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WO2018039972A1 - Inhibiteurs de processus métaboliques cellulaires - Google Patents

Inhibiteurs de processus métaboliques cellulaires Download PDF

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Publication number
WO2018039972A1
WO2018039972A1 PCT/CN2016/097524 CN2016097524W WO2018039972A1 WO 2018039972 A1 WO2018039972 A1 WO 2018039972A1 CN 2016097524 W CN2016097524 W CN 2016097524W WO 2018039972 A1 WO2018039972 A1 WO 2018039972A1
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mmol
compound
methoxyphenyl
pyrimidin
ring
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Inventor
Jeremy M. Travins
Zenon D. Konteatis
Zhihua Sui
Zhixiong Ye
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Agios Pharmaceuticals Inc
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Agios Pharmaceuticals Inc
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Priority to PCT/CN2016/097524 priority Critical patent/WO2018039972A1/fr
Priority to CA3034705A priority patent/CA3034705C/fr
Priority to BR112019003914-7A priority patent/BR112019003914B1/pt
Priority to PE2019000437A priority patent/PE20190761A1/es
Priority to IL265115A priority patent/IL265115B/en
Priority to SG11201901747VA priority patent/SG11201901747VA/en
Priority to UAA201902825A priority patent/UA125852C2/uk
Priority to PCT/US2017/049439 priority patent/WO2018045071A1/fr
Priority to JP2019531597A priority patent/JP6832430B2/ja
Priority to MA046092A priority patent/MA46092A/fr
Priority to NZ751515A priority patent/NZ751515B2/en
Priority to AU2017319500A priority patent/AU2017319500C1/en
Priority to CN201780066270.4A priority patent/CN109890822B/zh
Priority to CR20190157A priority patent/CR20190157A/es
Priority to KR1020197009218A priority patent/KR102411150B1/ko
Priority to MX2019002303A priority patent/MX390277B/es
Priority to US15/691,408 priority patent/US10329298B2/en
Priority to EP17764997.7A priority patent/EP3507290A1/fr
Priority to ARP170102433A priority patent/AR109495A1/es
Priority to TW106129811A priority patent/TWI762505B/zh
Publication of WO2018039972A1 publication Critical patent/WO2018039972A1/fr
Priority to US16/219,735 priority patent/US10800782B2/en
Priority to PH12019500368A priority patent/PH12019500368A1/en
Priority to NI201900019A priority patent/NI201900019A/es
Priority to CL2019000511A priority patent/CL2019000511A1/es
Anticipated expiration legal-status Critical
Priority to CONC2019/0002237A priority patent/CO2019002237A2/es
Priority to US17/000,411 priority patent/US11325914B1/en
Priority to AU2020277158A priority patent/AU2020277158A1/en
Priority to JP2021014131A priority patent/JP2021073269A/ja
Priority to US17/689,209 priority patent/USRE49934E1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of MAT2A enzyme which are useful for treating certain cancers.
  • Methionine adenosyltransferase also known as S-adenosylmethionine synthetase is a cellular enzyme that catalyzes the synthesis of S-adenosyl methionine (SAM or AdoMet) from methionine and ATP and is considered the rate-limiting step of the methionine cycle.
  • SAM is the propylamino donor in polyamine biosynthesis and the principal methyl donor for DNA methylation and is involved in gene transcription and cellular proliferation as well as the production of secondary metabolites.
  • MATlA and MAT2A encode two distinct catalytic MAT isoforms.
  • a third gene, MAT2B encodes a MAT2A regulatory subunit.
  • MATlA is specifically expressed in the adult liver, whereas MAT2A is widely distributed.
  • MAT isoforms differ in catalytic kinetics and regulatory properties, MATlA-expressing cells have considerably higher SAM levels than do MAT2A-expressing cells. It has been found that hypomethylation of the MAT2A promoter and histone acetylation causes upregulation of MAT2A expression.
  • MAT1A In hepatocellular carcinoma (HCC) , the downregulation of MAT1A and the up-regulation of MAT2A occur, which is known as the MAT1A: MAT2A switch.
  • the switch accompanied with up-regulation of MAT2B, results in lower SAM contents, which provide a growth advantage to hepatoma cells.
  • MAT2A plays a crucial role in facilitating the growth of hepatoma cells, it is a target for antineoplastic therapy. Recent studies have shown that silencing by using small interfering RNA substantially suppresses growth and induces apoptosis in hepatoma cells.
  • MTAP methylthioadenosine phosphorylase
  • MTA methylthioadenosine
  • the adenine is salvaged to generate adenosine monophosphate, and the 5-methylthioribose-1-phosphate is converted to methionine and formate. Because of this salvage pathway, MTA can serve as an alternative purine source when de novo purine synthesis is blocked, e.g., with antimetabolites, such as L-alanosine.
  • MTAP deficiency is not only found in tissue culture cells but the deficiency is also present in primary leukemias, gliomas, melanomas, pancreatic cancers, non-small cell lung cancers (NSLC) , bladder cancers, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcomas, ovarian cancers, endometrial cancers, breast cancers, soft tissue sarcomas, non-Hodgkin lymphomas, and mesotheliomas.
  • the gene encoding for human MTAP maps to region 9p21 on human chromosome 9p.
  • This region also contains the tumor suppressor genes p16INK4A (also known as CDKN2A) , and pl5INK4B. These genes code for p16 and p15, which are inhibitors of the cyclin D-dependent kinases cdk4 and cdk6, respectively.
  • the pl6INK4A transcript can alternatively be ARF spliced into a transcript encoding pl4ARF.
  • pl4ARF binds to MDM2 and prevents degradation of p53 (Pomerantz et al. (1998) Cell 92: 713-723) .
  • the 9p21 chromosomal region is of interest because it is frequently homozygously deleted in a variety of cancers, including leukemias, NSLC, pancreatic cancers, gliomas, melanomas, and mesothelioma. The deletions often inactivate more than one gene. For example, Cairns et al. ( (1995) Nat. Gen.
  • ring A and ring B are independently a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, amino, carboxy, CN and oxo;
  • ring C is a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, amino, carboxy, CN and oxo; and
  • R 1 is H or alkyl, a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, NO 2 , CN, oxo, carboxy, alkoxycarbonyl, alkoxyalkyl, aminocarbonyl, alkyl, acyl, alkoxy, alkylamino aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, aralkoxy, heteroaryloxy and heteroaralkoxy wherein said alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkoxyalkyl, aminocarbonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, aralkoxy, heteroaryloxy and heteroaralkoxy are optionally substituted with hydroxy, halogen, amino, alkylamino, carboxy, CN or oxo.
  • compositions comprising compounds of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • a method for treating a disease or condition mediated by the overexpression of MAT2A in a mammal in need thereof comprising administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of treating an MTAP null cancer in a subject comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Acyl means a carbonyl containing substituent represented by the formula -C (O) -R in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein.
  • Acyl groups include alkanoyl (e.g. acetyl) , aroyl (e.g. benzoyl) , and heteroaroyl.
  • Alkyl means a branched or unbranched, saturated or unsaturated (i.e. alkenyl, alkynyl) aliphatic hydrocarbon group, in an embodiment, having up to 12 carbon atoms unless otherwise specified.
  • alkylamino When used as part of another term, for example “alkylamino” , the alkyl portion may be a saturated hydrocarbon chain, however also includes unsaturated hydrocarbon carbon chains such as “alkenylamino” and “alkynylamino.
  • alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2, 2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2, 2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl, and the like.
  • lower alkyl C 1 -C 4 alkyl and “alkyl of 1 to 4 carbon atoms” are synonymous and used interchangeably to mean methyl, ethyl, 1-propyl, isopropyl, cyclopropyl, 1-butyl, sec-butyl or t-butyl.
  • substituted alkyl groups may contain one, for example two, three or four substituents which may be the same or different.
  • Amino means primary (i.e. –NH 2 ) , secondary (i.e. –NRH) and tertiary (i.e. –NRR) amines in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl.
  • Particular secondary and tertiary amines are alkylamine, dialkylamine, arylamine, diarylamine, aralkylamine and diaralkylamine wherein the alkyl is as herein defined and optionally substituted.
  • Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine, dipropylamine and disopropylamine.
  • Aryl when used alone or as part of another term means a carbocyclic aromatic group whether or not fused having the number of carbon atoms designated or if no number is designated, up to 14 carbon atoms.
  • Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g. Lang’s Handbook of Chemistry (Dean, J. A., ed) 13 th ed. Table 7-2 [1985] ) .
  • a particular aryl is phenyl.
  • Substituted phenyl or substituted aryl means a phenyl group or aryl group substituted with one, two, three, four or five, for example 1-2, 1-3 or 1-4 substituents chosen, unless otherwise specified, from halogen (F, Cl, Br, I) , hydroxy, protected hydroxy, cyano, nitro, alkyl (for example C 1 -C 6 alkyl) , alkoxy (for example C 1 -C 6 alkoxy) , benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocycl
  • One or more methyne (CH) and/or methylene (CH 2 ) groups in these substituents may in turn be substituted with a similar group as those denoted above.
  • substituted phenyl includes but is not limited to a mono-or di (halo) phenyl group such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2, 6-dichlorophenyl, 2, 5-dichlorophenyl, 3, 4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3, 4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono-or di (hydroxy) phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2, 4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as
  • substituted phenyl represents disubstituted phenyl groups where the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenyl groups where the substituents are different, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino, 3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted phenyl groups where the substituents are different such as 3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino.
  • Particular substituted phenyl groups include the 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3, 4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4- (1-chloromethyl) benzyloxy-phenyl, 3-methoxy-4- (1-chloromethyl) benzyloxy-6-methyl sulfonyl aminophenyl groups.
  • Fused aryl rings may also be substituted with any, for example 1, 2 or 3, of the substituents specified herein in the same manner as substituted alkyl groups.
  • Carbocyclyl refers to a mono-, bi-, or tricyclic carbon ring having 3 to 14 carbon atoms, for example 3 to 7 carbon atoms, which may be saturated, unsaturated, partially unsaturated, aromatic (aryl) or non-aromatic having the number of atoms designated, generally from 5 to about 14 ring atoms.
  • Particular saturated carbocyclic groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • a particular saturated carbocycle is cyclopropyl.
  • Another particular saturated carbocycle is cyclohexyl.
  • Particular unsaturated carbocycles are aromatic e.g. aryl groups as previously defined, for example phenyl.
  • Particular partially unsaturated carbocyclic groups are cyclobutene, cyclopentene, cyclohexene and cycloheptene.
  • substituted carbocyclyl “carbocycle” and “carbocyclo” mean these groups substituted by the same substituents as the “substituted alkyl” group unless specified otherwise.
  • Heterocyclic group “heterocyclic” , “heterocycle” , “heterocyclyl” , or “heterocyclo” alone and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, or tricyclic, saturated, unsaturated, partially unsaturated, aromatic (heteroaryl) or non-aromatic ring having the number of atoms designated, generally from 5 to about 14 ring atoms, where the ring atoms are carbon and at least one heteroatom (nitrogen, sulfur or oxygen) , for example 1 to 4 heteroatoms.
  • a 5-membered ring has 0 to 2 double bonds and 6-or 7-membered ring has 0 to 3 double bonds and the nitrogen or sulfur heteroatoms may optionally be oxidized (e.g. SO, SO 2 ) , and any nitrogen heteroatom may optionally be quaternized.
  • non-aromatic heterocycles are morpholinyl (morpholino) , pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2, 3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl, aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl, piperazinyl and piperidinyl.
  • a “heterocycloalkyl” group is a heterocycle group as defined above covalently bonded to an alkyl group as defined above.
  • Particular 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, in particular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular 1, 3, 4-thiadiazol-5-yl and 1, 2, 4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as 1, 3, 4-oxadiazol-5-yl, and 1, 2, 4-oxadiazol-5-yl.
  • Particular 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1, 3, 4-triazol-5-yl; 1, 2, 3-triazol-5-yl, 1, 2, 4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl.
  • Particular benzo-fused 5-membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
  • Particular 6-membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1, 3, 4-triazin-2-yl and 1, 3, 5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl.
  • pyridyl such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl
  • pyrimidyl such as pyrimid-2-yl and pyrimid-4-yl
  • triazinyl such as 1, 3, 4-triazin-2-yl and 1, 3, 5-triazin-4-yl
  • pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1, 3, 4-triazin-2-yl groups are a particular group.
  • Substituents for “optionally substituted heterocycles” , and further examples of the 5-and 6-membered ring systems discussed above can be found in W. Druckheimer et al., U.S. Patent No. 4,278,793.
  • such optionally substittuted heterocycle groups are substituted with hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino and guanidino.
  • Heteroaryl alone and when used as a moiety in a complex group such as a heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromatic ring system having the number of atoms designated where at least one ring is a 5-, 6-or 7-membered ring containing from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur, and in a particular embodiment at least one heteroatom is nitrogen (Lang’s Handbook of Chemistry, supra) . Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to a benzene ring. Particular heteroaryls incorporate a nitrogen or oxygen heteroatom.
  • heteroaryl whether substituted or unsubstituted groups denoted by the term “heteroaryl” : thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazin
  • a particular “heteroaryl” is: 1, 3-thiazol-2-yl, 4- (carboxymethyl) -5-methyl-1, 3-thiazol-2-yl, 4- (carboxymethyl) -5-methyl-1, 3-thiazol-2-yl sodium salt, 1, 2, 4-thiadiazol-5-yl, 3-methyl-1, 2, 4-thiadiazol-5-yl, 1, 3, 4-triazol-5-yl, 2-methyl-1, 3, 4-triazol-5-yl, 2-hydroxy-1, 3, 4-triazol-5-yl, 2-carboxy-4-methyl-1, 3, 4-triazol-5-yl sodium salt, 2-carboxy-4-methyl-1, 3, 4-triazol-5-yl, 1, 3-oxazol-2-yl, 1, 3, 4-oxadiazol-5-yl, 2-methyl-1, 3, 4-oxadiazol-5-yl, 2- (hydroxymethyl) -1, 3, 4-oxadiazol-5-yl, 1, 2, 4-oxadiazol-5-yl, 1, 3, 4-thiadiazol-5-yl, 2-thio
  • heteroaryl includes; 4- (carboxymethyl) -5-methyl-1, 3-thiazol-2-yl, 1, 3, 4-triazol-5-yl, 2-methyl-1, 3, 4-triazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1- (1- (dimethylamino) eth-2-yl) -1H-tetrazol-5-yl, 1- (carboxymethyl) -1H-tetrazol-5-yl, 1- (methylsulfonic acid) -1H-tetrazol-5-yl, 1, 2, 3-triazol-5-yl, 1, 4, 5, 6-tetrahydro-5, 6-dioxo-4-methyl-as-triazin-3-yl, 1, 4, 5, 6-tetrahydro-4- (2-formylmethyl) -5, 6-dioxo-as-triazin-3-yl, 2, 5-dihydro-5-oxo-6-
  • “Inhibitor” means a compound which prevents or reduces the amount of synthesis of S-adenosylmethionine (SAM) from methionine and ATP by MAT2A. In an embodiment, an inhibitor binds to MAT2A.
  • SAM S-adenosylmethionine
  • Optionally substituted unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g. 2, 3 or 4) of the substituents listed for that group in which said substituents may be the same or different.
  • an optionally substituted group has 1 substituent.
  • an optionally substituted group has 2 substituents.
  • an optionally substituted group has 3 substituents.
  • “Pharmaceutically acceptable salts” include both acid and base addition salts.
