| (11) | EP 3 074 390 B1 |
(12) | EUROPEAN PATENT SPECIFICATION |
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(54) | AMINOPYRIDINE DERIVATIVES AS TAM FAMILY KINASE INHIBITORS AMINOPYRIDINDERIVATE ALS KINASEINHIBITOREN DER TAM-FAMILIE DÉRIVÉS D'AMINOPYRIDINE UTILISÉS COMME INHIBITEURS DE KINASES DE LA FAMILLE TAM |
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Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
BACKGROUND
Technical Field
Description of the Related Art
SUMMARY
W is
each A, A1 and A2 is the same or different and independently -N=, - CR5= , or -O-;
L is heterocyclyl, -N(R6)-, -O-, -C(O)-, -C(O)O-, -S(O)t- where t is 0, 1, or 2, -CON(R6)-, -N(R6)CO-, -SO2N(R6)-, -N(R6)CON(R6)- or heteroaryl selected from the group consisting of azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, isoindolyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl;
R1 is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
R2 is hydrogen, heterocyclyl, heterocyclylalkyl, cycloalkyl, alkyl, aralkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl;
each R3 and R4 is the same or different and independently hydrogen, alkyl, aralkyl, alkenyl, aralkenyl, alkynyl, aralkynyl, cycloalkyl, cycloalkylalkyl, halo, or haloalkyl;
R5, at each occurrence, is hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, halo, or haloalkyl;
R6 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, or haloalkyl,
a stereoisomer, enantiomer or tautomer thereof, an isotopically enriched derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof, wherein the prodrug is acetate, formate, benzoate, or phosphate derivatives of alcohol or amine functional groups in the compounds defined herein.
A, A1, A2, R1, R3, and R4 are as defined above.
A, A1, A2, R1, R3, R4, and R5 are as defined above,
L is heteroaryl or heterocycle;
R7 is hydrogen, alkyl, alkoxy, or halo;
X is -O-, -NR8-, or -C(R9)2-;
R8 is hydrogen, alkyl, or -C(O)R10-;
each R9 is independently hydrogen, alkyl, alkoxy, or halo; and
R10 is alkyl, cycloalkyl, aryl, alkoxy, or aralkyl.
DETAILED DESCRIPTION
Definitions
"Amino" refers to the -NH2 radical.
"Methoxy" refers to the -OCH3 radical.
"Cyano" refers to the -CN radical.
"Nitro" refers to the -NO2 radical.
"Trifluoromethyl" refers to the -CF3 radical.
"Oxo" refers to the =O.
"Thioxo" refers to the =S.
"Acyl" refers to -C(O)R14 radical, wherein R14 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
"Alkyl" refers to a straight or branched hydrocarbon chain radical, when unsubstituted, consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted by one or more substituents, as defined herein. "Alkenyl" refers to a straight or branched hydrocarbon chain radical group, when unsubstituted, consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted by one of or more substituents, as defined herein.
"Alkynyl" refers to a straight or branched hydrocarbon chain radical group, when unsubstituted, consisting solely of carbon and hydrogen atoms, containing at least one triple bond, optionally containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted by one or more substituents, as defined herein. "Alkylene" and "alkylene chain" refer to a straight or branched divalent hydrocarbon chain, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain may be attached to the rest of the molecule and to the radical group through one carbon within the chain or through any two carbons within the chain.
"Alkenylene" and "alkenylene chain" refer to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
"Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above. The alkyl part of the alkoxy radical may be optionally substituted as defined above for an alkyl radical.
"Aryl" refers to aromatic monocyclic or multi-cyclic hydrocarbon ring system, when unsubstituted, consisting only of hydrogen and carbon and containing from 6 to 19 carbon atoms, preferably 6 to 10 carbon atoms, where the ring system may be partially or fully saturated. Aryl groups include, but are not limited to groups such as fluorenyl, phenyl and naphthyl. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents, as defined herein. "Aralkyl" refers to a radical of the formula -RaRb where Ra is an alkyl radical as defined above and Rb is one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl and the like. The aryl part of the aralkyl radical may be optionally substituted as described above for an aryl group. The alkyl part of the aralkyl radical may be optionally substituted as defined above for an alkyl group.
"Aralkenyl" refers to a radical of the formula -RcRb where Rc is an alkenyl radical as defined above and Rb is one or more aryl radicals as defined above, which may be optionally substituted as described above. The aryl part of the aralkenyl radical may be optionally substituted as described above for an aryl group. The alkenyl part of the aralkenyl radical may be optionally substituted as defined above for an alkenyl group.
"Aralkynyl" refers to a radical of the formula -RdRb where Rd is an alkynyl radical as defined above and Rb is one or more aryl radicals as defined above. The aryl part of the aralkynyl radical may be optionally substituted as described above for an aryl group. The alkynyl part of the aralkynyl radical may be optionally substituted as defined above for an alkynyl group.
"Cycloalkyl" refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon radical, when unsubstituted, consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, preferably having from three to twelve carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl and the like. Unless otherwise stated specifically in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents, as defined herein. "Cycloalkylalkyl" refers to a radical of the formula -RaRd where Ra is an alkyl radical as defined above and Rd is a cycloalkyl radical as defined above. The cycloalkyl part of the cycloalkyl radical may be optionally substituted as defined above for a cycloalkyl radical. The alkyl part of the cycloalkyl radical may be optionally substituted as defined above for an alkyl radical.
"Halo" refers to bromo, chloro, fluoro or iodo.
"Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above. One or more carbons of the alkyl radical may be substituted by the one or more halo radicals. Examples of haloalkyl include, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoro-propyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group.
"Haloalkenyl" refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 2-bromoethenyl, 3-bromoprop-1-enyl, and the like. The alkenyl part of the haloalkenyl radical may be optionally substituted as defined above for an alkyl group.
"Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical including, as ring atoms, at least one carbon atom and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this disclosure, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; and the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents, as defined herein. When the heterocyclyl is a substituent of another moiety, the heterocyclyl is monovalent, which means that the heterocyclyl is connected to the other moiety by a single ring atom. An example of a monovalent heterocyclyl can be found in the radical of heterocyclylalkyl, in which a heterocyclyl group is a substituent of an alkyl group. When heterocyclyl is a linker moiety (L) of Formula (I), the heterocyclyl is a divalent radical. In this occurrence, the heterocyclyl (as L) is linked, by two of its ring atoms, to the 2-aminopyridine moiety and R2 of Formula (I). An example of a divalent heterocyclyl is 1,4-piperidinyl, shown below:
"Heterocyclylalkyl" refers to a radical of the formula -RaRe where Ra is an alkyl radical as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. The alkyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for an alkyl group. The heterocyclyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for a heterocyclyl group.
"Heteroaryl" refers to a 5- to 18-membered aromatic ring radical including, as ring atoms, at least one carbon atom and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this disclosure, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; and the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents, as defined herein. Heteroaryl, as defined herein, may be monovalent or divalent. When heteroaryl is a substituent of another moiety, the heteroaryl is monovalent, which means that the heteroaryl is connected to the other moiety by a single ring atom. An example of a monovalent heteroaryl can be found in the radical of heteroarylalkyl, in which an alkyl group is substituted with a heteroaryl group. When heteroaryl is a linker moiety (L) of Formula (I), the heteroaryl is a divalent radical. In this occurrence, the heteroaryl (as L) is linked, by two of its ring atoms, to the 2-aminopyridine moiety and R2 of Formula (I). An example of a divalent heteroaryl is 1H-pyrazol-4-yl, shown below:
"Heteroarylalkyl" refers to a radical of the formula -RaRf where Ra is an alkyl radical as defined above and Rf is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above for a heteroaryl group. The alkyl part of the heteroarylalkyl radical may be optionally substituted as defined above for an alkyl group.
"Heteroarylalkenyl" refers to a radical of the formula -RcRg where Rc is an alkenyl radical as defined above and Rg is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkenyl radical may be optionally substituted as defined above for a heteroaryl group. The alkenyl part of the heteroarylalkenyl radical may be optionally substituted as defined above for an alkenyl group.
"N-heteroaryl" is a subset of heteroaryl, and refers to a heteroaryl having at least one nitrogen ring atom. Heteroaryl is otherwise as defined as herein. Examples of N-heteroaryls include, without limitation, benzimidazolyl, benzindolyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, imidazolyl, indolyl, indazolyl, isoindolyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl.
"N-heterocyclyl" is a subset of heterocyclyl, and refers to a heterocyclyl having at least one nitrogen ring atom. Heterocyclyl is otherwise as defined as herein. Examples of N- heterocyclyls include, without limitation, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.
"Substituent" refers to a radical (a single non-hydrogen atom or a functional group) that is or can be bonded to another molecule. An substituent is therefore any one of the following radicals: alkyl, alkenyl, amino, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR14, -OC(O)R14, - N(R14)2, -C(O)R14, -C(O)OR14, -C(O)N(R14)2, -N(R14)C(O)OR16, -N(R14)C(O)R16, - N(R14)(S(O)tR16) (where t is 1 to 2), -S(O)tOR16 (where t is 1 to 2), -S(O)tR16 (where t is 0 to 2), and -S(O)tN(R14)2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted unless otherwise indicated.
"Prodrugs" refers to a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of Formula (I) or any one of the substructures. Thus, the term "prodrug" refers to a metabolic precursor of a compound of Formula (I) or any one of the substructures, that is pharmaceutically acceptable; the latter is also referred to as a "parent compound." A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound, i.e., the parent compound. Prodrugs are typically rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24, Elsevier, Amsterdam).
A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
The term "prodrug" is also meant to include any covalently bonded carriers which release the active compound of the disclosure in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the disclosure may be prepared by modifying functional groups present in the compound of Formula (I) or any one of the substructures in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the disclosure wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug disclosure is administered to a mammalian subject, cleaves to restore the free hydroxy, free amino or free mercapto group, respectively. Prodrugs, in the sense of the present invention, include acetate, formate and benzoate, and phosphate derivatives of alcohol or amine functional groups in the compounds of Formula (I), (IA), (IB) or any one of the substructures.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
"Mammal" or "mammalian subject" includes humans and domestic animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like.
"Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
"Pharmaceutically acceptable carrier, diluent or excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.
"Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
Often crystallizations produce a solvate of the compound of the disclosure. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the disclosure with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the disclosure may be true solvates, while in other cases, the compound of the disclosure may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
A "pharmaceutical composition" refers to a formulation of a compound of the disclosure and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
"Therapeutically effective amount" refers to that amount of a compound of the disclosure which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of a disease or condition in the mammal, preferably a human. The amount of a compound of the disclosure which constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
"Treating" or "treatment" as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or disorder of interest, and includes:
As used herein, the terms "disease" and "condition" may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
The compounds of the disclosure, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposeable mirror images of one another.
A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any said compounds.
An "isotopically enriched derivative" refers to a compound wherein one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure comprises isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 38CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 31P, 32P and 33P, and sulphur, such as 35S. Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopically-enriched compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations Sections using an appropriate isotopically-enriched reagent in place of the non-enriched reagent previously employed.
Embodiments
W is
each A, A1 and A2 is the same or different and independently -N=, - CR5= , or -O-;
L is heterocyclyl, -N(R6)-, -O-, -C(O)-, -C(O)O-, -S(O)t- where t is 0, 1, or 2, -CON(R6)-, -N(R6)CO-, -SO2N(R6)-, -N(R6)CON(R6)-; or heteroaryl selected form the group consiting of azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, isoindolyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl;
R1 is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
R2 is hydrogen, heterocyclyl, heterocyclylalkyl, cycloalkyl, alkyl, aralkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl;
each R3 and R4 is the same or different and independently selected from hydrogen, alkyl, aralkyl, alkenyl, aralkenyl, alkynyl, aralkynyl, cycloalkyl, cycloalkylalkyl, halo, and haloalkyl;
R5, at each occurrence, is hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, halo, or haloalkyl;
R6 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, or haloalkyl,
a stereoisomer, enantiomer or tautomer thereof, an isotopically enriched derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof, wherein the prodrug is acetate, formate, benzoate, or phosphate derivatives of alcohol or amine functional groups in the compounds defined herein.
butyl-4-(4-(6-amino-5-(5-phenyloxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
3-(5-phenyloxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;
(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;
3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;
3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;
(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;
1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;
(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;
1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;
3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropan-1-one;
(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(4-fluorophenyl)methanone; or
5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine.
-phenyloxazol-2-yl)-5-(1-(tetrahydro-2pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; or
3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(tetrahydro-2pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.
3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine; 3-(5-(-chlorophenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine; or
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine.
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine;
3-(5-phenylisoxazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-phenylisoxazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; or
5-(1-(1-methylpipridin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine.
3-(5-phenylfuran-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine;
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine; or
3-(5-phenylfuran-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.
butyl 4-(4-(6-amino-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(2,6-dichloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-methylpentan-1 -one;
(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;
(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;
1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; or
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.
butyl 4-(4-(6-amino-5-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1 -carboxylate;
tert-butyl 4-(4-(6-amino-5-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1 -carboxylate;
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1 -carboxylate;
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
tert-butyl 4-(4-(6-amino-5-(5-(4-(trifluoromethyl)-thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; or
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(4-(trifluoromethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine.
butyl 4-(4-(6-amino-5-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
3-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-benzyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; or
3-(5-benzyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine; or
3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine.
