture was sparged with N 2 for 5 minutes, and the tube was sealed and stirred at 120 °C under N 2 for 18 hours.
• the mixture was cooled to ambient temperature, diluted with hot THF (100 mL), and filtered.
• the filtrate was concentrated in vacuo, and the resulting residue containing NMP was allowed to stand at room temperature for 5 hours.
• the solid formed was filtered, washed with CH 3 CN (5 mL) to provide the first batch of the desired product (1.3 g).
• Mother liquor was concentrated, and the resulting residue was dissolved in 5% MeOHrDCM (150 mL) and washed with 0.1% HC1 (50 mL) followed by saturated NaHC0 3 (30 mL) and brine (30 mL).
• Step 6 To a mixture of 2-(4-methoxybenzyl)-5-(2-(methylthio)pyrimidin-4- yl)pyridazin-3(2H)-one (1.78 g, 5.234 mmol) in anisole (10 mL) was carefully added TFA (30 mL) and concentrated H 2 S0 4 (5 mL). The resulting mixture was heated at 120 °C for 3 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue obtained was dissolved in ice water and very carefully poured into a solution of ice cold saturated NaHC0 3 solution. The pH of the mixture was adjusted to 7.5 with additional saturated NaHC0 3 and diluted with additional water (total volume was about 500 mL).
• Step 7 A mixture of 5-(2-(methylthio)pyrimidin-4-yl)pyridazin-3(2H)-one (205 mg, 0.931 mmol) and POCl 3 (5 mL) was stirred at 50 °C for 1 hour and concentrated in vacuo. The residue obtained was dissolved in 5% MeOH:DCM and washed with saturated NaHC0 3 (2 X) followed by brine. The organics were dried (MgS0 4 ), filtered and concentrated under reduced pressure.
• Step 8 A mixture of 3-chloro-5-(2-(methylthio)pyrimidin-4-yl)pyridazine (136 mg, 0.570 mmol) and hydrazine monohydrate (143 mg, 2.85 mmol) in 2-butanol (3798 ⁇ iL, 0.570 mmol) was heated at 78 °C for 1.5 hours. The solid formed with cooling was dissolved in DCM (100 mL) and washed with saturated aqueous NaHC0 3 (2 X 20 mL) and brine.
• Step 1 4-(2-Hydrazinylpyridin-4-yl)-N-(l-methyl-lH-pyrazol-5-yl)pyrimidin- 2-amine (0.40 g, 1.42 mmol) and tert-butyl 2-formylmorpholine-4-carboxylate (0.305 g, 1.42 mmol) were placed in EtOH (5 mL) and stirred at room temperature overnight. This was concentrate to dryness and suspended in DCM. Iodobenzene diacetate (0.593 g, 1.84 mmol) was added, and the mixture was stirred at room temperature for 3 hours. This was poured into water, and the organics were extracted with DCM.
• Step 2 rt-Butyl 2-(7-(2-((l -methyl- 1 H-pyrazol-5-yl)amino)pyrimidin-4-yl)- [l,2,4]triazolo[4,3- ⁇ ]pyridin-3-yl)mo holine-4-carboxylate (0.200 g, 0.41883 mmol) was placed in DCM. HCl (0.698 mL, 4.188 mmol) in IPA (6 M) was added, and this was stirred for 3 hours at room temperature.
• Step 3 JV " -(l-Methyl-lH ⁇ yi ⁇ l-5-ylH 3 morpholin-2-yl)-
• [l,2,4]triazolo[4,3-a]pyridin-7-yl)pyrimidin-2-amine hydrochloride (0.075 g, 0.181 mmol), 2-fluoro-6-methoxybenzaldehyde (0.0335 g, 0.217 mmol), NaBH(OAc) 3 (0.0576 g, 0.272 mmol), N,N-diisopropylethylamine (“DIEA”) (d 0.742) (0.0947 mL, 0.544 mmol) was placed in THF (5 mL) and stirred at room temperature for 24 hours. The mixture was poured into water and extracted with DCM.