  • compounds of the invention are in the form of a pharmaceutically acceptable salt.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, an
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylamin
  • Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
  • the compound of the invention is a salt.
  • the compound of the invention is a pharmaceutically acceptable salt.
  • the compound of the invention is an acetate.
  • the compound of the invention is a benzoate salt.
  • the compound of the invention is a besylate salt.
  • the compound of the invention is a bitartrate salt.
  • the compound of the invention is a bromide salt.
  • the compound of the invention is a carbonate salt.
  • the compound of the invention is a chloride salt.
  • the compound of the invention is a citrate salt. In an embodiment, the compound of the invention is an edetate salt. In an embodiment, the compound of the invention is an edisylate salt. In an embodiment, the compound of the invention is a estolate salt. In an embodiment, the compound of the invention is a fumerate salt. In an embodiment, the compound of the invention is a gluceptate salt. In an embodiment, the compound of the invention is a gluconate salt. In an embodiment, the compound of the invention is a hydrobromide salt. In an embodiment, the compound of the invention is a hydrochloride salt. In an embodiment, the compound of the invention is an iodide salt. In an embodiment, the compound of the invention is a lactate salt.
  • the compound of the invention is a lactobionate salt. In an embodiment, the compound of the invention is a malate salt. In an embodiment, the compound of the invention is a maleate salt. In an embodiment, the compound of the invention is a madelate salt. In an embodiment, the compound of the invention is a mesylate salt. In an embodiment, the compound of the invention is a methyl bromide salt.
  • the compound of the invention is a methyl sulfate salt. In an embodiment, the compound of the invention is a mcate salt. In an embodiment, the compound of the invention is a napsylate salt. In an embodiment, the compound of the invention is a nitrate salt. In an embodiment, the compound of the invention is a pamoate salt. In an embodiment, the compound of the invention is a phosphate salt. In an embodiment, the compound of the invention is a disphosphate salt. In an embodiment, the compound of the invention is a salicylate salt. In an embodiment, the compound of the invention is a disalicylate salt. In an embodiment, the compound of the invention is a stearate salt.
  • the compound of the invention is a succinate salt. In an embodiment, the compound of the invention is a sulfate salt. In an embodiment, the compound of the invention is a tartrate salt. In an embodiment, the compound of the invention is a tosylate salt. In an embodiment, the compound of the invention is a triethiodide salt. In an embodiment, the compound of the invention is a valerate salt. In an embodiment, the compound of the invention is an aluminum salt. In an embodiment, the compound of the invention is a benzathine salt. In an embodiment, the compound of the invention is a calcium salt. In an embodiment, the compound of the invention is a ethylenediamine salt. In an embodiment, the compound of the invention is a lysine salt.
  • the compound of the invention is a magnesium salt. In an embodiment, the compound of the invention is a meglumine salt. In an embodiment, the compound of the invention is a potassium salt. In an embodiment, the compound of the invention is a procaine salt. In an embodiment, the compound of the invention is a sodium salt. In an embodiment, the compound of the invention is a tromethamine salt. In an embodiment, the compound of the invention is a zinc salt.
  • Compounds of the invention may exist in different tautomeric forms. In an embodiment, the compounds are in the form as drawn or named. In another embodiment, the compounds are in a tautomeric form other than as drawn or named. Compounds of the inventions may exist as one or a mixture of salts and solvate forms. For example a compound of the invention may be substantially pure in one particular salt or solvate form or else may be mixtures of two or more salt or solvate forms. In an embodiment, the compounds are in solvate form. In a particular embodiment, the compounds exist as hydrates.
  • the present invention provides compounds having the general formula I:
  • ring A and ring B are independently a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, amino, carboxy, CN and oxo;
  • ring C is is a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, carboxy, CN, oxo, alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, NH 2 , carboxy, CN, oxo, a carbocycle or a heterocycle wherein said carbocycle and heterocycle are optionally substitued with OH, oxo, amino, halo and haloalkyl;
  • R 1 is H or alkyl, a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, NO 2 , CN, oxo, carboxy, alkoxycarbonyl, alkoxyalkyl, aminocarbonyl, alkyl, acyl, alkoxy, alkylamino aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, aralkoxy, heteroaryloxy and heteroaralkoxy wherein said alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkoxyalkyl, aminocarbonyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aryloxy, aralkoxy, heteroaryloxy and heteroaralkoxy are optionally substituted with hydroxy, halogen, amino, alkylamino, carboxy, CN or oxo.
  • ring A and ring B are independently a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, amino, carboxy, CN and oxo.
  • said optionally substituted carbocycle is aromatic.
  • ring A or ring B is optionally substituted phenyl.
  • said phenyl is substituted with one or more groups consisting of halogen, amino, hydroxy and alkoxy.
  • ring A or ring B is phenyl substituted with one or more groups consisting of F, Cl, NH 2 and OH.
  • ring A is phenyl.
  • ring A is 2-fluorophenyl.
  • ring A is 3-fluorophenyl.
  • ring A is 3-chlorophenyl.
  • ring A is 4-aminophenyl.
  • ring A is 4-hydroxyphenyl.
  • Ring A is a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH 2 , carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH 2 , carboxy, CN and oxo.
  • ring A is an optionally substituted carbocycle is saturated or partially unsaturated.
  • said saturated or partially unsaturated carbocycle is substituted with one or more of the group consisting of hydroxy, halogen, NH 2 , carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH 2 , carboxy, CN and oxo.
  • said said saturated or partially unsaturated carbocycle is substituted with one or more halogen.
  • said halogen is one or two F.
  • ring A is optionally substituted cyclohex-1-en-yl.
  • said saturated or partially unsaturated ring is deuterated.
  • said ring is fully deuterated.
  • ring A is cyclohex-1-en-1-yl (E) .
  • ring A is ( 2 H 9 ) cyclohex-1-en-1-yl.
  • ring A is cyclohexa-E, Z-1, 3-dien-1-yl.
  • ring A is 4, 4-difluorocyclohex-1-en-1-yl.
  • ring A is cyclopent-E1-en-1yl.
  • ring A is cyclopentyl.
  • ring A is a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH 2 , carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH 2 , carboxy, CN and oxo.
  • said heterocycle is aromatic i.e. heteroaryl.
  • said heteroaryl is pyridine.
  • said heteroaryl is pyridin-3-yl.
  • said heteroaryl is pyridin-2-yl.
  • said heteroaryl is pyrazole.
  • ring A is 4-methoxypyridin-3-yl. In a particular embodiment, ring A is pyridin-2-yl. In a particular embodiment, ring A is 1H-pyrazol-4-yl. In an embodiment, ring A is 1H-pyrrol-3-yl.
  • said heterocycle is non-aromatic. In an embodiment, said heterocycle is substituted with halogen or alkoxy. In an embodiment, said halogen is one or two F.
  • said heterocycle is deuterated. In an embodiment, said heterocycle is fully deuterated.
  • ring A is piperidin-1-yl. In a particular embodiment, ring A is ( 2 H 10 ) piperidin-1-yl. In a particular embodiment, ring A is 4, 4-difluoropiperidin-1-yl. In a particular embodiment, ring A is 5, 6-dihydro-2H-pyran-3-yl (Z) . In a particular embodiment, ring A is 3, 6-dihydro-2H-pyran-4-yl. In a particular embodiment, ring A is 1H-pyrrol-3-yl. In a particular embodiment, ring A is 1H-pyrrol-1-yl. In a particular embodiment, ring A is tetrahydrofuran-3-yl. In a particular embodiment, ring A is 3, 3-difluoropyrrolidin-1-yl.
  • ring A is 3, 6-dihydro-2H-pyran-4-yl.
  • Ring B is a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH 2 , carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH 2 , carboxy, CN and oxo.
  • ring B is phenyl.
  • ring B is 2-fluorophenyl.
  • ring B is 3-fluorophenyl.
  • ring B is 3-chlorophenyl.
  • ring B is 4-aminophenyl. In a particular embodiment ring B is 4-hydroxyphenyl.
  • ring B is an optionally substituted carbocycle that is saturated or partially unsaturated. In an embodiment said saturated or partially unsaturated carbocycle is substituted with one or more of the group consisting of hydroxy, halogen, NH 2 , carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH 2 , carboxy, CN or oxo. In an embodiment said said saturated or partially unsaturated carbocycle is substituted with one or more halogen.
  • said halogen is one or two F.
  • ring B is optionally substituted cyclohex-1-en-yl.
  • said saturated or partially unsaturated ring is deuterated.
  • said ring is fully deuterated.
  • ring B is cyclohex-1-en-1-yl (E) .
  • ring B is ( 2 H 9 ) cyclohex-1-en-1-yl.
  • ring B is cyclohexa-E, Z-1, 3-dien-1-yl.
  • ring B is 4, 4-difluorocyclohex-1-en-1-yl.
  • ring B is cyclopent-E1-en-1yl.
  • ring B is cyclopentyl.
  • ring B is a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH 2 , carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH 2 , carboxy, CN and oxo.
  • said heterocycle is aromatic i.e. heteroaryl.
  • said heteroaryl is pyridine.
  • said heteroaryl is pyridin-3-yl.
  • said heteroaryl is pyridin-2-yl.
  • said heteroaryl is pyrazole.
  • ring B is 4-methoxypyridin-3-yl. In a particular embodiment, ring B is pyridin-2-yl. In a particular embodiment, ring B is 1H-pyrazol-4-yl. In an embodiment, ring B is 1H-pyrrol-3-yl.
  • said heterocycle is non-aromatic. In an embodiment, said heterocycle is substituted with halogen or alkoxy. In an embodiment, said halogen is one or two F. In an embodiment, said heterocycle is deuterated. In an embodiment, said heterocycle is fully deuterated.
  • ring B is piperidin-1-yl. In a particular embodiment, ring B is ( 2 H 10 ) piperidin-1-yl. In a particular embodiment, ring B is 4, 4-difluoropiperidin-1-yl. In a particular embodiment, ring B is 5, 6-dihydro-2H-pyran-3-yl (Z) .
  • ring B is 3, 6-dihydro-2H-pyran-4-yl. In a particular embodiment, ring B is 1H-pyrrol-3-yl. In a particular embodiment, ring B is 1H-pyrrol-1-yl. In a particular embodiment, ring B is tetrahydrofuran-3-yl. In a particular embodiment, ring B is 3, 3-difluoropyrrolidin-1-yl.
  • ring B is 3, 6-dihydro-2H-pyran-4-yl.
  • ring A and ring B are the same as defined herein. In an embodiment ring A and ring B are both phenyl. In an embodiment, ring A and ring B are different and are as defined herein. In an embodiment, ring A is phenyl and ring B is selected from the group consisting of 2-fluorophenyl, 3-fluorophenyl, 4-aminophenyl, 4-hydroxyphenyl, 4-methoxypyridin-3-yl, pyridin-2-yl, 1H-pyrazol-4-yl, 3, 6-dihydro-2H-pyran-4-yl, and 1H-pyrrol-3-yl,.
  • ring B is phenyl and ring A is selected from the group consisting of 2-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, piperidin-1-yl, ( 2 H 10 ) piperidin-1-yl, 4, 4-difluoropiperidin-1-yl, cyclohex-1-en-1-yl (E) , ( 2 H 9 ) cyclohex-1-en-1-yl, cyclohexa-E, Z-1, 3-dien-1-yl, 4, 4-difluorocyclohex-1-en-1-yl, 5, 6-dihydro-2H-pyran-3-yl (Z) , 3, 6-dihydro-2H-pyran-4-yl, cyclopentyl, cyclopent-E1-en-1yl, 1H-pyrrol-3-yl, 1H-pyrrol-1-yl, tetrahydrofuran-3-yl, and 3, 3-difluor
  • ring B is phenyl and ring A is cyclohex-1-en-1-yl (E) .
  • ring B is phenyl and ring A is 2-fluorophenyl.
  • ring B is phenyl and ring A is 3-fluorophenyl.
  • ring B is phenyl and ring A is 3-chlorophenyl.
  • ring B is phenyl and ring A is piperidin-1-yl.
  • ring B is phenyl and ring A is ( 2 H 10 ) piperidin-1-yl.
  • ring B is phenyl and ring A is 4, 4-difluoropiperidin-1-yl. In an embodiment, ring B is phenyl and ring A is cyclohex-1-en-1-yl (E) . In an embodiment, ring B is phenyl and ring A is ( 2 H 9 ) cyclohex-1-en-1-yl.
  • ring B is phenyl and ring A is cyclohexa-E, Z-1, 3-dien-1-yl. In an embodiment, ring B is phenyl and ring A is 4, 4-difluorocyclohex-1-en-1-yl. In an embodiment, ring B is phenyl and ring A is 5, 6-dihydro-2H-pyran-3-yl (Z) . In an embodiment, ring B is phenyl and ring A is 3, 6-dihydro-2H-pyran-4-yl. In an embodiment, ring B is phenyl and ring A is cyclopentyl.
  • ring B is phenyl and ring A is cyclopent-E1-en-1yl. In an embodiment, ring B is phenyl and ring A is 1H-pyrrol-3-yl. In an embodiment, ring B is phenyl and ring A is 1H-pyrrol-1-yl. In an embodiment, ring B is phenyl and ring A is tetrahydrofuran-3-yl. In an embodiment, ring B is phenyl and ring A is 3, 3-difluoropyrrolidin-1-yl. In an embodiment, ring B is pyridin-2-yl and ring A is phenyl.
  • Ring C is is a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, carboxy, CN, oxo, alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, NH 2 , carboxy, CN, oxo, a carbocycle or a heterocycle wherein said carbocycle and heterocycle are optionally substitued with OH, oxo, amino, halo and haloalkyl.
  • ring C is a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, amino, carboxy, CN and oxo.
  • ring C is a carbocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, carboxy, CN, oxo, phosphate, sulfate, alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, NH 2 , carboxy, CN, oxo, phosphate, sulfate, a carbocycle or a heterocycle wherein said carbocycle and heterocycle are optionally substitued with OH, oxo, amino, halo and haloalkyl.
  • substituents selected from the group consisting of hydroxy, halogen, amino
  • said optionally substituted carbocycle is aromatic i.e. aryl.
  • said aryl group is substituted with one or more substituents selected from the group consisting of OH, amino, halogen, alkyl, alkoxy and cycloalkoxy wherein said alkyl, alkoxy, cycloalkoxy are optionally substituted with one or more OH, halogen, amino, oxo, a carbocycle or heterocycle wherein said carbocycle and heterocycle are optionally substituted with hydroxy, halogen, oxo, alkyl and haloalkyl.
  • said aryl group is optionally substituted with OH, halogen, alkoxy, amino, haloalkoxy, aminoethoxy and hydroxyethoxy.
  • said aryl group is phenyl.
  • ring C is phenyl.
  • ring C is phenyl substituted with OH, F, Cl, methyl, methoxy, ethoxy, trifluoromethoxy, 2, 2, 2-trifluoroethoxy, dimethylaminoethoxy, 2-hydroxyethoxy and phosphate.
  • ring C is 3-hydroxyphenyl.
  • ring C is 4-hydroxyphenyl.
  • ring C is 4-chlorophenyl.
  • ring C is 4-fluorophenyl. In a particular embodiment ring C is 4-methoxyphenyl. In a particular embodiment ring C is 4-ethoxyphenyl. In a particular embodiment ring C is 4-trifluoromethoxyphenyl. In a particular embodiment ring C is 4-hydroxy-2-methylphenyl. In a particular embodiment ring C is 4-hydroxy-2-methoxyphenyl. In a particular embodiment ring C is 3, 4-dihydroxyphenyl. In a particular embodiment ring C is 4- (2, 2, 2-trifluoroethoxy) phenyl. In a particular embodiment ring C is 4- (2- (dimethylamino) ethoxy) phenyl.