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine.
-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; or
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.
3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;
(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;
5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin- 2-amine;
(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;
1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine; or
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine;
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine;
3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; or
3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine.
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
3-(5-phcnyl-1,2,4-oxadiazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
3-(5-(2,5-dichlorophenyl)-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine.
A, A1, A2, R1, R3, R4, and R5 are as defined above,
L is heteroaryl or heterocycle;
R7 is hydrogen, alkyl, alkoxy, or halo;
X is -O-, -NR8-, or -C(R9)2-;
R8 is hydrogen, alkyl, or -C(O)R10 ;
each R9 is independently hydrogen, alkyl, alkoxy, or halo; and
R10 is alkyl, cycloalkyl, aryl, alkoxy, or aralkyl.
each A, A1 and A2 is the same or different and independently -N=, - CR5= , or -O-;
R1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, aralkyl, or cycloalkylalkyl;
each of R3, R4 and R7 is hydrogen,
R8 is hydrogen, alkyl, or -C(O)R10-; and
R10 is alkyl, cycloalkyl, aryl, alkoxy, or aralkyl.
each A, A1 and A2 is the same or different and independently -N=, - CR5= , or -O-;
R1 is aryl, heteroaryl, cycloalkyl, or heterocyclyl; and
each of R3, R4 and R7 is hydrogen.
each A, A1 and A2 is the same or different and independently -N=, - CR5= , or -O-;
R1 is aryl, heteroaryl, cycloalkyl, or heterocyclyl; and
each of R3, R4, R7 and R9 is hydrogen;
Utility and Testing of the Compounds of the Disclosure
Pharmaceutical Compositions of the Disclosure and Administration
Isotopic Enrichment of Compounds
Preparation of the Compounds of Formula (I), (IA) or (IB)
PREPARATIONS
PREPARATION 1
PREPARATION OF 2-AMINO-1-PHENYLETHANONE HYDROCHLORIDE
PREPARATION 1.1
PREPARATION OF 2-AMINO-1-(4-CHLOROPHENYL)ETHANONE HYDROCHLORIDE
PREPARATION 1.2
PREPARATION OF 2-AMINO-1-(3-CHLOROPHENYL)ETHANONE HYDROCHLORIDE
PREPARATION 2
PREPARATION OF 2-AMINO-5-BROMO-N-(2-OXO-2-PHENYLETHYL)NICOTINAMIDE
PREPARATION 2.1
PREPARATION OF 2-AMINO-5-BROMO-N-(2-(4-CHLOROPHENYL)-2-OXOETHYL)NICOTINAMIDE
PREPARATION 3
PREPARATION OF 5-BROMO-3-(5-PHENYLOXAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 3.1
PREPARATION OF 5 -BROMO-3 -(5 -(4-CHLOROPHENYL)OXAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 4
PREPARATION OF 5-BROMO-3-(5-(3-CHLOROPHENYL)OXAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 5
PREPARATION OF 5-BROMO-3-(5-PHENYLISOXAZOL-3-YL)PYRIDIN-2-AMINE
PREPARATION 6
PREPARATION OF 5-BROMO-3-(5-PHENYLFURAN-2-YL)PYRIDIN-2-AMINE
PREPARATION 7
PREPARATION OF 5-BROMO-3-(5-(PYRIDIN-3-YL)OXAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 8
PREPARATION OF 2-AMINO-5-BROMONICOTINOHYDRAZIDE
PREPARATION 9
PREPARATION OF 2-AMINO-5-BROMO-N'-(2,6-DICHLORO-3-FLUOROBENZOYL)NICOTINOHYDRAZIDE
PREPARATION 9.1
PREPARATION OF 2-AMINO-N'-BENZOYL-5-BROMONICOTINOHYDRAZIDE
PREPARATION 9.2
PREPARATION OF SYNTHESIS OF 2-AMINO-5-BROMO-N'-(4-(TERT-BUTYL)BENZOYL)NICOTINOHYDRAZIDE
PREPARATION 9.3
PREPARATION OF 2-AMINO-S-BROMO-N'-(2,5-DIFLUOROBENZOYL)NICOTINOHYDRAZIDE
PREPARATION 9.4
PREPARATION OF 2-AMINO-5-BROMO-N'-(2,6-DICHLOROBENZOYL)NICOTINOHYDRAZIDE
PREPARATION 9.5
PREPARATION OF 2-AMINO-5-BROMO-N'-(4-FLUOROBENZOYL)NICOTINOHYDRAZIDE
PREPARATION 9.6
PREPARATION OF 2-AMINO-5-BROMO-N'-(CYCLOHEXANECARBONYL)NICOTINOHYDRAZIDE
PREPARATION 10
PREPARATION OF 5-BROMO-3-(5-(PYRIDIN-2-YL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 10.1
PREPARATION OF 5-BROMO-3-(5-(PYRIDIN-3-YL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 10.2
PREPARATION OF 5 -BROMO-3 -(5 -(PYRAZIN-2-YL)-1,3 ,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 10.3
PREPARATION OF 3-(5-BENZYL-1,3,4-OXADIAZOL-2-YL)-5-BROMOPYRIDIN-2-AMINE
PREPARATION 10.4
PREPARATION OF 5-BROMO-3-(5-(CYCLOPROPYLMETHYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 10.5
PREPARATION OF 5-BROMO-3-(5-(THIAZOL-2-YL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 10.6
PREPARATION OF 5-BROMO-3-(5-(4-(TRIFLUOROMETHYL)THIAZOL-2-YL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 11
PREPARATION OF 5-BROMO-3-(5-(2,6-DICHLORO-3-FLUOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 11.1
PREPARATION OF 5-BROMO-3-(5-PHENYL-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 11.2
PREPARATION OF 5-BROMO-3-(5-(4-(TERT-BUTYL)PHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 11.3
PREPARATION OF 5-BROMO-3-(5-(2,5-DIFLUOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 11.4
PREPARATION OF 5-BROMO-3-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 11.5
PREPARATION OF 5-BROMO-3-(5-(4-FLUOROPHENYL)-1,3,4-OXADIAZOL-2-YL)-PYRIDIN-2-AMINE
PREPARATION 12
PREPARATION OF 1-CYCLOHEXYL-4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-1H-PYRAZOLE
PREPARATION 13
PREPARATION OF N'-HYDROXYBENZAMIDINE
PREPARATION 13.1
PREPARATION OF (Z)-2,6-DICHLORO-N'-HYDROXYBENZAMIDINE
PREPARATION 14
PREPARATION OF N'-((2-AMINO-5-BROMONICOTINOYL)OXY)BENZIMIDAMIDE
PREPARATION 14.1
PREPARATION OF (Z)-N'-((2-AMINO-5-BROMONICOTINOYL)OXY)-2,6-DICHLOROBENZIMIDAMIDE
PREPARATION 15
PREPARATION OF 5-BROMO-3-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)PYRIDIN-2-AMINE
PREPARATION 15.1
PREPARATION OF 5-BROMO-3-(3-(2,6-DICHLOROPHENYL)-1,2,4-OXADIAZOL-5-YL)PYRIDIN-2-AMINE
PREPARATION 16
PREPARATION OF (Z)-2-AMINO-5-BROMO-N'-HYDROXYNICOTINIMIDAMIDE
PREPARATION 17
PREPARATION OF 5-BROMO-3-(5-PHENYL-1,2,4-OXADIAZOL-3-YL)PYRIDIN-2-AMINE
PREPARATION 18
PREPARATION OF 5-BROMO-3-(5-(2,5-DICHLOROPHENYL)-1,2,4-OXADIAZOL-3-YL)PYRIDIN-2-AMINE
PREPARATION 19
PREPARATION OF TERT-BUTYL 4-(4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-1H-PYRAZOL-1-YL)PIPERIDINE-1-CARBOXYLATE
PREPARATION 20
PREPARATION OF 5-BROMO-3-(5-CYCLOHEXYL-1,3,4-OXADIAZOL-2-YL)PYRIDIN-2-AMINE
PREPARATION 21
PREPARATION OF TERT-BUTYL 4-(3-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-1H-PYRROL-1-YL)PIPERIDINE-1-CARBOXYLATE
PREPARATION 22
PREPARATION OF 1-(TETRAHYDRO-2H-PYRAN-4-YL)-4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-1H-PYRAZOLE
EXAMPLES
EXAMPLE 1
SYNTHESIS OF TERT-BUTYL 4-(4-(6-AMINO-5-(5-PHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDINE-1-CARBOXYLATE
Ex. No. | Chemical Name | Starting Material and Yield | Characterization Data |
1.1 | tert-butyl 4-(4-(6-amino-5-(5-(2,6-dichloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | 5-bromo-3-(5-(2,6-dichloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 16% | 1H 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 2.4 Hz, 1H), 8.10 (d, J= 2.4 Hz, 1H), 7.73 (d, J= 0.8 Hz, 1H), 7.64 (d, J= 0.8 Hz, 1H), 7.52-7.48 (m, 1H), 7.40-7.36 (m, 1H), 6.62 (br s, 2H), 4.35-4.22 (m, 3H), 2.96-2.84 (m, 2H), 2.18-2.12 (m, 2H), 1.98-1.91 (m, 2H), 1.46 (s, 9H). |
1.2 | tert-butyl 4-(4-(5-(5-(4-tert-butylphenyl)-1,3,4-oxadiazol-2-yl)-6-aminopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | 3-(5-(4-tert-butylphenyl)-1,3,4-oxadiazol-2-yl)-5-bromopyridin-2-amine and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 22% | 1H 1H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.11-8.07 (m, 2H), 7.78 (d, J = 0.8 Hz, 1H), 7.67 (d, J = 0.8 Hz, 1H), 7.60-7.56 (m, 2H), 6.61 (br s, 2H), 4.38-4.20 (m, 3H), 2.98-2.86 (m, 2H), 2.24-2.16 (m, 2H), 2.04-1.83 (m, 2H), 1.48 (s, 9H), 1.38 (s, 9H). |
1.3 | tert-butyl 4-(4-(6-amino-5-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | 5-bromo-3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 18% | 1H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.90-7.84 (m, 1H), 7.77 (d, J= 0.8 Hz, 1H), 7.66 (d, J= 0.8 Hz, 1H), 7.30-7.26 (m, 2H), 6.60 (br s, 2H), 4.36-4.22 (m, 3H), 2.98-2.86 (m, 2H), 2.24-2.16 (m, 2H), 2.03-1.83 (m, 2H), 1.48 (s, 9H). |
1.4 | tert-butyl 4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | 5-bromo-3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-pyridin-2-amine and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 34% | 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J= 2.4 Hz, 1H), 8.12 (d, J= 2.4 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H), 7.65 (d, J = 0.8 Hz, 1H), 7.52-7.49 (m, 3H), 6.63 (br s, 2H), 4.36-4.18 (m, 3H), 2.96-2.84 (m, 2H), 2.20-2.13 (m, 2H), 2.02-1.88 (m, 2H), 1.48 (s, 9H). |
1.5 | tert-butyl 4-(4-(6-amino-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | 5-bromo-3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-pyridin-2-amine and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 35% | 1H NMR (400 MHz, CDCl3): δ 8.40 (d, J= 2.4 Hz, 1H), 8.21-8.15 (m, 2H), 8.14 (d, J= 2.4 Hz, 1H), 7.78 (d, J = 0.8 Hz, 1H), 7.67 (d, J = 0.8 Hz, 1H), 7.30-7.24 (m, 2H), 6.60 (br s, 2H), 4.39-4.23 (m, 3H), 2.98-2.87 (m, 2H), 2.24-2.16 (m, 2H), 2.04-1.83 (m, 2H), 1.48 (s, 9H). |
1.6 | 3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | 5-bromo-3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-pyridin-2-amine and pyrazole-4-boronic acid pinacol ester; 12% | 1H NMR (400 MHz, DMSO-d6): δ 12.9 (br s, 1H), 8.58-8.55 (m, 1H), 8.24-8.21 (m, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.79-7.71 (m, 2H), 7.32 (br s, 2H); MS (ES+): m/z 373.2, 374.2 and 375.2 (M + 1). |
1.7 | - 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | pyrazole-4-boronic acid pinacol ester and 5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine; 21% | 1H NMR (400 MHz, DMSO-d6): δ 12.9 (br s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.40 (d, J= 2.4 Hz, 1H), 8.26-8.19 (m, 3H), 7.99 (s, 1H), 7.67-7.59 (m, 3H), 7.26 (br s, 2H); MS (ES+): m/z 305.3 (M + 1). |
1.8 | 3-(5-(4-tert-butylphenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | 5-bromo-3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine and pyrazole-4-boronic acid pinacol ester; 21% | 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 8.14-8.10 (m, 2H), 7.97 (s, 1H), 7.64-7.60 (m, 2H), 7.25 (br s, 2H), 1.33 (s, 9H). MS (ES+): m/z 361.3 (M + 1). |
1.9 | 3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | 5-bromo-3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-pyridin-2-amine and pyrazole-4-boronic acid pinacol ester; 20% | 1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H) 8.20-8.13 (m, 2H), 8.09 (s, 1H), 7.59-7.53 (m, 2H) 7.28 (br s, 2H); MS (ES+): m/z 341.3 (M + 1). |
1.10 | 3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | 5-bromo-3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-pyridin-2-amine and pyrazole-4-boronic acid pinacol ester; 26% | 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J= 2.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.30-8.24 (m, 2H), 8.21 (s, 1H), 7.97 (s, 1H), 7.49-7.42 (m, 2H), 7.24 (br s, 2H); MS (ES+): m/z 323.3 (M + 1). |
1.11 | 3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine | 5-bromo-3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-pyridin-2-amine and 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole; 38% | 1H NMR (400 MHz, CDCl3): δ 8.40 (d, J= 2.0 Hz, 1H), 8.13 (d, J= 2.4 Hz, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.52-7.48 (m, 3H), 6.86-6.60 (br s, 2H), 4.15-4.11 (m, 1H), 2.24-2.16 (m, 2H), 1.96-1.86 (m, 2H), 1.76-1.70 (m, 2H), 1.45-1.39 (m, 2H), 1.33-1.20 (m, 2H). MS (ES+): m/z 455.3, 456.3 and 457.3 (M + 1). |
EXAMPLE 2