• DIEA N,N-diisopropylethylamine
• Step 1 A mixture of 4-(2-hydrazinylpyridin-4-yl)-N-(l -methyl- lH-pyrazol-5- yl)pyrimidin-2-amine (0.050 g, 0.177 mmol), lH-benzo[i ][l ,2,3]triazol-l-ol (0.0239 g, 0.177 mmol), 2-(4-(methylthio)phenyl)acetic acid (0.0339 g, 0.186 mmol), Nl- ((ethylimino)methylene)-N3 V3-dimethylpropane-l,3-diamine hydrochloride (0.034 g, 0.177 mmol) and Hunig's base (0.0617 mL, 0.354 mmol) in DMF (1 mL, 0.177 mmol) was stirred overnight at room temperature.
• Step 2 A mixture of N'-(4-(2-((l -methyl-lH-pyrazol-5-yl)amino)pyrimidin-4- yl)pyridin-2-yl)-2-(4-(methylthio)phenyl)acetohydrazide (0.08 g, 0.179 mmol) in acetic acid (1 mL) was heated to 180 °C for 10 minutes in the microwave. The mixture was concentrated down and purified on a column using DCMrMeOHrNLLiOH (90: 10: 1).
• N-(l-Methyl-lH-pyrazol-5-yl)-4-(3-(thiophen-2-ylmethyl)-[l,2,4]triazolo[4,3- a]pyridin-7-yl)pyrimidin-2-amine (0.035 g, 0.090 mmol, 46% yield) was made according to the procedure of Example 6, substituting 2-(thiophen-2-yl)acetic acid for 2-(4- (methylthio)phenyl)acetic acid.
• N-(l-Methyl-lH-pyrazol-5-yl)-4-(3-(2-methylbutyl)-[l,2,4]triazolo[4,3- a]pyridin-7-yl)pyrimidin-2-amine (0.0189 g, 0.0521 mmol, 36.8% yield) was made according to the procedure of Example 4, substituting 3-methylpentanoic acid for 2-(3- bromophenyl)acetic acid.
• Step 1 Methylmagnesium bromide (0.249 mL, 0.748 mmol) was added to (lS,2S)-ethyl 2-(7-(2-((l-methyl-lH-pyrazol-5-yl)amino)pyrimidin-4-yl)-[l,2,4]triazolo[4,3- a]pyridin-3-yl)cyclopropanecarboxylate (0.072 g, 0.178 mmol) in ether (1.78 mL, 0.178 mmol) at 0 °C. The mixture was then stirred at room temp for 30 minutes. This was then quenched with NLL4CI at 0 °C.
• Step 2 DAST (0.00690 mL, 0.0564 mmol) was added to 2-((15*,2S*)-2-(7-(2- (( 1 -methyl- 1 H-pyrazol-5-yl)amino)pyrimidin-4-yl)-[ 1 ,2,4]triazolo[4,3-a]pyridin-3- yl)cyclopropyl)propan-2-ol (0.020 g, 0.051 mmol) in DCM (0.17 mL, 0.051 mmol) at -78 °C. This was stirred for 1 hour. This was then quenched with saturated NaHC0 3 and worked up with DCM and water.
• Step 1 4-(2-Hydrazinylpyridin-4-yl)-N-( 1 -methyl- 1 H-pyrazol-5-yl)pyrimidin- 2-amine (80 mg, 0.28 mmol) was dissolved in DMF (4 mL) and treated with (S)-3- hydroxypentanoic acid (40.1 mg, 0.34 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride (59.76 mg, 0.31 17 mmol), 1-hydroxybenzotriazole (42.12 mg, 0.3117 mmol), and N ⁇ V-diisopropylethylamine (74.0402 0.425074 mmol).
• the mixture was stirred at room temperature for 1 hour and LC/MS showed complete conversion to the desired product.
• the mixture was diluted with water, and the aqueous layer was extracted with 20% IPA:DCM, then dried, filtered and concentrated. The crude product was taken forward to the next step.
• Step 2 A solution of (5)-3-hydroxy-N'-(4-(2-((l-methyl-lH-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin-2-yl)pentanehydrazide (108 mg, 0.282 mmol) in acetic acid (3 mL) was place in a microwave reactor at 180 °C for 30 minutes.
