USRE49128E1 - Hydroxyl purine compounds and applications thereof - Google Patents

Hydroxyl purine compounds and applications thereof Download PDF

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Publication number
USRE49128E1
USRE49128E1 US16/795,419 US201516795419A USRE49128E US RE49128 E1 USRE49128 E1 US RE49128E1 US 201516795419 A US201516795419 A US 201516795419A US RE49128 E USRE49128 E US RE49128E
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mmol
methyl
dione
purine
dimethyl
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Lingyun Wu
Chaofeng LONG
Peng Zhang
Xiaoxin Chen
Li Zhang
Zhuowei LIU
Jian Li
Shuhui Chen
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Guangdong Raynovent Biotech Co Ltd
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Guangdong Raynovent Biotech Co Ltd
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Priority claimed from CN201410529928.9A external-priority patent/CN105566324B/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/14—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with two methyl radicals in positions 1 and 3 and two methyl radicals in positions 7, 8, or 9

Definitions

  • the present invention relates to a series of hydroxyl purine compounds and applications thereof as PDE2 or TNF- ⁇ inhibitors, specifically relates to a compound having a structure of formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof.
  • Phosphodiesterases catalyzes the hydrolization of cyclic nucleotides cGMP and cAMP, and regulates various physiological responses by controlling the intramolecular concentrations of these two important second messengers.
  • the abnormal intramolecular regulation of the cyclic nucleotides cGMP and cAMP is the cause of many diseases, there are already a number of drugs can improve and treat diseases by inhibiting the PDE activity, such as PDE5 inhibitors for pulmonary hypertension and PDE4 inhibitors for arthritis caused by psoriasis.
  • PDE5 inhibitors for pulmonary hypertension and PDE4 inhibitors for arthritis caused by psoriasis There are eleven categories of the currently known phosphodiesterase genes, each category can be expressed in several subtypes, with a total of more than 100 PDE subtypes. Different subtypes have different structure and different tissue distribution, the activity of cyclic nucleotides cGMP and cAMP and the physiological function of regulation are also very different.
  • PDE2 phosphodiesterase can catalyzes the hydrolization of cyclic nucleotides cGMP and cAMP, meanwhile cAMP activity is regulated by cGMP, which plays a key role in intracellular balance of cGMP and cAMP function.
  • PDE2 is widely expressed in human tissues, mainly distributed in the heart, central nervous system, liver, adrenal gland, endothelial cells, and platelets and so on. PDE2 is involved in regulating various physiological activity, such as learning, memory and cognitive processes of the maincenter, the maintenance of the basic rhythm of the heart, smooth muscle and endothelial cells, the maintenance of the permeability of endothelial cells, the regulation of inflammatory response. The knockout of the PDE2 gene will lead to the death of mouse embryos. Inhibition of PDE2 activity may be used for a variety of maincenter diseases, cardiovascular diseases, and controlling inflammation.
  • PDE2 activity has been approved for clinical use in lower limbs claudication caused by peripheral vascular occlusion, the main functions of which are reducing blood viscosity, improving erythrocyte deformation, inhibiting platelet aggregation, etc.
  • Novel high-selectivitive PDE2 inhibitors have also been reported to control the division of endothelial cells and the regeneration of blood vessels, and to improve maincenter disgnosia.
  • novel selectivitive PDE2 inhibitors are still very limited, and the discovery and application of novel PDE2 inhibitors has broad prospects.
  • Tumor necrosis factor alpha is a cytokine with multiple biological activities, which has a significant impact on the occurrence, development and prognosis of multiple diseases.
  • TNF- ⁇ is mainly produced by monocytes and macrophage cells, which is involved in the immunomodulation and the cytokine network coordination. Under normal circumstances, TNF- ⁇ plays an important role in immune defense and immune surveillance, but in some cases it has adverse effects.
  • TNF- ⁇ can induce the expression of proinflammatory cytokines such as interleukon 1 (IL-1) and IL-6, increase the permeability of endothelial cells and up-regulate the expression of adhesion molecules and activate neutrophils and eosinophils, and induce bone synovial cells and cartilage cells to secrete acute phase substances and tissue-degrading enzymes and the like to promote the occurrence of inflammation.
  • IMID immune-mediated inflammatory diseases
  • RA rheumatoid arthritis
  • PsA psoriatic arthritis
  • AS ankylosing spondylitis
  • IBD inflammatory bowel disease
  • JCA juvenile chronic arthritis
  • TNF- ⁇ TNF- ⁇ antagonists
  • PDE2 regulates the expression of TNF- ⁇ according to the mechanism, therefor the level of TNF- ⁇ can be controlled by regulating the PDE2 activity, so as to control the inflammation.
  • the present invention provides a compound having a structure of formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof,
  • L 11 is selected from absence, or C(R)(R′);
  • each of R, R′ is independently selected from H, a halogen, OH, NH 2 , CN, or, an optionally substituted 1- to 6-membered alkyl or heteroalkyl;
  • R, R′ can form a 3- to 6-membered cycloalkyl, heterocyoalkyl by cyclization
  • A represents absence, or is selected from cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
  • L 12 is selected from an optionally substituted 1- to 6-membered alkyl or heteroalkyl
  • R 1 is selected from an optionally substituted 1- to 6-membered alkyl or heteroalkyl
  • hetero represents N, O, S, C( ⁇ O), S( ⁇ O), or S( ⁇ O) 2 , the number of the heteroatom on each group is selected from 1, 2, 3 or 4.
  • the substituents in the R, R′, A, L 12 and R 1 are independently selected from the halogen, OH, NH 2 , CN, or, the optionally substituted 1- to 6-membered alkyl or heteroalkyl, the number of the substituent on each group is independently selected from 1, 2 or 3.
  • the substituents in the R, R′, A, L 12 and R 1 are independently selected from the halogen, CF 3 , CN, OH, Me, Et, n-propyl, isopropyl, cyclopropyl,
  • the R and R′ are independently selected from H, Me, CF 3 , or Et.
  • the L 11 is selected from
  • the A is selected from the 3- to 12-membered alkyl or cycloalkyl, or the 5- to 12-membered aryl or heteroaryl, each of which is optionally substituted.
  • the A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypentyl, phenyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, or bicyclo[1.1.1]pentane, or a bicyclic group, a spiro group or a fused cyclic group consisting of any two of the above groups, each of which is optionally substituted.
  • the A is selected from
  • the A is selected from
  • the L 12 is selected from methylene
  • the R 1 is selected from Me, CHF 2 , CF 3 , Et, CH 2 CF 3 , isopropyl,
  • the present invention is selected from the group consisting of:
  • the present invention is selected from the group consisting of:
  • the present invention also provides an application of the compound, the tautomer thereof or the pharmaceutically acceptable salt thereof in manufacturing a PDE2 inhibitor and a TNF- ⁇ inhibitor.
