methods of synthesis and purification of heteroaryl

专利摘要:
METHODS OF HETEROARYL SYNTHESIS AND PURIFICATIONThe present invention deals with methods for the preparation of Heteroaryl compounds that have the following structure: Formula (I) or Formula (II): in which R1-R4 are as defined herein. Heteroaryl compounds are useful for the treatment or prevention of cancer, inflammatory conditions, immunological conditions, neurodegenerative diseases, diabetes, obesity, neurological disorders, age-related diseases or cardiovascular conditions.
公开号:BR112012009751A2
申请号:R112012009751-2
申请日:2010-10-22
公开日:2020-09-24
发明作者:Roy L. Harris；Jennifer Riggs；Juan Antonio GAMBOA；Marie Georges Beauchamps；Matthew Michael Kreilein；Mohit Atul Kothare；Sophie Perrin-Ninkovic；Philip Pye；William Wei-Hwa Leong；Jan Elsner；Anusuya Choudhury；John Sapienza；Graziella Shevlin；Patrick Papa；Branden Gingsee Lee；Garrick Packard；Jingjing Zhao；Anthony Patrick Jokiel；Deborah Mortensen
申请人:Signal Pharmaceuticals, Llc；
IPC主号:

专利说明:

“METHODS OF SYNTHESIS AND PURIFICATION OF HETEROARILLA”
COMPOSTS This patent application claims the benefit of provisional patent application No. US 61 / 254,917, filed on October 26, 2009 and provisional patent application No. US 61 / 328,480, filed on April 27, 2010, with the total contents of each of these are incorporated by reference in this document.
1. FIELD In this document, processes generally belonging to the field of chemical synthesis and purification and, more specifically, methods of synthesis and / or purification of certain heteroaryl compounds are provided.
2. BACKGROUND The connection between abnormal protein phosphorylation and the cause or consequence of disease has been known for more than 20 years. Accordingly, protein kinases are becoming a very important group of drug targets. See, Cohen, Nature, 1: 309 to 315 (2002).
Several protein kinase inhibitors have been used clinically to treat a wide variety of diseases, such as cancer and chronic inflammatory diseases, including diabetes and stroke. See, Cohen, Eur. JJ. Biochem., 268: 5001 to 5010 (2001).
The elucidation of the obscurity of protein kinase trajectories and the complexity of the relationship and interaction between and between the various protein kinases and kinase trajectories highlights the importance of the development of pharmaceutical agents capable of acting as modulators, regulators or inhibitors of protein kinase, which have beneficial activity in numerous kinases or numerous kinase trajectories. Accordingly, there is still a need for new kinase modulators.
The protein called mTOR (target of rapamycin in mammals), which is also called FRAP, RAFTI or RAPT1), is a 2549 amino acid Ser / Thr protein kinase, which has proved to be one of the most critical proteins in the mTOR / PI3K / Akt pathway that regulates cell growth and proliferation. Georgakis and Younes Expert Rev.
Anticancer Ther. 6 (1): 131 to 140 (2006). mTOR exists within two complexes, mTORC1i and mTORC2. mTORC1 is sensitive to rapamycin analogues (such as temsirolimus or everolimus) and mTORC2 is enormously insensitive to rapamycin. Numerous mTOR inhibitors have been or are evaluated in clinical trials for the treatment of cancer. Temsirolimus was approved for use in renal cell carcinoma in 2007 and everolimus was approved in 2009 for patients with renal cell carcinoma who progressed to vascular endothelial growth factor receptor inhibitors.
In addition, sirolimus was approved in 1999 for transplant rejection prophylaxis. The interesting but limited clinical success of these mTORC1I compounds demonstrates the usefulness of mTOR inhibitors in the treatment of cancer and transplant rejection, and the increased potential for compounds with inhibitory activity of mTORC1 and mTORC2.
The citation or identification of any reference in Section 2 of that patent application should not be interpreted as an admission that the reference is the technique prior to the present patent application.
3. SUMMARY
Methods are provided in this document for preparing compounds having the following formula (1): 2 | Rd N N. Rº
TX IS N o
H (1) and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, where R-Rº are defined herein.
In addition, methods of preparing compounds having the following formula (II) are provided in this document: Re R1 N Í o * IX
T N Ns Rº (II) and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, where R ', Rà and Rº are as defined herein.
In addition, chemical intermediates useful in the methods provided in this document are provided herein.
The compounds of formula (1) and (II), or pharmaceutically acceptable salts, tautomers and stereoisomers thereof (each being referred to herein as "Heteroaryl Compounds"), are useful for treating or preventing cancer, inflammatory conditions, conditions immunological disorders, neurodegenerative diseases, diabetes,
obesity, neurological disorders, age-related diseases and cardiovascular conditions, and conditions treatable or preventable by inhibiting a kinase pathway, for example, the mTOR / PBK / AKkt pathway.
The present modalities can be more fully understood by reference to the detailed description and examples, which are intended to exemplify non-limiting modalities.
4. DETAILED DESCRIPTION
4.1 DEFINITIONS An "alkyl" group is branched or partially saturated or saturated unsaturated straight chain hydrocarbon, which has 1 to 10 carbon atoms, typically 1 to 8 carbons or, in some embodiments, 1 to 6, 1 to 4, or 2 to 6 carbon atoms. Representative alkyl groups include -methyl, ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2.3 = dimethylbutyl and the like. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH = CH (CH; 3), —-CH = C (CH3) 2, -C (CH3) = CH ;, - C (CH3) = CH (CH; 3), —-C (CHXCH3) = CH ;, -C = CH, -C = C (CH3), - C = C (CHCH;), -CHC = CH, -CHC = C (CH;) and -CHC = C (CH; CH;), among others. When the alkyl groups described in this document are said to be "substituted," they can be replaced by any substituent or substituents such as those found in the exemplifying compounds and modalities disclosed in this document, as well as halogen (chlorine, iodine, bromine or fluorine) ; alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyan; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; Phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxiamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (= O0); B (OH), or O (alkyl) aminocarbonyl.
An alkyl group can be substituted or unsubstituted.
A "cycloalkyl" group is a saturated, partially saturated, or unsaturated cyclic alkyl group of 3 to 10 carbon atoms that has a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted by 1 to 3 groups alkyl.
In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments the number of ring carbon atoms is in the range of 3 to 5, 3a6, ou3a7 ”7. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, l1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcycloctyl, and the like, or bridge-linked ring structures or multiple such as adamantil and the like.
Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others.
A cycloalkyl group can be substituted or unsubstituted.
Such substituted cycloalkyl groups include, by way of example, cyclohexanone and the like. An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms that have a single ring (for example, phenyl) or multiple condensed rings (for example, naphthyl or anthryl). In some embodiments, aryl groups contain 6 to 14 carbons, and in others 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups. Particular aryls include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted. The phrase "aryl groups" also includes groups that contain fused rings, such as fused aromatic-aliphatic ring systems (for example, indanyl, tetrahydronaphthyl, and the like).
A "heteroaryl" group is an aryl ring system that has one to four heteroatoms as ring atoms in a heteroaromatic ring system, where the rest of the atoms are carbon atoms. In some embodiments, heteroaryl groups contain 5 to 6 ring atoms, and in others 6 to 59 or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiofenil, benzothiophyl, isobenzofuran-1,3-diimine), indolyl, azaindolyl (for example, pyrrolopyridyl or lH-pyrrole (2,3-
blpiridyl), indazolyl, benzimidazolyl (for example, 1H-benzo [d] imidazolyl), imidazopyridyl (for example, azabenzimidazolyl, 3H-imidazo [4,5-b] pyridyl or 1H-imidazo ([4,5-b] pyridyl ), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, tianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinoline, quinoline, tetrahydroquinoline
A "heterocyclyl" is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl in which one or four of the ring carbon atoms are independently replaced with a hetero atom of the group consisting of O, S and N. In some embodiments , heterocyclyl groups include 3 to 10 ring members, while other groups have 3 to 5, 3 to 6, or 3 to 8 ring members Heterocyclyl can also be linked to other groups on any ring atom (ie, in any carbon atom or heterocyclic ring heteroatom) A heterocycloalkyl group can be substituted or unsubstituted Heterocyclyl groups include saturated, partially saturated and unsaturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. includes fused ring species, which includes those comprising non-aromatic and fused aromatic groups, such as, for example, benzotriazolyl, 273 dihydrobenzo [1,4] dioxinyl, and benzo [1,3] dioxolyl. The phrase also includes bridged polycyclic ring systems that contain a hetero atom such as, but not limited to,
quinuclidyl.
Representative examples of a heterocyclyl group include, but are not limited to, aziridinila, azetidinyl, pirrolidila, imidazolidinila, pirazolidinila, tiazolidinila, tetraidrotiofenila, tetraidrofuranila, dioxolila, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinila, pirazolila, pirazolinila, triazolila, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, eg, tetrahydro-pyranyl, pyridyl, pyramidyl, pyridyl, pyridyl, pyridyl, pyridine, tetrahydro, pyro pyridazinyl, pyrazinyl, triazinila, diidropiridila, diidroditiinila, diidroditionila, homopiperazinila, quinuclidila, indolyl, indolinyl, isoindolila, azaindolila (pirrolopiridila) indazolila, indolizinila, benzotriazolila, benzimidazolila, benzofuranyl, benzotiofenila, benztiazolila, benzoxadiazolila, benzoxazinila, benzoditinila, benzoxatinila, benzotiazini la, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [1,3] dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl; for example, lH-imidazo [4,5-b] pyridyl, or lH-imidazole (4,5-blpiridin-2 (3H) -onyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl,
tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Substituted heterocycline groups can be substituted once or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are substituted 2, 3, 4, 5, or 6 times, or disubstituted with several substituents such as those listed below.
A "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups can be substituted on alkyl, cycloalkyl, or on both the alkyl and cycloalkyl moieties of the group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and cyclohexylpropyl. Representative substituted cycloalkylalkyl groups can be monosubstituted or substituted more than once.
An "aralkyl" group is a radical of the formula: - alkyl-aryl, where alkyl and aryl are defined above. Substituted aralkyl groups can be substituted on the alkyl, on the aryl, or on both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups and fused (cycloalkylaryl) alkyl groups such as 4-ethyl-indanyl.
A "heterocyclylalkyl" group is a radical of the formula: -alkylheterocyclyl, where alkyl and heterocyclyl are defined above. Substituted heterocyclyl groups can be substituted on alkyl, heterocyclyl, or on both the alkyl and heterocyclyl portions of the group. Representative heterocyclyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, (tetrahydro-2H-pyran-4 - yl) methyl, (tetrahydro-2H-pyran-4-yl) ethyl, tetrahydrofuran-2-yl methyl, tetrahydrofuran-2-yl ethyl and indol-2-yl propyl.
A "halogen" is fluorine, chlorine, bromine or iodine.
A "hydroxyalkyl" group is an alkyl group as described above substituted with one or more hydroxyl groups.
An "alkoxy" group is -O- (alkyl), where alkyl is defined above.
An "alkoxyalkyl" group is - (alkyl) -O- (alkyl), where alkyl is defined above.
An "amino" group is a radical of the formula: -NH>.
An "alkylamino" group is a radical of the formula: - NH-alkyl or -N (alkyl), where each alkyl is independently as defined above.
A "carboxy" group is a radical of the formula: - C (0) OH.
An "aminocarbonyl” group r is a radical of the formula: -C (O) N (IRÍ)., -C (O) NHIRI) or -C (O) NH, where each R * is independently an alkyl, cycloalkyl, aryl, aralkyl, substituted or unsubstituted heterocyclyl, or a heterocyclyl group as defined herein.
An "acylamino" group is a radical of the formula: - NHC (O) (Rº) or -N (alkyl) C (O) (R), where each alkyl and Rº are independently as defined above.
An "alkylsulfonylamino" group is a radical of the formula: -NHSOX (R ') or -N (alkyl) SO. (R), where each alkyl and Rº are defined above.
A "urea" group is a radical of the formula: - N (alkyl) C (O) N (R ")>, -N (alkyl) C (O) NH (R '), - Nickel) C (O) NH , —-NHC (O) N (R)., - -NHC (O) NH (R), or - NH (CO) NHR ', where each alkyl and R are independently as defined above.
When the groups described in this document, with the exception of the alkyl group, are considered "substituted," they can be substituted with any suitable substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and modalities disclosed in this document, as well as halogen (chlorine, iodine, bromine, or fluorine); alkyl; hydroxy; alkoxy; alkoxyalkyl; the mine; alkylamine; carboxyl; nitro; cyan; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminacarbonyl; acylamine; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxiamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (= 0); B (OH) ', O (alkyl) aminocarbonyl; cycloalkyl, which may be monocyclic or fused, or unfused polycyclic (eg, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclic or fused or polycyclic, unfused (eg, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); unfused monocyclic or fused or polycyclic aryl or heteroalyl (eg S, phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl , pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy;
heterocyclyloxy; and heterocyclyl alkoxy.
As used herein, the term "pharmaceutically acceptable salt (salts)" refers to a salt prepared from a non-toxic pharmaceutically acceptable base or acid, including an organic acid and base and an organic acid and base.
Suitable pharmaceutically acceptable base addition salts of the Heteroaryl Compounds include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
Suitable non-toxic acids include, but are not limited to, organic and inorganic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethylene sulfonic, formic, fumaric, furonic, galacturonic, gluconic, glucuronic, glutamic, glycolic , hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, music, nitric,
pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts therefore include hydrochloride and mesylate salts. Others are well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18th editions, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th editions, Mack Publishing, Easton PA (1995).
As used herein and unless otherwise specified, the term "stereoisomer" or "stereomerically pure" means a stereoisomer of a Heteroaryl Compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound that has a chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound that has two chiral centers will be substantially free of other diastereoisomers in the compound. A typical stereomerically pure compound comprises more than about 80% by weight of a stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of a stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, more than about 95% by weight of a stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound , or more than about 97% by weight of a stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. Heteroaryl Compounds can have chiral centers and can occur as racemic mixtures, enantiomers or individual diastereoisomers, and the mixture thereof. All such isomeric forms are included in the modalities disclosed in this document, including mixtures thereof. The modalities disclosed in this document include the use of stereomerically pure forms of such Heteroaryl Compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular Heteroaryl Compound can be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or redissolved using standard techniques such as chiral columns or chiral redissolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, Nova Torque, 1981); Wilen, S. H., et al, Tetrahedron 33: 2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Edition, Univ. Of Notre Dame Press, Notre Dame, IN, 1972).
It should also be noted that the Heteroaryl Compounds can include E and Z isomers, or a mixture of them, and cis and trans isomers or a mixture of them. In certain embodiments, the Heteroaryl Compounds are isolated as the cis or O trans isomer. In other embodiments, Heteroaryl Compounds are a mixture of cis and trans isomers.
"Tautomers" refer to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is found and may be different depending, for example, on whether the compound is a solid or whether it is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles can exhibit the following isomeric forms, which are designated as tautomers of each: SN.
As readily understood by a person skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism and all tautomers of compounds of formula (1) and formula (II) are within the scope of the present invention.
It should also be noted that Heteroaryl Compounds may contain unnatural proportions of atomic isotopes in one or more of the atoms. For example, compounds can be radiolabeled with radioactive isotopes, such as tritium (* H), iodine-125 (** 1), sulfur-35 (* S), or carbon-14 (* C), or they can be isotopically enriched, such as with deuterium (* H), carbon-13 (* C), or nitrogen-15 (* N). As used in this document, an "isotopologist" is an isotopically enriched compound. the term "isotopically enriched" refers to an atom that has an isotopic composition different from a natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound that contains at least one atom that has an isotopic composition different from a natural isotopic composition of that atom.
The term "isotopic composition" refers to the amount of each isotope present for a given atom.
Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, for example, therapeutic agents for cancer and inflammation, research reagents, for example, binding analysis reagents, and diagnostic agents, for example, in vivo imaging agents.
All isotopic variations of the Heteroaryl Compounds as described in this document, whether radioactive or not, must be included within the scope of the modalities presented herein.
In some modalities, isotopologists of Heteroaryl Compounds are presented, for example, isotopologists are Heteroaryl Compounds enriched with deuterium, carbon 13 or nitrogen 15. The term "treatment", as used in this document, means a relief, total or partial, of the disease Or disorder, or of the symptoms associated with the disease or disorder, or slowing down, or interrupting the further progression or worsening of the disease or disorder, or of the symptoms associated with the disease and disorder.
The term "prevention", as used herein, means preventing the onset, recurrence, or proliferation of the disease or disorder, or the symptoms associated with the disorder or disease, in a patient at risk of developing the disease and disorder.
The term "effective amount" in connection with a Heteroaryl Compound means, in one embodiment, an amount capable of alleviating, in whole or in part, symptoms associated with the disorder or disease, or slowing or stopping the further progression or worsening of those symptoms, or in another embodiment, an amount capable of preventing or providing prophylaxis for the disease and disorder in an individual at risk of developing the disease and disorder as disclosed in this document, such as cancer, inflammatory conditions, immune conditions, neurodegenerative diseases, diabetes, obesity , neurological disorders, age-related diseases, or cardiovascular conditions, and conditions treatable or preventable by inhibiting a kinase pathway, for example, the mTOR / PI3K / Akt pathway.
In one embodiment an effective amount of a Heteroaryl Compound is an amount that inhibits a kinase in a cell, such as, for example, in vitro or in vivo.
In one embodiment the kinase is mTOR, DNA-PK, PI3K or a combination thereof.
In some embodiments, the effective amount of the Heteroaryl Compound inhibits kinase in a cell by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%, in comparison with kinase activity in an untreated cell.
The effective amount of the Heteroaryl Compound, for example, in a pharmaceutical composition, can be at a level that will exercise the desired effect; for example, about 0.005 mg / kg of an individual's body weight to about 100 mg / kg of a patient's body weight in dosage unit for both oral and parenteral administration.
As will be evident to those skilled in the art, it is expected that the effective amount of a Heteroaryl Compound now disclosed may vary depending on the indication to be treated, for example, the effective amount of a Heteroaryl Compound would probably be different for the treatment of patients who suffer from, or are at risk for, an inflammatory condition, in relation to the effective amount of the Compound for the treatment of patients who suffer from, or are at risk for, a different disorder, for example, cancer or a metabolic disorder.
The term "patient" includes an animal, including, but not limited to, an animal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or piglet. of India, in one modality a mammal, in another modality a human.
The term "cancer" refers to any of several malignant neoplasms characterized by the proliferation of cells that can invade adjacent tissue and metastasize to new parts of the body.
Both benign and malignant tumors are classified according to the type of tissue in which they are found.
For example, fibroids “are neoplasms of fibrous connective tissues, and melanomas are abnormal proliferations of pigment cells (melanin). Malignant tumors that originate from epithelial tissue, for example, in the skin, bronchi, and stomach, are called carcinomas.
Malignancies of epithelial glandular tissue as found in the sinus, prostate, and colon are known as adenocarcinomas.
Malignant proliferations of connective tissue, for example, muscle, cartilage, lymphatic tissue, and bone, are called sarcomas.
Lymphomas and leukemias are malignancies that arise between white blood cells.
Through the process of metastasis, the migration of tumor cells to other areas of the body establishes neoplasms in areas distant from the site of initial appearance. Bone tissues are one of the most favored sites of metastasis of malignant tumors, occurring in about 30% of all cancer cases. Among malignant tumors, cancers of the lung, breast, prostate or the like are particularly known to be likely to metastasize to the BONE. In the context of neoplasm, cancer, tumor proliferation or tumor cell proliferation, inhibition can be assessed by the delayed appearance of primary or secondary tumors, delayed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, delayed severity or decreased side effects of disease, interrupted tumor proliferation and tumor regression, among others. In an extreme way, complete inhibition is called prevention or chemoprevention. In this context, the term "prevention" includes either preventing the onset of a clinically evident neoplasm in general or preventing the onset of a pre-clinically evident stage of neoplasia in individuals at risk. This definition is also intended to prevent the transformation into malignant cells or to stop or reverse the progression from pre-malignant cells to malignant cells. This includes the prophylactic treatment of those who are at risk of developing the neoplasm.
4.2 SUMMARY OF HETEROARYL COMPOUNDS Methods are provided in this document to prepare compounds that have the following formula (1):
ne [LF RÃ N. N Rº
TX Õ NO
H (1) and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, wherein: R 'is substituted or unsubstituted C1 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or heterocyclylalkyl substituted or unsubstituted; Rº is H, substituted or unsubstituted C1is alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; Rº and Rº each is independently H, C 1-3 alkyl; substituted or unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkylalkyl, or Re Rº, together with the atoms to which they are attached to, form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;
or Rº and one of Rº and Ri, together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclyl; the compound is provided other than the compounds described below, that is: Po NQON. THE, NINTH
H 6- (4-hydroxyphenyl) -4- (3-methoxybenzyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; CX
H “Ox 4 DARI) Node NO SO
H 6- (4- (1H-1,2,4-triazol-5-yl) phenyl) -3- (cyclohexylmethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - one ; or, ex Ne HA “O. ALL Node NO To
R (R) -6- (4- (1H-1,2,4-triazol-5-yl) phenyl) -3- (cyclohexylmethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 ( 1H) - ona. Methods are provided in this document to prepare a compound of the formula (1), 1 a: “es nER O: 2 CNOCO No." (1)
the method comprises contacting a compound of the formula (III)
RR X. AN. ER Tl NN o (III) with R | -Y in a solvent, in the presence of a palladium catalyst, in which said contact occurs under suitable conditions to provide a compound of formula (1), in which RI, Rà, Rº and Rº are as defined in this, ex is halogen, B (OR '), or Sn (R **); 3; Y is halogen, triflate, B (OR '); or Sn (R '*) ;; where a) when X is halogen (for example, Br, cl, or 1), then Y is B (OR '), or SN (R *) 3; or b) when Y is halogen (for example, Br, Cl, or 1) or triflate, then X is B (OR), or Sn (R *) 3; where each R is independently hydrogen or C13 alkyl; substituted or unsubstituted, or each R ', together with the boron atom and the atoms to which they are attached, form a cyclic boronate; and R * is Cia alkyl.
Typically the solvent is dimethylformamide, isopropanol, dioxane, toluene, dimethylacetamide, tetrahydrofuran, acetonitrile, isopropyl acetate, dimethyl sulfoxide, acetone, methanol, t-butyl methyl ether or a combination thereof, with or without the presence of water, and the catalyst palladium is dichloro [1,1'-bis (diphenylphosphino) -ferrocene] palladium (II) dichloromethane), palladium (dba), / tri-o-tolylphosphine, dichloro [1,1'-bis (ditherc-
butylphosphino) ferrocenolpaladium, dichlorobis (p-dimethylamino phenylditbutylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), or palladium (11) acetate / 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene.
In some embodiments when X or Y is a halogen, the halogen is Br.
In some embodiments when X or Y is B (OR), ', contact occurs in the presence of a base such as sodium carbonate, triethylamine, diisopropylethylamine, piperidine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate, or sodium hydroxide.
In some of these modalities, B (OR '); is B (OH), or B (-OC (CH3) 2C (CH3) 20-). In other embodiments, when X or Y is Sn (R *) 3 the contact optionally occurs in the presence of a base such as triethylamine, sodium carbonate, diisopropylethylamine, piperidine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate, or sodium hydroxide.
In some of these modalities, R ** is methyl or n-butyl.
Methods are also provided to prepare a compound of the formula (III), Re o vs Fi (III) the method comprises contacting a compound of the formula (IV) "ALA, 2 Hal (IV)
with Rº-NH, in a solvent, such as acetonitrile or tetrahydrofuran, in the presence of a base, such as triethylamine or diisopropylethylamine, in which said contact occurs under conditions suitable to provide a compound of formula (III), in which Rº is as defined in this, Rº and Rº are H, X is a halogen like Br, Hal is a halogen like Br, and Hal is Br or T. Methods are also provided to prepare a compound of formula (III), RR
Ç E Ps o
H (III) the method comprises cyclizing a compound of the formula (V) Hal AN 2 Hal CALA om DER
VW in a solvent, such as acetonitrile, in the presence "of a palladium catalyst, such as palladium (II) acetate, a binder, such as 4,5-bis- (diphenylphosphine) -9,9-dimethylxanthene, and a base , such as sodium bicarbonate, in which said cyclization occurs under suitable conditions to provide a compound of the formula (III), in which R is as defined herein, Rº and Rº are as described herein, X is a halogen such as Br, and Hal is a halogen such as Br. In certain embodiments, solvates and hydrates of compounds of formula (III), formula (IV) and formula (V) are provided in this salt (which includes pharmaceutically acceptable salts). of compounds of formula (1), Rº is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
In one embodiment, Rº is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, lH-pyrrolo [2,3-blpiridyl, l1H-imidazo [4,5-b] pyridyl, lH-imidazo [4,5- blpiridin- 2 (3H) -onyl, 3H-imidazo [4,5-b] pyridyl, or pyrazolyl, each is optionally substituted.
In some embodiments, R 'is phenyl substituted with one or more substituents selected independently from the group consisting of substituted or unsubstituted C1-1 alkyl (eg, methyl), substituted or unsubstituted heterocyclyl (eg, substituted or triazolyl) unsubstituted or pyrazolyl), halogen (eg, fluorine), aminocarbonyl, cyan, hydroxyalkyl (eg, hydroxypropyl), and hydroxy.
In other embodiments, R 'is substituted pyridyl with one or more substituents selected independently from the group consisting of substituted or unsubstituted C1-alkyl, substituted or unsubstituted heterocyclyl (for example, substituted or unsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl, -OR, and - NR ", where each R is independently H, or a substituted or unsubstituted C17-« alkyl.
In still other embodiments, R is 1H-pyrrolo [2,3-b] lpyridyl or benzimidazolyl, each optionally substituted with one or more substituents selected independently from the group consisting of substituted or unsubstituted C1s alkyl, and -NR , where each R is independently H, or a Ciasubstituted or unsubstituted alkyl. In some modalities of compounds of formula (1), Rº is (CEreraor Bá Sa TIreraor so À <o Rar Da ER nN o RN et dan NA 1 m and NO A Ra Á mM o ns TO & NA WS Fr. CFR. RE rs RO AR a no THE NR
And 5. where R is at each occurrence independently H, or a substituted or unsubstituted C 1 alkyl (e.g., methyl); R 'is in each occurrence independently a C1- alkyl, substituted or unsubstituted, halogen (for example, fluorine), cyano, -OR, or -NRº; m is 0-3; and n is 0-
3. It will be understood by those skilled in the art that any of the substituents R 'can be attached to any suitable atom of any of the rings in the fused ring systems. It will also be understood by those skilled in the art that the R * connector (designated by the bisecting wavy line) can be attached to any of the atoms in any of the rings in the fused ring systems. In some modalities of the compounds of formula (1), RÁ
205 ele IS "2N HACRZ) OR LO" 2 R R R Er, Rr, À O, .or SME where R is in each occurrence independently H, or a substituted or unsubstituted C1 alkyl; R 'is in each occurrence independently a substituted or unsubstituted C7 alkyl, halogen, cyano, -OR, or - NR; right 0a3; enéõdai.
In some modalities of compounds of the formula (1), R is H, substituted or unsubstituted Cis alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl heterocyclyl, substituted or unsubstituted Cia alkyl aryl substituted, or substituted or unsubstituted alkyl cycloalkyl Cia.
For example, Rº is EH, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, (C1 alkyl), -phenyl, (Cia alkyl) - cyclopropyl, (Cia alkyl) -cyclobutyl, (Cira alkyl) - cyclopentyl, (C4 alkyl) -cyclohexyl, (C14 alkyl) - pyrrolidyl, (C14 alkyl) -piperidyl, (Cra alkyl) - piperazinyl, (C14a alkyl) -morpholinyl, (C14 alkyl) - tetrahydrofuranoyl, or (C1- alkyl) -tetrahydropyranyl, each is optionally substituted.
In other modalities, Rº is H, Cia alkyl, (alkyl 1-4) (OR),
R R AR EO ta 2 R R R
A O Xi HEX o to x
FAAO JL If HOR where R is in each occurrence independently H, or a substituted or unsubstituted Cia alkyl (for example, methyl); R 'is at each occurrence independently H, -OR, cyano, or a substituted or unsubstituted C 1 alkyl (for example, methyl); and p is 0 to 3. In some of these modalities, Rº is H, Co. 4 alkyl, (1-4 alkyl) (OR),
R R R q oo xt METRO EC No.
AAAÇTE À or LOVE; where R is at each occurrence independently H, or a substituted or unsubstituted C 1 alkyl; R 'is in each occurrence independently H, -OR, cyano, or a substituted or unsubstituted C1.> Alkyl; and p is 0 to 1.
In some other modalities of compounds of formula (1), R and one of Rº and Rº together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl. For example, in some embodiments, the compound of formula (1) is
Rº o “es SA As &“ E Ah. IL. "Axo
R OR Pro R1 if and EE VV, o a A o where R is in each occurrence independently H, or a substituted or unsubstituted C 1 alkyl; R "is H, OR, or a substituted or unsubstituted C1.4 alkyl; and R is as defined herein. In some embodiments of compounds of formula (1), Rº and Rº are both H. In others, one of R and D H and the other one is H. In still others, one of Rº and Rº is Ci alkyl, (for example, methyl) and the other is H. In still others, both Rº and Rº are Ci alkyl, (for example, In some of the modalities described above, Rº is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. For example, R 'is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, lH-pyrrole [2,3 -b] pyridyl, l1H-imidazo [4,5-blpyridyl, lH-imidazo [4,5-b] pyridin-2 (3H) -onyl, 3H- imidazo [4,5-b] lpyridyl, or pyrazolyl, each one is optionally substituted In some embodiments, RU is phenyl substituted with one or more substituents selected - “independently from the group consisting of C1- alkyl; substituted or unsubstituted, substituted or unsubstituted heterocyclyl a, halogen, aminocarbonyl, cyano, hydroxyalkyl and hydroxy. In others, R 'is pyridyl substituted with one or more selected substituents - “independently from the group consisting of cyano, substituted or unsubstituted Cris alkyl, substituted or unsubstituted heterocyclyl, hydroxyalkyl, halogen, aminocarbonyl, -OR, e- NR, where each R is independently H, or a substituted or unsubstituted C1 alkyl.
In others, R 'is 1H-pyrrolo [2,3-b] pyridyl or benzimidazolyl, optionally substituted with one or more substituents selected independently from the group consisting of substituted or unsubstituted Cris alkyl, and -NR', where R is independently H, or substituted or unsubstituted C 1a alkyl.
In certain embodiments, the compounds of formula (1) have an R 'group established in this and a Rº group established in this.
In some embodiments of compounds of formula (1), the compound at a concentration of 10 pM inhibits mTOR, DNA-PK, or PI3K or a combination thereof, by at least about 50%. The compounds of formula (1) can be shown to be inhibitors of the above kinases in any suitable test system, such as those described in the Examples herein.