• Step 3 To a cold (-78 °C) solution of deoxyfluor (11 mg, 0.045 mmol) in DCM (5 mL) was added (S)-l-(7-(2-((l-methyl-lH-pyrazol-5-yl)amino)pyrimidin-4-yl)- [l,2,4]triazolo[4,3-fl]pyridin-3-yl)butan-2-ol (0.015 g, 0.041 mmol) as a solution in DCM (2 mL). LC/MS after 1 hour showed no reaction. To this was added another 1.0 equivalent of deoxyfluor, and the mixture was stirred at room temperature for another hour.
• Step 1 4-(2-Hydrazinylpyridin-4-yl)-N-(l -methyl- lH-pyrazol-5 -yl)pyrimidin- 2-amine (76.8 mg, 0.272 mmol) was dissolved in DMF (4 mL) and treated with 2-(6- chloropyridin-2-yl)acetic acid (49.0 mg, 0.286 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride (57.4 mg, 0.299 mmol), 1-hydroxybenzotriazole (40.4 mg, 0.299 mmol), and N,N-diisopropylethylamine (0.0948 mL, 0.544 mmol).
• Step 2 In a microwave vessel, 2-(6-chloropyridin-2-yl)-jV-(4-(2-((l-methyl- lH-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetohydrazide (80 mg, 0.1835 mmol) was dissolved in ACN (6 mL) and treated with phosphorous oxychloride (85.54 ⁇ , 0.9177 mmol). The mixture was heated to 100 °C overnight. The mixture was cooled and concentrated.
• Step 1 4-(2-Hydrazinylpyridin-4-yl)-N-(l -methyl- lH-pyrazol-5-yl)pyrimidin- 2-amine (200 mg, 0.708 mmol) was dissolved in DMF (4 mL) and treated with 2-(5- bromopyridin-3-yl)acetic acid (160.7 mg, 0.744 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride (149.4 mg, 0.7793 mmol), 1-hydroxybenzotriazole (105.3 mg, 0.7793 mmol), and N,N-diisopropylethylamine (185.1 ⁇ ,, 1.063 mmol).
• Step 2 A solution of 2-(5-bromopyridin-3-yl)-iV-(4-(2-((l -methyl- IH- pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetohydrazide (340 mg, 0.708 mmol) in acetic acid was placed in a microwave reactor at 180 °C for 30 minutes.
• Step 1 To a solution of (E)-methyl 4-methylpent-2-enoate (3.71 g, 28.9 mmol) in MeOH (10 mL) was added by trimethylphosphine (0.599 mL, 5.79 mmol). The reaction vessel was sealed, and the mixture was heated to 45 °C for 7 days. The mixture was concentrated, and the residue was taken up in MeOH (5 mL) and stirred with 4N sodium hydroxide (14.5 mL, 57.9 mmol) at room temperature overnight. The next morning, the mixture was concentrated to remove MeOH, and the residue was washed with ethyl acetate (2 X).
• Step 2 4-(2-Hydrazinylpyridin-4-yl)- V-(l-methyl-lH-pyrazol-5-yl)pyrimidin- 2-amine (160 mg, 0.567 mmol) was dissolved in DMF (4 mL) and treated with 3-methoxy-4- methylpentanoic acid (124 mg, 0.85 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride (119.5 mg, 0.623 mmol), 1 -hydroxybenzotriazole (84.24 mg, 0.6234 mmol), and N ⁇ V-diisopropylethylamine (148.1 ⁇ , 0.8501 mmol).
• Step 3 A solution of 3-methoxy-4-methyl-N'-(4-(2-((l -methyl- lH-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin-2-yl)pentanehydrazide (232 mg, 0.565 mmol) in acetic acid (3 mL) was placed in a microwave reactor at 150 °C for 15 minutes.
• Step 1 A suspension of 2-(4-methoxyphenyl)acetic acid (3.33 g, 20.0 mmol), l-chloropropan-2-one (1.68 mL, 20.0 mmol), K 2 C0 3 (9.97 g, 72.1 mmol) in ACN (40 mL) was refluxed for 12 hours. The mixture was cooled to room temperature, and the insolubles were removed by filtration. The filtrate was concentrated to give 3-(4-methoxyphenyl)-4- methylfuran-2(5H)-one (3.5 g, 85.5%).