  • ring C is 3-fluoro-4-hydroxyphenyl. In a particular embodiment ring C is 3-fluoro-4-methoxyphenyl. In a particular embodiment ring C is 2-chloro-4-hydroxyphenyl. In a particular embodiment ring C is 2-fluoro-4-methoxyphenyl. In a particular embodiment ring C is 3-amino-4-hydroxyphenyl. In a particular embodiment ring C is 3-amino-4-fluorophenyl. In a particular embodiment ring C is 3- (N, N-dimethylaminoethoxy) -4-hydroxyphenyl. In a particular embodiment ring C is 3-chloro-2-hydroxyphenyl. In a particular embodiment ring C is 3-hydroxyethoxy-4-hydroxyphenyl. In another embodiment, ring C is selected from the group consisting of:
  • ring C is a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, carboxyl, CN, oxo, phosphate, sulfate, alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, a carbocycle or a heterocycle wherein said alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, NH 2 , carboxy, CN, oxo, phosphate, sulfate, a carbocycle or a heterocycle wherein said carbocycle and heterocycle are optionally substitued with OH, oxo, amino, halo and haloalkyl.
  • substituents selected from the group consisting of hydroxy, halogen, amino
  • said optionally substituted heterocycle is aromatic i.e. heteroaryl.
  • said heteroaryl is optionally substituted with one or more substituents selected from the group consisting of OH, amino, halogen, alkyl, alkoxy and cycloalkoxy wherein said alkyl, alkoxy and cycloalkoxy are optionally substituted with one or more OH, halogen, amino, oxo, a carbocycle or heterocycle wherein said carbocycle and heterocycle are optionally substituted with hydroxy, halogen, oxo, alkyl and haloalkyl.
  • ring C is a heteroaryl group optionally substituted with OH, amino, alkyl, carboxyl, alkyl, alkoxy and cycloalkoxy wherein said alkyl is optionally substituted with OH, amino, oxo, alkoxy, a heterocycle optionally substituted with oxo and wherein said cycloalkoxy is optionally substituted with OH.
  • ring C is 6-methoxypyridin-3-yl.
  • ring C is 2-methoxypyridin-4-yl.
  • ring C is 1H-pyrazol-4-yl.
  • ring C is quinolin-6-yl.
  • ring C is 2-methylquinolin-6-yl. In an embodiment, ring C is 2-methoxyquinolin-6-yl. In an embodiment, ring C is 2-hydroxymethylquinolin-6-yl. In an embodiment, ring C is 3-hydroxy-2-methylquinolin-6-yl. In an embodiment, ring C is 2-aminoquniazolin-6-yl. In an embodiment, ring C is 4-aminoquinazolin-6-yl. In an embodiment, ring C is cinnolin-6-yl. In an embodiment, ring C is quinoxalin-6-yl. In an embodiment, ring C is 2-chloroquinoxalin-6-yl.
  • ring C is 3-chloroquinoxalin-6-yl. In an embodiment, ring C is 3-aminoquinoxalin-6-yl. In an embodiment, ring C is 3-hydroxyquinoxalin-6-yl. In an embodiment, ring C is 3-methoxyquinoxalin-6-yl. In an embodiment, ring C is 1, 8-naphthyridin-3-yl. In an embodiment, ring C is imidazo [1, 2-a] pyridin-6-yl.
  • ring C is optionally substituted benzo [d] thiazol-6-yl. In another embodiment, ring C is selected from the group consisting of
  • ring C is optionally substituted 1H-benzo [d] imidazol-5-yl. In another embodiment, ring C is selected from the group consisting of
  • ring C is optionally substituted quinolin-6-yl. In another embodiment, ring C is selected from the group consisting of
  • ring C is selected from the group consisting of
  • R 1 is H or alkyl, a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH 2 , NO 2 , carboxy, alkoxycarbonyl, alkoxyalkyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino wherein said alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkoxyalkyl and alkylaminocarbonyl are optionally substituted with hydroxy, halogen, amino, alkylamino, carboxy, CN and oxo.
  • R 1 is alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH 2 , NO 2 , carboxy, alkoxycarbonyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino wherein said alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkylaminocarbonyl are optionally substituted with hydroxy, halogen, NH 2 , alkylamino, carboxy, CN and oxo.
  • R 1 is alkyl substituted with OH and oxo.
  • R 1 is hydroxyethanoyl.
  • R 1 is a carbocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH 2 , NO 2 , carboxy, alkoxycarbonyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino wherein said alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkylaminocarbonyl are optionally substituted with hydroxy, halogen, NH 2 , alkylamino, carboxy, CN and oxo.
  • R 1 is a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH 2 , NO 2 , carboxy, alkoxycarbonyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino wherein said alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkylaminocarbonyl are optionally substituted with hydroxy, halogen, NH 2 , alkylamino, carboxy, CN and oxo.
  • said optionally substituted heterocycle is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1, 3, 5-triazinyl or 1, 2, 4-triazinyl.
  • said optionally substituted heterocycle is pyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, 1, 3, 5-triazin-2-yl or 1, 2, 4-triazin-3-yl.
  • R 1 is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1, 3, 5-triazinyl or 1, 2, 4-triazinyl each of which is optionally substituted with one or more F, Cl, CN, OH, NO 2 , NH 2 , NHMe –C (O) NH 2 and methoxy.
  • the substituent is F, Cl, CN or OH.
  • said optionally substituted heterocycle is pyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, 1, 3, 5-triazin-2-yl or 1, 2, 4-triazin-3-yl each of which is optionally substituted with one or more F, Cl, CN, OH, NO 2 , NH 2 , NHMe –C (O) NH 2 and methoxy.
  • the substituent is F, Cl, CN or OH.
  • R 1 is selected from the group consisting of
  • R 1 is a 5-member heterocycle optionally substituted with OH, amino, alkyl, alkoxy and alkoxyalkyl wherein said alkyl, alkoxy and alkoxyalkyl are optionally substituted with one or more OH, oxo, amino, alkoxy and acyloxy.
  • R 1 is imidazole, pyrazolyl, isoxazole, thiazolyl, 4, 5-dihydrothiazolyl, 1H-1, 2, 4-triazolyl, 2H-1, 2, 3-triazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-thiadiazolyl or 1, 3, 4-thiadiazol-2-yl optionally substituted with OH, amino, alkyl, alkoxy, alkoxyalkyl, wherein said alkyl, alkoxy and alkoxyalkyl groups are optionally substituted with OH, oxo and amino.
  • R1 is imidazol-2-yl, imidazol-4-yl, pyrazol-3-yl, pyrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, 4, 5-dihydrothiazol-2-yl, 1H-1, 2, 4-triazol-3-yl, 2H-1, 2, 3-triazol-4-yl, 1, 3, 4-oxadiazol-2-yl, 1, 2, 5-oxadiazol-3-yl, 1, 2, 4-thiadiazol-5-yl or1, 3, 4-thiadiazol-2-yl optionally substituted with OH, amino, alkyl, alkoxy, alkoxyalkyl, wherein said alkyl, alkoxy and alkoxyalkyl groups are optionally substituted with OH, oxo and amino.
  • R 1 is selected from the group consisting of
  • H may be in any isotopic form, including 1H, 2H (D or deuterium) , and 3H (T or tritium) ;
  • C may be in any isotopic form, including 11C, 12C, 13C, and 14C;
  • N may be in any isotopic form, including 13N, 14N and 15N;
  • O may be in any isotopic form, including 15O, 16O and 18O;
  • F may be in any isotopic form, including 18F; and the like.
  • the compound is enriched in a specific isotopic form of H, C, N, O and/or F by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • Such compounds may be referred to as “isotopologues” and may be useful of the methods of treatment disclosed herein or may be useful in assays for detection of the compound, for example, in competition assays to test other non-isotope containing compounds.
  • compounds of the invention comprise an isotope.
  • the isotope is deuterium.
  • Particular compounds of formula (I) include the following:
  • prodrugs of the compounds described above include known amino-protecting and carboxy-protecting groups which are released, for example hydrolyzed, to yield the parent compound under physiologic conditions.
  • a particular class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidino group is substituted with a hydroxy (OH) group, an alkylcarbonyl (-CO-R) group, an alkoxycarbonyl (-CO-OR) , an acyloxyalkyl-alkoxycarbonyl (-CO-O-R-O-CO-R) group where R is a monovalent or divalent group and as defined above or a group having the formula -C (O) -O-CP1P2-haloalkyl, where P1 and P2 are the same or different and are H, lower alkyl, lower alkoxy, cyano, halo lower alkyl
  • the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the invention.
  • These prodrug compounds are prepared reacting the compounds of the invention described above with an activated acyl compound to bond a nitrogen atom in the compound of the invention to the carbonyl of the activated acyl compound.
  • Suitable activated carbonyl compounds contain a good leaving group bonded to the carbonyl carbon and include acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, in particular acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and difluorophenoxy acyl.
  • the reactions are generally exothermic and are carried out in inert solvents at reduced temperatures such as –78 to about 50C.
  • the reactions are usually also carried out in the presence of an inorganic base such as potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, triethylamine, etc.
  • an inorganic base such as potassium carbonate or sodium bicarbonate
  • an organic base such as an amine, including pyridine, triethylamine, etc.
  • step A of scheme 1 acetate starting material a incorporating ring C is reacted with dimethyl carbonate in presence of a suitable strong base such as potassium t-butoxide to provide dimethyl malonate intermediate b which is reacted in a suitable solvent such as xylene with intermediate c , 1H-pyrazol-5-amine substiuted with rings A and B, to provide the 5-hydroxy substituted pyrazolopyrimidone intermediate d incorporating rings A, B and C.
  • the 5-hydroxy group is then converted to the chloro intermediate e by reacting with phosphoryl chloride which also converts the 7-keto group to a chloro.
  • the 7-chloro group is converted to a methoxy group in step D by reacting intermediate e with sodium methoxide to give intermediate f which is then aminated at the 5-position of the pyrazolopyrimidone ring in step E by reacting with the amine intermediate g in the presence of a palladium catalyst to give intermediate h .
  • the 7-methoxy group is hydrolyzed to a ketone in step F to give the final product of formula (I) .
  • Aminopyrazole intermediate c from scheme 1 may be prepared using standard organic synthetic techniques from commercially available starting materials and reagents.
  • Scheme 2 illustrates a general procedure for preparing the intermediate.
  • Acetonitrile intermediate m incorporating ring A is reacted with ester n incorporating ring B with an appropriate base catalyst such as sodium hexamethyldisilazide to form 3-oxo-propanenitrile intermediate o containing both ring A and ring B. This is then reacted with hydrazine hydrate to form 5-aminopyrazolo intermediate c which may be used in scheme 1 to prepare compounds of the invention.
  • an appropriate base catalyst such as sodium hexamethyldisilazide
  • R 1 is as defined herein.
  • X is Cl.
  • the reaction is catalyzed with a palladium complex.
  • the reaction is catalyzed with a palladium-Xantphos complex.
  • the reaction is catalyzed with Pd (OAc) 2 -Xantphos complex.
  • the reaction is performed in dioxane solvent.
  • reaction is performed in methanol.
  • reaction is heated.
  • the MAT2A enzyme catalyzes the synthesis of S-adenosyl methionine (SAM) from methionine and ATP in cells. Accordingly, in another aspect of the invention there is provided a method of inhibiting the synthesis of SAM in a cell from methionine and ATP comprising introducing into said cell an effective amount of a compound of formula (I) or a salt thereof.
  • compounds of formula (I) may be used to identify other compounds that are inhibitors of MAT2A, for example, in a competition assay for binding to MAT2A or for the inhibition of SAM production. Binding to MAT2A or the inhibition of SAM by a test compound having a detectable label can be measured with and without the presence of an unlabelled compound of the invention.
  • a method for treating a cancer mediated by the overexpression of MAT2A comprising contacting said cancer with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for treating a disease or condition mediated by the overexpression of MAT2A in a mammal comprising administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the cancer is neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tong carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroidea carcinoma, papillary thyroidea carcinoma, renal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphom
  • the cancer is lung cancer, non-small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, he
  • Methylthioadenosine phosphorylase is an enzyme found in all normal tissues that catalyzes the conversion of methylthioadenosine (MTA) into adenine and 5-methylthioribose-1-phosphate.
  • MTA methylthioadenosine
  • the adenine is salvaged to generate adenosine monophosphate, and the 5-methylthioribose-1-phosphate is converted to methionine and formate. Because of this salvage pathway, MTA can serve as an alternative purine source when de novo purine synthesis is blocked, e.g., with antimetabolites, such as L-alanosine.
  • Many human and murine malignant cells lack MTAP activity.
  • MTAP deficiency is not only found in tissue culture cells but the deficiency is also present in primary leukemias, gliomas, melanomas, pancreatic cancers, non-small cell lung cancers (NSLC) , bladder cancers, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcomas, ovarian cancers, endometrial cancers, breast cancers, soft tissue sarcomas, non-Hodgkin lymphomas, and mesotheliomas.
  • NSLC non-small cell lung cancers
  • a method for treating a cancer in a subject wherein said is characterized by a reduction or absence of MTAP expression or absence of the MTAP gene or reduced function of MTAP protein said method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the MTAP null cancer is leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer (NSLC) , bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma or mesothelioma.
  • the MTAP null cancer is pancreatic cancer.
  • the MTAP null cancer is bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, esophageal cancer, head and neck cancer, kidney cancer, colon cancer, diffuse large B cell lymphoma (DLBCL) , acute lymphoblastic leukemia (ALL) or mantle cell lymphoma (MCL) .
  • the MTAP null cancer is pancreatic cancer.
  • the MTAP null cancer is gastric cancer.
  • the cancer is colon cancer.
  • the MTAP null cancer is liver cancer.
  • the MTAP null cancer is GBM.
  • the MTAP null cancer is bladder cancer.
  • the MTAP null cancer is esophageal cancer. In an embodiment, the MTAP null cancer is breast cancer. In an embodiment, the MTAP null cancer is NSCLC. In an embodiment, the MTAP null cancer is MCL. In an embodiment, the MTAP null cancer is DLBCL. In an embodiment, the MTAP null cancer is ALL.
  • the present invention provides a method for treating a cancer in a subject wherein said cancer is characterized by reduction or absence of MTAP expression or absence of the MTAP gene or reduced function of MTAP protein said method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) , wherein said cancer is further characterized by the presence of mutant KRAS or mutant p53.
  • a method of treating an MTAP null cancer having a mutant KRAS or mutant p53 in a subject comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the cancer is MTAP null and KRAS mutant.
  • the cancer is MTAP null and p53 mutant.
  • the cancer is MTAP null, KRAS mutant and p53 mutant.
  • mutant KRAS, or KRAS mutation is meant KRAS protein incorporating an activating mutation that alters its normal function and the gene encoding such a protein.
  • a mutant KRAS protein may incorporate a single amino acid substitution at position 12 or 13.
  • the KRAS mutant incorporates a G12X or G13X substitution.
  • the substitution is G12V, G12R, G12C or G13D.
  • the substitution is G13D.
  • mutant p53 or “p53 mutation” is meant p53 protein (or gene encoding said protein) incorporating a mutation that inhibits or eliminates its tumor suppressor function.
  • said p53 mutation is, Y126_splice, K132Q, M133K, R174fs, R175H, R196*, C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C, R282W, A159V or R280K.
