WO2018045071A1 - Inhibitors of cellular metabolic processes - Google Patents

Inhibitors of cellular metabolic processes Download PDF

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Publication number
WO2018045071A1
WO2018045071A1 PCT/US2017/049439 US2017049439W WO2018045071A1 WO 2018045071 A1 WO2018045071 A1 WO 2018045071A1 US 2017049439 W US2017049439 W US 2017049439W WO 2018045071 A1 WO2018045071 A1 WO 2018045071A1
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Prior art keywords
alkyl
mmol
pyrimidin
methoxyphenyl
alkoxy
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PCT/US2017/049439
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French (fr)
Inventor
Zenon D. Konteatis
Zhihua Sui
Jeremy M. Travins
Zhixiong Ye
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Agios Pharmaceuticals, Inc.
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Priority claimed from PCT/CN2016/097524 external-priority patent/WO2018039972A1/en
Priority to SG11201901747VA priority Critical patent/SG11201901747VA/en
Priority to CR20190157A priority patent/CR20190157A/en
Priority to CN201780066270.4A priority patent/CN109890822B/en
Priority to CA3034705A priority patent/CA3034705C/en
Priority to AU2017319500A priority patent/AU2017319500C1/en
Priority to EA201990556A priority patent/EA201990556A1/en
Priority to NZ751515A priority patent/NZ751515B2/en
Priority to UAA201902825A priority patent/UA125852C2/en
Priority to IL265115A priority patent/IL265115B/en
Application filed by Agios Pharmaceuticals, Inc. filed Critical Agios Pharmaceuticals, Inc.
Priority to PE2019000437A priority patent/PE20190761A1/en
Priority to KR1020197009218A priority patent/KR102411150B1/en
Priority to JP2019531597A priority patent/JP6832430B2/en
Priority to BR112019003914A priority patent/BR112019003914A2/en
Priority to MX2019002303A priority patent/MX2019002303A/en
Priority to EP17764997.7A priority patent/EP3507290A1/en
Publication of WO2018045071A1 publication Critical patent/WO2018045071A1/en
Priority to PH12019500368A priority patent/PH12019500368A1/en
Priority to NI201900019A priority patent/NI201900019A/en
Priority to CONC2019/0002237A priority patent/CO2019002237A2/en
Priority to AU2020277158A priority patent/AU2020277158A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/141—Esters of phosphorous acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present disclosure 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 hepatocellular carcinoma
  • MAT2A switch a switch that switches 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.
  • silencing by using small interfering RNA substantially suppresses growth and induces apoptosis in hepatoma cells. See, e.g., T. Li et al., J. Cancer 7(10) (2016) 1317-1327.
  • MTAP methylthioadenosine phosphorylase
  • 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.
  • 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.
  • Cairns et al. ((1995) Nat. Gen. 11:210--212) reported that after studying more than 500 primary tumors, almost all the deletions identified in such tumors involved a 170 kb region containing MTAP, pl4ARF and Pl6INK4A.
  • Carson et al (WO 99/67634) reported that a correlation exists between the stage of tumor development and loss of homozygosity of the gene encoding MTAP and the gene encoding p16. For example, deletion of the MTAP gene, but not pl6INK4A was reported to be indicative of a cancer at an early stage of development, whereas deletion of the genes encoding for p16 and MTAP was reported to be indicative of a cancer at a more advanced stage of tumor development.
  • Garcia- Castellano et al reported that in some osteosarcoma patients, the MTAP gene was present at diagnosis but was deleted at a later time point (Garcia-Castellano et al., supra).
  • the present disclosure satisifies a significant need for safe and effective compounds and methods for treating, preventing and managing cancers while reducing or avoiding the toxicities and/or side effects associated with the conventional therapies.
  • the cancers include those that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy.
  • the present disclosure provides a compound according to formula IA or a pharmaceutically acceptable salt thereof:
  • R A is selected from the group consisting of H, C1-C6-alkyl, C2-C6- alkenyl, C 1 -C 6 -alkoxy, C 3 -C 14 -carbocycle, (C 3 -C 14 -carbocyclo)-C 1 -C 6 -alkyl-, 3- to 14- membered heterocycle or heterocyclo-C 1 -C 6 -alkyl- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), (3- to 14-membered heterocyclo)oxy-, C6-C14- aryl, (C 6 -C 14 -aryl)-C 1 -C 6 -alkyl-, C 6 -C 14 -aryloxy-, -(CH 2 ) 0-6 NR 1 (CH 2 ) 0-6 C(O)R 2 , -NR 1 R 2 , - C(O)NR 1 R 2 ,
  • R B is selected from the group consisting of H, C2-C6-alkenyl, and C1-C6-alkyl, wherein R B is optionally substituted by one or more R 1 .
  • R C , R D , and R E are independently selected from the group consisting of C 3 -C 14 - carbocycle, C6-C14-aryl, and 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S).
  • R C , R D , and R E are optionally substituted with one or more substituents selected from the group consisting of R 1 ,–OR 1 , halo, -NR 1 R 2 , -(C1-C6-alkyl)-NR 1 R 2 , -C(O)OR 1 , -C(O)NR 1 R 2 , -NO2, -CN, and oxo.
  • R 1 and R 2 are independently selected from the group consisting of H, D ( 2 H), -CN, - OH, C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, NH2, C2-C6-alkynyl, -S(O)0-2-(C1-C6-alkyl), - S(O) 0-2 -(C 6 -C 14 -aryl), -C(O)(C 1 -C 6 -alkyl), -C(O)(C 3 -C 14 -carbocyclo), -C 3 -C 14 -carbocycle, C 6 - C 14 -aryl, 3- to 14-membered heterocycle or heterocyclo(C 1 -C 6 -alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S).
  • Each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocycle, and heterocycle moiety of R 1 and R 2 is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, -NH2, -NHC(O)(OC1-C6-alkyl), -NO2, -CN, oxo, -C(O)OH, - C(O)O(C1-C6-alkyl), -C1-C6-alkyl(C1-C6-alkoxy), -C(O)NH2, C1-C6-alkyl, -C(O)C1-C6-alkyl, -OC 1 -C 6 -alkyl, -Si(C 1 -C 6 -alkyl) 3 , C 6 -C 14 -aryl, -(C 1 -C 6 -alkyl)( C 6 -C 14 -
  • Another embodiment is a method for treating a disease or condition mediated by the overexpression of MAT2A in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof.
  • Yet another embodiment is a method of treating an MTAP null cancer in a subject comprising administering to the subject an effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for inhibiting the synthesis of S-adenosyl methionine (SAM) from methionine and ATP by MAT2A in a cell, comprising contacting the cell with an effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof.
  • SAM S-adenosyl methionine
  • Also provided in an embodiment is a method for treating a cancer in a subject suffering therefrom, wherein the cancer is characterized by a reduction or absence of methylthioadenosine phosphorylase (MTAP) gene expression, the absence of the MTAP gene, or reduced function of MTAP protein, comprising administering to the subject a therapeutically effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof.
  • MTAP methylthioadenosine phosphorylase
  • the present disclosure provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof, for inhibiting the synthesis of S-adenosyl methionine (SAM) from methionine and ATP by MAT2A in a cell.
  • SAM S-adenosyl methionine
  • a compound of formula (IA) or a pharmaceutically acceptable salt thereof for treating a disease or condition in a subject suffering therefrom, wherein the disease or condition is mediated by the overexpression of MAT2A.
  • Yet another embodiment provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof, for treating a cancer in a subject suffering therefrom, wherein the cancer is characterized by a reduction or absence of methylthioadenosine phosphorylase (MTAP) gene expression, the absence of the MTAP gene, or reduced function of MTAP protein.
  • MTAP methylthioadenosine phosphorylase
  • “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, such as a C1-C6-alkyl.
  • alkyl portion may be a saturated hydrocarbon chain, but 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 C1-C4 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, and are chosen, unless otherwise specified, from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, 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
  • “Amino” means primary (i.e.–NH2), 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, such as a C6-C14-aryl.
  • 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
  • heterocyclylsulfonylamino heterocyclylsulfonylamino
  • heterocyclylsulfonylaminoalkyl heterocyclyl, aryl, or other groups specified.
  • 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 3- or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group
  • di(alkoxy)phenyl group for example, 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4- (t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4- trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such 4-carboxyphenyl, ; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected amino
  • 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”,“carbocyclylic”,“carbocycle” and“carbocyclo” alone and when used as a moiety in a complex group such as a carbocycloalkyl group 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, SO2), and any nitrogen heteroatom may optionally be quaternized.
  • nitrogen or sulfur heteroatoms may optionally be oxidized (e.g. SO, SO2), and any nitrogen heteroatom may optionally be quaternized.
  • heterocycles are morpholinyl (morpholino), pyrrolidinyl, oxiranyl, oxetanyl,
  • 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 substituted heterocycle groups are substituted with one or more of 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, dithiadiazinyl
  • tetrahydropyrimidyl tetrazolo[1,5-b]pyridazinyl and purinyl
  • benzo-fused derivatives for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl.
  • 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,
  • 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-
  • Heteroaryl groups are optionally substituted as described for heterocycles.
  • “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.
  • “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. In an embodiment, an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents.
  • “Pharmaceutically acceptable salts” include both acid and base addition salts.
  • compounds of the present disclosure 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, cit
  • 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.
  • Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
  • the compound of the present disclosure is a salt.
  • the compound of the present disclosure is a pharmaceutically acceptable salt.
  • the compound of the present disclosure is an acetate.
  • the compound of the present disclosure is a benzoate salt.
  • the compound of the present disclosure is a besylate salt.
  • the compound of the present disclosure is a bitartrate salt.
  • the compound of the present disclosure is a bromide salt.
  • the compound of the present disclosure is a carbonate salt.
  • the compound of the present disclosure is a chloride salt. In an embodiment, the compound of the present disclosure is a citrate salt. In an embodiment, the compound of the present disclosure is an edetate salt. In an embodiment, the compound of the present disclosure is an edisylate salt. In an embodiment, the compound of the present disclosure is a estolate salt. In an embodiment, the compound of the present disclosure is a fumerate salt. In an embodiment, the compound of the present disclosure is a gluceptate salt. In an embodiment, the compound of the present disclosure is a gluconate salt. In an embodiment, the compound of the present disclosure is a hydrobromide salt. In an embodiment, the compound of the present disclosure is a hydrochloride salt.
  • the compound of the present disclosure is an iodide salt. In an embodiment, the compound of the present disclosure is a lactate salt. In an embodiment, the compound of the present disclosure is a lactobionate salt. In an embodiment, the compound of the present disclosure is a malate salt. In an embodiment, the compound of the present disclosure is a maleate salt. In an embodiment, the compound of the present disclosure is a madelate salt. In an embodiment, the compound of the present disclosure is a mesylate salt. In an embodiment, the compound of the present disclosure is a methyl bromide salt. [0034] In an embodiment, the compound of the present disclosure is a methyl sulfate salt. In an embodiment, the compound of the present disclosure is a napsylate salt. In an embodiment,
  • the compound of the present disclosure is a nitrate salt. In an embodiment, the compound of the present disclosure is a pamoate salt. In an embodiment, the compound of the present disclosure is a phosphate salt. In an embodiment, the compound of the present disclosure is a disphosphate salt. In an embodiment, the compound of the present disclosure is a salicylate salt. In an embodiment, the compound of the present disclosure is a disalicylate salt. In an embodiment, the compound of the present disclosure is a stearate salt. In an embodiment, the compound of the present disclosure is a succinate salt. In an embodiment, the compound of the present disclosure is a sulfate salt. In an embodiment, the compound of the present disclosure is a tartrate salt.
  • the compound of the present disclosure is a tosylate salt. In an embodiment, the compound of the present disclosure is a triethiodide salt. In an embodiment, the compound of the present disclosure is a valerate salt. In an embodiment, the compound of the present disclosure is an aluminum salt. In an embodiment, the compound of the present disclosure is a benzathine salt. In an embodiment, the compound of the present disclosure is a calcium salt. In an embodiment, the compound of the present disclosure is a ethylenediamine salt. In an embodiment, the compound of the present disclosure is a lysine salt. In an embodiment, the compound of the present disclosure is a magnesium salt. In an embodiment, the compound of the present disclosure is a meglumine salt.
  • the compound of the present disclosure is a potassium salt. In an embodiment, the compound of the present disclosure is a procaine salt. In an embodiment, the compound of the present disclosure is a sodium salt. In an embodiment, the compound of the present disclosure is a tromethamine salt. In an embodiment, the compound of the present disclosure is a zinc salt. [0035] Compounds of the present disclosure 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 present disclosure may exist as one or a mixture of salts and solvate forms.
  • a compound of the present disclosure may be substantially pure in one particular salt or solvate form or else may be mixtures of two or more salt or solvate forms.
  • the compounds are in solvate form.
  • the compounds exist as hydrates.
  • R A is selected from the group consisting of H, C 1 -C 6 -alkyl, C 2 -C 6 - alkenyl, C 1 -C 6 -alkoxy, C 3 -C 14 -carbocycle, (C 3 -C 14 -carbocyclo)-C 1 -C 6 -alkyl-, 3- to 14- membered heterocycle or heterocyclo(C1-C6-alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), (3- to 14-membered heterocyclo)oxy-, C 6 -C 14 -aryl, (C 6 -C 14 -aryl)-C 1 -C 6 -alkyl-, C 6 -C 14 -aryloxy-, -(CH 2 ) 0-6 NR 1 (CH 2 ) 0-6 C(O)R 2 , NR 1 R 2 , C(O)
  • R B is selected from the group consisting of H, C 2 -C 6 -alkenyl, and C 1 -C 6 -alkyl, wherein R B is optionally substituted by one or more R 1 ;
  • R C , R D , and R E are independently selected from the group consisting of C3-C14- carbocycle, C 6 -C 14 -aryl, and 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S).
  • R C , R D , and R E are optionally substituted with one or more substituents independently selected from the group consisting of R 1 ,–OR 1 , halo, -NR 1 R 2 , -(C 1 -C 6 -alkyl)-NR 1 R 2 , -C(O)OR 1 , -C(O)NR 1 R 2 , -NO 2 , -CN, and oxo.
  • R 1 and R 2 are independently selected from the group consisting of H, D ( 2 H), -CN, - OH, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, NH 2 , C 2 -C 6 -alkynyl, -S(O) 0-2 -(C 1 -C 6 -alkyl), - S(O) 0-2 -(C 6 -C 14 -aryl), -C(O)(C 1 -C 6 -alkyl), -C(O)(C 3 -C 14 -carbocyclo), -C 3 -C 14 -carbocycle, C 6 - C14-aryl, 3- to 14-membered heterocycle or heterocyclo(C1-C6-alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S).
  • Each R 1 and R 2 is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halo, -NH2, -NHC(O)(OC1-C6-alkyl), -NO2, - CN, oxo, -C(O)OH, -C(O)O(C 1 -C 6 -alkyl), -C 1 -C 6 -alkyl(C 1 -C 6 -alkoxy), -C(O)NH 2 , C 1 -C 6 - alkyl, -C(O)C1-C6-alkyl, -OC1-C6-alkyl, -Si(C1-C6-alkyl)3, C6-C14-aryl, -(C1-C6-alkyl)( C6- C 14 -aryl), 3- to 14-membered heterocycle or heterocyclo(C 1 -C 6 -alkyl)- (where
  • R 1 and R 2 are optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, -OC 1 -C 6 -alkyl, halo, -NH 2 , -(C 1 -C 6 -alkyl)NH 2 , -C(O)OH, CN, and oxo.
  • R D and R E are independently selected from C3-C14-carbocycle, C6-C14-aryl, and 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S). More
  • R D and R E are independently selected from C3-C14-carbocycle and C6-C14-aryl, or C5-C7-carbocycle and C6-C10-aryl.
  • R D and R E are independently selected from C3-C14-carbocycle and C6-C14-aryl, or C5-C7-carbocycle and C6-C10-aryl.
  • R D and R E are independently selected from C3-C14-carbocycle and C6-C14-aryl, or C5-C7-carbocycle and C6-C10-aryl.
  • R D and R E are independently selected from C3-C14-carbocycle and C6-C14-aryl, or C5-C7-carbocycle and C6-C10-aryl.
  • R D and R E independently selected from cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and phenyl.
  • one of R D and R E is cyclohexyl or cyclohexenyl and the other is phenyl.
  • R A is selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C1- C6-alkoxy, C3-C14-carbocycle, (C3-C14-carbocyclo)-C1-C6-alkyl-, 3- to 14-membered heterocycle or heterocyclo(C 1 -C 6 -alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), C 6 -C 14 -aryl, (C 6 -C 14 -aryl)-C 1 -C 6 -alkyl-, C 6 -C 14 - aryloxy, -(CH2)0-6NR 1 (CH2)0-6C(O)R 2 , NR 1 R 2 , NR 1 C(NR 2 )NR 1 R 2 , -CN, and -OH.
  • R 1 and R 2 have the meanings described herein above for Formula IA.
  • R A is selected from the group consisting of H, OH, NH2, CN, C1-C6-alkyl, hydroxy-C1-C6-alkyl-, NC-C1- C 6 -alkyl-, -C 1 -C 6 -alkyl-NH(C 1 -C 6 -alkyl), NH 2 -C 1 -C 6 -alkyl-, -(CH 2 ) 0-1 -NH-C(O)R 2 (where R 2 is NH 2 , C 1 -C 6 -alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy-C1-C6-alkyl-, 3- to 14-membered heterocycle optionally substituted with one or more of C1-C6-alkyl and oxo, and C
  • R A is selected from the group consisting of C 1 -C 6 -alkyl, - (CH 2 ) 0-6 NR 1 (CH 2 ) 0-6 C(O)R 2 , NR 1 R 2 , and NR 1 C(NR 2 )NR 1 R 2 .
  • R A can be C 1 -C 6 - alkyl or NR 1 R 2 .
  • R A is NR 1 R 2 .
  • Some Formula IA compounds in accordance with various embodiments, have R A as a secondary amino group, i.e., R A is NR 1 R 2 , where R 1 is H and R 2 is as defined hereinabove. [0046] In various embodiments, some Formula IA compounds conform to Formula IB:
  • R C is a C3-C14-carbocycle or a 3- to 14-membered heterocycle
  • R C is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, C6-C14-aryl, (C6-C14-aryl)-C1-C6-alkyl-, carboxy, -CN, oxo, C1-C6- alkyl, C 1 -C 6 -alkoxy, and–NH(C 1 -C 6 -alkyl).
  • the C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and NH(C 1 -C 6 - alkyl) are independently and optionally substituted with one or more of hydroxy, halogen, - NH2, carboxy, -CN, and oxo.
  • Substituents R D and R E are independently a C 3 -C 14 -carbocycle or a 3- to 14- membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S).
  • R D and R E are optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH 2 , C 6 -C 14 -aryl, (C 6 -C 14 -aryl)-C 1 - C6-alkyl-, carboxy, -CN, oxo, C1-C6-alkyl, C1-C6-alkoxy, and–NH(C1-C6-alkyl).
  • the C1-C6- alkyl, C1-C6-alkoxy, and NH(C1-C6-alkyl) are independently and optionally substituted with one or more of hydroxy, halogen, -NH 2 , carboxy, -CN, and oxo.
  • Substituent R 1 is selected from the group consisting of H, C 1 -C 6 -alkyl, C 3 -C 14 - carbocycle, and 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S).
  • R 1 is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH 2 , -NO 2 , -CN, oxo, carboxy, -C(O)OC1-C6-alkyl, (C1-C6-alkyl)OC1-C6-alkyl-, -C(O)NH2, C1-C6-alkyl, -C(O)H, C 1 -C 6 -alkoxy, (C 1 -C 6 -alkyl)N(H)-aryl-, (C 6 -C 14 -aryl)C 1 -C 6 -alkyl-, 5- to 7-membered heteroaryl, (5- to 7-membered heteroaryl)-C1-C6-alkyl-, C6-C14-aryloxy, (C6-C14-aryl)(C1-C6- alkoxy)-, (5- to 7-membered heteroaryl
  • each heteroaryl in R 1 has 1 to 4 heteroaryl ring members that are heteroatoms selected from N, O, and S.
  • R D is C3-C14- carbocycle optionally substituted with one or more members of the group consisting of hydroxy, halogen, -NH 2 , -C(O)OH, -CN, oxo, alkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and (C 1 -C 6 - alkyl)N(H)-.
  • C1-C6-alkyl, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)- are optionally substituted with one or more of hydroxy, halogen, -NH2, -C(O)OH, -CN, and oxo.
  • R D is phenyl. In other embodiments, R D is cyclohex-1-en-1-yl.
  • R E is C 3 -C 14 -carbocycle optionally substituted with one or more members of the group consisting of hydroxy, halogen, -NH 2 , -C(O)OH, -CN, oxo, alkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and (C 1 - C6-alkyl)N(H)-.
  • the C1-C6-alkyl, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)- are optionally substituted with one or more of hydroxy, halogen, -NH 2 , -C(O)OH, -CN, and oxo.
  • R E include but are not limited to a member selected from the group consisting of cyclohex-1-en-1-yl, ( 2 H9)cyclohex-1-en-1-yl, cyclohexan-1,3-dien-1-yl, 4,4-difluorocyclohex-1-en-1-yl, cyclopent-1-en-1yl, cyclopentyl, pyridin-3-yl, pyridin-2-yl, 4-methoxypyridin-3-yl, pyridin-2-yl, 1H-pyrazol-4-yl, 1H-pyrrol-3-yl, 4,4-difluoropiperidin- 1-yl, 5,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 1H-pyrrol-3-yl, 1H-pyrrol-1-yl, tetrahydrofuran-3-yl, 3,3-d
  • R D is cyclohex-1-en-1-yl.
  • R D or R E is phenyl optionally substituted, such as with one or more groups consisting of halogen, amino, hydroxy and alkoxy.
  • R D or R E is phenyl substituted with one or more groups consisting of F, Cl, NH 2 and OH.
  • ring R D is phenyl, such as 2-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4- aminophenyl, or 4-hydroxyphenyl.
  • R C is C 3 -C 14 -carbocycle or 3- to 14- membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S) and that is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, -C(O)OH, -CN, oxo, C1-C6-alkyl, C1- C6-alkoxy, and (C1-C6-alkyl)N(H)-.