  • the term “pharmaceutically acceptable” is aimed at those compounds, materials, compositions and/or dosage forms, which are within the scope of reliable medical judgment and applicable for use in contact with human and animal tissue but without too much toxicity, irritation, allergic reactions or other problems or complications, also meet the reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to the salt of the compound of the present invention, which is prepared by the compound with specific substituent discovered by the present invention and relatively non-toxic acid or alkali.
  • an alkali-addition salt can be obtained by contacting the compound in a neutral form with sufficient amount of alkali in a pure solution or suitable inert solvent.
  • the pharmaceutically acceptable alkali-addition salt includes the salt of sodium, potassium, calcium, ammonium, organic ammonia or magnesium or the like.
  • an acid-addition salt can be obtained by contacting the compound in a neutral form with sufficient amount of acid in a pure solution or suitable inert solvent.
  • the pharmaceutically acceptable acid-addition salt include a salt of inorganic acid, the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydriodic acid, phosphorous acid etc; and salt of organic acid, the organic acid includes such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, phenylsulfonic acid, p-toluene sulfonic acid, citric acid, tartaric acid,
  • Some specific compound of the present invention contains both alkaline and acidic functional groups so as to be transformed to be any alkali-addition or acid-addition salt.
  • the neutral form of a compound is regenerated by contacting a salt with a base or an acid in a conventional manner and then separating the parent compound.
  • the difference between a parent form of a compound and the various salt forms lies in some physical properties, such as that the solubility in a polar solvent is different.
  • the “pharmaceutically acceptable salt” in the present invention is the derivatives of the compound of the present invention, wherein, the parent compound is modified by salifying with an acid or an alkali.
  • the pharmaceutically acceptable salt include but not limited to: an inorganic acid or organic acid salt of an alkali such as amine, an alkali metal or organic salt of acid radical such as carboxylic acid and so on.
  • the pharmaceutically acceptable salt includes conventionally non-toxic salts or quaternary ammonium salts of the parent compound, such as a salt formed by a non-toxic inorganic acid or organic acid.
  • the conventionally non-toxic salt includes but not limited to those salts derived from inorganic acids and organic acids, the inorganic acids or organic acids are selected from 2-acetoxybenzoic acid, 2-isethionic acid, acetic acid, ascorbic acid, phenylsulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydriodate, hydroxyl, hydroxynaphthoic, isethionic acid, lactic acid, lactose, dodecanesulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid
  • the pharmaceutically acceptable salt of the present invention can be prepared by a conventional method with a parent compound containing an acidic or alkaline group.
  • the preparation method of the salt comprises that in water or an organic solvent or the mixture of water and organic solvent, reacting these compounds in forms of free acids or alkalis with stoichiometric amount of proper alkalis or acids.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile and so on.
  • prodrug for the compound in the present invention is easily transformed to be the compound of the present invention via chemical changes under physiological conditions.
  • the prodrug can be transformed to be the compound of the present invention via chemical or biochemical method in vivo environment.
  • Some compounds of the present invention can exist in the form of non-solvate or solvate forms, including hydrate forms.
  • the solvate form is similar to the non-solvate form, both of which are included within the scope of the present invention.
  • Some compounds of the present invention can contain asymmetric carbon atoms (optical center) or double bonds.
  • the racemic isomers, diastereomers, geometric isomers and single isomers are included within the scope of the present invention.
  • the compound of the present invention may exist as a specific geometric or stereoisomeric isomer.
  • the present invention envisages all of this class of compounds, including cis- and trans-isomers, ( ⁇ )- and (+)-antimers, (R)- and (S)-antimers, diastereomers, (D)-isomer, (L)-isomer, as well as racemic mixtures and other mixtures, such as enantiomers- or diastereoisomers-enriched mixtures, all of these mixtures are within the scope of the present invention.
  • Other asymmetric carbon atoms may exist in substituents such as in an alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers, (D)- and (L)-isomers can be prepared by asymmetric synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention are wanted, asymmetric synthesis or derivatization action of the chiral auxiliaries can be employed in preparation, in which the resulting diastereomer mixtures are isolated, and the auxiliary groups are cleaved to provide the pure desired enantiomer.
  • a salt of diastereomer is formed with an appropriate optical active acid or alkali, and then the pure enantiomer can be recycled after resolution on the salt of diastereomer by common methods which is known in the art.
  • the separation of an enantiomer and a diastereomer is usually realized by the chromatographic method, the chromatography method employs a chiral stationary phase, and optionally combined with the chemical derivatization method (e.g. an amine generates a carbamate).
  • One or more atoms constituting the compound of the present invention may comprise an unnatural proportion of atomic isotopes.
  • the compound can be labeled by a radioactive isotope, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). All the variations in the isotopic composition of the compound disclosed in the present invention, whether radioactive or not, are included within the scope of the present invention.
  • a pharmaceutically acceptable carrier refers to any formulation or carrier medium which is capable of delivering effective amount of the active substance disclosed in the present invention, does not interfere with the biological activity of the active substance, and is with no toxic side-effects on host or patient
  • representative carrier includes water, oil, vegetables and minerals, cream base, lotion matrix, ointment matrix etc.
  • the matrix comprises a suspension, a viscosity increaser, transdermal enhancers etc.
  • Their formulation are well known to the person in cosmetic or topical drug art. Other information about the carrier can refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the content of which is incorporated into this article as reference.
  • excipient usually refers to a carrier, diluent and/or medium required for the preparation of an effective pharmaceutical composition.
  • an effective amount refers to enough quantity of the drug or formulation that can achieve desired effects but is with no toxicity.
  • an effective amount of one active substance in the composition is the amount required to achieve desired effects in combination with another active substance in the composition. The determination of the effective amount varies from person to person, which depends on the age and the general situation of the recipient, also on the specific active substance. In one case, an appropriate effective amount can be determined by the person skilled in the art according to conventional tests.
  • active ingredient refers to a chemical entity, which can effectively treat disorder, illness or disease of a target subject.
  • substituted refers to one or more hydrogen atoms in a specific atom optionally substituted by a substituent, including a deuterium and a variant of hydrogen, as long as the valence state of the specific atom is normal and the compound obtained after substitution is stable.
  • substituent is a ketone group (i.e. ⁇ O)
  • it means that two hydrogen atoms are substituted.
  • a substitution of ketone group does not occur in an aryl.