  • the foregoing cancer is non-small cell lung cancer (NSCLC) , pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer or ovarian cancer.
  • Suitable cytostatic chemotherapy compounds include, but are not limited to (i) antimetabolites, such as cytarabine, fludarabine, 5-fluoro-2‘-deoxyuiridine, gemcitabine, hydroxyurea or methotrexate; (ii) DNA-fragmenting agents, such as bleomycin, (iii) DNA-crosslinking agents, such as chlorambucil, cisplatin, cyclophosphamide or nitrogen mustard; (iv) intercalating agents such as adriamycin (doxorubicin) or mitoxantrone; (v) protein synthesis inhibitors, such as L-asparaginase, cycloheximide, puromycin or diphtheria toxin; (Vi) topoisomerase I poisons, such as camptothecin or topotecan; (vii) topo
  • antimetabolites such as cytarabine, fludarabine, 5-fluoro-2‘-deoxyuir
  • compounds of the present invention are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C.
  • the cytostatic compound is doxorubicin.
  • compounds of the invention may be used alone as an immuno-oncology therapy or in combination with an immuno-oncology therapy.
  • the compound of the invention is administered prior to, concomitantly with, or following administration of an immune checkpoint inhibitor.
  • the checkpoint inhibitor is a PD-1 inhibitor.
  • the checkpoint inhibitor is a PD-L1 inhibitor.
  • the checkpoint inhibitor is ipilimumab. In an embodiment, the checkpoint inhibitor is pembrolizumab. In an embodiment, the checkpoint inhibitor is nivolumab. In an embodiment, the checkpoint inhibitor is atezolizumab.
  • the compounds of the present invention can be also used in combination with radiation therapy.
  • radiation therapy refers to the use of electromagnetic or particulate radiation in the treatment of neoplasia. Radiation therapy is based on the principle that high-dose radiation delivered to a target area will result in the death of reproducing cells in both tumor and normal tissues.
  • the radiation dosage regimen is generally defined in terms of radiation absorbed dose (rad) , time and fractionation, and must be carefully defined by the oncologist.
  • the amount of radiation a patient receives will depend on various consideration but the two most important considerations are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread.
  • radiotherapeutic agents are provided in, but not limited to, radiation therapy and is known in the art (Hellman, Principles of Radiation Therapy, Cancer, in Principles I and Practice of Oncology, 24875 (Devita et al., 4th ed., vol 1, 1993) .
  • Recent advances in radiation therapy include three-dimensional conformal external beam radiation, intensity modulated radiation therapy (IMRT) , stereotactic radiosurgery and brachytherapy (interstitial radiation therapy) , the latter placing the source of radiation directly into the tumor as implanted "seeds" .
  • IMRT intensity modulated radiation therapy
  • brachytherapy interstitial radiation therapy
  • Ionizing radiation with beta-emitting radionuclides is considered the most useful for radiotherapeutic applications because of the moderate linear energy transfer (LET) of the ionizing particle (electron) and its intermediate range (typically several millimeters in tissue) .
  • LET linear energy transfer
  • Gamma rays deliver dosage at lower levels over much greater distances.
  • Alpha particles represent the other extreme, they deliver very high LET dosage, but have an extremely limited range and must, therefore, be in intimate contact with the cells of the tissue to be treated.
  • alpha emitters are generally heavy metals, which limits the possible chemistry and presents undue hazards from leakage of radionuclide from the area to be treated. Depending on the tumor to be treated all kinds of emitters are conceivable within the scope of the present invention.
  • the present invention encompasses types of non-ionizing radiation like e.g. ultraviolet (UV) radiation, high energy visible light, microwave radiation (hyperthermia therapy) , infrared (IR) radiation and lasers.
  • UV radiation is applied.
  • the invention also includes pharmaceutical compositions or medicaments containing the compounds of the invention and a pharmaceutically acceptable carrier, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.
  • the compounds of formula (I) used in the methods of the invention are formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but may range anywhere from about 3 to about 8.
  • Formulation in an acetate buffer at pH 5 is a suitable embodiment.
  • the inhibitory compound for use herein is sterile. The compound ordinarily will be stored as a solid composition, although lyophilized formulations or aqueous solutions are acceptable.
  • compositions of the invention may comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more polymer (s) as part of a solid dispersion (e.g., an amorphous solid dispersion) .
  • the solid dispersion further comprises one or more surfactants.
  • the pharmaceutical composition comprising a compound of the invention is a solid spray-dried disperson.
  • Pharmaceutical compositions comprising solid dispersions of a compound of the invention in a matrix may provide improved chemical and physical properties and can be prepared by forming a homogeneous solution or melt of the compound of the invention and matrix material followed by solidifying the mixture by cooling, or removal of the solvent.
  • a dispersion refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle) .
  • the size of the dispersed phase can vary considerably (e.g., colloidal particles of nanometer dimension, to multiple microns in size) .
  • the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids.
  • a solid dispersion can include a crystalline therapeutically active compound (dispersed phase) in an amorphous polymer (s) (continuous phase) , or alternatively, an amorphous therapeutically active compound (dispersed phase) in an amorphous polymer (continuous phase) .
  • An amorphous solid dispersion generally refers to a solid dispersion of two or more components, such as a compound of the invention and polymer (or plurality of polymers) , but possibly containing other components such as surfactants or other pharmaceutical excipients, where the compound of the invention is in the amorphous phase.
  • an amorphous solid dispersion includes the polymer (s) (and optionally a surfactant) constituting the dispersed phase, and the compound of the invention constitutes the continuous phase. In some embodiments, an amorphous solid dispersion includes the polymer (s) (and optionally a surfactant) constituting the continuous phase, and the compound of the invention constitutes the dispersed phase.
  • An exemplary solid dispersion is a co-precipitate or a co-melt of a compound of the invention with one or more polymer (s) .
  • a "co-precipitate" is produced after dissolving a compound of the invention and one or more polymers in a solvent or solvent mixture followed by the removal of the solvent or solvent mixture. Sometimes the one or more polymers can be suspended in the solvent or solvent mixture.
  • the solvent or solvent mixture includes organic solvents and supercritical fluids.
  • the solvent or solvent mixture can also contain a non-volatile solvent.
  • a "co-melt” is produced after heating a compound of the invention and one or more polymers to melt, optionally in the presence of a solvent or solvent mixture, followed by mixing, removal of at least a portion of the solvent if applicable, and cooling to room temperature at a selected rate.
  • solid dispersions are prepared by adding a solution of a therapeutically active compound and solid polymers followed by mixing and removal of the solvent or solvent mixture.
  • vacuum drying, spray drying, tray drying, lyophilization, and other drying procedures may be applied. Applying any of these methods using appropriate processing parameters, according to this disclosure, would provide the particular therapeutically active compound in an amorphous state in the final solid dispersion product.
  • composition of the invention will be formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit MAT2A activity. Such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.
  • the initial pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-2000 mg/kg, for example about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • Oral unit dosage forms, such as tablets and capsules, may contain from about 25 to about 200 mg of the compound of the invention.
  • the compound of the invention may be administered by any suitable means, including oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • An example of a suitable oral dosage form is a tablet containing about 1mg, 2mg, 5mg, 10gm, 15mg 25mg, 50mg, 100mg, 250mg, 500mg, 750mg, 1000mg, 1250mg, 1500mg, 1750mg or 2000mg of the compound of the invention compounded with about 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • An aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • a suitable buffer solution e.g. a phosphate buffer
  • a tonicifier e.g. a salt such sodium chloride
  • the solution is typically filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants.
  • the reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company) , and used without further purification. Flash chromatography was performed on an Ez Purifier III using column with silica gel particles of 200-300 mesh. Analytical and preparative thin layer chromatography (TLC) plates were HSGF 254 (0.15-0.2 mm thickness, Shanghai Anbang Company, China) . Nuclear magnetic resonance (NMR) spectra were obtained on a Brucker AMX-400 NMR (Brucker, Switzerland) . Chemical shifts were reported in parts per million (ppm, ⁇ ) downfield from tetramethylsilane.
  • TLC Analytical and preparative thin layer chromatography
  • Step C 5, 7-dichloro-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidine
  • Step D 5-chloro-7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidine
  • Step E 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (pyridazin-3-yl) pyrazolo [1, 5-a] pyrimidin-5-amine
  • Step F 6- (4-methoxyphenyl) -2, 3-diphenyl-5- (pyridazin-3-ylamino) pyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • Step E was performed using appropriate amine 9, base (Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , and etc. ) and catalyst/ligand under microwave or thermal heating, in 1, 4-dioxane unless otherwise noted.
  • Step F was performed using 5 mL of 4M HCl in dioxane unless otherwise noted. Purifications were performed using the methods used in Example 1, unless otherwise noted.
  • Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol) , pyridin-2-amine (213 mg, 2.26 mmol) , Pd (OAc) 2 (50 mg, 0.23 mmol) , xantphos (165 mg, 0.28 mmol) , and Na 2 CO 3 (240 mg, 2.26 mmol) in 1, 4-dioxane (10 mL) under heating at 100 °C for 4h under N 2 .
  • LC-MS m/z 500.0 (M+H) + .
  • Step F 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (pyridin-2-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (300 mg, 0.6 mmol) was dissolved in HCl/1, 4-dioxane (5 mL) . The solution was stirred at r.t. overnight. The precipitate was filtered off and washed with CH 2 Cl 2 (3*1 mL) to give a yellow solid. The solid was then dissolved in CH 2 Cl 2 /MeOH (10/1, 3 mL) . After 3 mL of NH 3 -MeOH was added, the solution was stirred at r.t. overnight. The precipitate was filtered off and washed with H 2 O (3*3 mL) and MeOH (3*1 mL) , and dried in vacuo to give the title compound as a light yellow solid.
  • Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol) , pyridin-3-amine (117 mg, 1.24 mmol) , Pd (OAc) 2 (25 mg, 0.113 mmol) , xantphos (131 mg, 0.226 mmol) , Cs 2 CO 3 (737 mg, 2.26 mmo) in dioxane (20 mL) under heating to 110 °C for 4h under N 2 .
  • LC-MS m/z 500.2 (M+H) + .
  • Step F To a solution of 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (pyridin-3-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (150 mg, 0.309 mmol) in MeOH (10 mL) was added 4N HCl solution in dioxane (10 mL) . The reaction mixture was heated to 50 °C for 2h. The mixture was concentrated in vacuo. The residue was suspended in saturated NaHCO 3 solution.
  • Step E stoichiometry: Intermediate 5 (300 mg, 0.68 mmol) , 6-aminonicotinonitrile (161.7 mg, 1.36 mmol) , palladium diacetate (30.5 mg, 0.14 mmol) , Xantphos (117.8 mg, 0.20 mmol) and Cesium carbonate (553.0 mg, 1.70 mmol) in 1, 4-dioxane (10 mL) under heating to 110 °C for 12 hours under nitrogen atmosphere.
  • LC-MS m/z 525.2 (M+H) + .
  • Step F The solution of 6- ( (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) nicotinonitrile (40 mg, 0.07 mmol) in HCl solution (1.0 M in 1, 4-dioxane, 6 mL) was stirred at room temperature for 12 hours. The mixture was concentrated, and NH 4 OH (5 mL) was added thereto.
  • Step E stoichiometry: Intermediate 5 (220 mg, 0.5mmol) , 5-fluoropyridin-2-amine (112 mg, 1.0 mmol) , Pd (OAc) 2 (56 mg, 0.25 mmol) , xantphos (173 mg, 0.3 mmol) , Cs 2 CO 3 (117 mg, 1.1mmo) in dioxane (20 mL) under heating to 100 °C for 4h under N 2 .
  • LC-MS m/z 518.2 (M+H) + .
  • Step F To a solution of N- (5-fluoropyridin-2-yl) -7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-amine (50 mg, 0.10 mmol) in MeOH (10 mL) was added 4N HCl solution in dioxane (10 mL) . The reaction mixture was heated to 50 °C for 2h. The mixture was concentrated in vacuo. The residue was suspended in saturated NaHCO 3 solution.
  • Step E stoichiometry: Intermediate 5 (200 mg, 0.45 mmol) , 5-chloropyridin-2-amine (135 mg, 0.9 mmol) , Pd (OAc) 2 (51 mg, 0.23 mmol) , xantphos (156 mg, 0.27 mmol) , and Na 2 CO 3 (105 mg, 0.9 mmol) in 1, 4-dioxane (5 mL) under heating at 100 °C for 16h under N 2 .
  • LC-MS m/z 533.9, 535.9 (M+H) + .
  • Step F N- (5-chloropyridin-2-yl) -7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-amine (80 mg, 0.15 mmol) was dissolved in HCl-1, 4-dioxane (5 mL) . The solution was stirred at r.t. overnight. The precipitate was filtered off and washed with CH 2 Cl 2 (3 mL) to give a yellow solid. The solid was then dissolved in CH 2 Cl 2 /MeOH (10/1, 2 mL) . After 1 mL of NH 3 -MeOH was added, the solution was stirred at r.t. overnight. The precipitate was filtered off and washed with H 2 O (3 mL) and MeOH (3 mL) , and dried in vacuo to give the title compound 7 as a light yellow solid.
  • Step E stoichiometry: Intermediate 5 (500mg, 1.13mmol) and 5-nitropyridin-2-amine (472mg, 3.39 mmol, 3 eq) and Pd (OAc) 2 (51 mg, 0.23 mmol, 0.2 eq) , Xantphos (262mg, 0.45 mmol, 0.4 eq) and Na 2 CO 3 (360 mg, 3.394 mmol, 3 eq) in 1.4-dioxane (10 mL) was stirred and warmed up to 100 °C under microwave irradiation for 1 hours under N 2 atmosphere.
  • Step F A solution of 7-methoxy-6- (4-methoxyphenyl) -N- (5-nitropyridin-2-yl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-amine (50 mg, 0.092 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrate in vacuo, The residue was dissolved in 7N amine in methanol and stirred at room temperature for 2h. The mixture was concentrated in vacuo.
  • Step E stoichiometry: Intermediate 5 (160 mg, 0.362 mmol) , 5- (tert-butyldimethylsilyloxy) pyridin-2-amine (162 mg, 0.724 mmol) , palladium (II) acetate (16 mg, 0.0724 mmol) , xantphos (84 mg, 0.145 mmol) and sodium carbonate (77 mg, 0.724 mmol) in 1.4-dioxane (10 mL) under heating to reflux for 4 hours under nitrogen atmosphere.
  • LC-MS m/z 630.3 (M+H) + .
  • Step F A mixture of N- (5- (tert-butyldimethyl -silyloxy) pyridin-2-yl) -7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-amine (80 mg, 0.127 mmol) and HCl solution (4N in dioxane, 10 mL) was stirred at room temperature for 6 h. Then conc. HCl (0.5 mL) was added into the mixture. The resulting mixture was stirred at the same temperature for 4 h. The mixture was quenched with ammonia solution (7N in methanol) to pH 7 and concentrated to dryness.
  • Step E stoichiometry: Intermediate 5 (80 mg, 0.18 mmol) and 2-aminopyridin-4-ol (30 mg, 0.27 mmol, 1.5 eq) and Pd (OAc) 2 (6.1 mg, 0.03 mmol, 0.15 eq) , Xantphos (15.7 mg, 0.03 mmol, 0.15 eq) and Cs 2 CO 3 (120 mg, 0.36 mmol, 2.0 eq) in 1.4-dioxane (3 mL) at 110°Cfor 1h under microwave raditation under N 2 atmosphere.