SYNTHESIS OF 3-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)-5-(1-(TETRAHYDRO-2H-PYRAN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE
Ex. No. | Chemical Name | Starting Material and Yield | Characterization Data |
2.1 | tert-butyl 4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine; 60% | 1H NMR (400 MHz, CDCl3): δ 8.45 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.17-8.12 (m, 2H), 7.78 (s, 1H), 7.68 (s, 1H), 7.56-7.50 (m, 3H), 6.68 (br s, 2H), 4.38-4.22 (m, 3H), 3.00-2.84 (m, 2H), 2.24-2.14 (m, 2H), 2.06-1.92 (m, 2H), 1.49 (s, 9H). |
2.2 | tert-butyl 4-(4-(6-amino-5-(5-(pyridin-2-yl)-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine; 46% | 1H NMR (400 MHz, CDCl3): δ 8.83 (d, J = 4.8 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.96-7.90 (m, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.54-7.48 (m, 1H), 6.85-6.65 (br s, 2H), 4.38-4.20 (m, 3H), 3.00-2.85 (m, 2H), 2.22-2.14 (m, 2H), 2.04-1.90 (m, 2H), 1.49 (s, 9H). |
2.3 | tert-butyl 4-(4-(6-amino-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine; 34% | 1H NMR (400 MHz, CDCl3): δ 9.36 (s, 1H), 8.81 (dd, J = 4.8, 1.2 Hz, 1H), 8.43 (dt, J= 8.0, 2.0 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.07 (s, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 6.75-6.60 (br s, 2H), 4.38-4.20 (m, 3H), 3.00-2.85 (m, 2H), 2.22-2.14 (m, 2H), 2.04-1.90 (m, 2H), 1.47 (s, 9H). |
2.4 | tert-butyl 4-(4-(6-amino-5-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine; 62% | 1H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.80 (s, 2H), 8.42 (s, 1H), 8.28 (s, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 6.85-6.65 (br s, 2H), 4.38-4.20 (m, 3H), 3.00-2.85 (m, 2H), 2.22-2.14 (m, 2H), 2.04-1.90 (m, 2H), 1.49(s, 9H). |
2.5 | tert-butyl 4-(4-(6-amino-5-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine; 46% | 1H 1 NMR (400 MHz, CDCl3): δ 8.35 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 6.70-6.55 (br s, 2H), 4.38-4.20 (m, 3H), 3.00-2.86 (m, 2H), 2.86 (d, J = 6.4 Hz, 2H), 2.22-2.14 (m, 2H), 2.04-1.90 (m, 2H), 1.48 (s, 9H), 1.28-1.18 (m, 1H), 0.70-0.58 (m, 2H), 0.38-0.28 (m, 2H). |
2.6 | tert-butyl 4-(4-(6-amino-5-(5-benzyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 3-(5-benzyl-1,3,4-oxadiazol-2-yl)-5-bromopyridin-2-amine; 36% | 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.41-7.29 (m, 5H), 6.70-6.50 (br s, 2H), 4.38-4.20 (m, 5H), 3.00-2.85 (m, 2H), 2.22-2.14 (m, 2H), 2.04-1.90 (m, 2H), 1.49 (s, 9H). |
2.7 | tert-butyl 4-(4-(6-amino-5-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine; 62% | 1H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.71-7.68 (m, 2H), 6.85-6.65 (br s, 2H), 4.38-4.20 (m, 3H), 3.00-2.86 (m, 2H), 2.22-2.14 (m, 2H), 2.04-1.90 (m, 2H), 1.48 (s, 9H). |
2.8 | tert-butyl 4-(4-(6-amino-5-(5-(4-(trifluoromethyl)thiaz ol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-(4-(trifluoromethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine; 36% | 1H NMR (400 MHz, CDCl3): δ 8.43 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 6.70-6.55 (br s, 2H), 4.38-4.20 (m, 3H), 3.00-2.84 (m, 2H), 2.24-2.16 (m, 2H), 2.05-1.93 (m, 2H), 1.48 (s, 9H). |
2.9 | 3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine; 5% | 1H NMR (400 MHz, CD3OD): δ 8.60 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.27-8.22 (m, 2H), 7.96 (br s, 2H), 7.71-7.65 (m, 1H), 7.64-7.59 (m, 2H); MS (ES+): m/z 305.3 (M + 1). |
2.10 | 3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine; 5% | 1H NMR (400 MHz, 15% CD3OD in CDCl3): δ 8.42 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.15-8.09 (m, 2H), 7.81 (s, 2H), 7.54-7.46 (m, 3H). MS (ES+): m/z 305.3 (M + H). |
2.11 | tert-butyl 4-(4-(6-amino-5-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine; 33% | 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 6.59 (br s, 2H), 4.38-4.34 (m, 3H), 3.05-2.97 (m, 1H), 2.97-2.85 (m, 2H), 2.23-2.12 (m, 4H), 2.05-1.98 (m, 2H), 1.95-1.86 (m, 2H), 1.81-1.63 (m, 4H), 1.49 (s, 9H), 1.46-1.38 (m, 2H). |
2.12 | 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine | 5-bromo-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine and 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole; 15% | 1H NMR (400 MHz, CDCl3): δ 8.47 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.19-1.14 (m, 2H), 7.78 (s, 1H), 7.69 (s, 1H), 7.57-7.51 (m, 3H), 6.65 (br s, 2H), 4.23-4.13 (m, 1H), 2.28-2.20 (m, 2H), 1.98-1.91 (m, 2H), 1.85-1.74 (m, 3H), 1.54-1.40 (m, 2H), 1.37-1.29 (m, 1H); MS (ES+) m/z 387.4 (M + 1). |
2.13 | 3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | 5-bromo-3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole; 35% | 1H NMR (400 MHz, CDCl3): δ 8.44 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.52-7.49 (m, 3H), 6.70-6.55 (br s, 2H), 4.42-4.36 (m, 1H), 4.16-4.10 (m, 2H), 3.60-3.50 (m, 2H), 2.16-2.06 (m, 4H). MS (ES+): m/z 457.2 and 459.2 (M + 1). |
2.14 | 5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine | 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine; 50% | 1H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 2.4 Hz, 1H), 8.20-8.14 (m, 3H), 7.79 (s, 1H), 7.70 (s, 1H), 7.63-7.54 (m, 3H), 6.75-6.50 (br s, 2H), 4.47-4.38 (m, 1H), 4.19-4.14 (m, 2H), 3.63-3.54 (m, 2H), 2.23-2.10 (m, 4H). MS (ES+): m/z 389.4 (M + 1), 411.4 (M + Na). |
2.15 | 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine | 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine; 8% | 1H NMR (400 MHz, CDCl3): δ 8.40 (d, J = 2.4 Hz, 1H), 8.20-8.14 (m, 3H), 7.76 (s, 1H), 7.68 (s, 1H), 7.63-7.54 (m, 3H), 6.70-6.50 (br s, 2H), 4.20-4.13 (m, 1H), 2.38-2.30 (m, 2H), 2.00-1.90 (m, 2H), 1.85-1.75 (m, 3H), 1.54-1.40 (m, 2H), 1.37-1.25 (m, 1H). MS (ES+): m/z 387.4 (M + 1), 409.4 (M + Na). |
2.16 | tert-butyl 4-(4-(6-amino-5-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | 5-bromo-3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 20% | 1H NMR (400 MHz, CDCl3): δ 8.46 (m, 1H), 8.37 (m, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 7.50-7.40 (m, 3H), 6.70-6.50 (br s, 2H), 4.37-4.14 (m, 3H), 3.00-2.82 (m, 2H), 2.22-2.10 (m, 2H), 2.07-1.88 (m, 2H), 1.48 (s, 9H). |
2.17 | 3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4--yl)-1H-pyrazol-4-yl)pyridin-2-amine | 5-bromo-3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole; 6% | 1H NMR (400 MHz, CDCl3): δ 8.48 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.50-7.41 (m, 3H), 6.54 (br s, 2H), 4.48-4.37 (m, 1H), 4.19-4.13 (m, 2H), 3.62-3.55 (m, 2H), 2.22 -2.12 (m, 4H); MS (ES+): m/z 457.2, 458.2 and 459.2 (M + 1). |
2.18 | 3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine | 5-bromo-3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine and 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole; 20% | 1H NMR (400 MHz, CDCl3): δ 8.48 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.49-7.41 (m, 3H), 6.54 (br s, 2H), 4.22-4.13 (m, 1H), 2.28-2.22 (m, 2H), 1.96-1.93 (m, 2H), 1.81-1.75 (m, 3H), 1.53-1.49 (m, 2H), 1.48-1.46 (m, 1H); MS (ES+): m/z 455.3, 456.3 and 457.3 (M + 1). |
2.19 | tert-butyl 4-(3-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrrol-1-yl)piperidine-1-carboxylate | 5-bromo-3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine and tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrol-1-yl)piperidine-1-carboxylate; 46% | 1H NMR (400 MHz, CDCl3): δ 8.45 (d, J = 2.4 Hz, 1H), 8.13 (J = 2.4 Hz, 1H), 7.53-7.48 (m, 3H), 6.99-6.97 (m, 1H), 6.78-6.75 (m, 1H), 6.55 (br s, 2H), 6.43-6.40 (m, 1H), 4.35-4.22 (m, 2H), 4.02-3.92 (m, 1H), 2.80-2.78 (m, 2H), 2.12-2.05 (m, 2H), 1.92-1.80 (m, 2H), 1.48 (s, 9H). |
EXAMPLE 3
SYNTHESIS OF 3-(5-(2,6-DICHLORO-3-FLUOROPHENYL)-1,3,4-OXADIAZOL-2-YL)-5-(1-PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE
Ex. No. | Chemical Name | Starting Material and Yield | Characterization Data |
3.1 | 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-phenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 76% | 1H NMR (400 MHz, CDCl3): δ 8.40 (d, J = 2.4 Hz, 1H), 8.19-8.15 (m, 3H), 7.77 (d, J = 0.8 Hz, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.61-7.55 (m, 3H), 6.59 (br s, 2H), 4.34-4.25 (m, 1H), 3.32-3.25 (m, 2H), 2.85-2.77 (m, 2H), 2.26-2.19 (m, 2H), 2.03-1.91 (m, 2H); MS (ES+): m/z 388.3 (M + 1). |
3.2 | 3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(5-(5-(4-tert-butylphenyl)-1,3,4-oxadiazol-2-yl)-6-aminopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 100% | 1H NMR (300 Hz, CDCl3): δ 8.39 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.11-8.06 (m, 2H), 7.77 (s, 1H), 7.70 (s, 1H), 7.61-7.56 (m, 2H), 6.60 (br s, 2H), 4.35-4.27 (m, 1H), 3.36-3.28 (m, 2H), 2.88-2.78 (m, 2H), 2.28-2.23 (m, 2H), 2.07-1.95 (m, 2H), 1.38 (s, 9H); MS (ES+): m/z 444.4 (M + 1). |
3.3 | 3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 88% | 1H NMR (300 Hz, CDCl3) δ 8.42 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.90-7.84 (m, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.30-7.26 (m, 2H), 6.58 (br s, 2H), 4.33-4.24 (m, 1H), 3.31-3.24 (m, 2H), 2.85-2.75 (m, 2H), 2.26-2.17 (m, 2H), 2.02-1.90 (m, 2H); MS (ES+): m/z 424.3 (M + 1). |
3.4 | 3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 90% | 1H NMR (300 Hz, CDCl3) δ 8.42 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.54-7.47 (m, 3H), 6.62 (br s, 2H), 4.31-4.20 (m, 1H), 3.31-3.22 (m, 2H), 2.84-2.73 (m, 2H), 2.24-2.16 (m, 2H), 1.98-1.76 (m, 2H); MS (ES+): m/z 456.2, 457.3 and 458.3 (M + 1). |
3.5 | 3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 87% | 1H NMR (300 Hz, CDCl3): δ 8.40 (d, J = 2.4 Hz, 1H), 8.21-8.15 (m, 2H), 8.14 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.70 (d, J = 0.8 Hz, 1H), 7.30-7.24 (m, 2H), 6.60 (br s, 2H), 4.33-4.25 (m, 1H), 3.32-3.25 (m, 2H), 2.85-2.76 (m, 2H), 2.26-2.18 (m, 2H), 2.02-1.90 (m, 2H); MS (ES+): m/z 406.4 (M + 1). |
3.6 | 3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)-piperidine-1-carboxylate; 77% | 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.18-8.12 (m, 2H), 7.77 (s, 1H), 7.70 (s, 1H), 7.58-7.50 (m, 3H), 6.66 (br s, 2H), 4.32-4.22 (m, 1H), 3.32-3.22 (m, 2H), 2.85-2.74 (m, 2H), 2.26-2.17 (m, 2H), 2.00-1.88 (m, 2H); MS (ES+): m/z 388.4 (M + 1). |
3.7 | 3-(5-(cyclopropylmethyl) -1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 77% | 1H NMR (400 MHz, CD3OD): δ 8.36 (d, J = 2.4 Hz, 1H), 8.20 (d, J= 2.4 Hz, 1H), 8.06 (s, 1H), 7.82 (s, 1H), 4.45-4.35 (m, 1H), 3.38-3.30 (m, 2H), 2.98-2.88 (m, 2H), 2.87 (d, J = 8.0 Hz, 2H), 2.24-2.16 (m, 2H), 2.14-2.02 (m, 2H), 1.28-1.17 (m, 1H), 0.67-0.61 (m, 2H), 0.38-0.32 (m, 2H); MS (ES+): m/z 366.4 (M + 1). |
3.8 | 5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 61% | 1H NMR (400 MHz, CD3OD): δ 8.79 (d, J = 4.4 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 12.0 1H), 8.19 (s, 7.69-7.64 (m, 1H), 4.65-4.56 (m, 1H), 3.63-3.55 (m, 2H), 3.30-3.20 (m, 2H), 2.42-2.26 (m, 4H); MS (ES+): m/z 389.3 (M + 1). |
3.9 | 5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 68% | 1H NMR (400 MHz, CD3OD): δ 9.36 (d, J = 1.6 Hz, 1H), 8.81-8.76 (m, 1H), 8.65-8.60 (m, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.40 (d, J= 2.4 Hz, 1H), 8.17 (d, J = 0.4 Hz, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.70-7.75 (m, 1H), 4.62-4.53 (m, 1H), 3.50-3.42 (m, 2H), 3.26-3.17 (m, 2H), 2.40-2.24 (m, 4H); MS (ES+): m/z 389.4 (M + 1). |
3.10 | 5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 100% | 1H NMR (400 MHz, CD3OD): δ 9.54 (d, J = 1.6 Hz, 1H), 8.87-8.82 (m, 2H), 8.80 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 0.40 Hz, 1H), 7.99 (d, J = 0.80 Hz, 1H), 4.66-4.57 (m, 1H), 3.62-3.54 (m, 2H), 3.30-3.20 (m, 2H), 2.42-2.26 (m, 4H); MS (ES+): m/z 390.4 (M + 1). |