  • R D is a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH2, 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.
  • R D is an optionally substituted carbocycle that is saturated or partially unsaturated.
  • the carbocycle is optionally substituted with one or more members 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, NH2, carboxy, CN and oxo.
  • the saturated or partially unsaturated carbocycle is substituted with one or more halogen, such as one or two F.
  • R D include optionally substituted cyclohex-1-en-yl and a saturated or partially unsaturated ring that is deuterated. In a particular embodiment, the ring is fully deuterated.
  • Illustrative examples of R D include 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, cyclopent-E1-en-1yl, and cyclopentyl.
  • R D 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, NH2, carboxy, CN and oxo.
  • the heterocycle is aromatic, i.e. heteroaryl. Examples include pyridyl, such as pyridin-3-yl or pyridin-2-yl.
  • pyrazolyl 4-methoxypyridin-3-yl, 1H-pyrazol-4-yl, 1H-pyrrol-3-yl, 4,4-difluoropiperidin-1-yl, 5,6-dihydro-2H-pyran-3-yl (Z), 3,6-dihydro-2H-pyran-4-yl, 1H- pyrrol-3-yl, 1H-pyrrol-1-yl, tetrahydrofuran-3-yl, 3,3-difluoropyrrolidin-1-yl, and 3,6- dihydro-2H-pyran-4-yl.
  • R D is a non-aromatic heterocycle that is optionally substituted with one or more halogen or alkoxy.
  • the halogen is one or two F.
  • R D is a deuterated heterocycle.
  • the heterocycle is fully deuterated.
  • R D is piperidin-1-yl, such as ( 2 H10)piperidin-1-yl.
  • R E is a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH2, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH2, carboxy, CN and oxo.
  • R E is phenyl, such as 2-fluorophenyl, 3-fluorophenyl, 3- chlorophenyl, 4-aminophenyl, and 4-hydroxyphenyl.
  • R E is a saturated or partially unsaturated carbocycle that is optionally substituted with one or more members 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, NH2, carboxy, CN or oxo.
  • the saturated or partially unsaturated carbocycle is substituted with one or more halogen, such as one or two F.
  • R E is optionally substituted cyclohex-1-en-yl, or is a saturated or partially unsaturated ring that is partially or fully deuterated.
  • R E examples include 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, cyclopent-E1-en-1yl, and cyclopentyl.
  • R E 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, NH2, carboxy, CN and oxo.
  • the heterocycle is aromatic, i.e. heteroaryl, including pyridyl such as pyridin-3-yl and pyridin-2- yl.
  • the heteroaryl is pyrazole, 4-methoxypyridin-3-yl, 1H-pyrazol-4- yl, or 1H-pyrrol-3-yl.
  • R E is a non-aromatic heterocycle that is optionally substituted with one or more halogen or alkoxy.
  • the halogen is one or two F.
  • the heterocycle is deuterated, such as fully deuterated.
  • R E examples include piperidin-1-yl, ( 2 H 10 )piperidin- 1-yl, 4,4-difluoropiperidin-1-yl, 5,6-dihydro-2H-pyran-3-yl (Z), 3,6-dihydro-2H-pyran-4-yl, 1H-pyrrol-3-yl, 1H-pyrrol-1-yl, tetrahydrofuran-3-yl, 3,3-difluoropyrrolidin-1-yl, and 3,6- dihydro-2H-pyran-4-yl.
  • R D and R E are the same as defined herein.
  • ring A and ring B are both phenyl.
  • ring A and ring B are different and are as defined herein.
  • 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 H10)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-difluoropyr
  • R E is phenyl and R D is cyclohex-1-en-1-yl (E).
  • R E /R D combinations are contemplated in additional embodiments, such as phenyl/2-fluorophenyl, phenyl/3-fluorophenyl, phenyl/3-chlorophenyl, phenyl/piperidin-1-yl, phenyl/( 2 H 10 )piperidin- 1-yl, phenyl/4,4-difluoropiperidin-1-yl, phenyl/cyclohex-1-en-1-yl (E),
  • R 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, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, a carbocycle or a heterocycle wherein the alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, NH2, carboxy, CN, oxo, a carbocycle or a heterocycle wherein the carbocycle and heterocycle are optionally substitued with one or more OH, oxo, amino, halo and haloalkyl.
  • R 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
  • R 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 the 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 the carbocycle and heterocycle
  • the optionally substituted carbocycle is aromatic, i.e. aryl, optionally substituted with one or more substituents selected from the group consisting of OH, amino, halogen, alkyl, alkoxy and cycloalkoxy wherein the alkyl, alkoxy, cycloalkoxy are optionally substituted with one or more OH, halogen, amino, oxo, a carbocycle or heterocycle wherein the carbocycle and heterocycle are optionally substituted with one or more hydroxy, halogen, oxo, alkyl and haloalkyl.
  • substituents selected from the group consisting of OH, amino, halogen, alkyl, alkoxy and cycloalkoxy wherein the alkyl, alkoxy, cycloalkoxy are optionally substituted with one or more OH, halogen, amino, oxo, a carbocycle or heterocycle wherein the carbocycle and heterocycle are optionally substituted with one or more hydroxy,
  • the aryl group such as phenyl
  • R C include phenyl optionally substituted with a substituent selected from OH, F, Cl, methyl, methoxy, ethoxy,
  • R C is selected from the group consisting of 3- hydroxyphenyl, 4-hydroxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4- ethoxyphenyl, 4-trifluoromethoxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-2- methoxyphenyl,3,4-dihydroxyphenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(2- (dimethylamino)ethoxy)phenyl, 3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, 2- chloro-4-hydroxyphenyl, 2-fluoro-4-methoxyphenyl, 3-amino-4-hydroxyphenyl, 3-amino-4- fluorophenyl, 3-(N,N
  • R 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 the alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle are optionally substituted with one or more 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.
  • the heterocycle is aromatic, such as a heteroaryl 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.
  • R C is a heteroaryl group optionally substituted with one or more OH, amino, alkyl, carboxyl, alkyl, alkoxy and cycloalkoxy wherein the alkyl is optionally substituted with OH, amino, oxo, alkoxy, a heterocycle optionally substituted with oxo and wherein the cycloalkoxy is optionally substituted with OH.
  • R C include 6-methoxypyridin-3-yl, 2-methoxypyridin-4-yl, 1H- pyrazol-4-yl, quinolin-6-yl, 2-methylquinolin-6-yl, 2-methoxyquinolin-6-yl, 2- hydroxymethylquinolin-6-yl, 3-hydroxy-2-methylquinolin-6-yl, 2-aminoquniazolin-6-yl, 4- aminoquinazolin-6-yl, cinnolin-6-yl, quinoxalin-6-yl, 2-chloroquinoxalin-6-yl, 3- chloroquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3-hydroxyquinoxalin-6-yl, 3- methoxyquinoxalin-6-yl, 1,8-naphthyridin-3-yl, or imidazo[1,2-a]pyridin-6-yl.
  • R C is selected from the group consisting of 6-methoxypyridin- 3-yl, 2-methoxypyridin-4-yl, 1H-pyrazol-4-yl, quinolin-6-yl, 2-methylquinolin-6-yl, 2- methoxyquinolin-6-yl, 2-hydroxymethylquinolin-6-yl, 3-hydroxy-2-methylquinolin-6-yl, 2- aminoquniazolin-6-yl,4-aminoquinazolin-6-yl, cinnolin-6-yl, quinoxalin-6-yl, 2- chloroquinoxalin-6-yl, 3-chloroquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3- hydroxyquinoxalin-6-yl,3-methoxyquinoxalin-6-yl, 1,8-naphthyridin-3-yl, imidazo[1,2- a]pyridin-6-yl,
  • 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, NH2, NO2, carboxy, alkoxycarbonyl, alkoxyalkyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino, and wherein the alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkoxyalkyl and alkylaminocarbonyl are optionally substituted with hydroxy, halogen, amino, alkylamino, carboxy, CN and oxo.
  • R1 is alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH2, NO2, carboxy, alkoxycarbonyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino wherein the 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.
  • R1 is hydroxyethanoyl; 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; or a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH2, NO2, carboxy, alkoxycarbonyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino wherein said alkyl, alk
  • the optionally substituted heterocycle is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 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.
  • R1 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.
  • the 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, NO2, NH2 , NHMe–C(O)NH2 and methoxy.
  • the substituent is F, Cl, CN or OH.
  • R 1 is selected from a 3- to 14-membered heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH 2 , -NO 2 , - C(O)OH, -C(O)OC1-C6-alkyl, (C1-C6-alkyl)N(H)C(O)-, -CN, oxo, C1-C6-alkyl, -C(O)H, C1- C6-alkoxy, and (C1-C6-alkyl)N(H)-.
  • the C1-C6-alkyl, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)-, C(O)OC 1 -C 6 -alkyl, and (C 1 -C 6 -alkyl)N(H)C(O)- are optionally substituted with one or more of hydroxy, halogen, -NH 2 , (C 1 -C 6 -alkyl)N(H)-, -C(O)H, -CN, and oxo.
  • R 1 is selected from the group consisting of pyridin-2- yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, 1,3,5-triazin- 2-yl, 1,2,4-triazin-3-yl, each of which is optionally substituted with one or more of F, Cl, CN, OH, -NO2, -NH2 , -NHMe,–C(O)NH2, and methoxy.
  • Illustrative moieties for R 1 are selected from the group consisting of: .
  • R1 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 the alkyl, alkoxy and alkoxyalkyl groups are optionally substituted with OH, oxo and amino.
  • R 1 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 the alkyl, alkoxy and alkoxyalkyl groups are optionally substituted with OH, oxo and amino.
  • 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,
  • Compounds of the present disclosure may also comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
  • C may be in any isotopic form, including 11 C, 12 C, 13 C, and 14 C;
  • N may be in any isotopic form, including 13 N, 14 N and 15 N;
  • O may be in any isotopic form, including 15 O, 16 O and 18 O;
  • F may be in any isotopic form, including 18 F; 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 present disclosure comprise an isotope.
  • the isotope is deuterium.
  • 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 or aryl.
  • the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the present disclosure.
  • prodrug compounds are prepared reacting the compounds of the present disclosure described above with an activated acyl compound to bond a nitrogen atom in the compound of the present disclosure 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 50 oC.
  • 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.
  • WO 9846576 One manner of preparing prodrugs is described in WO 9846576, the content of which is incorporated herein by reference in its entirety.
  • Compounds of the present disclosure may exist in different resonance forms and that all such resonance forms are within the scope of the present disclosure herein.
  • Compounds of the present disclosure are prepared using standard organic synthetic techniques from commercially available starting materials and reagents.
  • step A of scheme 1 acetate starting material a incorporating R 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 substituted with R D and R E , to provide the 5- hydroxy substituted pyrazolopyrimidone intermediate d incorporating rings R C , R D , and R E .
  • 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. Finally, the 7-methoxy group is hydrolyzed to a ketone in step F to give the final product of formula (IB).
  • 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.
  • R C , R D , R E , and R 1 are as defined herein, comprising hydrolyzing a compound of formula h
  • X is Cl.
  • the reaction is catalyzed with a palladium complex, such as a palladium-Xantphos complex.
  • the reaction is catalyzed with Pd(OAc) 2 -Xantphos complex.
  • the reaction is performed in dioxane solvent.
  • the MAT2A enzyme catalyzes the synthesis of S-adenosyl methionine (SAM) from methionine and ATP in cells. Accordingly, in another aspect of the present disclosure there is provided a method of inhibiting in a cell the synthesis of SAM from methionine and ATP comprising introducing into said cell an effective amount of a compound of formula IA or IB or a salt thereof.
  • compounds of formula IA or IB 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 production by a test compound having a detectable label can be measured with and without the presence of an unlabeled compound of the present disclosure.
  • Overexpression of the enzyme MAT2A has been demonstrated to mediate certain cancers. Accordingly, in an aspect of the present disclosure there is provided 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 IA or IB 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 IA or IB 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 (NSLC) 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. The adenine is salvaged to generate adenosine
  • 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. It has been reported by K.
  • An MTAP null cancer is a cancer in which the MTAP gene has been deleted or lost or otherwise deactivated or a cancer in which the MTAP protein has a reduced or impaired function.
  • a method for treating an MTAP null cancer in a subject wherein said cancer is characterized by a reduction or absence of MTAP expression or absence of the MTAP gene or reduced function of MTAP protein as compared to cancers where the MTAP gene is present and fully functioning, said method comprising administering to the subject a therapeutically effective amount of a compound of formula IA or IB 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 IA or IB 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 glioblastoma multiforme (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 NSLCC. 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. [00101] Genomic analysis of MTAP null cell lines revealed that in cell lines that also incorporate a KRAS mutation or a p53 mutation were sensitive to MAT2A inhibition.
  • one aspect of the present disclosure 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 IA or IB, 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
  • the cancer is MTAP null and KRAS mutant. In an embodiment, the cancer is MTAP null and p53 mutant. In an embodiment, the cancer is MTAP null, KRAS mutant and p53 mutant.
  • the term“mutant KRAS” or“KRAS mutation” refers to KRAS protein incorporating an activating mutation that alters its normal function and the gene encoding such a protein. For example, 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, wherein X represents any amino acid change at the indicated position.
  • 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 (NSLCC), pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer or ovarian cancer.
  • NSLCC non-small cell lung cancer
  • pancreatic cancer pancreatic cancer
  • gastric cancer gastric cancer
  • breast cancer colon cancer or ovarian cancer.
  • Suitable cytostatic chemotherapy compounds include, but are not limited to (i)
  • DNA-fragmenting agents such as bleomycin
  • DNA- crosslinking agents such as chlorambucil, cisplatin, cyclophosphamide or nitrogen mustard
  • intercalating agents such as adriamycin (doxorubicin) or mitoxantrone
  • protein synthesis inhibitors such as L-asparaginase, cycloheximide, puromycin or diphtheria toxin
  • topoisomerase I poisons such as camptothecin or topotecan
  • topoisomerase II poisons such as etoposide (VP-16) or teniposide
  • microtubule-directed agents such as colcemid, colchicine, pac
  • compounds of the present disclosure 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 present disclosure may be used alone as an immuno-oncology therapy or in combination with an immuno-oncology therapy.
  • the compound of the present disclosure 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, nivolumab, or atezolizumab.
  • 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.
  • radiotherapeutic agents are provided in, but not limited to, radiation therapies 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
  • stereotactic radiosurgery stereotactic radiosurgery
  • 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 moderate 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.
  • the present disclosure 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.
  • compositions or medicaments containing the compounds of the present disclosure and a pharmaceutically acceptable carrier, as well as methods of using the compounds of the present disclosure to prepare such compositions and medicaments.
  • the compounds of formula IA or IB used in the methods of the present disclosure 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
  • compositions of the present disclosure may comprise a compound of formula IA or IB or a pharmaceutically acceptable salt thereof, and one or more polymer(s) as part of a solid dispersion (e.g., an amorphous solid
  • the solid dispersion further comprises one or more surfactants.
  • the pharmaceutical composition comprising a compound of the present disclosure is a solid spray-dried dispersion.
  • Pharmaceutical compositions comprising solid dispersions of a compound of the present disclosure 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 present disclosure and matrix material followed by solidifying the mixture by cooling, or removal of the solvent. Such solid dispersions may show enhanced bioavailability when administered orally relative to oral compositions comprising the undispersed compound.
  • 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 present disclosure and polymer (or plurality of polymers), but possibly containing other components such as surfactants or other pharmaceutical excipients, where the compound of the present disclosure 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 present disclosure 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 present disclosure constitutes the dispersed phase.
  • An exemplary solid dispersion is a co-precipitate or a co-melt of a compound of the present disclosure with one or more polymer(s). A "co-precipitate" is produced after dissolving a compound of the present disclosure and one or more polymers in a solvent or solvent mixture followed by the removal of the solvent or solvent mixture.
  • 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 present disclosure 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. To remove the solvent or solvent mixture, vacuum drying, spray drying, tray drying,
  • composition of the present disclosure 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.
  • the initial pharmaceutically effective amount of the compound of the present disclosure administered parenterally per dose will be in the range of about 0.01-2000 mg/kg, for example about 0.01 to about 200 mg/kg, 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 present disclosure.
  • the compound of the present disclosure 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 present disclosure.
  • Step B 5-hydroxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l i]pyrimidin-7(4H)-one
  • Step C 5,7-dichloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[ 1 ,5- ajpyrimidine
  • Step D 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5- a]pyrimidine
  • the 5, 7-dichloro-6-(4-methoxyphenyl)-2, 3-diphenylpyrazolo [1, 5-a] pyrimidine 4 (1.78 kg, 4 mol) and DCM (20 L) were added into the 30L reactor. The mixture was cooled to -10 °C. The sodium methoxide (1.48L, 8mol, 30% in MeOH) was dropwise such that the internal temperature is maintained below 0 °C. The reaction mixture was stirred at RT for 2h. TLC indicated that the reaction was completed.
  • 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 101, 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 C0 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[l,5-a]pyrimidin-5-amine (300 mg, 0.6 mmol) was dissolved in HC1/l,4-dioxane (5 mL). The solution was stirred at r.t. overnight. The precipitate was filtered off and washed with CH 2 C1 2 (3*1 mL) to give a yellow solid. The solid was then dissolved in CH 2 C1 2 /MeOH (10/1, 3 mL). After 3 mL of NH 3 -MeOH was added, the solution was stirred at r.t. overnight to give the title compound.
  • Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol), pyridin-3 -amine (1 17 mg, 1.24 mmol), Pd(OAc) 2 (25 mg, 0.113 mmol), xantphos (131 mg, 0.226 mmol), Cs 2 C0 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[l,5-a]pyrimidin-5-amine (150 mg, 0.309 mmol) in MeOH (10 mL) was added 4N HC1 solution in dioxane (10 mL). The reaction mixture was heated to 50 °C for 2h. The mixture was concentrated in vacuo.
  • 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 (1 17.8 mg, 0.20 mmol) and Cesium carbonate (553.0 mg, 1.70 mmol) in 1,4- dioxane (10 mL) under heating to 1 10 °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[l,5-a]pyrimidin-5-yl)amino)nicotinonitrile (40 mg, 0.07 mmol) in HC1 solution (1.0 M in 1,4-dioxane, 6 mL) was stirred at room temperature for 12 hours.
  • 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 C0 3 (117 mg, 1. lmmo) 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[l,5-a]pyrimidin-5-amine (50 mg, 0.10 mmol) in MeOH (10 mL) was added 4N HC1 solution in dioxane (10 mL). The reaction mixture was heated to 50 °C for 2h. The mixture was concentrated in vacuo.
  • 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 C0 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[l,5-a]pyrimidin-5-amine (80 mg, 0.15 mmol) was dissolved in HC1-1,4- dioxane (5 mL). The solution was stirred at r.t. overnight. The precipitate was filtered off and washed with CH 2 C1 2 (3 mL) to give a yellow solid. The solid was then dissolved in
  • 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 C0 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[l,5-a]pyrimidin-5-amine (50 mg, 0.092 mmol) in 4M HC1 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.
  • Step E stoichiometry: Intermediate 5 (160 mg, 0.362 mmol), 5-((erl- 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[l,5-a]pyrimidin-5-amine (80 mg, 0.127 mmol) and HC1 solution (4N in dioxane, 10 mL) was stirred at room temperature for 6 h. Then cone. HC1 (0.5 mL) was added into the mixture. The resulting mixture was stirred at the same temperature for 4 h.
  • 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 C0 3 (120 mg, 0.36 mmol, 2.0 eq) in 1.4-dioxane (3 mL) at 1 10°Cfor lh 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[l,5-a]pyrimidin-5-yl)amino)pyridin-4-ol (40 mg, 0.08 mmol) in 4M HC1 in 1 4-dioxane (10 mL) was stirred at 30 °C for 2 hours to obtain the title compound.
  • Step E stoichiometry: Intermediate 5 (200 mg, 0.45 mmol), 6-fluoropyridin- amine (101 mg, 0.9 mmol), Pd(OAc) 2 (20 mg, 0.09 mmol), xantphos (65 mg, 0.1 1 mmol), and Cs 2 C0 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[l,5-a]pyrimidin-5-amine (120 mg, 0.23 mmol) was dissolved in HC1-1,4- dioxane (5 mL). The solution was stirred at r.t. overnight. The precipitate was filtered off and washed with CFfcCb (3 mL) to give a yellow solid. The solid was then dissolved in
  • 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 C0 3 (1.2 g, 3.63 mmol, 2.0 eq) in 1.4- dioxane (15 mL) at 1 10°C for lh 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[l,5-a]pyrimidin-5-yl)amino)picolinonitrile (220 mg, 0.42 mmol) in 4M HC1 in 1.4-dioxane (10 mL) was stirred at 30 °C for 5 hours to obtain the title compounds 6- ((6-(4 ⁇ methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5-a]pyrirnidin-5- yl)amino)picolinonitrile and 6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)amino)picolinamide.
  • 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 C0 3 (327 mg, 1.0 mmol) in 1.4-dioxane (10 mL) under heating to 1 10 °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[l,5-a]pyrimidin- 5-ylamino) isonicotinonitrile (15 mg, 0.03 mmol) in HC1 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 to afford 6-(4-methoxyphenyl)-5- (2-methoxypyrimidin-4-ylamino)-2,3- diphenyl pyrazolo [1,5-a] pyrimidin-7f4H, ) -one.
  • 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(l 16 mg, 0.2 mmol, 0.2 eq.) and Cs 2 C0 (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[l,5-a]pyrimidin-5-amine (260 mg, 0.52 mmol) in 4M HC1 in 1.4- dioxane (10 mL) was stirred at r.t. for 16 hours to give the title compound.
  • Step E stoichiometry: Intermediate 5 (237 mg, 0.538 mmol), pyrimidine-4,6- diamine (1 18.2 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 C0 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[l ,5-a]pyrimidin-5-yl)pyrimidine-4,6-diamine (90 mg, 0.17 mmol) in 4M HC1 in 1.4-dioxane (3 mL) was stirred at r.t. for 3 hours to give the title compound.