In some embodiments of compounds of formula (1), the compound is 6- (1H-pyrrolo [2,3-b] pyridin-3-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [| 2,3-b] pyrazin-2 (1H) -one; 6- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- (((tetrahydro-2H-pyran-4-yl) methyl) -3, 4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -4- ((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [ 2,3-b] pyrazin-2 (1H) -one;
6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
il) phenyl) -4 - ((cis-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl1) -4- ((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one;
6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
il) phenyl) -4 - ((trans-4-hydroxycyclohexyl) methyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- ((cis-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine | 2,3-
blpirazin-2 (1H) -one;
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-1i1) -4- ((trans-4-hydroxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one;
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- (cis-
4-hydroxycyclohexyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- ((cis-4-hydroxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one;
6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) -4-trans-methoxycyclohexyl) -3, -4-dihydropyrazine [2,3-b] pyrazin - 2 (1H) -one;
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-11) -4-
(trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-
blpirazin-2 (1H) -one;
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- (trans-4-hydroxycyclohexyl) -3,4-dihydropyrazine [2,3-blpirazin-2 (1H) -one; 6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -4 - ((cis-4-hydroxycyclohexyl) methyl) 3,4-dihydropyrazine [2 , 3-b] pyrazin-2 (1H) -one; 6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- (cis-4-methoxycyclohexyl) -3,4-dihydropyrazine [(2,3-b] pyrazin-2 (1H) - one; 6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- (2-methoxyethyl) -3,4-dihydropyrazine [ 2,3-b] pyrazin-2 (1H) -one; 6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-i11) -4-isopropyl-3,4- dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -4- (cis-4-hydroxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (5-fluoro-2-methyl-4- (1H-1,2,4 -triazole-3- 11) phenyl1) -4- (cis-4-methoxycyclohexyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 6- (5-fluoro-2- methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -4- (2-methoxyethyl) -3,4-dihydropyrazine (| 2,3-blpyrazin-2 (1H) -one; 6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-11) -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrazine [2,3 - blpirazin-2 (1H) -one; 6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl1) -4-ethyl-3,4-dihydropyrazine [2,3 -b] pyrazin-2 (1H) -one; 6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3- 11) pheni1) -4- (trans-4- hydroxycyclohexyl) - 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -4- (tetrahydro-2H-pyran-4-11) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -4-isopropyl-3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 4-ethyl-6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -3,4-dihydropyrazine [2 blpirazin-2 (1H) -one ;
6- (3-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
il) phenyl) -4- (tetrahydro-2H-pyran-4-11) -3,4-dihydropyrazino [2,3-bl] pyrazin-2 (1H) -one;
6- (3-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
il) phenyl) -4- (cis-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (3-fluoro-2-methyl-4- (1H-1,2,4-triazol-3- i1) phenyl) -4- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3 -b] pyrazin-2 (1H) -one;
4- (2-methoxyethyl) -6- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b ] pyrazin-2 (1H) -
ona;
6- (3- (1H-1,2,4-triazol-5-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [| 2 , 3-blpirazin-2 (1H) -one;
5- (8- (2-methoxyethyl) -6-0x0-5,6,7,8-
tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-methylpicolinamide; 3- (6-0x0-8- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) benzamide; 3- (6-0x0-8- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -
5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) benzonitrile;
5- (8- (trans-4-methoxycyclohexyl) -6-0x0-5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-methylpicolinamide; 6- (1H-imidazo [4,5-b] pyridin-6-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-
blpirazin-2 (1H) -one;
6- (1H-indazol-6-yl) -4- (2- (tetrahydro-2H-pyran-4-yl1) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
4 - ((1R, 3S) -3-methoxycyclopentyl) -6- (2-methyl-6- (4H, 2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2 , 3-
Dblpirazin-2 (1H) -one;
4 - ((18,3R) -3-methoxycyclopentyl) -6- (2-methyl-6- (4H, 2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine (| 2,3-blpirazin-2 (1H) -one;
4 - ((1R, 3R) -3-methoxycyclopentyl) -6- (2-methyl-6- (4H
, 2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine (| 2,3-
blpirazin-2 (1H) -one;
4 - ((18,3S) -3-methoxycyclopentyl) -6- (2-methyl-6- (4H, 2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2 , 3-bl] pyrazin-2 (1H) -one;
4-ethyl-6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine ([2,3-blpirazin-2 ( 1H) - one;
6- (1H-pyrrolo [2,3-b] pyridin-5-i1) -4- (2 (tetrahydro-2H-pyran-4-yl) ethyl) —3,4-dihydropyrazine [2,3-
blpirazin-2 (1H) -one;
6- (1H-indol-6-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
6- (1H-indole-5-1i1) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
4 - ((((1R, 3S) -3-methoxycyclopentyl) methyl) -6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3, 4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
4 - ((((18,3R) -3-methoxycyclopentyl) methyl) -6- (2-
methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-
dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (3-fluoro-2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (3-fluoro-2-methyl-4- (4H-1,2,4-triazol-3- 11) phenyl) -4- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-bl ] lpirazin-2 (1H) -one;
3,3-dimethyl-6- (4-methyl-6- (4H-1,2,4-triazol-3 Si) pyridin-s-yl) -4- ((tetrahydro-2H-pyran-4-yl ) methyl) -3,4-
dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- ((1R, 38S) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H ) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-
((18,3R) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3-
bl] lpirazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) 4 ((((18,38) -3-methoxycyclopentyl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin- 2 (1H) -one;
6-6 (2-hydroxypropan-2-yl) pyridin-3-yl) -4- ((((IR, 3R) -3-methoxycyclopentyl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin- 2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- ((18,38S) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H ) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- ((1R, 3R) -3-methoxycyclopentyl) -3,4-dihydropyrazine [| 2,3-blpirazin-2 ( 1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-
((((1R, 3S) -3-methoxycyclopentyl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-1i1) -4- ((((18,3R) -3-methoxycyclopentyl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (3-fluoro-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2-methoxyethyl) -3,4-dihydropyrazino [2,3-bl] pyrazin-2 (1H) -one;
6- (3-fluoro-4 4H-1,2,4-triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [ 2,3-b] pyrazin-2 (1H) -one;
7 '- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -1'- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-spiro [ cyclopentane-1,2'-pyrazine [2,3-b] pyrazin] -3 '(4'H) -one;
7 '- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -1'- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-spiro [ cyclobutane-
1,2'-pyrazine [2,3-blpyrazin]) - 3 '(4'H) -one;
4- (cyclopropylmethyl) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
7T '- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -1'H-
spiro [cyclopentane-1,2'-pyrazine ([2,3-b] pyrazin]) - 3 '(4'H) - one;
7 '- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -H-spiro [cyclobutane-1,2'-pyrazine [2,3-blpyrazin] -3' (4'H) - one;
. 37 7 '- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -H-spiro [cyclopropane-1l, 2'-pyrazine [2,3-b] pyrazin] ) -3 '(4'H) - one;
(R) -6- (4- (4H-1,2,4-triazol-3-yl) phenyl) -4-
((tetrahydrofuran-2-yl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
(8) -6- (4- (4H-1,2,4-triazol-3-yl) phenyl) -4- ((tetrahydrofuran-2-yl) methyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one;
6- (1H-indazol-5-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
4- (6-0x0-8- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) benzamide;
4- (2-methoxyethyl) -3,3-dimethyl-6- (2-methyl-4-
(4H, 2,4-triazol-3-yl) phenyl) -3,4-dihydropyrazine (| 2,3-blpyrazin-2 (1H) -one; 4-ethyl-3,3-dimethyl-6- (2 -methyl-4- (4H-1,2,4 triazol-3-yl) phenyl) -3,4-dihydropyrazine [2,3-b] lpyrazin-2 (1H) -one; 6- (2-methyl- 4- (4H-1,2,4-triazol-3-yl) phenyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 3,3-dimethyl-6- ( 2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -4 - ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one; (R) -6- (6- (1-hydroxyethyl) pyridin-3-11) -4- (2- (tetrahydro-2H-pyran-4-yl ) ethyl) -3,4-dihydropyrazine ([2,3- Ê blpirazin-2 (1H) -one; 3,3-dimethyl-6- (2-methyl-4- (4H-1,2,4-triazole -3- 11) phenyl) -4- ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) -4-methylpyridin-3-yl) - 4- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 ( 1H) -one;
6- (6- (2-hydroxypropan-2-yl) -4-methylpyridin-3-yl) -
4 - ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3-
b] pyrazin-2 (1H) -one;
3,3-dimethyl-6- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H ) -one;
3,3-dimethyl-6- (2-methyl-6- (4H-1,2,4-triazole-3-
il) pyridin-3-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) -2-methylpyridin-3-yl) - 4- ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine (2,3 - blpirazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) -2-methylpyridin-3-yl) - 4- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-blpirazin-2 (1H) -one;
(S) -6- (6- (1I-hydroxyethyl) pyridin-3-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3- Dblpirazin-2 (1H) -one; 3,3-dimethyl-6- (2-methyl-4- (4H-1,2,4-triazol-3-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H ) -one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,3-dimethyl-4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-
dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (4- (2-hydroxypropan-2-yl) phenyl) -4- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
6- (4- (2-hydroxypropan-2-yl) phenyl) -4 - ((trans-41-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one ;
4- (cis-4-methoxycyclohexyl) -6- (2-methyl-6- (4H-
1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
4- (trans-4-methoxycyclohexyl) -6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-1yl) -3,4-dihydropyrazine [2,3 - blpirazin-2 (1H) -one;
6- (4- (2-hydroxypropan-2-yl) phenyl) -4 - ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 ( 1H) -one;
4- (2-methoxyethyl) -6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b ] pyrazin-2 (1H) -
ona;
9- (6- (4H-1,2,4-triazol-3-yl) -3-pyridyl) -6, 11,4a- trihydromorpholine [4,3-el] pyrazine [| 2,3-b] pyrazin -5S-one;
6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-
yl) -4- ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
5- (8- (cis-4-methoxycyclohexyl) -6-0x0-5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) -6-methylpicolinonitrile;
6- (6- (4H, 1,2,4-triazol-3-yl) pyridin-3-yl) -4 2
(tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
9- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) -3- (2-methoxyacetyl) -6,11,4a-trihydropiperazino [1,2-e] pyrazine (| 2,3-blpirazin-5-one;
9- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) -6,11,4a-trihydropiperazine [1,2-elpyrazino [2,3-b] pyrazin-5- ona; 9- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) -3- (2-methoxyethyl) -6,11,4a-trihydropiperazino [1,2-e] lpyrazino [ 2,3-blpirazin-5-one; 4- (cyclopentylmethyl) -6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one; 9- (6- (4H-1,2,4-triazol-3-yl) -2-methyl-3-pyridyl) -
10. 6.1 1,4a-trihydromorpholine [4,3-elpyrazino [2,3-b] pyrazin-5-one; 4- (trans-4-hydroxycyclohexyl) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one; 4- (cis-4-hydroxycyclohexyl) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (((tetrahydrofuran-3-yl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 ( 1H) -one; 4- (cyclopentylmethyl) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-neopentyl-3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-isobutyl-3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 3-methyl-6- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-i1) -4- (piperidin-4-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-11) -4- (2- s (tetrahydro-2H-pyran-3-yl) ethyl) -3,4-dihydropyrazine [2,3 - blpirazin-2 (1H) -one; 8- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) (3aS, 2R) -2-methoxy-5, 10,3a-trihydropyrazine [| 2,3-blpyrrolidine [ 1,2-elpirazin-4-one; 8- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) (2R, 3aR) -2-methoxy-5, 10,3a-trihydropyrazine [2,3-blpyrrolidine [1 , 2-el] pyrazin-4-one; 8- (4- (4H-1,2,4-triazol-3-11) -2-methylphenyl) (2S, 3aR) -2-methoxy-5,10,3a-trihydropyrazine [2,3-blpyrrolidine [1 , 2-elpirazin-4d-one; 8— (4 (4H-1,2,4A — triazgol-3S-yl) -2-methylphenyl) (28.3aS) -2-methoxy-5,10,3a-trihydropyrazine [| 2,3-bl] pyrrolidine [1,2-e] pyrazin-4-one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (3-methoxypropyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; (S) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- ((tetrahydrofuran-2-yl) methyl) -3,4-dihydropyrazine (| 2,3-blpirazin -2 (1H) -one; (R) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- ((tetrahydrofuran-2-yl) methyl) -3,4- dihydropyrazine [2,3-blpyrazin-2 (1H) -one; 6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3- 11) -4- (2 - (tetrahydro-2H-pyran-4-11) ethyl-3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
9- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) -3-methyl-6,11,4a-trihydropiperazine [1,2-e] pyrazine [2,3- blpirazin-5-one; 9- (4- (4H-1,2,4-triazol-3-yl) phenyl) -6,11,4a- trihydromorpholine [4,3-e] pyrazine [2,3-b] pyrazin-5-one ; 9- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) -6, 11,4a-trihydropiperidine [1,2-e] pyrazine [2,3-b] pyrazin- 5-one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-
(trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (cis-4d-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) - one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (2-
morpholinoethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-phenothy1l-3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrazine [(2,3-
blpirazin-2 (1H) -one;
4- (cyclohexylmethyl) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) - one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-
((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4 - ((c 5- 4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H ) -one;
& 43 (R) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (tetrahydrofuran-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin - 2 (1H) -one; (8) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (tetrahydrofuran-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-phenyl-3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
(S) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3-
methyl-4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
9- [6- (1-hydroxy-isopropyl) -3-pyridyl] -6, 11,4a-
trihydromorpholine [4,3-e] pyrazine [2,3-b] pyrazin-5-one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-
((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazino [2,3-bl] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) n4-12-methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (2-amino-7-methyl-1H-benzo [d] imidazol-5-yl) -4-
(3- (trifluoromethyl) benzyl) -3,4-dihydropyrazine (2,3-blpyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-11) -4- (3- (trifluoromethyl) benzyl) -3,4-dihydropyrazine [2,3-bl] pyrazin-2 (1H) -one;
9- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) -6, 11,4a-triidromorpholine [4,3-e] pyrazine [2,3-b] pyrazin- 5-one;
6- (4-methyl-2- (methylamino) -1H-benzo [d] imidazol-6- 11) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4- dihydropyrazine (2,3-b] pyrazin-2 (1H) -one;
Ss: * 44 8- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) - 5,10,3a-trihydropyrazino [2,3-b] pyrrolidine [1,2- elpirazin-4-one; 6- (4- (4H-1,2,4-triazol-3-yl) phenyl) -4-ethyl-3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 6- (4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3- bl] lpirazin-2 (1H) -one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one; 6- (4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona; 6- (4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (3- (trifluoromethyl) benzyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 ( 1H) -one; 6- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4- dihydropyrazine [2,3-blpyrazin-2 (1H) -one; 6- (4-methyl-11H-benzo [d] imidazol-6-1yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpirazin -2 (1H) -one; 6- (4- (2-hydroxypropan-2-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-Dblpyrazin-2 ( 1H) -one; or 6- (4- (1H-1,2,4-triazol-5-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2 , 3-blpirazin-2 (1H) -one.
In addition, methods for preparing compounds having the following formula (IL) are provided:
.: 45 "DO Í o
AL Ê s 3 (II) and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, in which: R 'is substituted or unsubstituted C 1 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl , or substituted or unsubstituted heterocyclylalkyl; R is H, substituted or unsubstituted Cris alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; Rº is H, or a substituted or unsubstituted Cis alkyl; provided the compound of formula (II) is not 7- (4-hydroxyphenyl) -1- (3-methoxybenzyl) -3,4-dihydropyrazine [2,3-Dblpirazin-2 (1H) -one, described below: ”" O, e
NECTION a Methods are also provided for preparing a compound of formula (II),
at 46
RR RAN, u
TAL (II) and the method comprises contacting a compound of the formula (VI) Re x Ne o (VI) with R | -Y in a solvent, in the presence of a palladium catalyst, in which said contact occurs under suitable conditions to provide a compound of formula (1), where R, R, and Rº are as defined herein, and a) when X is halogen (for example, Br, CL, or 1) and then Y is B (OR ') , or SN (R **) 3; or b) when Y is halogen (for example, Br, C1, eu 1) or triflate, then X is B (OR); or SN (R ”) 3; wherein each R 'is independently hydrogen or C1 alkyl; substituted or unsubstituted, or each R ', together with the boron atom and the atoms to which they are attached, form a cyclic boronate; and each R * is C1-3 alkyl.
Typically, the solvent is dimethylformamide, isopropanol, dioxane, toluene, dimethylacetamide, tetrahydrofuran, acetonitrile, isopropyl acetate, dimethyl sulfoxide, acetone, methanol, t-butyl methyl ether or a combination thereof, with or without the presence of water, and the palladium catalyst is dichloro [ll, 1'-bis (diphenylphosphino) -ferrocene] palladium (II) dichloro-methane), palladium (dba) 2 / tri-o-tolylphosphine, dichloro [1,1'-bis (ditherc-
. 47 butylphosphino) ferrocene] palladium, dichlorobis (p-dimethylamino phenylditbutylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), dichloro (2-diphenylphosphine ethyl trimethylammonium) or palladium (TT) acetate / - bis (diphenylphosphine) -9,9-dimethylxanthene. In some modalities when X or Y is a halogen, halogen is Br. In some modalities when X or Y is B (OR) », contact occurs in the presence of a base such as sodium carbonate, triethylamine, diisopropylethylamine, piperidine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate, or sodium hydroxide. In some of these modalities, B (OR '); is B (OH); or B (-OC (CH3) 2C (CH;) 20-). In other modalities, when X or Y is Sn (R *); contact optionally occurs in the presence of a base such as triethylamine, sodium carbonate, diisopropylethylamine, piperidine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate, or sodium hydroxide. In some of these modalities, R ”is methyl or n-butyl. Methods are also provided for preparing a compound of the formula (VI), i X and ANQZNÇO TEL.
H (VT) and the method comprises cyclizing a compound of the formula (VIT) * ua ”La ne o (VIT)
and 48 in the presence of a base, such as potassium butoxide, or an acid, such as acetic acid, TFA, HCl, or phosphoric acid, wherein said cyclization occurs under conditions suitable to provide a compound of formula (VI), where R and R are as defined herein, Hal is a halogen such as Br, and R is H or alkyl Creates, or The alkali metal salt of the carboxylate, for example, the sodium salt. Typically, cyclization is performed in a solvent, such as, for example, methanol or water. Methods are also provided for preparing a compound of formula (VII),
R Hal ANQONH 5
CLA o (VIT) and the method comprises contacting a compound of the formula (VIII) fe an "" No. o o (VIII) with R º-NH2 in a solvent, such as dimethylsulfoxide or N-methylpyrrolidinone, optionally in the presence of a base, such as triethylamine or diisopropylethylamine, in which said contact occurs under conditions suitable to provide a compound of formula (VII), in which Rº and Rº are as defined herein, and Hal is a halogen such as Br. In certain embodiments , are provided in these salts (which includes pharmaceutically acceptable salts), solvates and hydrates of compounds of the formula (VI), formula (VII) and formula (VIII) In some embodiments of compounds of the formula (IT), R 'is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
For example, R * is phenyl, pyridyl, pyrimidyl, benzimidazolyl, 1H-pyrrolo [2,3-b] pyridyl, indazolyl, indolyl, 1H-imidazo [4,5-b] pyridyl, lH-imidazo [4,5- b] pyridin-2 (3H) -onyl, 3H-imidazo [4,5-blpiridyl, or pyrazolyl, each is optionally substituted.
In some embodiments, R 'is phenyl substituted with one or more selected substituents - “independently from the group consisting of substituted or unsubstituted C1.g alkyl (eg, methyl), substituted or unsubstituted heterocyclyl (eg, a substituted or unsubstituted triazolyl or pyrazolyl), aminocarbonyl, halogen (for example, fluorine), cyan, hydroxyalkyl and hydroxy.
In other embodiments, R 'is substituted pyridyl with one or more substituents selected independently from the group consisting of substituted or unsubstituted C1- alkyl (eg, methyl), substituted or unsubstituted heterocyclyl (eg, a triazolyl substituted or unsubstituted), halogen, aminocarbonyl, cyano, hydroxyalkyl (for example, hydroxypropyl), - OR, e-NRº, where each R is independently H, or C1.4 alkyl. one substituted or unsubstituted.
In some embodiments, Rº is 1H-pyrrolo [2,3-b] pyridyl or benzimidazolyl, optionally substituted with one or more selected substituents — regardless of the group consisting of C 1 alkyl; substituted or unsubstituted,
á 50 NRº, where R is independently H, or a substituted or unsubstituted C14 alkyl. In some modalities, R 'is
R N- o [I-toRoR TT (3 TI roR DP RA à FL tos * ”» Rm 7 s R o R ma r Bh O E RCA RO LE.: Wai
R N A e. Ee NR Ag, 7 ex. IT A.
FE Rm where R is at each occurrence independently H, or a substituted or unsubstituted C 1 alkyl (for example, methyl); R 'is in each occurrence independently substituted or unsubstituted Cia alkyl (for example, methyl), halogen (for example, fluoro), cyan, -OR, or - NRº; m is 0-3; and n is 0-3. It will be understood by those skilled in the art that any of the substituents R 'can be attached to any suitable atom of any of the rings in the fused ring systems. In some modalities of compounds of the formula (IT), R is
ON AIR (CR2, OR ANACROR ERROR O O xXx TT x "If Re:
R R If à O IS, 2 Te, à NORA, "Rm bs PDR where R is in each occurrence independently H, or the C 1 alkyl, substituted or unsubstituted; R 'is in
S 51 each occurrence independently a C1-substituted or unsubstituted alkyl, halogen, cyano, -OR or - NR; mean 0 to 3; enébõai. In some modalities of compounds of the formula (II), RÀ is H, substituted or unsubstituted Cris alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C1-4 alkyl heterocyclyl, substituted C1-1 alkyl aryl or unsubstituted, or substituted or unsubstituted C 1-6 alkyl cycloalkyl. For example, Rº is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, (C14 alkyl) - phenyl, (C4 alkyl) - cyclopropyl, (C14 alkyl) -cyclobutyl, (C14 alkyl) - cyclopentyl, (C4 alkyl) -cyclohexyl, (Cia alkyl) - pyrrolidyl, (Ci, alkyl) - piperidyl, (Cia alkyl) - piperazinyl, (C14 alkyl) -morpholinyl, (C14 alkyl) -tetrahydrofuranoyl, or (C14 alkyl) -tetrahydropyranyl, each is optionally substituted. In other modalities, Rº is H, Cia alkyl, (1-4 alkyl) (OR), x
R NEC RITO) mucus,
R R R O, AO; x and a to 0 OR where R is in each occurrence independently H, or a substituted or unsubstituted C 1 alkyl (for example, methyl); R 'is in each occurrence independently
. 52 H, -OR, cyano, or a substituted or unsubstituted C 1 alkyl (for example, methyl); and p is 0 to 3. In other modalities of compounds of the formula (IT), Rº is H, C1.4 alkyl, (C14 alkyl) (OR),
R R R AO TA Ea A xr xa HEX O In LUONR - R AÇO, th OR where R is in each occurrence independently H, or a substituted or unsubstituted C1 alkyl. R 'is in each occurrence independently H, -OR, cyano, or a substituted or unsubstituted C1 .alkyl; and p is 0 to 1. In other modalities of compounds of the formula (IT), Ré HE. In some of the modalities described in this, Rº is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. For example, Rº is phenyl, pyridyl, pyrimidyl, benzimidazolyl, lH-pyrrolo [2,3-blpyridyl, indazolyl, indolyl, lH-imidazo [4,5-blpiridine, pyridyl, lH-imidazo [4,5-b] pyridin -2 (3H) -onyl, 3H-imidazo [4,5-b] pyridyl, or pyrazolyl, each is optionally substituted. In some embodiments, Rº is substituted phenyl with one or more selected substituents — regardless of the group consisting of substituted or unsubstituted Cris alkyl, substituted or unsubstituted heterocyclyl, aminocarbonyl, halogen, cyano, hydroxyalkyl and hydroxy. In others, R 'is pyridyl substituted with one or more substituents selected independently from the
It is a group consisting of substituted or unsubstituted C 1-8 alkyl, halogen, aminocarbonyl, cyano, hydroxyalkyl, -OR, and -NR, where each R is independently H, or a substituted or unsubstituted Ciras alkyl. In still others, R 'is 1H-pyrrolol2,3-blpyridyl or benzimidazolyl, optionally substituted with one or more substituents selected independently from the group consisting of substituted or unsubstituted C 1 -alkyl, e-NRº, where R is independently H, or substituted or unsubstituted C 1 alkyl.
In certain embodiments, the compounds of the formula (II) have a group R 'established in this and a group Rº established in this.
In some embodiments of compounds of formula (II), the compound at a concentration of 10 µM inhibits mTOR, DNA-PK, PI3K, or a combination thereof by at least about 50%. The compounds of formula (II) can be shown to be inhibitors of the above kinases in any suitable test system, such as those described in the Examples herein.
In some embodiments of compounds of formula (II), The compound is T- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3- 11) phenyl) -1- ((trans -4-methoxycyclohexyl) methyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; T7T- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1- (cis-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin -2 (1H) - one; 7- (1H-pyrrolo [2,3-b] pyridin-3-11) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine ([2,3- blpirazin-2 (1H) -one;
N 54 7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3- 11) phenyl) -1- ((cis-4-methoxycyclohexyl) methyl) -3,4- dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; l1-ethyl-7- (iH-pyrrolo [3,2-b] pyridin-5-yl) -3,4-
dihydropyrazine [| 2,3-blpyrazin-2 (1H) -one;
7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1- ((cis-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one;
T7- (1H-benzo [d] imidazol-4-yl) -1- (2- (tetrahydro-2H-
pyran-4-yl) ethyl) -3,4-dihydropyrazine (2,3-blpyrazin-2 (1H) -
ona;
7- (1H-pyrrolo [2,3-b] pyridin-4-i11) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpirazin -2 (1H) -one;
T7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1- ((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine (2,3- b] pyrazin-2 (1H) -one;
T7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1- ((trans-4-hydroxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one; T7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1-1- (cis-4-hydroxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin - 2 (1H) -one; 7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
il) phenyl) -1- (cis-4-hydroxycyclohexyl) -3,4-
dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-11) -1- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrazine (2,3 - blpirazin-2 (1H) -one;
S 55 7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-11) -1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin -2 (1H) -one;
7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1-ethyl-3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona;
7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1- ((cis-4-hydroxycyclohexyl) methyl) -3,4-dihydropyrazine [ 2,3-b] pyrazin-2 (1H) -one;
7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1-1- (tetrahydro-2H-pyran-4-1yl1) -3,4-dihydropyrazine (2,3-b] lpyrazin-2 (1H) -one; 7- (1H-indol-4-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3.4 -dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 7- (5S-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1 - (trans-4-hydroxycyclohexyl) methyl) -3,4-
dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-1yl) -1- ((cis-4-hydroxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one;
7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl1) -1-
(trans-4-hydroxycyclohexyl) -3,4-dihydropyrazine [| 2,3-blpyrazin-2 (1H) -one;
7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-i1) -1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-blpirazin-2 (1H) -one;
7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1- isopropyl-3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona;
7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3- 11) phenyl) -1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3 -b] pyrazin-2 (1H) -one;
S 56 T7T- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1- (trans-4-hydroxycyclohexyl) -3,4-dihydropyrazine [2 , 3-b] pyrazin-2 (1H) -one; T7- (S-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
il) phenyl) -1- (2-methoxyethyl) -3,4-dihydropyrazine [| 2,3-
bl] lpirazin-2 (1H) -one; 7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
il) phenyl) -1-isopropyl-3,4-dihydropyrazine [2 b] pyrazin-2 (1H) -
ona;
1-ethyl-7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -3,4-dihydropyrazine [| 2,3-b] pyrazin- 2 (1H) -one;
T7- (2-hydroxypyridin-4-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) - ona;
l1-isopropyl-7- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydroppyrazine [2,3-b] pyrazin-2 (1H) - one;
5- (8-isopropyl-7-ox0-5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-methylpicolinamide;
T7- (11H-indazol-4-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona;
7- (2-aminopyrimidin-5-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) - ona;
7- (2-aminopyridin-4-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona;
T7- (6- (methylamino) pyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 ( 1H) -
ona;
NS 57 T- (6-hydroxypyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H ) - one; T7- (4- (1H-pyrazol-3-yl) phenyl) -1-1- (2-methoxyethyl) -
3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (pyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
7- (1H-indazol-4-yl) -1- (2-methoxyethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
7- (1H-indazol-6-yl) -1- (2-methoxyethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
7- (pyrimidin-5-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-diiropyrazine [2,3-bl] pyrazin-2 (1H) -one; 7- (6-methoxypyridin-3-yl) -1- (2- (tetrahydro-2H-
pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-bl] pyrazin-2 (1H) -one;
1- (2-methoxyethyl) -7- (1H-pyrrolo [2,3-b] pyridin-5-i1) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 1-ethyl-7- (1H-pyrrolo [2,3-b] pyridin-5-yl) -3,4-
dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
1-ethyl-7- (1H-indazol-4-1l) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
T7- (pyridin-4-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
T7- (6-aminopyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) - ona;
1-methyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] lpyrazin-2 (1H) -
ona;
: 58
2- (2-hydroxypropan-2-1yl) -5- (8- (trans-4-methoxycyclohexyl) -7-ox0-5,6,7,8-tetrahydropyrazino [2,3-blpyazin-2-yl) pyridine 1-oxide;
4-methyl-5- (7-0x0-8 - ((tetrahydro-2H-pyran-4-
il) methyl) -5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) picolinamide;
5- (8- ((cis-4-methoxycyclohexyl) methyl) -7-oxo-5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-methylpicolinamide;
T7- (1H-pyrazol-4-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona;
1- (trans-4-methoxycyclohexyl) -7- (4-methyl-6- (1H- 1,2,4-triazol-3-yl) pyridin-3-11) -3,4-dihydropyrazine (| 2, 3-blpirazin-2 (1H) -one;
3 - ((7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin- 3-11) -2-0x0-3,4-dihydropyrazine [2,3-b ] pyrazin-1 (2H) -yl) methyl) benzonitrile;
1 - ((trans-4-methoxycyclohexyl) methyl) -7- (4-methyl-6- (1H-1,2, 4-triazol-3-yl) pyridine-3-11) -3,4-
dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
3- (7-0x0-8- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) benzamide;
5- (8- ((trans-4-methoxycyclohexyl) methyl) -7-oxo- 5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-
methylpicolinamide;
3 - (((7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -2-ox0-3,4-dihydropyrazino [2,3-b] pyrazin-1 (2H) - yl) methyl) benzonitrile;
: 59
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1
((1R, 3R) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3-bl] lpyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1-
((18,3R) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-11) -1-
((18,38) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3-bl] lpyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- ((1R, 3S) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H ) -one;
T7- (1H-indazol-6-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3- 31) -1- (2-morpholinoethyl) -3,4-dihydropyrazine [2,3-b ] pyrazin-2 (1H) -one;
1- (trans-4-hydroxycyclohexyl) -7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3 -
b] lpirazin-2 (1H) -one;
1- (cis-4-hydroxycyclohexyl) -7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine ([2, 3-bl] lpirazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (2-
morpholinoethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
1-isopropyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydroppyrazine [2,3-bl] pyrazin-2 (1H) - one;
É 60 7T- (1H-imidazo [4,5-b] pyridin-6-1i1) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3 bl] lpirazin-2 (1H) -one; 1 - ((cis-4-methoxycyclohexyl) methyl) -7- (2-methyl-6-
(1H-1,2,4-triazol-3-yl) pyridine-3-yl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
1- (trans-4-hydroxycyclohexyl) -7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona;
1- (cis-4-hydroxycyclohexyl) -7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazine (2,3-blpyrazin-2 (1H) -one;
4- (7-0x0-8- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) benzamide;
7- (1H-indazol-5-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona;
7- (1H-pyrrolo [2,3-b] pyridin-5-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [| 2,3- b] pyrazin-2 (1H) -one;
7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3- 31) -1- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrazine [| 2,3-blpirazin-2 (1H) -one;
1 - (((18,3R) -3-methoxycyclopentyl) -7- (2-methyl-6- (4H, 2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2 , 3-
blpirazin-2 (1H) -one;
1 - ((1R, 3R) -3-methoxycyclopentyl) -7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [| 2,3-bl] lpirazin-2 (1H) -one;
At 61
1 - ((1R, 3S) -3-methoxycyclopentyl) -7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-1yl) -3,4-dihydropyrazine [2,3-blpirazin-2 (1H) -one;
1 - ((18.38S) -3-methoxycyclopentyl) -7- (2-methyl-6- (4H
, 2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
T7- (1H-indol-5-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
1-ethyl-7- (2-methyl-6- (4H-1,2,4-triazole-3-
il) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
T7- (1H-indol-6-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona;
7- (4- (2-hydroxypropan-2-yl) phenyl) -1- (trans-4-
methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
1- ((trans-4-methoxycyclohexyl) methyl) -7- (2-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-i1) -3,4-dihydropyrazine [ 2,3-bl] pyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1 - ((cis-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3-bl] pyrazin-
2 (1H) -one;
1- (2-methoxyethyl) -7- (4-methyl-2- (methylamino) -1H-benzo [d] imidazol-6-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 ( 1H) -one;
k 62 7- (T-methyl-2-0x0-2,3-dihydro-1H-benzo [d] imidazole- 5-11) -1 - ((tetrahydro-2H-pyran-4-yl) methyl) -3 , 4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
1- (2-methoxyethyl) -7- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-1yl) -3,4-dihydropyrazine [2,3-b ] pyrazin-2 (1H) - one;
l1-benzyl-7- (2-methyl-4- (4H-1,2,4-triazole-3-
il) phenyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (3-fluoro-4- (4H-1,2,4-triazol-3-yl) phenyl) -1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
T- (3-fluoro-4 4H-1,2,4-triazol-3-yl) phenyl) -1-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [ 2.3-
blpirazin-2 (1H) -one; 7- (3-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-blpirazin -2 (1H) -one; 1- (trans-4-methoxycyclohexyl) -7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydroppyrazine [2,3 - blpirazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine (| 2,3-blpyrazin-2 (1H) -one ;
T7T- (5-fluoro-2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (3-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
1- (2-methoxyethyl) -7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b ] pyrazin-2 (1H) - one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1-
((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3-b] lpyrazin-2 (1H) -one;
1- (cyclopentylmethyl) -7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (4- (2-hydroxypropan-2-yl) phenyl) -1- (2-methoxyethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
(8) -7- (6- (1-hydroxyethyl) pyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine (| 2,3 - blpirazin-2 (1H) -one;
(R) -7- (6- (1-hydroxyethyl) pyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one;
7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3- 11) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -3, 4-
dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
7- (4- (2-hydroxypropan-2-yl) phenyl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin- 2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (4-
(trifluoromethyl) benzyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (3- (trifluoromethyl) benzyl) -3,4-dihydropyrazine (2,3-blpyrazin-2 (1H) -one ;
. 64 7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (3-methoxypropyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one ; 7- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3- 11) -1- (2- (tetrahydro-2H-pyran-4-1yl) ethyl) - 3.4-
dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (2-methoxyethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3-
bl] lpirazin-2 (1H) -one;
7- (4-methyl-2- (methylamino) -1H-benzo [d] imidazol-6-yl) -1 - ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2 , 3-b] pyrazin-2 (1H) -one;
T7- (2-amino-4-methyl-1 H-benzold] limidazol-6-yl) -1-
((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine ([2,3-
b] lpirazin-2 (1H) -one; T7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-
11) -1- (2- (tetrahydro-2H-pyran-4-1yl) ethyl) -3,4-
dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
(R) -7- (6- (2-hydroxypropan-2-yl) pyridin-3-i1) -3-methyl-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3, 4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
(S) -7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3-methyl-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3, 4-
dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-1yl) -3,3-dimethyl-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4- dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
. 65 7T- (2-amino-4-methyl-11H-benzo [d] imidazol-6-yl) -1- (2- (tetrahydro-2H-pyran-4-1yl) ethyl) -3,4-dihydropyrazine [ 2,3-blpirazin-2 (1H) -one; 7- (6- (2-hydroxypropan-2-yl) pyridin-3-1yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one; 7- (2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4- dihydropyrazine [2,3-bl] pyrazin-2 (1H) -one; 7- (4- (1H-1,2,4-triazol-5-1yl1) phenyl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2, 3-blpirazin-2 (1H) -one; 1- (1-hydroxypropan-2-yl) -7- (2-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2 , 3-blpirazin-2 (1H) -one; or 1- (2-hydroxyethyl) -7- (2-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [| 2, 3 -b] pyrazin-2 (1H) - one.
4.3 METHODS FOR MANUFACTURING COMPOUNDS
HETEROARYL The heteroaryl compounds are prepared as outlined in Schemes 1 through 9 shown below, as well as in the Examples set out in section 5.1. It should be noted that a person skilled in the art can modify the procedures set out in the illustrative schemes and in the Examples to achieve the desired product.
k 66 Br RIB (OR) s Rr NES RL ONQÇÊ Tr sa fo ia ES [AA TOA, E CE Scheme 1 The synthesis of the compounds of the formula (TI) is shown in Scheme 1. Starting from 5-bromopyrazin-2 -amine A, the group R can be introduced by using the appropriate boronic acid or borate ester (R * is H, or together with the boron atom and the atoms to which they are attached, form a cyclic boronate), catalyst palladium (such as, for example, dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane), solvent (such as dimethylformamide) and base (such as sodium carbonate) via a Suzuki coupling , or alternatively with the appropriate stanane (R * is C 1 alkyl), palladium catalyst (such as dichloro (1,1'-bis (diphenylphosphino) ferrocene) palladium (I11) dichloromethane or palladium (dba), / tri-o- tolylphosphine) and solvent (such as dimethylformamide with or without the addition of a base such as triethylamine) using a Stille coupling methodology.
Reaction conditions and typical reagents for the Suzuki and Stille reactions can be found in this one (see also Rossi, et al, Synthesis 15: 2419 to 2440 (2004), Buchvald et al.
Accounts of Chemical Research, 41: 1461 to 1473 (2008), Fu.
Accounts of Chemical Research, 41: 1555 to 1564 (2008), and Echavarren et al.
Angew.
Chem.
Int.
Ed., 43: 4704 to 4734 (2004) and the
. 67 references in these). the resulting R 'amino pyrazine B can be brominated by using NBS or other standard bromination conditions to confer the brominated intermediate C, which is then reacted with a bromoacetic anhydride to confer the acylated intermediate D.
The Rº substituent is introduced by adding amine to D and subsequently closing the ring in the presence of a base amine (such as, for example, triethylamine) and heating in an appropriate solvent (such as acetonitrile) to give the desired products . cn AA action Ra steel, RSS ma.
MA O AA O AA CEO ADA, E F Ss Scheme 2 Alternatively, as shown in Scheme 2, 3,5-dibromopyrazin-2-amine E, is treated with 2-bromoacetic anhydride as above to provide intermediate Oo F.
As described above, the Rº substituent is introduced by adding amine to F and the subsequent closing of the ring to confer the intermediate G.
The R 'group can then be introduced using the methods described above, that is, by reacting with the appropriate boronic acid or borate ester, in the presence of a palladium catalyst and a base through a Suzuki coupling , or alternatively with the appropriate stannane, in the presence of a palladium catalyst using the Stille coupling methodology as described above, to provide the desired products. oo R ss 8 & éóm en DA a ss er RUN, N Gs, 2. Nal CA To E F2
: 68 Scheme 3 In another approach (Scheme 3), 3,5-dibromopyrazin-2-amine E is treated with 2-chloroacetic anhydride followed by sodium iodide to provide intermediate iodine F2. The intermediate F2 is converted to the desired products followed by the procedures outlined in Scheme 2 for F.
E R Ar 1. Gas bonding agent. N ER RESORO q E to ENANE TAZ E RL s NÔONH, '
3. Deprotection
4. Pd cat., Base Scheme 4 To provide analogs with alpha substitution to carbonyl (Scheme 4), the appropriately substituted amino-protected amino acid H (Pv, is an amino protecting group such as Boc), is reacted with 3.5 -dibromopyrazin-2-amine in the presence of a binding agent, such as, for example, 1,1'-carbonyldiimidazole. Deprotection conditions (for example, when Pv is Boc, deprotection is achieved by, for example, treatment with TFA or HCl), followed by palladium-catalyzed ring closure (using, for example, sodium bicarbonate, acetate palladium (II) and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene) to provide intermediate I. As mentioned above, the group R 'can be introduced using boronic acid or borate ester, the catalyst palladium, solvent and base through a Suzuki bond, or alternatively with the appropriate stannane, the palladium and solvent catalyst using the Stille bond methodology (described
. 69 above) to provide the desired products. This method can also be used to provide analogs in which R it's hydrogen. In addition, this route can be used to provide compounds in which Rº and Rº, together with the atom to which they are both attached, form a spirocyclic ring, through the use of appropriate starting amino acids. Ros Ls and PESE Pp "RÉ Né go
J Scheme 5 The analogs in which Rº and Rº together with the atoms to which they are attached form a ring (see Scheme 5) can be obtained similarly to the chemistry shown in Scheme 4, starting with the appropriate cyclic amino acid J.. z BN, À R DUGARE Si ”" E RB RQON À FR Ah Es ——— OE e. IT'S NO NB a O AE
Y K2 Figure 6 To obtain the desired products, the reactivity of the liaison partners can be reversed. For example, as shown in Scheme 6, intermediate I can be converted to the corresponding stannane K, by reaction with, for example, hexamethylditine (R * is methyl) in the presence of a palladium catalyst (such as tetracis (triphenylphosphine) - palladium) and the group R 'can be introduced using an appropriate leaving group, for example, halogen (such as bromide) or triflate, and solvent using Stille's binding methodology as described above to provide the desired products.
Alternatively, intermediate I can be converted to the corresponding boronate ester K2 by reaction with 4.4.4 ', 4', 5.5.5 ', 5'-octamethyl-2,2'-bi (1,3 , 2-dioxaborolane) in the presence of a palladium catalyst (such as 1, - bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane) and a base (such as potassium acetate) in a solvent such as dioxane.
The R * group can be introduced using an appropriate leaving group, for example, halogen (such as bromide) or triflate, palladium catalyst and solvent than its Suzuki binding methodology as described above, to provide the desired products.
Br if cn BN Lia e NÃo PO: mm from TX.
OT Los 2H orbasa TAS RSS TT and NDA / "Scheme 7 The compounds of formula (II) can be obtained as shown in Scheme 7, The reductive amination of 3,5-dibromopyrazin-2-amine E with ethyl 2-oxoacetate ( in the presence of, for example, sodium borohydride as a reducing agent) provides intermediate L.
Alternatively, 3,5-dibromopyrazin-2-amine E can be converted to intermediate L by reaction with ethyl 2-chloroacetam under basic conditions (using, for example, Cs3CO03). The substituent Rº is introduced by adding amine to L, in the presence of an amine base, such as diisopropylethylamine, and heating in a solvent
. 71 appropriate (such as DMSO) and subsequent acid-catalyzed ring closure (using, for example, acetic acid) to provide intermediate M.
Ring closure of the amine addition product L can also proceed under basic catalyzed conditions, such as treatment with potassium t-butoxide in an appropriate solvent.