3.11 | 3-(5-benzyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-benzyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 57% | 1H NMR (400 MHz, CD3OD): δ 8.34 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 8.05 (d, J= 0.80 Hz, 1H), 7.82 (d, J = 0.80 Hz, 1H), 7.39-7.25 (m, 5H), 4.56-4.46 (m, 1H), 4.33 (s, 2H), 3.54-3.46 (m, 2H), 3.19-3.10 (m, 2H), 2.34-2.16 (m, 4H); MS (ES+): m/z 402.4 (M + 1). |
3.12 | 5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 80% | 1H NMR (400 MHz, CD3OD): δ 8.80 (d, J = 2.0 Hz, 1H), 8.45 (d, J= 2.0 Hz, 1H), 8.28 (s, 1H), 8.18 (d, J = 2.8 Hz, 1H), 8.05 (d, J= 3.2 Hz, 1H), 7.99 (s, 1H), 4.65-4.57 (m, 1H), 3.62-3.54 (m, 2H), 3.30-3.20 (m, 2H), 2.42-2.25 (m, 4H); MS (ES+): m/z 395.3 (M + 1). |
3.13 | 5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(4-(trifluoromethyl)thia zol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(4-(trifluoromethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)-pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 96% | 1H NMR (400 MHz, CD3OD): δ 8.71 (d, J = 2.0 Hz, 1H), 8.61 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 4.65-4.55 (m, 1H), 3.51-3.42 (m, 2H), 3.28-3.18 (m, 2H), 2.40-2.24 (m, 4H). MS (ES+): m/z 463.3 (M + 1). |
3.14 | 3-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 95% | 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.87 (s, 1H), 7.19 (br s, 2H), 4.28-4.19 (m, 1H), 3.15-3.08 (m, 2H), 3.05-2.95 (m, 1H), 2.75-2.65 (m, 2H), 2.13-1.97 (m, 4H), 1.95-1.80 (m, 2H), 1.80-1.70 (m, 2H), 1.68-1.53 (m, 3H),1.45-1.32 (m, 2H), 1.32-1.24 (m, 1H); (ES+): m/z 394.4 (M + 1). |
3.15 | 3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 98% | 1H NMR (400 M Hz, CD3OD): δ 8.49 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 7.60-7.52 (m, 3H), 4.37-4.27 (m, 1H), 3.24-3.16 (m, 2H), 2.82-2.73 (m, 2H), 2.17-2.09 (m, 2H), 2.03-1.91 (m, 2H). MS (ES+): m/z 457.3, 458.3 and 459.3 (M + 1). |
3.16 | 3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrrol-3-yl)pyridin-2-amine | tert-butyl 4-(3-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrrol-1-yl)piperidine-1-carboxylate; 69% | 1H NMR (400 MHz, CDCl3): δ 8.45 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.53-7.46 (m, 3H), 7.01-6.98 (m, 1H), 6.79-6.76 (m, 1H), 6.52 (br s, 2H), 6.41-6.38 (m, 1H), 3.95-3.87 (m, 1H), 3.26-3.20 (m, 2H), 2.78-2.70 (m, 2H), 2.13-2.06 (m, 2H), 1.92-1.82 (m, 2H); MS (ES+): m/z 455.1, 456.1 and 457.1 (M + 1). |
EXAMPLE 4
SYNTHESIS OF 1-(4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)ETHANONE
EXAMPLE 4.1
SYNTHESIS OF 1-(4-(4-(6-AMINO-5-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)ETHANONE
EXAMPLE 5
SYNTHESIS OF 3-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)-5-(1-(1-METHYLPIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDINE-2-AMINE
Ex. No. | Chemical Name | Starting Material and Yield | Characterization Data |
5.1 | 5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine | 3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and formaldehyde, 58% | 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.27-8.23 (m, 2H), 7.79 (s, 1H), 7.71 (s, 1H), 7.67-7.62 (m, 1H), 7.61-7.56 (m, 2H), 6.19 (br s, 2H), 423-4.14 (m, 1H), 3.06-2.98 (m, 2H), 2.36 (s, 3H), 2.26-2.09 (m, 6H); (ES+): m/z 402.4 (M + 1). |
5.2 | 5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine | 3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and formaldehyde; 39% | 1H NMR (400 MHz, DMSO-d6): δ 8.60 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.33 (s, 1H), 8.17-8.13 (m, 2H), 7.96 (s, 1H), 7.63-7.54 (m, 3H), 7.48 (br s, 2H), 4.33-4.22 (m, 1H) 3.24-3.12 (m, 2H), 2.73-2.60 (m, 2H), 2.52 (s, 3H), 2.20-2.00 (m, 4H); MS (ES+): m/z 402.4 (M + 1). |
5.3 | 3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | 3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and formaldehyde; 28% | 1H NMR (400 MHz, CDCl3): δ 8.47 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.50-7.40 (m, 3H), 6.52 (br s, 2H), 4.25-4.15 (m, 1H), 3.08-2.98 (m, 2H), 2.37 (s, 3H), 2.28-2.10 (m, 6H); MS (ES+): m/z 470.3, 471.3 and 472.3 (M + 1). |
5.4 | 3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | 3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and acetaldehyde; 43% | 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.19-8.14 (m, 2H), 7.77 (s, 1H), 7.68 (s, 1H), 7.57-7.50 (m, 3H), 6.52 (br s, 2H), 4.25-4.16 (m, 1H), 3.15-3.08 (m, 2H), 2.50 (q, J= 7.2 Hz, 2H), 2.30-2.03 (m, 2H), 2.18-2.08 (m, 4H), 1.14 (t, J = 7.2 Hz, 3H); (ES+): m/z 416.4 (M + 1). |
5.5 | 3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | 3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and dodecyl aldehyde; 20% | 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.51-7.41 (m, 3H), 6.52 (br s, 2H), 4.23-4.16 (m, 1H), 3.13-3.06 (m, 2H), 2.43-2.35 (m, 2H), 2.25-2.18 (m, 2H), 2.16-2.06 (m, 4H), 1.55-1.47 (m, 2H), 1.35-1.24 (m, 18H), 0.89 (t, J = 6.8 Hz, 3H); MS (ES+): m/z 624.5, 625.5 and 626.5 (M + 1). |
5.6 | 3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | 3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and acetaldehyde; 25% | 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 8.36 (s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.50-7.38 (m, 3H), 6.70-6.40 (br s, 2H), 4.27-4.15 (m, 1H), 3.60-3.50 (m, 2H), 2.60-2.45 (m, 2H), 2.30-2.00 (m, 6H), 1.14 (t, J= 6.8 Hz, 3H); MS (ES+): m/z 484.3, 485.3 and 486.4 (M + 1). |
5.7 | 3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | acetaldehyde and 3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; 61% | 1H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.53-7.46 (m, 3H), 6.72-6.54 (br s, 2H), 4.24-4.14 (m, 1H), 3.07-2.98 (m, 2H), 2.55-2.45 (m, 2H), 2.28-2.04 (m, 6H), 1.33 (t, J = 7.2 Hz, 3H); MS (ES+): m/z 484.3, 485.3 and 486.3 (M + 1). |
5.8 | 3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | dodecyl aldehyde and 3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; 51% | 1H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.54-7.46 (m, 3H), 6.76-6.50 (br s, 2H), 4.23-4.13 (m, 1H), 3.13-3.05 (m, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.25-2.00 (m, 6H), 1.55-1.45 (m, 2H), 1.35-1.20 (m, 18H), 0.88 (t, J = 7.2 Hz, 3H). MS (ES+): m/z 624.4, 625.4 and 626.4 (M + 1). |
EXAMPLE 6
SYNTHESIS OF 1-(4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)-4-METHYLPENTAN-1-ONE
EXAMPLE 7
SYNTHESIS OF (4-(4-(6-AMINO-5-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)(CYCLOPROPYL)METHANONE
EXAMPLE 7.1
SYNTHESIS OF (4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)(CYCLOPROPYL)METHANONE
EXAMPLE 7.2
SYNTHESIS OF (4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)(PHENYL)METHANONE
EXAMPLE 8
SYNTHESIS OF 5-(1-CYCLOHEXYL-1H-PYRAZOL-4-YL)-3-(5-PHENYL-1,2,4-OXADIAZOL-3-YL)PYRIDIN-2-AMINE
EXAMPLE 9
SYNTHESIS OF 3-(5-(2,5-DICHLOROPHENYL)-1,2,4-OXADIAZOL-3-YL)-5-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE
EXAMPLE 10
SYNTHESIS OF 3-(5-PHENYL-1,2,4-OXADIAZOL-3-YL)-5-(1-(TETRAHYDRO-2H-PYRAN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE
EXAMPLE 11
SYNTHESIS OF 3-(5-PHENYL-1,2,4-OXADIAZOL-3-YL)-5-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE
EXAMPLE 12
SYNTHESIS OF 1-(4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)-2-PHENYLETHANONE
EXAMPLE 12.1
SYNTHESIS OF (4-(4-(6-AMINO-5-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)(PHENYL)METHANONE
EXAMPLE 12.2
SYNTHESIS OF 1-(4-(4-(6-AMINO-5-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)-2-PHENYLETHANONE
EXAMPLE 13
SYNTHESIS OF 3-(5-PHENYLOXAZOL-2-YL)-5-(1-(TETRAHYDRO-2H-PYRAN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE
Ex. No. | Chemical Name | Starting Material and Yield | Characterization Data |
13.1 | tert-butyl 4-(4-(6-amino-5-(5-phenyloxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-phenyloxazol-2-yl)pyridin-2-amine; 75% | 1H NMR (400 MHz, CDCl3): δ 830 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 7.75-7.71 (m, 2H), 7.66 (s, 1H), 7.50-7.44 (m, 3H), 7.40-7.34 (m, 1H), 6.68 (br s, 2H), 4.38-4.22 (m, 3H), 3.00-2.86 (m, 2H), 2.24-2.14 (m, 2H), 2.06-1.92 (m, 2H), 1.47 (s, 9H). |
13.2 | 3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | 5-bromo-3-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-2-amine and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole; 12% | 1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.28 (s, 1H), 7.97-7.91 (m, 4H), 7.55 (d, J = 8.4 Hz, 2H), 7.34 (br s, 2H), 4.44-4.34 (m, 1H), 3.98-3.90 (m, 2H), 3.50-3.41 (m, 2H), 2.04-1.90 (m, 4H); MS (ES+): m/z 422.3 (M + 1): |
13.3 | tert-butyl 4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-2-amine; 90% | 1H NMR (400 MHz, CDCl3): δ 831 (d, J= 2.4 Hz, 1H), 8.20 (d, J= 2.4 Hz, 1H), 7.77 (s, 1H), 7.68-7.64 (m, 3H), 7.47-7.42 (m, 3H), 6.68 (br s, 2H), 4.38-4.22 (m, 3H), 3.00-2.84 (m, 2H), 2.24-2.14 (m, 2H), 2.06-1.92 (m, 2H), 1.48 (s, 9H). |
13.4 | tert-butyl 4-(4-(6-amino-5-(5-(4-chlorophenyl)oxaz ol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-2-amine; 43% | 1H NMR (400 MHz, CDCl3): δ 8.40 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.73-7.70 (m, 1H), 7.68 (s, 1H), 7.63-7.59 (m, 1H), 7.49 (s, 1H), 7.44-7.38 (m, 1H), 7.36-7.32 (m, 1H), 6.68 (br s, 2H), 4.40-4.25 (m, 3H), 3.00-2.87 (m, 2H), 2.24-2.16 (m, 2H), 2.06-1.94 (m, 2H), 1.49 (s, 9H). |
13.5 | 3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine | 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-3-(5-(3 -chlorophenyl)oxazol-2-yl)pyridin-2-amine; 19% | 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.74-7.71 (m, 1H), 7.68 (s, 1H), 7.63-7.60 (m, 1H), 7.49 (s, 1H), 7.43-7.39 (m, 1H), 7.36-7.33 (m, 1H), 6.66 (br s, 2H), 4.23-4.13 (m, 1H), 2.28-2.20 (m, 2H), 1.98-1.91 (m, 2H), 1.87-1.74 (m, 3H), 1.54-1.40 (m, 2H), 1.37-1.29 (m, 1H); MS (ES+): m/z 420.3 and 422.3 (M + 1). |
13.6 | 3-(5-(4-Chlorophenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridine-2-amine | 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-3-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-2-amine; 4% | 1H NMR (400 MHz, CDCl3): δ 8.34-8.30 (m, 1H), 8.22 (d, J = 2.4Hz, 1H), 7.56 (s, 1H), 7.69-7.64 (m, 3H), 7.47-7.43 (m, 3H), 6.65 (s, 2H), 4.22-4.12 (m, 1H), 2.26-2.19 (m, 2H), 1.99-1.80 (m, 2H), 1.85-1.74 (m, 3H), 1.53-1.40 (m, 2H), 1.36-1.25 (m, 1H); (ES+): m/z 420.4, and 422.4 (M + 1). |
13.7 | 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine | 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-3-(5-phenyloxazol-2-yl)pyridin-2-amine; 24% | 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.77-7.72 (m, 3H), 7.66 (s, 1H), 7.52-7.44 (m, 3H), 7.41-7.35 (m, 1H), 6.64 (br s, 2H), 4.22-4.10 (m, 1H), 2.28-2.20 (m, 2H), 1.98-1.92 (m, 2H), 1.86-1.73 (m, 3H), 1.53-1.40 (m, 2H), 1.36-1.25 (m, 1H); MS (ES+): m/z 386.4 (M + 1). |
13.8 | 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine | 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-3-(5-phenylisoxazol-3-yl)pyridin-2-amine; 35% | 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 2.0 Hz, 1H), 7.89-7.84 (m, 3H), 7.74 (s, 1H), 7.65 (s, 1H), 7.55-7.45 (m, 3H), 6.95 (s, 1H), 6.28-6.18 (br s, 2H), 4.20-4.12 (m, 1H), 2.27-2.18 (m, 2H), 1.98-1.90 (m, 2H), 1.84-1.72 (m, 3H), 1.53-1.40 (m, 2H), 1.36-1.23 (m, 1H). MS (ES+): m/z 386.2 (M + 1). |
13.9 | 5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine | 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-3-(5-phenylisoxazol-3-yl)pyridin-2-amine; 24% | 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 2.0 Hz, 1H), 7.89-7.84 (m, 3H), 7.76 (s, 1H), 7.67 (s, 1H), 7.55-7.45 (m, 3H), 6.95 (s, 1H), 6.38-6.28 (br s, 2H), 4.45-4.35 (m, 1H), 4.18-4.12 (m, 2H), 3.62-3.54 (m, 2H), 2.21-2.08 (m, 4H). MS (ES+): m/z 386.2 (M + 1). |