• Step 2 To a solution of 3-(4-methoxyphenyl)-4-methylfuran-2(5H)-one (0.99 g, 4.8 mmol) in MeOHrethyl acetate (1 :1, 20 mL) was added Pd/C (0.52 g, 0.48 mmol). The mixture was purged with N 2 for 10 minutes and then placed under a H 2 balloon at room temperature for 12 hours. The Pd was removed by filtration, and the filtrate was concentrated to give (3S*,45*)-3-(4-methoxyphenyl)-4-methyldihydrofuran-2(3H)-one (0.95 g, 95%).
• Step 3 To a cold (-78 °C) solution of (3S*,4S*)-3-(4-methoxyphenyl)-4- methyldihydrofuran-2(3H)-one (0.56 g, 2.72 mmol) in THF (6 mL) was added 1.5 M DIBAL-H (2.44 mL, 3.67 mmol) in toluene dropwise, and the reaction mixture was stirred for 30 minutes, at which time the bath temperature had reached -30 °C. TLC showed complete conversion to a more polar spot. The reaction mixture was carefully quenched with water and then diluted with ethyl acetate and 0.5 N sodium potassium tartrate.
• Step 4 To a solution of (2S*,3S*,4S*)-3-(4-methoxyphenyl)-4- methyltetrahydrofuran-2-ol (0.27 g, 1.3 mmol) in DMF (4 mL) was added tert- butyldimethylsilyl chloride ("TBDMS-C1") (0.250 g, 1.66 mmol), imidazole (0.124 g, 1.82 mmol) and l,8-diazabicycloundec-7-ene (“DBU”) (0.0194 mL, 0.130 mmol). The reaction mixture was stirred at room temperature for 3 hours. LC/MS showed complete conversion to two less polar peaks.
• TDMS-C1 tert- butyldimethylsilyl chloride
• imidazole (0.124 g, 1.82 mmol
• DBU l,8-diazabicycloundec-7-ene
• Step 5 4-(2-Hydrazinylpyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin- 2-amine (0.116 g, 0.406 mmol) was dissolved in EtOH (6 mL) and treated with (25'*,3S'*)-4- (tert-butyldimethylsilyloxy)-2-(4-methoxyphenyl)-3-methylbutanal (0.131 g, 0.406 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was dissolved in DCM (6 mL) and treated with iodobenzene diacetate (0.170 g, 0.528 mmol).
• Step 1 A solution of (3S,4S)-3-(4-methoxyphenyl)-4-methyldihydrofuran- 2(3H)-one (0.40 g, 1.94 mmol) in MeOH (5 mL) was treated with DBU (0.0289 mL, 0.194 mmol) at room temperature for 12 hours. Crude NMR showed a 9:1 ratio of trans/cis mixture.
• Step 2 To a cold (-78 °C) solution of (3J?*,4S*)-3-(4-methoxyphenyl)-4- methyldihydrofuran-2(3H)-one (0.284 g, 1.377 mmol) in THF (6 mL) was added 1.5 M DIBAL-H (1.239 mL, 1.859 mmol) in toluene dropwise, and the mixture was stirred for 30 minutes, at which time the bath temperature has reached -30 °C. TLC showed formation of a more polar spot along with some starting material. The reaction mixture was cooled to -60 °C, and to this was added additional 1.5 M DIBAL (0.2 mL).
• Step 3 To a solution of (3#* 4S*)-3-(4-methoxyphenyl)-4- methyltetrahydrofuran-2-ol (0.263 g, 1.263 mmol) in DMF (4 mL) was added TBDMS-C1 (0.2436 g, 1.616 mmol) and imidazole (0.1204 g, 1.768 mmol). The mixture was stirred at ambient temperature for 2 hours. The mixture was diluted with EtOAc, and the organics were washed with brine (2 X), dried, filtered and concentrated.
• Step 4 4-(2-Hydrazinylpyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin- 2-amine (0.032 g, 0.1 1 mmol) was dissolved in EtOH (6 mL) and treated with (2 ⁇ ,35)-4- ((/er/-butyldimethylsilyl)oxy)-2-(4-methoxyphenyl)-3-methylbutanal (0.036 g, 0.11 mmol). The mixture was stirred at ambient temperature for 12 hours. The mixture was concentrated, and the residue was dissolved in DCM (6 mL) and treated with iodobenzene diacetate (0.047 g, 0.15 mmol).