  • 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 C0 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[l,5-a]pyrimidin-5-amine (100 mg, 0.19mmol) in MeOH (10 mL) was added 4N HC1 solution in dioxane (10 mL). The reaction mixture was heated to 50 °C for 2h. The mixture was concentrated in vacuo.
  • 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 C0 3 (327 mg, 1 mmol, 2.2 eq.) in 1.4-dioxane (4 mL) under heating at 1 10 °C for 1 hour through microwave irradiation under N 2 atmosphere.
  • LC-MS m/z 501.6 (M+H) + .
  • 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 (1 17 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[l,5-a]pyrimidin-5-amine (50 mg, 0.1 mmol) in HC1 solution (4.0 M in 1,4-dioxane, 5 mL) was stirred at room temperature for 2 hours.
  • Step E stoichiometry: Intermediate 5 (132mg, 0.3mmol) and N-(6- aminopyridazin-3-yl)acetamide (93 mg, 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 C0 3 (65mg, 0.2 mmol, 2 eq) in 1.4- dioxane (5 mL) under heating at 120 °C through 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[l,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.
  • 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 C0 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 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 C0 3 (293 mg, 0.9 mmol, 2.0 eq.) in 1.4-dioxane (5 mL) under heating at 120 °C through 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[l,5-a]pyrimidin-5-amine (60 mg, 0.12 mmol) in 4M HC1 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 NaHC0 3 . The organic phase was separated and washed with brine, dried over anhydrous Na 2 S0 4 and concentrated in vacuo to afford the title compound.
  • 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.
  • 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 (1 1 mg, 0.05 mmol, 0.15 eq), Xantphos (29 mg, 0.05 mmol, 0.15 eq) and Cs 2 C0 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[l,5-a]pyrimidin-5-yl)amino)pyrazin-2-ol (15 mg, 0.03 mmol) in 4M HC1 in 1.4-dioxane (5 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum to obtain the title compound.
  • Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol), 5-aminopyrazine- 2-carbonitrile (163 mg, 1.36 mmol), tris(dibenzylideneacetone)dipalladium(0) (31 1 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[l,5-a]pyrimidin-5- ylamino)pyrazine-2-carbonitrile (100 mg, 0.19 mmol) in dichloromethane (6 mL) was added HC1 solution (4M in dioxane, 10 mL). The reaction mixture was stirred at room temperature for 16h.
  • 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 1 10 °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 ? -(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l ,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.
  • 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 1 10 °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[l,5-a] pyrimidin- 5-ylamino) pyrazine-2-carbonitrile (100 mg, 0.19 mmol) in dichloromethane (6 mL) was added HC1 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.
  • Step E stoichiometry: Intermediate 5 (800 mg, 1.81 mmol), l,3,5-triazin-2- amine (348 mg, 3.62 mmol), and Pd(OAc). (81 mg, 0.36 mmol), Xantphos (260 mg, 0.45 mmol) and Na 2 C0 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-(l,3,5-triazin-2- yl)pyrazolo[l,5-a]pyrimidin-5-amine (500 mg, 1.0 mmol) was dissolved in HC1-l,4-dioxane (10 mL). The solution was stirred at r.t. for 2h. The precipitate was filtered off and washed with CH 2 C1 2 (3*1 mL) to give a yellow solid. The solid was then dissolved in CH 2 C1 2 /MeOH (10/1 , 3 mL). After 3 mL of NH 3 -MeOH was added, the solution was stirred at r.t. overnight to give the title compound.
  • Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol), l,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[l,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.
  • Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol), l ,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 C0 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-l ,3,5-triazin-2-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4Fi)-one (156 mg, 0.3 mmol) in 4M HC1 in 1.4-dioxane (5 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum to obtain the title compound. [00259] 1H NMR (DMSO-d 6 ): ⁇ 13.80 (s, 1H), 8.17 (s, 2H), 7.66 (s, 1H), 7.51 (m, 4H),
  • 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 C0 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 mix 531.0 (M+H) + .
  • Step F A solution of N 2 -(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-N4-methyl-l,3,5-triazine-2,4-diamine (100 mg, 0.19 mmol) in 4M HC1 in 1.4-dioxane (15 mL) was stirred at r.t. for 6 hours to afford the title compound.
  • Step A 5-((4-methoxy-l,3,5-triazin-2-yl)amino)-6-(4-methoxyphi diphenylpyrazolo [l,5-a]pyrimidin-7(4H)-one
  • Step B 5-((4-hydroxy-l,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo [l,5-a]pyrimidin-7(4H)-one
  • 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 C0 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[l,5-a]pyrimidin-5-yl)thiazol-2-amine (1 10 mg, 0.23 mmol) in 4M HC1 in 1 4-dioxane (10 mL) was stirred at r.t. for 10 h to afford the title compound.
  • 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 C0 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 C0 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[l,5-a]pyrimidin-5-yl)isoxazol-4-amine (38 mg, 0.08 mmol) in 4M HC1 in 1.4-dioxane (5 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound. [00281] 1 H NMR (DMSO-d 6 ): ⁇ 9.24 (br. s., 1H), 8.74 (br. s., 1H), 7.98 (br.
  • Step E stoichiometry: Intermediate 5 (100 mg, 0.226 mmol), l-methyl-/H- imidazol-2-amine (33 mg, 0.340 mmol), tris(dibenzylideneacetone)dipalladium (0) (206 mg,
  • Step F A mixture of 7-methoxy-6-(4-methoxyphenyl)-N-(l -methyl- 1 H- imidazol-2-yl)- 2,3- diphenylpyrazolo [l,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.
  • Step E stoichiometry: Intermediate 5 (441 mg, 1.0 mmol), 1 H-imidazol-2- amine (83 mg, 1 mmol, 2 eq.), Pd 2 (dba) 3 (91.5 mg, 0.1 mmol, 0.1 eq.), Xantphos (1 15.6 mg, 0.2 mmol, 0.2 eq.) and Na 2 C0 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 (1 15.6 mg, 0.2 mmol, 0.2 eq.) and Na 2 C0 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 .Ommol) 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 C0 3 (212mg, 2.0mmol, 2.0 eq) in toluene (40 mL) under heating at 1 10 °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[l,5-a]pyrimidin-5-yl)-l,3,4-thiadiazol-2-amine (1 12mg, 0.2mmol) in 4N HC1 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 to afford the title compound.
  • 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 C0 3 (887 mg, 2.72 mmol, 2.0 eq.) in 1.4- dioxane (18 mL) under heating at 120 °C through 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[l,5-a]pyrimidin-5-yl)-l,3,4-thiadiazole-2,5-diamine (100 mg, 0.19 mmol) in 4M HC1 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 NaHC0 3 . The organic phase was separated and washed with brine, dried over anhydrous Na 2 S0 4 and concentrated in vacuo to afford the title compound.
  • Step E stoichiometry: Intermediate 5 (442mg, 1 .Ommol) and 5-methoxy- l,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 (1 15.6mg, 0.2mmol, 0.2 eq) and Na 2 C0 3 (212mg, 2. Ommol, 2.0 eq) in toluene (40 mL) under heating at 1 10 °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[l,5-a]pyrimidin-5-yl)-l,3,4-thiadiazol-2-amine (51.8mg, 0. lmmol) in 4N HC1 in 1.4-dioxane (15 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was stirred with methanol and saturated sodium hydrogen carbonate solution to afford the title compound.
  • 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 C0 (844 mg, 2.72 mmol, 2.0 eq) in 1.4-dioxane (15 mL) under heating at lOOC 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[l,5-a]pyrimidin-5-yl)-l,2,4-thiadiazol-5-amine (214 mg, 0.42 mmol) in 4M HC1 in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
  • Step E stoichiometry: Intermediate 5 (400 mg, 0.91 mmol) and 3-methoxy- l,2,4-thiadiazol-5-amine (155 mg, 1.18 mmol, 1.3 eq), Pd(OAc) 2 (1 1 mg, 0.14 mmol, 0.15 eq), Xantphos (78.7 mg, 0.14 mmol, 0.15 eq) and Cs 2 C0 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[l,5-a]pyrimidin-5-yl)-l,2,4-thiadiazol-5-amine (100 mg, 0.19 mmol) in 4M HC1 in 1.4-dioxane (5 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
  • Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol), N3-(7-methoxy-6- (4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,2,5-oxadiazole-3,4- diamine (101 mg, 1.0 mmol, 2.0 eq), Pd(OAc) 2 (1 1 mg, 0.05 mmol, 0.1 eq), Xantphos (1 16 mg, 0.2 mmol, 0.4 eq) and Cs 2 C0 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.
  • Step F A solution of N3-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,2,5-oxadiazole-3,4-diamine (237 mg, 0.47 mmol) in 4M HC1 in 1.4-dioxane (20 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
  • 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 C0 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[l,5-a]pyrimidin-5-yl)amino)thiazole-4-carboxylate (450 mg, 0.78mmol) in 4M HC1 in 1.4-dioxane (16 mL) was stirred at r.t. for 18hours.
  • Step E stoichiometry: Intermediate 5 (200 mg, 0.450 mmol), 7H-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 °C through 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 [l,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.
  • This compound was prepared according to the procedure for preparing compound 101 by using Intermediate 8 as 4-(cyclohex-l-en-l-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 HC1 (6N, 600 mL) were added with stirring vigorously for 0.5 h.
  • Step C A solution of 3-(cyclohex-l-en-l-yl)-5-hydroxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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.
  • 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 (1 1.8 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 NH4CI (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[l,5- a]pyrimidine-5,7(4H,6H)-dione (18 g, 42 mmol), DMAP(1 g) and PC1 5 (80 mg) in POCb (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[l,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 NH4CI (150 mL) was added to quench the reaction.
  • Step B A suspension of dimethyl 2-(quinolin-6-yl)malonate (1.95 g, 7.52 mmol) and 4-(cyclohex-l-en-l-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.
  • Step C The solution of 3 -(cyclohex- 1 -en- 1 -yl)-2-phenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione (3.1 g, 7.13 mmol) in POCh (12 ml) was stirred at 1 10 °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[l,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 NH4CI (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-l-en-l-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-l-en-l-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 NH4CI (50 ml) and brine (30 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • Step C The solution of 3-(cyclohex-l -en-1 -yl)-2-phenyl-6-(quinoxalin-6- yl)pyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione (1.0 g, 2.30 mmol) in POCb (6 ml) in a sealed tube was stirred at 1 10 °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-l-en-l-yl)-2- phenylpyrazolo[l,5-a]pyrimidin-6-yl)quinoxaline (800 mg, crude, 2.30 mmol) in
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l -en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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,
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 C0 3 (293 mg, 0.90 mmo) in dioxane (20 mL) under heating at 1 10 °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[l,5-a]pyrimidin-5-amine (60 mg,
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 C0 3 (285.2 mg, 2.691 mmol, 3 eq) in 1.4-dioxane (10 mL) under heating at 100 °C through microwave irradiation for 1 hour under N 2 atmosphere.
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 C0 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[l,5-a]pyrimidin-5-amine (55 mg, 0.103 mmol) and HC1 solution (4N in dioxane, 6 mL) was stirred at room temperature overnight.
  • Step E stoichiometry: 5-chloro-3-(cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 C0 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.
  • Step F A solution of 3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenyl-N-(pyridazin-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine (70 mg, 0.14 mmol) in 4M HC1 in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 (lOmL) under heating at 100 °C through microwave irradiation for 1 hour under nitrogen atmosphere.
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 1 10 °C for 4 hours under nitrogen atmosphere.
  • 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.
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 1 10 °C for 1 hour under nitrogen atmosphere.
  • Step F A mixture of N ? -(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.
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 C0 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-(l ,2,4-triazin-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine (30 mg, 0.06 mmol) in 4M HC1 in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum to obtain the title compound.
  • Step E stoichiometry: 5-chloro-3-cyclohexenyl-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo [l,5-a]pyrimidine (110 mg, 0.25 mmol), l,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.
  • Step F A mixture of 3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2- phenyl-N-( 1,2,4- triazin-5-yl) pyrazolo[l,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.
  • reaction was then cooled to room temperature, diluted with saturated sodium hydrogen carbonate solution, and extracted with EtOAc (20X3 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the title compound.
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l ,5-a]pyrimidine (222 g, 0.5 mmol), l ,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 C0 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-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,3,5-triazine-2,4-diamine (80 mg, 0.15 mmol) in HC1- 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 NaHC0 3 . The organic phase was separated and washed with brine, dried over anhydrous Na 2 S0 4 and concentrated in vacuo to afford the title compound.
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 1 10 °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[l,5-a]pyrimidin-5-yl)isoxazol-3-amine (450 mg,
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l ,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 C0 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-l-en-l -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,2,4-thiadiazol-5-amine (51 mg, 0.1 mmol) in 4M HC1 in 1.4-dioxane (10 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
  • Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidine (446mg, 1 Ommol), l,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 (1 15.6mg, 0.2mmol, 0.2 eq) and Na 2 C0 3 (212mg, 2. Ommol, 2.0 eq) in toluene (40 mL)under heating at 1 10 °C for 5 hour under nitrogen atmosphere.
  • LC-MS m/z 51 1.2 (M+H) + .
  • Step F A mixture of N-(3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-5-yl)-l ,3,4-thiadiazol-2-aminein (102mg, 0.2mmol) in 4N HC1 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 to afford the title compound.
  • Step E 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,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 (1 12 mg, 0.19 mmol, 0.15 eq) and Cs 2 C0 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.
  • Step F A solution of 7-methoxy-2,3-diphenyl-N-(pyrimidin-4-yl)-6-(quinolin- 6-yl)pyrazolo[l,5-a]pyrimidin-5-amine (271 mg, 0.52 mmol) in 4M HC1 in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound. [00426] 1 H NMR (DMSO-d 6 ): ⁇ 14.65 (s, 1H), 9.64 (s, 1H), 8.92 (s, 1H), 8.43 (m, 4H),
  • Step E stoichiometry: 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,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 51 1.2 (M+H) + .
  • Step F A mixture of N-(7-methoxy-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l ,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.
  • Step E stoichiometry: 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,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 C0 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[l,5-a]pyrimidin-5-yl)acetamide (100 mg, 0.21 mmol) in 4M HC1 in 1.4-dioxane (20 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
  • 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[l,5-a] pyrimidin-5-yl)acetamide
  • Step E 6-(5-chloro-3-cyclohexenyl-7-methoxy-2- phenylpyrazolo[l,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 1 10 °C for 1 hour through microwave irradiation under nitrogen atmosphere.
  • Step F A mixture of 7-methoxy -2,3 -diphenyl-N-(pyrazin-2-yl)-6-(quinolin-6- yl)pyrazolo[l,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.
  • Step E 6-(5-chloro-3-cyclohexenyl-7-methoxy-2- phenylpyrazolo[l,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 1 10 °C for 1 hour through microwave irradiation under nitrogen atmosphere.
  • Step F A mixture of 7-methoxy -2,3 -diphenyl-N-(pyrazin-2-yl)-6-(quinolin-6- yl)pyrazolo[l,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.
  • Step E stoichiometry: 6-(5-chloro-3-cyclohexenyl-7-methoxy-2- phenylpyrazolo[l,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 (1 19 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+Hf.
  • Step F A mixture of N-(3-cyclohexenyl-7-methoxy- 2-phenyl-6-(quinolin-6- yl)pyrazolo[l,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.
  • 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-l-en-l-yl)-5-(isoxazol-3-ylamino)-2-phenyl-6- (quinoxalin-6-yl)pyrazolo [ 1 , 5-a]pyrimidin-7(4H)-one
  • reaction was quenched by saturated NH4CI (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- 1 H-pyrazol-5 -amine
  • Step C 3- ⁇ 3-chlorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
  • Step D 5,7-dichloro-3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a] pyrimidine
  • Step F 3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N- (pyridin-2-yl)pyrazolo [l,5-a]pyrimidin-5-amine
  • Step G 3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2- ylamino)pyrazolo[l,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[l,5-a] pyrimidine
  • Step E 5-chloro-3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine
  • Step F 3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N- (pyridin-2-yl)pyrazolo [l,5-a]pyrimidin-5-amine
  • Step G 3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
  • Step A 3-oxo-2-phenyl-3-(pyridin-2-yl)propanenitrile
  • Step C 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[l,5- a]pyrimidine-5,7(4H,6H)-dione
  • 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[l,5-a] pyrimidin-5-amine
  • Step G 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)-5-(pyridin-2- ylamino)pyrazolo[l ,5-a]pyrimidin-7(4H)-one
  • Step A 5-hydroxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
  • tributylamine 25mL was warmed up tol 80 °C for 2.5 hours under N 2 protection. The mixture was cooled to the room temperature and stirred with petroleum ether. The precipitates was filtered and washed with EtOAc to afford 5-hydroxy-6-(4-methoxyphenyl)- 2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (3g) as a yellow solid.
  • LC- MS m/z 417.2 (M+H) ⁇ .
  • Step B 5,7-dichloro-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l- yl)pyrazolo[ 1 ,5-a]pyrimidine
  • Step C 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l- yl)pyrazolo[l,5-a]pyrimidine
  • Step D 7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l-yl)-N- (pyridin-2-yl)pyrazolo[l ,5-a]pyrimidin-5-amine
  • Step E 6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l-yl)-5-(pyridin-2- ylamino)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
  • Step A 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(l-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrazol-3-yl)pyrazolo[l,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[l,5-a]pyrimidin-5-amine
  • Step C 5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a] pyrimidin-7(4H)-one
  • Step A A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (441 mg, 1 mmol), 5-methoxy-l-((2-aminoethoxyethyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (441 mg, 1 mmol), 5-methoxy-l-((2-
  • 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[l,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-l-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-3-yl)amino)-6- (4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (100 mg, 0.19 mmol) in 4M HC1 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 NaHC0 3 . The organic phase was separated and washed with brine, dried over anhydrous Na 2 S0 4 , and concentrated in vacuo to afford the title compound.
  • Step A 6-(4-methoxyphenyl)-2,3-diphenyl-5-((l-((2-)
  • Step B 5-((1H-imidazol-4-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a] pyrimidin-7(4H)-one
  • Step A A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (50 mg, 0.1 1 mmol), 2-((2-aminoethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (50 mg, 0.1 1 mmol), 2-((2-aminoethoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (50 mg, 0.1 1 mmol), 2-((2-aminoethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxy
  • Step B A solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(2-((2- (trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-yl)pyrazolo[l,5-a]pyrimidin-5-amine (1 10 mg, 0.18 mmol) and KO3 ⁇ 4u (50 mg, 0.44 mmol) in 1.4-dioxane (5 mL) was stirred at reflux for 2 hours.
  • Step C A solution of 6-(4-methoxyphenyl)-2,3-diphenyl-5-((2-((2- (trimethylsilyl)ethoxy)-methyl)-2H-l,2,3-triazol-4-yl)amino)pyrazolo[l,5-a]pyrimidin-
  • Step A N3-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5- a]pyrimidin-5-yl)-l-(4-methoxybenzyl)-1H-pyrazole-3,5-diamine
  • Step B 5-((5-amino-l-(4-methoxybenzyl)-1H-pyrazol-3-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
  • Step C 5- ⁇ (5-amino-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
  • Step A 2,3-diphenyl-6-(quinolin-6-yl)-5-((l-(2-)
  • Step B 5-((1H-pyrazol-3-yl)amino)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one
  • This compound was prepared according to the procedure for preparing compound 182 by using Intermediate 1 as 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l ,5- a]pyrimidin-6-yl)quinoline and Intermediate 5 as 5-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine in step A .
  • Step E stoichiometry: 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,5- a]pyrimidin-6-yl)quinoline (200 mg, 0.432 mmol), 5-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (147 mg,0.65 mmol), Pd(OAc) 2 (10 mg, 0.043 mmol), xantphos (50 mg, 0.086 mmol), Cs 2 C0 3 (281 mg, 0.86 mmo) in dioxane (15 mL) under heating to 110 °C overnight under N 2 .
  • LC-MS m/z 640.3 (M+H) + .
  • Step F To a solution of 5-((5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l H- pyrazol-3-yl)amino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (40 mg, 0.63 mmol) in DCM (90 mL) was added TFA (3 mL). The reaction mixture was stirred for 30 mins at room temperature. The mixture was concentrated in vacuo. The residue was basified with ammonia (4 mL) and concentrated to to give the desired product.
  • Step A 3 -(cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N- (l-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine
  • reaction mixture was diluted with DCM (100 mL), filtered with celite, washed with aqueous NH4CI (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step B 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5-((l-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
  • Step C 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenyl pyrazolo[l ,5-a]pyrimidin-7(4H)-one
  • Step A 3-(cyclohex-l-en-l-yl)-2-phenyl-6-(quinolin-6-yl)-5-((l-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
  • Step B 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-l-en-l-yl)-2-phenyl-6- (quinolin-6-yl)pyrazolo [l,5-a]pyrimidin-7(4H)-one
  • Step A 3 -(cyclohex- 1 -en- 1 -yl)-7-methoxy-2-phenyl-6-(quinoxalin-6-yl)-N-( 1 - ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine
  • reaction mixture was diluted with DCM (100 mL), filtered with celite, washed with aqueous NH4CI (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated.
  • Step B 3-(cyclohex-l-en-l-yl)-2-phenyl-6-(quinoxalin-6-yl)-5-((l-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
  • Step C 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-l-en-l-yl)-2-phenyl-6- (quinoxalin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
  • Step B N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5- a]pyrimidin-5-yl)thiazol-4-amine
  • Step C 6- ⁇ 4-methoxyphenyl)-2,3-diphenyl-5-(thiazol-4-ylamino)pyrazolo[l,5- a]pyrimidin-7(4H)-one
  • This compound was prepared according to the procedures for preparing compound 192, step B-C, starting from 7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-5-amine.
  • Step B stoichiometry: 7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-amine (210 mg, 0.5 mmol), 7-chloro-[l,2,4]triazolo[l,5- cjpyrimidine (135 mg, 0.9 mmol), Pd(OAc) 2 (62 mg, 0.25 mmol, 0.5 eq.), xantphos ( 310 mg, 0.5 mmol, 1 eq.), and Cs 2 C0 3 (500 mg, 1.5 mmol, 3 eq.) in 1,4-dioxane (15 mL) under heating at 100 °C through microwave irradiation for 1 hour under N 2 atmosphere.