13.10 | tert-butyl 4-(4-(6-amino-5-(5-phenylisoxazol-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-phenylisoxazol-3-vl)pvridin-2-amine; 44% | 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 2.4 Hz, 1H), 7.90-7.85 (m, 3H), 7.75 (s, 1H), 7.66 (s, 1H), 7.55-7.48 (m, 3H), 6.93 (s, 1H), 6.32-6.24 (br s, 2H),), 4.37-4.16 (m, 3H), 3.00-2.82 (m, 2H), 2.22-2.10 (m, 2H), 2.10-1.88 (m, 2H), 1.50 (s, 9H). |
13.11 | tert-butyl 4-(4-(6-amino-5-(5-phenylfuran-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and 5-bromo-3-(5-phenylfuran-2-yl)pyridin-2-amine; 64% | 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 2.4 Hz, 1H), 7.86 (d, J= 2.4 Hz, 1H), 7.76-7.68 (m, 3H), 7.64 (s, 1H), 7.45-7.39 (m, 2H), 7.33-7.28 (m, 1H), 6.82-6.77 (m, 2H), 5.22 (br s, 2H), 4.36-4.20 (m, 3H), 2.95-2.70 (m, 2H), 2.22-2.15 (m, 2H), 2.05-1.92 (m, 2H), 1.48 (s, 9H). |
13.12 | 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine | 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-3-(5-phenylfuran-2-yl)pyridin-2-amine; 24% | 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.73 (s, 1H), 7.72-7.68 (m, 2H), 7.64 (s, 1H), 7.45-7.40 (m, 2H), 7.33-7.28 (m, 1H), 6.80 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 5.23 (br s, 2H), 4.20-4.10 (m, 1H), 2.26-2.18 (m, 2H), 1.97-1.89 (m, 2H), 1.84-1.72 (m, 2H), 1.52-1.39 (m, 2H), 1.35-1.20 (m, 2H). MS (ES+): m/z 385.3 (M + 1), 407.3 (M + Na). |
13.13 | 5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine | 5-bromo-3-(5-phenylfuran-2-yl)pyridin-2-amine and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole; 29% | 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H), 7.74-7.71 (m, 1H), 7.71-7.69 (m, 1H), 7.66 (s, 1H), 7.45-7.40 (m, 2H), 7.33-7.28 (m, 1H), 6.80 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 5.22 (br s, 2H), 4.44-4.35 (m, 1H), 4.18-4.10 (m, 2H), 3.61-3.53 (m, 2H), 2.20-2.08 (m, 4H). MS (ES+): m/z 387.4 (M + 1). |
13.14 | tert-butyl 4-(4-(6-amino-5-(5-(pyridin-3-yl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | 5-bromo-3-(5-(pyridin-3-yl)oxazol-2-yl)pyridin-2-amine and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 59% | 1H NMR (400 MHz, CDCl3): δ 9.04-9.01 (m, 1H), 8.64-8.60 (m, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.05-7.99 (m, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 7.57 (s, 1H), 7.46-7.40 (m, 1H), 6.72 (br s, 2H), 4.40-4.20 (m, 3H), 3.00-2.85 (m, 2H), 2.24-2.17 (m, 2H), 2.05-1.94 (m, 2H), 1.49 (s, 9H). |
EXAMPLE 14
SYNTHESIS OF 3-(5-PHENYLOXAZOL-2-YL)-5-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE
Ex. No. | Chemical Name | Starting Material and Yield | Characterization Data |
14.1 | 3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 53% | 1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.24 (s, 1H), 7.97-7.90 (m, 4H), 7.58-7.54 (m, 2H), 7.34 (br s, 2H), 4.24-4.14 (m, 1H), 3.10-3.00 (m, 2H), 2.66-2.55 (m, 2H), 2.02-1.93 (m, 2H), 1.88-1.74 (m, 2H); MS (ES+): m/z 421.3 (M + 1). |
14.2 | 3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 98% | 1H NMR (400 MHz, DMSO-d6): δ9.32 (br s, 1H), 9.10 (br s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 8.14 (s, 1H), 8.13 (s, 1H), 8.11-8.09 (m, 1H), 7.99-7.95 (m, 1H), 7.57-7.52 (m, 1H), 7.49-7.45 (m, 1H), 4.57-4.48 (m, 1H), 3.42-3.33 (m, 2H), 3.14-3.02 (m, 2H), 2.28-2.15 (m, 4H); MS (ES+): m/z 421.3 and 423.3 (M + 1). |
14.3 | 3-(5-phenylisoxazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-phenylisoxazol-3-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 31% | 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 2.4 Hz, 1H), 7.90-7.85 (m, 3H), 7.75 (s, 1H), 7.67 (s, 1H), 7.55-7.47 (m, 3H), 6.95 (s, 1H), 6.35-6.20 (br s, 2H), 4.32-4.23 (m, 1H), 3.31-3.24 (m, 2H), 2.85-2.75 (m, 2H), 2.26-2.18 (m, 2H), 2.02-1.90 (m, 2H). MS (ES+): m/z 387.4 (M + 1). |
14.4 | 3-(5-phenylfuran-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-phenylfuran-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 65% | 1H NMR (400 MHz, CD3OD): δ 8.13 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.72-7.66 (m, 4H), 7.43-7.37 (m, 2H), 7.31-7.25 (m, 1H), 6.78 (d, J = 3.6 Hz, 1H), 6.76 (d, J = 3.6 Hz, 1H), 4.30-4.20 (m, 1H), 3.28-3.20 (m, 2H), 2.82-2.74 (m, 2H), 2.23-2.15 (m, 2H), 2.00-1.88 (m, 2H). MS (ES+): m/z 386.4 (M + 1). |
14.5 | 5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)oxazol-2-yl)pyridin-2-amine | tert-butyl 4-(4-(6-amino-5-(5-(pyridin-3-yl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate; 69% | 1H NMR (400 MHz, DMSO-d6): δ 9.41-9.37 (m, 1H), 9.27-9.18 (m, 1H), 9.10-8.98 (m, 1H), 8.95 (d, J = 2.4 Hz, 1H), 8.73-8.68 (m, 1H), 8.65-8.61 (m, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.49 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.79-7.73 (m, 1H), 4.57-4.48 (m, 1H), 3.43-3.33 (m, 2H), 3.14-3.02 (m, 2H), 2.28-2.12 (m, 4H); MS (ES+): m/z 388.2 (M + 1). |
EXAMPLE 15
SYNTHESIS OF 1-(4-(4-(6-AMINO-5-(5-(4-CHLOROPHENYL)OXAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)ETHANONE
EXAMPLE 15.1
SYNTHESIS OF 1-(4-(4-(6-AMINO-5-(5-(3-CHLOROPHENYL)OXAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)ETHANONE
EXAMPLE 16
SYNTHESIS OF (4-(4-(6-AMINO-5-(5-(4-CHLOROPHENYL)OXAZOL-2-YL)PYRIDIN-3-YL)-1H-PYRAZOL-1-YL)PIPERIDIN-1-YL)(CYCLOPROPYL)METHANONE
Ex. No. | Chemical Name | Starting Material and Yield | Characterization Data |
16.1 | (4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl) methanone | 3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and cyclopropane-carbonyl chloride; 36% | 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.73-7.71 (m, 1H), 7.68 (s, 1H), 7.63-7.59 (m, 1H), 7.49 (s, 1H), 7.43-7.39 (m, 1H), 7.36-7.32 (m, 1H), 6.67 (br s, 2H), 4.85-4.70 (m, 1H), 4.50-4.35 (m, 2H), 3.40-3.25 (m, 1H), 2.90-2.75 (m, 1H), 2.37-2.17 (m, 2H), 2.17-1.95 (m, 2H), 1.84-1.78 (m, 1H), 1.05-0.98 (m, 2H), 0.82-0.76 (m, 2H); MS (ES+): m/z 489.3 and 491.3 (M + 1). |
16.2 | (4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone | 3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and benzoyl chloride; 30% | 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.80 (s, 1H), 7.74-7.72 (m, 1H), 7.70 (s, 1H), 7.64-7.60 (m, 1H), 7.50 (s, 1H), 7.48-7.44 (m, 5H), 7.43-7.40 (m, 1H), 7.37-7.33 (m, 1H), 6.69 (br s, 2H), 5.00-4.80 (m, 1H), 4.50-4.41 (m, 1H), 4.08-3.93 (m, 1H), 3.25-3.00 (m, 2H), 2.38-2.20 (m, 2H), 2.20-2.00 (m, 2H); MS (ES+): m/z 525.3 and 527.3 (M + 1). |
16.3 | 1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone | 3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and phenylacetyl chloride; 37% | 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.73-7.71 (m, 1H), 7.63-7.59 (m, 2H), 7.50 (s, 1H), 7.46-7.39 (m, 1H), 7.38-7.33 (m, 3H), 7.31-7.26 (m, 3H), 6.70 (br s, 2H), 4.85-4.76 (m, 1H), 4.42-4.32 (m, 1H), 4.10-4.01 (m, 1H), 3.80 (s, 2H), 3.24-3.15 (m, 1H), 2.88-2.78 (m, 1H), 2.37-2.20 (m, 1H), 2.18-2.08 (m, 1H), 2.05-1.92 (m, 1H), 1.81-1.68 (m, 1H); MS (ES+): m/z 539.3 and 541.3 (M + 1). |
16.4 | (4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone | benzoyl chloride and 3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; 54% | 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.69-7.65 (m, 3H), 7.48-7.42 (m, 8H), 6.69 (br s, 2H), 4.95-4.80 (m, 1H), 4.50-4.41 (m, 1H), 4.08-3.93 (m, 1H), 3.25-3.00 (m, 2H), 2.38-2.20 (m, 2H), 2.20-2.00 (m, 2H); MS (ES+): m/z 525.3 and 527.3 (M+1). |
16.5 | 1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone | phenylacetyl chloride and 3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; 36% | 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H), 7.69-7.64 (m, 2H), 7.58 (s, 1H), 7.48-7.42 (m, 3H), 7.38-7.32 (m, 2H), 7.31-7.25 (m, 3H), 6.68 (br s, 2H), 4.85-4.76 (m, 1H), 4.41-4.32 (m, 1H), 4.10-4.01 (m, 1H), 3.80 (s, 2H), 3.24-3.13 (m, 1H), 2.89-2.78 (m, 1H), 2.28-2.19 (m, 1H), 2.17-2.08 (m, 1H), 2.04-1.92 (m, 1H), 1.79-1.68 (m, 1H); MS (ES+): m/z 539.3 and 541.3 (M + 1). |
16.6 | 1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropan-1-one | pivaloyl chloride and 3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; 10% | 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.74-7.72 (m, 1H), 7.69 (s, 1H), 7.64-7.60 (m, 1H), 7.50 (s, 1H), 7.44-7.40 (m, 1H), 7.37-7.33 (m, 1H), 6.67 (br s, 2H), 4.65-4.55 (m, 2H), 4.48-4.35 (m, 1H), 3.08-2.95 (m, 2H), 2.30-2.23 (m, 2H), 2.10-1.97 (m, 2H), 1.33 (s, 9H); MS (ES+): m/z 505.5 and 507.5 (M + 1). |
16.7 | (4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(4-fluorophenyl)methanone | 4-fluorobenzoyl chloride and 3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine; 12% | 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.80 (s, 1H), 7.74-7.72 (m, 1H), 7.70 (s, 1H), 7.64-7.60 (m, 1H), 7.51-7.46 (m, 3H), 7.44-7.39 (m, 1H), 7.37-7.33 (m, 1H), 7.16-7.09 (m, 2H), 6.70 (br s, 2H), 4.48-4.35 (m, 2H), 4.51-4.42 (m, 1H), 3.22-3.04 (m, 2H), 2.34-2.20 (m, 2H), 2.19-2.05 (m, 2H); MS (ES+): m/z 543.3 and 545.3 (M + 1). |
EXAMPLE 17
SYNTHESIS OF 3-(5-(3-CHLOROPHENYL)OXAZOL-2-YL)-5-(1-(1-METHYLPIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE
Ex. No. | Chemical Name | Starting Material and Yield | Characterization Data |
17.1 | 3-(5-(4-Chlorophenyl)-oxazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | 3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and formaldehyde; 75% | 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.70-7.66 (m, 3H), 7.48-7.44 (m, 3H), 6.63 (br s, 2H), 4.24-4.15 (m, 1H), 3.06-2.99 (m, 2H), 2.36 (s, 3H), 2.26-2.09 (m, 6H); (ES+): m/z 435.4 and 437.4 (M + 1). |
17.2 | 5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine | 3-(5-phenyloxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and acetaldehyde; 13% | 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 7.78-7.73 (m, 3H), 7.70 (s, 1H), 7.51-7.45 (m, 3H), 7.41-7.35 (m, 1H), 6.66 (br s, 2H), 4.27-4.18 (m, 1H), 3.17-3.10 (m, 2H), 2.50 (q, J = 7.2 Hz, 2H), 2.30-2.23 (m, 2H), 2.18-2.08 (m, 4H), 1.15 (t, J = 7.2 Hz, 3H); MS (ES+): m/z 415.4 (M + 1). |
17.3 | 5-(1-(1-dodecylpiperidin -4-yl)-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine | 3-(5-phenyloxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and dodecyl aldehyde; 23% | 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 7.77-7.72 (m, 3H), 7.69 (s, 1H), 7.51-7.45 (m, 3H), 7.40-7.35 (m, 1H), 6.65 (br s, 2H), 4.25-4.15 (m, 1H), 3.13-3.06 (m, 2H), 2.43-2.35 (m, 2H), 2.25-2.18 (m, 2H), 2.16-2.06 (m, 4H), 1.57-1.47 (m, 2H), 1.35-1.24 (m, 18H), 0.89 (t, J = 6.8 Hz, 3H); MS (ES+): m/z 555.5 (M + 1). |
17.4 | 5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-phenylisoxazol-3-yl)pyridin-2-amine | 3-(5-phenylisoxazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and formaldehyde; 61% | 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 2.4 Hz, 1H), 7.88-7.83 (m, 3H), 7.74 (s, 1H), 7.66 (s, 1H), 7.54-7.44 (m, 3H), 6.94 (s, 1H), 6.32-6.22 (br s, 2H), 4.23-4.13 (m, 1H), 3.07-2.98 (m, 2H), 2.37 (s, 3H), 2.28-2.06 (m, 6H); MS (ES+): m/z 401.4 (M + 1). |
17.5 | 5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine | 3-(5-phenylfuran-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and formaldehyde; 30% | 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.76-7.70 (m, 3H), 7.66 (s, 1H), 7.46-7.41 (m, 2H), 7.33-7.29 (m, 1H), 6.81 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 5.20 (s, 2H), 4.25-4.16 (m, 1H), 3.10-3.00 (m, 2H), 2.25 (s, 3H), 2.32-2.10 (m, 6H); MS (ES+): m/z 400.4 (M + 1). |
BIOLOGICAL EXAMPLES
EXAMPLE 18
KINASE ENZYMATIC ACTIVITY ASSAYS
Preparation of active recombinant kinase proteins:
