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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/18—Bridged systems
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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  • A61P25/16—Anti-Parkinson drugs
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
• • C—CHEMISTRY; METALLURGY
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  • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

• the disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds.
• the compounds inhibit GSK-3 and may be useful for the treatment of various disorders of the central nervous system.
• GSK-3 is a proline directed serine/threonine kinase that carries out the phosphorylation of multiple protein substrates. Many of these proteins are involved in the regulation of numerous diverse cellular functions, including metabolism, differentiation, proliferation and apoptosis.
• GSK-3 is constitutively active, with its base level of activity being positively modulated by phosphorylation on Tyr216/219, depending on isoform.
• GSK-3 has a unique substrate selectivity profile that is distinguished by the strong preference for the presence of a phosphorylated residue optimally located four amino acids C-terminal to the site of GSK-3 phosphorylation. Most commonly, GSK-3 activity is associated with inducing a loss of substrate function, such that GSK-3 inhibition will frequently result in increased downstream substrate activity.
• GSK-3 exists in two isoforms, GSK-3oc (51 kDa) and GSK-3 (47 kDa), that share 84% overall identity and greater than 98% identity within their respective catalytic domains. Both primary isoforms are ubiquitously expressed, with high levels observed in the brain, particularly in the cortex and hippocampus. In most brain areas, GSK-3 ⁇ is the predominant isoform. However, some studies suggest that GKS-3oc and GSK-3 share very similar, if not entirely redundant functions in a number of cellular processes. The activity of GSK-3 ⁇ is significantly reduced by phosphorylation at Ser9 in the N-terminal domain, most notably by protein kinase B (PKB or AKT). This inhibitory pathway has been proposed to result in neuroprotection, neurogenesis, and favorable outcomes following pharmacological treatment in various mood disorders.
• PKT protein kinase B
• AD pathology is prominently associated with the formation of beta-amyloid ( ⁇ ) plaques, soluble forms of ⁇ such as ⁇ 1-42 that are associated with increased neuronal toxicity, and neurofibrillary tangles (NFTs).
• ⁇ beta-amyloid
• NFTs neurofibrillary tangles
• the uncomplexed hyperphosphorylated tau assembles into paired helical filaments (PHFs) that aggregate to produce the stereotypic intracellular NFTs associated with AD.
• PHFs paired helical filaments
• Other potential pathological consequences of over-activation of GSK-3 include neuroinflammation and neuronal apoptosis.
• GSK-3 has been demonstrated to be involved in mechanisms underlying memory and learning, and dysregulation of GSK-3 function may explain some of the early cognitive deficits observed in AD.
• GSK-3 is also known to play a key role in glucose metabolism, and was first identified as the enzyme responsible for effecting the inhibitory phosphorylation of glycogen synthase, the result of which is to reduce the rate of conversion of glucose to glycogen, giving rise to elevated blood glucose levels. This function of GSK-3 is controlled by insulin. Binding of insulin to its receptor leads indirectly to the activation of AKT and subsequent inhibitory Ser9 phosphorylation of GSK-3.
• Alzheimer's disease as well as other neurodegenerative diseases. These include, but are not limited to, tauopathies (for example, frontotemporal dementia, progressive supranuclear palsy, argyophilic grain disease, corticobasal degeneration, Pick's disease), Parkinson's disease, amyotrophic lateral schlerosis, stroke, Huntington's disease, peripheral neuropathies, traumatic brain injury, spinal cord trauma, and vascular dementias.
• tauopathies for example, frontotemporal dementia, progressive supranuclear palsy, argyophilic grain disease, corticobasal degeneration, Pick's disease
• Parkinson's disease amyotrophic lateral schlerosis
• stroke Huntington's disease
• peripheral neuropathies for example, traumatic brain injury, spinal cord trauma, and vascular dementias.
• Compounds that inhibit GSK-3 may also have utility in the treatment of diabetes, inflammatory diseases such as rheumatoid arthritis and osteoarthritis, treatment-resistant depression, schizophrenia, bipolar disorder, manic depression, osteoporosis,
• the compounds are novel inhibitors of GSK-3 and may be useful for the treatment of various disorders of the central nervous system. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
• the invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, pharmaceutical compositions, and their use in treating disorders associated with GSK-3.