  • LC-MS m/z 516.0 (M+H) + .
  • Step F A solution of 2- ( (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) pyridin-4-ol (40 mg, 0.08 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at 30 °C for 2 hours. The reaction mixture was concentrated in vacuum. The residue was purified to obtain the title compound as a white solid.
  • Step E stoichiometry: Intermediate 5 (200 mg, 0.45 mmol) , 6-fluoropyridin-2-amine (101 mg, 0.9 mmol) , Pd (OAc) 2 (20 mg, 0.09 mmol) , xantphos (65 mg, 0.11 mmol) , and Cs 2 CO 3 (293 mg, 0.9 mmol) in 1, 4-dioxane (5 mL) under heating at 100 °C for 16h under N 2 .
  • LC-MS m/z 518.1 (M+H) + .
  • Step F N- (6-fluoropyridin-2-yl) -7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-amine (120 mg, 0.23 mmol) was dissolved in HCl-1, 4-dioxane (5 mL) . The solution was stirred at r.t. overnight. The precipitate was filtered off and washed with CH 2 Cl 2 (3 mL) to give a yellow solid. The solid was then dissolved in CH 2 Cl 2 /MeOH (10/1, 2 mL) . After 1 mL of NH 3 -MeOH was added, the solution was stirred at r.t. overnight. The precipitate was filtered off and washed with H 2 O (3 mL) and MeOH (3 mL) , and dried in vacuo to give the title compound 7 as a light yellow solid.
  • Step E stoichiometry: Intermediate 5 (800 mg, 1.8 mmol) and 6-aminopicolinonitrile (281 mg, 2.36 mmol, 1.3 eq) and Pd (OAc) 2 (61.2 mg, 0.27 mmol, 0.15 eq) , Xantphos (157.4 mg, 0.27 mmol, 0.15 eq) and Cs 2 CO 3 (1.2 g, 3.63 mmol, 2.0 eq) in 1.4-dioxane (15 mL) at 110°C for 1h under microwave irradiation under N 2 atmosphere. .
  • LC-MS m/z 524.9 (M+H) + .
  • Step F A solution of 6- ( (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) picolinonitrile (220 mg, 0.42 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum.
  • Step E stoichiometry: Intermediate 5 (200 mg, 0.452 mmol) and 2-aminoisonicotinonitrile (108 mg, 0.9 mmol) and Pd (OAc) 2 (102 mg, 0.434 mmol) , Xantphos (315 mg, 0.54 mmol) and Cs 2 CO 3 (327 mg, 1.0 mmol) in 1.4-dioxane (10 mL) under heating to 110 °C for 1 hour through microwave irradiation under N 2 atmosphere.
  • LC-MS m/z 525.2 (M+H) + .
  • Step F A mixture of 2- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-ylamino) isonicotinonitrile (15 mg, 0.03 mmol) in HCl solution (4 M in dioxane, 1 mL) was stirred at room temperature overnight. The mixture was quenched with NH 3 solution (7M in methanol) to pH 7-8 and then evaporated to dryness.
  • Step E stoichiometry: Intermediate 5 (440 mg, 1 mmol) , pyrimidin-4-amine (190 mg, 2 mmol, 2 eq. ) , Pd (OAc) 2 (22 mg, 0.1 mmol, 0.1 eq. ) , Xantphos (116 mg, 0.2 mmol, 0.2 eq. ) and Cs 2 CO 3 (390 mg, 1.2 mmol, 1.2 eq. ) in 1.4-dioxane (10 mL) under heating at 100 °C through microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 501.5 (M+H) + .
  • Step F A solution of 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (pyrimidin-4-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (260 mg, 0.52 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at r.t. for 16 hours. Solvent and volatile were removed in vacuo. Then 20 mL MeOH was added. The resultant mixture was stirred for 5min and filtered. The filter cake was washed with EA (10mL) and PE (10mL) , and dried to give the title compound as a yellow solid.
  • Step E stoichiometry: Intermediate 5 (237 mg, 0.538 mmol) , pyrimidine-4, 6-diamine (118.2 mg, 1.07 mmol, 2 eq. ) , Pd (OAc) 2 (60 mg, 0.269 mmol, 0.5 eq. ) , Xantphos (186.5 mg, 0.322 mmol, 0.6 eq. ) and Na 2 CO 3 (125 mg, 1.184 mmol, 2.2 eq. ) in 1.4-dioxane (5 mL) under heating at 100 °C for 3 hour under N 2 atmosphere.
  • LC-MS m/z 516.5 (M+H) + .
  • Step F A solution of N4- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) pyrimidine-4, 6-diamine (90 mg, 0.17 mmol) in 4M HCl in 1.4-dioxane (3 mL) was stirred at r.t. for 3 hours. Solvent and volatile were removed in vacuo. The resultant solid was washed with dioxane and dried to give the title compound as a yellow solid.
  • Step E stoichiometry: Intermediate 5 (300 mg, 0.67 mmol) , 2-methoxypyrimidin-4-amine (169 mg, 1.25 mmol) , Pd (OAc) 2 (48mg, 0.067mmol) , xantphos (72 mg, 0.13mmol) , Cs 2 CO 3 (409 mg, 1.25 mmo) in dioxane (20 mL) under heating to 110 °C for 4h under N 2 .
  • LC-MS m/z 531.2 (M+H) + .
  • Step F To a solution of 7-methoxy-6- (4-methoxyphenyl) -N- (2-methoxypyrimidin-4-yl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-amine (100 mg, 0.19mmol) in MeOH (10 mL) was added 4N HCl solution in dioxane (10 mL) . The reaction mixture was heated to 50 °C for 2h. The mixture was concentrated in vacuo. The residue was suspended in saturated NaHCO 3 solution.
  • Step E stoichiometry: Intermediate 5 (200 mg, 0.4535 mmol) , pyrimidin-2-amine (86 mg, 0.91 mmol, 2 eq. ) , Pd (OAc) 2 (102 mg, 0.4535 mmol, 1 eq. ) , Xantphos (314.5 mg, 0.54 mmol, 1.2 eq. ) and Cs 2 CO 3 (327 mg, 1 mmol, 2.2 eq. ) in 1.4-dioxane (4 mL) under heating at 110 °C for 1 hour through microwave irradiation under N 2 atmosphere.
  • LC-MS m/z 501.6 (M+H) + .
  • Step F A solution of 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (pyrimidin-2-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (60 mg, 0.12 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at r.t. for 2 hours. Solvent and volatile were removed in vacuo. The residue was dissolved in DCM (5 mL) and treated with saturated NaHCO 3 . The organic phase was separated and washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified to afford the title compound as a yellow solid.
  • Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol) , 5-chloropyrimidin-2-amine (129 mg, 1.0 mmol) , palladium diacetate (56 mg, 0.2 mmol) , Xantphos (173 mg, 0.3 mmol) and sodium carbonate (117 mg, 1.1 mmol) in 1, 4-dioxane (20 mL) under refluxing for 4 hours under nitrogen atmosphere.
  • LC-MS m/z 535.1 (M+H) + .
  • Step F The solution of N- (5-chloropyrimidin-2-yl) -7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-amine (50 mg, 0.1 mmol) in HCl solution (4.0 M in 1, 4-dioxane, 5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated, and NH 4 OH (8 mL) was added thereto.
  • Step E stoichiometry: Intermediate 5 (132mg, 0.3mmol) and N- (6-aminopyridazin-3-yl) acetamide (93mg, 0.2mmol, 2 eq) and Pd (OAc) 2 (10 mg, 0.04 mmol, 0.4eq) , Xantphos (24mg, 0.04 mmol, 0.4 eq) and Cs 2 CO 3 (65mg, 0.2 mmol, 2 eq) in 1.4-dioxane (5 mL) under heating at 120 °Cthrough microwave irradiation for 1 hours under N 2 atmosphere.
  • LC-MS m/z 558.2 (M+H) + .
  • Step F A mixture of N- (6- ( (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) pyridazin-3-yl) acetamide (55.7 mg, 0.1 mmol) and potassium tert-butoxide in 1.4-dioxane (5 mL) was stirred at 100 °C for 16 hours. The mixture was filtered and concentrated in vacuo.
  • Step E stoichiometry: Intermediate 5 (200mg, 0.453mmol) and 6-methoxypyridazin-3-amine (169.8mg, 1.358 mmol, 3 eq) , Pd (OAc) 2 (20.3 mg, 0.091 mmol, 0.2 eq) , Xant-phos (104.7mg, 0.181 mmol, 0.4 eq) and Na 2 CO 3 (143.9 mg, 1.358 mmol, 3 eq) in 1.4-dioxane (5 mL) under heating at 100 °C through microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 531.2 (M+H) + .
  • Step F A solution of 7-methoxy-6- (4-methoxyphenyl) -N- (6-methoxypyridazin-3-yl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-amine (50 mg, 0.094 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrate in vacuo, The resultant solid was washed with methanol and concentrated to give the title compound as a white solid.
  • Step E stoichiometry: Intermediate 5 (200 mg, 0.45 mmol) , 6-chloropyridazin-3-amine (101 mg, 0.9 mmol, 2 eq. ) , and Pd (OAc) 2 (20 mg, 0.09 mmol, 0.2 eq. ) , Xantphos (65 mg, 0.11 mmol, 0.3 eq. ) and Cs 2 CO 3 (293 mg, 0.9 mmol, 2.0 eq. ) in 1.4-dioxane (5 mL) under heating at 120 °Cthrough microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 534.9, 536.9 (M+H) + .
  • Step F The solution of N- (6-chloropyridazin-3-yl) -7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-amine (60 mg, 0.12 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at r.t. overnight. Solvent and volatile were removed in vacuo. The residue was dissolved in DCM (5 mL) and treated with saturated NaHCO 3 . The organic phase was separated and washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified to afford the title compound as a yellow solid.
  • Step E stoichiometry: Intermediate 5 (100 mg, 0.230 mmol) , pyrazin-2-amine (44 mg, 0.460 mmol) , palladium (II) acetate (57 mg, 0.250 mmol) , xantphos (160 mg, 0.276 mmol) and cesium carbonate (165 mg, 0.506 mmol) in 1, 4-dioxane (10 mL) under heating at 100 °C through microwave irradiation for 1 hour under nitrogen atmosphere.
  • LC-MS m/z 501.2 (M+H) + .
  • Step F A mixture of 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (pyrazin-2-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (50 mg, 0.0996 mmol) in hydrogen chloride solution (4 M in dioxane, 3 mL) was stirred at room temperature for 10 hours. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) , basified with aqueous ammonia to pH 8, and then evaporated to dryness.
  • Step E stoichiometry: Intermediate 5 (150 mg, 0.34 mmol) and 3-aminopyrazin-2-ol (49 mg, 0.44 mmol, 1.3 eq) , Pd (OAc) 2 (11 mg, 0.05 mmol, 0.15 eq) , Xantphos (29 mg, 0.05 mmol, 0.15 eq) and Cs 2 CO 3 (221 mg, 0.68 mmol, 2.0 eq) in 1.4-dioxane (10 mL) . under heating at 110 °C through microwave irradiation for 1 hour under nitrogen atmosphere.
  • LC-MS m/z 516.9 (M+H) + .
  • Step F A solution of 3- ( (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) pyrazin-2-ol (15 mg, 0.03 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum. The residue was purified to obtain the title compound as a white solid.
  • Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol) , 5-aminopyrazine-2-carbonitrile (163 mg, 1.36 mmol) , tris (dibenzylideneacetone) dipalladium (0) (311 mg, 0.34 mmol) , xantphos (216 mg, 0.374 mmol) and sodium carbonate (264 mg, 2.5 mmol) in 1, 4-dioxane (20 mL) under heating to reflux for 1 hour under N 2 atmosphere.
  • LC-MS m/z 526.2 (M+H) + .
  • Step F To a solution of 5- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-ylamino) pyrazine-2-carbonitrile (100 mg, 0.19 mmol) in dichloromethane (6 mL) was added HCl solution (4M in dioxane, 10 mL) . The reaction mixture was stirred at room temperature for 16h. The reaction mixture was quenched with ammonia solution (7M in methanol) to pH 7-8, and then evaporated to dryness.
  • Step E stoichiometry: Intermediate 5 (440 mg, 1.0 mmol) , pyrazine-2, 5-diamine (293 mg, 2.0 mmol) , palladium (II) acetate (112 mg, 0.50 mmol) , xantphos (347 mg, 0.6 mmol) and cesium carbonate (1.2 g, 4.0 mmol) in 1, 4-dioxane (20 mL) under heating at 110 °C for 1 hour through microwave irradiation under N 2 atmosphere.
  • LC-MS m/z 516.2 (M+H) + .
  • Step F A mixture of N 2 - (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) pyrazine-2, 5-diamine (50 mg, 0.10 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL) was stirred at room temperature for 16 hours. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) , basified with aqueous ammonia to pH 8 and then evaporated to dryness.
  • Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol) , 6-aminopyrazine-2-carbonitrile (163 mg, 1.36 mmol) , palladium (II) acetate (84 mg, 0.374 mmol) , xantphos (215 mg, 0.374 mmol) and cesium carbonate (741 mg, 2.27 mmol) in 1, 4-dioxane (10 mL) under heating at 110 °C for 1 hour through microwave irradiation under N 2 atmosphere.
  • LC-MS m/z 526.2 (M+H) + .
  • Step F To a solution of 6- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-ylamino) pyrazine-2-carbonitrile (100 mg, 0.19 mmol) in dichloromethane (6 mL) was added HCl solution (4M in dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 18 h. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) and washed with aqueous sodium bicarbonate to pH 8. The organic phase was dried over sodium sulfate and evaporated to dryness.
  • Step E stoichiometry: Intermediate 5 (800 mg, 1.81 mmol) , 1, 3, 5-triazin-2-amine (348 mg, 3.62 mmol) , and Pd (OAc) 2 (81 mg, 0.36 mmol) , Xantphos (260 mg, 0.45 mmol) and Na 2 CO 3 (384 mg, 3.62 mmol) in 1.4-dioxane (15 mL) under heating at 120 °C for 4 hours under N 2 atmosphere.
  • LC-MS m/z 502.0 (M+H) + .
  • Step F 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (1, 3, 5-triazin-2-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (500 mg, 1.0 mmol) was dissolved in HCl-1, 4-dioxane (10 mL) . The solution was stirred at r.t. for 2h. The precipitate was filtered off and washed with CH 2 Cl 2 (3*1 mL) to give a yellow solid. The solid was then dissolved in CH 2 Cl 2 /MeOH (10/1, 3 mL) . After 3 mL of NH 3 -MeOH was added, the solution was stirred at r.t. overnight. The precipitate was filtered off and washed with H 2 O (3*2 mL) and MeOH (3*1 mL) , and dried in vacuo to give the title compound as a light yellow solid.
  • Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol) , 1, 2, 4-triazin-5-amine (100 mg, 1.0 mmol) , palladium (II) acetate (56 mg, 0.25 mmol) , xantphos (170 mg, 0.30 mmol) and cesium carbonate (375 mg, 1.1 mmol) in 1, 4-dioxane (15 mL) under heating at 105 °C through microwave irradiation for 45 min under N 2 atmosphere.
  • LC-MS m/z 502.2 (M+H) + .
  • Step F A mixture of 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (1, 2, 4-triazin-5-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (100 mg, 0.20 mmol) in hydrogen chloride solution (4 M in dioxane, 15 mL) was stirred at room temperature for 4 hours. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) , basified with aqueous ammonia to pH 8 and then evaporated to dryness.
  • Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol) , 1, 3, 5-triazine-2, 4-diamine (189 mg, 1.7 mmol, 1.5 eq) , Pd (OAc) 2 (38 mg, 0.17 mmol, 0.15 eq) , Xantphos (98 mg, 0.17 mmol, 0.15 eq) and Cs 2 CO 3 (360 mg, 3.34 mmol, 3.0 eq) in 1.4-dioxane (15 mL) under heating at 105 °C through microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 516.9 (M+H) + .
  • Step F A solution of 5- ( (4-amino-1, 3, 5-triazin-2-yl) amino) -6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-7 (4H) -one (156 mg, 0.3 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum. The residue was purified to obtain the title compound as a white solid.
  • Step E stoichiometry: Intermediate 5 (249 mg, 0.57 mmol) , N2-methyl-1, 3, 5-triazine-2, 4-diamine (106 mg, 0.85 mmol, 1.5 eq. ) , Pd (OAc) 2 (64 mg, 0.28 mmol, 0.5 eq. ) , Xantphos (197 mg, 0.34 mmol, 0.6 eq. ) and Cs 2 CO 3 (370 mg, 1.13 mmol, 2.0 eq. ) in 1.4-dioxane (10 mL) under heating at 100 °C through microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 531.0 (M+H) + .
  • Step F A solution of N 2 - (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) -N4-methyl-1, 3, 5-triazine-2, 4-diamine (100 mg, 0.19 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at r.t. for 6 hours. Solvent and volatile were removed in vacuo. The residue was purified to afford the title compound as a yellow solid.
  • Step A 5- ( (4-methoxy-1, 3, 5-triazin-2-yl) amino) -6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • Step B 5- ( (4-hydroxy-1, 3, 5-triazin-2-yl) amino) -6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • the filter cake was purified to obtain 5- ( (4-hydroxy-1, 3, 5-triazin-2-yl) amino) -6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-7 (4H) -one as a yellow solid.
  • Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol) , thiazol-2-amine (100 mg, 1.0 mmol, 2 eq. ) , Pd (OAc) 2 (56 mg, 0.25 mmol, 0.5 eq. ) , Xantphos (174 mg, 0.3 mmol, 0.6 eq. ) and Na 2 CO 3 (117 mg, 1.1 mmol, 2.2 eq. ) in 1.4-dioxane (5 mL) under heating at 100 °C for 3 h under N 2 atmosphere.
  • LC-MS m/z 506.1 (M+H) + .
  • Step F The solution of N- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) thiazol-2-amine (110 mg, 0.23 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at r.t. for 10 h. The precipitate was collected and washed with EA to afford the title compound as a yellow solid.
  • Step E stoichiometry: Intermediate 5 (400 mg, 0.9 mmol) , isoxazol-3-amine (150 mg, 1.8 mmol, 2 eq. ) , Pd (OAc) 2 (20 mg, 0.09 mmol, 0.1 eq. ) , Xantphos (104 mg, 0.18 mmol, 0.2 eq. ) and Na 2 CO 3 (190 mg, 1.8mmol, 2eq. ) in 1.4-dioxane (5 mL) under heating at 100 °C for 16 hours under N 2 atmosphere.
  • LC-MS m/z 490.5 (M+H) + .
  • Step E stoichiometry: Intermediate 5 (150 mg, 0.34 mmol) and isoxazol-4-amine (57 mg, 0.68 mmol, 2.0 eq) , Pd (OAc) 2 (16 mg, 0.07 mmol, 0.2 eq) , Xantphos (41 mg, 0.07 mmol, 0.2 eq) and Cs 2 CO 3 (442 mg, 1.36 mmol, 4.0 eq) in 1.4-dioxane (10 mL) under heating at 100 °C through microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 490.2 (M+H) + .
  • Step F A solution of N- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) isoxazol-4-amine (38 mg, 0.08 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at 30 °Cfor 5 hours. The reaction mixture was concentrated in vacuum. The residue was purified to obtain the title compound as a white solid.
  • Step E stoichiometry: Intermediate 5 (100 mg, 0.226 mmol) , 1-methyl-1H-imidazol-2-amine (33 mg, 0.340 mmol) , tris (dibenzylideneacetone) dipalladium (0) (206 mg, 0.226 mmol) , xantphos (130 mg, 0.226 mmol) and sodium carbonate (48 mg, 0.515 mmol) in 1, 4-dioxane (5 mL) under heating at 110 °C through microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 503.2 (M+H) + .
  • Step F A mixture of 7-methoxy-6- (4-methoxyphenyl) -N- (1-methyl-1H-imidazol-2-yl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-amine (50 mg, 1 mmol) in hydrogen chloride solution (4 M in dioxane, 10 mL) was stirred at 70 °C for 16 h. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) and washed with aqueous sodium bicarbonate to pH 8. The organic phase was dried over sodium sulfate and evaporated to dryness.
  • Step E stoichiometry: Intermediate 5 (441 mg, 1.0 mmol) , 1H-imidazol-2-amine (83 mg, 1 mmol, 2 eq. ) , Pd 2 (dba) 3 (91.5 mg, 0.1 mmol, 0.1 eq. ) , Xantphos (115.6 mg, 0.2 mmol, 0.2 eq. ) and Na 2 CO 3 (212 mg, 2mmol, 2eq. ) in toluene (40 mL) under heating at 105 °C for 5 hour under N 2 atmosphere.
  • LC-MS m/z 489.5 (M+H) + .
  • Step E stoichiometry: Intermediate 5 (441 mg, 1.0 mmol) , thiazol-2-amine (102 mg, 1 mmol, 2 eq. ) , Pd 2 (dba) 3 (91.5 mg, 0.1 mmol, 0.1 eq. ) , Xantphos (115.6 mg, 0.2 mmol, 0.2 eq. ) and Na 2 CO 3 (212 mg, 2mmol, 2eq. ) in toluene (40 mL) under heating at 105 °C for 5 hour under N 2 atmosphere.
  • LC-MS m/z 506.5 (M+H) + .
  • Step E stoichiometry: Intermediate 5 (442mg, 1 . 0mmol) and 1, 3, 4-thiadiazol-2-amine (101mg, 1.0 mmol, 1 eq) and Pd (OAc) 2 (91.5 mg, 0.1 mmol, 0.1 eq) , Xant-phos (115.6mg, 0.2mmol, 0.2 eq) and Na 2 CO 3 (212mg, 2.0mmol, 2.0 eq) in toluene (40 mL) under heating at 110 °C for 5 hour under N 2 atmosphere.
  • LC-MS m/z 507.1 (M+H) + .
  • Step F A mixture of N- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) -1, 3, 4-thiadiazol-2-amine (112mg, 0.2mmol) in 4N HCl in 1.4-dioxane (15 mL) was stirred at room temperature overnight. The reaction mixture was concentrate in vacuo. The residue was stirred with methanol and saturated sodium hydrogen carbonate solution. The precipitates were collected by filtration and dried to afford the title compound as a white solid.
  • Step E stoichiometry: Intermediate 5 (600 mg, 1.36 mmol) and 1, 3, 4-thiadiazole-2, 5-diamine (315 mg, 2.72 mmol, 2 eq. ) , Pd (OAc) 2 (306 mg, 0.1.36 mmol, 1 eq. ) , Xantphos (786 mg, 1.36 mmol, 1 eq. ) and Cs 2 CO 3 (887 mg, 2.72 mmol, 2.0 eq. ) in 1.4-dioxane (18 mL) under heating at 120 °Cthrough microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 522.0 (M+H) + .
  • Step F A solution of N2- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) -1, 3, 4-thiadiazole-2, 5-diamine (100 mg, 0.19 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at r.t. overnight. Solvent and volatile were removed in vacuo. The residue was dissolved in DCM (5 mL) and basified with saturated NaHCO 3 . The organic phase was separated and washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified to afford the title compound as a yellow solid.
  • Step E stoichiometry: Intermediate 5 (442mg, 1 . 0mmol) and 5-methoxy-1, 3, 4-thiadiazol-2-amine (113mg, 1.0 mmol, 1 eq) , Pd (OAc) 2 (91.5 mg, 0.1 mmol, 0.1 eq) , Xant-phos (115.6mg, 0.2mmol, 0.2 eq) and Na 2 CO 3 (212mg, 2.0mmol, 2.0 eq) in toluene (40 mL) under heating at 110 °C for 5 hour under N 2 atmosphere.
  • LC-MS m/z 537.1 (M+H) + .
  • Step F A mixture of 5-methoxy-N- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) -1, 3, 4-thiadiazol-2-amine (51.8mg, 0.1mmol) in 4N HCl in 1.4-dioxane (15 mL) was stirred at room temperature overnight. The reaction mixture was concentrate in vacuo. The residue was stirred with methanol and saturated sodium hydrogen carbonate solution. The solid was collected by filtration and dried to afford the title compound as a white solid.
  • Step E stoichiometry: Intermediate 5 (600 mg, 1.3 mmol) and 1, 2, 4-thiadiazol-5-amine (179 mg, 1.77 mmol, 1.3 eq) , Pd (OAc) 2 (46 mg, 0.2 mmol, 0.15 eq) , Xantphos (118 mg, 0.2 mmol, 0.15 eq) and Cs 2 CO 3 (844 mg, 2.72 mmol, 2.0 eq) in 1.4-dioxane (15 mL) under heating at 100C through microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 506.9H) + .
  • Step F A solution of N- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) -1, 2, 4-thiadiazol-5-amine (214 mg, 0.42 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum. The residue was purified to obtain the title compound as a white solid.
  • Step E stoichiometry: Intermediate 5 (400 mg, 0.91 mmol) and 3-methoxy-1, 2, 4-thiadiazol-5-amine (155 mg, 1.18 mmol, 1.3 eq) , Pd (OAc) 2 (11 mg, 0.14 mmol, 0.15 eq) , Xantphos (78.7 mg, 0.14 mmol, 0.15 eq) and Cs 2 CO 3 (590 mg, 1.8 mmol, 2.0 eq) in 1.4-dioxane (10 mL) under heating at 110 °C through microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 537.0 (M+H) + .
  • Step F A solution of 3-methoxy-N- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) -1, 2, 4-thiadiazol-5-amine (100 mg, 0.19 mmol) in 4M HCl in 1.4-dioxane (5 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum. The residue was purified to obtain the title compound as a white solid.
  • Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol) , N3- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) -1, 2, 5-oxadiazole-3, 4-diamine (101 mg, 1.0 mmol, 2.0 eq) , Pd (OAc) 2 (11 mg, 0.05 mmol, 0.1 eq) , Xantphos (116 mg, 0.2 mmol, 0.4 eq) and Cs 2 CO 3 (325 mg, 1.0 mmol, 2.0 eq) in 1.4-dioxane (10 mL) under heating at 100 °C through microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 506.1 (M+H) + .
  • Step F A solution of N3- (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) -1, 2, 5-oxadiazole-3, 4-diamine (237 mg, 0.47 mmol) in 4M HCl in 1.4-dioxane (20 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum. The residue was purified by to obtain the title compound as a white solid.
  • Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol) , ethyl 5-aminothiazole-4-carboxylate (292.3 mg, 1.70 mmol) , and Pd (OAc) 2 (76.2 mg, 0.34 mmol) , Xantphos (196.4 mg, 0.34 mmol) and Cs 2 CO 3 (553.0 mg, 0.34 mmol) in 1.4-dioxane (10 mL) under heating at 120 °C through microwave irradiation for 1.5 hours under N 2 atmosphere.
  • LC-MS m/z 578.3 (M+H) + .
  • Step F A solution of ethyl 5- ( (7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-5-yl) amino) thiazole-4-carboxylate (450 mg, 0.78mmol) in 4M HCl in 1.4-dioxane (16 mL) was stirred at r.t. for 18hours. The mixture was concentrated, and saturated NaHCO 3 (10 mL) was added. The precipitate was filtered and washed with water (4 mL) .
  • Step E stoichiometry: Intermediate 5 (200 mg, 0.450 mmol) , 1H-pyrrolo [2, 3-c] pyridin-5-amine (120 mg, 0.90 mmol) , palladium (II) acetate (50 mg, 0.225 mmol) , xantphos (196 mg, 0.340 mmol) and potassium carbonate (124 mg, 0.90 mmol) in 1, 4-dioxane (10 mL) under heating at 100 °Cthrough microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 539.2 (M+H) + .
  • Step F A mixture of 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (1H-pyrrolo [2, 3-c] pyridin-5-yl) -pyrazolo [1, 5-a] pyrimidin-5-amine (80 mg, 0.148 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL) was stirred at room temperature for 16 hours. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) , basified with aqueous ammonia to pH 8, and then evaporated to dryness.
  • This compound was prepared according to the procedure for preparing compound 101 by using Intermediate 8 as 4- (cyclohex-1-en-1-yl) -3-phenyl-1H-pyrazol-5-amine in step B.
  • Step B To a solution of dimethyl 2- (4-methoxyphenyl) malonate (39.6 g, 166 mmol) in tri-n-butylamine (80 ml) at 198 °C was added 4-cyclohexenyl-3-phenyl-1H-pyrazol-5-amine (47.3 g, 199 mmol) in portions, and the resultant mixture was stirred for 1 h at 198 °C. The mixture was cooled to the room temperature, and solvent was decanted. THF (150 mL) and HCl (6N, 600 mL) were added with stirring vigorously for 0.5 h.
  • Step C A solution of 3- (cyclohex-1-en-1-yl) -5-hydroxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidin-7 (4H) -one (47.0 g, 104 mmol) in phosphorus oxychloride (100 mL) was stirred at reflux for 16 hrs. The solvent was removed in vacuum. The residue was added slowly to methanol (100 mL) cooled at 0°C.
  • Step D To a solution of 5, 7-dichloro-3- (cyclohex-1-en-1-yl) -6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (40 g, 88 mmol) in dichloromethane (400 ml) at 0 °C was added sodium methoxide (30%in methanol, 80 g) dropwise. The resultant mixture was stirred for 10 min at 0 °C. The reaction was quenched by adding ice water (100 mL) and extracted with dichloromethane (200 mL) three times.
  • This compound was prepared according to the procedure for preparing compound 101 by using Intermediate 1 as methyl 2- (quinolin-6-yl) acetate in step A.
  • Step A To dimethyl carbonate (150 mL) cooled at 0 °C was added potassium tert-butanolate (24 g, 216 mmol) in portions. The resultant mixture was stirred at 0 °C for 1 hour. Methyl 2- (quinolin-6-yl) acetate (20 g, 100 mmol) was added. The resultant mixture was slowly warmed up to room temperature and stirred for 1 hour. The reaction mixture was heated to 80 °C with stirring overnight.
  • Step B A suspension of dimethyl 2- (quinolin-6-yl) malonate (13 g, 50 mmol) and 3, 4-diphenyl-1H-pyrazol-5-amine (11.8 g, 50 mmol) in tributylamine (100 mL) was stirred at 185 °C for 4 hours. After cooling to room temperature, the mixture was filtered. The residue was diluted with DCM (450 mL) , washed with saturated NH 4 Cl (150 ml) and brine (100 ml) , dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • Step C The solution of 2, 3-diphenyl-6- (quinolin-6-yl) pyrazolo [1, 5-a] pyrimidine-5, 7 (4H, 6H) -dione (18 g, 42 mmol) , DMAP (1 g) and PCl 5 (80 mg) in POCl 3 (180 ml) was stirred at 100 °C overnight. After cooling to room temperature, the solvent was removed by vacuum. The residue was cooled to 0 °C. MeOH (60mL) was added to quench the reaction.