Preparation of assay reagents:
Assay procedure:
Chemical Name | IC50 (nM) | ||
Tyro3 | Axl | Mer | |
tert-butyl 4-(4-(6-amino-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | ++ | ++ |
tert-butyl 4-(4-(6-amino-5-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | +++ | +++ + |
tert-butyl 4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | +++ | ND |
tert-butyl 4-(4-(6-amino-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | ++ | ++ |
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ |
3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | + | ++ | + |
3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | ++ |
3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ |
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine | + | + | + |
3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | + | + | + |
tert-butyl 4-(4-(6-amino-5-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | +++ + | ++ |
tert-butyl 4-(4-(6-amino-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | +++ | ++ |
tert-butyl 4-(4-(6-amino-5-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | +++ + | ++ |
tert-butyl 4-(4-(6-amino-5-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | +++ + | +++ |
tert-butyl 4-(4-(6-amino-5-(5-benzyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | +++ + | ++ |
tert-butyl 4-(4-(6-amino-5-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | +++ | ++ |
tert-butyl 4-(4-(6-amino-5-(5-(4-(trifluoromethyl)-thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | +++ + | + |
3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | ++ |
3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine | ++ | +++ | ++ |
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine | ++ | ++ | + |
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine | ++ | ++ | + |
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | ++ | ++ |
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine | ++++ | ++ | ++ |
3-(5-(2,6-dichloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | ND |
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | ND |
3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(pipcridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine | ++++ | +++ + | +++ |
3-(5-benzyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(thiazol-2-yl-1,3,4-oxadiazol-2-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(4-(trifluoromethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrrol-3-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone | ++++ | +++ + | +++ + |
1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone | ++++ | +++ + | +++ + |
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine | ++++ | +++ + | +++ |
5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | ++ | +++ + |
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | +++ | ++ | ++ |
1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-methylpentan-1-one | +++ | +++ + | +++ + |
(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone | ++ | ++ | ++ |
(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone | ++++ | +++ + | ++ |
(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone | ++++ | +++ + | +++ + |
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine | + | + | + |
3-(5-(2,5-dichlorophenyl)-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ |
3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | +++ | +++ + | ++ |
3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone | ++ | ++ | ++ |
(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone | ++ | ++ | ++ |
1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone | ++ | +++ | ++ |
3-(5-phenyloxazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | + |
tert-butyl 4-(4-(6-amino-5-(5-phenyloxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | +++ | +++ + | ++ |
3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | + | + | + |
tert-butyl 4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | ++ | +++ | ++ |
3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine | ++ | ++ | ++ |
3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine | + | + | + |
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine | ++ | ++ | + |
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine | ++ | ++ | ++ |
3-(5-phenylisoxazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | ++ |
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine | ++ | ++ | ++ |
3-(5-phenylfuran-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++ | ++ | ++ |
3-(5-phenyloxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-phenylisoxazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-phenylfuran-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ |
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)oxazol-2-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone | + | + | + |
1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone | ++++ | +++ + | +++ + |
(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone | ++++ | +++ + | + |
(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone | +++ | +++ + | ++ |
(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone | ++++ | +++ + | ++ |
1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone | ++++ | +++ + | ++ |
(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone | ++++ | +++ + | ++ |
1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone | ++++ | +++ + | ++ |
1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropan-1-one | ++++ | +++ + | ++ |
(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(4-fluorophenyl)methanone | ++++ | +++ + | ++ |
3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine | ++++ | +++ + | +++ |
5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine | ++++ | +++ + | +++ + |
5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine | ++++ | +++ + | ++ |
EXAMPLE 19
CELL VIABILITY ASSAY
EXAMPLE 20
THYMIDINE INCORPORATION ASSAY
EXAMPLE 21
COLONY FORMATION ASSAY (METHOD #1)
EXAMPLE 22
COLONY FORMATION ASSAY (METHOD #2)
EXAMPLE 23
WESTERN BLOT ASSAY
W is
each A, A1 and A2 is the same or different and independently -N=, -CR5=, or -O-;
L is a heterocyclyl, -N(R6)-, -O-, -C(O)-, -C(O)O-, -S(O)t- where t is 0, 1, or 2, - CON(R6)-, -N(R6)CO-, -SO2N(R6)-, -N(R6)CON(R6)- or heteroaryl selected from the group consisting of azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, isoindolyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl;
R1 is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
R2 is hydrogen, heterocyclyl, heterocyclylalkyl, cycloalkyl, alkyl, aralkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl;
each R3 and R4 is the same or different and independently selected from hydrogen, alkyl, aralkyl, alkenyl, aralkenyl, alkynyl, aralkynyl, cycloalkyl, cycloalkylalkyl, halo, or haloalkyl;
R5, at each occurrence, is hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, halo, or haloalkyl; and
R6 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, or haloalkyl,
a stereoisomer, enantiomer or tautomer thereof, an isotopically enriched derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof, wherein the prodrug is acetate, formate, benzoate, or phosphate derivatives of alcohol or amine functional groups in the compounds defined herein.
each A, A1 and A2 is the same or different and independently -N=, -CR5=, or -O-;
each R3, R4 and R5 is independently hydrogen or alkyl;
L is heteroaryl or heterocycle;
R7 is hydrogen, alkyl, alkoxy, or halo;
X is -O-, -NR8-, or -C(R9)2-;
R8 is hydrogen, alkyl, or -C(O)R10-;
each R9 is independently hydrogen, alkyl, alkoxy, or halo; and
R10 is alkyl, cycloalkyl, aryl, alkoxy, or aralkyl.
each A, A1 and A2 is the same or different and independently -N=, -CR5=, or -O-;
R1 is aryl, heteroaryl, cycloalkyl, heterocyclyl, aralkyl, or cycloalkylalkyl;
each of R3, R4 and R7 is hydrogen,
R8 is hydrogen, alkyl, or -C(O)R10-; and
R10 is alkyl, cycloalkyl, aryl, alkoxy, or aralkyl.
each A, A1 and A2 is the same or different and independently -N=, -CR5=, or -O-;
R1 is aryl, heteroaryl, cycloalkyl, or heterocyclyl; and
each of R3, R4 and R7 is hydrogen.
tert-butyl-4-(4-(6-amino-5-(5-phenyloxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
3-(5-phenyloxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;
(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;
3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;
3-(5-(3-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;
(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-y1)(phenyl)methanone;
1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;
(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-y1)(phenyl)methanone;
1-(4-(4-(6-amino-5-(5-(4-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;
3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
1-(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropan-1-one;
(4-(4-(6-amino-5-(5-(3-chlorophenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(4-fluorophenyl)methanone;
5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine;
3-(5-phenyloxazol-2-yl)-5-(1-(tetrahydro-2pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-(tetrahydro-2pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(3-chlorophenyl)oxazol-2-y1)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(4-chlorophenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine;
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amine;
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)oxazol-2-yl)pyridin-2-amine;
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine;
3-(5-phenylisoxazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-phenylisoxazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amine;
3-(5-phenylfuran-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine;
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylfuran-2-yl)pyridin-2-amine;
3-(5-phenylfuran-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(2,6-dichloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1 -carboxylate;
3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-methylpentan-1 -one;
(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;
(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanone;
1-(4-(4-(6-amino-5-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
tert-butyl 4-(4-(6-amino-5-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
tert-butyl 4-(4-(6-amino-5-(5-(4-(trifluoromethyl)-thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(4-(trifluoromethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1 -carboxylate;
3-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
tert-butyl 4-(4-(6-amino-5-(5-benzyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;
3-(5-benzyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(2,5-difluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine;
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone;
(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanone;
5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine;
(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-y1)(phenyl)methanone;
1-(4-(4-(6-amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanone;
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine;
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amine;
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine;
3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine;
5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
3-(5-(2,5-dichlorophenyl)-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine; or
3-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrrol-3-yl)pyridin-2-amine.