  • LC-MS m/z 541.2 (M+H) + .
  • Step C The solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-5-yl)-[ 1 ,2,4]triazolo[ 1 ,5-c]pyrimidin-7-amine ( 100 mg, 0.19 mmol) in HC1- 1,4-dioxane (15 mL) was stirred at r.t. for 3h. Solvent and volatile were removed in vacuo. The residue was dissolved in DCM (5 mL) and treated with saturated NaHC0 3 . The organic phase was separated and washed with brine, dried over anhydrous Na 2 S0 4 and concentrated in vacuo to afford the title compound.
  • Step A To the solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N- (l-((2-(trimethylsilyl)ethoxy)methyl)-1H-l,2,4-triazol-3-yl)pyrazolo[l,5-a]pyrimidin-5- amine 1 (80 mg, 0.1 mmol) in DCM (2 mL) cooled to 0 °C was added BBr 3 (1.0 M in DCM, 1.5 mL) dropwise . The mixture was then stirred at 0 °C for 2h. The reaction was quenched by carefully adding MeOH and concentrated in vacuo to give the product.
  • Step A dimethyl 2-(2-methylbenzo[d]thiazol-6-yl)malonate
  • Step C 6-(5,7-dichloro-2,3-diphenylpyrazolo[l,5-a]pyrimidin-6-yl)-2- methylbenzo[d] thiazole
  • Step D 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,5-a]pyrimidin-6-yl)-2- methylbenzo[d] thiazole
  • Step E 6-(2-methylbenzo[d]thiazol-6-yl)-2,3-diphenyl-5-(pyridin-2- ylamino)pyrazolo[l,5-a] pyrimidin-7(4H)-one

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Abstract

The present disclosure provides MAT2A inhibitor compounds that are useful as therapeutic agents for treating malignancies, and wherein the compounds conform to general formula (IA), wherein RA, RB, RC, RD, and RE are defined herein.

Description

INHIBITORS OF CELLULAR METABOLIC PROCESSES CLAIM FOR PRIORITY
[0001] This application claims the benefit of priority to U.S. Application Serial No.
62/548,738, filed August 22, 2017 and is also a continuation-in-part of International Patent Application Serial No. PCT/CN2016/097524, filed August 31, 2016, the contents of which are each incorporated herein by reference in their entirety.
FIELD OF THE DISCLOSURE
[0002] The present disclosure 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. BACKGROUND
[0003] Methionine adenosyltransferase (MAT) 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.
[0004] Two genes, 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. Because 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.
[0005] 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. Because 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. See, e.g., T. Li et al., J. Cancer 7(10) (2016) 1317-1327. [0006] It has been reported by Marjon et al (Cell Reports 15(3) (2016) 574–587) that cancer cell lines that are MTAP deficient are particularly sensitive to inhibition of MAT2A. MTAP (methylthioadenosine phosphorylase) is an enzyme widely expressed in normal tissues that catalyzes the conversion of methylthioadenosine (MTA) into adenine and 5- methylthioribose-1-phosphate. 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. [0007] 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. 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. [0008] 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. 11:210--212) reported that after studying more than 500 primary tumors, almost all the deletions identified in such tumors involved a 170 kb region containing MTAP, pl4ARF and Pl6INK4A. Carson et al (WO 99/67634) reported that a correlation exists between the stage of tumor development and loss of homozygosity of the gene encoding MTAP and the gene encoding p16. For example, deletion of the MTAP gene, but not pl6INK4A was reported to be indicative of a cancer at an early stage of development, whereas deletion of the genes encoding for p16 and MTAP was reported to be indicative of a cancer at a more advanced stage of tumor development. Garcia- Castellano et al reported that in some osteosarcoma patients, the MTAP gene was present at diagnosis but was deleted at a later time point (Garcia-Castellano et al., supra). SUMMARY [0009] For the reasons above, the present disclosure satisifies a significant need for safe and effective compounds and methods for treating, preventing and managing cancers while reducing or avoiding the toxicities and/or side effects associated with the conventional therapies. The cancers include those that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy. [0010] In accordance with some embodiments, the present disclosure provides a compound according to formula IA or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
[0011] In Formula IA, RA is selected from the group consisting of H, C1-C6-alkyl, C2-C6- alkenyl, C1-C6-alkoxy, C3-C14-carbocycle, (C3-C14-carbocyclo)-C1-C6-alkyl-, 3- to 14- membered heterocycle or heterocyclo-C1-C6-alkyl- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), (3- to 14-membered heterocyclo)oxy-, C6-C14- aryl, (C6-C14-aryl)-C1-C6-alkyl-, C6-C14-aryloxy-, -(CH2)0-6NR1(CH2)0-6C(O)R2, -NR1R2, - C(O)NR1R2, NR1C(NR2)NR1R2, NR1C(NR2)(=NR1), SR1, -CN, and -OH. Each alkyl, alkenyl, alkoxy, aryl, and heterocycle is optionally substituted with one or more substituents
1 1 1 1 2 1 2 selected from the group consisting of R , OR , halo, -N=N-R , NR R , -(C1-C6-alkyl)NR R , -C(O)OR1, -C(O)NR1R2, -OC(O)R1, -CN, -OP(O)(OR1)1-2, and oxo. [0012] RB is selected from the group consisting of H, C2-C6-alkenyl, and C1-C6-alkyl, wherein RB is optionally substituted by one or more R1. [0013] RC, RD, and RE are independently selected from the group consisting of C3-C14- carbocycle, C6-C14-aryl, and 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S). RC, RD, and RE are optionally substituted with one or more substituents selected from the group consisting of R1,–OR1, halo, -NR1R2, -(C1-C6-alkyl)-NR1R2, -C(O)OR1, -C(O)NR1R2, -NO2, -CN, and oxo. [0014] R1 and R2 are independently selected from the group consisting of H, D (2H), -CN, - OH, C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, NH2, C2-C6-alkynyl, -S(O)0-2-(C1-C6-alkyl), - S(O)0-2-(C6-C14-aryl), -C(O)(C1-C6-alkyl), -C(O)(C3-C14-carbocyclo), -C3-C14-carbocycle, C6- C14-aryl, 3- to 14-membered heterocycle or heterocyclo(C1-C6-alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S). [0015] Each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocycle, and heterocycle moiety of R1 and R2 is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, -NH2, -NHC(O)(OC1-C6-alkyl), -NO2, -CN, oxo, -C(O)OH, - C(O)O(C1-C6-alkyl), -C1-C6-alkyl(C1-C6-alkoxy), -C(O)NH2, C1-C6-alkyl, -C(O)C1-C6-alkyl, -OC1-C6-alkyl, -Si(C1-C6-alkyl)3, C6-C14-aryl, -(C1-C6-alkyl)( C6-C14-aryl), 3- to 14- membered heterocycle or heterocyclo(C1-C6-alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), and -O(C6-C14-aryl). [0016] In another embodiment, there is provided a pharmaceutical composition comprising s compound of formula (IA) or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier. [0017] Another embodiment is a method for treating a disease or condition mediated by the overexpression of MAT2A in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof. [0018] Yet another embodiment is a method of treating an MTAP null cancer in a subject comprising administering to the subject an effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof. [0019] In yet anotherembodiment, the present disclosure provides a method for inhibiting the synthesis of S-adenosyl methionine (SAM) from methionine and ATP by MAT2A in a cell, comprising contacting the cell with an effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof. [0020] Also provided in an embodiment is a method for treating a cancer in a subject suffering therefrom, wherein the cancer is characterized by a reduction or absence of methylthioadenosine phosphorylase (MTAP) gene expression, the absence of the MTAP gene, or reduced function of MTAP protein, comprising administering to the subject a therapeutically effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof. [0021] In another embodiment, the present disclosure provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof, for inhibiting the synthesis of S-adenosyl methionine (SAM) from methionine and ATP by MAT2A in a cell. [0022] In still another embodiment, there is provided a compound of formula (IA) or a pharmaceutically acceptable salt thereof, for treating a disease or condition in a subject suffering therefrom, wherein the disease or condition is mediated by the overexpression of MAT2A. [0023] Yet another embodiment provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof, for treating a cancer in a subject suffering therefrom, wherein the cancer is characterized by a reduction or absence of methylthioadenosine phosphorylase (MTAP) gene expression, the absence of the MTAP gene, or reduced function of MTAP protein. DETAILED DESCRIPTION [0024]“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. [0025]“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, such as a C1-C6-alkyl. When used as part of another term, for example“alkylamino”, the alkyl portion may be a saturated hydrocarbon chain, but also includes unsaturated hydrocarbon carbon chains such as“alkenylamino” and“alkynylamino. Examples of particular 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. The terms“lower alkyl” “C1-C4 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. Unless specified, substituted alkyl groups may contain one, for example two, three or four substituents which may be the same or different, and are chosen, unless otherwise specified, from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkoxy (for example C1-C6 alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl,
arylsulfonylamino, arylsulonylaminoalkyl, heterocyclylsulfonylamino,
heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other groups specified. [0026]“Amino” means primary (i.e.–NH2), 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. [0027]“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, such as a C6-C14-aryl. Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g. Lang’s Handbook of Chemistry (Dean, J. A., ed) 13th 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 C1-C6 alkyl), alkoxy (for example C1-C6 alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected
hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulonylaminoalkyl,
heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other groups specified. One or more methyne (CH) and/or methylene (CH2) groups in these substituents may in turn be substituted with a similar group as those denoted above.
Examples of the term“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 3- or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4- (iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; a mono or
di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4- (t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4- trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such 4-carboxyphenyl, ; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N- methylsulfonylamino))phenyl. Also, the term“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. [0028]“Carbocyclyl”,“carbocyclylic”,“carbocycle” and“carbocyclo” alone and when used as a moiety in a complex group such as a carbocycloalkyl group, 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. The terms“substituted carbocyclyl”,“carbocycle” and“carbocyclo” mean these groups substituted by the same substituents as the“substituted alkyl” group unless specified otherwise. [0029]“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. Typically, 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, SO2), and any nitrogen heteroatom may optionally be quaternized. Particular 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. The 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. In a particular embodiment, such optionally substituted heterocycle groups are substituted with one or more of hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino, and guanidino. [0030]“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. The following ring systems are examples of the 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, dithiadiazinyl, imidazolinyl, dihydropyrimidyl,
tetrahydropyrimidyl, tetrazolo[1,5-b]pyridazinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl. 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-thiol-1,3,4-thiadiazol-5-yl, 2-(methylthio)-1,3,4-thiadiazol-5-yl, 2- amino-1,3,4-thiadiazol-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, 2-methyl-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, 1- methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5-yl, 4-methyl-1,2,3-triazol-5-yl, pyrid-2-yl N-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl, 1-methylpyrid-2-yl, 1- methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin- 3-yl, 1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6- hydroxy-astriazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro- 5-oxo-6-methoxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-as-triazin-3-yl, 2,5-dihydro-5- oxo-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl, tetrazolo[1,5- b]pyridazin-6-yl and 8-aminotetrazolo[1,5-b]-pyridazin-6-yl. An alternative group of “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-hydroxy-2-methyl-as-triazin-3-yl, tetrazolo[1,5-b]pyridazin-6-yl, and 8- aminotetrazolo[1,5-b]pyridazin-6-yl. Heteroaryl groups are optionally substituted as described for heterocycles. [0031]“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. [0032]“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. In an embodiment, an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents. [0033]“Pharmaceutically acceptable salts” include both acid and base addition salts. In an embodiment, compounds of the present disclosure 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, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicyclic acid and the like.“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. Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine. In an embodiment the compound of the present disclosure is a salt. In an embodiment, the compound of the present disclosure is a pharmaceutically acceptable salt. In an embodiment, the compound of the present disclosure is an acetate. In an embodiment, the compound of the present disclosure is a benzoate salt. In an embodiment, the compound of the present disclosure is a besylate salt. In an embodiment, the compound of the present disclosure is a bitartrate salt. In an embodiment, the compound of the present disclosure is a bromide salt. In an embodiment, the compound of the present disclosure is a carbonate salt. In an embodiment, the compound of the present disclosure is a chloride salt. In an embodiment, the compound of the present disclosure is a citrate salt. In an embodiment, the compound of the present disclosure is an edetate salt. In an embodiment, the compound of the present disclosure is an edisylate salt. In an embodiment, the compound of the present disclosure is a estolate salt. In an embodiment, the compound of the present disclosure is a fumerate salt. In an embodiment, the compound of the present disclosure is a gluceptate salt. In an embodiment, the compound of the present disclosure is a gluconate salt. In an embodiment, the compound of the present disclosure is a hydrobromide salt. In an embodiment, the compound of the present disclosure is a hydrochloride salt. In an embodiment, the compound of the present disclosure is an iodide salt. In an embodiment, the compound of the present disclosure is a lactate salt. In an embodiment, the compound of the present disclosure is a lactobionate salt. In an embodiment, the compound of the present disclosure is a malate salt. In an embodiment, the compound of the present disclosure is a maleate salt. In an embodiment, the compound of the present disclosure is a madelate salt. In an embodiment, the compound of the present disclosure is a mesylate salt. In an embodiment, the compound of the present disclosure is a methyl bromide salt. [0034] In an embodiment, the compound of the present disclosure is a methyl sulfate salt. In an embodiment, the compound of the present disclosure is a napsylate salt. In an
embodiment, the compound of the present disclosure is a nitrate salt. In an embodiment, the compound of the present disclosure is a pamoate salt. In an embodiment, the compound of the present disclosure is a phosphate salt. In an embodiment, the compound of the present disclosure is a disphosphate salt. In an embodiment, the compound of the present disclosure is a salicylate salt. In an embodiment, the compound of the present disclosure is a disalicylate salt. In an embodiment, the compound of the present disclosure is a stearate salt. In an embodiment, the compound of the present disclosure is a succinate salt. In an embodiment, the compound of the present disclosure is a sulfate salt. In an embodiment, the compound of the present disclosure is a tartrate salt. In an embodiment, the compound of the present disclosure is a tosylate salt. In an embodiment, the compound of the present disclosure is a triethiodide salt. In an embodiment, the compound of the present disclosure is a valerate salt. In an embodiment, the compound of the present disclosure is an aluminum salt. In an embodiment, the compound of the present disclosure is a benzathine salt. In an embodiment, the compound of the present disclosure is a calcium salt. In an embodiment, the compound of the present disclosure is a ethylenediamine salt. In an embodiment, the compound of the present disclosure is a lysine salt. In an embodiment, the compound of the present disclosure is a magnesium salt. In an embodiment, the compound of the present disclosure is a meglumine salt. In an embodiment, the compound of the present disclosure is a potassium salt. In an embodiment, the compound of the present disclosure is a procaine salt. In an embodiment, the compound of the present disclosure is a sodium salt. In an embodiment, the compound of the present disclosure is a tromethamine salt. In an embodiment, the compound of the present disclosure is a zinc salt. [0035] Compounds of the present disclosure 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 present disclosure may exist as one or a mixture of salts and solvate forms. For example a compound of the present disclosure 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. Compounds [0036] As described generally above, the present disclosure provides compounds and pharmaceutically acceptable salts thereof, wherein the compounds conform to formula (IA):
(IA)
Figure imgf000014_0001
. [0037] In Formula IA, RA is selected from the group consisting of H, C1-C6-alkyl, C2-C6- alkenyl, C1-C6-alkoxy, C3-C14-carbocycle, (C3-C14-carbocyclo)-C1-C6-alkyl-, 3- to 14- membered heterocycle or heterocyclo(C1-C6-alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), (3- to 14-membered heterocyclo)oxy-, C6-C14-aryl, (C6-C14-aryl)-C1-C6-alkyl-, C6-C14-aryloxy-, -(CH2)0-6NR1(CH2)0-6C(O)R2, NR1R2, C(O)NR1R2, NR1C(NR2)NR1R2, NR1C(NR2)(=NR1), SR1, -CN, and -OH. Each alkyl, alkenyl, alkoxy, aryl, and heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of R1, OR1, halo, -N=N-R1, NR1R2, -(C1-C6-alkyl)NR1R2, -C(O)OR1, -C(O)NR1R2, -OC(O)R1, -CN, -OP(O)(OR1)1-2, and oxo. [0038] RB is selected from the group consisting of H, C2-C6-alkenyl, and C1-C6-alkyl, wherein RB is optionally substituted by one or more R1; [0039] RC, RD, and RE are independently selected from the group consisting of C3-C14- carbocycle, C6-C14-aryl, and 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S). RC, RD, and RE are optionally substituted with one or more substituents independently selected from the group consisting of R1,–OR1, halo, -NR1R2, -(C1-C6-alkyl)-NR1R2, -C(O)OR1, -C(O)NR1R2, -NO2, -CN, and oxo. [0040] R1 and R2 are independently selected from the group consisting of H, D (2H), -CN, - OH, C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, NH2, C2-C6-alkynyl, -S(O)0-2-(C1-C6-alkyl), - S(O)0-2-(C6-C14-aryl), -C(O)(C1-C6-alkyl), -C(O)(C3-C14-carbocyclo), -C3-C14-carbocycle, C6- C14-aryl, 3- to 14-membered heterocycle or heterocyclo(C1-C6-alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S). [0041] Each R1 and R2 is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halo, -NH2, -NHC(O)(OC1-C6-alkyl), -NO2, - CN, oxo, -C(O)OH, -C(O)O(C1-C6-alkyl), -C1-C6-alkyl(C1-C6-alkoxy), -C(O)NH2, C1-C6- alkyl, -C(O)C1-C6-alkyl, -OC1-C6-alkyl, -Si(C1-C6-alkyl)3, C6-C14-aryl, -(C1-C6-alkyl)( C6- C14-aryl), 3- to 14-membered heterocycle or heterocyclo(C1-C6-alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), and -O(C6-C14-aryl). Each alkyl, aryl, and heterocyclo in R1 and R2 is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, -OC1-C6-alkyl, halo, -NH2, -(C1-C6-alkyl)NH2, -C(O)OH, CN, and oxo. [0042] In some embodiments of Formula IA compounds, RD and RE are independently selected from C3-C14-carbocycle, C6-C14-aryl, and 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S). More
specifically, RD and RE are independently selected from C3-C14-carbocycle and C6-C14-aryl, or C5-C7-carbocycle and C6-C10-aryl. In exemplary embodiments, RD and RE are
independently selected from cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and phenyl. For instance, one of RD and RE is cyclohexyl or cyclohexenyl and the other is phenyl. [0043] In other embodiments, optionally in combination with any other embodiment described herein, RA is selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C1- C6-alkoxy, C3-C14-carbocycle, (C3-C14-carbocyclo)-C1-C6-alkyl-, 3- to 14-membered heterocycle or heterocyclo(C1-C6-alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), C6-C14-aryl, (C6-C14-aryl)-C1-C6-alkyl-, C6-C14- aryloxy, -(CH2)0-6NR1(CH2)0-6C(O)R2, NR1R2, NR1C(NR2)NR1R2, -CN, and -OH.