Alternatively, the ethyl ester portion can be hydrolyzed (for example, by base treatment) prior to reaction with Rº-NHº in water, followed by acid-catalyzed ring closure.
As mentioned above, the group R '* can be introduced using the appropriate boronic acid or boroate ester, palladium catalyst, solvent and base through a Suzuki bond, or alternatively with the appropriate stannane, palladium and solvent catalyst that uses Stille's binding methodology (described above) to provide the desired products. hos * um r LX 1 RB MOÇA or EO RI-BMOR "e and 2H ON Y to NON RP” RS ”” N 3 Nos P Scheme 8 An alternative approach (Scheme 8) begins with the reaction of 2,6-dichloropyrazine N with the appropriate amino ester (Rº is C1-3 alkyl), followed by reductive dehalogenation with hydrogen and a palladium catalyst such as palladium hydroxide, a base such as potassium carbonate, in a solvent such as ethanol, and subsequent bromination by reaction with a bromination agent such as NBS to yield intermediate O.
As mentioned above, the substituent Rº is introduced by adding i amine to O and subsequent acid-catalyzed ring closure
: 72 to provide intermediate P.
The R 'group can be introduced using the appropriate boronic acid or borate ester, palladium catalyst, solvent and base through a Suzuki bond, or alternatively with the appropriate stannane, palladium and solvent catalyst using the bonding methodology to provide the desired products (described above). This route also allows the synthesis of analogues with alpha substitution Rº to the carbonyl group.
W Aa E [S Br, N o SMART Per RES RAN ARE A A RE, P a RAT A E from the ant! -. Ce Scheme 9 As mentioned above, to obtain the desired products, the reactivity of the binding partners can be reversed (Scheme 9). For example, the intermediate P can be converted to the corresponding stannane Q, and the group R 'can be introduced using an appropriate leaving group, for example, halogen (such as bromide) or triflate, palladium catalyst and solvent it uses the Stille binding methodology as described above to provide the desired products.
Alternatively, intermediate P can be converted to the corresponding boronate ester Q2, and the group R 'can be introduced using an appropriate leaving group, for example, halogen (such as bromide) or triflate, palladium catalyst and solvent which uses the Suzuki link methodology
| 73 as described above to provide the desired products. the pharmaceutically acceptable salts of the Heteroaryl Compounds can be formed by conventional and known techniques, such as by reacting a Heteroaryl Compound with a suitable acid as disclosed above. Such salts are typically formed in high yields at moderate temperatures, and are usually prepared merely by isolating the compounds from a suitable acid wash in the final stage of synthesis. The acid that forms the salt can be dissolved in a suitable organic solvent, or aqueous organic solvent, such as an alkanol, ketone or ester. On the other hand, if the Heteroaryl Compound is desired as a free base, it can be isolated from a basic final wash step, according to known techniques. For example, a typical technique for preparing hydrochloride salt is to dissolve the free base in a suitable solvent, and dry the solution thoroughly, as by molecular sieves, before bubbling hydrogen chloride gas through it. Chemical intermediates useful in the methods provided in the present invention include: (i) compounds having formula (III): Re XT Ns o OK
H (III) or a salt, tautomer or stereoisomer thereof, where: x is halogen, B (OR '), or SNn (R **) 3;
. 74 each R * is independently substituted or unsubstituted hydrogen or C1-3 alkyl, or each R *, together with the boron atom and the atoms to which they bond, form a cyclic boronate; each R "* is independently C1-4 alkyl; RR is H, substituted or unsubstituted C1s alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted, or substituted or cycloalkylalkyl unsubstituted; and Rº and Rº are each, independently, H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or substituted aralkyl unsubstituted, substituted or unsubstituted cycloalkylalkyl, or Re Rº, together with the atom to which they are attached, form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl, or Rº and one of Rº and Rº, together with O atoms which are linked, form a substituted or unsubstituted heterocyclyl; stos that have the formula (IV):
AI 2 nNê got av)
"75 or a salt, tautomer or stereoisomer thereof, where: each Hal is independently a halogen; and Halº is Br or I; (iii) compounds having the formula (V): Hal NQ Hal CALA eu
RR o or a salt, tautomer or stereoisomer thereof, where: RE A, Cisgsubstituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or cycloalkylalkyl substituted or unsubstituted; Rº and Rº are each, independently, H, substituted or unsubstituted C1- g alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclyl alkyl, substituted or unsubstituted aralkyl, cycloalkylalkyl substituted or unsubstituted, or Re Rº *, together with the atom to which they are attached, form a substituted or unsubstituted cycloalkyl Or substituted or unsubstituted heterocyclyl; or Rº and one of Rº and Ri, together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclyl; and
. 76 each Hal is independently a halogen; (iv) compounds that have the formula (VI): THERE NÔONOURI
H (VI) or a salt, tautomer or stereoisomer thereof, where: X is halogen, B (OR * '); or Sn (R **) 3; each R 'is independently hydrogen or Cysubstituted or unsubstituted alkyl, or each R', together with the boron atom and the atoms to which they are attached, form a cyclic boronate; each R ”* is independently C1-3 alkyl; R is H Cysubstituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; and Rº is H, or a substituted or unsubstituted C1 alkyl; (v) compounds that have the formula (VII): & Eee n ”o o (VII) or a salt, tautomer or stereoisomer thereof, where:
s 77 Hal is a halogen; R is H or C1.4 alkyl, or the alkali metal salt of the carboxylate; Re, Cissubstituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; and Rº is H, or a substituted or unsubstituted Cris alkyl; and (vi) compounds that have the formula (VIII): qo RR nº oo o (VIII) or a salt, tautomer or stereisomer thereof, where: each Hal is independently a halogen R is H or alkyl Cia, OR O salt alkali metal of the carboxylate; and Rº is H, or Cysubstituted or unsubstituted alkyl.
4.4 METHODS OF USE The Heteroaryl Compounds described in the present invention are useful as pharmaceutical products for treating or preventing diseases in animals or humans. In addition, the Heteroaryl Compounds described in the present invention are active against kinases (for example, protein kinases), including those involved in cancer,
+ 78 inflammatory conditions, immunological conditions, neurodegenerative diseases, diabetes, obesity, neurological disorders, age-related diseases, and cardiovascular conditions.
Without being limited by theory, Heteroaryl Compounds are believed to be effective in treating and preventing said diseases and conditions due to their ability to modulate (for example, inhibit) kinases that are involved in the etiology of these diseases and conditions.
In this way, many uses of Hetercoaryl Compounds are provided in the present invention, including the treatment or prevention of those diseases presented below.
The methods provided in the present invention comprise administering an effective amount of one or more Heteroaryl Compounds to a patient who needs it.
In some embodiments, the methods additionally comprise administering a second active agent as described in the present invention.
Representative immune conditions that Heteroaryl Compounds are useful to treat or prevent include, but are not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, multiple sclerosis, lupus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, Graves' disease, encephalomyelitis, Type I diabetes, dermatomyositis, and transplant rejection (for example, in the treatment of recipients of, for example, combined heart, lung, heart and lung transplants, liver, kidney, pancreatic, skin or cornea; or graft versus host disease, such as following bone marrow transplantation).
& 79 Representative inflammatory conditions that Heteroaryl Compounds are useful to treat or prevent include, but are not limited to, psoriasis, asthma and allergic rhinitis, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome , Crohn's disease, mucous colitis, ulcerative colitis, and obesity.
Representative cardiovascular diseases that Heteroaryl Compounds are useful to treat or prevent include, but are not limited to, restenosis, Wolf-Parkinson-White Syndrome, stroke, myocardial infarction or ischemic damage to the heart, lung, intestines, kidney, liver, pancreas, spleen or brain.
Representative neurodegenerative diseases that Heteroaryl Compounds are useful to treat or prevent include, but are not limited to, Huntington's disease, Alzheimer's disease, Parkinson's disease, dementia caused by tau mutations, type 3 spinocerebellar ataxia, motor neuron disease caused by SOD1 mutations, neuronal ceroid, lipofucinosis / Batten's disease (pediatric neurodegene diet) and HIV-associated encephalitis.
Representative age-related diseases that Heteroaryl Compounds are useful for treating or preventing include, but are not limited to, cancer, obesity, type II diabetes mellitus, autoimmune disease, cardiovascular disease and neuronal degeneration.
In another embodiment, methods for treating and preventing fibrotic diseases and disorders are provided in the present invention. In a particular embodiment, methods for the treatment and prevention of scleroderma, idiopathic pulmonary fibrosis, renal fibrosis, cystic fibrosis, myelofibrosis, liver fibrosis, steatofibrosis and steatohepatitis are provided in the present invention. Representative cancers that Heteroaryl Compounds are useful for treating or preventing include, but are not limited to, cancers of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system. Heteroaryl Compounds are also useful to treat or prevent solid tumors and blood-borne tumors.
Particular cancers within the scope of the methods provided in the present invention include those associated with trajectories involving mTOR, PI3K, or AKkt kinases and mutants or isoforms thereof. Other cancers within the scope of the methods provided in the present invention include those associated with the trajectories of the following kinases: PBKa, PBKEB, PBKô, KDR, GSK3a, GSK3, ATM, ATX, ATR, cFMS, and / or DNA-PK kinases and mutants or isoforms thereof. In some embodiments, cancers associated with mTOR / PI3K / Akt trajectories include blood-borne and solid tumors, for example, multiple myeloma, mantle cell lymphoma, widespread large B cell lymphoma, acute myeloid lymphoma, follicular lymphoma, chronic lymphocytic leukemia; breast, lung, endometrial, ovarian, gastric, cervical, and prostate cancer; glioblastoma; renal carcinoma; carcinoma
. 81 hepatocellular; colon carcinoma; neuroendocrine tumors; head and neck tumors; and sarcomas.
In a particular embodiment, methods for treating or preventing a disease or disorder associated with the activation of mTOR signaling are provided in the present invention, including, but not limited to, tumor syndromes that result directly or indirectly from genetic defects in PTEN ( Phosphatase and tensin homologue removed on chromosome 10), TSCl (Tuberous sclerosis 1), TSC2 (tuberous sclerosis 2), NFl (Neurofibromin 1), AMPK (AMP-dependent protein kinase STK11, serine / threonine kinase 11), LKBl, VHL (von Hippel-Lindau disease) and PKD1l (polycystic). Without being limited by theory, it is believed that genetic defects associated with these proteins result in hyperprolieferation of the path of mMTOR / PI3K / Akt. Some “particular diseases that are treatable or preventable by inhibiting the pathway of mTOR / PI3K / Akt include, but are not limited to, Cowden's disease, Cowden's syndrome, Cowden-like syndrome, Bannayan-Zonana syndrome, Bannayan syndrome -Riley- Ruvalcaba, Lhermitte-Duclos disease, endometrial carcinoma, tuberous sclerosis complex, lymphangioleiomyomatosis, neurofibromatosis 1, Peutz-Jeghers syndrome, renal cell carcinoma, von Hippel-Lindau disease, Proteus syndrome, and kidney disease polycystic.
In a particular embodiment, methods for the treatment or prevention of a disease or disorder associated with mTOR, PI3XK, Akt, and / or DNA-PK signaling are provided in the present invention. The particular diseases that are
: 82 treatable or preventable by inhibiting mMTOR, PI3K, Akt and / or DNA-PK signaling, include, but are not limited to, rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; drop; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; gastritis; esophagitis; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus; erythematous atherosclerosis; restenosis following angioplasty; left ventricular hypertrophy; myocardial infarction; leakage; ischemic damage to the heart, lung, intestines, kidney, liver, pancreas, spleen and brain; rejection of acute or chronic organ transplantation; preservation of the organ for transplantation; organ failure or limb loss (for example, including, but not limited to, that resulting from reperfusion damage due to ischemia, trauma, gross bodily harm, car accident, collision damage or transplant failure); graft versus host disease; endotoxin shock; multiple organ failure; psoriasis; burns from exposure to fire, chemicals or radiation; eczema; dermatitis; skin graft; ischemia; conditions - “ischemic associated with surgery or traumatic damage (for example, vehicle accident, gunshot wound or crushing of limb); epilepsy; Alzheimer's disease; Parkinson's disease; immune response to bacterial or viral infection; cachexia; angiogenic and proliferative diseases (including retinitis pigmentosa), solid tumors, and cancers of a variety of tissues such as colon, rectum, prostate, liver, lung,
bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary or uterus.
Also provided in the present invention are methods for inhibiting a kinase in a cell expressing said kinase, which comprises contacting the cell with an effective amount of a Heteroaryl Compound as described above. In one embodiment, the kinase is mTOR, DNA-PK, or PI3K or a combination thereof. In some embodiments, the cell is in a patient.
Also provided in the present invention are methods for treating or preventing a treatable or preventable condition by inhibiting a kinase pathway, for example, the pathway of mTOR / PBK / Akt and / or DNA-PK, which comprises administering to a patient in need therein an effective amount of a Heteroaryl Compound as described above. In some embodiments, conditions treatable or preventable by inhibiting the pathway of mTOR / PI3K / Akt include solid or blood-borning tumors, for example, multiple myeloma, mantle cell lymphoma, widespread large B cell lymphoma, acute myeloid lymphoma, follicular lymphoma, chronic Qlinfocytic leukemia; breast, lung, endometrial, ovarian, gastric, cervical, and prostate cancer; glioblastoma; renal carcinoma; hepatocellular carcinoma; colon carcinoma; neuroendocrine tumors; head and neck tumors; sarcomas; tumor syndromes that result directly or indirectly from genetic defects in PTEN (Homologous phosphatase and tensin removed on chromosome 10), TSCl (Tuberous sclerosis 1), TSC2 (tuberous sclerosis
. 84 2), NF1 (Neurofibromin 1), AMPK (AMP-dependent protein kinase STK11, serine / threonine kinase 11), LKB1, VHL (von Hippel-Lindau disease) and PKDl (polycystinal). Without being limited by theory, it is believed that genetic defects associated with these proteins result in hyperprolieferation of the mTOR / PI3K / Akt pathway.
Some particular diseases that are treatable or preventable by inhibiting the pathway of mTOR / PI3K / Akt include, but are not limited to, Cowden's disease, Cowden's syndrome, Cowden-like syndrome, Bannayan-Zonana syndrome, Bannayan- Riley-Ruvalcaba, Lhermitte-Duclos disease, endometrial carcinoma, tuberous sclerosis complex, lymphangioleiomyomatosis, neurofibromatosis 1, Peutz-Jeghers syndrome, renal cell carcinoma, von Hippel-Lindau disease, Proteus syndrome, and polycystic kidney disease ; rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; drop; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; gastritis; esophagitis; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus; erythematous atherosclerosis; restenosis following angioplasty; left ventricular hypertrophy; myocardial infarction; stroke; ischemic damage to heart, lung, intestines, kidney, liver, pancreas, spleen and brain; acute or chronic organ transplant rejection; organ preservation for transplantation; organ failure or limb loss (for example, including, but not limited to, that resulting from reperfusion damage due to ischemia, trauma, damage
- 85 gross body, car accident, collision damage or transplant failure); graft versus host disease; endotoxin shock; multiple organ failure; psoriasis; burns from exposure to fire, chemicals or radiation; eczema; dermatitis; skin graft; ischemia; ischemic conditions associated with surgery or traumatic damage (for example, vehicle accident, gunshot wound or crushing of a limb); epilepsy; Alzheimer's disease; Parkinson's disease; immune response to bacterial or viral infection; cachexia; angiogenic and proliferative diseases (including retinitis pigmentosa), solid tumors, and cancers of a variety of tissues such as colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary or uterus.
4.5 PHARMACEUTICAL COMPOSITIONS AND ROUTES OF
ADMINISTRATION The Heteroaryl Compounds produced by the processes provided in the present invention are useful for the preparation of pharmaceutical compositions, which comprises an effective amount of a Heteroaryl Compound and a pharmaceutically acceptable carrier or carrier. In some embodiments, the pharmaceutical composition described in the present invention is useful for oral, parenteral, mucosal, transdermal or topical administration.
5. EXAMPLES Chem-4D Draw (Chemlnnovation Software, Inc., San Diego, CA) or ChemDraw Ultra (Cambridgesoft, Cambridge, MA) was used to generate names for chemical structures.
V 86 The following abbreviations were used in the descriptions and examples: AmPhos: p-dimethylaminophenylditbutylphosphine Boc: tert-Butoxycarbonyl dba: dibenzylidenoacetone DIPEA: N, N-diisopropylethylamine DMSO: Dimethylsulfoxide ESI: ILC ionization: high performance HPLC melting point MS: NBS mass spectrometry: N-Bromosuccinimide NMR: nuclear magnetic resonance NMP: N-methylpyrrolidinone TFA: trifluoroacetic acid TLC: MTBE thin layer chromatography: tert-butyl methyl ether The following examples are presented by way of illustration, not limitation.
5.1 SYNTHETIC EXAMPLES Example 1: 7- (2-Amino-4-methyl-1H-benzo [d] imidazol-6-yl) -1 - ((tetrahydro-2H-pyran-4-yl) Methyl) - 3,4 -dihydropyrazine [2,3-b] lpyrazin-2 (1H) -one “OO Na NO
ES A. 2- (6-chloropyrazin-2-ylamino) ethyl acetate. 2,6-dichloropyrazine (50 g, 336 mmoles) and ethyl 2-aminoacetate (34.6 g, 336 mmoles) were added triethylamine (140 ml, 1,007 mmoles) and acetonitrile (350 ml). The reaction was heated to 80 ºC for 3 days. Triethylamine salts
: 87 precipitates were removed by filtration and washed with ethyl acetate and hexane (1: 1) multiple times. The filtrate and washing solvent were combined and concentrated. The resulting off-white yellow precipitate was filtered and washed with 20% ethyl acetate in hexane to provide an off-white solid. The filtrate was subjected to the same process to generate an additional batch of yellowish solid. The batches were combined to provide the title compound (35.5 g, 164 mmoles, 49% yield). MS (EST) m / z 216.1 [M + 1] *.
B. 2- (pyrazin-2-ylamino) ethyl acetate. Ethyl 2- (6-chloropyrazin-2-ylamino) acetate (23.6 gq, 109 mmoles) was dissolved in non-denatured ethanol (250 ml) and potassium carbonate (15.13 g, 109 mmoles) was added.
The reaction was put under nitrogen and palladium hydroxide (3.84 g, 5.47 mmoles) was added. The reaction was stirred under a hydrogen atmosphere for 18 hours. Additional palladium hydroxide (3.84 g, 5.47 mmoles) was added and the reaction was charged with additional hydrogen and allowed to stir overnight. The reaction was filtered through Celite and the solvent was removed under removed pressure to provide the title compound (15.13 g, 84 mmol, 76% yield). MS (ESI) m / z 182.3 [M + 1] ”.
ç. 2- (3,5-dibromopyrazin-2-ylamino) acetate - ethyl. Ethyl 2- (pyrazin-2-ylamino) acetate (7.6 g, 41.9 mmoles) was dissolved in dimethyl sulfoxide (80 ml) and water (4.00 ml) and cooled to 0 ºC. N-Bromosuccinimide (18.66 g, 105 mmoles) was added slowly over 15 minutes and the reaction was allowed to warm to the temperature
. 88 room and stirred for 48 hours.
An additional 1.5 equiv N-bromosuccinimide was added and the pit was allowed to stir overnight.
The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (150 ml). The aqueous layer was neutralized with sodium carbonate slowly, until pH-7 and extracted with ethyl acetate (3x150 ml). The organic layers were grouped, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was triturated with 25 to 33% ethyl acetate in hexane and the resulting precipitate was filtered to generate a yellow solid.
The remaining brown residue was purified using Biotage silica gel chromatography (0 to 60% ethyl acetate in hexane) to generate another batch of yellowish solid.
The two batches were combined to provide 24 g of the title compound (24 g, 71 mmoles, 75% yield). MS (ESI) m / z 338.1 [M] *,
340.1 [M + 2] *, 3421 [M + 4] *. D. 2- (5-bromo-3 - ((tetrahydro-2H-pyran-4-yl) methylamino) pyrazin-2-ylamino) ethyl acetate. 2- (3,5-dibromopyrazin-2-ylamino) ethyl acetate (2.00 g, 5.90 mmoles), (tetrahydro-2H-pyran-4-yl) methanamine (0. 713 o, 6.19 mmoles), N, N-diisopropylethylamine (3.08 ml, 17.70 mmoles) and dimethyl sulfoxide (4 ml) were combined in a microwave flask with a stir bar and heated in a Biotage Emrys microwave reactor Optimizer at 150 ºC for 1 hour.
The resulting mixture was transferred to a round bottom flask with methanol.
Methanol and N, N-diisopropylethylamine were removed under reduced pressure and the residue purified using flash chromatography
. 89 Biotage (5 to 100% ethyl acetate in hexane). The fractions containing the desired product were combined in a separating funnel and washed twice with water and once with brine. The organic products were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dried under high vacuum at 50 ° C to generate the desired impure product (1.578 g) as an amber wax solid which was taken in the next step without further purification. MS (EST) m / z 373.4 [M] ', 375.4 [M + 2] *.
E. 7-Bromo-1 - ((tetrahydro-2H-pyran-4-yl) methyl) - 3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one. A stirred solution of ethyl 2- (5-bromo-3 - ((tetrahydro-2H-pyran-4d-yl) methylamino) pyrazin-2-ylamino) acetate (1,474 g9g, 3.95 mmol) in acetic acid (13 ml) in a sealed vessel was heated to 120 ºC in an oil bath for 2 hours. Acetic acid was removed under reduced pressure. The residue was divided between ethyl acetate and saturated aqueous sodium bicarbonate, stirred and the layers separated. The water layer was extracted twice with ethyl acetate. The combined organic products were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in dichloromethane and hexane and the resulting solids collected by vacuum filtration. The solids were washed with hexane and dried under vacuum to generate the desired product (0.879 g, 2.688 mmoles, 68% yield) as a purple solid. MS (EST) m / z 327.1 [M] ", 329.0 [M + 2]".
F. 2-Methyl-6-nitro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline. 4-Bromo-2-methyl-6-nitroaniline (5 g, 21.64 mmoles), bis (pinacolate) diboro (5.50 g, 21.64 nmmoles), potassium acetate (6.37 g, 64.9 mmoles) and N, N-
; 90 dimethylformamide (100 ml) was combined and degassed under vacuum. Palladium acetate (0.243 g, 1.082 mmoles) was added and the system was degassed again. The reaction was heated to 90 ºC for 2 hours. The reaction was extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in hexanes) to generate yellow solid (5.3 g, 19.0 mmoles, 88% yield). MS (EST) m / z 279.0 [M + 1] *.
and. 3-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzene-1,2-diamine. A solution of 2-Methyl-6-nitro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (5.3 g, 19.06 mmol) in methanol (50 ml) was purified with nitrogen gas. Carbon palladium (10% by weight, 50 mg) was added and the reaction mixture was stirred under a hydrogen balloon for 16 hours. The reaction was filtered through Celite and the filter cake was washed with methanol. The filtrate was concentrated and the resulting material was purified by silica gel column chromatography (0 to 100% ethyl acetate in hexanes) to generate a dark oil. The oil was triturated with 10% ether in hexanes to generate a yellow-brown solid (4.2 g, 16.9 mmoles, 89% yield). MS (ESI) m / z 248.9 [M + 1] ".
H. 7- (3,4-Diamino-5-methylphenyl) -1 - ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) - ona. 3-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzene-1,2-diamine (0.523 g, 2.109 mmoles), 7-bromo-1-
.: 91 ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one (0.600 g, 1.834 mmol), bis (diphenylphosphine) - ns ferrocene] dichloropalladium (II), complex with dichloromethane (1: 1) (0.150 g, 0.183 mmol), sodium carbonate (1 M in water, 5.50 mmol), 1,4-dioxane (4.1 ml) and isopropanol (1.4 ml) was combined in a sealable vessel with a stir bar. The system was purified with nitrogen. The resulting mixture was sealed, stirred vigorously and heated to 100 ºC for 3.5 hours. The resulting mixture was diluted with 20% methanol in dichloromethane and all volatiles removed under reduced pressure. The residue was taken up in 20% methanol in dichloromethane and concentrated under reduced pressure with silica gel. The residue was purified with flash chromatography (1 to 10% methanol in dichloromethane) to generate the desired product (0.669 g, 1.818 mmoles, 99% yield) as a brown solid. MS (EST) m / z 369.1 [M + 1] *.
1. 7- (2-Amino-4-methyl-1H-benzo [d] imidazol-6-yl) - 1 - ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2 , 3-Dblpirazin-2 (1H) -one. Cyanogen bromide (0.059 g, 0.556 mmol) in N, N-dimethylformamide (0.5 ml) was added to a stirred solution of 7- (3,4-diamino-5S-methylphenyl) -1-1- ((tetrahydro-2H -pyran-4-yl) methyl) -3,4-dihydropyrazine [| 2,3-blpyrazin-2 (1H) -one (0.195 g, 0.529 mmol) in N, N-dimethylformamide (3 ml) at 0 ° C. The resulting dark brown mixture was capped and stirred at room temperature for 16 hours. The resulting mixture was diluted with methanol, filtered and purified using reverse phase preparatory HPLC (5 to 50% acetonitrile + 0.1% TFA in water + 0.1% TFA, for 30 minutes). The fractions containing the
: 92 desired product were combined and most of the solvent was removed under reduced pressure. The residue was loaded onto a Phenomenex Strata X-C ion exchange column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product was eluted with 5% ammonium hydroxide in eluent methanol and was concentrated under reduced pressure and dried under high vacuum at 50 ° C to obtain the desired product (0.130 g, 0.331 mmol, 62% yield) as an orange solid . NMR 'H (400 MHz, Dan and DMSO-ds) 3 (ppm) 8.13 (s, 1H), 7.56 (s, 1H), 7.36 (s, 1H), 4.18 (s, 2H), 4.03 (d, J = 6.64 Hz, 2H), 3.84 and 3.90 (m, 2H), 3.24 (t, J = 11.32 Hz, 2H), 2, 40 (s, 3H), 2.04 and 2.19 (m, 1H), 1.59 (d, J = 12.10 Hz, 2H), 1.25 and 1.41 (m, 2H); MS (EST) m / z 394.2 [M + 1] *.
Example 2: 3,3-Dimethyl-6- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4- il) ethyl) - 3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one EV 7 "Or E to
H A. 3- (4-Bromo-3-methylphenyl) -4H-1,2,4-triazole. 4- Bromo-3-methylbenzonitrile (10.0 g to 51.0 mmols) was dissolved in ethanol (200 ml) with stirring and cooled to O ºC under nitrogen. Hydrogen chloride gas was bubbled into the reaction mixture for 20 minutes. The resulting reaction mixture was capped and stirred while being slowly warmed to room temperature for 5.5 hours. The solvent was removed under reduced pressure and the residue dried under vacuum
. 93 to obtain 13.86 g of an off-white solid.
The off-white solid, formic hydrazide (4.48 g, 74.6 mmols), triethylamine (28.0 ml, 199 mmol) and ethanol (90 ml) were combined in a sealed tube and heated, with stirring, to 90 ºC for 6.5 hours.
All the solvent was removed under reduced pressure and the resulting residue was partitioned between ethyl acetate and water.
The layers were separated from the organic materials washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was dissolved in hot ethyl acetate (13 ml), capped and left to stand at room temperature overnight.
The solvent was decanted from the solids at the bottom of the flask.
The solids were washed with ethyl acetate and diethyl ether and vacuum dried at 45 ° C to obtain the desired product (7.47 g, 31.4 mmols, 63% yield) as a light yellow solid.
MS (EST) m / z 238.2 [M] ',
240.3 [M + 2] ”. B. 3- (4-Bromo-3-methylphenyl) -4- (tetrahydro-2H-pyran-2-1yl) -4H-1,2,4-triazole. 3- (4-Bromo-3-methylphenyl) -4H- 1,2,4-triazole (2.00 g, 8.40 mmoles) was dissolved in tetrahydrofuran (10 ml) at room temperature with stirring under nitrogen. 3,4-Dihydro-2H-pyran (3.80 ml, 42.0 mmol) and methanesulfonic acid (0.027 ml, 0.42 mmol) were added and the resulting mixture heated to 50 ° C in a reflux condenser under nitrogen for 20 hours.
The resulting mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine.
The organic materials were dried over magnesium sulfate, filtered and concentrated under reduced pressure.
Fast chromatography (10 to 30 to 50%
NR 94 of ethyl acetate in hexanes) provided the desired product (2.64 g, 8.22 mmol, 98% yield) as a yellow oil. MS (EST) m / z 322 [M] ", 324 [M + 2] *.
CC. 3- (3-Methyl-4- (4,4,5,5-tetramethyl-1,3,2- —dioxaborolan-2-yl) phenyl) -4- (tetrahydro-2H-pyran-2-1yl) - 4H- 1,2,4-triazole. 3- (4-Bromo-3-methylphenyl) -4- (tetrahydro-2H-pyran-2-yl) -4H-1,2,4-triazole (2.294 Gg, 712 mmol), bis (pinacolate) diboro (1,898 q, 7.48 mmols), [1,1'-bis (diphenylphosphino) -ferrocene] dichloropalladium (II), complex with dichloromethane (1: 1) (291 mg, 0.36 mmol), potassium acetate (2.096 g , 21.4 mmols) and dimethyl sulfoxide (15 ml) were combined in a round bottom flask and stirred. The atmosphere in the flask was removed in vacuo and replaced with nitrogen three times. The resulting mixture was heated to 90 ºC under nitrogen for 4 hours. The resulting mixture was diluted with ethyl acetate and filtered through Celite. The filter cake was washed completely with ethyl acetate. The filtered material was washed twice with water, once with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (30 to 50% ethyl acetate in hexanes) provided a waxy semisolid which was ground with hexane at 45 ºC. The resulting solids were vacuum dried to obtain the desired product (2.10 g, 5.69 mmols, 80% yield) as a pink powder. MS (ESI) m / z 370 [M + 1] ".
D. Terc-butyl 1- (3,5-dibromopyrazin-2-ylamino) -2-methyl-1-oxopropan-2-ylcarbamate. 1,1 '-Carbonyldiimidazole (2.63 g, 16.24 mmol) was added to a stirred solution of 2- (tert-butoxycarbonylamino) -2-methylpropanoic acid
. 95 (3.00 g, 14.76 mmols) in N, N-dimethylformamide (4 ml) and dichloromethane (8 ml) at room temperature.
The resulting clear colorless mixture was stirred at room temperature under nitrogen for 3 hours.
N, N-Diisopropylethylamine (3.86 Sm, 22.14 mmol) was added followed by 375 dibromopyrazin-2-amine (5.60 g, 22.14 mmol). The resulting mixture was heated to 50 ºC in a reflux condenser under nitrogen for 71 hours.
Dichloromethane was removed under reduced pressure.
The residue was diluted with ethyl acetate and washed with water.
The water layer was extracted with ethyl acetate.
The combined organic materials were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was triturated with 30% ethyl acetate in hexane and the solids were collected by vacuum filtration.
The filtered material was concentrated under reduced pressure and purified using flash chromatography (5 to 50% ethyl acetate in hexane). The fractions containing the desired product were combined with the solids obtained by filtration and concentrated under reduced pressure.
The residue was dried under high vacuum to obtain the desired product (2.38 g, 5.43 mmols, 37% yield) as an off-white solid.
MS (EST) m / z 439.3 [M + 1] *, 461.1 [M + Na] ”. AND.
N- (3,5-Dibromopyrazin-2-yl) -2-methyl-2- (2- (tetrahydro-2H-pyran-4-yl) ethylamino) propanamide trifluoroacetate.
TFA (3.66 ml, 47.5 mmols) was added to a stirred mixture of tert-butyl 1- (3,5-dibromopyrazin-2-ylamino) -2-methyl-1-oxopropan-2-ylcarbamate (1, 04 g, 2.374 mmols) in dichloromethane (20 ml). The resulting light yellow solution was stirred at room temperature
- 296 for 3 hours.
All volatile materials were removed under reduced pressure and the residue dried under high vacuum to obtain a yellow semi-solid.
MS (ESI) m / z 339.1 [M + 1] ". Sodium sulfate (1.686 g, 11.87 mmols) was added followed by 2- (tetrahydro-2H-pyran-4-yl) acetaldehyde (0.396 g , 3.09 mmols) and 1,2-dichloroethane (20 ml) The resulting mixture was stirred vigorously and heated to 80 ºC in a reflux condenser under nitrogen for 2.5 hours.
More 2- (tetrahydro-2H-pyran-4-yl) acetaldehyde (0.100 g, 0.780 mmol) and sodium sulfate (1.00 g, 7.04 mmols) were added and heating at 80 ° C continued for another 2 hours .
The resulting yellow solution was removed with a pipette of solid sodium sulfate into a dry 250 ml round bottom flask equipped with a stir bar.
The resulting mixture was stirred vigorously and cooled to 0 ºC under nitrogen.
Sodium triacetoxyborohydride (0.553 g, 2.61 mmol) was added slowly.
The resulting mixture was stirred vigorously at 0 ºC under nitrogen for 30 minutes.
The cold bath was removed and the resulting mixture stirred at room temperature under nitrogen for 2 hours.
The mixture was cooled to 0 ° C and more sodium triacetoxyborohydride (0.250 g, 1.180 mmols) was added.
The ice bath was removed and the resulting mixture stirred at room temperature under nitrogen for 1.5 hours.
More sodium triacetoxyborohydride (0.055 g, 0.260 mmol) was added.
The resulting mixture was stirred vigorously at room temperature under nitrogen for 1 h and then stirred overnight at 0 ºC.
The resulting mixture was diluted with methanol and the volatile materials removed under reduced pressure.
The residue was
. 97 collected in methanol, filtered and purified using reverse phase preparatory HPLC (10 to 40% acetonitrile + 0.1% TFA in water + 0.1% TFA, for 30 minutes). The fractions containing the desired product were combined and the solvent removed under reduced pressure.
The residue was vacuum dried to obtain the desired product (0.890 g, 1.978 mmols, 67% yield) as a slightly yellow foamed solid.
MS (EST) m / z 451.3 [M + 1] ". F. 6-Bromo-3,3-dimethyl-4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3, 4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one.
N- (3,5-Dibromopyrazin-2-yl) -2-methyl-2- (2- (tetrahydro-2H-pyran-4-yl) ethylamino) propanamide trifluoroacetate (0.856 g, 1.517 mmol), N, N -diisopropylethylamine (1.321 ml, 7.59 mmol) and 1,4-dioxane (25 ml) were combined in a sealable vessel with a stir bar.
The system was purged with nitrogen and the resulting mixture was sealed, vigorously stirred and heated to 110 ºC for 2.5 hours.
The reaction mixture was concentrated under reduced pressure and purified using flash chromatography (5 to 50% ethyl acetate in hexane) to obtain the desired product (0.394 g, 1.068 mmols, 70% yield) as a white solid. .
MS (EST) m / z 369.4 [M] *, 371.3 [M + 2] ". G. 3,3-Dimethyl-6- (2-methyl-4- (4- (tetrahydro-2H- pyran-2-yl) -4H-1,2,4-triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2 , 3-b] pyrazin-2 (1H) - one. 3- (3-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -4 - (tetrahydro-2H-pyran-2-yl) -4H-1,2,4-triazole (1 equivalent), 6-bromo-3,3-dimethyl-4- (2- (tetrahydro-2H-pyran-4 -yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (1 equivalent), [1,1'-bis (diphenylphosphino) -ferrocene]
. 98 dichloropalladium (II), complex with dichloromethane (1: 1) (0.1 equivalent), 1M sodium carbonate in water (3 equivalent), 1,4-dioxane and isopropanol were combined and the system was purged with nitrogen.
The resulting mixture was stirred vigorously and heated to 100 ºC for 1.5 hours.
The resulting mixture was cooled to room temperature, diluted with methanol and the volatile materials removed under reduced pressure.
The residue was partitioned between dichloromethane and water, shaken and the layers separated.
The water layer was extracted with dichloromethane.
The combined organic materials were dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was purified using flash chromatography (20 to 100% ethyl acetate in hexane followed by 0 to 10% methanol in dichloromethane) to obtain the desired product in 97% yield.
MS (EST) m / z 532.7 [M + 1] *. H. 3,3-Dimethyl-6- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl ) ethyl) -3,4-dihydropyrazine [2,3-b] lpyrazin-2 (1H) -one.
6N hydrochloric acid in water was added to a stirred mixture of 3,3-dimethyl-6- (2-methyl-4- (4- (tetrahydro-2H-pyran-2-yl) -4H-1,2,4- triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one in ethanol at 80 ºC.
The resulting mixture was stirred vigorously and heated to 80 ºC in a reflux condenser under nitrogen for 70 minutes.