W
ist,
A, A1 und A2 jeweils gleich oder verschieden und unabhängig voneinander -N=, -CR5= oder -O- ist;
L ein Heterocyclyl, -N(R6)-, -O-, -C(O)-, -C(O)O-, -S(O)t-, wobei t 0, 1 oder 2 ist, -CON(R6)-, -N(R6)CO-, -SO2N(R6)-, -N(R6)CON(R6)- oder Heteroaryl, ausgewählt aus der Gruppe bestehend aus Azepinyl, Acridinyl, Benzimidazolyl, Benzthiazolyl, Benzindolyl, Benzothiadiazolyl, Benzonaphthofuranyl, Benzoxazolyl, Benzodioxolyl, Benzodioxinyl, Benzopyranyl, Benzopyranonyl, Benzofuranyl, Benzofuranonyl, Benzothienyl (Benzothiophenyl), Benzotriazolyl, Benzo[4,6]imidazo[1,2-a]pyridinyl, Carbazolyl, Cinnolinyl, Dibenzofuranyl, Furanyl, Furanonyl, Isothiazolyl, Imidazolyl, Indazolyl, Isoindolyl, Isoindolinyl, Indolizinyl, Isoxazolyl, Naphthyridinyl, Oxadiazolyl, 2-Oxoazepinyl, Oxazolyl, Oxiranyl, Phenazinyl, Phenothiazinyl, Phenoxazinyl, Phthalazinyl, Pteridinyl, Purinyl, Pyrrolyl, Pyrazolyl, Pyrimidinyl, Pyridazinyl, Chinazolinyl, Chinoxalinyl, Chinolinyl, Chinuclidinyl, Isochinolinyl, Thiazolyl, Thiadiazolyl, Triazolyl, Tetrazolyl, Triazinyl und Thiophenyl, ist;
R1 Alkyl, Cycloalkyl, Cycloalkylalkyl, Halogenalkyl, Aryl, Aralkyl, Heterocyclyl, Heterocyclylalkyl, Heteroaryl oder Heteroarylalkyl ist;
R2 Wasserstoff, Heterocyclyl, Heterocyclylalkyl, Cycloalkyl, Alkyl, Aralkyl, Cycloalkylalkyl, Heteroaryl, Heteroarylalkyl oder Aryl ist;
R3 und R4 jeweils gleich oder verschieden und unabhängig voneinander ausgewählt ist aus Wasserstoff, Alkyl, Aralkyl, Alkenyl, Aralkenyl, Alkinyl, Aralkinyl, Cycloalkyl, Cycloalkylalkyl, Halogen oder Halogenalkyl;
R5 bei jedem Vorkommen Wasserstoff, Alkyl, Aralkyl, Cycloalkyl, Cycloalkylalkyl, Halogen oder Halogenalkyl ist; und
R6 Wasserstoff, Alkyl, Cycloalkyl, Cycloalkylalkyl oder Halogenalkyl,
ein Stereoisomer, Enantiomer oder Tautomer davon, ein isotopisch angereichertes Derivat davon, ein pharmazeutisch akzeptables Salz davon, eine pharmazeutische Zusammensetzung davon oder eine Prodrug davon ist, wobei die Prodrug Acetat-, Formiat-, Benzoat- oder Phosphatderivate von funktionellen Alkohol- oder Aminogruppen in den hierin definierten Verbindungen ist.
A, A1 und A2 jeweils gleich oder verschieden und unabhängig voneinander -N=, -CR5= oder -O- ist;
R3, R4 und R5 jeweils unabhängig voneinander Wasserstoff oder Alkyl ist;
L Heteroaryl oder Heterocyclyl ist;
R7 Wasserstoff, Alkyl, Alkoxy oder Halogen ist;
X -O-, -NR8- oder -C(R9)2- ist;
R8 Wasserstoff, Alkyl oder -C(O)R10- ist;
jedes R9 unabhängig voneinander Wasserstoff, Alkyl, Alkoxy oder Halogen ist; und
R10 Alkyl, Cycloalkyl, Aryl, Alkoxy oder Aralkyl ist.
A, A1 und A2 jeweils gleich oder verschieden und unabhängig voneinander -N=, -CR5= oder -O- ist;
R1 Aryl, Heteroaryl, Cycloalkyl, Heterocyclyl, Aralkyl oder Cycloalkylalkyl ist;
R3, R4 und R7 jeweils Wasserstoff ist,
R8 Wasserstoff, Alkyl oder -C(O)R10- ist; und
R10 Alkyl, Cycloalkyl, Aryl, Alkoxy oder Aralkyl ist.
A, A1 und A2 jeweils gleich oder verschieden und unabhängig voneinander -N=, -CR5= oder -O- ist;
R1 Aryl, Heteroaryl, Cycloalkyl oder Heterocyclyl ist; und
R3, R4 und R7 jeweils Wasserstoff ist.
tert-Butyl-4-(4-(6-amino-5-(5-phenyloxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
3-(5-Phenyloxazol-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
tert-Butyl 4-(4-(6-amino-5-(5-(4-chlorphenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
3-(5-4-Chlorphenyl)oxazol-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
1-(4-(4-(6-Amino-5-(5-(4-Chlorphenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanon;
(4-(4-(6-Amino-5-(5-(4-Chlorphenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanon;
3-(5-(3-Chlorphenyl)oxazol-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
1-(4-(4-(6-Amino-5-(5-(3-Chlorphenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanon;
3-(5-(3-Chlorphenyl)oxazol-2-yl)-5-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
(4-(4-(6-Amino-5-(5-(3-Chlorphenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanon;
(4-(4-(6-Amino-5-(5-(3-Chlorphenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanon;
1-(4-(4-(6-Amino-5-(5-(3-Chlorphenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanon;
(4-(4-(6-Amino-5-(5-(4-Chlorphenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanon;
1-(4-(4-(6-Amino-5-(5-(4-Chlorphenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanon;
3-(5-(4-(Chlorphenyl)oxazol-2-yl)-5-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
1-(4-(4-(6-Amino-5-(5-(3-Chlorphenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropan-1-on;
(4-(4-(6-Amino-5-(5-(3-Chlorphenyl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(4-fluorphenyl)methanon;
5-(1-(1-Ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amin;
3-(5-Phenyloxazol-2-yl)-5-(1-(Tetrahydro-2-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-(4-(Chlorphenyl)oxazol-2-yl)-5-(1-(Tetrahydro-2-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-(3-Chlorphenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-(4-(Chlorphenyl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amin;
5-(1-Cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyloxazol-2-yl)pyridin-2-amin;
5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(Pyridin-3-yl)oxazol-2-yl)pyridin-2-amin;
5-(1-Cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenylisoxazol-3-yl)pyridin-2-amin;
3-(5-Phenylisoxazol-3-yl)-5-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-Phenylisoxazol-3-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
5-(1-(1 -Methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-Phenylisoxazol-3-yl)pyridin-2-amin;
3-(5-Phenylfuran-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
5-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-Phenylfuran-2-yl)pyridin-2-amin;
5-(1-Cyclohexyl-1H-pyrazol-4-yl)-3-(5-Phenylfuran-2-yl)pyridin-2-amin;
3-(5-Phenylfuran-2-yl)-5-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
tert-Butyl 4-(4-(6-amino-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
3-(5-Phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-(2,6-Dichlor-3-fluorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-(4-(tert.-Butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
tert-Butyl 4-(4-(6-amino-5-(5-(4-(tert-Butyl)phenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
3-(5-(2,5-Difluorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-(2,6-Dichlorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
tert-Butyl 4-(4-(6-amino-5-(5-(2,6-dichlorphenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
3-(5-(4-Fluorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
tert-Butyl 4-(4-(6-amino-5-(5-(4-fluorphenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
1-(4-(4-(6-Amino-5-(5-(2,6-dichlorphenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanon;
3-(5-(2,6-Dichlorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
1-(4-(4-(6-Amino-5-(5-(2,6-dichlorphenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-4-methylpentan-1-on;
(4-(4-(6-Amino-5-(5-(2,6-dichlorphenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanon;
(4-(4-(6-Amino-5-(5-(2,6-dichlorphenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanon;
1-(4-(4-(6-Amino-5-(5-(2,6-dichlorphenyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanon;
3-(5-(2,6-Dichlorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-Ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-(2,6-Dichlorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-Dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
tert-Butyl 4-(4-(6-amino-5-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
tert-Butyl 4-(4-(6-amino-5-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(Pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amin;
5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(Pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amin;
tert.-Butyl 4-(4-(4-(6-amino-5-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(Thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amin;
5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(Pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amin;
tert-Butyl 4-(4-(4-(6-amino-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
tert-Butyl 4-(4-(6-amino-5-(5-(4-(trifluormethyl)-thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-(4-(Trifluormethyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amin;
tert-Butyl 4-(4-(6-amino-5-(5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
3-(5-(Cyclopropylmethyl)-1,3,4-oxadiazol-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
tert-Butyl 4-(4-(4-(6-amino-5-(5-benzyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylat;
3-(5-Benzyl-1,3,4-oxadiazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-(2,6-Dichlorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-Phenyl-1,3,4-oxadiazol-2-yl)-5-(1H-Pyrazol-4-yl)pyridin-2-amin;
3-(5-(4-(tert.-Butyl)phenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-Pyrazol-4-yl)pyridin-2-amin;
3-(5-(2,5-Difluorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-Pyrazol-4-yl)pyridin-2-amin;
3-(5-(4-Fluorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amin;
5-(1-Cyclohexyl-1H-pyrazol-4-yl)-3-(5-(2,6-dichlorphenyl)-1,3,4-oxadiazol-2-yl)pyridin-2-amin;
5-(1-Cyclohexyl-1H-pyrazol-4-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-pyridin-2-amin;
3-(5-(2,6-Dichlorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-Phenyl-1,3,4-oxadiazol-2-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(3-Phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
1-(4-(4-(6-Amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanon;
(4-(4-(6-Amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(cyclopropyl)methanon;
5-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-Phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amin;
(4-(4-(6-Amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(phenyl)methanon;
1-(4-(4-(6-Amino-5-(3-phenyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-phenylethanon;
3-(3-(2,6-Dichlorphenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(3-(2,6-Dichlorphenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(3-(2,6-Dichlorphenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-Ethylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
5-(1-(1-Ethylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(3-Phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amin;
3-(3-(2,6-Dichlorphenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-Dodecylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
5-(1-Cyclohexyl-1H-pyrazol-4-yl)-3-(3-Phenyl-1,2,4-oxadiazol-5-yl)pyridin-2-amin;
5-(1-Cyclohexyl-1H-pyrazol-4-yl)-3-(3-(2,6-dichlorphenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-amin;
3-(3-Phenyl-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(3-(2,6-Dichlorphenyl)-1,2,4-oxadiazol-5-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(3-Phenyl-1,2,4-oxadiazol-5-yl)-5-(1H-pyrazol-4-yl)-pyridin-2-amin;
5-(1-Cyclohexyl-1H-pyrazol-4-yl)-3-(5-Phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amin;
3-(5-Phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-Phenyl-1,2,4-oxadiazol-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
5-(1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3-(5-Phenyl-1,2,4-oxadiazol-3-yl)pyridin-2-amin;
3-(5-(2,5-Dichlorphenyl)-1,2,4-oxadiazol-3-yl)-5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amin;
3-(5-Phenyl-1,2,4-oxadiazol-3-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amin; oder
3-(5-(2,6-Dichlorphenyl)-1,3,4-oxadiazol-2-yl)-5-(1-(Piperidin-4-yl)-1H-pyrrol-3-yl)pyridin-2-amin.