• One aspect of the invention is a compound of formula I
• R 1 is hydrogen, halo, alkyl, haloalkyl, alkoxy or haloalkoxy;
• X is alkylene or alkenylene with 0-4 substituents selected from halo, alkyl, haloalkyl hydroxy, alkoxy, haloalkoxy, and (C3-7)spirocycloalkyl;
• Y is O, piperazinyl, or morpholinyl; or a pharmaceutically acceptable salt thereof.
• Another aspect of the invention is a compound of formula I where Y is O.
• Another aspect of the invention is a compound of formula I where Y is piperazinyl.
• Another aspect of the invention is a compound of formula I where Y is morpholinyl.
• Another aspect of the invention is a compound of formula I where X is (C5-7)-alkylene.
• Another aspect of the invention is a compound of formula I where X is (C5-6)-alkenylene.
• the scope of any instance of a variable substituent, including R 1 , X, and Y, can be used independently with the scope of any other instance of a variable substituent. As such, the invention includes combinations of the different aspects.
• Halo includes fluoro, chloro, bromo, and iodo.
• Alkyl means a straight or branched alkyl group composed of 1 to 6 carbons.
• Alkenyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond.
• Alkynyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one triple bond.
• Alkylene means a bidentate hydrocarbon chain with 4-8 carbons atoms in the chain.
• Alkenylene means a bidentate hydrocarbon chain with 4-8 carbons atoms in the chain with at least one double bond.
• Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons.
• Haloalkyl and haloalkoxy include all halogenated isomers from monohalo to perhalo. Terms with a hydrocarbon moiety (e.g. alkoxy) include straight and branched isomers for the hydrocarbon portion.
• Aryl means a monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms, or a bicyclic fused ring system wherein one or both of the rings is a phenyl group.
• Bicyclic fused ring systems consist of a phenyl group fused to a four- to six-membered aromatic or non-aromatic carbocyclic ring.
• Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
• Heteroaryl means a 5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromatic ring system with 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Spirocycloalkyl means a spirocyclic hydrocarbon moiety occurring on a hydrocarbon chain (see structures below). The number of carbons designated includes the spirocyclic carbon in the hydrocarbon chain. For example, below is shown
• the invention includes all pharmaceutically acceptable salt forms of the compounds.
• Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents.
• Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
• Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine,
• Some Formula I compounds contain at least one asymmetric carbon atom.
• the invention includes all stereoisomeric forms of the compounds, both mixtures and separated isomers. Mixtures of stereoisomers can be separated into individual isomers methods known in the art.
• the invention is intended to include all isotopes of atoms occurring in the present compounds.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium and tritium.
• Isotopes of carbon include 1 C and 14 C.
• Isotopically- labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
• Biological Methods include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium and tritium.
• the kinase assay was performed in V-bottom 384-well plates.
• the final assay volume was 30 ⁇ prepared from 15 ⁇ additions of enzyme, substrates (fluoresceinated peptide FL-KRREILSRRP[ps]ERYR-NH2 and ATP) and test compounds in assay buffer (100 mM HEPES pH 7.4, 10 mM MgCh, 25mM Beta-Glycerolphosphate, 0.015% Brij35 and 0.25 mM DTT).
• assay buffer 100 mM HEPES pH 7.4, 10 mM MgCh, 25mM Beta-Glycerolphosphate, 0.015% Brij35 and 0.25 mM DTT.
• the reaction mixture was analyzed on the Caliper LabChip3000 (Caliper, Hopkinton, MA) by electrophoretic separation of the unphosphorylated substrate and phosphorylated product. Inhibition data were calculated by comparison of the no enzyme control reactions for 100% inhibition and vehicle-only reactions for 0% inhibition.
• the final concentration of reagents in the assay were 250 pM GSK3a or GSK3 , 20 uM ATP, 1.5 uM FL-
• KRREILSRRP[ps]ERYR-NH2, and 1.6% DMSO Dose response curves were generated to determine the concentration required to inhibit 50% of the kinase activity (IC50). Compounds were dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at eleven concentrations. IC50 values were derived by non-linear regression analysis.
• compositions and Methods of Treatment Compounds of formula I can be useful in treating neurological or psychiatric disorders. Therefore, another aspect of the invention is a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a
• Another aspect of the invention is a method for the treatment for modulation of
• GSK-3 activity may be useful in the treatment of both the neuropathologic and symptomatic aspects of Alzheimer's disease, as well as other neurodegenerative diseases.