The resulting mixture was filtered and purified using reverse phase preparatory HPLC (10 to 65% acetonitrile + 0.1% TFA in water + 0.1% TFA, for 30 minutes). The fractions containing the desired product were combined, neutralized with
: 99 saturated aqueous sodium bicarbonate and acetonitrile removed under reduced pressure. The solids were collected by vacuum filtration, washed completely with water and diethyl ether and dried under high vacuum at 50 ºC to obtain the desired product in 48% yield. NMR 'H (400 MHz, DMSO-ds) 5 (ppm) 11.32 (br. S., 1H), 8.44 (br. S., 1H), 7.96 (s, 1H), 7, 90 (d, J = 8.59 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J = 7.81 Hz, 1H), 3.78 (dd, J = 2.93 , 11.13 Hz, 2H), 3.52 and 3.64 (m, 2H), 3.23 (t, 3 = 10.93 Hz, 2H), 2.48 (s, 20 3H) 1.51 and 1.65 (Mm 5494), 1.49 (S, / 6H) II 11 and 26 (m, 2H); MS (EST) m / z 448.3 [M + 1] ”.
Example 3: 7- (2-Methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one hydrochloride No HO HO No
XJ pn KH A. 2- (5-bromo-3- (2,4-dimethoxybenzylamino) pyrazin-2-ylamino) ethyl acetate. 2- (3,5-dibromopyrazin-2-ylamino) ethyl acetate (See Example 1.C) (1.06 gq, 3.13 mmol), (2,4-dimethoxyphenyl) methanamine (0.601 g, 3.60 mmols), N, N-diisopropylethylamine (1.63 ml, 9.38 mmols) and dimethyl sulfoxide (1.6 ml) were combined in a microwave vessel with a stir bar and heated in a microwave reactor at 150 ºC for 2 hours. The resulting mixture was purified using flash chromatography (5 to 60% ethyl acetate in hexane). The fractions containing the desired product were combined and concentrated almost to dryness under reduced pressure. Ethyl acetate
. 100 (2 ml) and hexane (18 ml) was added. The resulting solids were collected by vacuum filtration, washed with hexane and dried under high vacuum to obtain the desired product (0.636 g, 1.495 mmols, 48% yield) as a light pink solid. NMR * H (300 MHz, DMSO-ds) 3 (ppm) 7.24 (8 // 21H), / 17/19 (du = / 8.52 / H2, 1H), 7.11 4t, J / = 15.63 / Hz2, 1H), 6.84 (t, J = 4.81 Hz, 1H), 6.59 (d, J = 2.47 Hz, 1H), 6.50 (dad, J = 2 , 20, 8.24 Hz, 1H), 4.37 (dA, J = 4.67 Hz, 2H), 13.96 and 4.15 (mm, AH) 3, 81 (8, 3H) 13.75 (s, / 3H), 1:17 (t, 3H); MS (EST) m / z 425.3 [M] *, 426.9 [M + 2] *.
B. T7-Bromo-3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H8) -one trifluoroacetate. 2- (5-bromo-3- (2,4-dimethoxybenzylamino) pyrazin-2-ylamino) ethyl acetate (0.484 g, 1.138 mmol), methanol (0.461 ml, 11.38 mmol) and TFA (7 ml) were combined in a sealable vessel with a stir bar. The system was purged with nitrogen. The resulting mixture was sealed, stirred vigorously and heated to 75 ºC in an oil bath for 25 minutes. The resulting mixture was diluted with water (14 ml) and stirred at room temperature for 5 minutes. The solids were collected by vacuum filtration, washed with water and diethyl ether and dried under high vacuum to obtain the desired product (0.375 g, 1.093 mmols, 96% yield) as a pink solid. MS (ESI) m / z 229.0 [M] ', 231.3 [M + 2] *.
C. T7- (2-Methyl-4- (4- (tetrahydro-2H-pyran-2-yl) -4H- 1,2,4-triazol-3-1l) phenyl) -3,4-dihydropyrazine [2 , 3-b] pyrazin-2 (1H) -one. 3- (3-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -4- (tetrahydro-2H-pyran-2-yl) -4H - 1,2,4-triazole (See Example 2.C) (0.465 g, 1.259 mmol), T7-bromo-3,4-dihydropyrazine trifluoroacetate (| 2,3-
blpirazin-2 (1H) -one (0.432 Sr 1.259 mmol), [1.1 '"- bis (diphenylphosphine) - ferrocene] dichloropalladium (II), complex with dichloromethane (1: 1) (0.103 g, 0.126 mmol), sodium carbonate (1M in water, 3.78 ml, 3.78 mmols), 1,4-dioxane (2.5 ml) and isopropanol (1 ml) were combined in a sealable vessel with a stir bar.
The system was purged with nitrogen.
The resulting mixture was sealed, stirred vigorously and heated to 100 ºC for 70 minutes.
The resulting mixture was diluted with water and dichloromethane and filtered through a frit funnel.
The solids were washed with 20% methanol in dichloromethane.
The filtered and washed materials were combined and the solvent was removed under reduced pressure.
The residue was triturated with acetonitrile.
Water was added.
The solids were collected by vacuum filtration and washed thoroughly with water and diethyl ether.
The solids were washed with 20% methanol in dichloromethane.
The filtered and washed materials were combined and the solvent was removed under reduced pressure.
The residue was collected in hot DMSO and methanol, filtered and purified using reverse phase preparatory HPLC (20 to 65% acetonitrile + 0.1% TFA in water + 0.1% TFA, for 30 minutes) . The fractions containing the desired product were combined, neutralized with saturated aqueous sodium bicarbonate and concentrated almost to dryness under reduced pressure.
The solids were collected by vacuum filtration, washed with water and dried under high vacuum to obtain the desired product (0.072 g, 0.184 mmol, 15% yield)
like an off-white solid.
MS (EST) m / z 392.1 [M + 1] *. D.
7- (2-Methyl-4- (4H-1,2,4-triazole- hydrochloride)
3-yl) phenyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one.
. 102 Hydrochloric acid (6N in water 0.149 ml, 0.894 mmol) was added to a stirred mixture of 7- (2-methyl-4- (4- (tetrahydro-2H-pyran-2-yl) -4H-1,2, 4-triazol-3-yl) phenyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (0.070 g. 0.179 mmol) in ethanol (3 ml) at 80 ° C. The system was purged with nitrogen. The resulting mixture was sealed and heated to 80 ° C. The resulting mixture was heated to 80 ºC for 25 minutes and then cooled to room temperature. The solids were collected by filtration, washed with methanol and dried under high vacuum at 40 ºC to obtain the desired product (0.058 g, 0.169 mmol, 94% yield) as a white solid. NMR 'H (300 MHz, DMSO-ds) 5 (ppm) 11.32 (s, 1H), 8.66 (s, 1H), 7.97 (s, 1H), 7.92 (dd, J = 1.37, 7.97 Hz, 1H), 7.74 (s, 1H), 7.50 (d, IJ = 7.97 Hz, 1H), 4.14 (s, 2H), 2.44 ( s, 3H); MS (ESI) m / z 308.3 [M + 1] *. Example 4: 6- (4- (2-Hydroxypropan-2-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin -2 (1H) -one PO:
SL A. 2-Bromo-N- (3,5-dibromopyrazin-2-yl) acetamide. A solution of 2-amino-3,5-dibromopyrazine (6.17 gq, 23.7 mmols) and bromoacetic anhydride (3.0 g, 11.9 mmol) in acetonitrile (40 ml) was stirred at 70 ° C. After the complete consumption of the starting material (by TLC), the solution was condensed and partitioned between water and ethyl acetate (3X). The organic layers were combined, dried over magnesium sulfate, filtered and the solvent was removed
. 103 under reduced pressure. The resulting material was purified using Biotage column chromatography (5 to 80% ethyl acetate in hexanes) to provide the title compound (3.78 g, 10.1 mmols, 85% yield). MS (ESI) m / z 372.1 [M-2] *, 374.0 [M] *, 376.1 [M + 2] ', 378.3 [M + 4] *.
B. 6-Bromo-4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one. 2-Bromo-N- (3,5-dibromopyrazin-2-yl) acetamide (3.30 g, 8.83 mmol) and 2- (tetrahydro-2H-pyran-4-yl) ethanamine hydrochloride (1.46 , 8.83 mmol) and diisopropyl ethylamine (6.67 ml, 35.3 mmol) were combined and heated to 85 ° C. After the complete consumption of the starting material (by TLC), the reaction solution was condensed and purified by means of Biotage chromatography (0 to 100% ethyl acetate in hexanes) to provide the title compound (1.53 g, 4 , 48 mmols, 50% yield). MS (EST) m / z 341.4 [M] *, 343.1 [M + 2] *.
CC. 2- (4-Bromophenyl) propan-2-ol. 1- (4- Bromophenyl) ethanone (9.25 g, 46.5 mmols) was dissolved in tetrahydrofuran (200 ml). The solution was cooled in a -50 ºC bath. Methylmagnesium bromide (3M in ether, 46.5 ml, 139 mmols) was added over a period of 15 minutes. The reaction was allowed to warm to room temperature and then stirred for 20 hours. The reaction was quenched with saturated ammonium chloride and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain an oil. The oil was purified on a silica gel column (0 to 20% ethyl acetate in hexanes) to
. 104 obtain the product a colorless oil (9.1 g, 46.2 mmols, 91% yield). MS (EST) m / z 197.1 [M] *, 199.1 [M + 2] *. D. 2- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-01. 2- (4-Bromophenyl) propan-2-0l (4.7 g, 21.85 mmols), bis (pinacolato) diboro (6.66 g, 26.2 mmols), potassium acetate (6.43 g, 65.6 mmols) and dimethyl sulfoxide (50 ml) were stirred and degassed under vacuum for 10 minutes. [1,1'-Bis (diphenyl-phosphine) ferrocene] dichloro-palladium (II) complex with dichloromethane (1: 1) (0.892 g, 21.093 mmol,) was added and the reaction was degassed for another 5 minutes. The reaction was then heated to 80 ºC under nitrogen for 2 hours. The reaction was cooled to room temperature and then extracted with 1: 1 ether: ethyl acetate and water. The resulting black emulsion was filtered through a pad of celite and the filtered material combined with extraction layers. The organic layer was dried over magnesium sulfate, filtered and then purified on a silica gel column (0 to 25% ethyl acetate in hexanes). The product fractions were concentrated and then crushed in hexanes to a white solid (4.0 g, 15.3 mmols, 70% yield). MS (EST) m / z 263.3 [M + 1] *.
E. 6- (4- (2-Hydroxypropan-2-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin- 2 (1H) -one. 6-Bromo-4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one (0.250 g, 0.733 mmol), 2 - (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-01 (0.192 g, 0.733 mmol) and dichloride [1,1'-bis (diphenylphosphino) ferrocene] palladium (IL) dichloromethane (0.030g, 0.037 mmol) were combined in
+ 105 dimethylformamide (1.0 ml). Sodium carbonate (0.311 g, 2.93 mmols) in water (0.2 ml) was added and the reaction solution was then heated in a Biotage Emrys Optimizer microwave reactor at 120 ºC for 15 minutes. The cooled reaction solution was filtered through Celite and the filter cake was washed with ethyl acetate. The filtered material and ethyl acetate wash were combined and the solvent removed under reduced pressure. The resulting material was purified using Biotage column chromatography (0 to 5% methanol in ethyl acetate) followed by trituration with dimethylformamide and water to provide the title compound (0.074 g, 0.19 mmol, 25%) NMR '* H (400 MHz, DMSO-ds) S (ppm) 12.24 (s, 1H), 7.98 (s, 1H), 7.89 (d, 3 = 8.39 Hz, 2H), 7 , 53 (d, 9 = 8.39 Hz, 1H), 5.04 (s, 1H), 4.16 (s, 1H), 3.82 (dd, 3 = 11.1, 2.39 Hz, 2H), 3.61 (t, = 7.59 Hz, 2H), 3.25 (t, 3 = 9.59 Hz, 3H), 1.70 (s, 1H), 1.66 (s, 1H ), 1.58 (m, 3H), 1.44 (s, 6H), 1.25 (m, 2H); MS (EST) m / z 397.2 [M + 1] *; mp 210 at 212 ºC.
Example 5: 6- (6- (2-Hydroxypropan-2-yl) pyridin-3- 11) -4- (2-morpholinoethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one O N
S "AA is not A. A. 2-Chloro-N- (3,5-dibromopyrazin-2-yl) acetamide.
The solution of 2-amino-3,5-dibromopyrazine (3.0 g, 11.9 mmols) and chloroacetic anhydride (4.2 g, 8.7 mmols) were reacted in acetonitrile (10 ml) at 70 ºC for 16 hours. THE
. 106 solution was condensed and diluted with ethyl acetate. The organic materials were washed with a 1: 1 solution of sodium bicarbonate (saturated) and potassium carbonate (1.75 M in water) (4X). The organic materials were combined, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The resulting solid was triturated with 10% ethyl acetate in hexanes to provide the title compound (3.12 g, 9.3 mmol, 72% yield). MS (ESI) m / z 328.3 [M-1] *, 330.4 [M + 1] *, 332.3 [M + 3] *.
B. N- (3,5-Dibromopyrazin-2-yl) -2-iodoacetamide. To a solution of 2-chloro-N- (3,5-dibromopyrazin-2-yl) acetamide (3.0 g, 9.11 mmols) in acetone (40 ml) was added sodium iodide (13.65 g, 91 mmols) dissolved in acetone (20 ml). The solution was allowed to stir at room temperature for 16 hours. The solution was condensed under reduced pressure and diluted with ethyl acetate (500 ml) and washed consecutively with water (5X) to remove the blue color. The organic materials were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to provide the crude product. The solid was diluted with 10% ethyl acetate in hexanes (40 ml) and sonicated while rubbing the sides of the flask. The solution was then heated by a heat gun for 5 minutes, then cooled while sonicating at room temperature. The resulting solid was filtered and washed with additional hexanes and dried in vacuo to provide the title compound (3.0 g, 7.13 mmol, 78% yield). MS (ESI) m / z 420.3 [M-1] ', 422.0 [M + 1] ", 424.0 [M + 3] *.
»107 Cc. 6-Bromo-4- (2-morpholinoethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one. N- (3,5- Dibromopyrazin-2-yl) -2-iodoacetamide (0.5 g, 1.188 mmol), diisopropylethylamine (0.415 ml, 2.376 mmol) and morpholinoethanamine (0.162 g, 1.248 mmol) were combined in acetonitrile (5 ml). The solution was heated to 45 ºC for 1 hour. The solution was condensed and diluted with 75% ethyl acetate in hexanes. The resulting solid was filtered and the filtered material collected and condensed followed by purification by means of Biotage chromatography (0 to 75% ethyl acetate in hexanes, then 0 to 10% methanol in ethyl acetate) to provide the title compound ( 0.228 g, 0.67 mmol, 56% yield). MS (ESI) m / z 342.4 [M] *, 344.4 [M + 2] *.
D. 2- (5-Bromopyridin-2-yl) propan-2-ol. 2.5 Dibromopyridine (1.04 g, 4.39 mmols) was dissolved in toluene (22 ml) in a 100 ml round bottom flask. The mixture was cooled to -78 ° C. n-Butyl lithium (3.02 ml, 4.83 mmols) was added by dripping. The mixture was stirred 30 minutes, followed by the addition of acetone (2 ml). The mixture was stirred 40 minutes and then allowed to warm to room temperature. The mixture was washed with ammonium chloride (5% aqueous, 50 ml), water (50 ml) and then brine (50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by Biotage (16% ethyl acetate in hexanes). The concentration of the desired fractions provided the product (0.82 gq, 3.78 mmols, 86% yield). MS (ESI) m / z 216.0 [M] *, 218.1 [M + 2] *.
- 108 E. 2- (5- (Trimethylstanil) pyridin-2-yl) propan-2-ol. 2- (5-Bromopyridin-2-yl) propan-2-ol (0.34 g, 1.574 mmol), 1,1,1,2,2,2-hexamethyldiestanane (0.361 ml, 1.652 mmol) and tetracis (triphenylphosphine ) palladium (0) (0.182 1o, 0.157 mmol) were combined in toluene (5 ml) in a 50 ml refillable bottle.
The reaction was stirred at 115 ºC for 1.5 hours.
The mixture was then concentrated to about a volume of 2 ml.
The residue was purified by means of Biotage (16% ethyl acetate in hexanes). The concentration of the desired fractions provided the title compound (0.33 g, 1.10 mmols, 70% yield). MS (ESI) m / z 302.1 [M + 1] *. F. 6- (6- (2-Hydroxypropan-2-yl) pyridin-3-11) -4- (2-morpholinoethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one. 6-Bromo-4- (2-morpholinoethyl) -3,4-dihydropyrazine [2,3-bl] lpyrazin-2 (1H) -one (0.228 Ss, 0.666 mmol) and 2- (5- (trimethylstannyl) pyridin- 2-yl) propan-2-01 (0.220 g, 0.733 mmol) were combined in dimethylformamide (3 ml). The solution was purged with nitrogen gas followed by the addition of dichloroll1, bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane (0.109 g, 0.133 mmol). The solution was heated to 100 ºC for 2 hours.
The solution was condensed under reduced pressure and the resulting oil purified by means of preparative reverse phase HPLC (5 to 60% acetonitrile + 0.1% TFA in H20 + 0.1% TFA, for 30 minutes) and the desired fractions were loaded onto a Strata-XC ion exchange column.
The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol.
The product eluted with 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried
. 109 to provide the title compound (0.070 g, 0.18 mmol, 26% yield). NMR * H (400 MHz, DMSO-d6) 5 (ppm) 11.33 (br. S :, 1H), 9.05 (0d, U = I, 56 Hr, 1H), 8.27 (dd, O = 8.59, 2.34 Hz, 1H), 8.06 (s, 1H), 7.72 (d, 3 = 8.59 Hz, 1H), 5.27 s (er 21H), 4.29 (8, 2H), 3/71 (ty, UU = 6.44 Hz, 2H), 3.54 (Lt = 4.49 Hr, AH), 2.62 (t, JU = 6.44 Ho, 2H ), 2.40 2 2.48 (mM, 4H), 1.46 (s, 6H); MS (EST) m / z 399.2 [M + 1] * '; mp 239 to 241 e. Example 6: 1 - ((((trans) -4-Methoxycyclohexyl) methyl) - 7- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-11) -3 , 4-dihydropyrazine [2,3-b] lpyrazin-2 (1H) -one. HN- “o. and Ny YEAR
AND DO: A. 5-Bromo-4-methylpicolinonitrile. 2,5-Dibromo-4-methylpyridine (5.0 g, 19.9 mmol), copper cyanide (1.43 g, 15.9 mmol), sodium cyanide (0.801 g, 16.3 mmol) and dimethylformamide (30 ml) were combined in a sealed reaction vessel and heated to 158 ºC for 3 hours. The reaction mixture was purified by silica gel column chromatography (80% ethyl acetate in hexanes). The resulting material was subjected to a second column of silica gel (0 to 20% methanol in dichloromethane). The clean fractions were combined and concentrated to provide the title compound as a white solid (2.30 g, 11.6 mmol, 58% yield). MS (EST) m / z 198.0 (M + 1] *. B. 2- (3,5-dibromopyrazin-2-ylamino) ethyl acetate - * A 3,000 round neck three-necked flask
. 110 ml 3-was loaded with 2-amino-3,5-dibromopyrazine (172 g, 680 mmols) in dimethylformamide (860 ml) and cooled to 0 to ºC.
Cesium carbonate (288 g, 884 mmol) was added in one portion followed by adding portion to portion of 5 ethyl chloroacetate (87 ml, 816 mmol). The solution was allowed to be heated to 20 to 25 ºC, then heated to 55 ºC (observed exotherm, maximum observed temperature 76 ºC). Once the temperature of the internal reaction decreased to 65 ºC the reaction was heated to 65 ºC for -4 hours.
The reaction was cooled to 20 to 25 ° C and filtered through a paper filter to remove inorganic salts and the solid was washed with dimethylformamide (3 vol). The filtered material was added by dripping 16 vol of ice-water (8 vol of ice / 8 vol of water) and the aqueous slurry was allowed to stir for 12 to 24 hours.
The resulting brown solid was isolated after filtration and washed with water (10 vol) and dried in air.
The crude product was dissolved in methyl t-butyl ether (3.46 1, 15 vol). Coal (C-906 with Ecosorb, 20% by weight, 46.1 g) was added and the mixture was heated to reflux for 1 hour.
After drying at room temperature, the coal was removed by a bed of Celite and the filtered material was concentrated to dryness.
The raw material was dissolved in ethyl acetate (576 ml, 2.5 vol) and concentrated to a thick aqueous paste.
A solution of 2% ethyl acetate in heptane (1.15 1.5 vol) was added and the mixture was stirred at room temperature for 30 to 60 minutes.
The product was collected by filtration, washed with heptane (2 to 3 vol) and dried under high vacuum to 35 to 40 ºC for 16 hours to provide the desired compound as an off-white solid (109 g, 47%
. 111 yield). A second crop was isolated from the mother liquor as follows: the filtered material was concentrated to obtain a crude oil. Ethyl acetate (1 vol.) Was added. The resulting solution was seeded with previously isolated product and cooled to 0 to 5 ºC for 1 hour. The resulting solid was collected by filtration and washed with ice-cold ethyl acetate: heptane (1: 1 mixture, <1 vol). The solid was dried as previously described and combined with the first crop to provide the title compound (132 g, 57% total yield). MS (EST) m / z 337.8 [M-1] ", 339.8 [M + 1] ', 341.8 [M + 3] *.
C. T7-Bromo-1 - (((trans) -4-methoxycyclohexyl) methyl) - 3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one. A solution of 2- (3,5-dibromopyrazin-2-ylamino) ethyl acetate (500 mg, 1.47 mmols), ((trans) -4-methoxycyclohexyl) methanamine (317 mg, 2.21 mmols) and diisopropylethyl amine (0.77 ml, 4.42 mmols) in anhydrous dimethyl sulfoxide (8.0 ml) was placed in a microwave vessel (20 ml). The reaction was heated to 150 ºC for 1 hour. The reaction was poured into water, extracted with ethyl acetate (2x100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was dissolved in acetic acid (30 ml) and placed in a sealed tube. The reaction was heated to 120 ° C overnight. The solution was cooled, concentrated under reduced pressure, neutralized - with saturated sodium bicarbonate, extracted with ethyl acetate (3x100 ml), dried over sodium sulfate, filtered and adsorbed on silica gel. Purification by flash chromatography (50% ethyl acetate in hexanes) provided an
. 112 light orange solid (400 mg, 1.12 mmols, 76% yield). MS (ESI) m / z 355.2 [M +] *, 357.2 [M + 2] *. D. 1- (((trans) -4-Methoxycyclohexyl) methyl) -7- (trimethylstannyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -
ona. 7-Bromo-1 - ((((trans) -4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (2.71 g, 7.63 mmols) , 1,1,1,2,2,2-hexamethyldiestanane (3.00 g, 9.15 mmol) and tetracis (triphenylphosphino) palladium (0) (882 mg, 0.76 mmol) were combined in a sealed sealed tube with anhydrous dioxane (40 ml) and purged with nitrogen gas.
The reaction was heated to 100 ºC for 4 hours.
The reaction was diluted with ethyl acetate, filtered through Celite, washed with celite with ethyl acetate and the filtered material concentrated under reduced pressure.
The raw material was purified by flash chromatography (0 to 50% ethyl acetate in hexane) and the desired fractions were combined and concentrated to obtain a light yellow solid (2.32 9, 5.28 mmols, 69% yield) . MS (ESI) m / z 441.1 [M + 1] *,
E. 5- (8 - (((trans) -A4-Methoxycyclohexyl) methyl) -7-
oxo-5,6,7,8-tetrahydropyrazino [2,3-blpirazin-2-11) -4-methylpicolinonitrile. 1 - ((((trans) -4- methoxycyclohexyl) methyl) -7- (trimethylstannyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one (0.721 3. 1.64 mmol), 5 -bromo-4-methylpicolinonitrile (0.323 q, 1.64 mmol), tris (dibenzylidenoacetone) dipaladium (0) (0.150 o, 0.164 mmol), triethylamine (0.687 ml, 4.93 mmol), tri-ortho-toilphosphine (0.100 g, 0.328 mmol) and dimethylformamide (8 ml) were combined in a sealed reaction vessel.
Nitrogen was bubbled through the reaction for 5 minutes and the reaction was heated to 100 ºC for 3 hours.
The reaction was filtered,
13. concentrated and purified by silica gel column chromatography (0 to 80% ethyl acetate in hexanes). The fractions were combined and concentrated to provide the raw title compound used directly by the next step Ss (0.607 g, 1.55 mmols, 94% yield). MS (EST) m / z 393.5 IM + 11 ".
F. 5- (8 - (((trans) -4-Methoxycyclohexyl) methyl) -7-oxo0-5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-methylpicolinamide . 5- (8 - (((trans) -4- Methoxycyclohexyl) methyl) -7-ox0-5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-methylpicolinonitrile (0.607 g, 1/55 mmols), trifluroacetic acid (2.0 ml, 26.0 mmols) and sulfuric acid (0.5 ml, 9.38 mmols) were combined and heated to 65 ºC for 1 hour. The reaction pH was adjusted to 10 with sodium carbonate and the resulting solution was extracted with ethyl acetate (3 x 15 ml). The organic layers were collected, dried over magnesium sulfate, concentrated and purified using reverse phase preparatory HPLC (10 to 100% acetonitrile + 0.1% TFA in H20 + 0.1%) TFA, for 30 minutes). The clean fractions were combined and condensed under reduced pressure and dried under high vacuum to provide the title compound as a yellow solid (0.425 g, 1.04 mmol, 67% yield). MS (EST) m / z 411.5 DMA) ”, G. (Z) -N - ((Dimethylamino) methylene) -5- (8 - ((((trans) - 4-methoxycyclohexyl) methyl) -7-ox0 -5,6,7,8- tetrahydropyrazino [2,3-blpirazin-2-yl) -4-methylpicolinamide. 5- (8- ((((trans) -4-Methoxycyclohexyl) methyl) -7-0x0-5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-methylpicolinamide
. 114 (0.412 g, 1.00 mmol), dineopentylacetal dimethylformamide (1.5 ml) and tetrahydrofuran (10 ml) were combined and heated to 85 ºC for 3 hours.
The reaction was concentrated under a stream of nitrogen placed in a reaction vessel.
The crude product was used directly for the next step (0.467 g ,. 1.00 mmol, 100% yield). MS (ESI) m / z 466.6 [M + 1] *
H. 1 - ((((trans) -4-Methoxycyclohexyl) methyl) -7- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-11) -3, 4-
dihydropyrazine [(2,3-bl] lpyrazin-2 (1H) -one. (Z) -N- ((Dimethylamino) methylene) -5- (8 - ((((trans) -4-methoxycyclohexyl) methyl) -7 -0x0-5,6,7,8- tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-methylpicolinamide (0.467 g, 1.00 mmol) was added to acetic acid (6 ml). it was cooled to 0 ºC and hydrazine (1.00 ml, 32 mmols) was added by dripping.
The reaction was allowed to stir and warm at 25 ° C for 10 minutes.
The reaction was concentrated under a stream of nitrogen placed in a reaction vessel.
Water (5 ml) was added and the product was collected by filtration and purified using reverse phase semi-preparative HPLC (20 to 70% acetonitrile + 0.1% TFA in FLO + 0.1% TFA, for 30 minutes). The clean fractions were combined and condensed under reduced pressure and dried under high vacuum to provide the title compound as a yellow solid (0.046 g, 0.106 mmol, 11% yield). NMR * H (400 MHz, METANOL-da) 5 (ppm) 8.72 (s, 1H), 8.62 (s, 1H), 8.37 (s, JH), 7.93 (s, 1H) , 4.30 (s, 2H), 3.99 (df, J = 7.03 Hz, 2H), 3732 (e, 3H), 3.08 and 3.17 (mM, 1H), 2.71 / 8 2.76 (mM, 3H),
: 115 2.06 (br. S., 2H), 1.80 and 1.89 (m, 1H), 1.74 (br. S., 2H), 1.09 (d, 3 = 1 1, 32 Hz, 4H); MS (EST) m / z 435.5 [M + 1] *. Example 7: 7- (5-Fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1-isopropyl-3,4-dihydropyrazine [2,3-blpyrazin- 2 (1H) -one
TJ “Q x af No NO
SS A. 2- (5-bromo-3- (isopropylamino) pyrazin-2-ylamino) ethyl acetate. A mixture of 2- (3,5-dibromopyrazin-2-ylamino) ethyl acetate (see Example 6.B) (1.5 g, 4.43 mmoles), isopropylamine (0.17 g, 4.87 mmoles) ), N, N-diisopropylethylamine (1.14 g, 8.84 mmoles) and dimethyl sulfoxide (10 ml) in a reaction vessel was heated in an oil bath at 150ºC for 16 hours. After being cooled to room temperature, the resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, evaporated under reduced pressure and purified on silica gel column chromatography (10 and 20% ethyl acetate in petroleum ether) to obtain the title compound (780 mg, 55 , 7% yield). MS (ESLI) m / z 316.9 [M + 1] *. B. 7-Bromo-1-isopropyl-3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one. A mixture of 2- (5-bromo-3- (isopropylamino) pyrazin-2-ylamino) ethyl acetate (780 mg, 2.26 mmol), methanol (5 ml) and TFA (10 ml) in a sealable vessel was purged with nitrogen, sealed, shaken vigorously and heated to 90ºC with an oil bath for 16 hours. The resulting mixture was diluted with methanol and the
: 116 solvent was removed under reduced pressure.
Methanol (10 ml) was added and the solvent was removed under reduced pressure again.
Methanol (10 ml) and sodium bicarbonate were added.
The resulting mixture was stirred at room temperature until pH = 6 (in water), the solvent was removed under reduced pressure.
Water (20 ml) was added.
The mixture was extracted with methylene chloride (20 ml x 3). The organic layer was dried over anhydrous sodium sulfate, concentrated to obtain the crude product and purified by column chromatography on silica (10 to 20% ethyl acetate in petroleum ether) to obtain the title compound
(360 mg, 39.4% yield). CC. 1-Isopropyl-7- (trimethylstannyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one. 7-Bromo-1-isopropyl-3,4-dihydropyrazine [(2,3-b] pyrazin-2 (1H) -one (0.5 g, 1.844 mmol), hexamethylditin (0.725 g, 2.213 mmoles), tetracis ( triphenylphosphine) palladium (0) (0.213 g, 0.184 mmol) and 1,4-dioxane (3 ml) were combined in a sealable vessel with a stir bar.
Nitrogen gas was bubbled through the solution.
The vessel was sealed, shaken vigorously and heated at 100ºC for 2 hours.
The resulting cloudy black mixture was diluted with ethyl acetate, filtered and the filter cake was washed thoroughly with ethyl acetate.
The filtrate was concentrated under reduced pressure and purified using silica gel rapid column chromatography (20 to 80% ethyl acetate in hexanes) to obtain the desired product (0.49 g, 1.38 mmoles, 75% yield ) as a yellowish-white solid.
MS (EST) m / z 357.4 [M + 2] *. D. 4-Bromo-2-fluoro-5-methylbenzamide.
A solution of 4-bromo-2-fluoro-5-methylbenzonitrile (40 g, 190 mmoles) in a mixture of sulfuric acid (98%) and TFA (v / v = 4: 1, 480 ml) was stirred at 80 ° C for 16 hours. After the mixture was cooled to room temperature, the resulting mixture was poured into ice water. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to obtain the title compound (41 g, 95% yield) as a white solid. MS (ESI) m / z 232.0 [M + 1] *. E. 4-Bromo-N - ((dimethylamino) methylene) -2-fluoro-5-methylbenzamide. A solution of 4-bromo-2-fluoro-5-methylbenzamide (20 g, 86 mmoles) in N, N-dimethylformamide dimethylacetal (200 ml) was stirred at 100 ° C under nitrogen for 3 hours. The resulting mixture was concentrated and dried to obtain the desired product (24.6 g, 95% yield) as a yellow oil, which was used in the next step without further purification. MS (EST) m / z 287.0 [M + 1] *.
F. 3- (4-Bromo-2-fluoro-5-methylphenyl) -1H-1,2,4-triazole. To a solution of 4-bromo-N- ((dimethylamino) methylene) -2-fluoro-5-methylbenzamide (24.6 g, 86.2 mmoles) in acetic acid (200 ml) was added by dripping hydrazine hydrate ( 25 ml, 0.70 mol) at 0 ° C. The reaction mixture was stirred at room temperature overnight. The mixture was filtered, washed with water (500 ml x 3) and dried under reduced pressure to obtain the title compound (15 g, 68% yield) as a white solid. MS (ESI) m / z 256.0 [M + 1] *.
G. 3- (4-Bromo-2-fluoro-5-methylphenyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazole. A solution of 3- (4-bromo-2-fluoro-5-methylphenyl) -1H-1,2,4-triazole (15 9, 60 mmoles), toluene-4-sulfonic acid (2.0 g, 12 mmoles ) and
: 118 3,4-dihydro-2H-pyran (20 g, 240 mmoles) in tetrahydrofuran (200 ml) was stirred at 80 ° C under nitrogen for 15 hours. The resulting mixture was concentrated and purified on a silica gel column (1 to 25% ethyl acetate in petroleum ether) to obtain the protected triazole product (15 g9g, 75% yield) as a white solid. 1 H NMR (DMSO-ds, 400 MHz): 5 (ppm) 8.83 (s, 1H), 7.96 (d, JI = 7.6 Hz, 1H), 7.66 (d, 0 = 10 , 0 H>, 1H), 5.61 (dd, J; = 2.4 H7, Ja = 9.6 Ho, AH); 3.96 (d, J = 1.6 Hz, 1H), 3.69 (MM, 1H), 2.35 (S, 3H),
10. 2.00 (mM, 2H), 1.70 (mm, 2H), 1.57 (MM, 2H); MS (FEST) m / z 340.0 [M + 1] *.
H. 7- (5-Fluoro-2-methyl-4- (1- (tetrahydro-2H-pyran-2-1l1) -1H-1,2,4-triazol-3-yl) phenyl) -1-isopropyl -3,4- dihydropyrazine [2,3-bl] lpyrazin-2 (1H) -one. l-Isopropyl-7- 45 (trimethylstannyl) -3,4-dihydropyrazine [2,3-b] lpyrazin-2 (1H) - one (300 mg, 0.84 mmol), 3- (4-bromo-2- fluoro-5-methylphenyl) - 1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazole (428 mg, 1.26 mmol) and bis (triphenylphosphine) palladium (II) dichloride (56 mg, 0.08 mmol) were combined in N, N-dimethylformamide (5 ml). The mixture was degassed and heated at 140ºC under nitrogen for 3 hours. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (15 ml) and water (15 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 ml x 2). The combined organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative TLC (15% methanol in dichloromethane) to obtain the title compound (200 mg, 52% yield) as a solid.
. 119 T. 7- (5-Fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1-isopropyl-3,4-dihydropyrazine [2,3-b] lpirazin- 2 (1H) -one A solution of 7- (5-fluoro-2-methyl-4- (a- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazole-3 -yl) phenyl) -1- isopropyl-3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (200 mg, 0.44 mmol) in methanolic hydrochloride solution (20 ml, 2 M) was stirred for 5 hours at room temperature. The reaction was diluted with saturated aqueous sodium bicarbonate solution (25 ml) and the aqueous mixture was extracted with ethyl acetate (25 ml x 2). The organic phase was dried over sodium sulfate, filtered, evaporated under reduced pressure and purified on a silica gel column (50 to 100%) of ethyl acetate in petroleum ether). The desired fractions were combined and concentrated under reduced pressure to obtain the title compound (75 mg, 46% yield). NMR * H (DMSO-ds, 400 MHz): 5 (ppm) 14.25 (br, s., 1H), 8.20 (br, s., 1H), 7.90 (m, 2H), 7 .58 (s, 1H), 7.35 (s, 1H), 5.24 (mm, 1H), 4.10 (s, 2H), 2.43 (s, 3H), 1.44 (d, 3J = 7.2, 6H); MS (EST) m / z 368.2 [M + 1] *.
Example 8: 7 '- (2-Methyl-4- (4H-1,2,4-triazol-3- 11) phenyl) -1' "H-spiro [cyclopropane-1,2'-pyrazine [2,3 - bl] lpirazin] -3 '(4'H) -ona Ss Ss "O. and e, tert-butyl A. 1- (3,5-dibromopyrazin-2-ylcarbamoyl) cyclopropyl carbamate. 1,1'- Carbonyldiimidazole (4.37 g, 27.0 mmoles) was added to a stirred solution of 1- (tert-butoxycarbonylamino) cyclopropanecarboxylic acid (4.93 g, 24.50
. 120 mmoles) in N, N-dimethylformamide (6 ml) and dichloromethane (12 ml) at room temperature.
The resulting light yellow mixture was stirred at room temperature under nitrogen for 4 hours.
N, N-Diisopropylethylamine (8.54 ml, 49.0 mmoles) was added followed by 3,5-dibromopyrazin-2-amine (9.29 g, 36.8 mmoles). The resulting mixture was heated at 50ºC in a reflux condenser under nitrogen for 60 hours.
The resulting mixture was diluted with ethyl acetate and washed with water.
The layers were separated and the organic layer washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was taken up in dichloromethane and purified using flash chromatography (Biotage) (5 to 60% ethyl acetate in hexane). Fractions containing the desired product were combined and concentrated under reduced pressure.
The residue was triturated with 15% ethyl acetate in hexane and dried under high vacuum to obtain the desired product (5.349 g, 12.27 mmol, 50% yield) as an off-white solid.