Substituents R1 and R2 have the meanings described herein above for Formula IA. [0044] Various other embodiments provide a Formula IA compound wherein RA is selected from the group consisting of H, OH, NH2, CN, C1-C6-alkyl, hydroxy-C1-C6-alkyl-, NC-C1- C6-alkyl-, -C1-C6-alkyl-NH(C1-C6-alkyl), NH2-C1-C6-alkyl-, -(CH2)0-1-NH-C(O)R2 (where R2 is NH2, C1-C6-alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy-C1-C6-alkyl-, 3- to 14-membered heterocycle optionally substituted with one or more of C1-C6-alkyl and oxo, and C3-C14-carbocycle), -NHR2 (wherein R2 is 3- to 14-membered heterocycle optionally substituted with one or more substituents independently selected from the group consisting of R1, OR1, halo, -N=N-R1, NR1R2, -(C1-C6-alkyl)NR1R2, -C(O)OR1, -OC(O)R1, -CN, -OP(O)(OR1)1-2, and
oxo), -C(O)NR1R2 (wherein R1 and R2 are independently H, C1-C6-alkyl, hydroxy-C1-C6- alkyl-, 3- to 14-membered heterocyclo-C1-C6-alkyl-, C6-C14-aryloxy-, or (3- to 14-membered heterocyclo)oxy-). [0045] In some embodiments, RA is selected from the group consisting of C1-C6-alkyl, - (CH2)0-6NR1(CH2)0-6C(O)R2, NR1R2, and NR1C(NR2)NR1R2. For example, RA can be C1-C6- alkyl or NR1R2. In exemplary embodiments, RA is NR1R2. Some Formula IA compounds, in accordance with various embodiments, have RA as a secondary amino group, i.e., RA is NR1R2, where R1 is H and R2 is as defined hereinabove. [0046] In various embodiments, some Formula IA compounds conform to Formula IB:
Figure imgf000016_0001
. [0047] In Formula IB compounds and pharmaceutically acceptable salts thereof, according to various embodiments, RC is a C3-C14-carbocycle or a 3- to 14-membered heterocycle
(wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S). RC is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, C6-C14-aryl, (C6-C14-aryl)-C1-C6-alkyl-, carboxy, -CN, oxo, C1-C6- alkyl, C1-C6-alkoxy, and–NH(C1-C6-alkyl). The C1-C6-alkyl, C1-C6-alkoxy, and NH(C1-C6- alkyl) are independently and optionally substituted with one or more of hydroxy, halogen, - NH2, carboxy, -CN, and oxo. [0048] Substituents RD and RE are independently a C3-C14-carbocycle or a 3- to 14- membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S). RD and RE are optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, C6-C14-aryl, (C6-C14-aryl)-C1- C6-alkyl-, carboxy, -CN, oxo, C1-C6-alkyl, C1-C6-alkoxy, and–NH(C1-C6-alkyl). The C1-C6- alkyl, C1-C6-alkoxy, and NH(C1-C6-alkyl) are independently and optionally substituted with one or more of hydroxy, halogen, -NH2, carboxy, -CN, and oxo. [0049] Substituent R1 is selected from the group consisting of H, C1-C6-alkyl, C3-C14- carbocycle, and 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S). R1 is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, -NO2, -CN, oxo, carboxy, -C(O)OC1-C6-alkyl, (C1-C6-alkyl)OC1-C6-alkyl-, -C(O)NH2, C1-C6-alkyl, -C(O)H, C1-C6-alkoxy, (C1-C6-alkyl)N(H)-aryl-, (C6-C14-aryl)C1-C6-alkyl-, 5- to 7-membered heteroaryl, (5- to 7-membered heteroaryl)-C1-C6-alkyl-, C6-C14-aryloxy, (C6-C14-aryl)(C1-C6- alkoxy)-, (5- to 7-membered heteroaryl)oxy-, and (5- to 7-membered heteroaryl)(C1-C6- alkoxy)-. The C1-C6-alkyl, C1-C6-alkoxy, (C1-C6-alkyl)N(H)-, -C(O)OC1-C6-alkyl, (C1-C6- alkyl)OC1-C6-alkyl-, -C(O)NH2, C6-C14-aryl, (C6-C14-aryl)C1-C6-alkyl-, 5- to 7-membered heteroaryl, (5- to 7-membered heteroaryl)-C1-C6-alkyl-, C6-C14-aryloxy, (C6-C14-aryl)(C1-C6- alkoxy)-, (5- to 7-membered heteroaryl)oxy-, and (5- to 7-membered heteroaryl)(C1-C6- alkoxy)-, are optionally substituted with one or more of hydroxy, halogen, -NH2, (C1-C6- alkyl)N(H)-, -COOH, -CN, and oxo. Further, each heteroaryl in R1 has 1 to 4 heteroaryl ring members that are heteroatoms selected from N, O, and S. [0050] In some Formula IB compounds, according to various embodiments, RD is C3-C14- carbocycle optionally substituted with one or more members of the group consisting of hydroxy, halogen, -NH2, -C(O)OH, -CN, oxo, alkyl, C1-C6-alkyl, C1-C6-alkoxy, and (C1-C6- alkyl)N(H)-. The C1-C6-alkyl, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)- are optionally substituted with one or more of hydroxy, halogen, -NH2, -C(O)OH, -CN, and oxo. [0051] Some embodiments provide Formula IB compounds wherein RD is phenyl. In other embodiments, RD is cyclohex-1-en-1-yl. [0052] In other Formula IB compounds, in accordance with additional embodiments, RE is C3-C14-carbocycle optionally substituted with one or more members of the group consisting of hydroxy, halogen, -NH2, -C(O)OH, -CN, oxo, alkyl, C1-C6-alkyl, C1-C6-alkoxy, and (C1- C6-alkyl)N(H)-. The C1-C6-alkyl, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)- are optionally substituted with one or more of hydroxy, halogen, -NH2, -C(O)OH, -CN, and oxo. [0053] Specific examples of RE include but are not limited to a member selected from the group consisting of cyclohex-1-en-1-yl, (2H9)cyclohex-1-en-1-yl, cyclohexan-1,3-dien-1-yl, 4,4-difluorocyclohex-1-en-1-yl, cyclopent-1-en-1yl, cyclopentyl, pyridin-3-yl, pyridin-2-yl, 4-methoxypyridin-3-yl, pyridin-2-yl, 1H-pyrazol-4-yl, 1H-pyrrol-3-yl, 4,4-difluoropiperidin- 1-yl, 5,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 1H-pyrrol-3-yl, 1H-pyrrol-1-yl, tetrahydrofuran-3-yl, 3,3-difluoropyrrolidin-1-yl, and 3,6-dihydro-2H-pyran-4-yl. [0054] For example, in some Formula IB compounds RE is phenyl. Optionally in
combination with this embodiment, RD is cyclohex-1-en-1-yl. [0055] In another embodiment, RD or RE is phenyl optionally substituted, such as with one or more groups consisting of halogen, amino, hydroxy and alkoxy. For instance, RD or RE is phenyl substituted with one or more groups consisting of F, Cl, NH2 and OH. In a particular embodiment ring RD is phenyl, such as 2-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4- aminophenyl, or 4-hydroxyphenyl. [0056] In other embodiments concerning Formula IB, RC is C3-C14-carbocycle or 3- to 14- membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S) and that is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, -C(O)OH, -CN, oxo, C1-C6-alkyl, C1- C6-alkoxy, and (C1-C6-alkyl)N(H)-. The C1-C6-alkyl, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)- are optionally substituted with hydroxy, halogen, -NH2, -C(O)OH, -CN and oxo. [0057] In various embodiments, RD is a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH2, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH2, carboxy, CN and oxo. In one embodiment, RD is an optionally substituted carbocycle that is saturated or partially unsaturated. The carbocycle is optionally substituted with one or more members of the group consisting of hydroxy, halogen, NH2, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH2, carboxy, CN and oxo. In another embodiment, the saturated or partially unsaturated carbocycle is substituted with one or more halogen, such as one or two F. More specific examples of RD include optionally substituted cyclohex-1-en-yl and a saturated or partially unsaturated ring that is deuterated. In a particular embodiment, the ring is fully deuterated. Illustrative examples of RD include cyclohex-1-en-1-yl (E), (2H9)cyclohex-1-en-1-yl, cyclohexa-E,Z-1,3-dien-1-yl, 4,4-difluorocyclohex-1-en-1-yl, cyclopent-E1-en-1yl, and cyclopentyl. [0058] In some embodiments RD is a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH2, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH2, carboxy, CN and oxo. For example, the heterocycle is aromatic, i.e. heteroaryl. Examples include pyridyl, such as pyridin-3-yl or pyridin-2-yl. Other examples include pyrazolyl, 4-methoxypyridin-3-yl, 1H-pyrazol-4-yl, 1H-pyrrol-3-yl, 4,4-difluoropiperidin-1-yl, 5,6-dihydro-2H-pyran-3-yl (Z), 3,6-dihydro-2H-pyran-4-yl, 1H- pyrrol-3-yl, 1H-pyrrol-1-yl, tetrahydrofuran-3-yl, 3,3-difluoropyrrolidin-1-yl, and 3,6- dihydro-2H-pyran-4-yl. [0059] In other embodiments, RD is a non-aromatic heterocycle that is optionally substituted with one or more halogen or alkoxy. For instance, the halogen is one or two F. [0060] In other embodiments, RD is a deuterated heterocycle. In one embodiment, the heterocycle is fully deuterated. In a particular embodiment, RD is piperidin-1-yl, such as (2H10)piperidin-1-yl. [0061] In various embodiments RE is a carbocycle or a heterocycle each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH2, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH2, carboxy, CN and oxo. In a particular embodiment RE is phenyl, such as 2-fluorophenyl, 3-fluorophenyl, 3- chlorophenyl, 4-aminophenyl, and 4-hydroxyphenyl. In an embodiment, RE is a saturated or partially unsaturated carbocycle that is optionally substituted with one or more members of the group consisting of hydroxy, halogen, NH2, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH2, carboxy, CN or oxo. In some embodiments, the saturated or partially unsaturated carbocycle is substituted with one or more halogen, such as one or two F. For instance, RE is optionally substituted cyclohex-1-en-yl, or is a saturated or partially unsaturated ring that is partially or fully deuterated. Illustrative examples of RE include cyclohex-1-en-1-yl (E), (2H9)cyclohex-1-en-1-yl, cyclohexa-E,Z-1,3-dien-1-yl, 4,4- difluorocyclohex-1-en-1-yl, cyclopent-E1-en-1yl, and cyclopentyl. [0062] In other embodiments RE is a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH2, carboxy, CN, oxo, alkyl, alkoxy and alkylamino wherein said alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, NH2, carboxy, CN and oxo. In an embodiment, the heterocycle is aromatic, i.e. heteroaryl, including pyridyl such as pyridin-3-yl and pyridin-2- yl. In some embodiments the heteroaryl is pyrazole, 4-methoxypyridin-3-yl, 1H-pyrazol-4- yl, or 1H-pyrrol-3-yl. [0063] In an embodiment, RE is a non-aromatic heterocycle that is optionally substituted with one or more halogen or alkoxy. For instance, in one embodiment where RE is substituted by halogen, the halogen is one or two F. In other embodiments, the heterocycle is deuterated, such as fully deuterated. Illustrative examples of RE include piperidin-1-yl, (2H10)piperidin- 1-yl, 4,4-difluoropiperidin-1-yl, 5,6-dihydro-2H-pyran-3-yl (Z), 3,6-dihydro-2H-pyran-4-yl, 1H-pyrrol-3-yl, 1H-pyrrol-1-yl, tetrahydrofuran-3-yl, 3,3-difluoropyrrolidin-1-yl, and 3,6- dihydro-2H-pyran-4-yl. [0064] In other embodiments, RD and RE 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,. In an embodiment, ring B is phenyl and ring A is selected from the group consisting of 2-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, piperidin-1-yl, (2H10)piperidin- 1-yl, 4,4-difluoropiperidin-1-yl, cyclohex-1-en-1-yl (E), (2H9)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-difluoropyrrolidin-1-yl. [0065] In various embodiments, RE is phenyl and RD is cyclohex-1-en-1-yl (E). Other RE/RD combinations are contemplated in additional embodiments, such as phenyl/2-fluorophenyl, phenyl/3-fluorophenyl, phenyl/3-chlorophenyl, phenyl/piperidin-1-yl, phenyl/(2H10)piperidin- 1-yl, phenyl/4,4-difluoropiperidin-1-yl, phenyl/cyclohex-1-en-1-yl (E),
phenyl/(2H9)cyclohex-1-en-1-yl, phenyl/cyclohexa-E,Z-1,3-dien-1-yl, phenyl/4,4- difluorocyclohex-1-en-1-yl, phenyl/5,6-dihydro-2H-pyran-3-yl (Z), phenyl/3,6-dihydro-2H- pyran-4-yl, phenyl/cyclopentyl, phenyl/cyclopent-E1-en-1yl, phenyl/1H-pyrrol-3-yl, phenyl/1H-pyrrol-1-yl, phenyl/tetrahydrofuran-3-yl, phenyl/3,3-difluoropyrrolidin-1-yl, and pyridin-2-yl/phenyl. [0066] As described more generally above, in accordance with various embodiments, RC 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 the alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, NH2, carboxy, CN, oxo, a carbocycle or a heterocycle wherein the carbocycle and heterocycle are optionally substitued with one or more OH, oxo, amino, halo and haloalkyl. In additional embodiments, RC 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 the alkyl, alkoxy and alkylamino are optionally substituted with hydroxy, halogen, amino, carboxy, CN and oxo. Alternatively, RC 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 the alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, NH2, carboxy, CN, oxo, phosphate, sulfate, a carbocycle or a heterocycle wherein the carbocycle and heterocycle are optionally substitued with one or more OH, oxo, amino, halo and haloalkyl. For example, the optionally substituted carbocycle is aromatic, i.e. aryl, optionally substituted with one or more substituents selected from the group consisting of OH, amino, halogen, alkyl, alkoxy and cycloalkoxy wherein the alkyl, alkoxy, cycloalkoxy are optionally substituted with one or more OH, halogen, amino, oxo, a carbocycle or heterocycle wherein the carbocycle and heterocycle are optionally substituted with one or more hydroxy, halogen, oxo, alkyl and haloalkyl. In one embodiment, the aryl group, such as phenyl, is optionally substituted with OH, halogen, alkoxy, amino, haloalkoxy, aminoethoxy and hydroxyethoxy. Specific examples of RC include phenyl optionally substituted with a substituent selected from OH, F, Cl, methyl, methoxy, ethoxy,
trifluoromethoxy, 2,2,2-trifluoroethoxy, dimethylaminoethoxy, 2-hydroxyethoxy and phosphate. [0067] In various embodiments, RC is selected from the group consisting of 3- hydroxyphenyl, 4-hydroxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4- ethoxyphenyl, 4-trifluoromethoxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-2- methoxyphenyl,3,4-dihydroxyphenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(2- (dimethylamino)ethoxy)phenyl, 3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, 2- chloro-4-hydroxyphenyl, 2-fluoro-4-methoxyphenyl, 3-amino-4-hydroxyphenyl, 3-amino-4- fluorophenyl, 3-(N,N-dimethylaminoethoxy)-4-hydroxyphenyl, 3-chloro-2-hydroxyphenyl,
Figure imgf000021_0001
[0068] In still other embodiments, RC 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 the alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle are optionally substituted with one or more hydroxy, halogen, NH2, 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. For example, the heterocycle is aromatic, such as a heteroaryl 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. In some embodiments, RC is a heteroaryl group optionally substituted with one or more OH, amino, alkyl, carboxyl, alkyl, alkoxy and cycloalkoxy wherein the alkyl is optionally substituted with OH, amino, oxo, alkoxy, a heterocycle optionally substituted with oxo and wherein the cycloalkoxy is optionally substituted with OH. Specific examples of RC include 6-methoxypyridin-3-yl, 2-methoxypyridin-4-yl, 1H- pyrazol-4-yl, quinolin-6-yl, 2-methylquinolin-6-yl, 2-methoxyquinolin-6-yl, 2- hydroxymethylquinolin-6-yl, 3-hydroxy-2-methylquinolin-6-yl, 2-aminoquniazolin-6-yl, 4- aminoquinazolin-6-yl, cinnolin-6-yl, quinoxalin-6-yl, 2-chloroquinoxalin-6-yl, 3- chloroquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3-hydroxyquinoxalin-6-yl, 3- methoxyquinoxalin-6-yl, 1,8-naphthyridin-3-yl, or imidazo[1,2-a]pyridin-6-yl. [0069] In other embodiments, RC is selected from the group consisting of 6-methoxypyridin- 3-yl, 2-methoxypyridin-4-yl, 1H-pyrazol-4-yl, quinolin-6-yl, 2-methylquinolin-6-yl, 2- methoxyquinolin-6-yl, 2-hydroxymethylquinolin-6-yl, 3-hydroxy-2-methylquinolin-6-yl, 2- aminoquniazolin-6-yl,4-aminoquinazolin-6-yl, cinnolin-6-yl, quinoxalin-6-yl, 2- chloroquinoxalin-6-yl, 3-chloroquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3- hydroxyquinoxalin-6-yl,3-methoxyquinoxalin-6-yl, 1,8-naphthyridin-3-yl, imidazo[1,2- a]pyridin-6-yl,
Figure imgf000022_0001
,
Figure imgf000023_0001
.
[0070] Alternatively, illustrative Formula IB compounds provide for RC as 4-methoxyphenyl. [0071] In various embodiments, R1 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, NH2, NO2, carboxy, alkoxycarbonyl, alkoxyalkyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino, and wherein the alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkoxyalkyl and alkylaminocarbonyl are optionally substituted with hydroxy, halogen, amino, alkylamino, carboxy, CN and oxo. In one embodiment, R1 is alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH2, NO2, carboxy, alkoxycarbonyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino wherein the alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkylaminocarbonyl are optionally substituted with hydroxy, halogen, NH2, alkylamino, carboxy, CN and oxo. In another embodiment, R1 is alkyl substituted with OH and oxo. In various other embodiments, R1 is hydroxyethanoyl; a carbocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH2, NO2, carboxy, alkoxycarbonyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino wherein said alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkylaminocarbonyl are optionally substituted with hydroxy, halogen, NH2, alkylamino, carboxy, CN and oxo; or a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, NH2, NO2, carboxy, alkoxycarbonyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino wherein said alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkylaminocarbonyl are optionally substituted with hydroxy, halogen, NH2, alkylamino, carboxy, CN and oxo. In accordance with some embodiments, the optionally substituted heterocycle is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 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. In an embodiment, R1 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, NO2, NH2 , NHMe–C(O)NH2 and methoxy. In an embodiment the substituent is F, Cl, CN or OH. In another embodiment, the 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, NO2, NH2 , NHMe–C(O)NH2 and methoxy. In an embodiment the substituent is F, Cl, CN or OH. [0072] According to various embodiments, optionally in combination with any other embodiments described herein, the present disclosure provides for Formula IB compounds wherein R1 is selected from a 3- to 14-membered heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, -NO2, - C(O)OH, -C(O)OC1-C6-alkyl, (C1-C6-alkyl)N(H)C(O)-, -CN, oxo, C1-C6-alkyl, -C(O)H, C1- C6-alkoxy, and (C1-C6-alkyl)N(H)-. The C1-C6-alkyl, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)-, C(O)OC1-C6-alkyl, and (C1-C6-alkyl)N(H)C(O)- are optionally substituted with one or more of hydroxy, halogen, -NH2, (C1-C6-alkyl)N(H)-, -C(O)H, -CN, and oxo. [0073] In more specific embodiments, R1 is selected from the group consisting of pyridin-2- yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, 1,3,5-triazin- 2-yl, 1,2,4-triazin-3-yl, each of which is optionally substituted with one or more of F, Cl, CN, OH, -NO2, -NH2 , -NHMe,–C(O)NH2, and methoxy. [0074] Illustrative moieties for R1 are selected from the group consisting of:
Figure imgf000025_0001
Figure imgf000026_0001
. [0075] In an embodiment, R1 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. For example, R1 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 the alkyl, alkoxy and alkoxyalkyl groups are optionally substituted with OH, oxo and amino. [0076] Alternatively, in accordance with other embodiments, 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 the alkyl, alkoxy and alkoxyalkyl groups are optionally substituted with OH, oxo and amino. [0077] Specific examples of R1 are selected from the group consisting of:
,
Figure imgf000026_0002
Figure imgf000027_0001
, , , , ,
and . [0078] The present disclosures also provides compounds having the general formula I:
Figure imgf000027_0002
wherein 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; [0079] In this embodiment, 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, NH2, carboxy, CN, oxo, a carbocycle or a heterocycle wherein said carbocycle and heterocycle are optionally substitued with OH, oxo, amino, halo and haloalkyl; [0080] R1 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, NO2, 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. [0081] Compounds of the present disclosure may also comprise one or more isotopic substitutions. For example, 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. For example, 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. In an embodiment, compounds of the present disclosure comprise an isotope. In an embodiment the isotope is deuterium. [0082] Specific compounds conforming to formula IA, or pharmaceutically acceptable salts thereof, include those in Table 1 below:
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
[0083] Specific compounds conforming to formula IB, or pharmaceutically acceptable salts thereof, include those of Table 2:
TABLE 2
Figure imgf000041_0002
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
[0084] The present disclosure also encompasses prodrugs of the compounds described above. Suitable prodrugs where applicable 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 or aryl. In a particular embodiment, the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the present disclosure. These prodrug compounds are prepared reacting the compounds of the present disclosure described above with an activated acyl compound to bond a nitrogen atom in the compound of the present disclosure 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 50 ºC. 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. One manner of preparing prodrugs is described in WO 9846576, the content of which is incorporated herein by reference in its entirety. [0085] Compounds of the present disclosure may exist in different resonance forms and that all such resonance forms are within the scope of the present disclosure herein. [0086] Compounds of the present disclosure are prepared using standard organic synthetic techniques from commercially available starting materials and reagents. It will be appreciated that synthetic procedures employed in the preparation of compounds of the present disclosure will depend on the particular substituents present in a compound and that various protection and deprotection steps that are standard in organic synthesis may be required but may not be illustrated in the following general schemes. [0087] In a particular embodiment, compounds of the present disclosure conforming to formula IB may be prepared by the general Scheme 1. Scheme 1
RD c
Figure imgf000052_0001
[0088] In step A of scheme 1, acetate starting material a incorporating RC 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 substituted with RD and RE, to provide the 5- hydroxy substituted pyrazolopyrimidone intermediate d incorporating rings RC, RD, and RE. 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. Finally, the 7-methoxy group is hydrolyzed to a ketone in step F to give the final product of formula (IB). [0089] 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.
Scheme 2
Figure imgf000053_0001
[0090] Acetonitrile intermediate m incorporating RD is reacted with ester n incorporating RE with an appropriate base catalyst such as sodium hexamethyldisilazide to form 3-oxo- propanenitrile intermediate o containing both RD and RE. 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 present disclosure. [0091] In an aspect of the present disclosure, there is provided a process for preparing a compound of formula IA or IB
Figure imgf000053_0002
wherein RC, RD, RE, and R1 are as defined herein, comprising hydrolyzing a compound of formula h
R
Figure imgf000053_0003
[0092] There is provided a process for preparing a compound of formula h
Figure imgf000054_0001
comprising reacting a compound having the formula f
Figure imgf000054_0002
f
wherein X is a halogen, with an amine of formula g
Figure imgf000054_0003
wherein R1 is as defined herein. [0093] In an embodiment, X is Cl. In an embodiment, the reaction is catalyzed with a palladium complex, such as a palladium-Xantphos complex. For instance, the reaction is catalyzed with Pd(OAc)2-Xantphos complex. In one embodiment, the reaction is performed in dioxane solvent. [0094] In another embodiment, there is provided a process for preparing a compound of formula f
Figure imgf000054_0004
comprising reacting a compound of formula e
Figure imgf000054_0005
with sodium methoxide. In an embodiment the reaction is performed in methanol. [0095] In an embodiment, there is provided a process for preparing a compound of formula e
Figure imgf000055_0001
e
comprising reacting a compound of formula d
Figure imgf000055_0002
d
with phosphoryl chloride. In an embodiment, the reaction is heated. [0096] In an embodiment, there is provided a process for preparing a compound of formula d
Figure imgf000055_0003
d
comprising reacting a compound of formula c
Figure imgf000055_0004
c
with a compound of formula b
Figure imgf000055_0005
b [0097] In an embodiment, there is provided a process for preparing a compound of formula b
Figure imgf000056_0001
comprising reacting a compound of formula a
Figure imgf000056_0002
with dimethyl carbonate. Methods of Use [0098] The MAT2A enzyme catalyzes the synthesis of S-adenosyl methionine (SAM) from methionine and ATP in cells. Accordingly, in another aspect of the present disclosure there is provided a method of inhibiting in a cell the synthesis of SAM from methionine and ATP comprising introducing into said cell an effective amount of a compound of formula IA or IB or a salt thereof. In another aspect of the present disclosure, compounds of formula IA or IB 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 production by a test compound having a detectable label can be measured with and without the presence of an unlabeled compound of the present disclosure. [0099] Overexpression of the enzyme MAT2A has been demonstrated to mediate certain cancers. Accordingly, in an aspect of the present disclosure there is provided 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 IA or IB or a pharmaceutically acceptable salt thereof. In another aspect of the present disclosure there is provided 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 IA or IB or a pharmaceutically acceptable salt thereof. In an embodiment, 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 lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma. In an embodiment, the cancer is lung cancer, non-small cell lung (NSLC) 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, hepatocellular cancer, biliary cancer, chronic or acute leukemia, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenomas, including refractory versions of any of the above cancers, or a combination of one or more of the above cancers. Methylthioadenosine phosphorylase (MTAP) is an enzyme found in all normal tissues that catalyzes the conversion of methylthioadenosine (MTA) into adenine and 5- methylthioribose-1-phosphate. 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. It has been reported by K. Marjon et al., Cell Reports 15 (2016) 574– 587, incorporated herein by reference, that proliferation of cancer cells that are MTAP null is inhibited by knocking down MAT2A expression with shRNA which was confirmed using small molecule inhibitors of MAT2A such as those of the present disclosure. An MTAP null cancer is a cancer in which the MTAP gene has been deleted or lost or otherwise deactivated or a cancer in which the MTAP protein has a reduced or impaired function. [00100] Accordingly, in an embodiment of the present disclosure there is provided a method for treating an MTAP null cancer in a subject wherein said cancer is characterized by a reduction or absence of MTAP expression or absence of the MTAP gene or reduced function of MTAP protein as compared to cancers where the MTAP gene is present and fully functioning, said method comprising administering to the subject a therapeutically effective amount of a compound of formula IA or IB or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method of treating an MTAP null cancer in a subject comprising administering to the subject an effective amount of a compound of formula IA or IB or a pharmaceutically acceptable salt thereof. In an embodiment, 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. In an embodiment, the MTAP null cancer is pancreatic cancer. In an embodiment, 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). In an embodiment, the MTAP null cancer is pancreatic cancer. In an embodiment, the MTAP null cancer is gastric cancer. In an embodiment, the cancer is colon cancer. In an embodiment, the MTAP null cancer is liver cancer. In an embodiment, the MTAP null cancer is glioblastoma multiforme (GBM). In an embodiment, the MTAP null cancer is bladder cancer. In an embodiment, 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 NSLCC. 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. [00101] Genomic analysis of MTAP null cell lines revealed that in cell lines that also incorporate a KRAS mutation or a p53 mutation were sensitive to MAT2A inhibition.