• these include, but are not limited to, tauopathies (for example, frontotemporal dementia, progressive supranuclear palsy, argyophilic grain disease, corticobasal degeneration, Pick's disease), Parkinson's disease, amyotrophic lateral sclerosis, stroke, Huntington's disease, peripheral neuropathies, traumatic brain injury, spinal cord trauma, and vascular dementias, which comprises administering to a patient a therapeutically affective amount of a compound of formula I.
• Another aspect of the invention is a method for the treatment for diabetes, inflammatory diseases such as rheumatoid arthritis and osteoarthritis, treatment-resistant depression, schizophrenia, bipolar disorder, manic depression, osteoporosis,
• Another aspect of the invention is a method for the treatment of Alzheimer's disease which comprises administering to a patient a therapeutically affective amount of a compound of formula I.
• Another aspect of the invention is the use of a compound of formula I in the manufacture of a medicament for the treatment of Alzheimer's disease.
• Patient means a person suitable for therapy as understood by practitioners in the field of affective disorders, neurodegenerative disorders, psychiatric disorders, cancer, metabolic disorders, or inflammatory disorders.
• compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients.
• Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
• Compositions encompass all common solid and liquid forms including for example capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions.
• compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 17th edition, 1985.
• Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg.
• Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other agents will be present in a unit range similar to agents of that class used clinically.
• this is 1-100 mg/mL.
• the invention encompasses all conventional modes of administration; oral and parenteral methods are preferred.
• the dosing regimen will be similar to other agents used clinically.
• the daily dose will be 1-100 mg/kg body weight daily.
• more compound is required orally and less parenterally.
• the specific dosing regime will be determined by a physician using sound medical judgement.
• Compounds of Formula I may be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials.
• the variables (e.g. numbered "R" substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention. The schemes encompass reasonable variations known in the art.
• 6-Fluoro-4-(2-vinylmorpholino)pyridin-3-amine 6-Fluoro-4-(2-vinylmorpholino)pyridin-3-amine.
• 4-(2-fluoro-5-nitropyridin-4-yl)-2-vinylmo holine (348 mg, 1.374 mmol) in EtOH (8 ml) to give a yellow solution.
• TIN(II) CHLORIDE (1303 mg, 6.87 mmol) was added, and the mixture was heated at 70 °C under nitrogen. After 3 h, TLC indicated no starting material. Cooled to r.t. Most EtOH was evaporated and the residue was diluted with EtOAc. Aqueous NaHC03 was added to adjust pH around 7-8.
• N-(6-Fluoro-4-(2-vinylmorpholino)pyridin-3-yl)-2-(pent-4-en-l-ylamino)pyrimidine- 4-carboxamide was 2-chloro-N-(6-fluoro-4-(2-vinylmorpholino)pyridin- 3-yl)pyrimidine-4-carboxamide (58.7 mg, 0.161 mmol) and pent-4-en-l -amine (27.5 mg, 0.323 mmol) in NMP (0.3 mL) to give a tan solution. Hunig's base (0.085 mL, 0.484 mmol) was added. The mixture was heated at 100°C for 2 h.
• N-(4-(But-3-en-l-yloxy)pyridin-3-yl)-2-(pent-4-en-l-ylamino)pyrimidine-4- carboxamide was N-(4-(but-3-en-l-yloxy)pyridin-3-yl)-2- chloropyrirnidine-4-carboxarnide (115.9 mg, 0.380 mmol) and pent-4-en-l -amine (64.8 mg, 0.761 mmol) in NMP (0.7 mL) to give a tan solution. Hunig'sBase (0.199 mL, 1.141 mmol) was added. The mixture was heated at 100°C for 2 h.
• Aqueous NaHC03 was added to adjust pH around 7-8.
• the suspension was carefully filtered (through a plug of celite) and washed with EtOAc.
• the clear bilayer solution was separated.
• the organic layer was washed with brine, dried with Na2S04, and
• N-(4-(4-Allylpiperazin-l-yl)-6-fluoropyridin-3-yl)-2-chloropyrimidine-4- carboxamide was 2-chloropyrimidine-4-carboxylic acid (209 mg, 1.315 mmol) and 4-(4-allylpiperazin-l-yl)-6-fluoropyridin-3-amine (310.8 mg, 1.315 mmol) in ethyl acetate (3 mL) to give a tan solution.