  • optionally substituted means that it may be substituted or not be substituted, unless otherwise specified, the type and number of substituents can be arbitrary under the premise of stability available in chemistry.
  • any parameter e.g. R
  • the definition of each occurrence is independent. Therefore, for example, if a group is substituted by 0 ⁇ 2 of R, the group may optionally be substituted by at most two R, and R has an independent option in each case.
  • the combination of substituents and/or their variants is allowed only if such a combination will lead to a stable compound.
  • connection group When the number of the connection group is 0, such as —(CRR) 0 —, it indicates that the connection group is a single bond.
  • one of the parameters When one of the parameters is selected from a single bond, it indicates that the two groups which it is attached are directly connected, for example, when the L in A-L-Z represents a single bond, it indicates that the structure actually is A-Z.
  • connection can occur on any atom in the cyclohexyl or cyclohexadiene.
  • halogenated or “halogen” itself or as a part of another substituent refers to fluorine, chlorine, bromine or iodine atom.
  • halogenated alkyl is intended to include monohalogenated alkyl and polyhalogenated alkyl.
  • halogenated (C 1 -C 4 ) alkyl is intended to include but not limited to trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl and 3-bromopropyl, etc.
  • halogenated alkyl examples include but not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents that the alkyl group with a specific number of carbon atoms is connected by an oxygen bridge.
  • the C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy.
  • alkoxy include but not limited to: methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S-pentyloxy.
  • the “cycloalkyl” includes saturated cyclic group, such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3- to 7-membered cycloalkyl includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl.
  • the “alkenyl” includes linear or branched hydrocarbon chain, wherein any stable sites on the chain exist one or more C—C double bonds, such as vinyl and propenyl.
  • halo or “halogen” refers to fluorine, chlorine, bromine and iodine.
  • hetero refers to a heteroatom or a heteroatomic group (i.e. a group containing a heteroatom), including atoms except carbon (C) and hydrogen (H) and groups containing these heteroatoms, such as including oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), —O—, —S—, ⁇ O, ⁇ S, —C( ⁇ O)O—, —C( ⁇ O)—, —C( ⁇ S)—, —S( ⁇ O), —S( ⁇ O) 2 —, and optionally substituted —C( ⁇ O)N(H)—, —N(H)—, —C( ⁇ NH)—, —S( ⁇ O) 2 N(H)— or —S( ⁇ O) N(H)—.
  • the “ring” refers to substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • the ring includes a single ring, a joint ring, a spiro ring, a fused ring or a bridged ring.
  • a number of the atoms in the ring is usually defined as the member of the ring, for example, “5- to 7-membered ring” is a ring looped with 5 to 7 atoms.
  • the ring optionally contains 1-3 of heteroatoms.
  • “5- to 7-membered ring” includes, for example, phenyl pyridine and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • the term “ring” also includes a ring system containing at least one ring, wherein each ring is of the above definition independently.
  • heterocycle refers to a stable monocyclic, bicyclic or tricyclic ring containing a heteroatom and a heteroatomic group, they can be saturated, partially unsaturated or unsaturated (aromatic), they contain carbon atoms and 1, 2, 3 or 4 of heteroatom in the ring which is independently selected from the group consisting of N, O and S, wherein any of the heterocycle can be fused to a benzene ring to form a bicyclic ring.
  • Nitrogen and sulfur atoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituent that has been defined herein).
  • the heterocycle can be attached to the side group of any heteroatom or carbon atom to form a stable structure. If the formed compound is stable, the heterocycle described herein can be substituted on its carbon or nitrogen atom.
  • the nitrogen atom in the heterocycle is optionally quaternized. As a preferred embodiment of the present invention, when the total number of S and O atoms contained in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. As another preferred embodiment of the present invention, the total number of S and O atoms in the heterocycle is no more than 1.
  • aromatic heterocyclic group refers to a stable 5-, 6-, 7-membered monocycle or bicycle or 7-, 8-, 9- or 10-membered bicyclic heteroaromatic ring, which contains carbon atoms and 1, 2, 3 or 4 of heteroatom in the ring which independently selected from the group consisting of N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituent that has been defined herein).
  • Nitrogen and sulfur atoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the total number of S and O atoms in the heteroaromatic ring is no more than 1.
  • Bridged rings are also included in the definition of the heterocycle. When one or more atoms (i.e. C, O, N, or S) are connected to two nonadjacent carbon atoms or nitrogen atoms, a bridged ring is formed.
  • the preferred bridged ring includes but not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that, a bridge always converts a monocyclic ring into a tricyclic ring. In the bridged ring, the substituent in the ring can also locate on the bridge.
  • heterocyclic compound examples include but not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indoalkenyl
  • hydrocarbonyl or its specific concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) itself or as a part of another substituent represents a linear, branched or cyclic hydrocarbonyl or a combination thereof, which can be fully saturated, monocyclic or polycyclic unsaturated, can be monosubstituted, disubstituted or polysubstituted, can be univalent (such as methyl), bivalent (such as methylene) or multivalent (such as methenyl), can include bivalent or multivalent atomic groups, with a specified number of carbon atoms (such as that C 1 -C 10 refers to having 1 ⁇ 10 carbon atoms).
  • alkyl includes but not limited to an aliphatic hydrocarbonyl and aromatic hydrocarbonyl
  • the aliphatic hydrocarbonyl includes linear and cyclic structures, specifically includes but not limited to alkyl, alkenyl and alkynyl
  • the aromatic hydrocarbonyl includes but not limited to 6- to 12-membered aromatic hydrocarbonyl such as benzene, naphthalene and the like.
  • the term “hydrocarbonyl” refers to linear or branched groups or their combination, which can be completely saturated, monocyclic or polycyclic unsaturated, can include divalent and polyvalent groups.
  • saturated hydrocarbonyl examples include but not limited to homologues or isomers of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, iso-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropyl methyl, and n-amyl, n-hexyl, n-heptyl, n-octyl and the like.
  • Unsaturated alkyl has one or more double or triple bond, examples of which includes but not limited to vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-butadienyl, 2,4-(pentadienyl), 3-(1,4-pentadienyl), acetenyl, 1- and 3-propinyl, 3-butynyl, and more advanced homologues and isomers.
  • heterohydrocarbonyl or its specific concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) itself or the term combining with another term refers to a stable linear, branched or cyclic hydrocarbonyl or their combinations, which consists of a certain number of carbon atoms and at least one heteroatom.
  • heterohydrocarbonyl itself or the term combining with another term refers to a stable linear, branched hydrocarbonyl or their combinations, which consists of a certain number of carbon atoms and at least one heteroatom.