  • Step D To a solution of 6- (5, 7-dichloro-2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-6-yl) quinoline (13.0 g, crude, 27.8 mmol) in DCM/MeOH (200 mL, 1: 1) cooled at 0 °C was added sodium methoxide (14.9 mL, 5.0 M in methanol) dropwise. Then the mixture was stirred at 0 °C for 1 hour. Saturated NH 4 Cl (150 mL) was added to quench the reaction.
  • This compound was prepared according to the procedure for preparing compound 101 by using Intermediate 1 as methyl 2- (quinolin-6-yl) acetate e in step A and Intermediate 8 as 4- (cyclohex-1-en-1-yl) -3-phenyl-1H-pyrazol-5-amine in step B.
  • Step B A suspension of dimethyl 2- (quinolin-6-yl) malonate (1.95 g, 7.52 mmol) and 4- (cyclohex-1-en-1-yl) -3-phenyl-1H-pyrazol-5-amine (1.8 g, 7.52 mmol) in tributylamine (20 mL) was stirred at 185 °C for 4 hours. After cooling to room temperature, the mixture was filtered. The residue was diluted with DCM (150 mL) , washed with saturated NH 4 Cl (50 ml) and brine (50 ml) , dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • Step C The solution of 3- (cyclohex-1-en-1-yl) -2-phenyl-6- (quinolin-6-yl) pyrazolo [1, 5-a] pyrimidine-5, 7 (4H, 6H) -dione (3.1 g, 7.13 mmol) in POCl 3 (12 ml) was stirred at 110 °C overnight. After cooling to room temperature, the solvent was removed by vacuum. MeOH (60mL) was added slowly to the residue cooled at 0 °C to quench the reaction.
  • Step D To a solution of 6- (5, 7-dichloro-3- (cyclohex-1-en-1-yl) -2-phenylpyrazolo [1, 5-a] pyrimidin-6-yl) quinoline (300 mg, crude, 0.64 mmol) in DCM/MeOH (6 mL, 1: 1) cooled at 0 °C was added sodium methoxide (0.64 mL, 5.0 M in methanol) dropwise. Then the mixture was stirred at 0 °C for 1 hour. Saturated NH 4 Cl (50 mL) was added to quench the reaction.
  • This compound was prepared according to the procedure for preparing compound 101 by using Intermediate 1 as methyl 2- (quinoxalin-6-yl) acetate in step A and Intermediate 8 as 4- (cyclohex-1-en-1-yl) -3-phenyl-1H-pyrazol-5-amine in step B.
  • Step A To dimethyl carbonate (30 mL) cooled at 0 °C was added potassium tert-butanolate (3.8 g, 34.12 mmol) in portions. The resultant mixture was stirred at 0 °C for 1 hour. Methyl 2- (quinoxalin-6-yl) acetate (2.3 g, 11.37 mmol) was added. The resultant mixture was slowly warmed up to room temperature and stirred for 1 hour. The reaction mixture was heated to 90 °C and stirred for 1.5 hours.
  • Step B A suspension of 4- (cyclohex-1-en-1-yl) -3-phenyl-1H-pyrazol-5-amine (1.93 g, 8.07 mmol) and dimethyl 2- (quinoxalin-6-yl) malonate (2.1 g, 8.07 mmol) in tributylamine (20 mL) was stirred at 175 °C for 2 hours. After cooling to room temperature, the mixture was filtered. The residue was diluted with DCM (150 mL) , washed with saturated NH 4 Cl (50 ml) and brine (30 ml) , dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • Step C The solution of 3- (cyclohex-1-en-1-yl) -2-phenyl-6- (quinoxalin-6-yl) pyrazolo [1, 5-a] pyrimidine-5, 7 (4H, 6H) -dione (1.0 g, 2.30 mmol) in POCl 3 (6 ml) in a sealed tube was stirred at 110 °C for 8 hours. After cooling to room temperature, the solvent was removed by vacuum. The residue was cooled to 0 °C. MeOH (6 mL) was added to quench the reaction.
  • Step D To a solution of 6- (5, 7-dichloro-3- (cyclohex-1-en-1-yl) -2-phenylpyrazolo [1, 5-a] pyrimidin-6-yl) quinoxaline (800 mg, crude, 2.30 mmol) in DCM/MeOH (20 mL, 1: 1) cooled at 0 °C was added sodium methoxide (2.3 mL, 5.0 M in methanol) dropwise. Then the mixture was stirred at 0 °C for 1 hour. Saturated NH 4 Cl (50 mL) was added to quench the reaction.
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (200mg, 0.0449 mol) , pyridin-2-amine (63.4m g, 0.674 mol, 1.5 eq. ) , Pd (OAc) 2 (20.2mg, 0.0898 mol, 0.2 eq. ) , Xantphos (52mg, 0.0898 mol, 0.2 eq. ) and K 2 CO 3 (265mg, 1.12mol, 2.5eq. ) in dioxnae (5mL) under heating at 120 °C for 1 hour under N 2 atmosphere.
  • LC-MS m/z 504.9 (M+H) + .
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (200 mg, 0.45 mmol) , pyridin-3-amine (85 mg, 0.90 mmol) , Pd (OAc) 2 (36mg, 0.045mmol) , xantphos (58 mg, 0.09mmol) , and CS 2 CO 3 (293 mg, 0.90 mmo) in dioxane (20 mL) under heating at 110 °C for 4 hours under N 2 atmosphere.
  • LC-MS m/z 504.2 (M+H) + .
  • Step F To a solution of 3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenyl-N- (pyridin-3-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (60 mg, 0.12mmol) in MeOH (10 mL) was added 4N HCl solution in dioxane (10 mL) . The reaction mixture was heated to 50 °C for 2h. The mixture was concentrated in vacuo. The crude product was basified with saturated NaHCO 3 solution.
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (400mg, 0.897mmol) and pyrimidin-4-amine (255.9mg, 2.691 mmol, 3 eq) , Pd (OAc) 2 (40.3mg, 0.179 mmol, 0.2 eq) , Xant-phos (578.6mg, 0.359 mmol, 0.4 eq) and Cs 2 CO 3 (285.2 mg, 2.691 mmol, 3 eq) in 1.4-dioxane (10 mL) under heating at 100 °Cthrough microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 505.0 (M+H) + .
  • Step F A solution of 3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenyl-N- (pyrimidin-4-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (100 mg, 0.198mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in 7N NH 3 in methanol and stirred at room temperature for 2 hours. The precipitates were filtered, washed with methanol, and dried to afford the title compund as a white solid.
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (200 mg, 0.452 mmol) and 2-methoxypyrimidin-4-amine (113 mg, 0.904 mmol) and Pd (OAc) 2 (31 mg, 0.136 mmol) , Xantphos (157 mg, 0.272 mmol) and Na 2 CO 3 (96 g, 0.904 mmol) in 1.4-dioxane (10 mL) under heating at 110 °C for 4 hours under N 2 atmosphere.
  • Step F A mixture of 3-cyclohexenyl-7-methoxy-6- (4-methoxyphenyl) -N- (2-methoxy-pyrimidin-4-yl) -2-phenyl-pyrazolo [1, 5-a] pyrimidin-5-amine (55 mg, 0.103 mmol) and HCl solution (4N in dioxane, 6 mL) was stirred at room temperature overnight. The mixture was quenched with NH 3 solution (7N in methanol) to pH 7 and concentrated to dryness.
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (150 mg, 0.34 mmol) and pyridazin-3-amine (65 mg, 0.68 mmol, 2.0 eq) , Pd (OAc) 2 (16 mg, 0.07 mmol, 0.2 eq) , Xantphos (41 mg, 0.07 mmol, 0.2 eq) and Cs 2 CO 3 (442 mg, 1.36 mmol, 4.0 eq) in 1.4-dioxane (10 mL) under heating at 100 °C for 1 hour through microwave irradiation under nitrogen atmosphere.
  • LC-MS m/z 504.9 (M+H) + .
  • Step F A solution of 3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenyl-N- (pyridazin-3-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (70 mg, 0.14 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum. The residue was purified to obtain the title compound as a white solid.
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (200 mg, 0.450 mmol) and pyrazin-2-amine (86 mg, 0.900 mmol, 2 eq) and palladium (II) acetate (111 mg, 0.495 mmol, 1.1 eq) , Xantphos (312 mg, 0.540 mmol, 1.2 eq) and sodium carbonate (323 mg, 0.990 mmol, 2.2 eq) in 1.4-dioxane (10mL) under heating at 100 °C through microwave irradiation for 1 hour under nitrogen atmosphere.
  • LC-MS m/z 505.2 (M+H) + .
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (500 mg, 1.07 mmol) , 5-aminopyrazine-2-carbonitrile (257 mg, 2.15 mmol) , palladium (II) acetate (48 mg, 0.214 mmol) , xantphos (124 mg, 0.214 mmol) and sodium carbonate (230 mg, 0.215 mmol) in 1, 4-dioxane (10 mL) under heating at 110 °C for 4 hours under nitrogen atmosphere.
  • LC-MS m/z 530.2 (M+H) + .
  • Step F A mixture of 5- (3-cyclohexenyl-7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidin-5-ylamino) pyrazine-2-carbonitrile (170 mg, 0.321 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL) was stirred at room temperature for 16 h. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) and washed with aqueous sodium bicarbonate to pH 8. The organic phase was dried over sodium sulfate and evaporated to dryness.
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (44mg, 0.0998 mmol) , pyrazine-2, 5-diamine (30 mg, 0.204 mmol) , palladium (II) acetate (22 mg, 0.0998 mmol) , xantphos (70 mg, 0.121 mmol) and cesium carbonate (130 g, 0.4 mmol) in 1, 4-dioxane (6 mL) under heating at 110 °C for 1 hour under nitrogen atmosphere.
  • LC-MS m/z 520.2 (M+H) + .
  • Step F A mixture of N 2 - (3-cyclohexenyl-7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidin-5-yl) pyrazine-2, 5-diamine (90 mg, 0.18 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL) was stirred at 50 °C for 3 hours. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) , basified with aqueous ammonia to pH 8, and then evaporated to dryness.
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (150 mg, 0.34 mmol) and 1, 2, 4-triazin-3-amine (65 mg, 0.68 mmol, 2.0 eq) , Pd (OAc) 2 (16 mg, 0.07 mmol, 0.2 eq) , Xantphos (41 mg, 0.07 mmol, 0.2 eq) and Cs 2 CO 3 (442 mg, 1.36 mmol, 4.0 eq) in 1.4-dioxane (10 mL) under heating at 100 °C for 1 hour through microwave irradiation under nitrogen atmosphere.
  • LC-MS m/z 505.9 (M+H) + .
  • Step F A solution of 3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenyl-N- (1, 2, 4-triazin-3-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (30 mg, 0.06 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum. The residue was purified to obtain the title compound as a white solid.
  • Step E stoichiometry: 5-chloro-3-cyclohexenyl-7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (110 mg, 0.25 mmol) , 1, 2, 4-triazin-5-amine (50 mg, 0.50 mmol) , palladium (II) acetate (28 mg, 0.125 mmol) , xantphos (87 mg, 0.15 mmol) and cesium carbonate (180 mg, 0.55 mmol) in 1, 4-dioxane (15 mL) under heating at 105 °C through microwave irradiation for 45 min under nitrogen atmosphere.
  • LC-MS m/z 506.2 (M+H) + .
  • Step F A mixture of 3-cyclohexenyl-7-methoxy-6- (4-methoxyphenyl) -2-phenyl-N- (1, 2, 4-triazin-5-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (50 mg, 0.10 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL) was stirred at room temperature for 4 hours. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) , basified with aqueous ammonia to pH 8, and then evaporated to dryness.
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (222 g, 0.5 mmol) , 1, 3, 5-triazine-2, 4-diamine (83 mg, 0.75 mmol, 1.5 eq. ) , Pd (OAc) 2 (23 mg, 0.1 mmol, 0.2 eq. ) , Xantphos (115 mg, 0.2 mmol, 0.4 eq. ) and Cs 2 CO 3 (195 mg, 0.6 mmol, 12 eq. ) in 1.4-dioxane (4 mL) under heating at 100 °C through microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 521.0 (M+H) + .
  • Step F The solution of N 2 - (3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidin-5-yl) -1, 3, 5-triazine-2, 4-diamine (80 mg, 0.15 mmol) in HCl-1, 4-dioxane (5 mL) .
  • the solution was stirred at r.t. for 6 h. Solvent and volatile were removed in vacuo.
  • the residue was dissolved in DCM (5 mL) and treated with saturated NaHCO 3 .
  • the organic phase was separated and washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo.
  • the residue was purified to afford the title compound as a yellow solid.
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (1.0 g, 2.24 mmol) , isoxazol-3-amine (377.1 mg, 4.48 mmol) , and palladium diacetate (101.0 mg, 0.45 mmol) , Xantphos (388.8 mg, 0.67 mmol) and sodium carbonate (474.8 mg, 4.48 mmol) in 1, 4-dioxane (50 mL) under heating at 110 °C for 12 hours under nitrogen atmosphere.
  • LC-MS m/z 494.2 (M+H) + .
  • Step F A solution of N- (3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidin-5-yl) isoxazol-3-amine (450 mg, 0.91mmol) in 4M HCl in 1.4-dioxane (40 mL) was stirred at r.t. for 2 hours. The mixture was concentrated at low temperature ( ⁇ 25°C) , and saturated NaHCO 3 (8 mL) was added. The precipitate was filtered.
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (220 mg, 0.5 mmol) , 1, 2, 4-thiadiazol-5-amine (101 mg, 1.0 mmol, 2.0 eq) , Pd (OAc) 2 (22 mg, 0.1 mmol, 0.2 eq) , Xantphos (57.8 mg, 0.1 mmol, 0.2 eq) and Cs 2 CO 3 (325 mg, 1.0 mmol, 2.0 eq) in 1.4-dioxane (10 mL) under heating at 100 °C for 1 hour through microwave irradiation under nitrogen atmosphere.
  • LC-MS m/z 511.2 (M+H) + .
  • Step F A solution of N- (3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidin-5-yl) -1, 2, 4-thiadiazol-5-amine (51 mg, 0.1 mmol) in 4M HCl in 1.4-dioxane (10 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum. The residue was purified to obtain the title compound as a white solid.
  • Step E stoichiometry: 5-chloro-3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine (446mg, 1 . 0mmol) , 1, 3, 4-thiadiazol-2-amine (101mg, 1.0 mmol, 1 eq) and Pd (OAc) 2 (91.5 mg, 0.1 mmol, 0.1 eq) , xant-phos (115.6mg, 0.2mmol, 0.2 eq) and Na 2 CO 3 (212mg, 2.0mmol, 2.0 eq) in toluene (40 mL) . under heating at 110 °C for 5 hour under nitrogen atmosphere.
  • LC-MS m/z 511.2 (M+H) + .
  • Step F A mixture of N- (3- (cyclohex-1-en-1-yl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidin-5-yl) -1, 3, 4-thiadiazol-2-aminein (102mg, 0.2mmol) in 4N HCl in 1.4-dioxane (15 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was basified with saturated sodium hydrogen carbonate solution. The precipitate was collected by filtration and dried to afford the title compound as a yellowish solid.
  • 1 H NMR (DMSO-d 6 ) ⁇ 13.77 (br.