Accordingly, one aspect of the present disclosure 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 IA or IB, wherein said cancer is further characterized by the presence of mutant KRAS or mutant p53. In another aspect of the present disclosure there is provided 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 IA or IB or a pharmaceutically acceptable salt thereof. In an embodiment, the cancer is MTAP null and KRAS mutant. In an embodiment, the cancer is MTAP null and p53 mutant. In an embodiment, the cancer is MTAP null, KRAS mutant and p53 mutant. [00102] The term“mutant KRAS” or“KRAS mutation” refers to KRAS protein incorporating an activating mutation that alters its normal function and the gene encoding such a protein. For example, a mutant KRAS protein may incorporate a single amino acid substitution at position 12 or 13. In a particular embodiment, the KRAS mutant incorporates a G12X or G13X substitution, wherein X represents any amino acid change at the indicated position. In a particular embodiment, the substitution is G12V, G12R, G12C or G13D. In another embodiment, the substitution is G13D. By“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. In an embodiment, 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. In an embodiment, the foregoing cancer is non-small cell lung cancer (NSLCC), pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer or ovarian cancer. [00103] The compounds may be administered prior to, concomitantly with, or following administration of radiation therapy or cytostatic or antineoplastic chemotherapy. 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) topoisomerase II poisons, such as etoposide (VP-16) or teniposide; (viii) microtubule-directed agents, such as colcemid, colchicine, paclitaxel, vinblastine or vincristine; (ix) kinase inhibitors such as flavopiridol, staurosporin, STI571 (CPG 57148B) or UCN-01 (7-hydroxystaurosporine); (x) miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18- OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; (xi) hormones such as glucocorticoids or fenretinide; (xii) hormone antagonists, such as tamoxifen, finasteride or LHRH antagonists. In a particular embodiment, compounds of the present disclosure are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C. In a particular embodiment, the cytostatic compound is doxorubicin. [00104] In another embodiment, compounds of the present disclosure may be used alone as an immuno-oncology therapy or in combination with an immuno-oncology therapy. In an embodiment, the compound of the present disclosure is administered prior to, concomitantly with, or following administration of an immune checkpoint inhibitor. In an embodiment, the checkpoint inhibitor is a PD-1 inhibitor. In an embodiment, the checkpoint inhibitor is a PD-L1 inhibitor. In an embodiment, the checkpoint inhibitor is ipilimumab. In an embodiment, the checkpoint inhibitor is pembrolizumab, nivolumab, or atezolizumab. [00105] The compounds of the present disclosure can be also used in combination with radiation therapy. The phrase "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. [00106] Examples of radiotherapeutic agents are provided in, but not limited to, radiation therapies 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". These newer treatment modalities deliver greater doses of radiation to the tumor, which accounts for their increased effectiveness when compared to standard external beam 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). 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. In addition, 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 disclosure. Furthermore, the present disclosure 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. In a particular embodiment of the present disclosure UV radiation is applied.
Pharmaceutical Compositions [00107] The present disclosure also includes pharmaceutical compositions or medicaments containing the compounds of the present disclosure and a pharmaceutically acceptable carrier, as well as methods of using the compounds of the present disclosure to prepare such compositions and medicaments. Typically, the compounds of formula IA or IB used in the methods of the present disclosure 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. The pH of the formulation depends mainly on the particular use and the concentration of compound, and it can range from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment. In an 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. [00108] In another embodiment, pharmaceutical compositions of the present disclosure may comprise a compound of formula IA or IB or a pharmaceutically acceptable salt thereof, and one or more polymer(s) as part of a solid dispersion (e.g., an amorphous solid
dispersion). In an embodiment, the solid dispersion further comprises one or more surfactants. In an embodiment, the pharmaceutical composition comprising a compound of the present disclosure is a solid spray-dried dispersion. Pharmaceutical compositions comprising solid dispersions of a compound of the present disclosure 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 present disclosure and matrix material followed by solidifying the mixture by cooling, or removal of the solvent. Such solid dispersions may show enhanced bioavailability when administered orally relative to oral compositions comprising the undispersed compound. 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). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, 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 present disclosure and polymer (or plurality of polymers), but possibly containing other components such as surfactants or other pharmaceutical excipients, where the compound of the present disclosure is in the amorphous phase. In some embodiments, an amorphous solid dispersion includes the polymer(s) (and optionally a surfactant) constituting the dispersed phase, and the compound of the present disclosure 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 present disclosure constitutes the dispersed phase. [00109] An exemplary solid dispersion is a co-precipitate or a co-melt of a compound of the present disclosure with one or more polymer(s). A "co-precipitate" is produced after dissolving a compound of the present disclosure 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 present disclosure 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. In some cases, 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. To remove 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. [00110] The composition of the present disclosure 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. Generally, the initial pharmaceutically effective amount of the compound of the present disclosure administered parenterally per dose will be in the range of about 0.01-2000 mg/kg, for example about 0.01 to about 200 mg/kg, 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 present disclosure. [00111] The compound of the present disclosure 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 present disclosure.
EXAMPLES [00112] The present disclosure will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the present disclosure. Reagents and solvents were obtained from commercial sources and used as received. [00113] Abbreviations and terms list: anhy. anhydrous
aq. aqueous
min minute(s)
mL milliliter
mmol millimole(s)
mol mole(s)
MS mass spectrometry
NMR nuclear magnetic resonance
TLC thin layer chromatography
HPLC high-performance liquid chromatography
RT(r.t.) room temperature -Spectrum
Spectrum:
Hz hertz
į chemical shift
J coupling constant
s singlet
d doublet t triplet q quartet
m multiplet
br broad
qd quartet of doublets dquin doublet of quintets dd doublet of doublets dt doublet of triplets Solvents and Reagents:
CHCl3 chloroform
DCM dichloromethane DMF dimethylformamide Et2O diethyl ether EtOH ethyl alcohol EtOAc ethyl acetate EA ethyl acetate MeOH methyl alcohol MeCN acetonitrile
PE petroleum ether THF tetrahydrofuran AcOH acetic acid
HCl hydrochloric acid H2SO4 sulfuric acid NH4Cl ammonium chloride KOH potassium hydroxide NaOH sodium hydroxide K2CO3 potassium carbonate Na2CO3 sodium carbonate TFA trifluoroacetic acid Na2SO4 sodium sulfate NaBH4 sodium borohydride NaHCO3 sodium bicarbonate
Figure imgf000066_0001
[00114] Example 1 Synthesis of Compounds
General experimental notes [00115] In the following examples, the reagents (chemicals) 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, δ) downfield from tetramethylsilane. Mass spectra were given with electrospray ionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA). HPLC chromatographs were record on an Agilent 1200 Liquid
Chromattgraphy (Agilent, USA, column: Ultimate 4.6mmx50mm, 5µm, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile). Microwave reactions were run on an Initiator 2.5 Microwave Synthesizer (Biotage, Sweden). [00116] Compound 101: 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridazin-3- ylamino)pyrazolo[l,5-a]pyrirnidin-7(4H)-one
Figure imgf000067_0001
[00117] Step A: Dimethyl 2-(4-methoxyphenyl)malonate
Figure imgf000067_0002
[00118] To dimethyl carbonate (3.2L) was added slowly t-BuOK (500 g) at 0 °C and the mixture was stirred for 1 h at room temperature. Then methyl 2-(4~
methoxyphenyl)acetate (400 g) was added dropwise over 2 h and stirred at room temperature overnight. The reaction was quenched with water (1 ,5 L), followed by extraction with EA (1L* 3). The combined organic layers were washed with brine ( 1 1.), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by flash chromatography eluting with PE/EA (20/1-5/1) to obtain the desired product as white solid (4()()g).
[00119] 1H NMR (CHLOROFORM-d): δ 7.33 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8,9 Hz,
2H) , 4.61 (s, 1H), 3.80 (s, 3H), 3.75 (s, 6H), Step B: 5-hydroxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l i]pyrimidin-7(4H)-one
Figure imgf000068_0001
[00121] The mixture of 3, 4-diphenyl-l H-pyrazol-5-amine 8 (470g, 2mol) and dimethyl-2-(4-methoxyphenyl)-malonate 2 (571g, 2.4mol, 1.2 eq.) in xylene (5 L) was refluxed for 18h. The white precipitate was filtered off and washed with DCM (5L) to afford the title compound as white solid (610g) which was used in the next step without further purification. 1H NMR (DMSO-d6): δ 11.57 (br. s, 1H), 7.26 - 7.49 (m, 12H), 6.90 - 6.99 (m, 2H), 3.78 (s, 3H). LC- MS: m/z 410.2 (M+H)+.
[00122] Step C: 5,7-dichloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[ 1 ,5- ajpyrimidine
Figure imgf000068_0002
3] The 6-(4-methoxyphenyl)-2, 3-diphenylpyrazolo [1,5-a] pyrimidine-5, 7(4H,
6H)-dioxane (300g, 0.73mol) and phosphorus oxychloride (1200 mL, 12.90mol) were added into a 2L bottle. The reaction mixture was stirred at 100 °C for 16 h. TLC indicated that the reaction was complete. The solvent and volatile were removed in vacuo and the residue was dissolved in DCM (500 mL). The mixture was added dropwise into the MeOH (2500 mL) at 0 °C. A yellow suspension formed during the course of addition. The mixture was stirred at RT for 2h and the precipitate was collected by filtration and dried in vacuo to give desired product as yellow solid (290g) which was used in the next step without further purification, LC-MS: m/z 446.1 , 448.1 (M+H)+.
[00124] Step D: 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5- a]pyrimidine
Figure imgf000069_0001
[00125] The 5, 7-dichloro-6-(4-methoxyphenyl)-2, 3-diphenylpyrazolo [1, 5-a] pyrimidine 4 (1.78 kg, 4 mol) and DCM (20 L) were added into the 30L reactor. The mixture was cooled to -10 °C. The sodium methoxide (1.48L, 8mol, 30% in MeOH) was dropwise such that the internal temperature is maintained below 0 °C. The reaction mixture was stirred at RT for 2h. TLC indicated that the reaction was completed. The ice water (10L) was added and the reaction mixture was stirred at RT for 1h. The organic layer was collected and the aqueous layer was extracted with DCM (5L*1). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was dissolved in DCM (15L) and the MeOH (60L) was added. The turbid liquid was stirred at RT for 3h and the precipitate was collected by filtration and dried in vacuo to give the title Intermediate 5 as a yellow solid (1.35 kg). [00126] 1H NMR (CHLOROFORM-d):δ ^7.66 - 7.73 (m, 2H), 7.53 - 7.61 (m, 2H), 7.30 - 7.46 (m, 8H), 7.00 - 7.09 (m, 2H), 4.16 (s, 3H), 3.92 (s, 3H). LC-MS: m/z 442.1 (M+H)+. [00127] Step E: 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyridazin-3- yl)pyrazolo[1,5-a]pyrimidin-5-amine
Figure imgf000069_0002
[00128] A suspension of Intermediate 5, 5-chloro-7-methoxy-6-(4-methoxyphenyl)- 2,3-diphenylpyrazolo [1,5-a]pyrimidine, (600 mg, 1.36 mmol), 3-aminopyridazine (258 mg, 2.72 mmol, 2 eq.), Pd(OAc)2 (61 mg, 0.27 mmol, 0.2 eq.), Xantphos(197 mg, 0.34 mmol, 0.25 eq.) and Cs2CO3 (890 mg, 2.72 mmol, 2.0 eq.) in 1.4-dioxane (5 mL) was stirred at 120 °C through microwave irradiation for 1 hour under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford the desired product 6 as a yellow solid. LC-MS: m/z 501.0 (M+H)+. [00129] Step F: 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridazin-3- ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one
Figure imgf000070_0001
[00130] A solution of Intermediate 6 (360 mg, 0.72 mmol) in 4M HCl in 1.4-dioxane (5 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 aq saturated NaHCO3. The organic phase was separated and washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford the desired product 7. [00131] 1H NMR (DMSO-d6): δ 1 5.25 (br. s., 1H ). 9.21 (br. s., IH), 8.86 (br. s., 1H), 7.63 (br. s., 2H), 7.44 - 7.58 (m, 4H), 7.28 - 7.44 (m, 8H), 7.05 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H). LC-MS: m/z 486.9 (M+H)+.
[00132] The following compounds were prepared according to the procedure for compound 101, step E and F, starting from intermediate 5 therein. Step E was performed using appropriate amine 9, base (Cs2CO3, K2CO3, Na2CO3, 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 101, unless otherwise noted.
[00133] Compound 102: 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridin-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000071_0001
[00134] 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 Na2C03 (240 mg, 2.26 mmol) in 1,4-dioxane (10 mL) under heating at 100 °C for 4h under N2. LC-MS: m/z 500.0 (M+H)+.
[00135] Step F: 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyridin-2- yl)pyrazolo[l,5-a]pyrimidin-5-amine (300 mg, 0.6 mmol) was dissolved in HC1/l,4-dioxane (5 mL). The solution was stirred at r.t. overnight. The precipitate was filtered off and washed with CH2C12 (3*1 mL) to give a yellow solid. The solid was then dissolved in CH2C12/MeOH (10/1, 3 mL). After 3 mL of NH3-MeOH was added, the solution was stirred at r.t. overnight to give the title compound.
Ή NMR (TRIFLUOROACETIC ACID-d): δ 8.05 - 8.15 (m, 1H), 7.79 (d, J = 5.6 Hz, 1H), 7.59 (d, J = 7.2 Hz, 2H), 7.46 - 7.56 (m, 6H), 7.36 - 7.46 (m, 4H), 7.25 - 7.34 (m, 2H), 7.16 (d, J = 8.8 Hz, 2H), 3.97 (s, 3H). LC-MS: m/z 486.2 (M+H)'.
[00136] Compound 103: 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridin-3- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000071_0002
[00137] Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol), pyridin-3 -amine (1 17 mg, 1.24 mmol), Pd(OAc)2 (25 mg, 0.113 mmol), xantphos (131 mg, 0.226 mmol), Cs2C03 (737 mg, 2.26 mmo) in dioxane (20 mL) under heating to 110 °C for 4h under N2. LC-MS: m/z 500.2 (M+H)+. [00138] Step F: To a solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N- (pyridin-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine (150 mg, 0.309 mmol) in MeOH (10 mL) was added 4N HC1 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 NaHCOi solution to give the desired product 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridin- 3-ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00139] 1H NMR (DMSO-d6): δ 8.48 (br. s., 1H), 8.30 (br. s., 1H), 8.10 (d, J = 4.6 Hz,
1H), 7.71 (br. s., 1H), 7.46 (br. s., 3H), 7.14 - 7.41 (m, 1 1H), 6.93 (d, J = 8.1 Hz, 2H), 3.76(s, 3H). LC-MS: m/z 486.2 (M+H)+.
[00140] Compound 104: 6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)amino)nicotinonitrile
N
Figure imgf000072_0001
[00141] 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 (1 17.8 mg, 0.20 mmol) and Cesium carbonate (553.0 mg, 1.70 mmol) in 1,4- dioxane (10 mL) under heating to 1 10 °C for 12 hours under nitrogen atmosphere. LC-MS: m/z 525.2 (M+H)+.
[00142] Step F: The solution of 6-((7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)amino)nicotinonitrile (40 mg, 0.07 mmol) in HC1 solution (1.0 M in 1,4-dioxane, 6 mL) was stirred at room temperature for 12 hours. The mixture was concentrated, and NH4OH (5 mL) was added thereto to obtain 6-((6-(4- methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5-a]pyrimidin-5- yl)amino)nicotinonitrile. [00143] 1H NMR (DMSO-d6): δ 14.21 (br. s., 1H), 9.53 (s, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.1 1 (dd, J = 8.9, 2.1 Hz, 1H), 7.50 - 7.62 (m, 4H), 7.36 - 7.45 (m, 6H), 7.29 - 7.36 (m, 3H), 7.03 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H). LC-MS: m/z 51 1.3 (M+H)+. [00144] Compound 105: 5-((5-fluoropyridin-2-yl)amino)-6-(4-methoxyphi diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
F
Figure imgf000073_0001
[00145] 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), Cs2C03 (117 mg, 1. lmmo) in dioxane (20 mL) under heating to 100 °C for 4h under N2. LC- MS: m/z 518.2 (M+H)+.
[00146] Step F: To a solution of N-(5-fluoropyridin-2-yl)-7-methoxy-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-5-amine (50 mg, 0.10 mmol) in MeOH (10 mL) was added 4N HC1 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 NaHC03 solution to give the desired product 5-((5-fluoropyridin-2-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00147] 1H NMR (DMSO-d6): δ 14.87 (br. s., 1H), 9.08 (s, 1 H), 7.94 - 8.07 (m, 1H),
7.71 - 7.88 (m, 1H), 7.50 - 7.64 (m, 4H), 7.38 - 7.44 (m, 6H), 7.29 - 7.35 (m, J = 8.5 Hz, 2H), 6.99 - 7.10 (m, J = 8.5 Hz, 2H), 3.83(s, 3H). LC-MS: m/z 503.9 (M+H)+.
[00148] Compound 106: 5-((5-chloropyridin-2-yl)amino)-6-(4-methoxyphi diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
ci
Figure imgf000073_0002
[00149] 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 Na2C03 (105 mg, 0.9 mmol) in 1,4-dioxane (5 mL) under heating at 100 °C for 16h under N2. LC-MS: m/z 533.9, 535.9 (M+H)+.
[00150] Step F: N-(5-chloropyridin-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-amine (80 mg, 0.15 mmol) was dissolved in HC1-1,4- dioxane (5 mL). The solution was stirred at r.t. overnight. The precipitate was filtered off and washed with CH2C12(3 mL) to give a yellow solid. The solid was then dissolved in
CH2C12/MeOH (10/1, 2 mL) . After 1 mL of NH3-MeOH was added, the solution was stirred at r.t. overnight to give the title compound 7.
[00151] 1H NMR (DMSO-d6): δ 14.72 (s, 1H), 9.16 (s, 1H), 8.01 (s, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.49 - 7.66 (m, 4H), 7.40 (d, J = 7.2 Hz, 9H), 7.32 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 8.2 Hz, 2H), 3.82 (s, 3H). LC-MS: m/z 519.9, 521.9 (M+H)+ .
[00152] Compound 107: 6-(4-methoxyphenyl)-5-((5-nitropyridin-2-yl)amino)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000074_0001
[00153] 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 Na2C03 (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 N2 atmosphere.
[00154] 1H NMR (DMSO-d6) δ 9.03 (d, J = 2.7 Hz, 1 H), 8.55 - 8.66 (m, 2H), 8.12 (s,
1H), 7.58 - 7.65 (m, 2H), 7.43 - 7.54 (m, 9H), 7.31 - 7.36 (m, 1H), 7.19 (d, J = 8.5 Hz, 2H), 4.16 (s, 3H), 3.87 (s, 3H). LC-MS: m/z 545.2 (M+H) +.
[00155] Step F: A solution of 7-methoxy-6-(4-methoxyphenyl)-N-(5-nitropyridin-2- yl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-5-amine (50 mg, 0.092 mmol) in 4M HC1 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 to give 6-(4-methoxyphenyl)-5- ((5-nitropyridin-2-yl)amino)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00156] 1H NMR (DMSO-d6) δ: 13.95 (br. s., 1 H), 9.82 - 9.91 (m, 1 H), 8.85 (br. s., 1 H), 8.45 (br. s., 1 H), 7.54 (dd, J=6.18, 2.96 Hz, 4 H), 7.37 - 7.45 (m, 5 H), 7.33 (m, J=8.86 Hz, 2 H), 7.02 (m, J=8.60 Hz, 2 H), 3.81 (s, 3 H). LC-MS: m/z 531.0 (M+H) +.
[00157] Compound 108: 5-(5-hydroxypyridin-2-ylamino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a] pyrimidin-7(4H)-one
Figure imgf000075_0001
[00158] Step E stoichiometry: Intermediate 5 (160 mg, 0.362 mmol), 5-((erl- 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)+.