• N-(4-(4-Allylpiperazin-l-yl)-6-fluoropyridin-3-yl)-2-((2-hydroxypent-4-en-l- yl)amino)pyrimidine-4-carboxamide was N-(4-(4-allylpiperazin-l-yl)-6- fluoropyridin-3-yl)-2-chloropyrimidine-4-carboxarnide (65.4 mg, 0.174 mmol) and 1- aminopent-4-en-2-ol hydrochloride (47.8 mg, 0.347 mmol) in NMP (0.4 mL) to give a tan solution.
• Hunig's base (0.091 mL, 0.521 mmol) was added. The mixture was heated at 100°C for 17 h. LCMS showed good conversion to the desired product. The mixture was diluted with water and EtOAc. The layers were separated. The organic layer was washed with brine, dried and concentrated to a tan oil/solid.
• N-(4-(4-Allylpiperazin-l-yl)-6-fluoropyridin-3-yl)-2-((2-hydroxyhex-5-en-l- yl)amino)pyrimidine-4-carboxamide was N-(4-(4-allylpiperazin-l-yl)-6- fluoropyridin-3-yl)-2-chloropyrimidine-4-carboxamide (53.4 mg, 0.142 mmol) and 1- aminohex-5-en-2-ol hydrochloride (43.0 mg, 0.283 mmol) in NMP (0.3 mL) to give a tan solution.
• Hunig's base (0.074 mL, 0.425 mmol) was added. The mixture was heated at 100°C for 17 h. LCMS showed around half conversion (by parent ion peaks: SM and product overlap), which was comformed by TLC (10% MeOH/CH2C12). More reagents (2 equiv/3 equiv) were added and the mixture was heated at 120°C for 5 h. LCMS indicated a better conversion. The mixture was diluted with water and EtOAc. The layers were separated. The organic layer was washed with brine, dried and concentrated.
• N-(4-(4-Allylpiperazin-l-yl)-6-fluoropyridin-3-yl)-2-((2,2-dimethylpent-4-en-l- yl)amino)pyrimidine-4-carboxamide was N-(4-(4-allylpiperazin-l-yl)-6- fluoropyridin-3-yl)-2-chloropyrimidine-4-carboxamide (24.2 mg, 0.064 mmol) (last batch) and 2,2-dimethylpent-4-en-l -amine (14.54 mg, 0.128 mmol) in NMP (0.2 mL) to give a tan solution.
• Tetrahydrofuran (8 mL) to give a colorless solution. Allylmagnesium bromide (5.05 mL, 5.05 mmol) was slowly added. The mixture was stirred at rt for lh and was quenched with saturated NH4C1 solution. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to a tan oil (580 mg, 100%).
• N-(4-(4-Allylpiperazin-l-yl)-6-fluoropyridin-3-yl)-2-(((2S)-3-hydroxyhex-5-en-2- yl)amino)pyrimidine-4-carboxamide was N-(4-(4-allylpiperazin-l -yl)-6- fluoropyridin-3-yl)-2-chloropyrimidine-4-carboxarnide (55 mg, 0.146 mmol) and (2S)-2- aminohex-5-en-3-ol hydrochloride (44.3 mg, 0.292 mmol) in NMP (0.4 mL) to give a tan solution.
• N-(4-(4-Allylpiperazin-l-yl)-6-fluoropyridin-3-yl)-2-((2-hydroxy-2-methylpent-4-en- l-yl)amino)pyrimidine-4-carboxamide was N-(4-(4-allylpiperazin-l-yl)- 6-fluoropyridin-3-yl)-2-chloropyrimidine-4-carboxarnide (50 mg, 0.133 mmol) and 1 - amino-2-methylpent-4-en-2-ol hydrochloride (40.2 mg, 0.265 mmol) in NMP (0.3 mL) to give a tan solution.
• N-(4-(But-3-en-l-yloxy)pyridin-3-yl)-2-((2-hydroxy-2-methylpent-4-en-l- yl)amino)pyrimidine-4-carboxamide was N-(4-(but-3-en-l- yloxy)pyridin-3-yl)-2-chloropyrimidine-4-carboxamide (54.1 mg, 0.178 mmol) and 1- amino-2-methylpent-4-en-2-ol hydrochloride (53.8 mg, 0.355 mmol) in NMP (0.3 mL) to give a tan solution. Hunig's base (0.093 mL, 0.533 mmol) was added.

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