  • Step E stoichiometry: 6- (5-chloro-7-methoxy-2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-6-yl) quinoline (600 mg, 1.3 mmol) , pyrimidin-4-amine (148 mg, 1.56 mmol, 1.2 eq) , Pd (OAc) 2 (43.7 mg, 0.19 mmol, 0.15 eq) , Xantphos (112 mg, 0.19 mmol, 0.15 eq) and Cs 2 CO 3 (844 mg, 2.6 mmol, 2.0 eq) in 1.4-dioxane (15 mL) under heating at 110 °C through microwave irradiation for 1 hour under nitrogen atmosphere.
  • LC-MS m/z 521.9 (M+H) + .
  • Step F A solution of 7-methoxy-2, 3-diphenyl-N- (pyrimidin-4-yl) -6- (quinolin-6-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (271 mg, 0.52 mmol) in 4M HCl in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum. The residue was purified to obtain the title compound as a white solid.
  • Step E stoichiometry: 6- (5-chloro-7-methoxy-2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-6-yl) quinoline (100 mg, 0.216 mmol) , isoxazol-3-amine (92 mg, 0.432 mmol) , palladium (II) acetate (53 mg, 0.238 mmol) , xantphos (150 mg, 0.259 mmol) and sodium carbonate (51mg, 0.475 mmol) in 1, 4-dioxane (10 mL) under heating at 100 °C through microwave irradiation for 1 hour under nitrogen atmosphere.
  • LC-MS m/z 511.2 (M+H) + .
  • Step F A mixture of N- (7-methoxy-2, 3-diphenyl-6- (quinolin-6-yl) pyrazolo [1, 5-a] pyrimidin-5-yl) isoxazol-3-amine (90 mg, 0.097 mmol) in hydrogen chloride solution (4 M in dioxane, 4 mL) was stirred at room temperature for 10 h. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) , basified with aqueous ammonia to pH 8, and then evaporated to dryness.
  • Step E stoichiometry: 6- (5-chloro-7-methoxy-2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-6-yl) quinoline (230 mg, 0.5 mmol) and acetamide (59 mg, 1.0 mmol, 2.0 eq) , Pd (OAc) 2 (11 mg, 0.05 mmol, 0.1 eq) , Xantphos (116 mg, 0.2 mmol, 0.4 eq) and Cs 2 CO 3 (325 mg, 1.0 mmol, 2.0 eq) in 1.4-dioxane (10 mL) under heating at 100 °C through microwave irradiation for 1 hour under nitrogen atmosphere.
  • LC-MS m/z 586.2 (M+H) + .
  • Step F A solution of N- (7-methoxy-2, 3-diphenyl-6- (quinolin-6-yl) pyrazolo [1, 5-a] pyrimidin-5-yl) acetamide (100 mg, 0.21 mmol) in 4M HCl in 1.4-dioxane (20 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum. The residue was purified to obtain the title compound as a white solid.
  • Step A 2- (benzyloxy) -N- (7-oxo-2, 3-diphenyl-6- (quinolin-6-yl) -4, 7-dihydropyrazolo [1, 5-a] pyrimidin-5-yl) acetamide
  • Step B 2-hydroxy-N- (7-oxo-2, 3-diphenyl-6- (quinolin-6-yl) -4, 7-dihydropyrazolo [1, 5-a] pyrimidin-5-yl) acetamide
  • Step E stoichiometry: 6- (5-chloro-3-cyclohexenyl-7-methoxy-2-phenylpyrazolo [1, 5-a] pyrimidin-6-yl) quinoline (380 mg, 0.814 mmol) , pyridin-2-amine (153 mg, 1.63 mmol) , palladium (II) acetate (18 mg, 0.0814 mmol) , xantphos (45 mg, 0.0814 mmol) and sodium carbonate (173 mg, 1.63 mmol) in 1, 4-dioxane (10 mL) under heating at 110 °C for 1 hour through microwave irradiation under nitrogen atmosphere.
  • LC-MS m/z 525.2 (M+H) + .
  • Step F A mixture of 7-methoxy-2, 3-diphenyl-N- (pyrazin-2-yl) -6- (quinolin-6-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (125 mg, 0.238 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL) was stirred at room temperature for 16 h. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) and washed with aqueous sodium bicarbonate to pH 8. The organic phase was dried over sodium sulfate and evaporated to dryness.
  • Step E stoichiometry: 6- (5-chloro-3-cyclohexenyl-7-methoxy-2-phenylpyrazolo [1, 5-a] pyrimidin-6-yl) quinoline (120 mg, 0.257 mmol) , pyrazin-2-amine (50 mg, 0.515 mmol) , palladium (II) acetate (11 mg, 0.050 mmol) , xantphos (32 mg, 0.055 mmol) and cesium carbonate (171 mg, 0.515 mmol) in 1, 4-dioxane (5 mL) under heating at 110 °C for 1 hour through microwave irradiation under nitrogen atmosphere.
  • LC-MS m/z 526.2 (M+H) + .
  • Step F A mixture of 7-methoxy-2, 3-diphenyl-N- (pyrazin-2-yl) -6- (quinolin-6-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (70 mg, 0.133 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) and washed with aqueous sodium bicarbonate to pH 8. The organic phase was dried over sodium sulfate and evaporated to dryness.
  • Step E stoichiometry: 6- (5-chloro-3-cyclohexenyl-7-methoxy-2-phenylpyrazolo [1, 5-a] pyrimidin-6-yl) quinoline (240 mg, 0.510 mmol) , isoxazol-3-amine (218 mg, 1.02 mmol) , palladium (II) acetate (126 mg, 0.560 mmol) , xantphos (354 mg, 0.612 mmol) and sodium carbonate (119 mg, 1.12 mmol) in 1, 4-dioxane (10 mL) under heating at 100 °C for 16 hours under nitrogen atmosphere.
  • LC-MS m/z 515.2 (M+H) + .
  • Step F A mixture of N- (3-cyclohexenyl-7-methoxy-2-phenyl-6- (quinolin-6-yl) pyrazolo [1, 5-a] pyrimidin-5-yl) isoxazol-3-amine (50 mg, 0.097 mmol) in hydrogen chloride solution (4 M in dioxane, 4 mL) was stirred at room temperature for 2 h. The mixture was evaporated to dryness. The residue was resolved in dichloromethane solution (with 10 %methanol) , basified with aqueous ammonia to pH 8, and then evaporated to dryness.
  • Step A N- (3- (cyclohex-1-en-1-yl) -7-methoxy-2-phenyl-6- (quinoxalin-6-yl) pyrazolo [1, 5-a] pyrimidin-5-yl) isoxazol-3-amine
  • Step B 3- (cyclohex-1-en-1-yl) -5- (isoxazol-3-ylamino) -2-phenyl-6- (quinoxalin-6-yl) pyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • N- (3- (cyclohex-1-en-1-yl) -7-methoxy-2-phenyl-6- (quinoxalin-6-yl) pyrazolo [1, 5-a] pyrimidin-5-yl) isoxazol-3-amine (12 mg, 0.02mmol) in 4M HCl in 1.4-dioxane (2 mL) was stirred at r.t. for 2 hours. The mixture was concentrated, and saturated NaHCO 3 (3 mL) was added.
  • Step A 2- (3-chlorophenyl) -3-oxo-3-phenylpropanenitrile
  • reaction was quenched by saturated NH 4 Cl (150 mL) , extracted with ethyl acetate (200 mL) , washed with water (60 mL) and brine (60 mL) , dried over anhydrous sodium sulfate, and concentrated to obtain crude product (16 g) which was directly used in the next step without further purification.
  • Step B 4- (3-chlorophenyl) -3-phenyl-1H-pyrazol-5-amine
  • Step C 3- (3-chlorophenyl) -5-hydroxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • Step D 5, 7-dichloro-3- (3-chlorophenyl) -6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine
  • Step E 5-chloro-3- (3-chlorophenyl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine
  • Step F 3- (3-chlorophenyl) -7-methoxy-6- (4-methoxyphenyl) -2-phenyl-N- (pyridin-2-yl) pyrazolo [1, 5-a] pyrimidin-5-amine
  • Step G 3- (3-chlorophenyl) -6- (4-methoxyphenyl) -2-phenyl-5- (pyridin-2-ylamino) pyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • Step A 2- (2-fluorophenyl) -3-oxo-3-phenylpropanenitrile
  • Step B 4- (2-fluorophenyl) -3-phenyl-1H-pyrazol-5-amine
  • step C 3- (2-fluorophenyl) -5-hydroxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • Step D 5, 7-dichloro-3- (2-fluorophenyl) -6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine
  • Step E 5-chloro-3- (2-fluorophenyl) -7-methoxy-6- (4-methoxyphenyl) -2-phenylpyrazolo [1, 5-a] pyrimidine
  • Step F 3- (2-fluorophenyl) -7-methoxy-6- (4-methoxyphenyl) -2-phenyl-N- (pyridin-2-yl) pyrazolo [1, 5-a] pyrimidin-5-amine
  • Step G 3- (2-fluorophenyl) -6- (4-methoxyphenyl) -2-phenyl-5- (pyridin-2-ylamino) pyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • Step B 4-phenyl-3- (pyridin-2-yl) -1H-pyrazol-5-amine
  • Step C 6- (4-methoxyphenyl) -3-phenyl-2- (pyridin-2-yl) pyrazolo [1, 5-a] pyrimidine-5, 7 (4H, 6H) -dione
  • Step D 5, 7-dichloro-6- (4-methoxyphenyl) -3-phenyl-2- (pyridin-2-yl) pyrazolo [1, 5-a] pyrimidine
  • Step E 5-chloro-7-methoxy-6- (4-methoxyphenyl) -3-phenyl-2- (pyridin-2-yl) pyrazolo [1, 5-a] pyrimidine
  • Step F 7-methoxy-6- (4-methoxyphenyl) -3-phenyl-N, 2-di (pyridin-2-yl) pyrazolo [1, 5-a] pyrimidin-5-amine
  • Step G 6- (4-methoxyphenyl) -3-phenyl-2- (pyridin-2-yl) -5- (pyridin-2-ylamino) pyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • Step A 5-hydroxy-6- (4-methoxyphenyl) -2-phenyl-3- (piperidin-1-yl) pyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • Step B 5, 7-dichloro-6- (4-methoxyphenyl) -2-phenyl-3- (piperidin-1-yl) pyrazolo [1, 5-a] pyrimidine
  • Step C 5-chloro-7-methoxy-6- (4-methoxyphenyl) -2-phenyl-3- (piperidin-1-yl) pyrazolo [1, 5-a] pyrimidine
  • Step D 7-methoxy-6- (4-methoxyphenyl) -2-phenyl-3- (piperidin-1-yl) -N- (pyridin-2-yl) pyrazolo [1, 5-a] pyrimidin-5-amine
  • Step E 6- (4-methoxyphenyl) -2-phenyl-3- (piperidin-1-yl) -5- (pyridin-2-ylamino) pyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • Step A 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) pyrazolo [1, 5-a] pyrimidin-5-amine
  • Step B 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) pyrazolo [1, 5-a] pyrimidin-5-amine
  • Step C 5- ( (1H-pyrazol-3-yl) amino) -6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • This compound was prepared according to the procedure for preparing compound 182 by using Intermediate 5 as 5-methoxy-1- (4-methoxybenzyl) -1H-pyrazol-3-amine in step A.
  • Step A A suspension of 5-chloro-7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidine (441 mg, 1 mmol) , 5-methoxy-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-amine (243 mg, 1 mmol, 1 eq. ) , Pd (OAc) 2 (44.8 mg, 0.2 mmol, 0.2 eq. ) , Xantphos (57.8 mg, 0.1 mmol, 0.1 eq. ) and Cs 2 CO 3 (650 mg, 2mmol, 2eq.
  • Step B A mixture of 7-methoxy-N- (5-methoxy-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) -6- (4-methoxyphenyl) -3-phenyl-2- (pyridin-2-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (800mg, 1.23mmol) and sodium 2-methylpropan-2-olate (197mg, 4.9mmol) in dioxane (10 mL) was stirred at 100°C for 2h.
  • Step C A solution of 5- ( (5-methoxy-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-3-yl) amino) -6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-7 (4H) -one (100 mg, 0.19 mmol) in 4M HCl in dioxane (5 mL) was stirred at r.t. for 1 hour. Solvent and volatile were removed in vacuo. The residue was dissolved in DCM (5 mL) and treated with saturated NaHCO 3 . The organic phase was separated and washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified to afford the title compound as a white solid.
  • Step A 6- (4-methoxyphenyl) -2, 3-diphenyl-5- ( (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-4-yl) amino) pyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • Step B 5- ( (1H-imidazol-4-yl) amino) -6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidin-7 (4H) -one
  • This compound was prepared according to The procedure for preparing compound 182 by using Intermediate 5 as 2- ( (2- (trimethylsilyl) ethoxy) methyl) -2H-1, 2, 3-triazol-4-amine in step A.
  • Step A A suspension of 5-chloro-7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenylpyrazolo [1, 5-a] pyrimidine (50 mg, 0.11 mmol) , 2- ( (2- (trimethylsilyl) ethoxy) methyl) -2H-1, 2, 3-triazol-4-amine (31 mg, 0.147 mmol, 1.3 eq. ) , Pd (OAc) 2 (5.1 mg, 0.027 mmol, 0.2 eq. ) , Xantphos (13.1 mg, 0.027mmol, 0.2 eq. ) and Cs 2 CO 3 (66.7 mg, 0.283mmol, 2.5eq.
  • Step B A solution of 7-methoxy-6- (4-methoxyphenyl) -2, 3-diphenyl-N- (2- ( (2- (trimethylsilyl) ethoxy) methyl) -2H-1, 2, 3-triazol-4-yl) pyrazolo [1, 5-a] pyrimidin-5-amine (110 mg, 0.18 mmol) and KO t Bu (50 mg, 0.44 mmol) in 1.4-dioxane (5 mL) was stirred at reflux for 2 hours.

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Abstract

L'invention concerne des composés inhibiteurs de MAT2A qui sont utiles en tant qu'agents thérapeutiques pour le traitement de malignités, les composés ayant la formule générale (I) : dans laquelle le cycle A, le cycle B, le cycle C et, R 1 sont tels que décrits ici.
PCT/CN2016/097524 2016-08-31 2016-08-31 Inhibiteurs de processus métaboliques cellulaires Ceased WO2018039972A1 (fr)

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PCT/CN2016/097524 WO2018039972A1 (fr) 2016-08-31 2016-08-31 Inhibiteurs de processus métaboliques cellulaires
US15/691,408 US10329298B2 (en) 2016-08-31 2017-08-30 Inhibitors of cellular metabolic processes
MX2019002303A MX390277B (es) 2016-08-31 2017-08-30 Inhibidores de procesos metabolicos celulares.
PE2019000437A PE20190761A1 (es) 2016-08-31 2017-08-30 Inhibidores de procesos metabolicos celulares
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UAA201902825A UA125852C2 (uk) 2016-08-31 2017-08-30 Інгібітори клітинних метаболічних процесів
PCT/US2017/049439 WO2018045071A1 (fr) 2016-08-31 2017-08-30 Inhibiteurs de processus métaboliques cellulaires
JP2019531597A JP6832430B2 (ja) 2016-08-31 2017-08-30 細胞代謝過程の阻害剤
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CN201780066270.4A CN109890822B (zh) 2016-08-31 2017-08-30 细胞代谢过程的抑制剂
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KR1020197009218A KR102411150B1 (ko) 2016-08-31 2017-08-30 세포 대사 과정의 억제제
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TW106129811A TWI762505B (zh) 2016-08-31 2017-08-31 細胞代謝過程之抑制劑
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