NMR '* H (400 MHz, DMSO-d;) 3 (ppm) 9.92 (br, s., 1H), 8.76 (s, 1H), 7.70 (br, s., 1H), 1.41 (s, 9H), 1.34 and 1.40 (m, 2H), 1.02 and 1.09 (m, 2H); MS (ESI)
m / z 437.3 [M + 1] *, 459.1 [M + Na] ”. B.
1-amino-N- (3,5-dibromopyrazin-2-yl) cyclopropanecarboxamide bistrifluoroacetate.
TFA (6.02 ml, 78 mmoles) was added to a stirred mixture of tert-butyl 1- (3,5-dibromopyrazin-2-ylcarbamoyl) cyclopropylcarbamate (3.410 g, 7.82 mmoles) in dichloromethane (20 ml) . The resulting light yellow solution was stirred at room temperature for 4 hours.
All volatiles were removed under reduced pressure and the residue dried under high vacuum at 40ºC
. 121 to obtain the desired product (4.42 gq, 7.85 mmol, 100% yield) as a waxy yellow solid. MS (ESI) m / z 337.1 [M + 1] *. CC. 7 '-Bromo-1'H-spiro [cyclopropane-1,2'-pyrazine [2,3-blpyrazin] -3, (4, H) -one. 1-Amino-N- (3,5-dibromopyrazin-2-yl) cyclopropanecarboxamide bistrifluoroacetate (0.394 g, 0.700 mmol), N, N-diisopropylethylamine (0.610 ml, 3.50 mmoles) and 1,4-dioxane (6 ml) were combined in a sealable vessel with a stir bar. The system was purged with nitrogen. The resulting mixture was sealed, stirred vigorously and heated at 110ºC for 2 hours. Volatiles were removed under reduced pressure. The residue was dissolved in DMSO and methanol, filtered and purified using preparative reverse phase HPLC (10 to 65% acetonitrile + 0.1% TFA in water + 0.1% TFA, for 30 minutes). Fractions containing the desired product were combined, neutralized with saturated aqueous sodium bicarbonate and most of the solvent removed under reduced pressure. Solids were collected by vacuum filtration, washed thoroughly with water and dried under high vacuum to obtain the desired product (0.141 g, 0.553 mmol, 79% yield) as a light yellow solid. H NMR (400 MHz, DMSO-ds;) 5 (ppm) 11.27 (s, 1H), 8.04 (s, 1H), 7.46 (s, 1H), 1.29 and 1.38 (m, 2H), 0.91 and 1.01 (m, 2H); MS (EST) m / z
25. 255.1 (M] l +, 257.0 [M + 2] ", D. 7 '- (2-Methyl-4- (4- (tetrahydro-2H-pyran-2-yl) -4H trifluoroacetate) -4H -1,2,4-triazol-3-yl) phenyl) -1H-spiro [cyclopropane-1,2'-pyrazine [2,3-b] pyrazin] -3 '(4'H) - one. (3-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -4- (tetrahydro-2H-pyran-2-yl) -4H-1 , 2,4-triazole
. 122 (see Example 2C) (0.201 g, 0.545 mmol), 7'-bromo-1'H-spiro [cyclopropane-1,2'-pyrazine (2,3-b] pyrazin) - 3 '(4'H ) -one (0.139 g, 0.545 mmol), [1.1 bis (diphenylphosphino) - ferrocene] dichloropalladium (II), complex with dichloromethane (1: 1) (0.045 g, 0.054 mmol), sodium carbonate (1 M in water, 1.635 ml, 1.635 mmol), 1,4-dioxane (1.2 ml) and isopropanol (0.4 ml) were combined in a sealable vessel with a stir bar.
The system was purged with nitrogen.
The resulting mixture was sealed, stirred vigorously and heated at 100 ° C for 1 hour.
The resulting mixture was diluted with water and extracted three times with dichloromethane.
The combined organics were concentrated under reduced pressure.
The residue was absorbed in DMSO and methanol, filtered and purified using preparative reverse phase HPLC (20 to 70% acetonitrile + 0.1% TFA in water + 0.1% TFA, for 30 minutes). Fractions containing the desired product were combined and the solvent removed under reduced pressure.
The residue was dried under high vacuum to obtain the desired product (0.109 g, 0.205 mmol, 38% yield) as an orange solid.
MS (EST) m / z 418.4 [M + 1] *. E. 7 '- (2-Methyl-4- (4H-1,2,4-triazol-3-1yl) phenyl) - 1H-spiro [cyclopropane-1,2'-pyrazine [2,3-blpyrazin] - 3 '(4'H) -one.
6N hydrochloric acid in water (0.171 ml, 1.025 mmol) was added to a stirred mixture of 7 '- (2-methyl-4- (4- (tetrahydro-2H-pyran-2- 11) -4H-1 trifluoroacetate), 2,4-triazol-3-yl) phenyl) -1'H-spiro [cyclopropane-1,2'-pyrazine [2,3-b] pyrazin] -3 '(4'H) -one (0.109 g, 0.205 mmoles) in ethanol (4 ml) at 80ºC.
The resulting mixture was stirred vigorously and heated to 80 ° C under a condenser
S 123 of reflux under nitrogen for 30 minutes. The resulting mixture was filtered and purified using preparative reverse phase HPLC (10 to 60%) acetonitrile + 0.1% TFA in water + 0.1% TFA, for 30 minutes). Fractions containing the desired product were combined, neutralized with saturated aqueous sodium bicarbonate and most of the solvent removed under reduced pressure. Solids were collected by vacuum filtration, washed thoroughly with water and dried under high vacuum at 45 ° C to obtain the desired product (0.027 g, 0.079 mmol, 39% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-ds) 3 (ppm) 11.22 (br. S., 1H), 8.63 (br, s., 1H), 7.93 (s, 1H), 7, 89 (à, J = 7.81 Hz, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.47 (br, s., 1H), 2.43 (s, 3H), 1.29 and 1.38 (m, 2H), 0.95 and 1.04 (m, 2H); MS (EST) m / z 334.2 [M + 1] *.
Example 9: 7- (6- (2-Hydroxypropan-2-yl) pyridin-3- 11) -1- ((trans) -4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 ( 1H) -one and “O.
The. 2- (5-bromo-3- (trans-4-methoxycyclohexylamino) pyrazin-2-ylamino) ethyl acetate. 2- (3,5-dibromopyrazin-2-ylamino) ethyl acetate (see Example 6B) (30.0 g, 88 mmoles), trans-4-methoxycyclohexanamine (17.15 g, 133 mmoles), N, N - diisopropylethylamine (30.8 ml, 177 mmoles) and dimethyl sulfoxide “(70.8 ml) were combined in a reaction vessel with a stir bar and heated in an oil bath at 150ºC for 16 hours with stirring. THE
. The resulting mixture was diluted with ethyl acetate and the volatiles removed under reduced pressure. The residue was purified using silica gel chromatography on Biotage SP1l (12% ethyl acetate in hexanes). Fractions containing the desired product were combined and organic volatiles removed under reduced pressure. The residue was triturated with 5% ethyl acetate in hexane. Solids were collected by vacuum filtration, washed with hexane and dried under vacuum to provide ethyl of the title compound (15.37 g, 39.7 mmoles, 44.8% yield) as an off-white solid. MS (ESI) m / z 387.0 [M] +, 389.0 [M + 2] *.
B. 7-Bromo-1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one. The following reaction was divided into 3 separate sealed tubes and stimulated separately. The material was then combined following purification. 2- (5-bromo-3- (trans-4-methoxycyclohexylamino) pyrazin-2-ylamino) ethyl acetate (10 g, 25.7 mmoles), methanol (10.5 ml, 259 mmoles) and TFA (100 ml ) were combined in a sealable vessel with a stir bar. The system was purged with nitrogen and the resulting mixture was sealed, vigorously stirred and heated to 90ºC with an oil bath for 18.5 hours. The resulting mixture was diluted with methanol and the entire solvent was removed under reduced pressure. Methanol (100 ml) was added and the entire solvent was removed under reduced pressure again. Methanol (100 ml) and sodium bicarbonate (12.4 g, 147 mmoles) were added. The resulting mixture was stirred at room temperature until pH = 6 (in water). The mixture was concentrated almost to dryness. Water (100 ml) was added. The resulting brown solids
- 125 were collected by vacuum filtration and washed with water. the brown solids were dissolved in hot methanol and acetonitrile and purified using C18 reverse phase rapid column chromatography (20 to 100% acetonitrile in water). Fractions containing the desired product were combined and concentrated almost to dryness under reduced pressure.
Solids were collected by vacuum filtration, washed with water and dried under high vacuum to obtain the desired product (4.88 g, 14.3 mmoles, 55% yield) as a light brown solid.
1 H NMR (400 MHz, DMSO-d6) 5 (ppm) 7.71 (s, 1H), 7.59 (s, 1H), 4.66 (tt, J = 3.61, 12.20 Hz, 1H), 4.07 (d, J = 1.56 Hz, 2H), 3.25 (s, 3H), 3.06 and 3.17 (m, 1H), 2.42 (qd, 3 = 3 , 51, 12.89 Hz, 2H), 2.10 (d, J = 10.93 Hz, 2H), 1.61 (d, J 2H); MS (ESI) m / z 341.3 [M] +, 343.1 [M + 2] ”. CC.
T7- (6- (2-Hydroxypropan-2-yl) pyridin-3-yl) -1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one. 2- (5- (Trimethylstanil) pyridin-2-yl) propan-2-0l (see Example 5E) (9.43 gg, 31.4 mmol), 7-bromo-1- (trans-4-methoxycyclohexyl) -3,4- dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (10.02 g, 29.4 mmoles), [1,1 '-bis (diphenylphosphino) - ferrocene] adduct dichloropalladium (II) dichloromethane (2.398 g, 2.94 mmol) and N, N-dimethylformamide (25 ml) were combined in a round-bottomed flask with a stir bar.
The atmosphere in the vessel was removed under vacuum and replaced with nitrogen gas three times.
The resulting mixture was stirred vigorously and heated at 120ºC under nitrogen for 35 minutes.
The resulting mixture was purified using flash chromatography, divided into 4 separate columns, (2 to 15% methanol in dichloromethane). Fractions containing
. The desired product was combined and most of the solvent removed under reduced pressure. The resulting mixture was purified using preparative reverse phase HPLC (20 to 40% acetonitrile + 0.1% TFA in water + 0.1% TFA, in 30 minutes), divided into 6 phases. Fractions containing the desired product were combined and all acetonitrile and some water were removed under reduced pressure at 25ºC. The remaining yellow solution was loaded into 50 g of Strata X-C ion exchange resin from Phenomenex. The column was washed successively with water, acetonitrile, methanol and then 5% ammonium hydroxide in methanol. The product eluted in 5% ammonium hydroxide in methanol wash was concentrated under reduced pressure and dried under high vacuum to obtain the desired product (4.85 g, 12.20 mmoles, 42% yield) as a foam solid pink. H NMR (400 MHz, DMSO-d6) 3 (ppm) 9.03 (d, J = 1.56 Hz, 1H), 8.28 (s, 1H), 8.24 (dd, J = 2, 34, 8.20 Hz, 1H), 7.74 (d, 0 = 7.81 Hz, 1H), 7, 61 (ss, 1H), 5.260 (5, 1H), 4.90 (tt, = 3 , 71, 12.10 Hz, 1H), 4.13 (s, 2H), 3.28 (s, 3H), 3.20 (tt, J = 4.00, 10.84
20. Hz, 1H), 2.58 (QA, U = 2.93, 12.82 Hz, 2H), 2.14 (Ad, O = 120.15 Ho, 2H), 1.68 (d, = 10.93 Hz, 2H), 1.47 (s, 6H), 1.17 and 1.35 (m, 2H); MS (EST) m / z 398.3 [M + 1] +; 196 mp at 198ºC (uncorrected). D. 7- (6- (2-Hydroxypropan-2-yl) pyridin-3-yl) -1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) - ona (alternative approach). 2- (3,5- = dibromopyrazin-2-ylamino) ethyl acetate (1 equivalent) and trans-4-methoxycyclohexanamine hydrochloride (1575 equivalent), NMP and DIPEA were combined and heated to 127 ° C and maintained at that temperature for 18 hours. After
: 127 completion of reaction, the mixture was cooled to 35ºC in 4 hours. The solution was transferred to a mixture of ethyl acetate and 5% brine. The aqueous layer was removed and the organic layer was washed successively with 5% brine and water. The organic layer was concentrated by vacuum distillation at a low volume, cooled to room temperature and the solids were collected by vacuum filtration. The solids were washed with MTBE and the product was dried in a vacuum oven to obtain 41% yield of ethyl 2- (5-bromo-3- (trans-4-methoxycyclohexylamino) pyrazin-2-ylamino) acetate. A mixture of 2- (5-bromo-3- (trans-4-methoxycyclohexylamino) pyrazin-2-ylamino) ethyl acetate (1 equivalent), water and 85% phosphoric acid (3: 1) was heated to 80ºC in 1 hour. Heating was maintained for 18 hours to effect completion of the reaction. After completion of the reaction, the mixture was cooled to 25 ° C and filtered to obtain a crude product as a brown solid. The resulting solids were washed with water, suspended in water and filtered. The solids were washed with water until the pH of the filtrate was between 4 and 8. The resulting material was dried under vacuum to obtain 89% yield of 7-bromo-1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - one. T7-Bromo-1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one (1 equivalent), 5- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -2- (2- (trimethylsilyloxy) propan-2-yl) pyridine (1 equivalent), sodium carbonate (3 equivalents) and PdCl; (AmPhos)>, (0.003 equivalent) were combined in isopropanol and heated in
30. 70º for 1.5 hours. Standard stimulation and purification
. 128 provided the protected compound in 93% yield. Deprotection using standard conditions for removing a trimethylsilyl group and isolation obtained the title compound.
Alternatively, 2- (3,5-dibromopyrazin-2-ylamino) acetate (1 equivalent) and trans-4-methoxycyclohexanamine ethyl hydrochloride (1.5 equivalents), NMP and DIPEA were combined and heated to 125 ° C and maintained at that temperature for 18 hours. After completion of the reaction, the mixture was cooled to room temperature and transferred to a mixture of ethyl acetate and aqueous sodium chloride. The aqueous layer was removed and the organic layer was washed successively with aqueous sodium chloride and water. The organic layer was concentrated by vacuum distillation at a low volume, cooled to room temperature and the solids were collected and dried to obtain 2- (5-bromo-3- (trans-4-methoxycyclohexylamino) pyrazin-2-ylamino) acetate of ethyl. A mixture of ethyl 2- (5- bromo-3- (trans-4-methoxycyclohexylamino) pyrazin-2-ylamino) acetate (1 equivalent), water (161 equivalents) and 85% phosphoric acid (16.5 equivalents) was heated to 80ºC. After completion of the reaction, the mixture was cooled to ºC, filtered and the solids were washed with water. The solids were resuspended in water and filtration and washing 25 was repeated. The resulting material was dried to obtain 7-bromo-1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazino [2,3-bl] pyrazin-2 (1H) -one. 7-Bromo-1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - one (1 equivalent), 2- (5- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) propan-2-o0l (1.08
: 129 equivalents) and PdCl; (AmPhos); (0.0025 equivalent) were combined in tetrahydrofuran. The mixture was treated with a solution of potassium carbonate (2.5 equivalents) and heated to reflux. After cooling to 40ºC, toluene was added, and the layers were separated. The organic layer was washed with a potassium dihydrogen phosphate solution and treated with a metal cleaner (SiliaBondo Tiol). The mixture was filtered and distilled with the addition of toluene until the temperature reached 100 ºC. After cooling, the resulting solids were collected by filtration and dried. The solid was combined with butylhydroxy-toluene (BHT) (9 x 10º equivalents) in IPA and water (3x: 5x vol). The mixture was heated to 65ºC and while maintaining that temperature, water (5x vol) was added. A small amount of the title compound (0.02 equivalent) in water was added. The mixture was allowed to stand for 2 hours, cooled to room temperature and stirred. The resulting solids were collected by filtration and dried to obtain 7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2, 3- b] pyrazin-2 (1H) -one as an off-white solid.
Example 10: 9- (6- (4H-1,2,4-Triazol-3-1yl) -2-methyl-3-pyridyl) -6,11,4a-triidromorpholine [4,3-elpyrazine [2,3 - blpirazin-5-one & "A To A. 5-Bromo-6-methylpicolinonitrile. 3,6-Dibromo-2-methylpyridine (4.9 g, 19.53 mmoles), copper cyanide (TI) (1, 75 g, 19.53 mmoles) and N, N-dimethylformamide (20 ml) were combined in a sealable vessel with a stir bar.
The resulting mixture was sealed, stirred vigorously and heated at 110ºC for 4 hours.
The resulting mixture was diluted with ethyl acetate, poured into a separating funnel containing water and the layers were separated.
The water layer was extracted with ethyl acetate twice.
The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The resulting solids were purified by silica gel chromatography (10% ethyl acetate in hexanes) to obtain the title compound as a white solid (1.88 g, 9.54 mmol, 49% yield). MS (EST)
m / 2 197.3 [MT B. 3- (tert-butyl 3,5-dibromopyrazin-2-ylcarbamoyl) morpholine-4-carboxylate.
A solution of 4- (tert-butoxycarbonyl) morpholine-3-carboxylic acid (1,500 Gr 6,49 mmoles) and 1,1'-carbonyldiimidazole (1,578 g, 9.73 mmoles) in N, N-dimethylformamide (2 ml) and dichloromethane (6 ml) was stirred for 4.5 hours at room temperature under nitrogen.
N, N-Diisopropylethylamine (2,260 ml, 12.97 mmoles) was added followed by 3,5-dibromopyrazin-2-amine (3.28 g, 12.97 mmoles). The resulting mixture was stirred and heated to 50ºC in a reflux condenser under nitrogen for 2 days.
The resulting mixture was concentrated under reduced pressure.
The residue was diluted with water and extracted 3 times with ethyl acetate.
The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was purified using flash chromatography (20-30-50% ethyl acetate in hexanes) to obtain the desired product (2.136 g, 4.58 mmol, 71% yield) as a slightly yellow foamed solid.
MS (EST) m / z 467 [M + 1] *. CC. 9-Bromo-6,11,4a-trihydromorpholine [4,3-elpyrazine [2,3-b] lpyrazin-5-one. Tert-Butyl 3- (3,5-dibromopyrazin-2-ylcarbamoyl) morpholine-4-carboxylate (2,132 g, 4.57 mmol) was dissolved in dichloromethane (45 ml) with stirring at room temperature.
TFA (9 ml) was added and the resulting light yellow mixture was capped and stirred at room temperature for 2.5 hours.
The solvent was removed under reduced pressure and the residue dried under high vacuum at 45 ° C to obtain a viscous yellow oil.
The yellow oil was dissolved in isopropanol (wet) (50 ml) with stirring at room temperature.
Sodium bicarbonate (3.84 g, 45.7 mmoles), palladium acetate (IT) (0.103 9, 0.457 mmol) and 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (0.239 ml, 1.372 mmol) have been added.
The atmosphere in the flask was removed and replaced with nitrogen.
The resulting mixture was stirred vigorously and heated at 80ºC in a reflux condenser under nitrogen for 2 hours.
The resulting mixture was cooled to room temperature and diluted with water (30 ml). The resulting solids were collected by vacuum filtration, washed thoroughly with water and diethyl ether and dried under high vacuum to obtain the desired product in -90% purity (1.441 g, 5.05 mmoles, 99% yield) as a solid yellow.
MS (ESI) m / z 285 [M] +, 287 [M + 2] *. D. 9- (1,1-Dimethyl-1-stanethyl) -6,11,4a- trihydromorpholine [4,3-elpyrazino [2,3-blpirazin-5-one. 9- Bromo-6,11,4a-trihydromorpholine [4,3-elpyrazine [| 2,3-
b] lpirazin-5-one (0.30 g, 1.052 mmoles), hexamethylditin (0.414 g, 1.263 mmol), tetracis (triphenylphosphine) palladium (0) (0.122 g, 0.105 mmol) and 1, 4-dioxane (5 ml ) were combined in a sealable vessel with a stir bar.
Nitrogen gas was bubbled through the solution for five minutes. The vessel was sealed, shaken vigorously and heated at 100ºC for 2 hours. The resulting cloudy black mixture was diluted with ethyl acetate, filtered and the filter cake was washed thoroughly with ethyl acetate. The filtrate was concentrated under reduced pressure and purified using Biotage flash chromatography (20 to 80% ethyl acetate in hexanes) to obtain the desired product (0.350 g, 0.948 mmol, 90% yield) as a yellow-white solid. MS (EST) m / z 369.5 [M] *.
E. 6-Methyl-5- (5-oxo (6,11,4a-trihydromorpholine [4,3-elpyrazino [2,3-blpirazin-9-yl)) pyridine-2-carbonitrile. 5- Bromo-6-methylpicolinonitrile (0.080 g, 0.406 mmol), 9- (1,1-dimethyl-1-stanethyl) -6,11,4a-trihydromorpholine [4,3-elpyrazino [2,3-b] pyrazin -5-one (0.150 o, 0.406 mmol), tris (dibenzylidenoacetone) dipaladium (0) (0.041 gq, 0.045 mmol), tri-o-tolylphosphine (0.027 g, 0.089 mmol) and triethylamine (0.170 ml, 1.219 mmol) occurred in a sealed tube and N, N-dimethylformamide (2 ml) was added. Nitrogen gas was bubbled through the reaction mixture for five minutes and the reaction was sealed and heated at 100ºC for 1 hour. The resulting cloudy black mixture was diluted with methanol, filtered and the filter cake was washed thoroughly with methanol. The filtrate was concentrated under reduced pressure and purified using Biotage flash chromatography (50 to 100% ethyl acetate in hexanes) to obtain the desired product (0.117 g, 0.363 mmol, 89% yield). MS (EST) m / z 323.5 [M + 1] *
F. 6-Methyl-5- (5-oxo (6,11,4a-trihydromorpholine [4,3-elpyrazino [2,3-b] pyrazin-9-yl)) pyridine-2-carboxamide. 6-
Methyl-5- (5-ox0 (6,11,4a-triidromorpholine [4,3-e] pyrazine [| 2,3-b] pyrazin-9-yl)) pyridine-2-carbonitrile (0.18 g, 0.558 mmol) was added to a round bottom flask and while stirring, the mixture of TFA (1.6 ml) and sulfuric acid (0.4 ml) was added.
The resulting suspension was allowed to stir for 16 hours at room temperature.
The mixture was poured onto ice and the excess acid was carefully neutralized with solid potassium hydroxide.
The obtained solid was filtered, washed with water and dried under high vacuum to yield the title compound (0.153 g, 0.450 mmol, 81% yield) as a red solid.
MS (ESI) m / z 341.5 [M + 1] *
G. 9- (6- (4H-1,2,4-Triazol-3-yl) -2-methyl-3-pyridyl) -6,11,4a-triidromorpholine [4,3-elpyrazine [2,3- blporazin-5-one. 6-Methyl-5- (5-oxo (6, 11,4-
trihydromorpholine [4,3-e] pyrazine [2,3-b] pyrazin-9-
il)) pyridine-2-carboxamide (0.159 gg, 0.467 mmol), N, N-dimethylformamide dineopentyl acetal (2 ml, 8.85 mmoles) and dimethyl sulfoxide (0.5 ml) were carried out in a flask and heated to 85ºC for 1 hour.
The solution was diluted with acetic acid (5 ml, 87 mmoles) and hydrazine (0.468 ml, 14.90 mmoles) was added by dropping.
The reaction was allowed to stir at 25 ° C for 30 minutes.
The mixture was concentrated under reduced pressure and the residue was carefully neutralized with a saturated aqueous sodium carbonate solution.
This solution was then extracted with ethyl acetate three times, concentrated under reduced pressure and purified using semi-preparative reverse phase HPLC (5 to 50% acetonitrile + 0.1% TFA in water + 0.1% TFA, for 20 minutes) to provide the title compound (0.03 g, 0.082 mmol, 17.63% yield). H NMR (400 MHz, DMSO-ds) 5 (ppm) 7.96 and 8.04 (m, 2H), 7.88 (s, 1H), 4.33 (da, J = 3.71, 10 , 74 Hz, 1H), 4.15 and 4.23 (m, 2H), 3.98 (dd, J = 3.51, 11.71 Hz, 1H), 3.51 and 3.63 (m, 2H), 2.89 and 2.99 (m, 1H), 2.70 (s, 3H); MS (EST) m / z 365.5 [M + 1] "Example 11: 6- (6- (1H-1,2,4-Triazol-3-yl) pyridin-3-yl) -4- (tetrahydro -2h-pyran-4-1yl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one
TX O Lo A. 6-Bromo-4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrazine [2,3-6] lpyrazin-2 (1H) -one. To a solution of N- (3,5-dibromopyrazin-2-yl) -2-iodoacetamide (see Example 5B) (6.6 g, 15.8 mmol) and diisopropylethylamine (4.0 g, 31.6 mmol) ) in acetonitrile (50 ml) was added tetrahydro-2H-pyran-4-amine (6.4 g, 63.2 mmoles) and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue that was purified by silica gel chromatography (5 to 20% ethyl acetate in petroleum ether) to obtain the title compound (1.98 g, 40% yield). MS (ESI) m / z 313.1 [M + 1)] *.
EB. 4- (Tetrahydro-2H-pyran-4-yl) -6- (trimethylstannyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) - one. A degassed mixture of 6-bromo-4- (tetrahydro-2H-
pyran-4-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (1.98 g, 6.35 mmol), tetracis (triphenylphosphine) palladium (1.45 gq, 1.27 mmoles) and hexamethylditin (4.0 g, 12.7 mmoles) in dioxane (10 ml) was heated at 90ºC for 3 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and purified on a silica gel column (10 to 20% ethyl acetate in petroleum ether) to provide the product (1.07 g, 42.3% yield). MS (ESI) m / z 399.1 [M + 1] *.
ç. 6- (6- (1- (Tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- (tetrahydro-2H-pyran- 4-yl1) -3,4-dihydropyrazine [2,3-6] pyrazin-2 (1H) -one. A mixture of 4- (tetrahydro-2H-pyran-4-yl) -6- (trimethylstannyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (1 equivalent), 5- bromo-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl) pyridine (1.2 equivalents), tris (dibenzylideneacetone) dipaladium (0.1 equivalent), tri-o-tolylphosphine (0.2 equivalent), triethylamine (3 equivalents) and N, N-dimethylformamide was heated at 95ºC for 3 hours under nitrogen. Concentration and purification by chromatography gives the desired product in 39% yield. MS (EST) m / z 463.1 [M + 1] *.
D. 6- (6- (1H-1,2,4-Triazol-3-yl) pyridin-3-11) -4- (tetrahydro-2H-pyran-4-yl) -3,4-dihydro pyrazine [ 2,3-blpirazin-2 (1H) -one. A mixture of 6- (6- (1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- (tetrahydro-2H -pyran-4-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one in methanolic hydrochloride solution was stirred at room temperature for 0.5 hour. The solvent was evaporated under reduced pressure to obtain the crude product, which was washed with N, N-dimethylformamide to provide the title compound as a hydrochloride salt in 34% yield. 1 H NMR (DMSO-ds., 400 MHz) 3 (ppm) 11.44 (s, 1H), 9.30 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.46 (s, 1H), 8.22 (m, 2H), 4.70 (t, J = 10 Hz, 1H), 4.16 (s, 1H), 3.99 (m, 4H), 3.51 (t, J = 11.2 Hz, 2H), 1.86 (m, 2H), 1.69 (d, J = 12.8 Hz, 2H); MS (ESI) m / z 379.1 [M + 1] *. Example 12: 1-Ethyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-Dblpyrazin- 2 (1H) -one
And Oo
LIS A. 7-Bromo-1-Ethyl-3,4-dihydropyrazine [| 2,3-blpyrazin-2 (1H) -one. A mixture of 2- (3,5-dibromopyrazin-2-ylamino) ethyl acetate (see Example 6.B) (1 equivalent), ethylamine hydrochloride (3.1 equivalents), N, N-diisopropylethylamine (4 equivalents ) in N-methyl pyrrolidinone was heated at 105ºC under nitrogen for 14 hours. Standard ethyl acetate / water stimulus obtained oThe crude product in 77% yield. This material was used without further purification. 2- (5-bromo-3- (ethylamino) pyrazin-2-ylamino) crude ethyl acetate and acetic acid were combined in methanol. The reaction mixture had reflux at 60 to 62ºC under nitrogen for 16 hours. The reaction was concentrated under reduced pressure and the resulting residue was diluted with methanol and concentrated. The resulting residue was dissolved in ethyl acetate treated with sodium carbonate and stirred for 10 minutes until pH -7. The mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and purified by a silica gel buffer purification using (0 to 40% ethyl acetate in hexanes) obtained the product as a brown solid. In addition, the filter cake was suspended in water to remove potassium carbonate. The remaining solid product was collected by filtration. The process provided product in a combined yield of 75%.
B. 1-Ethyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) - ona. A mixture of 3-bromo-2-methyl-6- (1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl) pyridine (1 equivalent), bis ( pinacolate) diboron (1.05 equivalents), potassium acetate (2 equivalents), potassium carbonate (3 equivalents), [1,1'-bis (diphenylphosphine) - ferrocene] dichloropalladium (II), complex with dichloromethane (1: 1) (0.1 equivalent) in anhydrous dioxane (300 ml) was degassed and heated at 90ºC for 2 hours. The mixture was cooled to <40ºC and 7-bromo-1-Ethyl-3,4-dihydropyrazine ([2,3-b] pyrazin-2 (1H) -one (1 equivalent), water and [1,1'- bis (diphenylphosphino) - ferrocene] dichloropalladium (II), complex with dichloromethane (1: 1) (0.05 equivalent) were added, the mixture was degassed and heated at 65 to 70ºC under nitrogen for 1 hour. The mixture was cooled to <40ºC, diluted with water and ethyl acetate Standard ethyl acetate / water stimulus followed by rapid column chromatography (0 to 5% methanol in dichloromethane) and recrystallization from ethanol obtained the title compound in 57% yield H NMR (400 MHz, DMSO-ds) 5 (ppm) 7.99 (s, 2H), 7.93 (s, 1H), 7.72 (s, 1H), 4.22 (s, 2H ), 4.05 (q, J = 6.77 Hz, 2H), 2.71
(s, 3H), 1.18 (t, J = 7.03 Hz, 3H); MS (EST) m / z 337.6
[M + 1] *. CC. 1-Ethyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H ) -ona (Alternative approach). 2- (3,5-dibromopyrazin-2-ylamino) ethyl acetate (1 equiv), tetrahydrofuran and sodium hydroxide in water (1.1 equiv) were combined and stirred at room temperature overnight.
The reaction mixture was filtered and the collected solids were dried to obtain sodium 2- (3,5-dibromopyrazin-2-ylamino) acetate as an off-white solid. 2- (3,5-dibromopyrazin-2-ylamino) sodium acetate and ethylamine (3 equiv, 70% by weight of solution) were combined in water and the mixture was stirred at 90 ° C overnight.
The reaction mixture was cooled to 80 ºC, treated with phosphoric acid (10 equiv) and stirred for 3 hours.
The mixture was cooled to room temperature and the solids were collected by filtration.
The product was dried to obtain 7-bromo-1-ethyl-3,4-dihydropyrazino [2,3-bl] pyrazin-2 (1H) -one as a gray solid.
T7-Bromo-1-ethyl-3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (1 equiv), bispinacoldiborane (1.5 equiv) and potassium acetate (3.2 equiv) were combined in tetrahydrofuran.
The reaction was heated to reflux and PdCl12 (AmPhos) 2 (0.002 equiv) was added.
After 4 hours, the reaction was cooled to room temperature.
The mixture was filtered and the collected solids were washed with tetrahydrofuran.
The filtrate was concentrated under reduced pressure to 50% of the original volume and hexane was added.
The resulting solids were collected by filtration and dried to obtain l-ethyl-7- (4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - one as a brown solid. 1-Ethyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (1 equiv) and 3-bromo-2-methyl-6- (1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl) pyridine (0.96 equiv ), were combined in tetrahydrofuran. A solution of potassium carbonate (2 equiv) in water was added to the flask with stirring. The solution was treated with PACl2 (AmPhos) 2 (0.002 equiv) and heated to 65 ºC for 1 hour.
The solution was treated with MTBE and seeded. Additional MTBE and seed were added before adding the final portion of MTBE to the reaction mixture. The solids were collected by filtration and dried to obtain the desired intermediate as a brown solid. This intermediate and reagent alcohol (95% ethanol and 5% isopropanol) were combined and the mixture was treated with concentrated aqueous hydrogen chloride and heated to 60 ºC. a second charge of concentrated aqueous hydrogen chloride was made and the material was heated for 2 hours. The reaction mixture was cooled to room temperature and filtered. The solids were washed with IPA and dried to obtain 1-ethyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-1yl) -3.4 hydrochloride -dihydropyrazino [2,3-blpyrazin-2 (1H) -one as a pale yellow solid. The salt was dissolved in water and tetrahydrofuran and treated with a metal scavenger (SiliaBonde Thiol) (10% by weight) overnight. The aqueous slurry was filtered and the solids rinsed with 1: 1 tetrahydrofuran / water. The filtrate was treated with a concentrated aqueous ammonium hydroxide solution under reduced pressure to 70% of its volume. The solution was cooled to room temperature and the resulting solids were filtered and washed with water and ethanol. The dry solids were transferred to a flask, treated with ethanol and heated to 65 ºC for 2 hours. The mixture was cooled to room temperature and kept overnight. The solids were collected by vacuum filtration and dried to obtain 1-ethyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-i1) -3.4 - dihydropyrazine [2,3-b] pyrazin-2 (1H) -one as an off-white solid.
Example 13: 4 - ((cis) -4-Methoxycyclohexyl) -6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4- dihydropyrazine [2,3-b] pyrazin-2 (1H) -one o EN O
PO A. 5-Bromo-6-methylpicolinamide. A solution of 5-bromo-6-methylpicolinonitrile (1.8 g, 9.14 mmoles) in a mixture of TFA and sulfuric acid (30 ml, 4: 1, V / V) was stirred at 40 ºC for 16 hours. The reaction mixture was poured into ice water. The resulting solid was filtered and washed with water and dried to obtain the desired product as a white solid (1.0 g, 4.65 mmol, 54% yield). MS (EST) m / z 217.1 [M + 2] *. B. 3-Bromo-2-methyl-6- (1H-1,2,4-triazol-3-yl) pyridine. 5-Bromo-6-methylpicolinamide (1 g, 4.65 mmol) and N, N-dimethylformamide dimethylacetal (20 ml) were combined in a 100 ml round bottom flask with a stir bar and heated to 85 ºC under a reflux condenser under nitrogen for 3 hours.
The resulting mixture was concentrated under reduced pressure and dried under vacuum to obtain a yellow oil, which was used in the next step without purification.
The residue was diluted with acetic acid (10 ml) and hydrazine (2.5 ml, 70.3 mmol) was added dropwise and allowed to stir at room temperature for 5 hours.
The reaction mixture was poured into ice water.
The resulting solid was filtered, washed with water and dried to obtain the desired product as a white solid.
The aqueous filtrate was extracted with dichloromethane.
The organic layer was concentrated under reduced pressure almost to dryness to yield additional material.
The combination of two batches generated the desired product (0.7 g, 2.9 mmoles, 63% yield). MS (ESI) m / z 241.1 [M + 2] +. Alternative approach: 5-Bromo-6-methylpicolinonitrile (1 equiv) and hydrazine monohydrate (2.0 equiv) were combined in absolute ethanol (4X vol.) And heated at 55 ºC for 24 hours.
The aqueous slurry was cooled to room temperature and filtered.
The collected solids were washed with ethanol and methyl tert-Dbutyl ether and the solids were dried to deliver 5-bromo-6-methylpicolinimidoidrazide as a white powder. 5- Bromo-6-methylpicolinimidoidrazide and formic acid (15 equiv) were combined and heated to 100 ºC with stirring for 6 hours.
The solution reaction was cooled to 40 ҼC, treated with methanol, stirred for 30 minutes and concentrated under reduced pressure to 20% of the reaction volume.
The mixture was diluted with methanol and concentrated again under reduced pressure at 20% of the reaction volume.
The resulting solids were filtered, washed with water and dried to obtain the title compound as an off-white powder.
CC. 3-Bromo-2-methyl-6- (1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl) pyridine. 3-Bromo-2-methyl-6- (1H-1,2,4-triazol-3-yl) pyridine (0.7 g, 2.93 mmol) and 3.4-dihydro-2H-pyran (0.493 g , 5.86 mmoles) were dissolved in tetrahydrofuran (20 ml). TFA (3.34 mg, 0.029 mmol) was added and the resulting solution was heated to 70 ºC for 16 hours.
The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered and poured into a separating funnel containing water and ethyl acetate.
The organic layer was concentrated under reduced pressure.