  • the heteroatom is selected from the group consisting of B, O, N and S, in which the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • Heteroatoms B, O, N and S can be located in any internal position of the heterohydrocarbonyl (including the position where hydrocarbonyl is attached to the rest part of the molecule).
  • Examples include but not limited to —CH 2 —CH 2 —O—CH 3 , —CH 2 —CH 2 —NH—CH 3 , —CH 2 —CH 2 —N(CH 3 )—CH 3 , —CH 2 —S—CH 2 —CH 3 , —CH 2 —CH 2 , —S(O)—CH 3 , —CH 2 —CH 2 —S(O) 2 —CH 3 , —CH ⁇ CH—O—CH 3 , —CH 2 —CH ⁇ N—OCH 3 and —CH ⁇ CH—N(CH 3 )—CH 3 .
  • At most two heteroatoms are adjacent, such as —CH 2 —NH—OCH 3 .
  • alkoxy refers to the alkyl group is attached to the rest of molecule through an oxygen, an amino, or a sulfur atom, respectively.
  • cyclohydrocarbonyl “heterocyclohydrocarbonyl” or its specific concepts (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocyclovinyl, cycloalkynyl, heterocycloalkynyl, etc.) itself or the term combining with other terms respectively refers to a cyclic “hydrocarbonyl”, “heterohydrocarbonyl”.
  • heterohydrocarbonyl or heterocyclohydrocarbonyl such as heteroalkyl, heterocycloalkyl
  • heteroatoms can occupy the position where the heterocyclic ring is attached to the rest part of the molecule.
  • cycloalkyl examples include but not limited to cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl etc.
  • heterocyclyl examples include 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuranylindol-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl and 2-piperazinyl.
  • aryl refers to a polyunsaturated aromatic hydrocarbon substituent, which can be monosubstituted, disubstituted or multisubstituted, can be univalent, bivalent or multivalent. It can be monocyclic or polycyclic (preferably 1 ⁇ 3 rings). They fuse together or connect by a covalent linkage.
  • heteroaryl refers to an aryl (or ring) containing 1 ⁇ 4 heteroatoms. In an exemplary embodiment, the heteroatom is selected from the group consisting of B, N, O, and S, in which the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • the heteroaryl group can be connected to the rest part of the molecule via a heteroatom.
  • aryl or a heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl,
  • aryl when used in combination with other terms (e.g. aryloxy, arylthio, aralkyl), the aryl includes the definition of aryl and heteroaryl ring defined above. Therefore, the term “aralkyl” is intended to include the groups that aryl attached to alkyl (e.g. benzyl, phenyl ethyl, pyridyl methyl), including those alkyls wherein carbon atoms (such as methylene) has been replaced by such as oxygen atoms, such as phenoxy methyl, 2-pyridyloxymethyl-3-(1-naphthoxy) propyl, etc.
  • alkyl e.g. benzyl, phenyl ethyl, pyridyl methyl
  • leaving group refers to a functional group or atom which can be replaced by another functional group or atom through a substitution reaction (e.g., nucleophilic substitution reaction).
  • a substitution reaction e.g., nucleophilic substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate, such as mesylate, tosylate, p-bromobenzene sulfonate, p-tosylate etc.; acyloxy, such as acetoxy, trifluoroacetoxy and so on.
  • protecting group includes but not limited to “the protecting group of an amino”, “the protecting group of a hydroxyl”, or “the protecting group of a mercapto”.
  • the protecting group of an amino refers to a protecting group that is suitable for preventing side reactions occur at the nitrogen atom of an amino group.
  • a representative protecting group of an amino includes but not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); aryl methoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); aryl methyl, such as benzyl (Bn), triphenyl methyl (Tr), 1,1-bis-(4′-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and etc.
  • alkanoyl such as acetyl, trichloroacetyl or trifluoroacetyl
  • alkoxycarbonyl such as tert-butoxy
  • the protecting group of a hydroxyl refers to a protecting group that is suitable for preventing side reactions of a hydroxyl group.
  • a representative protecting group of a hydroxyl includes but not limited to: alkyl, such as methyl, ethyl, and tert-butyl; acyl, such as alkanoyl (such as acetyl); aryl methyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and etc.
  • alkyl such as methyl, ethyl, and tert-butyl
  • acyl such as alkanoyl (such as acetyl)
  • aryl methyl such as benzyl (Bn), p-meth
  • the compound of the present invention can be prepared through many synthetic methods which are well-known to the person skilled in the art, including the specific embodiments listed below and its combination with other chemical synthetic methods and the equivalent alternative methods which are known to the person skilled in the art, the preferred embodiments include but not limited to the embodiments of the present invention.
  • aq represents water
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • EDC represents N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride
  • m-CPBA represents m-chloroperbenzoic acid
  • eq represents equivalent, equal-quantitative
  • CDI represents carbonyl diimidazole
  • DCM represents dichloromethane
  • PE represents petroleum ether
  • DIAD represents diisopropyl azodicarboxylate
  • DMF represents N,N-dimethylformamide
  • DMSO represents dimethylsulfoxide
  • EtOAc represents ethyl acetate
  • EtOH represents ethanol
  • MeOH represents methanol
  • Cbz represents benzyl
  • THF tetrahydrofuran
  • Boc 2 O di-tert-butyl dicarbonate
  • TFA trifluoroacetic acid
  • DIPEA diisopropylethylamine
  • SOCl 2 thionyl chloride
  • CS 2 carbon disulfide
  • TsOH represents p-toluene sulfonic acid
  • NFSI represents N-fluorobenzenesulfonimide
  • NCS N-chlorosuccinimide
  • n-Bu 4 NF represents tetrabutylammonium fluoride
  • iPrOH represents 2-propanol
  • mp melting point
  • LDA lithium diisopropylamide
  • TMSCF 3 represents trifluoromethyltrimethylsilane
  • Ti(Oi-Pr) 4 represents tetraisopropyl titanate
  • MsCl represents methanesulfonyl chloride
  • DMAP represents N,N-di
  • ethylmagnesium bromide (3 M ether solvent, 1.1 mL, 3.24 mmol) was added at ⁇ 35° C. into a solution of ethyl 5-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-purine-1-yl)pentanoate (500 mg, 1.62 mmol) and tetraisopropyl titanate (461 mg, 1.62 mmol) in tetrahydrofuran (10 mL). The reaction solution was slowly warmed to 25° C. and stirred for 2 hours. The reaction was quenched by the addition of water (10 mL).