[00159] Step F: A mixture of N-(5-(tert-butyldimethyl -silyloxy)pyridin-2-yl)-7- methoxy- 6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-5-amine (80 mg, 0.127 mmol) and HC1 solution (4N in dioxane, 10 mL) was stirred at room temperature for 6 h. Then cone. HC1 (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 to afford 5-(5-hydroxypyridin-2-ylamino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a] pyrimidin-7(4H)-one as a white solid.
[00160] 1H NMR (TFA-d): δ 7.71-7.80 (m, 1 H), 7.57 (d, J=7.32 Hz, 2 H), 7.44-7.54
(m, 7 H) 7.30-7.43 (m, 4 H), 7.18 (d, J=9.46 Hz, 1 H), 7.13 (d, J=8.54 Hz, 2 H), 3.94 (s, 3 H). LC-MS: m/z 502. 4 (M+H)+. [00161] Compound 109: 5-((4-hydroxypyridin-2-yl)amino)-6-(4-methoxyphi diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000076_0001
[00162] 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 Cs2C03 (120 mg, 0.36 mmol, 2.0 eq) in 1.4-dioxane (3 mL) at 1 10°Cfor lh under microwave raditation under N2 atmosphere. LC-MS: m/z 516.0 (M+H)+.
[00163] Step F: A solution of 2-((7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)amino)pyridin-4-ol (40 mg, 0.08 mmol) in 4M HC1 in 1 4-dioxane (10 mL) was stirred at 30 °C for 2 hours to obtain the title compound.
[00164] 1H NMR (CHLOROFORM-d): δ 7.66 (s, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.54 - 7.44 (m, 6H), 7.44 - 7.34 (m, 4H), 7.1 1 (s, 2H), 6.72 (m, 2H), 3.99 (s, 1H), 3.94 (s, 3H). LC- MS: m/z 502.0 (M+H)+.
[00165] Compound 110: 5-((6-fluoropyridin-2-yl)amino)-6-(4-methoxyphi diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000076_0002
[00166] Step E stoichiometry: Intermediate 5 (200 mg, 0.45 mmol), 6-fluoropyridin- amine (101 mg, 0.9 mmol), Pd(OAc)2 (20 mg, 0.09 mmol), xantphos (65 mg, 0.1 1 mmol), and Cs2C03 (293 mg, 0.9 mmol) in 1, 4-dioxane (5 mL) under heating at 100 °C for 16h under N2. LC-MS: m/z 518.1 (M+H)+. [00167] Step F: N-(6-fluoropyridin-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-amine (120 mg, 0.23 mmol) was dissolved in HC1-1,4- dioxane (5 mL). The solution was stirred at r.t. overnight. The precipitate was filtered off and washed with CFfcCb (3 mL) to give a yellow solid. The solid was then dissolved in
CH2C12/MeOH (10/1 , 2 mL) . After 1 mL of NH3-MeOH was added, the solution was stirred at r.t. overnight to give the title compound 7.
[00168] 'H NIVTR (DMSO-d6): δ 13.33 (s, 1 H), 9.16 (s, 1 H), 7.86 (q, J = 8.4 Hz, 1H),
7.54-7.48 (m, 2H), 7.34 - 7.48 (m, 8H), 7.32 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.6 Hz,2H), 6.73 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H). LC-MS: m/z 503.9 (M+H)+ .
[00169] Compound 111: 6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)amino)picolinonitrile
Figure imgf000077_0001
[00170] Compound 112 6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)amino)picolinamide
Figure imgf000077_0002
[00171] 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 Cs2C03 (1.2 g, 3.63 mmol, 2.0 eq) in 1.4- dioxane (15 mL) at 1 10°C for lh under microwave irradiation under N2 atmosphere.. LC- MS: m/z 524.9 (M+H)+. [00172] Step F: A solution of 6-((7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)amino)picolinonitrile (220 mg, 0.42 mmol) in 4M HC1 in 1.4-dioxane (10 mL) was stirred at 30 °C for 5 hours to obtain the title compounds 6- ((6-(4~methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5-a]pyrirnidin-5- yl)amino)picolinonitrile and 6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)amino)picolinamide.
[00173] 6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l ,5- a]pyrimidin-5-yl)amino)picolinonitrile
[00174] 1H NMR (DMSO-d6) δ: 12.69 (s, 1H), 9.31 (s, 1H), 7.87 (dd, J= 8.8, 7.6 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.54 - 7.45 (m, 4H), 7.44 - 7.34 (m, 7H), 7.32 (d, J = 8.8 Hz, 2H , 7.01 (d, J= 8.8 Hz, 2H), 3.80 (s, 3H). LC-MS: m/z 510.9 (M+H)+.
[00175] 6-((6-(4-methoxy phenyl)-7-oxo-2, 3 -diphenyl-4, 7-dihydropyrazolo [1,5- a]pyrimidin-5-yl)amino)picolinamide
[00176] 'H NMR (DMSO-d6) 5: 12.42 (s, 1H), 9.00 (s, 1H), 7.97 (s, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.55 - 7.43 (m, 4H), 7.37 (m, 10H), 7.19 (d, J = 8.4 Hz, 1H), 7.00 (d, J= 8.4 Hz, 2H), 3.79 (s, 3H). LC-MS: m/z 529.0 (M+H)+.
[00177] Compound 113: 5-(3-hydroxypyridin-2-ylamino)-6-(4-methoxy- phenyl)-2,3- diphenylpyrazolo[l,5-a] pyrimidin-7(4H)-one
Figure imgf000078_0001
[00178] A suspension of Intermediate 5 (200 mg, 0.452 mmol), 3-(fert-butyl- dimethylsilyloxy)pyridin-2-amine (202 mg, 0.904 mmol), palladium(II) acetate (31 mg, 0.136 mmol), xantphos (157 mg, 0.272 mmol) and sodium carbonate (96 mg, 0.904 mmol) in 1.4- dioxane (10 mL) was stirred and heated to reflux for 4 hours under nitrogen atmosphere. The reaction was then cooled to room temperature and filtered. The filtrate was concentrated in vacuum to afford 5-(3-hydroxypyridin-2-ylamino)-6-(4-methoxy-phenyl)-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one. [00179] XU NMR (TFA-d): δ 8.33 (d, J=8.33 Hz, 1 H), 7.99 (d, J=5.10 Hz, 1 H), 7.56 -
7.71 (m, 8 H), 7.48 - 7.54 (m, 4 H), 7.42 (dd, J=8.33, 5.91 Hz, 1 H), 7.34 (d, J=8.60 Hz, 2 H), 4.10 (s, 3 H). LC-MS: m/z 502.4 (M+Hf .
[00180] Compound 114: 2-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-ylamino)isonicotinonitrile
Figure imgf000079_0001
[00181] 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 Cs2C03 (327 mg, 1.0 mmol) in 1.4-dioxane (10 mL) under heating to 1 10 °C for 1 hour through microwave irradiation under N2 atmosphere. LC-MS: m/z 525.2 (M+H)+.
[00182] Step F: A mixture of 2-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin- 5-ylamino) isonicotinonitrile (15 mg, 0.03 mmol) in HC1 solution (4 M in dioxane, 1 mL) was stirred at room temperature overnight. The mixture was quenched with NH3 solution (7M in methanol) to pH 7- 8 to afford 6-(4-methoxyphenyl)-5- (2-methoxypyrimidin-4-ylamino)-2,3- diphenyl pyrazolo [1,5-a] pyrimidin-7f4H,)-one.
[00183] 1H NMR (DMSO-d6): δ 8.25 (d, J=5.37 Hz, 1 H), 7.77 (s, 1 H), 7.49 - 7.63 (m,
4 H), 7.37 - 7.47 (m, 7 H), 7.34 (m, J=8.60 Hz, 2 H), 7.06 (m, J=8.60 Hz, 2 H), 3.84(s, 3H). LC-MS: m/z 51 1.2 (M+H) +. [00184] Compound 115: 2-(6-(4-methoxyphenyl)-7-oxo- 2,3- diphenyl-4,7- dihydropyrazolo [1,5-a] pyrimidin-5- ylamino)pyrimidine-5-carbonitrile
Figure imgf000080_0001
[0018S] A mixture of Intermediate 5 (200 mg, 0.452 mmol) and 2-aminopyrimidine-5- carbonitrile (108 mg, 0.904 mmol) and Pd(OAc)2 (31 mg, 0.136 mmol), Xantphos (157 mg, 0.272 mmol) and Na2C03 (96 g, 0.904 mmol) in 1.4-dioxane (10 mL) was stirred and heated to reflux for 4 hours under N2 atmosphere. The reaction was then cooled to room temperature and filtered. The filtrate was concentrated in vacuum to afford 2-(6-(4-methoxyphenyl)-7- oxo- 2,3- diphenyl-4,7-dihydropyrazolo[l ,5-a]pyrimidin-5-ylamino)pyrimidine-5- carbonitrile.
[00186] 1H NMR (DMSO-d6): 6 12.77 (bs, 1 H), 10.27 (bs, 1 H), 8.88 (s., 2 H), 7.43 - 7.52 (m, 4 H), 7.35 - 7.40 (m, 4 H), 7.32 (d, J=7.63 Hz, 2 H), 7.25 (d, J=8.54 Hz, 2 H), 6.93 (d, J=8.24 Hz, 2 H), 3.76 (s, 3 H). LC-MS: m/z 512.2 (M+H)+.
[00187] Compound 116: 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-4- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000080_0002
[00188] 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(l 16 mg, 0.2 mmol, 0.2 eq.) and Cs2C0 (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 N2 atmosphere. LC-MS: m/z 501.5 (M+H)+. [00189] Step F: A solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N- (pyrimidin-4-yl)pyrazolo[l,5-a]pyrimidin-5-amine (260 mg, 0.52 mmol) in 4M HC1 in 1.4- dioxane (10 mL) was stirred at r.t. for 16 hours to give the title compound.
[00190] 'H NMR (DMSO-d6): δ 13.13 (s, 1H), 11.25 (s, 1H), 8.90 (s, 1H), 8.45 (d, J = 7.0 Hz, 1H), 7.44 - 7.53 (m, 4H), 7.25 - 7.42 (m, 7H), 7.18 (d, J = 6.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H). LC-MS: m/z 487.0 (M+H)+.
[00191] Compound 117: 5-((6-aminopyrimidin-4-yl)amino)-6-(4-methoxyphenyl)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000081_0001
[00192] Step E stoichiometry: Intermediate 5 (237 mg, 0.538 mmol), pyrimidine-4,6- diamine (1 18.2 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 Na2C03 (125 mg, 1.184 mmol, 2.2 eq.) in 1.4-dioxane (5 mL) under heating at 100 °C for 3 hour under N2 atmosphere. LC-MS: m/z 516.5 (M+H)+. [00193] Step F: A solution of N4-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l ,5-a]pyrimidin-5-yl)pyrimidine-4,6-diamine (90 mg, 0.17 mmol) in 4M HC1 in 1.4-dioxane (3 mL) was stirred at r.t. for 3 hours to give the title compound.
[00194] 1H NMR (DMSO-d6): δ 13.54 (br. s., 1H), 9.94 (br. s., 1H), 8.27 (s, 1H), 7.82
(br. s., 2H), 7.43 - 7.52 (m, 4H), 7.31 - 7.42 (m, 6H), 7.28 (d, J = 8.6 Hz,2H), 6.98 (d, J = 8.6 Hz, 2H), 6.02 (br. s., 1H), 3.78 (s, 3H). LC-MS: m/z 502.9 (M+H)+. [00195] Compound 118: 6-(4-methoxyphenyl)-5-((2-methoxypyrimidin-4-yl)amino)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000082_0001
[00196] 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), Cs2C03 (409 mg, 1.25 mmo) in dioxane (20 mL) under heating to 110 °C for 4h under N2. LC-MS: m/z 531.2 (M+H)+.
[00197] Step F: To a solution of 7-methoxy-6-(4-methoxyphenyl)-N-(2- methoxypyrimidin-4-yl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-5-amine (100 mg, 0.19mmol) in MeOH (10 mL) was added 4N HC1 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 NaHC03 solution to give the desired product 6-(4-methoxyphenyl)-5-((2- methoxypyrimidin-4-yl)amino)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00198] 1H NMR (TFA): 6 8.30 (d, J = 7.0 Hz, 1H), 7.63 - 7.78 (m, 3H), 7.40 - 7.63 (m, 8H), 7.27 (d, J = 7.5 Hz, 2H), 7.04 (d, J = 7.0 Hz, 1H), 3.98 (s, 3H), 3.48 (s, 3H). LC-MS: m/z 517.0 (M+H)+.
[00199] Compound 119: 5-(2-hydroxypyrimidin-4-ylamino)-6-(4-methoxyphenyl)- 2,3-diphenyl-pyrazolo[l,5-a] pyrimidin-7(4H)-one
Figure imgf000082_0002
[00200] A mixture of 7-methoxy-6-(4-methoxyphenyl)-N-(2-methoxypyrimidin-4-yl)- 2,3- diphenyl- pyrazolo[l,5-a]pyrimidin-5-amine (126 mg, 0.244 mmol) and conc.HC1 (10 mL) was heated to reflux for 2 days. The mixture was quenched with ammonia solution (7N in methanol) to pH 7 and concentrated to afford 5-(2-hydroxypyrimidin-4-ylamino)-6-(4- methoxyphenyl)-2,3-diphenyl- pyrazolo[l,5-a] pyrimidin-7(4H)-one.
[00201] 1H NMR (DMSO-d6): δ 7.52 (d, J=6.71 Hz, 3 H), 7.45 (d, J=6.71 Hz, 2 H), 7.20-7.40 (m, 9 H), 7.05-7.19 (m, 2 H), 6.99 (bs, 2 H), 3.80 (s, 3 H). LC-MS: m/z 503.2 (M+H)+.
[00202] Compound 120: 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-5- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000083_0001
[00203] A suspension of Intermediate 5 (500mg, 1.13mmol) and pyrimidin-5-amine (323 mg, 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 Na2C03 (356 mg, 3.39 mmol, 3 eq) in 1.4-dioxane (10 mL) was stirred and warmed up to 100 °C with microwave irradiation for 1 hours under N2 atmosphere. The reaction was then cooled to r.t. to obtain 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-5- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00204] 1H NMR (DMSO-d6): δ 8.65 (s, 2 H), 8.52 (br. s., 1 H), 7.54 (d, j=8.87 Hz, 1
H), 7.34 - 7.49 (m, 8 H), 7.31 (br. s., 3 H), 6.93 (br. s., 1 H), 3.68 - 3.84 (m, 3 H ). LC-MS : m/z 487.0 (M+H) +.
[00205] Compound 121: 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000084_0001
[00206] 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 Cs2C03 (327 mg, 1 mmol, 2.2 eq.) in 1.4-dioxane (4 mL) under heating at 1 10 °C for 1 hour through microwave irradiation under N2 atmosphere. LC-MS: m/z 501.6 (M+H)+.
[00207] Step F: A solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N- (pyrimidin-2-yl)pyrazolo[l,5-a]pyrimidin-5-amine (60 mg, 0.12 mmol) in 4M HC1 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 NaHC03. The organic phase was separated and washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound. [00208] 1H NMR (DMSO-d6): δ 14.08 (br. s., 1 H), 8.60 (s, 1 H), 8.57 (d, J=4.84 Hz, 2
H), 7.52 - 7.62 (m, 4 H), 7.40 - 7.49 (m, 6 H), 7.37 (d, J=8.60 Hz, 2 H), 7.18 (t, J=4.97 Hz, 1 H), 7.08 (d, J=8.60 Hz, 2 H), 3.84 (s, 3 H). LC-MS: m/z 487.2 (M+H)+.
[00209] Compound 122: 5-((5-chloropyrimidin-2-yl)amino)-6-(4-methoxyphenyl)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
CI
Figure imgf000085_0001
[00210] 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 (1 17 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)+.
[00211] Step F: The solution of N-(5-chloropyrimidin-2-yl)-7-methoxy-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-5-amine (50 mg, 0.1 mmol) in HC1 solution (4.0 M in 1,4-dioxane, 5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated, and NH4OH (8 mL) was added thereto to obtain 6-((6-(4- methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5-a]pyrimidin-5- yl)amino)nicotinonitrile.
[00212] 1H NMR (DMSO-d6): δ 13.13 (s, 1H), 9.27 (s., 1H), 8.60(s, 2H), 7.29-7.55 (m, 12H), 7.00 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H). LC-MS: m/z 520.9 (M+H) +.
[00213] Compound 123: 5-((6-aminopyridazin-3-yl)amino)-6-(4-methoxyphenyl)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
NH2
Figure imgf000085_0002
[00214] Step E stoichiometry: Intermediate 5 (132mg, 0.3mmol) and N-(6- aminopyridazin-3-yl)acetamide (93 mg, 0.2mmol, 2 eq) and Pd(OAc)2 (10 mg, 0.04 mmol, 0.4eq), Xantphos (24mg, 0.04 mmol, 0.4 eq) and Cs2C03 (65mg, 0.2 mmol, 2 eq) in 1.4- dioxane (5 mL) under heating at 120 °C through microwave irradiation for 1 hours under N2 atmosphere. LC-MS: m/z 558.2 (M+H) +.
[00215] Step F: A mixture of N-(6-((7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,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 to give 5-((6-aminopyridazin-3-yl)amino)-6- (4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00216] 1H NMR (DMSO-d6): δ 7.50 (br. s., 2 H), 7.40 (br. s., 3 H), 7.33 (d, J=8.86 Hz, 8 H), 7.04 (d, J=8.06 Hz, 3 H), 6.89 (br. s., 1 H), 3.82 (s, 4 H). LC-MS: m/z 502.1 (M+H)
[00217] Compound 124: 6-(4-methoxyphenyl)-5-((6-methoxypyridazin-3-yl)amino)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H -one
Figure imgf000086_0001
[00218] 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 Na2C03 (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 N2 atmosphere. LC-MS: m/z 531.2 (M+H)+.
[00219] Step F: A solution of 7-methoxy-6-(4-methoxyphenyl)-N-(6- methoxypyridazin-3-yl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-5-amine (50 mg, 0.094 mmol) in 4M HC1 in 1.4-dioxane (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give the title compound. [00220] 1H NMR (CHLOROFORM-d): δ 7.74 (d,J=9.46 Hz, 1 H), 7.59 (d, J=9.46 Hz,
1 H), 7.22 - 7.48 (m, 12 H), 7.07 (d, J=6.41 Hz, 2 H), 4.07 (s, 3 H), 3.88 (s, 3 H). LC-MS: m/z 517.0 (M+H) +.
[00221] Compound 125: 5-((6-chloropyridazin-3-yl)amino)-6-(4-methoxyphenyl)- 2,3-diphenylpyrazolo[l ,5-a]pyrimidin-7(4H)-one
Figure imgf000087_0001
[00222] 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 Cs2C03 (293 mg, 0.9 mmol, 2.0 eq.) in 1.4-dioxane (5 mL) under heating at 120 °C through microwave irradiation for 1 hour under N2 atmosphere. LC- MS: m/z 534.9, 536.9 (M+H)+.
[00223] Step F: The solution of N-(6-chloropyridazin-3-yl)-7-methoxy-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-5-amine (60 mg, 0.12 mmol) in 4M HC1 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 NaHC03. The organic phase was separated and washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound.
[00224] 1H NMR (DMSO-d6/TRIFLUORO ACETIC ACID-d(v: 1/5)): δ 7.73 (d, J = 9.4 Hz, 1H), 7.65 (d, J = 9.4 Hz, 1H), 7.42 - 7.54 (m, 4H), 7.31 - 7.40 (m, 8H), 7.01 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H). LC-MS: m/z 520.9, 522.9 (M+H)+ . [00225] Compound 126: 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrazin-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000088_0001
[00226] 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)+.
[00227] 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) and basified with aqueous ammonia to pH 8 to afford 6-(4- methoxyphenyl)-2,3-diphenyl-5-(pyrazin-2-ylamino)- pyrazolo[ 1,5-a] pyrimidin- 7(4H)-one. [00228] 1H NMR (DMSO-d6): δ 14.27 (br. s., 1 H), 9.93 (s., 1 H), 9.38 (s, 1 H), 8.61
(s, 1 H), 8.23 (s, 1 H), 8.08 (s., 1 H), 7.56 (m, 5 H), 7.36 (d, J=8.60 Hz, 5 H), 7.06 (d, J=8.33 Hz, 3 H), 3.83 (s, 3 H). LC-MS: m/z 487.2 (M+H)+.
[00229] Compound 127: 5-((3-hydroxypyrazin-2-yl)amino)-6-(4-methoxyphenyl)- 2,3 -diphenylpyrazolo [1,5 -a]pyrimidin-7(4H)-one
Figure imgf000088_0002
[00230] 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 (1 1 mg, 0.05 mmol, 0.15 eq), Xantphos (29 mg, 0.05 mmol, 0.15 eq) and Cs2C03 (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)+.
[00231] Step F: A solution of 3-((7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)amino)pyrazin-2-ol (15 mg, 0.03 mmol) in 4M HC1 in 1.4-dioxane (5 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum to obtain the title compound.
[00232] 1H NMR (DMSO-d6): δ 14.12 (br. s., 1 H), 12.64 (br. s., 1 H), 8.50 (s, 1H), 7.51
- 7.65 (m, 4H), 7.33 - 7.47 (m, 8H), 7.02 - 7.17 (m, 3H), 6.78 (d, J = 4.4 Hz, 1H), 3.85 (s, 3H). LC-MS: m/z 503.0 (M+H)+.
[00233] Compound 128: 5-((3-aminopyrazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000089_0001
[00234] A suspension of Intermediate 5 (500 mg, 1.13 mmol), pyrazine-2, 3 -diamine (249 mg, 2.26 mmol, 2 eq.), Pd(OAc)2 (254 mg, 1.13 mmol, 1 eq.), Xantphos (653 mg, 1.13 mmol, 1 eq.) and Cs2C03 (737 mg, 2.26 mmol, 2.0 eq.) in 1.4-dioxane (15 mL) was stirred at 120 °C through microwave irradiation for 1 hour under N2 atmosphere. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford the title compound. [00235] 1H NMR (TRIFLUORO ACETIC ACID-d): δ 7.49 - 7.64 (m, 6H), 7.36 - 7.49
(m, 7H), 7.33 (d, J = 4.0 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 3.91 (s, 3H). LC-MS: m/z 502.1 (M+H)+. [00236] Compound 129: 5-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile
Figure imgf000090_0001
[00237] Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol), 5-aminopyrazine- 2-carbonitrile (163 mg, 1.36 mmol), tris(dibenzylideneacetone)dipalladium(0) (31 1 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 N2 atmosphere. LC-MS: m/z 526.2 (M+H)+.