Flash chromatography (0 to 60% ethyl acetate in hexane) gave the desired product as a white solid (0.40 g, 1.23 mmol, 42% yield). MS (ESI) m / z 325.1 [M + 2] '. Alternative approach: 3-Bromo-2-methyl-6- (1H- 1,2,4-triazol-3-yl) pyridine (1 equiv), 3,4-dihydro-2H-pyran (2 equiv) and methanesulfonic acid (0.08 equiv) were combined in tetrahydrofuran (8X vol.). The solution was heated and stirred at 68 ºC for 3.5 hours, then cooled to room temperature.
Triethylamine (0.4 equiv) was added and the resulting solution was concentrated under reduced pressure to an oil.
The oil was treated with acetonitrile and concentrated under reduced pressure iteratively until a solid was obtained.
The solid was dissolved in acetonitrile and treated with water.
The suspension was filtered and the solids were collected and dried.
The crude product was slurried in hexanes, filtered and dried to obtain the purified title compound as a light pink solid.
D. (cis) -4-Methoxycyclohexanamine hydrochloride.
To a round-bottom flask, under an atmosphere of nitrogen tert-butyl (cis) -4-hydroxycyclohexylcarbamate (7.8 g, 36.2 mmoles) was added and suspended in anhydrous tetrahydrofuran (181.0 ml) and cooled to 0 ºC .
Sodium hydride (2.174 gq, 54.3 mmoles) was then added and the resulting solution was allowed to stir for 5 minutes.
To a second flask under an atmosphere of nitrogen, methyl iodide (2.265 ml, 36.2 mmoles) was added and suspended in anhydride tetrahydrofuran (10.0 ml). The solution of methyl iodide in tetrahydrofuran was slowly added dropwise to the first flask over 3 minutes.
The reaction was allowed to stir at room temperature for 16 hours.
The organic volatiles were removed under reduced pressure and divided between ethyl acetate (3X) and water.
The organic fractions were grouped, dried over magnesium sulfate, filtered and condensed under reduced pressure.
The resulting material was purified by silica gel column chromatography (25 to 50% ethyl acetate in hexanes). The desired fractions were combined and the organic volatiles removed under reduced pressure followed by the addition of hydrochloric acid (4M in 1,4-dioxane, 23.5 ml). The resulting solution was heated to 40 ° C for 1 hour and the organic volatiles were removed under reduced pressure to provide the title compound (6.0 g, 36.2 mmoles, 100% yield). MS (ESI) m / z 130.1 [M + 1] *. E. 6-Bromo-4 - ((cis) -4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one.
To a solution of N- (3,5-dibromopyrazin-2-yl) -2-iodoacetamide (See Example 5, E) (1.0 g, 2.376 mmol) and diisopropylethylamine (1.038 ml, 5.94 mmol) in acetonitrile (10 ml) (cis) -4-methoxycyclohexanamine hydrochloride was added
(0.413 g, 2.495 mmoles). The solution was stirred at 55 ºC for 3 hours. The resulting precipitate was filtered and washed with acetonitrile and dried under reduced pressure to provide the title compound (0.442 gq, 1.29 mmol, 55% yield). MS (ESI) m / z 341.3 [M] *, 343.3 [M + 2] ”.
F. 4- (cis) -4-Methoxycyclohexyl) -6- (trimethylstannyl) -3,4-dihydropyrazino [2,3-bl] lpyrazin-2 (1H) -one. 6-Bromo-4 - ((cis) -4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one (0.442 9, 1.295, mmoles), tetracis (triphenylphosphine) palladium (0.225 g, 0.194 mmol) and hexamethylditine (0.322 ml, 1.554 mmol) were combined in dioxane (5 ml). The solution was purged with nitrogen gas and heated to 90 ºC in a screw-capped tube for 3 hours. The solution was condensed under reduced pressure and purified using Biotage column chromatography (0 to 50% ethyl acetate in hexanes) to provide the title compound (0.356 g, 0.837 mmol, 65% yield). MS (ESI) m / z 426.5 [M + 1] ', 427.5 [M + 1] *.
G. 4 - ((cis) -A-Methoxycyclohexyl) -6- (2-methyl-6- (4- (tetrahydro-2H-pyran-2-yl) -4H-1,2,4-triazole-3- il) pyridin-3- 11) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one. 4 - ((cis) -4- Methoxycyclohexyl) -6- (trimethylstannyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one 0.292 gs 0.687 mmol), 3-bromo-2-methyl- 6- (1- (tetrahydro-2H-pyran-2-yl) -1H- 1,2,4-triazol-3-yl) pyridine (0.244 g, 0.756 mmol), tris (dibenzylidenoacetone) dipaladium (0.063 g, 0.069 mmol), tri-o-tolylphosphine (0.042 g, 0.137 mmol), triethylamine (0.287 ml, 2.061 mmoles) and dimethylformamide (5.0 ml) were combined in a screw-capped flask and heated to 95 ºC for 1 hour. The solution was condensed under reduced pressure and purified using Biotage chromatography (0 to 80% ethyl acetate in hexanes followed by 0 to 10% methanol in ethyl acetate) to provide the title compound (0.279 g, 0.687 mmol, 80% yield). MS (ESI) m / z 505.6 [M + 1] *.
H. 4 - ((cis) -4-Methoxycyclohexyl) -6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-blpirazin-2 (1H) -one. 4 - ((cis) -4-Methoxycyclohexyl) -6- (2-methyl-6- (4- (tetrahydro-2H-pyran-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (0.279 g, 0.553 mmol) was diluted with ethanol (15 ml) and hydrogen chloride (4.0 N in dioxanes, 5 ml). The solution was stirred at 75 9% for 1 hour and at 80 ҼC for 2 hours. The solution was condensed to an aqueous slurry and diluted with ethanol and sonicated. The precipitate was filtered and washed with additional ethanol followed by acetonitrile. The crude solid was purified using semi-preparative reverse phase HPLC (10 to 100% acetonitrile + 0.1% TFA in water + 0.1% TFA, over 30 minutes) to provide the compound titer (0.040 g, 0.095 mmol, 17% yield). 1H NMR (400 MHz, METANOL ds) 5 (ppm) 7.88 and 8.13 (m, 2H), 7.65 (s, 1H), 4.58 (s, 1H), 4.16 (s, 2H), 3.47 (br, s., 1H), 3.22 and 3.32 (m, 66H), 2.73 (s, 3H), 2.08 (br, s., 2H), 1 , 91 (br, s., 2H), 1.56 (br, s., 4H); MS (EST) m / z 421.2 iM + 1) mp 192 to 195 0, Example 14: 1-Isopropyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-11) -3,4-dihydroppyrazine [2,3-b] razin-2 (1H) -one EX ONLY
146:
A. 1-Isopropyl-7- (trimethylstannyl) -3,4-
dihydropyrazine [2,3-b] pyrazin-2 (1H) -one. 7-Bromo-1-isopropyl-3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one
(See Example 7.B) (0.5 g, 1.844 mmoles),
hexamethylditine (0.725 Tr 27213 mmoles),
tetracis (triphenylphosphine) palladium (0) (0.213 g, 0.184 mmol) and
1,4-dioxane (3 ml) was combined in a sealable vessel with a stir bar.
Nitrogen gas was bubbled through the solution.
The vessel was sealed, shaken vigorously and heated to 100 ºC for 2 hours.
The resulting cloudy black mixture was diluted with ethyl acetate,
filtered and the filter cake washed thoroughly with ethyl acetate.
The filtrate was concentrated under reduced pressure and purified using silica gel flash column chromatography (20 to 80% ethyl acetate in hexanes)
to obtain the desired product (2.410 g, 77% yield)
like a light yellow solid.
MS (ESI) m / z 357.4 [M + 2] *
B. 1-Isopropyl-7- (2-methyl-6- (4- (tetrahydro-2H-
pyran-2-yl) -4H-1 12,4-triazol-3-yl) pyridin-3-i1) -3,4-
dihydropyrazine [2,3-blpyrazin-2 (1H) -one.
To a flask was added 3-Bromo-2-methyl-6- (1- (tetrahydro-2H-pyran-2-yl) -
1H-1,2,4-triazol-3-yl) pyridine (0.446 g, 1.380 mmol), 1-isopropyl-7- (trimethylstannyl) -3,4-dihydropyrazine [2,3-
blpirazin-2 (1H) -one (0.490 gq, 1.380 mmol),
tris (dibenzylidenoacetone) dipaladium (0) (0.139 g, 0.152 mmol), tri-o-tolylphosphine (0.092 g, 0.304 mmol),
triethylamine (0.577 ml, 4.14 mmol) and N, N-dimethylformamide
(3 ml). The nitrogen gas was bubbled through the reaction mixture for 5 minutes and the mixture was heated to
100 ºC for 1H.
After cooling to room temperature,
the reaction mixture was filtered through Celite, rinsed with methanol and concentrated to dryness. The resulting residue was purified by silica gel flash column chromatography (0 to 80% ethyl acetate in hexanes, followed by 0 to 10% methanol in dichloromethane) to yield the desired product (0.40 g, 0.921 mmol , 66.7% yield). MS (ESI) m / z 435.5 [M + 1) ”.
C. 1-Isopropyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) - ona. To a stirred mixture of 1l-isopropyl-7- (2-methyl-6- (4- (tetrahydro-2H-pyran-2-yl) -4H-1,2,4-triazol-3-yl) pyridin-3 - 11) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (0.400 dg, 0.921 mmol) in ethanol (40 ml) at 50 ° C hydrogen chloride (4 M in dioxane) was added , 1.381 ml, 5.52 mmoles). The resulting mixture was heated to 50 ºC under nitrogen for 1 hour. The suspension was concentrated under reduced pressure and the resulting solid was taken up in dimethylsulfoxide and purified using silica gel chromatography (0 to 10% methanol saturated with ammonia in dichloromethane) to provide the title compound (0.200 g, 0.571 mmol , 62.0% yield) as a reddish brown solid, which was further processed by recrystallization. 1H NMR (400 MHz, DMSO-d6) 3 (ppm) 8.10 (br, Ss. 1H), 8.01 (br, os ... 2H), 7.92 (5, 1H), 5.26 (QUin, = / 6.93 Hz, 1H), A /, 14 (Ss, 2H), 3.58 (d, = 5.08 Hz, 39), 1.47 (d, 0 = 6.64 Hz , 6H); MS (EST) m / 2 351.5 [M + 1).
D. 1-Isopropyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin -2 (1H) -one (alternative approach). T7-Bromo-11-isopropyl-3,4-dihydropyrazine [2,3-blpirazin-2 (1H) -one (equiv),
bis (pinacolato) diboron) (1 equiv), potassium acetate (3 equiv) and bis (1,1'-bis (diphenylphosphino) ferrocene) palladium (0.01 equiv) were combined in dioxane (1,2 1), degassed with nitrogen and heated to 95 ºC under nitrogen.
Dilution with ethyl acetate, filtration through Celite, concentration, trituration with ethyl acetate and hexanes, filtration and drying generated the boronate ester in 60% yield, tert-Butyl 3- (5-bromo-6- methylpyridin-2- il) -1H-1,2,4-triazole-1-carboxylate (1 equiv), 1-isopropyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - one (1.2 equiv), tetracis (triphenylphosphine) palladium (O) (0.05 equiv), sodium carbonate (3 equiv) were combined in (3:11) dimethyl acetamide and water.
The mixture was degassed and heated to 100 ° C overnight.
The standard ethyl acetate / water isolation and finish and subsequent crushing in ethyl acetate generated the desired product in 41% yield.
Example 15: 7- (1H-Pyrrol [2,3-blpiridin-5-yl) -1- (2- (tetrahydro-2h-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one ah Per Perho 2- (5-bromo-3- (2- (tetrahydro-2H-pyran-4-yl) ethylamino) pyrazin-2-ylamino) ethyl acetate. 2- (3,5-dibromopyrazin-2-ylamino) ethyl acetate (See Example 6.B) (1.0 g, 2.95 mmol) and 2- (tetrahydro-2H-pyran-4-yl) ethanamine (0.381 g, 2.95 mmoles) were placed in a microwave vessel, dimethyl sulfoxide (2 ml) was added and the resulting mixture was heated in a Biotage Emrys Optimizer microwave reactor at 150 ºC for 3600 seconds. The crude reaction mixture was purified using silica gel chromatography (33% ethyl acetate in hexanes) to yield the title compound (0.5 gq, 1.3 mmoles, 44% yield). MS (EST) m / z 387.1 [M] ', 389.1 [M + 2] *.
B. T7-Bromo-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one. 2- (5-bromo-3- (2- (tetrahydro-2H-pyran-4-yl) ethylamino) pyrazin-2-ylamino) ethyl acetate (0.5 g, 1.291 mmol) and hydrochloric acid (6 M in water, 0.215 ml, 1.291 mmoles) were combined in ethanol (2 ml) and the resulting mixture was heated in a Biotage Emrys Optimizer microwave reactor at 100 ºC for 2400 seconds. The reaction mixture was concentrated and purified using silica gel chromatography (33% ethyl acetate in hexanes) to yield the title compound (quantitative yield). MS (EST) m / z 341.1 [M] *, 343.1 [M + 2] *.
CC. 1- (2- (Tetrahydro-2H-pyran-4-yl) ethyl) -7- (trimethylstannyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) - one. 7-Bromo-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one (0.4 g, 1 , 29 mmoles), hexamethylditine (0.57 g, 175 mmoles) and tetracis (triphenylphosphine) palladium (0) (0.2 gg, 0.176 mmol) were placed in a tube sealed with 1,4-dioxane (5 ml). The flask was evacuated, washed with nitrogen, sealed and heated to 110 ºC for 1 hour. The reaction mixture was cooled to room temperature and filtered through Celite, washing with ethyl acetate. The filtrate was concentrated and sonicated with a small volume of solvent mixture (50% hexane in ethyl acetate) and isolated by filtration to yield the title compound (0.34 g, 0.8 mmol, 54.6% yield ). MS (EST) m / z 427 [M + 2] *.
D. 7- (1H-Pyrrol [2,3-b] pyridin-5-1yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3 - blpirazin-2 (1H) -one. 1- (2- (Tetrahydro-2H-pyran-4-yl) ethyl) -7- (trimethylstannyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) - one (1.0 g , 2,352 mmoles), 5-bromo-1H-pyrrole [2,3-blpiridine (0.556 g, 2.82 mmoles), tris (dibenzylidenoacetone) palladium (0) (0.237 g, 0.259 mmol), tri-o-tolylphosphine ( 0.158 g, 0.518 mmol) and triethylamine (0.984 ml, 7.06 mmoles) were combined in a sealed tube, dimethylformamide (5 ml) was added. The atmosphere in the vessel was removed under vacuum and replaced with nitrogen gas. The reaction was heated to 100 ºC for 1 hour. After cooling to room temperature, the reaction mixture was filtered through Celite. The filtered cake was washed with ethyl acetate. The filtrate and wash were combined and concentrated almost to dryness. The resulting solid was dissolved in hot methanol, filtered through Celite and purified by preparative reversed-phase HPLC (5 to 80% acetonitrile + 0.1% TFA in water + 0.1% TFA, over 30 minutes ). The clean fractions were collected, neutralized with ammonium hydroxide and concentrated to dryness. The obtained solid was filtered, washed with water and dried under high vacuum to yield the title compound (0.10 g, 0.264 mmol, 11.2% yield). 1H NMR (400 MHz, DMSO-ds) δ (ppm) 11.71 (br, s., 1H), 8.81 (s, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 7.49 (d, J = 10.54 Hz, 2H), 6.48 (br, s.,
1H), 4.18 (s, 2H), 4.13 (t, J = 6.44 Hz, 2H), 3.82 (d, 0 = 12.89 Hz, 2H), 3.27 (t, 3 = 11.13 Hz, 2H), 1.71 (dd, J = 12.49 Hz, 2H), 1.60 (br, s., 3H), 1.24 (d, 2H); MS (EST) m / z 379.2 [M + 1]; mp 255 at 258 ºC Example 16: 6- (6- (2-Hydroxypropan-2-yl) pyridin-3- 11) -4- ((tetrahydro-2H-pyran-4-yl) methyl) -3,4- dihydropyrazine [2,3-blpyrazin-2 (1H) -one speech A. 6-Bromo-4 - ((tetrahydro-2H-pyran-4-yl) methyl) - 3,4-dihydropyrazine [2,3-blpirazin -2 (1H) -one.
N- (3,5-Dibromopyrazin-2-yl) -2-iodoacetamide (See Example 5, B) (8.0 q, 19.01 mmoles), (tetrahydro-2H-pyran-4-yl) methanamine ( 2.63 g, 22.81 mmoles) and diisopropylethylamine (6.64 ml, 38.0 mmoles) were placed in a 250 ml round bottom flask, suspended in acetonitrile (80.0 ml) and heated to 40 ºC for 16 hours.
The resulting white precipitate was filtered, washed with acetonitrile followed by hexanes and dried in vacuo to provide the title compound (4.89 g, 14.95 mmol, 79% yield). MS (ESI) m / z 327.4 [M] ', 329.5 [M + 2] *. B. 6- (6- (2-Hydroxypropan-2-yl) pyridin-3-11) -4- (((tetrahydro-2H-pyran-4-1yl) methyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one. 6-Bromo-4- ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one (35.98 g, 110 mmol) , 2- (5- (trimethylstannyl) pyridin-2-yl) propan-2-01 (See Example 5, E) (33.0 g, 110 mmol) and [1,1'-bis (- diphenylphosphino) ferrocene] dichloro-palladium (II) with dichloromethane (1: 1) (8.05 g, 11.00 mmoles) were combined in a sealed tube and suspended in
N, N-dimethylformamide (288 ml). The reaction was then heated to 125 ºC for 2 hours. The reaction was cooled slightly and poured while still warm on a column of silica gel and purified using a Biotage SP1 (0 to 100% (5% methanol in ethyl acetate) in hexanes). The desired fractions were combined and organic volatiles removed under reduced pressure. The residue was triturated with 20% ethyl acetate in hexanes followed by several washes with denatured ethanol. The slightly yellow solid was dried under reduced pressure to provide the desired compound (15.08 g, 39.3 mmoles, 35.8% yield). 1H NMR (400 MHz, DMSO-d6) 3 (ppm) 11.32 (s, 1H), 9.07 (d, J = 1.56 Hz, 1H), 8.29 (dd, J = 8.59 , 2.34 Hz, 1H), 8.05 (s, AH) 7 72 (d, O0 = R, 20 He, 1H), 5.26 (Ss, IH), 4.21 (o, 28),
15. 3/83 (d, J = 2.73 Hz, 2H), 3.51 (d) U = 7.42 Hx, 28), 3.27 (t, U = 2 1.32 Hz, 2H) , 2.09 (br, S.,. 1H), 1.91 (dA, v = 11.3 Hz, 2H), 1.46 (Ss, H), 1.24 & 1.38 (Mm, 2 HH); MS (ESI) n / r 384.2 [M + 1]; mp 268 to 269 ºC. Example 17: 7- (6- (2-Hydroxypropan-2-yl) pyridin-3- i1) -1- (2-methoxyethyl) -3,4-dihydropyrazine 2,3-bl] lpyrazin-2 (1H) - ona of s N.
PO A. 7-Bromo-1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one. 2- (3 5 dibromopyrazin-2-ylamino) ethyl acetate (See Example 1.C) (1 equiv), 2-methoxyethanamine (1 equiv), diisopropylethylamine (3 equiv), were suspended in dimethylsulfoxide and heated in a reactor microwave
Emrys Biotage at 150 ºC for 1 hour. The standard ethyl acetate / water insulation and finish generated the raw material, which was suspended in 99.7% acetic acid. The reaction was sealed, heated to 120 ºC and allowed to stir for 2 hours. The reaction was extracted with ethyl acetate. The organic layers were grouped and washed with saturated sodium bicarbonate, followed by brine and dried over magnesium sulfate. Concentration and rapid column chromatography (0 to 100% ethyl acetate in hexanes) generated the desired product in 27% yield over two stages. MS (ESI) m / z 287.4 [M] ”, 289.4 [M + 2] *.
B. 7- (6- (2-Hydroxypropan-2-yl) pyridin-3-yl) -1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one. 7- Bromo-1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (1 equiv), 2- (5- (trimethylstannyl) pyridin-2-yl ) propan-2-01l (See Example 5, E) (1 equiv) and dichlorobis (triphenylphosphine) -palladium (II) (0.2 equiv) were suspended in dimethylformamide. The reaction was purged with nitrogen and heated to 140 ºC for 2 hours. The reaction was cooled to room temperature, filtered through Celite and washed with ethyl acetate. The volatiles were removed under reduced pressure and the resulting purple aqueous paste was purified using silica gel column chromatography (0 to 100% (5% methanol in ethyl acetate) in hexanes). The desired fractions were combined and organic volatiles removed under reduced pressure. The solid was triturated in 5% ethyl acetate in hexanes and washed with hexanes to provide the desired product in 38% yield. 1H NMR (400 MHz, DMSO-ds) 5 (ppm) 9.02 (d, J = 1.6 Hz, 1H), 8.27 (s, 1H), 8.24 (dd,
J = 8.6, 2.3 Hz, 1H), 7.71 (d, J = 0.8 Hz, 1H), 7.69 (s, 1H), 5.25 (s, 1H), 4, 28 (t, J = 6.2 Hz, 2H), 4.20 (d, 2H), 3.60 (t, J = 6.2 Hz, 2H), 3.26 (s, 3H), 1, 46 (s, 6H); MS (EST) m / z 344.3 [M + 1].
Example 18: 7- (1H-Pyrrol [2,3-blpiridin-4-yl) -1- [2- (tetrahydro-pyran-4-yl) -ethyl] -3,4-dihydro-1H-pyrazine [2 , 3-bl] lpirazin-2-one
9. Pain
K A. 7- (1H-Pyrrol [2,3-b] yridin-4-yl) -1- [2- (tetrahydro-pyran-4-yl) -ethyl] -3,4-dihydro-1H-pyrazine [2,3-b] pyrazin-2-one. A mixture of 1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -7- (trimethylstannyl) -3,4-dihydropyrazine [2,3-bl] lpyrazin-2 (1H) -one (See Example 15, C) (1 equiv), 4-bomo-pyrrole [2,3-blpyridine-1-carboxylic acid tert-butyl ester (1 equiv), tris (dibezylidenoacetone) palladium (0.13 equiv), tri -o-tolylphosphine (0.25 equiv) and triethylamine (2.8 equiv) in anhydride dioxane was purged, degassed for 2 minutes and stirred at 95 ºC under nitrogen for 3 to 4 hours. After completion of the reaction as indicated by TLC, the volatiles were removed under reduced pressure and the residue was purified by column chromatography to obtain the desired product in 35% yield. MS (ESI) m / z 479.7 [M + 1] *. 4- (7-0x0-8- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -5,6,7,8-tetrahydropyrazino [2,3-bl] pyrazin-2-yl) -1H tert-butyl-pyrrole [2,3- b] pyridine-1-carboxylate was stirred in the methanolic hydrochloride solution at room temperature. After completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the residue was purified on silica gel to obtain the title compound in 63% yield. 1H NMR (DMSO-d6, 400 MHz) 3 (ppm) 11.72 (Ss; 1H), 8.38 (so, 1H), 8.25 (Ad, J = 0.8 Hz, 1H), 7, 79 (Ss, S 1H), 7.53-7.51 (mM, 2H), 6.97 (q, U = sl, 6 Hz, 1H), 4.23 (Ss, 2H), 4.14 ( t, 3J = 7.6 Hz, 2H), 3.81 (dd, Ji = 2.4 Hz, 32 = 11.2 Hz, 2H), 3.25 (0, J = 10.8 Ho, 2H) , 1.67 (d, O = 13.2 Hz, 2H), 1.61 (m, 3H), 1.22 (m, 2H); MS (EST): n / 2 379.2 [M + 1). Example 19: 1- (2-Methoxyethyl) -7- (2-methyl-6- (4H- 1,2,4-triazol-3-yl) pyridin-3-11) -3,4-dihydropyrazine [| 2 , 3- blpirazin-2 (1H) -one re De int | A. 1- (2-Methoxyethyl) -7- (trimethylstannyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one.
T-Bromo-1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (See Example 17. A) (0.5 9, 1.741 mmoles), 1,1,1,2,2,2-hexamethyldistanan (0.856 g, 2.61 mmol) and tetracis (triphenylphosphine) palladium (O) (0.201 g, 0.174 mmol) were combined in 1,4-dioxane (20 ml) and heated to 140 ºC for 2 hours.
The resulting mixture is cooled to room temperature, diluted with ethyl acetate and filtered through Celite.
The filtrate was concentrated under reduced pressure.
Flash chromatography (0 to 30% ethyl acetate in hexane) gave the desired product as a clear oil (0.5 g, 1.34 mmol, 77% yield). MS (EST) m / z 373.0IM + 2] *. B. 1- (2-Methoxyethyl) -7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [| 2, 3-
blpirazin-2 (1H) -one. 1- (2-Methoxyethyl) -7- (trimethylstannyl) - 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one (0.5 g, 1.348 mmol), 3-bromo-2- methyl-6- (1- (tetrahydro-2H-pyran-2-yl) -1H- 1,2,4-triazol-3-yl) pyridine (0.436 g, 1.348 mmol), tris (dibenzylidinoacetone) dipaladium (0) (0.123 g, 0.135 mmoles), tri-o-tolylphosphine (0.082 g, 0.270 mmol), triethylamine (0.584 ml, 4.04 mmoles) and N, N-dimethylformamide (10 ml) were combined in a 75 ml sealable bottle , the atmosphere in the flask was removed and replaced with nitrogen.
The mixture was stirred at 130 ºC for 3 hours.
The resulting mixture was cooled to room temperature and filtered.
The organic layer was concentrated under reduced pressure.
The resulting residue was diluted with methanol and dimethylsulfoxide, filtered and purified using reverse phase preparatory HPLC (10 to 30% acetonitrile + 0.1% TFA in water + 0.1% TFA, over 30 minutes). The fractions containing the clean product were passed through a Phenomenex Strata-X-C solid phase extraction column.
The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol.
The product was eluted with the eluent of 5% ammonium hydroxide in methanol and was concentrated under reduced pressure.
The residue was triturated with ethyl ether in hexane to make a fine powder and dried under vacuum at 50 ° C to obtain the desired product (0.05 g, 0.136 mmol, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO- de) 5 (ppm) 8.10 (br, s., 1H), 7.98 (br, s., 1H), 7.94 (s, 1H), 7.73 (br, s., 1H), 4.13 and 4.28 (mM, 4H), 3.55 (t, J = 6.25 Hz, 2H), 3.24 (s, 3H), 2.70 (br, s., 3H); MS (EST) m / z 367.2 [M + 1]) *.
Example 20: 6- (4- (4H-1,2,4- Triazol-3-yl) phenyl) -4-ethyl-3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one hydrochloride
ALA FA, A. 6-Bromo-4-ethyl-3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one. To a solution of 2-bromo-N- (3,5-dibromopyrazin-2-yl) acetamide (See Example 4. A) (1 equiv) and diisopropylethylamine (3 equiv) in acetonitrile was added - “ethanamine hydrochloride ( 1.05 equiv).
The solution was allowed to be heated to 70 ºC for 30 minutes. The solution was condensed under reduced pressure and purified using column chromatography (0 to 75% ethyl acetate in hexanes) to provide the title compound in 36% yield. MS (EST) m / z 257.5 [M] *, 259.4 [M + 2] *.
B. 4-Ethyl-6- (4- (4- (tetrahydro-2H-pyran-2-1yl) -4H- 1,2,4-triazol-3-yl) phenyl) -3,4-dihydro-pyrazine [2,3-blpirazin-2 (1H) -one. 6-Bromo-4-ethyl-3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one (1.1 equiv), 4- (tetrahydro-2H-pyran-2-yl) -3- ( 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -4H-1,2,4-triazole (1 equiv) and dichloromethane dichloromethane [1,1 ' bis (diphenylphosphino) ferrocene] palladium (II) (0.05 equiv) were combined in 1,4-dioxane followed by the addition of sodium carbonate (3 equiv) in water. The solution was heated in a Biotage Emrys Optimizer microwave reactor at 120 ºC for 30 minutes. The solution was condensed under reduced pressure and purified using column chromatography (0 to 10% methanol in ethyl acetate) to provide the title compound in 45% yield. MS (EST) m / z 406.6 [M + 1] ”,. C. 6- (4- (4H-1,2,4-Triazol-3-yl) phenyl) -4-ethyl-3,4-dihydropyrazine [2,3-b] lpyrazin-2 (1H) hydrochloride - ona. 4-Ethyl-6- (4- (4- (tetrahydro-2H-pyran-2-yl) -4H- 1, 2,4-triazol-3-yl) phenyl) -3,4-dihydropyrazine [2,3 -b] pyrazin-2 (1H) - one in ethanol was treated with 2 N hydrogen chloride in dioxane. The solution was stirred at 75 ° C for 1 hour. The solution was partially condensed and cooled. Cold ethanol was added to the aqueous slurry and the resulting precipitate filtered and washed with additional cold ethanol followed by hexanes to provide the title compound as the hydrochloride salt in 82% yield. 1H NMR (400 MHz, METANOL-da)) 3 (ppm) 9.18 (s, 1H), 8.22 (d, J = 8.59 Hz, 2H), 8.04 and 8.09 (m, 3H), 7.66 - 7.74 (m, 1H), 7.58 and 7.64 (m, 1H), 4.24 (s, 2 H), 3.74 (q, 3 = 7.03 Hz, 2H), 1.29 (t, J = 7.03 Hz, 4H), 0.79 and 0.98 (m, 4H); MS (EST) m / z 322.2 [M + 11º.
CONSTRUCTION BLOCK SYNTHESIS The following building blocks were prepared and used in the preparations as described in the present invention or variations known in the art thereof. Tert-butyl 4-Bromo-1H-pyrrole [2,3-b] pyridine-1-carboxylate> Co
DS A. 4-Bromo-1H-pyrrole [2,3-blpiridine. A solution of trifluoromethyl sulfonic anhydride (9.3 g, 33 mmol) was added dropwise to a mixture of 1H- 7-oxide
pyrrole [2,3-b] pyridine (3 g, 22 mmoles) and tetrabutyl ammonium bromide (10.8 g, ss mmoles) in NN-dimethylformamide (30 ml) at 0 ºC. The resulting mixture was stirred at 0 ºC for 4 hours and at room temperature overnight. The reaction was quenched with water and neutralized with 1N sodium hydroxide at pH = 7. The resulting mixture was extracted twice with a mixture of methylene chloride and i-propanol (30 ml, Vn: V, = 4: 1). The organic layer was combined, dried over anhydrous sodium sulfate, concentrated and purified by a preparatory reversed-phase HPLC (0 to 30% acetonitrile + 0.1% TFA in water + 0.1% TFA, over 15 minutes.) to obtain the title compound (1.5 g, 34.3% yield). MS (ESIT) m / z 196.8 [M + 1], 198.8 [M + 3] *.
B. tert-Butyl 4-Bromo-1H-pyrrole [2,3-b] pyridine-1-carboxylate. A mixture of 4-bromo-1H-pyrrole (2,3-blpyridine (250 mg, 1.26 mmol), di-tert-butyl dicarbonate (302 mg, 1.38 mmol), dimethyl-pyridin-4-yl -amine (7.6 mg, 0.06 mmol) and triethylamine (127 mg, 1.26 mmol) in anhydride methylene chloride (15 ml) was stirred at room temperature for 3 hours. After completion of the reaction as indicated by TLC, the volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel (9 to 25% ethyl acetate in petroleum ether) to obtain the desired product (230 mg, 61% yield) as an oil MS (ESI) m / z 242.9 [M-56 + 1] * 1- (Tetrahydro-2H-pyran-2-i1) -4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1H- indazole TE & N
A. 4-Bromo-1H-indazole. To a solution of 3-bromo-2-methylaniline (5 g, 27 mmoles) in chloroform (1 ml) was added acetic anhydride (5 g, 27 mmoles) at 0 ºC and the mixture was stirred at room temperature for 1 hour. Potassium acetate (0.75 g, 7.8 mmoles) and isoamyl nitrite (0.78 gq, 58 mmoles) were added and the reaction mixture was refluxed for 18 hours. The volatiles were removed under reduced pressure and water (0.65 ml) was added. The mixture was concentrated, diluted with concentrated hydrochloric acid (1 ml) and heated at 50 ºC for 2 hours. After being cooled to room temperature, the aqueous sodium hydroxide solution (50%) was added until pH = 10. The aqueous mixture was extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with brine (150 ml), dried over anhydrous sodium sulfate, filtered, evaporated and purified on a column of silica gel (3% ethyl acetate in petroleum ether) to obtain the desired product (2 , 69 gg, 34% yield) as a solid. MS (EST): m / z 197.0 [M + 1] *. B. 4-Bromo-1- (tetrahydro-pyran-2-yl) -1H-indazole. A solution of 4-bromo-1H-indazole (1.82 g, 9.24 mmol), 3,4-dihydro-2H-pyran (1.55 g, 18.48 mmol) and toluene-4-sulfonic acid ( 0.26 g, 1.39 mmoles) in anhydrous tetrahydrofuran (40 ml) was heated to 80 ° C overnight under nitrogen. The solvent was removed under reduced pressure and the residue was purified on a silica gel column (3% ethyl acetate in petroleum ether) to obtain the title compound (2.13 g, 81% yield) as a yellow solid. .
MS (EST): m / z 280.9 [M + 1] *. ç. 1- (Tetrahydro-pyran-2-yl) -4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-Indazole.
A degassed mixture of 4-bromo-1- (tetrahydro-pyran-2-yl) - 1H-indazole (2.13 g, 7.45 mmol), bis (pinacolate) diborone (3.73 g, 14.9 mmol) ), potassium phosphate (2.70 g, 12.67 mmol), palladium acetate (0.174 g 0.75 mmol) and triphenylphosphine (0.59 g, 2.24 mmol) in 1,2-dimethoxy-ethane ( 50 ml) was heated to 100 ºC under nitrogen overnight.
After cooling to room temperature, the reaction mixture was filtered, concentrated under reduced pressure and purified on a silica gel column (10 to 30% ethyl acetate in petroleum ether) to obtain the product (1.83 g, 74 % yield) as a solid.
MS (ESI): m / z 329.2 [M + 21 3- (4-Bromo-2-fluoro-3-methylphenyl) -4- (tetrahydro-2h-pyran-2-yl) -4H-1,2, 4-triazole Er o À A. 4-Bromo-3-fluoro-2-methylaniline.
For a stirred solution of 3-fluoro-2-methylaniline (25 g, 200 mmoles) in acetic acid (140 ml) in O at 5 ºC, hydrogen bromide (100 ml, 200 mmoles) was added then dimethyl sulfoxide (72 ml) it was added slowly in drops (the reaction is exothermic and at a temperature above 5 to 15 ºC it produces dibromoisomer). The mixture was stirred at 5 to 15 ºC for 12 hours (the mixture became a clean solution). The resulting solution was cooled to 0 ° C and neutralized with sodium hydroxide then with sodium bicarbonate to pH 7. The mixture was extracted with ethyl acetate.
The organic layer was concentrated under reduced pressure.
Flash chromatography (0 to 10% ethyl acetate in hexane) gave the desired product as a white solid (23.3g, 114 mmoles, 57% yield). 'H NMR (400 MHz, CHLOROPHORM-d) 5 (ppm) 7.11 (t, J = 8.20 Hz, 1H), 6.35 (d, J = 8.98 Hz, 1H), 3.72 (br. s., 2H), 2.07 (d, J = 1.95 Hz, SH). B. 4-Amino-2-fluoro-3-methylbenzonitrile.
A mixture of 4-bromo-3-fluoro-2-methylaniline (23 g, 113 mmoles) and cyano-copper (20.19 g, 225 mmoles) N, N-dimethylformamide (200 ml) was heated to 140 ºC for 7 hours.
After the mixtures were cooled to room temperature, filtered and poured into a separating funnel containing water and ethyl acetate (1: 1). The layers were separated and the organic layer was concentrated under reduced pressure.
Flash chromatography (0 to 50% ethyl acetate in hexane) gave the desired product (11.4 dg, 76 mmoles, 67% yield) as a brown solid. 'H NMR (400 MHz, CHLOROPHORM-d) 5 (ppm) 7.22 (t, 1H), 6.45 (d, J = 8.59 Hz, 1H), 4.23 (br. S., 2H ), 2.07 (s, 3H); MS (ESI) m / z 151.1 [M + 1] *. ç. 4-Bromo-2-fluoro-3-methylbenzonitrile.
A mixture of dimethyl sulfoxide (400 ml) and potassium nitrite (22.67 g, 266 mmoles) was stirred to dissolve potassium nitrite and 4-amino-2-fluoro-3-methylbenzonitrile (10 g, 66.6 mmoles) and copper (I) bromide (1.911 g, 13.32 mmoles) were added.
48% aqueous hydrogen bromide (33 ml, 266 mmoles), diluted with dimethyl sulfoxide (200 ml), was added by dripping and the reaction stirred for
2 hours.
After complete conversion of starting materials, the reaction mixture was poured into ice-cold water and neutralized to pH 7 with cold concentrated sodium hydroxide.