  • 1,1,1-Trifluoro-2-(1-(hydroxymethyl)cyclopropyl)propan-2-ol 100 mg, 0.543 mmol
  • dichloromethane 5 mL
  • triethylamine 110 mg, 1.08 mmol
  • methanesulfonyl chloride 62.2 mg, 0.543 mmol
  • reaction was quenched by the addition of a saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane (10 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to deliver (1-(1,1,1-trifluoro-2-hydroxypropan-2-yl)cyclopropyl)methylmethanesulfonate (80.0 mg, yellow oil), yield: 56%.
  • reaction solution was cooled to 20° C., filtered, and purified by preparative high performance liquid chromatography to deliver 3,7-dimethyl-1-((1-(1,1,1-trifluoro-2-hydroxypropan-2-yl)cyclopropyl)methyl)-1H-purine-2,6-(3H, 7H)-dione (40.0 mg, white solid), yield: 38%.
  • Methyl-3-oxocyclobutanecarboxylate (25.0 g, 195 mmol), ethylene glycol (35.0 g, 564 mmol) and p-toluenesulfonic acid (3.50 g, 20.0 mmol) were dissolved in toluene (250 mL), after equipped with a water separator, the reaction mixture was heated to reflux overnight. The reaction solution was cooled to 25° C. and washed successively with water (300 mL ⁇ 2), saturated sodium bicarbonate aqueous solution (500 mL ⁇ 2).
  • lithium aluminum hydride (5.20 g, 136 mmol) was slowly dissolved in tetrahydrofuran (240 mL) at 0° C., and then methyl 5,8-dioxaspiro[3.4]octane-2-carboxylate (19.5 g, 113 mmol) dissolved in tetrahydrofuran (60 mL) was added dropwise. The reaction was slowly warmed to 25° C. and stirred for 3.5 hours. The reaction solution was cooled to 0° C.
  • reaction solution was diluted with dichloromethane (10 mL), the organic phase was washed with water (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to deliver methyl 3-(((methylsulfonyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (50.0 mg, yellow oil), yield: 83%.
  • Methyl-3-methylene cyclobutanecarboxylate (2.00 g, 15.8 mmol) was dissolved in tetrahydrofuran (30 mL), borane dimethyl sulfide (3.61 g, 47.5 mmol) was added dropwise at ⁇ 10° C. and then reacted at ⁇ 10° C.
  • Methyl 3-oxocyclopentanecarboxylate (16.0 g, 110 mmol), p-toluenesulfonic acid (14.0 g, 220 mmol) and ethylene glycol (969 mg, 5.60 mmol) were dissolved in anhydrous toluene (160 mL), after equipped with a water separator, the reaction mixture was heated to reflux for 4 hours. The reaction was quenched by the addition of water (200 mL), extracted with ethyl acetate, and the organic phases were combined. The combined organic phase was washed successively with water (200 mL ⁇ 2), saturated sodium chloride aqueous solution (200 mL ⁇ 2), dried over anhydrous magnesium sulfate and filtered.
  • Methyl 1,4-dioxaspiro[4.4]nonane-7-carboxylate (1.00 g, 10.7 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), under the nitrogen gas atmosphere, lithium aluminum hydride (531 mg, 13.9 mmol) was slowly added at ⁇ 10° C. The reaction solution was slowly warmed to 25° C. and stirred for 3 hours. Water (0.5 mL), 15% sodium hydroxide solution (0.5 mL) and water (1.5 mL) were added successively to the reaction solution.
  • 1,4-Dioxaspiro[4.4]nonan-7-ylmethyl methanesulfonate 300 mg, 1.27 mmol was dissolved in anhydrous N,N-dimethylformamide (10 mL), under the nitrogen gas atmosphere, potassium carbonate (350 mg, 2.54 mmol), potassium iodide (21.0 mg, 0.130 mmol), 2,6-hydroxy-3,7-dimethylpurine (275 mg, 1.52 mmol) were added at 25° C. The reaction solution was heated to 130° C. and stirred for 3 hours. The reaction solution was cooled to 25° C., quenched by the addition of water (40 mL), and extracted with ethyl acetate (30 mL ⁇ 2).
  • reaction solution was diluted with water (50 mL) and the pH value was adjusted to 7 with saturated sodium bicarbonate aqueous solution (10 mL) and extracted with ethyl acetate (30 mL ⁇ 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to give two isomeric products.
  • 1,4-Dioxaspiro[4.5]decan-8-ylmethanol (2.00 g, 12.0 mmol) and diisopropylethylamine (3.10 g, 24.0 mmol) were dissolved in dichloromethane (40 mL), methanesulfonyl chloride (3.90 g, 30.0 mmol) was slowly added at 0° C. The reaction solution was warmed to 25° C. and stirred overnight. The reaction was quenched by the addition of a saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (200 mL ⁇ 3).
  • 1,4-Dioxaspiro[4.5]decan-8-ylmethyl methanesulfonate (1.50 g, 6.00 mmol), 3,7-dimethyl-1H-purine-2,6-(3H,7H)-dione (1.00 g, 6.00 mmol), potassium carbonate (2.50 g, 18.0 mmol), potassium iodide (100 mg, 0.600 mmol) were dissolved in N,N-dimethylformamide (20 mL), the reaction solution was heated to 130° C. and stirred for 3 hours. The reaction solution was cooled to 25° C., quenched with saturated brine (100 mL) and extracted with ethyl acetate (500 mL ⁇ 3).
  • reaction solution was concentrated and diluted with ethyl acetate (100 mL), the organic phase was washed with saturated sodium bicarbonate aqueous solution (50 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and separated by preparative SFC to deliver product 1 (2.5 g, white solid) (isomer 1, the first peak), yield: 19%.
  • the separation conditions column: Chiralpak AD-3 150 ⁇ 4.6 mm, I.D: 3 um, mobile phase: ethanol (0.05% diethylamine) in CO 2 from 5% to 40% at 2.5 mL/min, wavelength: 220 nm.
  • Triethyl phosphonoacetate (12.2 g, 54.4 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydride (1.92 g, 48.0 mmol) was added in portions at 0° C., the reaction was stirred under the nitrogen gas atmosphere for 30 minutes.
  • a solution of 1,4-cyclohexanedione monoethylene acetal (5.00 g, 32.0 mmol) dissolved in tetrahydrofuran (15 mL) was added dropwise to the reaction solution at 0° C., and the reaction was stirred at 25° C. for 3 hours. The reaction was quenched by the addition of water (25 mL) and extracted with dichloromethane (20 mL ⁇ 3).
  • Eethyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate (3.80 g, 17.9 mmol) was dissolved in methanol (50 mL), dry palladium on carbon (palladium 10%, water 1%, 400 mg) was added, the reaction was reacted under hydrogen gas atmosphere (50 psi) for 18 hours at room temperature. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to deliver ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate (3.50 g, colorless oil), yield: 91%.
  • Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester (5.00 g, 23.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), under the nitrogen gas atmosphere, a solution of lithium diisopropylamide (2 M tetrahydrofuran solution, 14.0 mL, 28.0 mmol) was slowly added dropwise at ⁇ 78° C., the reaction solution was stirred at ⁇ 78° C. for 1 hour. Iodomethane (6.62 g, 46.7 mmol) was slowly added and the reaction mixture was stirred for a further 1 hour. The reaction was quenched by the addition of water (100 mL).
  • Ethyl-8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (5.00 g, 21.9 mmol) was dissolved in tetrahydrofuran (50 mL), and 1 N hydrochloric acid aqueous solution (20 mL) was added dropwise at 0° C., and then stirred at 20° C. for 1 hour. The mixture was cooled to 0° C. and the reaction was quenched by the addition of a sodium bicarbonate aqueous solution (50 mL). The mixture was extracted with ethyl acetate (100 mL ⁇ 3).
  • reaction was quenched by the addition of a saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane (50 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to deliver (4-hydroxy-1-methyl-4-(trifluoromethyl)cyclohexyl)methyl methanesulfonate (2.00 g, yellow oil), yield 73%.
  • Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (5.00 g, 23.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), under the nitrogen gas atmosphere, a solution of lithium diisopropylamide (2 M n-hexane solution, 14.0 mL, 28.0 mmol) was slowly added dropwise at ⁇ 78° C., and the reaction was stirred at ⁇ 78° C. for 1 hour. Methoxybromomethane (5.83 g, 46.7 mmol) was slowly added and the reaction mixture was stirred for a further 1 hour. The reaction was quenched by the addition of water (100 mL).
  • Ethyl 8-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (5.00 g, 19.4 mmol) was dissolved in tetrahydrofuran (50 mL), 1 N dilute hydrochloric acid (10 mL) was added dropwise at 0° C. and stirred at 20° C. for 1 hour. The mixture was cooled to 0° C. and quenched by the addition of a sodium bicarbonate aqueous solution (50 mL). The mixture was extracted with ethyl acetate (100 mL ⁇ 3).
  • reaction was quenched by the addition of the saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane (50 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to deliver (4-hydroxy-1-methyl-4-(trifluoromethyl)cyclohexyl)methyl methanesulfonate (1.30 g, yellow oil), yield: 92%.
  • Methyl 4-(hydroxymethyl)cyclohexanecarboxylate (900 mg, 5.20 mmol) and triethylamine (1.58 g, 15.6 mmol) were dissolved in anhydrous dichloromethane (5 mL), under the nitrogen gas atmosphere, methanesulfonyl chloride (720 mg, 6.30 mmol) was added at 0° C. The reaction solution was warmed to 25° C. and stirred for 2 hours. The reaction was quenched by the addition of water (60 mL) and the reaction solution was extracted with ethyl acetate.
  • Methyl 4-(((methylsulfonyl)oxy)methyl)cyclohexanecarboxylate (350 mg, 2.32 mmol) was dissolved in 5 mL anhydrous N,N-dimethylformamide, under the nitrogen gas atmosphere, potassium carbonate (640 mg, 4.64 mmol), potassium iodide (38.0 mg, 0.230 mmol) and 2,6-hydroxy-3,7-dimethylpurine (501 mg, 2.80 mmol) were added at 25° C. The reaction solution was stirred at 130° C. for 3 hours.
  • Methyl 4-((3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)cyclohexanecarboxylate (100 mg, 0.30 mmol) was dissolved in 5 mL anhydrous tetrahydrofuran, under the nitrogen gas atmosphere, ethyl magnesium bromide solution (3 M solution in ether, 1 mL, 3.00 mmol) was slowly added dropwise at ⁇ 65° C. and the reaction was stirred at ⁇ 65 C for 2 hours.
  • reaction solution was added with water (40 mL) and extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure, the residue was purified by preparative high performance liquid chromatography to deliver the product 1-((4-(3-hydroxypentan-3-yl)-cyclohexyl)methyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (20.0 mg, white solid), yield: 19%.
  • trans-Cyclohexane-1,4-dicarboxylic acid monomethyl ester (5.00 g, 26.8 mmol) was dissolved in tetrahydrofuran (100 mL), borane dimethyl sulfide (3.06 g, 40.3 mmol) was added at 0° C. and the reaction mixture was reacted at room temperature for 2 hours. The reaction was quenched by the addition of the saturated methanol (50 mL).
  • Methyl trans-4-hydroxymethylcyclohexanecarboxylate (3.00 g, 23.2 mmol) and triethylamine (7.05 g, 69.6 mmol) were dissolved in dichloromethane (50 mL), and methanesulfonyl chloride (7.98 g, 69.6 mmol) was added at 0° C.
  • the reaction solution was slowly warmed to room temperature and stirred for 2 hours.
  • the reaction was quenched by the addition of sodium bicarbonate aqueous solution (50 mL).
  • the resulting mixture was extracted with dichloromethane (20 mL ⁇ 3).
  • trans-Methyl 4-(((methylsulfonyl)oxy)methyl)cyclohexanecarboxylate (1.00 g, 4.00 mmol), 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (719 mg, 4.00 mmol), potassium iodide (66.0 mg, 0.397 mmol) and potassium carbonate (1.10 g, 7.96 mmol) were dissolved in N,N-dimethylformamide (10 mL).
  • the reaction solution was heated to 120° C. and stirred for 3 hours.
  • the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure.
  • Ethyl 3-acetylbenzoate 500 mg, 2.60 mmol was dissolved in tetrahydrofuran (20 mL), trifluoromethyltrimethylsilane (370 mg, 2.60 mmol) and cesium fluoride (79.0 mg, 0.520 mmol) were added at room temperature.
  • Ethyl 3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate 500 mg, 1.91 mmol was dissolved in tetrahydrofuran (20 mL), and lithium aluminum hydride (108 mg, 2.87 mmol) was added to the reaction solution at 0° C., the mixture was stirred at room temperature for 2 hours, water (0.1 mL), 15% sodium hydroxide (0.1 mL) and water (0.3 mL) were added separately to the reaction solution and stirred for 20 minutes.
  • reaction solution was diluted with ethyl acetate (30 mL) and the organic phase was washed with water (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to deliver 1,1,1-trifluoro-2-(3-hydroxymethyl)phenyl)propan-2-ol (400 mg, yellow solid), yield: 95%.