• Step 5 A solution of 4-(3-((li?*,25*)-3-((/ert-butyldimethylsilyl)oxy)-l-(4- methoxyphenyl)-2-methylpropyl)-[l,2,4]triazolo[4,3-a]pyridin-7-yl)-N-(tetrahydro-2H- pyran-4-yl)pyrimidin-2-amine (0.052 g, 0.088 mmol) in THF (5 mL) was treated with 1.0 M TBAF at ambient temperature for 30 minutes. The mixture was concentrated, and the residue was taken up in EtOAc and washed with brine twice. The organics were dried, filtered and concentrated.
• Step 1 To a -78 °C solution of diisopropylamine (5.84 mL, 41.7 mmol) in THF (12 mL) was added a solution of 2.5 M butyllithium (16.7 mL, 41.7 mmol) in hexanes via a syringe. The mixture was stirred at -78 °C for 10 minutes, warmed to 0 °C for 5 minutes and cooled to -78 °C for 10 minutes.
• Step 2 To a cold (-78 °C) solution of 3-(4-methoxyphenyl)dihydrofuran- 2(3H)-one (0.22 g, 1.14 mmol) in THF (6 mL) was added 1.5 M DIBAL-H (1.03 mL, 1.55 mmol) in toluene drop wise, and the mixture was stirred for 30 minutes at which time the bath temperature had reached -30 °C. The mixture was carefully quenched with water and diluted with EtOAc and 0.5 N sodium potassium tartrate. The mixture was stirred for 1 hour, and the layers were separated. The organics were dried, filtered and concentrated.
• Step 3 To a solution of 3-(4-methoxyphenyl)tetrahydrofuran-2-ol (0.140 g, 0.721 mmol) in DMF (4 mL) was added TBDMS-C1 (0.139 g, 0.923 mmol), imidazole (0.0687 g, 1.01 mmol) and DBU (0.0108 mL, 0.0721 mmol). The mixture was stirred at ambient temperature overnight. LC/MS showed complete conversion to a less polar peak. The mixture was diluted with EtOAc, and the organics were washed with brine (2 X), dried, filtered and concentrated.
• Step 4 4-(2-Hydrazinylpyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin- 2-amine (0.0687 g, 0.240 mmol) was dissolved in EtOH (6 mL) and treated with A- ⁇ tert- butyldimethylsilyloxy)-2-(4-methoxyphenyl)butanal (0.074 g, 0.240 mmol). The reaction mixture was stirred at ambient for 1 hour. The mixture was concentrated, and the residue was dissolved in DCM (6 mL) and treated with Iodobenzene diacetate (0.100 g, 0.312 mmol). The reaction mixture was stirred at ambient temperature for 24 hours.
• Step 1 Ethyl 2-cyclobutylideneacetate (408.9 mg, 2.917 mmol) was dissolved in THF (14.6 mL, 0.2 M). The solution was degassed with N 2 , and treated with copper (I) iodide (61 1.1 mg, 3.209 mmol). This was cooled to 0 °C and treated with chlorotrimethylsilane (405.8 ⁇ , 3.209 mmol). The mixture was stirred at 0 °C for 10 minutes and then treated with ethylmagnesium bromide (2917 ⁇ , 2.917 mmol). This was stirred at 0 °C for 1 hour.
• Step 2 Ethyl 2-(l-ethylcyclobutyl)acetate (267.5 mg, 1.571 mmol) was dissolved in 4: 1 THF:MeOH (7.9 mL, 0.2 M) and treated with potassium hydroxide (2 M in water) (2357 ⁇ , 4.714 mmol). This was stirred for 16 hours at ambient temperature. The mixture was worked up with DCM and 4.0 N HCl. The organics were extracted twice with DCM, washed with brine and dried with Na 2 S0 4 . This was concentrated down to give 2-(l - ethylcyclobutyl)acetic acid.
• Step 3 4-(2-Hydrazinylpyridin-4-yl)-N-(l -methyl- lH-pyrazol-5-yl)pyrimidin- 2-amine (63.6 mg, 0.225 mmol) was dissolved in DMF (1.2 mL, 0.2 M) and treated with 2- (l-ethylcyclobutyl)acetic acid (35.24 mg, 0.2478 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodimidehydrochloride (47.51 mg, 0.2478 mmol), 1 -hydroxybenzotriazole (33.49 mg, 0.2478 mmol), and N ⁇ V-diisopropylethylamine (78.48 ⁇ ,, 0.4506 mmol). The mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated down and taken forward to the next step as crude.