The resulting solid was collected by filtration to provide the desired product (11.4 g, 53.3 mmoles, 80% yield) as a white solid. 'H NMR (400 MHz, CHLOROPHORM-d) 5 (ppm) 7.47 (d, J = 9.37 Hz, 1H), 7.33 (t, 1H), 2.39 (d, U = 2, 34 Hz, 3H), D. 4-Bromo-2-fluoro-3-methylbenzamide. 4-Bromo-2-fluoro-3i-methylbenzonitrile (11 gg, 51.4 mmoles) in a mixture of 100 ml of TFA sulfuric acid (4: 1, V / V) was stirred at 40 ºC for 16 hours.
After complete conversion of starting material, the reaction mixture was poured into ice-cold water.
The resulting solid was filtered and washed with water and dried to provide the desired product (11.24 g, 48.4 mmoles, 94% yield) as a white solid.
MS (EST) m / z 234.1 [M + 2] *. E. 3- (4-Bromo-2-fluoro-3-methylphenyl) -1H-1,2,4-triazole. 4-Bromo-2-fluoro-3-methylbenzamide (11 g, 47.4 mmoles) and N, N-dimethylformamide dimethylacetal (60 ml) were combined in a 100 ml distillation flask with a stir bar and heated at 55 ° C. ºC under a reflux condenser under nitrogen for 3 hours.
The resulting mixture was concentrated under reduced pressure and dried under vacuum to give yellow oil, which was used in the next step without purification.
The residue was diluted with acetic acid (60 ml) in O ºC and hydrazine monohydrate (20 ml) was added by dripping and allowed to stir in rt for 5 hours.
After complete conversion of starting material, the reaction mixture was poured into ice-cold water.
cold and neutralized to pH 7 with cold concentrated sodium hydroxide.
The resulting solids were collected by vacuum filtration.
The solid was dissolved in ethyl acetate (400 ml) and stirred for 15 minutes, filtered the insoluble solid, the filtrate dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried under vacuum to give pure brown solid (4.3 g, 16.79 mmoles, 35% yield) o Which was used in the next step without purification. 'H NMR (400 MHz, CHLOROFORM-d) & (pom) 8.12 (s, 1H), 7.97 (t, J = 8.00 Hz, 1H), 7.52 (Ad, J = 8.59 Hz , 1H), 2.44 (d, 3H). F. 3- (4-Bromo-2-fluoro-3-methylphenyl) -4- (tetrahydro-2H-pyran-2-yl) -4H-1,2,4-triazole.
Methanesulfonic acid (0.090 ml, 1.390 mmol) was added to a stirred solution of 3- (4-bromo-2-fluoro-3-methylphenyl) -1H-1,2,4-triazole (7.0 g, 27.3 mmoles) and 3,4-dihydro-2H-pyran (12.68 ml, 139 mmoles) in tetrahydrofuran (33 ml). The resulting stirred mixture at 85 ºC in a reflux condenser under nitrogen for 20 hours.
The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine.
The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was purified using flash chromatography (20 to 30 to 50% ethyl acetate in hexane). Product containing fractions were combined and the solvent removed under reduced pressure to give the desired product (8.8 g, 95% yield) as a yellow solid.
MS (EST) m / z 340.0 [M] + Note: As understood by someone skilled in the art, protection, such as, for example, Boc or THP groups, from heterocyclic chemical moieties that are subject to tautomerism, for example, moieties triazolyl chemicals, can potentially give rise to different regiosiomerically protected compounds that may not be readily characterized or distinguished by standard analytical methods such as 1ID-NMR. Such regioisomers are designated in this specifically by the chemical name of only one of the regioisomers, however, it is understood that the name refers to any and all possible regioisomers and their mixtures potentially formed by the reaction. The unique regioisomeric designation is now also applied in the name of the subsequent products formed by the reaction with the protected intermediate. As understood by someone skilled in the art, with the removal of the protective group, only one product is formed, regardless of the regioisomerically protected compound of departure. 3-Bromo-2-methyl-6- (1- (tetrahydro-2H-pyran-2-yl) - pA-1,2, Arbriazol-s-ll) piciáina
SE A. 3-Bromo-6-iodo-2-methylpyridine. Sodium todetide (2 equivalents) and 3,6-dibromo-2-methylpyridine (1 equivalent) were combined in propionitrile and the resulting aqueous paste was stirred in nitrogen for 5 minutes Iodotrimethylsilane (0.2 equivalent) was added and the reaction was heated at 95 ºC, with stirring, in nitrogen for 24 hours. The aqueous slurry was cooled to room temperature, diluted with 1: 1 of the mixture of ethyl acetate and water. The mixture was stirred for 15 minutes and the aqueous and organic phases were then separated. The organic layer was washed sequentially with equal volumes of saturated aqueous sodium bicarbonate solution, sodium thiosulfate (5% aqueous solution), and saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product in 95% yield, such as an oil, which was crystallized from an off-white solid. MS (ESI) m / z 297.8 [M] +, 299.8 [M + 2] +.
B. 5-Bromo-6-methylpicolinonitrile. In an inert atmosphere, 3-bromo-6-iodo-2-methylpyridine (1 equivalent) and acetonitrile were combined and stirred for 10 minutes, copper cyanide (0.5 equivalent), sodium cyanide (0.8 equivalent) and more acetonitrile was added. The aqueous slurry of the reaction was heated, with stirring, at 80 ºC for 24 hours. The reaction solution was cooled to room temperature and diluted with ammonium hydroxide (0.5 M aqueous solution). The mixture was stirred for 15 to 30 minutes, filtered through diatomaceous earth and the filter cake was washed with ethyl acetate. The filtrate and wash were combined and further diluted with ethyl acetate and the solution was stirred for 15 minutes. The aqueous and organic phases were separated and the organic layer was washed sequentially with ammonium hydroxide (0.5 M aqueous solution; four times) and the saturated aqueous sodium chloride (twice), dried over anhydrous sodium sulfate, filtered , and concentrated under reduced pressure to provide 5-bromo-6-methylpicolinonitrile in 92% yield, as an off-white solid. MS (EST) m / z 196.9 [M] +, 198.9 [M + 2] *.
ç. 5-Bromo-6-methylpicolinimidohydrazide.
Hydrazine monohydrate (2 equiv) was added to a di: M suspension while stirring 5-bromo-6-methylpicolinonitrile (1 equiv) in ethanol under nitrogen.
The reaction mixture was heated to 50 ºC for 24 hours.
The reaction was cooled to room temperature and then filtered.
The collected solid was washed with cold ethanol by cold t-butyl methyl ether.
The washed solid was dried under vacuum to provide the title compound in 89% yield, as a yellow solid.
MS (EST) m / z 228.9 [M] ', 230.9 [M + 2] *. D. 3-Bromo-2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridine. 5-Bromo-6-methylpicolin-imido-hydrazide (1 equiv) and formic acid (15 equiv) were combined and heated with stirring at 100 ºC for 6 hours.
The reaction was cooled to room temperature and diluted with methanol.
The resulting aqueous slurry was stirred for 30 minutes and then partially concentrated under reduced pressure to -20% of the total volume.
The resulting mixture was again diluted with methanol and partially concentrated under reduced pressure to -20% of the total volume.
The resulting solids were collected by filtration, washed three times and dried under reduced pressure to provide the desired product in 84% yield, as an off-white solid.
MS (ESI) m / 2 238.9 [M] *, 240.9 [M + 2] ". E. 3-Bromo-2-methyl-6- (1- (tetrahydro-2H-pyran-2- 11) - 1H-1,2,4-triazol-3-yl) pyridine 3-Bromo-2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridine (1 equiv), 3,4 -dihydro-2H-pyran (2 equiv) and methanesulfonic acid (0.1 equiv) were combined in tetrahydrofuran during stirring under nitrogen.
The reaction was heated to 68 ºC for 3.5 hours.
After cooling to room temperature for 1 hour, triethylamine (0.4 equiv) was added and the resulting solution was stirred for 10 minutes and then concentrated under reduced pressure.
Acetonitrile was added and the excess tetrahydrofuran was removed by codistillation under reduced pressure, with heating to 35 ºC (twice). The resulting residue was dissolved in acetonitrile (1 volume) and water (2.25 volumes) was added.
The resulting suspension was stirred 30 minutes.
The solids were collected by filtration, washed with a 20% solution of acetonitrile in water and dried under reduced pressure.
The crude product was triturated with hexanes, filtered, still washed with hexanes and dried in a vacuum oven at 35 ºC to provide the desired product in 80% yield, as an off-white solid.
MS (ESI) m / z 324.9 [M + 2] *. 3- (4-Bromo-2-fluorophenyl) -4H-1,2,4-triazole is THERE, if A. 4-Bromo-2-fluorobenzamide.
A solution of 4-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmols) in a mixture of 70 ml of TFA (56.0 ml, 727 mmols) -sulfuric acid (14.0 ml, 263 mmols) (4: 1 V / V) was stirred at 40 ºC for 16 hours.
The reaction was poured while still warm on ice water.
The precipitated product and the solid was filtered and dried to generate 4-bromo-2-fluorobenzamide (9.53 g, 43.7 mmols, 87% yield) as a white solid.
MS (EST) m / z 218.1 [M] *, 220.1 [M + 2] *. B. 3- (4-Bromo-2-fluorophenyl) -4H-1,2,4-triazole. 4-Bromo-2-fluorobenzamide (9.53 g, 43.7 mmols) and N, N-
dimethylformamide dimethylacetal (75.0 ml) were combined in a 500 ml round bottom flask and purified with nitrogen. The reaction was heated to reflux at 85 ° C for 2 hours. The resulting mixture was concentrated under reduced pressure and dried in vacuo to provide a yellow oil. The oil was suspended in concentrated acetic acid (75.0 ml) and cooled to 0 ºC. Hydrazine hydrate (21.88 g, 437 mmols) was added by dripping and the mixture was allowed to stir at room temperature for 5 hours. The reaction was poured hot on cold ice and extracted with dichloromethane (3x200 ml). The organic volatiles were removed under reduced pressure to provide 3- (4-bromo-2-fluorophenyl) -4H-1,2,4-triazole (7.20 g, 29.7 mmol, 68.1% yield) as a white solid. MS (ESI) m / z 241.9 [M] ', 243.9 [M + 2] *. 2- (4-Methyl-5- (trimethylstannyl) pyridin-2-yl) propan-2-o0l
FO A. 2- (5-Bromo-4-methylpyridin-2-yl) propan-2-ol. 2,5-Dibromo-4-methylpyridine (4.0 o, 15.94 mmol) was dissolved in toluene (60.0 ml) and the reaction was cooled to -78 ° C. Butyllithium (7.01 mL, 17.54 mmol) was added in drops and the reaction was allowed to stir for 30 minutes. Acetone (4.69 mL, 63.8 mmol) was then added and the reaction was allowed to warm to room temperature and stir for 16 hours. The reaction was cooled with saturated ammonium chloride, extracted in ethyl acetate (3x200 mL) and washed with water followed by brine. The organics were dried with magnesium sulfate and volatiles were removed under reduced pressure. The compound was purified on silica gel chromatography (0 to 50% ethyl acetate in hexanes) to obtain 2- (5-bromo-4-methylpyridin-2-yl) propan-2-0l (2.33 9, 10 , 13 mmol, 63.5% yield). MS (EST) m / z 230.3 [M] +, S ai, 3 [MN + 2]).
B. 2- (4-Methyl-5- (trimethilstanyl) pyridin-2-yl) propan-2-0l. 2- (5-Bromo-4-methylpyridin-2-yl) propan-2-ol (2.33 g, 10.13 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.045 g, 1.013 mmol) were added to a pressure tube and were suspended in 1,4-dioxane (33.8 ml). 1,1,1,2,2,2-Hexamethyldistanane (2.99 mL, 12.15 mmol) was then added and heated to 150 ºC for 30 minutes. The reaction was allowed to cool to room temperature and was filtered through celite and washed with ethyl acetate. The organic volatiles were removed under reduced pressure followed by an extraction in ethyl acetate (3x200 mL) and water. The organic volatiles were removed under reduced pressure and the compound was purified using silica gel column chromatography on a Biotage column (10 to 50% ethyl acetate in hexanes) to obtain 2- (4- methyl-5- ( trimetilstanil) pyridin-2-yl) propan-2-01l (1.75 9, 5.57 mmol, yield 55.0%). * H NMR (400 MHz, DMSO-ds) 3 (ppm) 8.31 (8, IH), 7.51 (Ss, IH), 5.205 (br. Ss. 11H), 2.37 (s, 3H) , 1.41 (s, 6H), 0.65 (br. S., 3H), 0.34 (s, 6H).
Terc-butyl 3- (5-bromo-6-methylpyridin-2-1l1) - 1H- 1 r2,4-triazole-11-carboxylate Xe 4 eu 1
A. 5-Bromo-6-methylpicolinonitrile. The 1-L, three-necked round-bottom flask equipped with a mechanical stirrer and a nitrogen inlet was loaded with 3,6-dibromo-2-methylpyridine (150 gg, 0.59 mol), copper (1) cyanide ( 42.8 g, 0.47 mol) and sodium cyanide (23 g, 0.47 mol). To the mixture, N, N-dimethylformamide (300 ml) was added. The mixture was heated to 95 ºC and stirred for 48 hours.
The reaction mixture was stirred at room temperature and poured into ethanol (3 L) while stirring. The mixture was filtered through a block of Celite, with the filtrate being concentrated under reduced pressure and divided between water (3 L) and ethyl acetate (3 L). The organic layer was separated and washed with brine (2 x 600 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by purifying silica gel buffer (0 to 5% ethyl acetate in hexanes) to obtain the product (61.5 g, 45% yield) as a white solid. In addition, 19.32 g (14%) of the mixture of the starting material and the product was isolated. Alternative approach: 3,6- Dibromo-2-methylpyridine (1 equiv) and sodium iodide (2 equiv), were combined in propionitrile (15X vol). The mixture was stirred and iodotrimethylsilane (0.2 egive) was added. The reaction mixture was heated and stirred at 95 ºC for 24 h, cooled to room temperature and diluted with ethyl acetate and water. The organic phase was washed with aqueous sodium bicarbonate, aqueous sodium thiosulfate, and aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure with the addition of ethyl acetate to a residue. The product was vacuum-solidified to produce 3-bromo-6-
iodine-2-methylpyridine as an off-white solid. 3-Bromo-6-iodo-2-methylpyridine (1 equiv) in acetonitrile (7X vol) was treated with copper cyanide (0.5 equiv), sodium cyanide (0.8 equiv), and additional acetonitrile (3X vol ). The aqueous slurry of the reaction was heated to 80 ºC for 24 h.
The reaction mixture was cooled to room temperature, treated with aqueous ammonium hydroxide (1.2 equiv), and filtered through Celite. The filtrate was diluted with ethyl acetate and the phases were separated.
The organic layer was washed with aqueous ammonium hydroxide and aqueous sodium chloride, dried with sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to obtain the title compound as an off-white solid.
B. 5-Bromo-6-methylpicolinoidrazonamide.
A 500 ml three-necked round-bottom flask was equipped with 5-bromo-6-methylpicolinonitrile (101.5 g, 0.515 mol), ethanol (122 ml) and hydrazine hydrate (50 ml, 1.03 moles). The resulting very thick mixture was allowed to stir at room temperature for 24 hours.
More ethanol (50 ml) was added and the mixture was allowed to stir over the weekend.
The mixture was filtered and washed with cold ethanol (100 ml) and cold hexanes (50 ml). the solids were dried in a vacuum oven to provide the product (110 g, 93% yield) as an off-white solid. ç. 3-Bromo-2-methyl-6- (1H-1,2,4-triazol-3-yl) pyridine.
A 500 ml three-neck round-bottom flask was equipped with a mechanical stirrer, a thermocouple connected to a J-KEM temperature controller and a reflux condenser.
The flask was loaded with 5-bromo-
6-methylpicolinoidrazonamide (100 g, 0.463 mol) and formic acid (250 ml). The resulting solution was heated to 100 ºC and stirred for 48 hours.
The formic acid was removed under reduced pressure and the resulting aqueous slurry was treated with water (1.51) while stirring vigorously.
The mixture was filtered and washed with water (300 ml). The solids were transferred into a round bottom flask and treated with water (1 1) and 1 M sodium hydroxide to pH 7. The mixture was allowed to stir for 30 minutes, filtered, washed with water (300 ml) and dried in a vacuum oven at 30 to 35 ºC for 48 hours to provide the product (96 g, 92%
yield) as a white solid.
D. 3-Bromo-2-methyl-6- (1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl) pyridine.
To a suspension of 3-bromo-2-methyl-6- (1H-1,2,4-triazol-3-yl) pyridine (96.0 g, 0.4 mol) in tetrahydrofuran (780 ml) was added 3 , 4-dihydro-2H-pyran (72.5 ml, 0.8 mol) and methanesulfonic acid (3.2 ml). The mixture was heated to 65 ° C and the resulting yellow solution was allowed to stir at 65 ° C for 6 hours.
The mixture was cooled to room temperature, quenched with triethylamine (23 ml), concentrated under reduced pressure and further dried in a high vacuum for 1 hour.
The resulting oil was dissolved in acetonitrile (250 ml) and the solution was added to water (750 ml) while stirring vigorously.
More acetonitrile (80 ml) was added and the mixture was allowed to stir for 1 hour.
The resulting solids were filtered, washed with 1: 4 acetonitrile / water (800 ml) and dried in a vacuum oven for 48 hours to provide the product (110 g, 85% yield) as a white solid.
The product was further purified by purification of silica gel buffer (1: 1 hexanes / ethyl acetate) to obtain 88 g of pure product as a white solid and 16.2 g of less pure product. MS (ESI) m / z 239.1 [M] *, 241.1 [M + 2] *.
E. tert-butyl 3- (5-Bromo-6-methylpyridin-2-yl) -1H-1,2,4-triazole-1-carboxylate. To a mixture of 3-bromo-2-methyl-6- (1H-1,2,4-triazol-3-yl) pyridine (300 g, 1.25 moles) in dioxane (4 1) was added sodium carbonate (398 g, 3.75 moles), followed by water (41).
Di-tert-Butyl dicarbonate (274 gg, 1.25 moles) was added and the mixture was stirred for 1 hour at room temperature. The mixture was then diluted with ice water (-10 1) and extracted with ethyl acetate (4 1 x 3). The combined ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered and concentrated to provide the product (254 g, 60% yield) as a slightly yellow solid.
4- (Tetrahydro-2H-pyran-2-11) -3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) - 4H-1,2 , 4-triazole Po.
OX A. Ethyl 4-bromobenzimidate hydrochloride. A solution of 4-bromobenzonitrile (17.65 9g, 97 mmoles) in ethanol (500 ml) was acidified with hydrogen chloride gas at 0ºC for fifteen minutes. The solution was allowed to stir for 16 h. The solution was condensed under reduced pressure to provide the title compound (25.35 g, 99%). MS (EST) m / z 228.1 [M] *, 230.4 [M + 2] ”.
B. 3- (4-Bromophenyl) -4H-1,2,4-triazole. Ethyl 4-bromobenzimidate hydrochloride (35.6 g, 135 mmoles),
formic hydrazide (16.16 g, 269 mmoles) and triethylamine (75 ml, 538 mmoles) were combined in a screw cap jar and heated to 85ºC for 16 h. The solution was condensed under reduced pressure to provide a solid, which was partitioned between water and ethyl acetate (3X), dried over magnesium sulfate and the solvent was removed under reduced pressure. The resulting solid was sonicated with 20% ethyl acetate in hexanes, filtered and dried to provide the title compound (14.6 g, 65.2 mmoles, 48% yield). MS (ESI) m / z 224.1 [M] *, 226.1 [M + 2] *.
C. 3- (4-Bromophenyl) -4- (tetrahydro-2H-pyran-2-yl) - 4H-1,2,4-triazole. A solution of 3- (4-Bromophenyl) -4H-1,2,4-triazole (14.1 g, 62.9 mmol), 3,4-dihydro-2H-pyran (10.59 mmol) and methanesulfonic acid (1.19 g, 6.29 mmoles) in tetrahydrofuran (150 ml) were heated to 75ºC for 2 h. The solution was condensed and partitioned between sodium bicarbonate solution and ethyl acetate (3X), the organic products were dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The solid was triturated with 10% ethyl acetate in hexanes to provide the title compound (8.1 g, 26.3 mmoles, 70% yield). MS (EST) m / z 308.4 [M] ', 310.5 [M + 2] *.
D. 4- (Tetrahydro-2H-pyran-2-11) -3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -4H-1 , 2,4-triazole.
3- (4-Bromophenyl) -4- (tetrahydro-2H-pyran-2-yl) -4H-1,2,4-triazole (8.1 g, 26.3 mmoles), bis (pinacolate) diboro (6 , 67 g, 26.3 mmoles) and potassium acetate (10.32 g, 105 mmoles) were combined in dimethylformamide (100 ml). The solution was purged with nitrogen gas for 2 minutes. Dichloro [1,1'-bis (diphenylphosphino) ferrocenolpaladium (11) dichloromethane
(1.07 g, 1.31 mmoles) was then added and the solution was heated at 100ºC for 16 h. The solution was filtered through celite and the filtrate was condensed under reduced pressure to provide a dark oil. The oil was purified by means of Biotage chromatography (0 to 70% ethyl acetate in hexanes) to provide a solid upon drying. The solid was diluted with hexanes, sonicated, filtered and dried to provide the title compound (7.1 g, 20.0 mmol, 71% yield). MS (ESI) m / z 356.5 [M + 1] *. 5-Bromo-2- (1- (tetrahydro-2H-pyran-2-1yl) -1H-1,2,4-triazol-3-yl) pyridine
Br CQ (E) -5-bromo-N- ((dimethylamino) methylene) picolinamide. A solution of 5-bromopicolinamide (0.500 g, 2.49 mmoles) and dimethylformamide dimethylacetal (20 ml) was heated to 85ºC for 3 h. The reaction was concentrated and the product was used directly in the next step (0.604 g, 95% yield). MS (ESI) m / z
20. 257.1 [M + 11%, B. 5-Bromo-2- (1H-1,2,4-triazol-3-yl) pyridine. A solution of (E) -5-bromo-N- ((dimethylamino) methylene) picolinamide (0.604 mg, 2.36 mmol) and hydrazine (2.12 g, 66.1 mmol) was stirred at 25 ° C for 3 h. The reaction was concentrated and diluted with water. The resulting precipitate was collected by filtration and vacuum dried to obtain the title compound (0.442 g, 83% yield). MS (ESI) m / z 226.1 [M + 1] "*.
CC. 5-Bromo-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl) pyridine. A solution of 5-bromo-2- (1H-1,2,4-triazol-3-yl) pyridine (0.342 mg, 1.52 mmol), 3,4-dihydro-2H-pyran (0.255 gQg, 3, 04 mmoles) and 4-methylbenzenesulfonic acid (0.058 g. 0.30 mmoles) in tetrahydrofuran was heated to 75ºC for 6 h. The reaction was concentrated and purified using Biotage column chromatography (0 to 20% methanol in dichloromethane) to provide a semitransparent product such as an oil (0.614 g, 1.9 mmoles,> 100% yield). This material was used without further purification. MS (EST) m / z 309.4 [M] *, 311.1 [M + 2] *. Tert-butyl 6-bromo-4-methyl-2- (methylamino) -1H-benzo [d] imidazole-1-carboxylate +
NT Toe A. (6-Bromo-4-methylbenzimidazol-2-yl) -N-methylamine. Isothiocyanatomethane (0.055 g, 0.746 mmol) in N, N-dimethylformamide (1.0 ml) was added lightly to a stirred solution of 5-bromo-3-methylbenzene-1,2-diamine (0.150 g, 0.746 mmol) in N, N-dimethylformamide (1.5 ml) at 0ºC. The cold bath was removed, the reaction mixture was capped and stirred at room temperature for 48 hours. N- (3-Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (0.157o, 0.821mmol) was added and the reaction mixture capped and heated at 40 ° C overnight. The resulting mixture was diluted with methanol, filtered and purified using preparative reverse phase HPLC (10 to 50% acetonitrile + 0.1% TFA in HO + 0.1% TFA, for 30 minutes). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure.
Acetonitrile was added and the resulting mixture loaded onto a Strata ion exchange column.
The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol.
The product was eluted with 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried under high vacuum to obtain the desired product (0.128 g, 0.53 mmol, 72% yield) as a slightly yellow waxy solid. .
MS (EST) m / z 240 [M] *, 242 [M + 2] *. B.
Terc-Butyl 6-bromo-4-methyl-2- (methylamino) -11H-benzoldlimidazole-1-carboxylate. (6-Bromo-4-methylbenzimidazol-2-yl) -N-methylamine (0.128 g, 0.533 mmol), diisopropylethylamine (0.464 ml, 2.67 mmoles), di-tert-Butyl dicarbonate (0.349 g, 1.599 mmoles) and N, N-dimethylformamide (5 ml) were combined in a 100 ml round bottom flask, capped and stirred at room temperature for 21 hours.
The resulting mixture was partitioned between water and ethyl acetate.
The layers were separated and the organics were washed with water and brine.
The organics were dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified using flash chromatography (10 to 30% ethyl acetate in hexanes) to obtain the desired product (0.092 g, 0.27 mmol, 51% yield ) as a yellow waxy solid.
MS (ESI) m / z 340 [M] *, 342 [M + 2] ”*. 7-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [d] limidazole-2-amine
O, sn -.
A. T7-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [d] imidazole-2-amine. 3-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzene-1,2-diamine (see Example 1.G) (500 mg, 2.015 mmoles ) and cyanic bromide (0.484 ml, 2.418 mmoles) were added to a round-bottom flask at room temperature, suspended in methanol (10.0 ml) and allowed to stir for 1.5 hours. Volatiles were removed under reduced pressure followed by the addition of saturated sodium bicarbonate. The precipitate was collected by filtration, washed with ethyl acetate and dried under reduced pressure to provide the title compound (557 mg, 2.039 mmoles, quantity yield). The compound was carried over without further purification or characterization. MS (ESI) m / z 273.8 [M + 1] *.
4-Methyl-1- (tetrahydro-2H-pyran-2-1yl) -6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [d] imidazole *
SP A. 6-Bromo-4-methyl-1- (tetrahydro-2H-pyran-2-yl) - 1H-benzo [d] imidazole. 6-Bromo-4-methyl-1H-benzo [d] imidazole (1.02 g, 4.83 mmoles) was dissolved in tetrahydrofuran (10 ml) at room temperature with stirring under nitrogen. 3,4-Dihydro-2H-pyran (3.5 tl, 38.4 mmoles) and methanesulfonic acid (0.032 ml, 0.48 mmol) were added and the resulting mixture heated at 75ºC for 49 hours. The resulting mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (50 to 100% ethyl acetate in hexanes) obtained the desired product (1.32 g, 4.47 mmoles, 93% yield) as a light yellow solid. MS (EST) m / z 295.1 [M] *, 297.3 [M + 2] *. B. 4-Methyl-1- (tetrahydro-2H-pyran-2-yl) -6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzo [ d] imidazole. 6-Bromo-4-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-benzo [d] imidazole (1,320 g. 4.47 mmoles), bis (pinacolate) diboro (1.192 a, 4, 70 mmnoles), [EXT bis (diphenylphosphino) ferrocene] dichloropalladium (II), complex with dichloromethane (1: 1) (183 mg, 0.22 mmol), potassium acetate (1.317 g, 13.4 mmoles) and dimethyl (9 ml) were combined in a round bottom flask and stirred. The atmosphere in the flask was removed under vacuum and replaced with nitrogen three times. The resulting mixture was heated to 90ºC under nitrogen for 1.5 hours. The resulting mixture was diluted with ethyl acetate and filtered through Celite. The filter cake was washed completely with ethyl acetate. The filtrate was washed twice with water, once with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (50 to 100% ethyl acetate in hexanes) obtained the desired product at -90% purity (1.31 g, 3.83 mmoles, 77% yield) as a yellowish-brown foamed solid. MS (EST) m / z 343.2 [M + 1] *.
5.2 BIOLOGICAL EXAMPLES
5.2.1 Biological tests TOR HTR-FRET test. The following is an example of an assay that can be used to determine the TOR kinase inhibitory activity of a test compound. TOR kinase inhibitors were dissolved in DMSO and prepared as 10 mM stocks and diluted accordingly for the experiments. The reagents were prepared as follows: "Simple TOR Buffer" (used to dilute TOR fraction with high glycerol content): 10 mM Tris, pH 7.4, 100 mM NaCl, 0.1% Tween- 20, 1 mM DTT. The recombinant TOR enzyme Invitrogen (category No. PV4753) was diluted in its buffer to a test concentration of 0.200 pg / ml.
ATP / Substrate Solution: 0.075 mM ATP, 12.5 mM MnCl2, 50 mM Hepes, pH 7.4, 50 mM B-GOP, 250 nM Microcystin LR, 0.25 mM EDTA, 5 mM DTT and 3.5 ug / ml GST-p70S6.
Detection reagent solution: 50 mM HEPES, pH 7.4, 0.01% Triton X-100, 0.01% BSA, 0.1 mM EDTA, 12.7 po / ml Cy5-aGST Amersham (category No. PA92002V), 9 ng / ml of a-phospho p70S6 (Thr389) (Cell Signaling Mouse Monoclonal No. 9206L), 627 ng / ml of a-mouse Lance Eu (Perkin Elmer category No.ADO077).
To 20 µl of the Simple TOR buffer, 0.5 µl of the test compound in DMSO was added. To start the reaction, 5 pl of ATP / Substrate solution was added to 20 pl of the Simple TOR buffer solution (control) and to the compound solution prepared above. The test was stopped after 60 minutes by adding 5 µl of a 60 mM EDTA solution; 10 pl of detection reagent solution was then added and the mixture was allowed to set for at least 2 hours prior to reading on a Perkin-Elmer Envision Microplate Reader set to detect LANCE Eu TR-FRET (excitation a 320 nm and emission at 495/520 nm).
5.3 HETEROARILLA COMPOUND ACTIVITY The Heteroaryl Compounds, as described in this document, were tested in the TOR HTR-FRET assay and it was found that there is activity in it, with all compounds having an ICso below 10 pM in the assay, with some compounds that have an ICT, between 0.005 nM and 250 nM, others that have an IC, between 250 nM and 500 nM, others that have an IC, between 500 nM and 1 pM, and others that have an ICso between 1 pM and 10 µM. The IC values, for compounds of Formula (1) and (IL) can be found in Patent Application No. US 12 / 605,791, filed on October 26, 2009 (see Table 1 on pages 141 to 187), the which is incorporated in this document as a reference in its entirety.
The modalities presented in this document should not be limited in scope by the specific modalities “presented in the examples, which are intended to illustrate some aspects of the modalities presented and any modalities that are functionally equivalent are covered by this description. In fact, several modifications to the modalities presented in this document, which are complementary to those shown and described in this document, will become apparent to those skilled in the art and are intended to be within the scope of the attached claims.
Several references have been cited, the descriptions of which are incorporated in this document as a reference in their entirety.

权利要求:
Claims (1)
[1]
FP 1
And is
1. Method of preparing a compound, characterized by the fact that it has the formula (IT):
R
RN N | TAL | 5 ace | (11) being that the method comprises contacting a compound of formula (VI)
R x Net o
TX (VT) With R'-Y in a solvent, in the presence of an E palladium catalyst selected from dichloride [1,1'-. bis (ditherc-butylphosphino) ferrocene] palladium and dichlorobis (p-dimethylaminophenylditbutilphosphine) palladium (II), wherein said contact occurs under conditions suitable to provide a compound of formula (1), in which a) when X is halogen, then , Y is B (OR ')> or SNn (R **) 3; or b) when Y is halogen or triflate, then X is B (OR '), or Sn (R' *); wherein each R * is independently substituted or unsubstituted hydrogen or C1-.3 alkyl, or each R ', next to the boron atom and the atoms to which they are attached, forms a cyclic boronate; and each R ** is C1-3 alkyl; and where: | R 'is substituted or unsubstituted Cris alkyl, | 25 substituted or unsubstituted aryl, cycloalkyl | P-,------. .. ..s> and ..— .. uwupi e
It is substituted or unsubstituted, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl; R is EH, substituted or unsubstituted Cr alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; R is H, or a substituted or unsubstituted Cris alkyl; provided that the compound of formula (II) is not 7- (4-hydroxyphenyl) -1- (3-methoxybenzyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one. É 15 ê 2. Method of preparing a compound of formula (1), Re
RN AER ISOs (1) and the method is characterized by the fact that it comprises understanding the contact of a compound of formula (III)
RE Xe ANs + eo (III) | —Ss] sssssm — m — m—
€ and | with R'-Y in a solvent, in the presence of a palladium catalyst selected from dichloro [1,1'-bis (ditherc-butylphosphino) ferrocene]) palladium and dichlorobis (p-dimethylaminophenylditbutylphosphine) palladium (II), where said | 5 contact occurs under suitable conditions to provide a compound of formula (1), in which: x is halogen, B (OR '), or SN (R **) 3; Y is halogen, triflate, B (OR '), or Sn (R **) 3; where a) when X is halogen, then Y is B (OR *) 2 Or Sn (R '*) 3; or b) when Y is halogen or triflate, then X is B (OR); or Sn (R *); s; wherein each R 'is independently substituted or unsubstituted hydrogen or C1-3 alkyl, or each R', next to the boron atom and the atoms to which they are attached, forms a cyclic boronate; and R * is C 1 alkyl; s and where Rº is substituted or unsubstituted Cis alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl; R is H, Cir alkyl; substituted or unsubstituted, substituted or unsubstituted cycloalkyl, i substituted or unsubstituted heterocyclyl, | Substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted cycloalkylalkyl; —————————— ssssO c = csp> —- sprmmm —— mmm —————————— = =>> ** —— ** --——
mm o 4 be z Rº and Rº are each independently H, substituted or unsubstituted C1-s alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, aralkyl substituted or unsubstituted, substituted or unsubstituted cycloalkylalkyl, or Rº and Rº, next to the atom to which they are attached, form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl; or Rº and one of Rº and Rº (, next to the atoms to which they are attached, form a substituted or unsubstituted heterocyclyl; provided the compound is not 6- (4-hydroxyphenyl) - ê 15 4- (3-methoxybenzyl) - 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -Sone, 6- (4- (1H-1,2,4-triazol-5-1yl) phenyl) -3- (cyclohexylmethyl) -: 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one, or (R) -6- (4- (1H- 1,2,4-triazol-5-yl) phenyl) -3- (cyclohexylmethyl) -3,4- dihydropyrazine ([2,3-b] pyrazin-2 (1H) -one.
3. Method according to claim 1 or 2, characterized by the fact that, when X or Y is a halogen, the halogen is Br, or In which the solvent is dimethylformamide, isopropanol, dioxane, toluene, dimethylacetamide, tetrahydrofuran, or a combination thereof, with or without the presence of water; Or where the palladium catalyst is dichlorobis (p-dimethylamino phenylditbutylphosphine) palladium (II); or | | | EEE aa AE ê is where, when X or Y is B (OR ')', the contact occurs in the presence of a base, optionally where the base is sodium carbonate, more optionally, where B (OR ') ); is B (OH) 2 or B (-OC (CH3) 2C (CH3) 20-); or 5 where, when X or Y is Sn (R **) 3, contact occurs optionally in the presence of a base, or optionally when the base is triethylamine, or more optionally, when R ** is methyl or n-butyl .
4. Method, according to claim 1, characterized by the fact that it also comprises preparing a compound of formula (VI),
RE * Xn Ns,.
TX (VI) the method comprising cyclizing a compound of formula (VII) and, AIR La O (VII) in the presence of a base or an acid, wherein said cyclization occurs under conditions suitable to provide a compound of formula (VI), where Hal is a halogen, and D H or C1-4 alkyl, or alkali metal salt of the carboxylate. | 5. Method according to claim 4, characterized by the fact that the base is | potassium; or | E rr E EEE Eh
: Where the acid is acetic acid, TFA, HCl or phosphoric acid; or Where Hal is Br; or where the cyclization is carried out in a solvent; or Where the solvent is methanol or water.
6. Method, according to claim 4, characterized by the fact that it also comprises preparing a compound of formula (VII), and “Cr to EASA in (VIT) in which method it comprises putting in contact a compound of formula (VIII) and Hal AN, Hal py: TA zo (VITI) with Rº-NH; in a solvent, optionally in the presence of a base, in which said contact occurs under conditions suitable to provide a compound of formula (VII), in which Hal is halogen. ;
Method according to claim 6, characterized by the fact that the solvent is dimethyl sulfoxide or N-methylpyrrolidinone; or | Where the base is triethylamine or diisopropyl ethyl | the mine; or. Where the halogen is Br. Sena esae— ww ww n — p— asss—— s rr raE— .. «- A.