  • 1,1,1-Trifluoro-2-(3-hydroxymethyl)phenyl)propan-2-ol 400 mg, 1.82 mmol
  • triethylamine 275 mg, 2.72 mmol
  • dichloromethane 20 mL
  • methanesulfonyl chloride 250 mg, 2.18 mmol
  • reaction solution was diluted by dichloromethane (30 mL), and the organic phase was washed with water (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to deliver 3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzyl methanesulfonate (500 mg, yellow oil), yield: 92%.
  • methyl 4-acetylbenzoate (10.0 g, 56.1 mmol) and trimethyl(trifluoromethyl)silane (16.0 g, 112 mmol) were dissolved in anhydrous tetrahydrofuran (150 mL) at 0° C., tetrabutylammonium fluoride (22.0 g, 84.2 mmol) was slowly added. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched by the addition of water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • lithium aluminum hydride (1.61 g, 42.3 mmol) was slowly added to a solution of methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (7.00 g, 28.2 mmol) in tetrahydrofuran (150 mL).
  • the reaction solution was stirred at 0° C. for 3 hours.
  • Water (1.60 mL), 15% sodium hydroxide solution (1.60 mL) and water (4.80 mL) were slowly added successively at 0° C.
  • 1,1,1-Trifluoro-2-(4-(hydroxymethyl)phenyl)propan-2-ol (5.80 g, 26.3 mmol) and diisopropylethylamine (10.2 g, 79.0 mmol) were dissolved in dichloromethane (80 mL), methanesulfonyl chloride (4.53 g, 39.5 mmol) was slowly added at 0° C. The reaction solution was stirred at 0° C. for 0.5 hour. The reaction was quenched by the addition of saturated ammonium chloride aqueous solution (50 mL) and extracted with dichloromethane (20 mL ⁇ 3).
  • 6-Bromonicotinic acid (1.00 g, 4.95 mmol) was dissolved in N,N-dimethylformamide (30 mL), iodomethane (0.703 g, 4.95 mmol) and potassium carbonate (1.03 g, 7.43 mmol) were added. The reaction solution was stirred at 20° C. for 12 hours.
  • Methyl 6-bromonicotinate (1.00 g, 4.63 mmol) was dissolved in tetrahydrofuran (20 mL), and lithium aluminum hydride (351 mg, 9.26 mmol) was added at 0° C. and reacted for 1 hour. The reaction was quenched by the addition of water (10 mL).
  • reaction solution was stirred at room temperature for 12 hours, tetrabutylammonium fluoride (50.0 mg, 0.207 mmol) was added, after stirring at room temperature for 30 minutes, the reaction mixture was diluted by ethyl acetate (20 mL) and the organic phase was washed with saturated sodium bicarbonate aqueous solution (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography to deliver 3,7-dimethyl-1-((6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyridin-3-yl)-1H-purine-2,6(3H,7H)-dione (50 mg, white solid), yield: 27%.
  • N-methoxy-N,5-dimethylpyrazine-2-carboxamide (1.50 g, 8.28 mmol) was dissolved in tetrahydrofuran (30 mL), methylmagnesium bromide (3 M ether solution, 13.3 mL, 39.9 mmol) was added at 0° C., followed by stirring at 25° C. for 1 hour. The mixture was cooled to 0° C. and the reaction was quenched by the addition of water (10 mL). The mixture was extracted with ethyl acetate (30 mL ⁇ 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Methyl 5-methylisoxazole-3-carboxylic acid ethyl ester (5.00 g, 35.4 mmol), N-bromosuccinimide (6.31 g, 35.4 mmol), benzoyl peroxide (858 mg, 3.54 mmol) were dissolved in carbon tetrachloride (20 mL), which was then reacted at 80° C. for 12 hours. The reaction was quenched by the addition of saturated sodium thiosulfate aqueous solution (30 mL).
  • Ethyl 5-(bromomethyl) isoxazole-3-carboxylate (2.00 g, 9.09 mmol), 3,7-dimethyl-1H-purine-2,6-(3H,7H)-dione (1.64 g, 9.09 mmol), potassium iodide (151 mg, 0.909 mmol) and potassium carbonate (2.51 g, 18.2 mmol) were dissolved in N,N-dimethylformamide (50 mL). The reaction solution was heated to 120° C. and stirred for 3 hours.
  • Methyl magnesium bromide solution (3 M tetrahydrofuran solution, 0.43 mL, 1.29 mmol) was slowly added dropwise to a solution of ethyl 2-(2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethoxy)acetate in tetrahydrofuran (5 mL) at ⁇ 78° C.
  • the reaction solution was stirred at ⁇ 78° C. for 2 hours.
  • the reaction was quenched by the addition of saturated ammonium chloride aqueous solution (20 mL).
  • the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • Triethylamine (600 mg, 6.00 mmol) and methanesulfonyl chloride (342 mg, 3.00 mmol) were added to a solution of 1-(2-hydroxyethyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (448 mg, 2.00 mmol) in dichloromethane (25 mL).
  • the reaction solution was stirred at 0° C. for 0.5 hour.
  • the reaction was quenched by the addition of saturated sodium bicarbonate aqueous solution (30 mL) and extracted with dichloromethane (20 mL ⁇ 3).
  • reaction solution was diluted with ethyl acetate (30 mL) and the organic phase was washed with water (20 mL ⁇ 2), dried over anhydrous sodium sulfate and concentrated to deliver a mixture of 1-(1,4-dioxaspiro[4.5]decan-8-ylmethyl)-7-(difluoromethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione and 1-(1,4-dioxaspiro[4.5]decan-8-ylmethyl)-9-(difluoromethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (234 mg, yellow oil), yield: 68%.
  • reaction solution was stirred at room temperature for 12 hours, tetrabutylammonium fluoride (50.0 mg, 0.207 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes, then was diluted by ethyl acetate (20 mL) and the organic phase was washed with saturated sodium bicarbonate aqueous solution (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography to deliver 7-(difluoromethyl)-1-(4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (54 mg, white solid), yield: 23%.
  • Ethyl 5-(7-ethyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl) valate (0.100 g, 0.310 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and ethyl magnesium bromide (3 M tetrahydrofuran solution, 0.62 mL, 1.86 mmol) was slowly added dropwise at ⁇ 78° C. The reaction solution was reacted at ⁇ 78° C. for 0.5 hour and slowly warmed to 0° C. and reacted for 0.5 hour.
  • reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL ⁇ 3).
  • the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography to deliver 7-ethyl-1-(5-ethyl-5-hydroxyheptyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (30.0 mg, colorless oil), yield: 30%.