• Step 4 2-(l-Ethylcyclobutyl)-7V-(4-(2-((l -methyl-lH-pyrazol-5- yl)amino)pyrimidin-4-yl)pyridin-2-yl)acetohydrazide (91.0 mg, 0.224 mmol) was dissolved in AcOH (2.3 mL, 0.1 M) and heated to 180 °C for 10 minutes in the microwave.
• N-(l-Methyl-lH-pyrazol-5-yl)-4-(3-((l-(trifluoromethyl)cyclopropyl)methyl)- [l,2,4]triazolo[4,3-a]pyridin-7-yl)pyrimidin-2-amine (0.0502 g, 34.2%) was made according to the procedure of Example 6, substituting 2-(l-(trifluoromethyl)cyclopropyl)acetic acid for 2-(4-(methylthio)phenyl)acetic acid.
• Step 1 2'-Hydrazinyl-N-(l-methyl-lH-pyrazol-5-yl)-[4,4'-bipyridin]-2-amine (89.7 mg, 0.319 mmol) was dissolved in DMF (1.6 mL, 0.2 M) and treated with 2-(l - ethylcyclopropyl)acetic acid (44.95 mg, 0.3507 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride (67.24 mg, 0.3507 mmol), 1-hydroxybenzotriazole (47.39 mg, 0.3507 mmol), and N,N-diisopropylethylamine (111.08 ⁇ , 0.6377 mmol). The mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated down and taken to the next step as crude.
• Step 2 2-(l-Ethylcyclopropyl)-jV-(2'-((l -methyl- lH-pyrazol-5-yl)amino)- [4,4'-bipyridin]-2-yl)acetohydrazide (124.0 mg, 0.3168 mmol) was dissolved in AcOH (1.6 mL, 0.1 M) and heated to 180 °C for 10 minutes in the microwave.
• N- ⁇ 1 -Methyl- 1 H-pyrazol-5-yl)-4-(3-((l -methylcyclopropyl)methyl)- [l,2,4]triazolo[4,3-a]pyridin-7-yl)pyrimidin-2-amine (0.0028 g, 5.25%) was made according to the procedure of Example 6, substituting 2-(l -methyl cyclopropyl)acetic acid for 2-(4- (methylthio)phenyl)acetic acid.
• Step 1 2'-Hydrazinyl-N-(l-methyl-lH-pyrazol-5-yl)-[4,4'-bipyridin]-2-amine (40 mg, 0.14 mmol), hydroxybenzotriazole (“HOBT”) (21 mg, 0.16 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg, 0.16 mmol) and 2-(2,3- difluoro-4-methoxyphenyl)acetic acid (29 mg, 0.14 mmol) were diluted with DMF (1 mL), followed by the addition of DIEA (d 0.742) (50 0.28 mmol).
• DIEA 0.742
• Step 2 2-(2,3-Difluoro-4-methoxyphenyl)-N'-(2'-((l-methyl-lH-pyrazol-5- yl)amino)-[4,4'-bipyridin]-2-yl)acetohydrazide (55 mg, 0.12 mmol) was diluted with neat glacial acetic acid (1 mL), sealed and heated to 150 °C in the microwave for 10 minutes. The reaction was allowed to cool and then concentrated.
• N-(l-Methyl-lH-pyrazol-5-yl)-4-(3-((phenylthio)methyl)-[l,2,4]triazolo[4,3- a]pyridin-7-yl)pyrimidin-2-amine (0.056 g, 74%) was made according to the procedure of Example 6, substituting 2-(phenylthio)acetic acid for 2-(4-(methylthio)phenyl)acetic acid.
• N-(l-Methyl-lH-pyrazol-5-yl)-4-(3-(2-(phenylthio)ethyl)-[l,2,4]triazolo[4,3- a]pyridin-7-yl)pyrimidin-2-amine (0.070 g, 83%) was made according to the procedure of Example 6, substituting 3-(phenylthio)propanoic acid for 2-(4-(methylthio)phenyl)acetic acid.

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