W est un groupe
les groupes A, A1 et A2 sont identiques ou différents et représentent chacun indépendamment -N=, -CR5=, ou -O- ;
L est un groupe hétérocyclyle, -N(R6)-, -O-, -C(O)-, -C(O)O-, -S(O)t- où t vaut 0, 1, ou 2, -CON(R6)-, -N(R6)CO-, -SO2N(R6)-, -N(R6)CON(R6)- ou un groupe hétéroaryle choisi dans l'ensemble constitué par les groupes azépinyle, acridinyle, benzimidazolyle, benzothiazolyle, benzo-indolyle, benzothiadiazolyle, benzonaphtofuranyle, benzoxazolyle, benzodioxolyle, benzodioxinyle, benzopyranyle, benzopyranonyle, benzofuranyle, benzofuranonyle, benzothiényle (benzothiophényle), benzotriazolyle, benzo[4,6]imidazo[l,2-a]pyridinyle, carbazolyle, cinnolinyle, dibenzofuranyle, furanyle, furanonyle, isothiazolyle, imidazolyle, indazolyle, iso-indolyle, iso-indolinyle, indolizinyle, isoxazolyle, naphtyridinyle, oxadiazolyle, 2-oxo-azépinyle, oxazolyle, oxiranyle, phénazinyle, phénothiazinyle, phénoxazinyle, phthalazinyle, ptéridinyle, purinyle, pyrrolyle, pyrazolyle, pyrimidinyle, pyridazinyle, quinazolinyle, quinoxalinyle, quinolinyle, quinuclidinyle, isoquinolinyle, thiazolyle, thiadiazolyle, triazolyle, tétrazolyle, triazinyle, et thiophényle ;
R1 est un groupe alkyle, cycloalkyle, cycloalkylalkyle, halogénoalkyle, aryle, aralkyle, hétérocyclyle, hétérocyclylalkyle, hétéroaryle, ou hétéroarylalkyle ;
R2 est un atome d'hydrogène, un groupe hétérocyclyle, hétérocyclylalkyle, cycloalkyle, alkyle, aralkyle, cycloalkylalkyle, hétéroaryle, hétéroarylalkyle, ou aryle ;
R3 et R4 sont identiques ou différents et sont choisis chacun indépendamment parmi un atome d'hydrogène, un groupe alkyle, aralkyle, alcényle, aralcényle, alcynyle, aralcynyle, cycloalkyle, cycloalkylalkyle, halogéno, ou halogénoalkyle ;
R5, à chaque occurrence, est un atome d'hydrogène, un groupe alkyle, aralkyle, cycloalkyle, cycloalkylalkyle, halogéno, ou halogénoalkyle ; et
R6 est un atome d'hydrogène, un groupe alkyle, cycloalkyle, cycloalkylalkyle, ou halogénoalkyle,
stéréoisomère, énantiomère ou tautomère d'un tel composé, ou dérivé à enrichissement isotopique d'un tel composé, sel pharmaceutiquement acceptable d'un tel composé, composition pharmaceutique d'un tel composé ou précurseur d'un tel composé, le précurseur consistant en des dérivés acétate, formiate, benzoate, ou phosphate de groupes fonctionnels alcool ou amino dans les composés définis ici.
les groupes A, A1 et A2 sont identiques ou différents et représentent chacun indépendamment -N=, -CR5=, ou -O- ;
les groupes R3, R4 et R5 représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle ;
L est un groupe hétéroaryle ou un hétérocycle ;
R7 est un atome d'hydrogène ou d'halogène ou un groupe alkyle ou alcoxy ; X est -O-, -NR8-, ou -C(R9)2- ;
R8 est un atome d'hydrogène, un groupe alkyle ou -C(O)R10- ;
chaque groupe R9 est indépendamment un atome d'hydrogène ou d'halogène, un groupe alkyle ou alcoxy ; et
R10 est un groupe alkyle, cycloalkyle, aryle, alcoxy, ou aralkyle.
les groupes A, A1 et A2 sont identiques ou différents et représentent chacun indépendamment -N=, -CR5=, ou -O- ;
R1 est un groupe aryle, hétéroaryle, cycloalkyle, hétérocyclyle, aralkyle, ou cycloalkylalkyle ;
les groupes R3, R4 et R7 représentent chacun un atome d'hydrogène
R8 est un atome d'hydrogène, un groupe alkyle ou -C(O)R10- ; et
R10 est un groupe alkyle, cycloalkyle, aryle, alcoxy, ou aralkyle.
les groupes A, A1 et A2 sont identiques ou différents et représentent chacun indépendamment -N=, -CR5=, ou -O- ;
R1 est un groupe aryle, hétéroaryle, cycloalkyle, ou hétérocyclyle ; et
les groupes R3, R4 et R7 représentent chacun un atome d'hydrogène.
le 4-(4-(6-amino-5-(5-phényloxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)-pipéridine-1-carboxylate de tert-butyle ;
la 3-(5-phényloxazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
le 4-(4-(6-amino-5-(5-(4-chlorophényl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
la 3-(5-(4-chlorophényl)oxazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-pyridin-2-amine ;
la 1-(4-(4-(6-amino-5-(5-(4-chlorophényl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)éthanone ;
la (4-(4-(6-amino-5-(5-(4-chlorophényl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)(cyclopropyl)méthanone ;
la 3-(5-(3-chlorophényl)oxazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-pyridin-2-amine ;
la 1-(4-(4-(6-amino-5-(5-(3-chlorophényl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)éthanone ;
la 3-(5-(3-chlorophényl)oxazol-2-yl)-5-(1-(1-méthylpipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la (4-(4-(6-amino-5-(5-(3-chlorophényl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéiidin-1-yl)(cyclopropyl)méthanone ;
la (4-(4-(6-amino-5-(5-(3-chlorophényl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)(phényl)méthanone ;
la 1-(4-(4-(6-amino-5-(5-(3-chlorophényl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)-2-phényléthanone ;
la (4-(4-(6-amino-5-(5-(4-chlorophényl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)(phényl)méthanone ;
la 1-(4-(4-(6-amino-5-(5-(4-chlorophényl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)-2-phényléthanone ;
la 3-(5-(4-chlorophényl)oxazol-2-yl)-5-(1-(1-méthylpipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 1-(4-(4-(6-amino-5-(5-(3-chlorophényl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)-2,2-diméthylpropan-1-one ;
la (4-(4-(6-amino-5-(5-(3-chlorophényl)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)(4-fluorophényl)méthanone ;
la 5-(1-(1-éthylpipéridin-4-yl)-1H-pyrazol-4-yl)-3-(5-phényloxazol-2-yl)-pyridin-2-amine ;
la 3-(5-phényloxazol-2-yl)-5-(1-(tétrahydro-2-pyran-4-yl)-1H-pyrazol-4-yl)-pyridin-2-amine ;
la 3-(5-(4-chlorophényl)oxazol-2-yl)-5-(1-(tétrahydro-2-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(5-(3-chlorophényl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(5-(4-chlorophényl)oxazol-2-yl)-5-(1-cyclohexyl-1H-pyrazol-4-yl)pyridin-2-amine ;
la 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phényloxazol-2-yl)pyridin-2-amine ;
la 5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)oxazol-2-yl)-pyridin-2-amine ;
la 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phénylisoxazol-3-yl)pyridin-2-amine ;
la 3-(5-phénylisoxazol-3-yl)-5-(1-(tétrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(5-phénylisoxazol-3-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 5-(1-(1-méthylpipéridin-4-yl)-1H-pyrazol-4-yl)-3-(5-phénylisoxazol-3-yl)-pyridin-2-amine ;
la 3-(5-phénylfuran-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 5-(1-(1-méthylpipéridin-4-yl)-1H-pyrazol-4-yl)-3-(5-phénylfuran-2-yl)-pyridin-2-amine ;
la 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phénylfuran-2-yl)pyridin-2-amine ;
la 3-(5-phénylfuran-2-yl)-5-(1-(tétrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-pyridin-2-amine ;
le 4-(4-(6-amino-5-(5-phényl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
la 3-(5-phényl-1,3,4-oxadiazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-pyridin-2-amine ;
la 3-(5-(2,6-dichloro-3-fluorophényl)-1,3,4-oxadiazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
la 3-(5-(4-(tert-butyl)phényl)-1,3,4-oxadiazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
le 4-(4-(6-amino-5-(5-(4-(tert-butyl)phényl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
la 3-(5-(2,5-difluorophényl)-1,3,4-oxadiazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
le 4-(4-(6-amino-5-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
la 3-(5-(4-fluorophényl)-1,3,4-oxadiazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
le 4-(4-(6-amino-5-(5-(4-fluorophényl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
la 1-(4-(4-(6-amino-5-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)éthanone ;
la 3-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-méthylpipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
la 1-(4-(4-(6-amino-5-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)-4-méthylpentan-1-one ;
la (4-(4-(6-amino-5-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)(cyclopropyl)méthanone ;
la (4-(4-(6-amino-5-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)(phényl)méthanone ;
la 1-(4-(4-(6-amino-5-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)-2-phényléthanone ;
la 3-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-éthylpipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)-5-(1-(1-dodecylpipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
le 4-(4-(6-amino-5-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
le 4-(4-(6-amino-5-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
la 5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine ;
la 5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine ;
le 4-(4-(6-amino-5-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
la 5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-3-(5-(thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine ;
la 5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-3-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine ;
le 4-(4-(6-amino-5-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
le 4-(4-(6-amino-5-(5-(4-(trifluorométhyl)-thiazol-2-yl)-l,3,4-oxadiazol-2-yl)-pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
la 5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-3-(5-(4-(trifluorométhyl)thiazol-2-yl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine ;
le 4-(4-(6-amino-5-(5-(cyclopropylméthyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
la 3-(5-(cyclopropylméthyl)-1,3,4-oxadiazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
le 4-(4-(6-amino-5-(5-benzyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridine-1-carboxylate de tert-butyle ;
la 3-(5-benzyl-1,3,4-oxadiazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-pyridin-2-amine ;
la 3-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(5-phényl-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(5-(4-(tert-butyl)phényl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)-pyridin-2-amine ;
la 3-(5-(2,5-difluorophényl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(5-(4-fluorophényl)-1,3,4-oxadiazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine ;
la 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)pyridin-2-amine ;
la 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phényl-1,3,4-oxadiazol-2-yl)pyridin-2-amine ;
la 3-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)-5-(1-(tétrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(5-phényl-1,3,4-oxadiazol-2-yl)-5-(1-(tétrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(3-phényl-1,2,4-oxadiazol-5-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-pyridin-2-amine ;
la 1-(4-(4-(6-amino-5-(3-phényl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)éthanone ;
la (4-(4-(6-amino-5-(3-phényl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéndin-1-yl)(cyclopropyl)méthanone ;
la 5-(1-(1-méthylpipéridin-4-yl)-1H-pyrazol-4-yl)-3-(3-phényl-1,2,4-oxadiazol-5-yl)pyridin-2-amine ;
la (4-(4-(6-amino-5-(3-phényl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)(phényl)méthanone ;
la 1-(4-(4-(6-amino-5-(3-phényl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)pipéridin-1-yl)-2-phényléthanone ;
la 3-(3-(2,6-dichlorophényl)-1,2,4-oxadiazol-5-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(3-(2,6-dichlorophényl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-méthylpipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(3-(2,6-dichlorophényl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-éthylpipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 5-(1-(1-éthylpipéridin-4-yl)-1H-pyrazol-4-yl)-3-(3-phényl-1,2,4-oxadiazol-5-yl)pyridin-2-amine ;
la 3-(3-(2,6-dichlorophényl)-1,2,4-oxadiazol-5-yl)-5-(1-(1-dodécylpipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine;
la 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-phényl-1,2,4-oxadiazol-5-yl)pyridin-2-amine ;
la 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(3-(2,6-dichlorophényl)-1,2,4-oxadiazol-5-yl)pyridin-2-amine ;
la 3-(3-phényl-1,2,4-oxadiazol-5-yl)-5-(1-(tétrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(3-(2,6-dichlorophényl)-1,2,4-oxadiazol-5-yl)-5-(1-(tétrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(3-phényl-1,2,4-oxadiazol-5-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine ;
la 5-(1-cyclohexyl-1H-pyrazol-4-yl)-3-(5-phényl-1,2,4-oxadiazol-3-yl)pyridin-2-amine ;
la 3-(5-phényl-1,2,4-oxadiazol-3-yl)-5-(1-(tétrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(5-phényl-1,2,4-oxadiazol-3-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)-pyridin-2-amine ;
la 5-(1-(1-méthylpipéridin-4-yl)-1H-pyrazol-4-yl)-3-(5-phényl-1,2,4-oxadiazol-3-yl)pyridin-2-amine ;
la 3-(5-(2,5-dichlorophényl)-1,2,4-oxadiazol-3-yl)-5-(1-(pipéridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine ;
la 3-(5-phényl-1,2,4-oxadiazol-3-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine ; ou
la 3-(5-(2,6-dichlorophényl)-1,3,4-oxadiazol-2-yl)-5-(1-(pipéridin-4-yl)-1H-pyrrol-3-yl)pyridin-2-amine.
REFERENCES CITED IN THE DESCRIPTION
Patent documents cited in the description
Non-patent literature cited in the description