  • 1,4-Dioxaspiro[4.5]decan-8-ylmethyl methanesulfonate 200 mg, 0.800 mmol
  • 3-methyl-7-(2,2,2-trifluoroethyl)-1H-purine-2,6(3H,7H)-dione 200 g, 0.800 mmol
  • potassium carbonate 334 mg, 2.42 mmol
  • potassium iodide 14.0 mg, 0.0800 mmol
  • 1,4-Dioxaspiro[4,5]decan-8-ylmethyl methanesulfonate (603 mg, 2.41 mmol), 3-methyl-7-(2,2,2-trifluoroethyl)-1H-purine-2,6-(3H,7H)-dione (500 mg, 2.01 mmol) and potassium iodide (33.3 mg, 0.201 mmol) were dissolved in N,N-dimethylformamide (8 mL), potassium carbonate (555 mg, 4.02 mmol) was added and the reaction was heated to 130° C. for 4 hours.
  • 6-Amino-5-bromo-1-methylpyrimidine-2,4(1H,3H)-dione (2.19 g, 10.0 mmol) was dissolved in a mixed solvent of cyclopropylamine (20 mL) and water (5 mL). The reaction solution was heated to reflux for 5 hours. The reaction solution was filtered to remove the solvent to give the crude product 6-amino-5-(cyclopropylamine)-1-methylpyrimidine-2,4(1H,3H)-dione, which was used directly for the next step.
  • 6-amino-5-(cyclopropylamine)-1-methylpyrimidine-2,4(1H,3H)-dione (1.96 g, 10.0 mmol)
  • trimethyl orthoformate (2.12 g, 20.0 mmol)
  • p-toluenesulfonic acid 86.0 mg, 0.500 mmol
  • the reaction solution was heated to 100° C. overnight.
  • the reaction solution was filtered and the solvent was removed to deliver the crude product 7-cyclopropyl-3-methyl-1H-purine-2,6(3H,7H)-dione, which was used directly for the next step.
  • 1,4-Dioxaspiro[4.5]decan-8-ylmethyl methanesulfonate 250 mg, 1.00 mmol
  • 7-isopropyl-3-methyl-1H-purine-2,6(3H,7H)-dione 208 mg, 1.00 mmol
  • potassium iodide 15.8 mg, 0.100 mmol
  • potassium carbonate 276 mg, 2.00 mmol
  • 1,4-Dioxaspiro[4.5]decan-8-ylmethyl methanesulfonate (682 mg, 2.72 mmol), 7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6-(3H,7H)-dione (500 mg, 2.27 mmol) and potassium iodide (37.7 mg, 0.227 mmol) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (627 mg, 4.54 mmol) was added and the reaction was heated to 130° C. for 4 hours.
  • reaction solution was cooled to 20° C., filtered, and the redidue was purified by preparative high performance liquid chromatography to deliver 1-((4-hydroxy-1-methyl-4-(trifluoromethyl)cyclohexyl)methyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (10.0 mg, white solid), yield: 6%.
  • reaction solution was cooled to 20° C., filtered, concentrated and then the residue was purified by preparative high performance liquid chromatography to deliver 7-(cyclopropylmethyl)-1-((4-hydroxy-1-methyl-4-(trifluoromethyl)cyclohexyl)-3-methyl-1H-purine-2,6-(3H,7H)-dione (10.0 mg, white solid), yield: 7%.

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CAS Registry No. 1320707-84-3,2/3/6/7-tetrahydro-N-[(2-hydroxyphenyl)methyl]-N/3/7-trimethyl-2,6-dioxo-IH-purine-l-acetamide, entered STN Aug. 21, 2011, in Chemical Library from FCH group.
CAS Registry No. 1321454-21-0,N-[5-(l,l-dioxido-2-isothiazolidinyl)-2-hydroxyphenyl]-2,3,6,7-tetrahydro-3,7-dimethyl-2,6-dioxolH-purine-l-acetamide, entered STN Aug. 23, 2011, in Chemical Library from FCH group.
CAS Registry No. 1321454-21-0,N45-(1,1-dioxido-2-isothiazolidiny1)-2-hydroxypheny11-2,3,6,7-tetrahydro-3,7-dimethy1-2,6-dioxoIH-purine-l-acetamide, entered STN Aug. 23, 2011, in Chemical Library from FCH group.
CAS Registry No. 1326165-12-1,2/3/6/7-tetrahydro-N-(2-hydroxy-4-methylphenyI)-3/7-dimethyl-2,6-dioxo-IH-purine-l-acetamide, entered STN Aug. 31, 2011, in Chemical Library from Ambinter SARL.
CAS Registry No. 1326165-12-1,2/3/6/7-tetrahydro-N-(2-hydroxy-4-methylphenyl)-3/7-dimethyl-2,6-dioxo-IH-purine-l-acetamide, entered STN Aug. 31, 2011, in Chemical Library from Ambinter SARL.
CAS Registry No. 1326382-53-9, N-[5-(1,1-dimethylethyl)-2-hydroxyphenyl]-2,3,6,7-tetrahydro-3,7-dimethy1-2,6-dioxo-IH-purine-l-acetamide, entered STN Sep. 1, 2011, in Chemical Library from Ambinter SARL.
CAS Registry No. 1326382-53-9, N-[5-(l,l-dimethylethyl)-2-hydroxyphenyl]-2,3,6,7-tetrahydro-3,7-dimethyl-2,6-dioxo-IH-purine-l-acetamide, entered STN Sep. 1, 2011, in Chemical Library from Ambinter SARL.
CAS Registry No. 1326534-26-2,2/3/6/7-tetrahydro-N-(2-hydroxwheny1)-3/7-dimethy1-2/6-dioxo- -IH-purine-l-acetamide, entered STN Sep. 1, 2011, in Chemical Library from AmbinterSARL-.
CAS Registry No. 1326534-26-2,2/3/6/7-tetrahydro-N-(2-hydroxyphenyl)-3/7-dimethyl-2/6-dioxo-IH-purine-l-acetamide, entered STN Sep. 1, 2011, in Chemical Library from AmbinterSARL-.
CAS Registry No. I390155-28-8,3,7-dihydro-l-[3-[[l-(3-hydroxyphenyl)ethyl]methylamino]propyl]-3,7-dimethyl-IH-purine-2,6-dione, entered STN Aug. 12, 2012, in Chemical Library from Ukrorgsyntez Ltd.
CASRegistryNumber1390155-28-8,3,7-dihydro-1-[3-[[1-(3-hydroxwhenyl)ethyl]methylamino]propyl1-3,7-dimethyl-IH-p. urine-2,6-dione, entered STN Aug. 12, 2012, in Chemical Library from Ukrorgsyntez Ltd.
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