: s
8. Method according to claim 1, characterized by the fact that the compound is: 7- (S-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1 - (((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine ([2,3-b] pyrazin-2 (1H) -one; 7- (6- (1H-1,2,4- triazol-3-yl) pyridin-3-yl) -1- (cis-4-methoxycyclohexyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 7- (11H-pyrrole [2,3-b] pyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H ) - one; 7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1 - ((cis-4-methoxycyclohexyl) methyl) -3, 4- dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; z 15 1-ethyl-7- (1H-pyrrolo [3,2-b] pyridin-5-yl) -3,4- F dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; f 7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1 - ((cis - 4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (11H-benzo [d] imidazol-4-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (1H-pyrrolo [2,3-b] pyridin- 4-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-diid ropyrazine [([2,3-b] pyrazin-2 (1H) - | ona; 7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1- ((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3- b] pyrazin-2 (1H) -one; - «222 CCF —.. —— .——— s —— s-s — s ———— <- ÂRÂDRÂRP —— .. r.s — s .-- cs—— a
7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1- ((trans-4-hydroxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3- b] lpirazin-2 (1H) -one; 7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1-1- (cis-
4-hydroxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -
ona; 7T- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1- (cis-4-hydroxycyclohexyl) -3,4-dihydropyrazine [2,3 -b] pyrazin-2 (1H) -one;
7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-11) -1- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrazine [2,3 -b] pyrazin-2 (1H) -one;
7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-1i1) -1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; E 15 7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1-ethyl-. 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (5-fluoro-2- i-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1 - ((cis-4-hydroxycyclohexyl) methyl) 3,4-dihydropyrazine [ 2,3-b] pyrazin-2 (1H) -one;
7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
11) phenyl) -1- (tetrahydro-2H-pyran-4-yl) -3,4-
dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (1H-indol-4-yl) -1- (2- (tetrahydro-2H-pyran-4-
il) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (S5-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
il) phenyl) 1- (cis-, 4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; "
t 7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1 - ((cis-4-hydroxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3 -b] pyrazin-2 (1H) -one; T7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-11) -1- (trans-4-hydroxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin -2 (1H) -one; 7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin - 2 (1H) -one; 7- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-i1) -1- isopropyl-3,4-dihydropyrazine (2,3-b] pyrazin-2 (1H) - one; 7T- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1- (tetrahydro-2H-pyran-4-yl) 3,4- dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; t 15 7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-: yl) phenyl) -l1- (trans-4-hydroxycyclohexyl) -3,4- Ú dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (5S-fluoro-2-methyl-4- (1H-1 , 2,4-triazol-3-yl) phenyl) -1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b]) pyrazin-2 (1H) -one; 7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1-isopropyl-3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 1-ethyl-7- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -3,4-dihydroppyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (2-hydroxypyridin-4-yl) -1- (2- (tetrahydro-2H- | pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; | | ——— sssssa oassassssssssssmq] nn = —— "- dmdsssssss f 1-isopropyl-7- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) - 3,4-dihydropyrazine ([2,3-b] pyrazin-2 (1H) -one; 5- (8-isopropyl-7-ox0-5,6,7,8-tetrahydropyrazine [2,3-b] pyrazin -2-yl) -4-methylpicolinamide; 7- (1H-indazol-4-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [([2 , 3-b] pyrazin-2 (1H) -one; 7- (2-aminopyrimidin-5-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (2-aminopyridin-4-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3.4 -dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 7- (6- (methylamino) pyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl ) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (6-hydroxypyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl ) ethyl) -3,4-dihydropyrazine (2,3-b] pyrazin-2 (1H) -one; E 15 7- (4- (1H-pyrazol-3-yl) phenyl) -1- (2-methoxyethyl ) -3,4-: dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; Ô 7T- (pyridin-3-i1) -1- (2- (tetrahydro-2H-pyran-4-yl) ) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (1H-indazol-4-yl) -1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (1H-indazol-6-1yl) -1- (2-methoxyethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 7T- (pyrimidin-5-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 7- (6-methoxypyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona; 1- (2-methoxyethyl) -7- (11H-pyrrolo [2,3-b] pyridin-5- 11) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
1-ethyl-7- (11H-pyrrolo [2,3-b] pyridin-5-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 1-ethyl-7- (1H-indazol-4-1yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7T- (pyridin-4-yl1) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 7- (6-aminopyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-11) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona; 1-methyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 2- (2-hydroxypropan-2-yl) -5- (8- (trans-4-methoxycyclohexyl) -7-ox0-5,6,7,8-tetrahydropyrazino [2,3-blpyrazin-2-yl) pyridine 1-oxide; 4-methyl-5- (7-0x0-8 - (((tetrahydro-2H-pyran-4-yl) methyl) -5,6,7,8-tetrahydropyrazine ([2,3-b] pyrazin-2- z 15 il) picolinamide; 5- (8- ((cis-4-methoxycyclohexyl) methyl) 7-7-oxo-5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-11) -4-: methylpicolinamide; 7- (11H-pyrazol-4-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin -2 (1H) -one;
o 1- (trans-4-methoxycyclohexyl) -7- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2, 3- b] pyrazin-2 (1H) -one;
3- ((7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3- 11) -2-0x0-3,4-dihydropyrazine [2,3-b ] pyrazin-1 (2H) -yl) methyl) benzonitrile;
|
Give the
1 - ((trans-4-methoxycyclohexyl) -7- (4-methyl-6- (11H-1,2,4-triazol-3-yl) pyridin-3-yl) 3,4-dihydropyrazine [2,3 bl] pyrazin-2 (1H) -one;
3- (7-ox0-8- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -
5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) benzamide;
5- (8- ((trans-4-methoxycyclohexyl) methyl) -7-oxo-5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-methylpicolinamide;
3- ((7- (6- (2-hydroxypropan-2-yl) pyridin-3-i1) -2-
oxo-3,4-dihydropyrazine [2,3-b] pyrazin-1 (2H) -
il) methyl) benzonitrile;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-1yl) -1- ((1R, 3R) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
E 15 7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- ((18,3R) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3-L b] pyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1-
| ((18,38) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3-
| 20 b] lpirazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- ((1R, 3S) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (1H-indazol-6-1yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona; 7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) - 1- (2-morpholinoethyl) -3,4-dihydropyrazine [2,3-b ] pyrazin-2 (1H) - one; The -
s 1- (trans-4-hydroxycyclohexyl) -7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl1) -3,4-dihydropyrazine [2, 3- b] pyrazin-2 (1H) -one; 1- (cis-4-hydroxycyclohexyl) -7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [(2, 3- b] pyrazin-2 (1H) -one; 7- (6- (2-hydroxypropan-2-yl) pyridin-3-11) -1- (2-morpholinoethyl) -3,4-dihydropyrazine [2, 3-b] pyrazin-2 (1H) -one; 1-isopropyl-7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl1) -3, 4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (11H-imidazo [4,5-b] pyridin-6-1yl) -1- (2- (tetrahydro-2H-pyran -4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) - one; 1 - ((cis-4-methoxycyclohexyl) methyl) -7- (2-methyl-6 - $ 15 (1H-1,2,4-triazol-3-yl) pyridine-3-11) -3,4-; dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; Ú 1- (trans-4-hydroxycyclohexyl) -7- (6- (2-hydroxypropan-2-yl) pyridin-3-i1) -3,4-dihydropyrazine [([2,3-b] pyrazin-2 (1H) - ona; 1- (cis-4-hydroxycyclohexyl) -7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H ) - one; 4- (7-ox0-8- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2- yl) benzamide; 7- (1H-indazol-5-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-d hydroxypyrazine [2,3-b] pyrazin-2 (1H) -one; | | .
| A EEE aa aa a cc
7- (11H-pyrrolo [2,3-b] pyridin-5-i1) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b ] pyrazin-2 (1H) - one; 7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -
l1- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrazine [2,3-
bl] pyrazin-2 (1H) -one;
1 - (((18,3R) - 3-methoxycyclopentyl) -7- (2-methyl-6- (4H, 2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [( [2,3-blpirazin-2 (1H) -one;
1 - ((1R, 3R) -3-methoxycyclopentyl) -7- (2-methyl-6- (4H, 2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2 , 3-bl] lpirazin-2 (1H) -one;
1 - ((1R, 38S) -3-methoxycyclopentyl) -7- (2-methyl-6- (4H, 2,4-triazol-3-yl) pyridin-3-1yl) -3,4-dihydropyrazine [( 2,3- E 15 bjpirazin-2 (1H) -one; | - 1 - ((18,3S) -3-methoxycyclopentyl) -7- (2-methyl-6- | Ú (4H, 2,4-triazole -3-yl) pyridin-3-1yl) -3,4-dihydropyrazine [([2,3- | b] pyrazin-2 (1H) -one; | 7- (1H-indole-5-11) -1 - (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 1-ethyl-7- (2-methyl- 6- (4H-1,2,4-triazol-3- 'yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (1H -indol-6-11) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
7- (4- (2-hydroxypropan-2-yl) phenyl) -1- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
t &.
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 1- ((trans-4-methoxycyclohexyl) methyl -7- (2-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) 3,4-dihydropyrazine [2, 3- b] pyrazin-2 (1H) -one; 7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1 - (((cis-4-methoxycyclohexyl) methyl) -3.4 -dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 1- (2-methoxyethyl) -7- (4-methyl-2- (methylamino) -1H-benzo [d] imidazole-6-1i1l ) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (T-methyl-2-0x0-2,3-dihydro-1H-benzo [d] imidazole-5- yl) -1 - ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-: 15 dihydropyrazine ([2,3-b] pyrazin-2 (1H) -one; 7- (2-methyl -4- (4H-1,2,4-triazol-3-yl) phenyl) -3,4- dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 1- (2-methoxyethyl) -7- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-11) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 1-benzyl-7- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 ( 1H) -one; 7- (3-fluoro-4- (4H-1,2,4-triazol-3-yl) phenyl) -1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3- b] pyrazin-2 (1H) -one; 7T- (3-fluoro-4- (4H-1,2,4-triazol-3-yl) phenyl) -1- (2- (tetrahydro-2H-pyre) n-4-yl) ethyl) -3,4-dihydropyrazine [2,3- | blpirazin-2 (1H) -one;
7- (3-fluoro-2-methyl-4- (1H-1,2,4-triazol-3- 11) phenyl) -1- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b ] pyrazin-2 (1H) -one;
1- (trans-4-methoxycyclohexyl) -7- (2-methyl-6- (4H-
1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine (2,3-b] pyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (trans-4-methoxycyclohexyl) -3,4-dihydroppyrazine [2,3-b] pyrazin-2 (1H) - ona;
7T- (5-fluoro-2-methyl-4- (4H-1,2,4-triazol-3- i1) phenyl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (3-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 3,4-: 15 dihydropyrazine (2,3-b] pyrazin-2 (1H) -one; E 1- (2-methoxyethyl) -7- (2-methyl-6- (4H-1,2,4- triazol-3- "yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1-
((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [(2,3-b] pyrazin-2 (1H) -one; 1- (cyclopentylmethyl) -7- (6- (2-hydroxypropan-2 - yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (4- (2-hydroxypropan-2-yl) phenyl) -1- (2-
| 25 methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
(S) -7- (6- (1-hydroxyethyl) pyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3- bl] lpirazin-2 (1H) -one;
OE -
(R) -7- (6- (1-hydroxyethyl) pyridin-3-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3- b] pyrazin-2 (1H) -one;
7- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -
1 - ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
7- (4- (2-hydroxypropan-2-yl) phenyl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin- 2 (1H) - one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (4- (trifluoromethyl) benzyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (3- (trifluoromethyl) benzyl) -3,4-dihydropyrazine [2,3-b] pyrazin-
at 15 2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-11) -1- (3-
methoxypropyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) - 1- (2-tetrahydro-2H-pyran-4-yl) ethyl) -3 , 4-dihydropyrazine [(2,3-
bl] pyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- (2-methoxyethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3-
blpirazin-2 (1H) -one;
7- (4-methyl-2- (methylamino) -1H-benzo [d] imidazol-6-yl) -1 - (((tetrahydro-2H-pyran-4-yl) methyl) -3,4-
| dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
|
|
EEA or a
| 18 7- (2-amino-4-methyl-1H-benzo [d] imidazol-6-yl) -1- (((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2, 3- b] pyrazin-2 (1H) -one; 7T- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) - 1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) 3 , 4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; | (R) -7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3-methyl-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3, 4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; (S) -7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3-methyl-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3, 4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 7- (6- (2-hydroxypropan-2-yl) pyridin-3-i1) -3,3-dimethyl-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4- 15 dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; Fl 7- (2-amino-4-methyl-1H-benzo [d] imidazol-6-yl) -1- (2- É. (Tetrahydro-2H-pyran-4-11) ethyl) -3,4- dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; | 7- (6- (2-hydroxypropan-2-yl) pyridin-3-1yl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3- b] lpirazin-2 (1H) -one; 7- (2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4- dihydropyrazine [2,3-bl] lpyrazin-2 (1H) -one; 7- (4- (1H-1,2,4-triazol-5-yl) phenyl) -1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2, 3-bl] lpirazin-2 (1H) -one;
CC
= 19 & 1- (1-hydroxypropan-2-yl) -7- (2-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-i1) -3,4- dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; or 1- (2-hydroxyethyl) -7- (2-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3- b] pyrazin-2 (1H) - one.
9. Method, according to claim 2, characterized by the fact that it comprises the preparation of a compound of formula (III):
R x NAN TR
TA K 9 (III) and the method comprises establishing the D contact of a compound of formula (IV) Í With Rº-NH> in a solvent, in the presence of a base, “and 15 in which said contact occurs under conditions suitable to provide a compound of formula (III), where X is halogen, Rº and Rº are H, Hal is a halogen and Hal is Br or I.
10. Method, according to claim 9, characterized by the fact that X is Br; or where the solvent is acetonitrile or tetrahydrofuran; or Where the base is triethylamine or diisopropylamine; or Where Hal is Br.
j
%
11. Method according to claim 2, characterized by the fact that it comprises the preparation of a compound of formula (III):
R x R
CAX NN o (III) being that the method comprises the cyclization of a compound of formula (V) Hal NQ Hal CA eme "RR (V) in a solvent, in the presence of a palladium catalyst, a binder, and a base, wherein said cyclization occurs under conditions suitable to provide a compound of formula (III), where X is a halogen, and Hal is a & halogen.
12. Method, according to claim 11, characterized by the fact that X is Br; or Where the solvent is acetonitrile; or Where the palladium catalyst is palladium (II) acetate; or Where the linker is 4,5-bis- (diphenylphosphino) -9,9-dimethylxanthene; or Where the base is sodium bicarbonate; or Where Hal is Br.
13. Method according to claim 2, characterized by the fact that the compound of formula (1) is |
$ 6- (1H-pyrrolo [2,3-b] pyridin-3-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3- b] pyrazin-2 (1H) - one; 6- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) - 4- ((tetrahydro-2H-pyran-4-yl) methyl) -3, 4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (S-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -4 - ((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [ 2,3-b] pyrazin-2 (1H) -one; 6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -4 - ((cis-4-methoxycyclohexyl) methyl) 3,4-dihydropyrazine [2 , 3-b] pyrazin-2 (1H) -one; 6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-1i1) -4- ((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3- at 15 bl] lpirazin-2 (1H) -one; $ 6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3- is useful) phenyl) -4 - ((trans-4-hydroxycyclohexyl) methyl) -3,4- dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4 - ((cis- | 20 4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2, 3-b] pyrazin- | 2 (1H) -one; | 6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- ((trans-4-hydroxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3- b] pyrazin-2 (1H) -one; 6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- (cis- | 4-hydroxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - one; pr
- t
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4 - ((cis-4-hydroxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3- b] pyrazin-2 (1H) -one;
6- (5S-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
il) phenyl) -4- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin - 2 (1H) -one;
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4- (trans-4-hydroxycyclohexyl) -3 4-dihydropyrazine [2,3-blpyrazin-2 ( 1H) -one;
6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
11) phenyl) -4 - ((cis-4-hydroxycyclohexyl) methyl) -3,4-2 2 15 dihydropyrazine (2,3-b] pyrazin-2 (1H) -one; & 6- (6- (1H- 1,2,4-triazol-3-yl) pyridin-3-yl) -4- (cis- and 4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - one ;
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-i1) -4- (2-
methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4-isopropyl-3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona;
6- (5S-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
il) phenyl) -4- (cis-4-hydroxycyclohexyl) -3,4-
dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazole-3-
il) phenyl) -4- (cis-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one;
& 6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -4- (2-methoxyethyl) -3,4-dihydropyrazine [2,3- b] pyrazin-2 (1H) -one; 6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-1i1) -4- (tetrahydro-2H-pyran-4-11) -3,4-dihydropyrazine [2,3 -b] pyrazin-2 (1H) -one; 6- (6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -4-ethyl-3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona; 6- (5S-fluoro-2-methyl-4- (1H-1,2,4-triazol-3- i1) phenyl) -4- (trans-4-hydroxycyclohexyl) -3,4-dihydropyrazine [2,3 -b] pyrazin-2 (1H) -one; 6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -4- (tetrahydro-2H-pyran-4-11) -3,4-dihydropyrazine ([2,3-b] pyrazin-2 (1H) -one; Is 15 6- (5-fluoro-2-methyl-4- (1H-1,2,4-triazol-3- Is useful) phenyl) -4-isopropyl-3,4-dihydropyrazino [2,3-b] pyrazin- 2 (1H) -one; 4-ethyl-6- (5-fluoro-2-methyl-4- (1H-1,2 , 4-triazol-3-yl) phenyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (3-fluoro-2-methyl-4- (1H-1 , 2,4-triazol-3-yl) phenyl1) -4- (tetrahydro-2H-pyran-4-11) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 6 - (3-fluoro-2-methyl-4- (1H-1,2,4-triazol-3- 11) phenyl) -4- (cis-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one; 6- (3-fluoro-2-methyl-4- (1H-1,2,4-triazol-3-yl) phenyl) -4- (trans-4-methoxycyclohexyl) - 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
| 24 is £ | 4- (2-methoxyethyl) -6- (4-methyl-6- (1H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b ] pyrazin-2 (1H) -one; 6- (3- (1H-1,2,4-triazol-5-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2, 3- b] pyrazin-2 (1H) -one; | 5- (8- (2-methoxyethyl) -6-0x0-5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-methylpicolinamide; 3- (6-0x0-8- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) benzamide; 3- (6-0x0-8- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) benzonitrile; 5- (8- (trans-4-methoxycyclohexyl) -6-0x0-5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) -4-methylpicolinamide; 6- (1H-imidazo [4,5-b] pyridin-6-yl) -4- (2- (tetrahydro- to 2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3 -b] pyrazin-2 (1H) - &ona; N 6- (1H-indazol-6-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 4- ((1R, 38S) -3-methoxycyclopentyl) -6- (2-methyl-6- (4H, 2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2 , 3-bl] pyrazin-2 (1H) -one; | 4- ((18,3R) -3-methoxycyclopentyl) -6- (2-methyl-6- | (4H, 2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [ 2,3-b] pyrazin-2 (1H) -one; 4- ((1R, 3R) -3-methoxycyclopentyl) -6- (2-methyl-6- (2- | methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3- 1i1) -3,4- dihydroppyrazine [2,3-b] pyrazin-2 (1H) -one; | a —————— nnttt ———
4- ((18,38) -3-methoxycyclopentyl) -6- (2-methyl-6- (4H, 2,4-triazol-3-yl) pyridin-3-11) -3,4-dihydropyrazine [2 , 3-bl] lpirazin-2 (1H) -one; 4-ethyl-6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-11) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (1H-pyrrolo [2,3-b] pyridin-5-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b ] pyrazin-2 (1H) - one; 6- (1H-indol-6-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) - ona; 6- (1H-indol-5-yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona; 4- ((((1R, 3S) -3-methoxycyclopentyl) methyl) -6- (2-methyl- 6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3, 4- to 15 dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; It is 4- ((((18,3R) -3-methoxycyclopentyl) methyl) -6- (2-methyl-f 6- (4H-1,2,4-triazol-3-yl) pyridin-3-1yl1) - 3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (3-fluoro-2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 3,4-dihydropyrazine [(2,3-b] pyrazin-2 (1H) -one; 6- (3-fluoro-2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 3, 3-dimethyl-6- (4-methyl-6- (4H- 1,2,4-triazol-3-yl) pyridin-3-yl) -4 - ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazino [2,3-b] pyrazin- 2 (1H) -one;
| & 6- (6- (2-hydroxypropan-2-yl) pyridin-3-11) -4- ((1R, 38S) -3-methoxycyclopentyl) -3,4-dihydropyrazine [2,3- b] pyrazin- 2 (1H) -one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-
((18,3R) -3-methoxycyclopentyl) -3,4-dihydropyrazine ([2,3-bl] lpyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl1) -4- ((((18,38S) - 3-methoxycyclopentyl) methyl) -3,4-dihydropyrazine [(2,3-blpirazin -2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- ((((1R, 3R) -3-methoxycyclopentyl) methyl) -3,4-dihydropyrazine (2,3-blpirazin- 2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- ((18,38) - 3-methoxycyclopentyl) -3,4-dihydropyrazine [([2,3- to 15 b ] lpirazin-2 (1H) -one; & 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- It is ((1R, 3R) -3-methoxycyclopentyl) -3.4 -dihydropyrazine [2,3- b] lpyrazin-2 (1H) -one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-
((((1R, 3S) - 3-methoxycyclopentyl) methyl) -3,4-dihydropyrazine [2,3-
bl] pyrazin-2 (1H) -one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl1) -4- ((((18,3R) - 3-methoxycyclopentyl) methyl) -3,4-dihydropyrazine [2,3-bl] lpirazin-2 (1H) -one;
6- (3-fluoro-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
It is
It is 6- (3-fluoro-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3.4 dihydropyrazino [2,3-bl] lpyrazin-2 (1H) -one; 7 '- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -1'- (((tetrahydro-2H-pyran-4-yl) methyl) -l'H- spiro [cyclopentane-1,2'-pyrazine [2,3-b] pyrazin] -3 '(4'H) -one; 7 '- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -1'- (((tetrahydro-2H-pyran-4-yl) methyl) -l'H- spiro [cyclobutane-1,2'-pyrazine [2,3-b] pyrazin]) - 3 '(4'H) -one; 4- (cyclopropylmethyl) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazine (2,3-b] pyrazin-2 (1H) -one; 7 ' - (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -1'H-spiro [cyclopentane-1l, 2'-pyrazine [2,3-b] pyrazin] - 3 '(4'H) - one;: 15 7' - (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -H- & spiro [cyclobutane-1,2 '-pyrazino [2,3-b] pyrazin] -3' (4'H) -one; r 7 '- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl ) -H- spiro [cyclopropane-1,2-pyrazine [2,3-b] pyrazin] -3 '(4'H) -one; (R) -6- (4- (4H-1,2, 4-triazol-3-yl) phenyl) -4- ((tetrahydrofuran-2-yl) methyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one; (S) -6- ( 4- (4H-1,2,4-triazole-3-1i1l1) phenyl) -4- ((tetrahydrofuran-2-yl) methyl) -3,4-dihydropyrazino [2,3-bl] lpirazin-2 (1H ) -one; 6- (1H-indazol-5-1yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
gs 4- (6-0x0-8- (2- (tetrahydro-2H-pyran-4-yl) ethyl) - 5,6,7,8-tetrahydropyrazino [2,3-b] pyrazin-2-yl) benzamide ; 4- (2-methoxyethyl) -3,3-dimethyl-6- (2-methyl-4- (4H, 2,4-triazol-3-yl) phenyl) -3,4-dihydropyrazine [2,3-b ] pyrazin-2 (1H) - one; 4-ethyl-3,3-dimethyl-6- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -3,4-dihydroppyrazine [2,3-b] pyrazin -2 (1H) -one; 6- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -3,4-dihydropyrazino [2,3-bl] pyrazin-2 (1H) -one; 3, 3-dimethyl-6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -4 - ((tetrahydro-2H-pyran-4-yl ) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; (R) -6- (6- (I-hydroxyethyl) pyridin-3-11) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3- & 15 bl] lpirazin-2 (1H) -one; 4 3, 3-dimethyl-6- (2-methyl-4- (4H-1,2,4-triazol-3- 7 yl) phenyl) -4 - ((tetrahydro-2H-pyran-4-yl) methyl ) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (6- (2-hydroxypropan-2-yl) -4-methylpyridin-3-yl) - d4- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine (2,3-b] pyrazin-2 ( 1H) -one; 6- (6- (2-hydroxypropan-2-yl) -4-methylpyridin-3-yl) - 4- ((tetrahydro-2H-pyran-4-yl) methyl) -3,4- dihydropyrazine [2,3-bl] lpyrazin-2 (1H) -one; 3,3-dimethyl-6- (2-methyl-4- (4H-1,2,4-triazol-3- 11) phenyl) - 3,4-dihydropyrazine (2,3-b] pyrazin-2 (1H) -one; | | | | —ssssss- s | ss | ss.sm. | ÕxÕm) xô-Õ- smnmmmssccsss ssss - = ——— ————————— pm—
t
3,3-dimethyl-6- (2-methyl-6- (4H-1,2,4-triazole-3-
il) pyridin-3-yl) -4- (2- (tetrahydro-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) -2-methylpyridin-3-yl) -
4- ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) -2-methylpyridin-3-yl) - 4- (trans-4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 ( 1H) -one;
(S) -6- (6- (I-hydroxyethyl) pyridin-3-11) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [([2, 3- b] pyrazin-2 (1H) -one;
3,3-dimethyl-6- (2-methyl-4- (4H-1,2,4-triazole-3-
11) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-2 2 15 dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 4 6- (6- (2-hydroxypropan-2-yl) pyridin-3-i1) -3,3- ”dimethyl-4- (2- (tetrahydro-2H-pyran-4-1i1) ethyl) -3, 4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (4- (2-hydroxypropan-2-yl) phenyl) -4- (trans-4-
methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (4- (2-hydroxypropan-2-yl) phenyl) -4 - ((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one ;
4- (cis-4-methoxycyclohexyl) -6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-11) -3,4-dihydroppyrazine [2,3 -b] pyrazin-2 (1H) -one;
t s
4- (trans-4-methoxycyclohexyl) -6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-1yl) -3,4-dihydropyrazine [(2, 3- | blpirazin-2 (1H) -one;
6- (4- (2-hydroxypropan-2-yl) phenyl) -4 - ((tetrahydro-
2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
4- (2-methoxyethyl) -6- (2-methyl-6- (4H-1,2,4-triazol-3- | yl) pyridin-3-yl1) -3,4-dihydropyrazine [2,3- b] pyrazin-2 (1H) -one; | 9- (6- (4H-1,2,4-triazol-3-yl) -3-pyridil) -6,11,4a- trihydromorpholine [4,3-e] pyrazine [2,3-b] pyrazin- 5-one;
6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -
4- ((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
5- (8- (cis-4-methoxycyclohexyl) -6-0x0-5,6,7,8-
is 15 tetrahydropyrazine (2,3-b] pyrazin-2-yl) -6- = methylpicolinonitrile; 6- (6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl1) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3.4 dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; | 20 9- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) -3- (2-methoxyacetyl) -6, 11, 4a-trihydropiperazino [1,2-elpyrazine [2 , 3-b] pyrazin-5-one; : 9- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) - 6,11,4a-trihydropiperazine [1,2-e] pyrazine [2,3-b] pyrazin -5- one; | 9- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) -3- (2- | methoxyethyl) -6,11,4a-trihydropiperazine ([1,2-el] pyrazine [2,3-bl] lpyrazin-5-one;
The
É é - 4- (cyclopentylmethyl) -6- (2-methyl-6- (4H-1,2,4-triazol-3-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3- b] pyrazin-2 (1H) -one; 9- (6- (4H-1,2,4-triazol-3-yl) -2-methyl-3-pyridyl) - 6.11,4a-trihydromorpholine [4,3-e] pyrazine [2,3- b] pyrazin-5-one; 4- (trans-4-hydroxycyclohexyl) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-bl] lpyrazin-2 (1H) - ona; 4- (cis-4-hydroxycyclohexyl) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydroppyrazine [2,3-b] pyrazin-2 (1H) - ona; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- '((tetrahydrofuran-3-yl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; à 15 4- (cyclopentylmethyl) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one ; It is 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-neopentyl-3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-isobutyl-3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; p 3-methyl-6- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-1yl) -4- (piperidin-4-111) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (2- (tetrahydro-2H-pyran-3-yl) ethyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one; | i ———— ww «x ————-. —Q.R.RR.R.R..e ——— c
IT IS
It is 8—- (4- (4H-1,2,4-triazol-3-1yl) -2-methylphenyl) (3aS, 2R) -2-methoxy-5,10,3a-trihydropyrazine [2,3-b ] pyrrolidine [1,2-e] pyrazin-4-one; 8- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) (2R, 3aR) -2-methoxy-5, 10,3a-trihydropyrazino [2,3-b] lpyrrolidine [1,2-e] pyrazin-4-one; 8—- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) (2S, 3aR) -2-methoxy-5,10,3a-trihydropyrazine [2,3-blpyrrolidine [ 1,2-e] pyrazin-4-one; 8— (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) (2S, 3aS) -2-methoxy-5,10,3a-trihydropyrazine [2,3-blpyrrolidine [1 , 2-e] pyrazin-4-one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (3-methoxypropyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; & 15 (S) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-11) -4- & ((tetrahydrofuran-2-yl) methyl) -3,4-dihydropyrazine [(2, 3- E blpirazin-2 (1H) -one; (R) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-i1) -4- ((tetrahydrofuran-2-yl) methyl) - 3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one; 6- (2-methyl-6- (4H, 1,2,4-triazol-3-yl) pyridin-3-yl) - 4- (2- (teijahydro-2H-pyran-4-1yl) and dihydropyrazine (2,3-bl] lpyrazin-2 (1H) -one; 9- (4- (4H-1,2,4-triazole- 3-yl) -2-methylphenyl) -3-methyl-6,11,4a-trihydropiperazine [(1,2-el] pyrazine [2,3-b] pyrazin-5S-one; 9- (4- (4H -1,2,4-triazol-3-yl) phenyl) -6,11,4a- trihydromorpholine [4,3-e] pyrazine [2,3-b] pyrazin-5-one;
4 is -: 9- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) - 6,11,4a-trihydropiperidine [1,2-e] pyrazine [2,3 -b] pyrazin-5-one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (trans-
4-methoxycyclohexyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (cis-4-methoxycyclohexyl) -3,4-dihydropyrazine [(2,3-b] pyrazin-2 (1H) - ona;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (2-morpholinoethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-phenethyl-3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-
a 15 (tetrahydro-2H-pyran-4-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-
& 2 (1H) -one;
F 4- (cyclohexylmethyl) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-i1) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-
((trans-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4 - ((cis-4-methoxycyclohexyl) methyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 ( 1H) -one;
(R) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (tetrahydrofuran-3-yl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
& * «(S) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (tetrahydrofuran-3-1i1) -3,4-dihydropyrazine [2,3-b] pirazin- | 2 (1H) -one; | 6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4-phenyl-3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one;
(S) -6- (6- (2-hydroxypropan-2-yl) pyridin-3-i1) -3-methyl-4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3, 4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
9- [6- (1-hydroxy-isopropyl) -3-pyridol] -6,11,4a-
trihydromorpholine ([4,3-e] pyrazine [2,3-blpyrazin-5-one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -4- (((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3-b] lpirazin-2 (1H) -one;
6- (6- (2-hydroxypropan-2-yl) pyridin-3-1yl) -4- (2-
to 15 methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one; % 6- (2-amino-7-methyl-1H-benzo [d] imidazol-5-1yl) -4- (3- - (trifluoromethyl) benzyl) -3,4-dihydropyrazine [2,3-b] pyrazin -
2 (1H) -one; Í
6- (6- (2-hydroxypropan-2-yl) pyridin-3-1yl) -4- (3-
(trifluoromethyl) benzyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) -one;
9- (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) - 6,11,4a-trihydromorpholine [4,3-e] pyrazine [2,3-b] pyrazin- 5-one;
6- (4-methyl-2- (methylamino) -1H-benzo [d] imidazole-6-
yl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; p — p ———————— s
Cr o, 35 ú
ES 8— (4- (4H-1,2,4-triazol-3-yl) -2-methylphenyl) - 5,10,3a-trihydropyrazino [2,3-b] pyrrolidine [1,2-e] pyrazin -4- one; 6- (4- (4H-1,2,4-triazol-3-yl) phenyl) -4-ethyl-3,4-dihydropyrazino [2,3-b] pyrazin-2 (1H) -one; 6- (4- (4H-1,2,4-triazol-3-yl) phenyl) -4 - (((tetrahydro-2H-pyran-4-yl) methyl) -3,4-dihydropyrazine [2,3- b] pyrazin-2 (1H) - one; 6- (6- (2-hydroxypropan-2-yl) pyridin-3-1i1) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3- blpirazin-2 (1H) -one; 6- (4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2-methoxyethyl) -3,4-dihydropyrazine [2,3-b] pyrazin-2 (1H) - ona; 6- (4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (3- 4 15 (trifluoromethyl) benzyl) -3,4-dihydropyrazine [2,3-b] pyrazin- ú 2 (1H) -one; ç 6- (2-methyl-4- (4H-1,2,4-triazol-3-yl) phenyl) -4- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -3.4 -dihydropyrazine ([2,3-b] pyrazin-2 (1H) -one; 6- (4-methyl-1H-benzo [d] imidazole-6-1yl) -4- (2- (tetrahydro-2H-pyran -4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) -one; 6- (4- (2-hydroxypropan-2-yl) phenyl) -4- (2- ( tetrahydro-2H-pyran-4-yl) ethyl) -3,4-dihydropyrazine [2,3-blpyrazin-2 (1H) - Oona; or 6- (4- (1H-1,2,4-triazole-5 -yl) phenyl) -4- (2- | (tetrahydro-2H-pyran-4-1yl) ethyl) -3,4-dihydropyrazine ([2,3-bl] lpyrazin-2 (1H) -one. —— —————— ssssoe = -sqssssmssssss-SSS] .m] ceamnnnmmn — np]] -—— = - nsmu - = ——— ee € -
s & í
14. Compound characterized by comprising the formula (IIL):
Ú x NER
SUCH
NON
H (111) or a salt, tautomer or stereoisomer thereof, where: x is halogen, B (OR '), or SNn (R **) 3; each R * is independently substituted or unsubstituted hydrogen or C1-3 alkyl, or each R *, next to the boron atom and the atoms to which they are attached, forms a cyclic boronate; each R * is independently C 1-4 alkyl; R is H, substituted or unsubstituted C1-8 alkyl * & substituted, substituted or unsubstituted cycloalkyl, & 15 substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; and Rº and Rº are each independently H, substituted or unsubstituted C 1 -alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, substituted cycloalkylalkyl or unsubstituted, or Rº and Rº, next to the atom to which they are attached, forms a substituted cycloalkyl or unsubstituted t ú 2 or substituted or unsubstituted heterocyclyl; or Rº and one of Rº and RÔ, next to the atoms to which they are attached, form a substituted or unsubstituted heterocyclyl; or a compound of formula (IV): “E | To walnut Nº € qN
H (IV) 'or a salt, tautomer or stereoisomer thereof, where: each Hal is independently a halogen; and Hal is Br or I; or A compound of formula (V): Hal Na Hat: AX and & 2 NHR 't NOR 2 Rº Rº V) or a salt, tautomer or stereoisomer thereof, where: R is H, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; Rº and Rº are each independently H, substituted or unsubstituted C 1 -alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl,
MN 38 s
Substituted or unsubstituted heterocyclyl ES, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkylalkyl, or Rº and Rº, next to the atom to which they are attached, form a substituted or unsubstituted or unsubstituted or heterocyclyl cycloalkyl replaced; or Rº and one of Rº and R, next to the atoms to which they are attached, form a substituted or unsubstituted heterocyclyl; and each Hal is independently a halogen; or a compound of formula (VI): it is XÁ AN À the
CE 3 H (VT): or a salt, tautomer or stereoisomer thereof, where: X is halogen, B (OR '), or Sn (R *) 3; each R * is independently substituted or unsubstituted hydrogen or C1-3 alkyl, or each R ', next to the boron atom and the atoms to which they are attached, form a cyclic boronate; each R * is independently C1-3 alkyl; R is H, substituted or unsubstituted C 1 -alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl,
Z 39 s <C.
T 2 “+ substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; R is H, or an alkyl Cr; substituted or unsubstituted; or a compound of formula (VII):
AND
PSC
EO o (VIT) or salt, tautomer or stereoisomer thereof, where: Hal is a halogen; R is H or alkyl Creates, or The alkali metal salt of the carboxylate; Rº is H, substituted or unsubstituted Cirg alkyl, substituted or unsubstituted cycloalkyl, 3 t substituted or unsubstituted heterocyclyl, t substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl; and Rº is H, or a Cr alkyl; substituted or unsubstituted; or A compound of formula (VIII): SO Rn Fa R NS Ox o (VIII) or a salt, tautomer or stereoisomer thereof, wherein: each Hal is independently a halogen;
ae 40 to CL “ç: R is H or alkyl Cria, OR The alkali metal salt of the carboxylate; and Rº is H, or an alkyl Cri; replaced or unsubstituted. . t *

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法律状态:
2020-10-06| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-10-13| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-11-03| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 10A ANUIDADE. |

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2021-02-23| B08K| Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]|Free format text: EM VIRTUDE DO ARQUIVAMENTO PUBLICADO NA RPI 2600 DE 03-11-2020 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDO O ARQUIVAMENTO DO PEDIDO DE PATENTE, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |

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2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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