[00238] Step F: To a solution of 5-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5- ylamino)pyrazine-2-carbonitrile (100 mg, 0.19 mmol) in dichloromethane (6 mL) was added HC1 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 to give 5-(6-(4-methoxyphenyl)-7-oxo-2,3- diphenyl-4,7-dihydropyrazolo[l,5-a]pyrimidin-5- ylamino)pyrazine-2-carbonitrile. [00239] 1H NMR (DMSO-d6): 6 9.79 (s, 1 H), 8.60 (s, 1 H), 7.95 (s, 1 H), 7.57 (d,
J=6.45 Hz, 2 H), 7.47 (d, J=7.25 Hz, 2 H), 7.27 - 7.42 (m, 7 H), 7.17 (d, J=6.72 Hz, 1 H), 7.01 (d, J=8.33 Hz, 2 H), 3.81 (s, 3 H). LC-MS: m/z 512.2 (M+H)÷.
[00240] Compound 130: 5-((5-aminopyrazin-2-yl)amino)-6-(4-methoxyphi diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000091_0001
[00241] 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 1 10 °C for 1 hour through microwave irradiation under N2 atmosphere. LC-MS: m/z 516.2 (M+H)+.
[00242] Step F: A mixture of N?-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l ,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 to afford 5-(5- aminopyrazin-2-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l ,5-a] pyrimidin- 7(4H)-one.
[00243] 1H NMR (DMSO-d6): 6 14.30 (s, 1H), 8.77 (s., 1H), 8.07 (s, 1H), 7.54 - 7.51
(m, 4H), 731-7.43 (m, 7H), 7.05 (d, J = 8.4 Hz, 2H), 6.23 (s., 2H), 3.83 (s, 1H). LC-MS: m/z 502.0 (M+H)+.
[00244] Compound 131: 6-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile
Figure imgf000092_0001
[0024S] 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 1 10 °C for 1 hour through microwave irradiation under N2 atmosphere. LC- MS: m/z 526.2 (M+H) +.
[00246] Step F: To a solution of 6-(7-methoxy-6-(4-methoxyphenyl)- 2,3- diphenylpyrazolo[l,5-a] pyrimidin- 5-ylamino) pyrazine-2-carbonitrile (100 mg, 0.19 mmol) in dichloromethane (6 mL) was added HC1 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 afford 6-(6- (4-methoxyphenyl)- 7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5-a]pyrimidin-5-ylamino)- pyrazine-2-carbonitrile.
[00247] 1H NMR (DMSO-^): δ 8.57 - 8.71 (m, 2 H) 7.44 - 7.65 (m, 4 H) 7.21 - 7.42
(m, 8 H) 6.99 (d, J=8.55 Hz, 2 H), 3.80 (s, 3 H). LC-MS: m/z 512.2 (M+H) +.
[00248] Compound 132: 5-((l,3,5-triazin-2-yl)amino)-6-(4-methoxyphi diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000093_0001
[00249] Step E stoichiometry: Intermediate 5 (800 mg, 1.81 mmol), l,3,5-triazin-2- amine (348 mg, 3.62 mmol), and Pd(OAc). (81 mg, 0.36 mmol), Xantphos (260 mg, 0.45 mmol) and Na2C03 (384 mg, 3.62 mmol) in 1.4-dioxane (15 mL) under heating at 120 °C for 4 hours under N2 atmosphere. LC-MS: m/z 502.0 (M+H)+.
[00250] Step F: 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(l,3,5-triazin-2- yl)pyrazolo[l,5-a]pyrimidin-5-amine (500 mg, 1.0 mmol) was dissolved in HC1-l,4-dioxane (10 mL). The solution was stirred at r.t. for 2h. The precipitate was filtered off and washed with CH2C12 (3*1 mL) to give a yellow solid. The solid was then dissolved in CH2C12/MeOH (10/1 , 3 mL). After 3 mL of NH3-MeOH was added, the solution was stirred at r.t. overnight to give the title compound.
[00251] 1H NMR (DMSO-d6): δ 12.71 (br. s, 1H), 10.24 (br. s., 1H), 8.70 (s, 2H), 7.41 - 7.50 (m, 4H), 7.29 - 7.41 (m, 6H), 7.21 - 7.27 (m, 2H), 6.93 (d, J = 8.6 Hz, 2H), 3.76 (s, 3H). LC-MS: m/z 488.0 (M+H)+.
[00252] Compound 133: 5-((l,2,4-triazin-5-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000093_0002
[00253] Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol), l,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 N2 atmosphere. LC-MS: m/z 502.2 (M+H)+.
[00254] Step F: A mixture of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-( 1,2,4- triazin-5-yl) pyrazolo[l,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 to afford 5-(l,2,4-triazin-5-ylamino)-6- (4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a] pyrimidin-7(4H)-one. [00255] 1H NMR (DMSO-d6): δ 9.14 (s, 1H), 8.74 (s., 1 H), 7.31- 7.51(m, 12H), 6.76
(d, J = 8.6 Hz, 2H), 3.79 (s, 3H). LC-MS: m/z 488.2 (M+H)+.
[00256] Compound 134: 5-((4-amino-l,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000094_0001
[00257] Step E stoichiometry: Intermediate 5 (500 mg, 1.13 mmol), l ,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 Cs2C03 (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 N2 atmosphere. LC- MS: m/z 516.9 (M+H) +.
[00258] Step F: A solution of 5-((4-amino-l ,3,5-triazin-2-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4Fi)-one (156 mg, 0.3 mmol) in 4M HC1 in 1.4-dioxane (5 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum to obtain the title compound. [00259] 1H NMR (DMSO-d6): δ 13.80 (s, 1H), 8.17 (s, 2H), 7.66 (s, 1H), 7.51 (m, 4H),
7.38 (dd, J= 9.8, 6.1 Hz, 7H), 7.33 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H). LC-MS: m/z 503.0 (M+H)+. [00260] Compound 135: 6-(4-methoxyphenyl)-5-((4-(methylamino)-l,3,5-triazin-2- yl)amino)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000095_0001
[00261] 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 Cs2C03 (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 N2 atmosphere. LC-MS: mix 531.0 (M+H) +. [00262] Step F: A solution of N2-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-N4-methyl-l,3,5-triazine-2,4-diamine (100 mg, 0.19 mmol) in 4M HC1 in 1.4-dioxane (15 mL) was stirred at r.t. for 6 hours to afford the title compound.
[00263] 1H NMR (DMSO-d6&TRIFLUORO ACETIC ACID-d(v: 1/5)): δ 8.40 (s, 1H), 7.55 (d, J = 6.2 Hz, 2H), 7.33 - 7.47 (m, 10H), 7.04 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H), 2.08 (s, 3H). LC-MS: m/z 517.0 (M+H)+.
[00264] Compound 136: 5-((4-hydroxy-l,3,5-triazin-2-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H -one
Figure imgf000095_0002
[00265] Step A: 5-((4-methoxy-l,3,5-triazin-2-yl)amino)-6-(4-methoxyphi diphenylpyrazolo [l,5-a]pyrimidin-7(4H)-one
Figure imgf000096_0001
[00266] The mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (1.0 g, 2.26 mmol), 4-methoxy-l,3,5-triazin-2-amine (424.7 mg, 3.39 mmol), palladium diacetate (253.7 mg, 1.13 mmol), Xantphos (784.6 mg, 1.36 mmol) and sodium carbonate (383.3 mg, 3.62 mmol) in 1,4-dioxane (40 mL) was refluxed for 12 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered with celite, diluted with DCM (150 mL), washed with saturated brine (50mL), dried over anhydrous sodium sulfate and concentrated to drynesss. The residue was purified to obtain 5-((4-methoxy-l,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one as yellow solid. LC-MS: m/z 518.2 (M+H)+.
[00267] Step B: 5-((4-hydroxy-l,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo [l,5-a]pyrimidin-7(4H)-one
Figure imgf000096_0002
[00268] A solution of 5-((4-methoxy-l ,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (350 mg, 0.68mmol) in 4M HC1 in 1.4- dioxane (40 mL) was stirred at r.t. for 16 hours. The mixture was concentrated, and saturated NaHC03 (10 mL) was added to obtain 5-((4-hydroxy-l,3,5-triazin-2-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one.
[00269] 1H NMR (DMSO-d*,): δ 8.07 (br. s., 1 H), 7.47 (br. s., 3H), 7.16 - 7.43 (m, 15H), 6.94 (br. s., 2H), 3.78 (s, 3H). LC-MS: m/z 504.3 (M+H)+. [00270] Compound 137: 6-(4-methoxyphenyl)-2,3-diphenyl-5-(thiazol-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000097_0001
[00271] 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 Na2C03 (117 mg, 1.1 mmol, 2.2 eq.) in 1 4-dioxane (5 mL) under heating at 100 °C for 3 h under N2 atmosphere. LC-MS: m/z 506.1 (M+H)+.
[00272] Step F: The solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)thiazol-2-amine (1 10 mg, 0.23 mmol) in 4M HC1 in 1 4-dioxane (10 mL) was stirred at r.t. for 10 h to afford the title compound.
[00273] 1H NMR (DMSO-d6): δ 10.39 (br. s., 1H), 7.47 - 7.58 (m, 4H), 7.35 - 7.46 (m,
6H), 7.27 - 7.35 (m, 3H), 7.21 (d, J = 3.6 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H). LC- MS: m/z 491.9 (M+H)'
[00274] Compound 138: 5-(isoxazol-3-ylamino)-6-(4-methoxyphi
diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000097_0002
[00275] 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 Na2C03 (190 mg, 1.8mmol, 2eq.) in 1.4-dioxane (5 mL) under heating at 100 °C for 16 hours under N2 atmosphere. LC-MS: m/z 490.5 (M+H)+.
[00276] Step F: A solution of 5-(isoxazol-3-ylamino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (90 mg, 0.17 mmol) in 4M HC1 in 1.4-dioxane (3 mL) was stirred at r.t. for 2 hours. Solvent and volatile were removed in vacuo. The mixture was basified with NaHCO? solution to PH=8 and concentrated in vacuo to give the the title compound
[00277] 1H NMR (DMSO-d6): δ 12.01 (s, 1H), 9.39 (s, 1H), 8.75 (d, J = 1.9 Hz, 1H), 7.45 - 7.52 (m, 3H), 7.36 - 7.45 (m, 6H), 7.30 - 7.36 (m, J = 8.6 Hz, 2H), 6.99 - 7.10 (m, J = 8.9 Hz, 2H), 6.49 (d, J = 1.9 Hz, 1H), 3.83 (s, 3H). LC-MS: m/z 476.5 (M+H)+.
[00278] Compound 139: 5-(isoxazol-4-ylamino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000098_0001
[00279] 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 Cs2C03 (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 N2 atmosphere. LC-MS: m/z 490.2 (M+H)+.
[00280] Step F: A solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)isoxazol-4-amine (38 mg, 0.08 mmol) in 4M HC1 in 1.4-dioxane (5 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound. [00281] 1H NMR (DMSO-d6): δ 9.24 (br. s., 1H), 8.74 (br. s., 1H), 7.98 (br. s., 1H), 7.31 - 7.45 (m, 6H), 7.09 - 7.31 (m, 9H), 7.04 (br. s., 2H), 3.81 (br. s., 3H). LC-MS: m/z 476.1 (M+H)+. [00282] Compound 140: 5-(isoxazol-5-ylamino)-6-(4-methoxyphi
diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000099_0001
[00283] A suspension of intermediate 5 (100 mg, 0.22 mmol), isoxazol-5 -amine (23 mg, 0.27 mmol, 1.2 eq.), Pd(OAc)2 (20 mg, 0.09 mmol, 0.4 eq.), Xantphos (53 mg,
0.09mmol, 0.4 eq.) and K2C03 (63 mg, 0.45 mmol, 2.5eq.) in dioxnae (4 mL) was stirred at 100 °C through microwave irradiation for 1 hour under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the title compound.
[00284] 1H NMR (DMSO-d6): δ 12.38 (br. s., 1H), 10.40 (br. s., 1H), 7.24 - 7.54 (m, 15H), 7.00 (d, J = 8.1 Hz, 2H), 3.81 (s, 3H). LC-MS: m/z 475.9 (M+H) +.
[00285] Compound 141: 6-(4-methoxyphenyl)-5-(l -methyl- 1 H-imidazol-2-ylamino)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000099_0002
[00286] Step E stoichiometry: Intermediate 5 (100 mg, 0.226 mmol), l-methyl-/H- 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 N2 atmosphere. LC-MS: m/z 503.2 (M+H)+. [00287] Step F: A mixture of 7-methoxy-6-(4-methoxyphenyl)-N-(l -methyl- 1 H- imidazol-2-yl)- 2,3- diphenylpyrazolo [l,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 to afford 6-(4-methoxyphenyl)-5-(l- methyWH- imidazol-2- ylamino)-2,3-diphenylpyrazolo[ 1 ,5-a] pyrimidin-7(4H)-one.
[00288] 1H NMR (DMSO-d6): δ 7.49-7.31 (m, 14 H), 6.99 (d, J=7.63 Hz, 2 H), 3.78 (s,
3 H), 3.52 (s, 3 H). LC-MS: m/z 489.2 (M+H) +.
[00289] Compound 142: 5-((1H-imidazol-2-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000100_0001
[00290] Step E stoichiometry: Intermediate 5 (441 mg, 1.0 mmol), 1 H-imidazol-2- amine (83 mg, 1 mmol, 2 eq.), Pd2(dba)3 (91.5 mg, 0.1 mmol, 0.1 eq.), Xantphos (1 15.6 mg, 0.2 mmol, 0.2 eq.) and Na2C03 (212 mg, 2mmol, 2eq.) in toluene (40 mL) under heating at 105 °C for 5 hour under N2 atmosphere. LC-MS: m/z 489.5 (M+H)+.
[00291] Step F: A solution of N-(1H-imidazol-2-yl)-7-methoxy-6-(4-methoxyphenyl)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-5-amine (40 mg, 0.08 mmol) in 4M HC1 in 1.4- dioxane (15 mL) was stirred at r.t. for 16 hours. Solvent and volatile were removed in vacuo. The resultant residue was basified with NaHC03 solution to pH=8 and concentrated to afford the title compound.
[00292] 1H NMR (DMSO-d6): 6 12.73 (br. s., 1H), 7.51 (br. s., 2H), 7.39 - 7.48 (m, 6H), 7.21 - 7.39 (m, 3H), 7.06 (s, 3H), 3.81 (s, 3H). LC-MS: m/z 475.5 (M+H)+.
[00293] Compound 143: 5-((4,5-dihydrothiazol-2-yl)amino)-6-(4-methoxyphenyl)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000101_0001
[00294] Step E stoichiometry: Intermediate 5 (441 mg, 1.0 mmol), thiazol-2-amine (102 mg, 1 mmol, 2 eq.), Pd2(dba)3 (91.5 mg, 0.1 mmol, 0.1 eq.), Xantphos (1 15.6 mg, 0.2 mmol, 0.2 eq.) and Na2C03 (212 mg, 2mmol, 2eq.) in toluene (40 mL) under heating at 105 °C for 5 hour under N2 atmosphere. LC-MS: m/z 506.5 (M+H)+.
[00295] Step F: A solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)thiazol-2-amine (40 mg, 0.08 mmol) in 4M HC1 in 1.4-dioxane (15 mL) was stirred at r.t. for 16 hours. Solvent and volatile were removed in vacuo. The resultant residue was basified with NaHC03 solution to pH=8 and concentrated to afford the title compound.
[00296] 1H NMR (DMSO-d6): δ 7.31 - 7.49 (m, 9H), 7.26 (d, J = 8.5 Hz, 3H), 6.94 (br. s., 2H), 3.78 (s, 3H), 3.60 (br. s., 1H), 3.50 (br. s., 1H), 3.31 (br. s., 2H). LC-MS: m/z 494.5 (M+H)+.
[00297] Compound 144: 5-((l,3,4-thiadiazol-2-yl)amino)-6-(4-methoxyphi diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000101_0002
[00298] Step E stoichiometry: Intermediate 5 (442mg, 1 .Ommol) 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 Na2C03 (212mg, 2.0mmol, 2.0 eq) in toluene (40 mL) under heating at 1 10 °C for 5 hour under N2 atmosphere. LC-MS: m/z 507.1 (M+H)+. [00299] Step F: A mixture of N-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,3,4-thiadiazol-2-amine (1 12mg, 0.2mmol) in 4N HC1 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 to afford the title compound.
[00300] 1H NMR (DMSO-d6): δ 13.83 (br. s., 1 H), 10.57 (br. s., 1 H), 9.05 (br. s., 1 H), 7.54 (br. s., 4 H), 7.42 (br. s., 5 H), 7.34 (br. s., 3 H), 7.08 (d, J=7.79 Hz, 2 H), 3.85 (s, 3 H). LC-MS: m/z 493.1 (M+H) +.
[00301] Compound 145: 5-((5-amino-l,3,4-thiadiazol-2-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l ,5-a]pyrimidin-7(4H)-one
Figure imgf000102_0001
[00302] 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 Cs2C03 (887 mg, 2.72 mmol, 2.0 eq.) in 1.4- dioxane (18 mL) under heating at 120 °C through microwave irradiation for 1 hour under N2 atmosphere. LC-MS: m/z 522.0 (M+H)+.
[00303] Step F: A solution of N2-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,3,4-thiadiazole-2,5-diamine (100 mg, 0.19 mmol) in 4M HC1 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 NaHC03. The organic phase was separated and washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound.
[00304]1H NMR (DMSO-d6): δ 9.96 (br. s., 1H), 7.37 - 7.57 (m, 9H), 7.32 - 7.37 (m, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H). LC-MS: m/z 508.0 (M+H)+. [00305] Compound 146: 5-((5-hydroxy-l,3,4-thiadiazol-2-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000103_0001
[00306] Step E stoichiometry: Intermediate 5 (442mg, 1 .Ommol) and 5-methoxy- l,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 (1 15.6mg, 0.2mmol, 0.2 eq) and Na2C03 (212mg, 2. Ommol, 2.0 eq) in toluene (40 mL) under heating at 1 10 °C for 5 hour under N2 atmosphere. LC-MS: m/z 537.1 (M+H)+.
[00307] Step F: A mixture of 5-methoxy-N-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,3,4-thiadiazol-2-amine (51.8mg, 0. lmmol) in 4N HC1 in 1.4-dioxane (15 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was stirred with methanol and saturated sodium hydrogen carbonate solution to afford the title compound.
[00308] 1H NMR (DMSO-d6): δ 12.43 (s, 0.5 H), 12.12 (s, 0.5 H), 11.87 (s, 0.5 H),
9.80 (s, 0.5H), 7.50 (br. s., 3 H), 7.41 (br. s., 4 H), 7.30 (br. s., 4 H), 7.04 (d, J=8.55 Hz, 2 H), 3.82 (s, 3 H). LC-MS: m/z 509.1 (M+H) +.
[00309] Compound 147: 5-((l,2,4-thiadiazol-5-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000103_0002
[00310] 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 Cs2C0 (844 mg, 2.72 mmol, 2.0 eq) in 1.4-dioxane (15 mL) under heating at lOOC through microwave irradiation for 1 hour under N2 atmosphere. LC- MS: m/z 506.9H)+.
[00311] Step F: A solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,2,4-thiadiazol-5-amine (214 mg, 0.42 mmol) in 4M HC1 in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
[00312] NMR (DMSO-d6) δ: 10.13 (s, 1H), 8.21 (s, 1H), 7.55 (dd, J= 7.6, 1.6 Hz,
2H), 7.53 - 7.38 (m, 8H), 7.35 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.28 (s, 2H), 3.84 (s, 3H . LC-MS: m/z 492.9 (M+H)÷.
[00313] Compound 148: 5-((3-methoxy-l,2,4-thiadiazol-5-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
O—
Figure imgf000104_0001
[00314] Step E stoichiometry: Intermediate 5 (400 mg, 0.91 mmol) and 3-methoxy- l,2,4-thiadiazol-5-amine (155 mg, 1.18 mmol, 1.3 eq), Pd(OAc)2 (1 1 mg, 0.14 mmol, 0.15 eq), Xantphos (78.7 mg, 0.14 mmol, 0.15 eq) and Cs2C03 (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 N2 atmosphere. LC-MS: m/z 537.0 (M+H)".
[00315] Step F: A solution of 3-methoxy-N-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,2,4-thiadiazol-5-amine (100 mg, 0.19 mmol) in 4M HC1 in 1.4-dioxane (5 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
[00316] 'H NMR (DMSO-d6): 6 10.27 (s, 1H), 7.57 - 7.52 (m, 2H), 7.51 - 7.36 (m,
8H), 7.31 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 3.82 (s, 6H). LC-MS: m/z 523.0 (M+H)+. [00317] Compound 149: 5-((4-amino-l,2,5-oxadiazol-3-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000105_0001
[00318] Step E stoichiometry: Intermediate 5 (220 mg, 0.5 mmol), N3-(7-methoxy-6- (4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,2,5-oxadiazole-3,4- diamine (101 mg, 1.0 mmol, 2.0 eq), Pd(OAc)2 (1 1 mg, 0.05 mmol, 0.1 eq), Xantphos (1 16 mg, 0.2 mmol, 0.4 eq) and Cs2C03 (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 N2 atmosphere. LC-MS: m/z 506.1 (M+H)+. [00319] Step F: A solution of N3-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,2,5-oxadiazole-3,4-diamine (237 mg, 0.47 mmol) in 4M HC1 in 1.4-dioxane (20 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
[00320] NMR (DMSO-d6): δ 8.51 (br. s., 1H), 7.25 - 7.55 (m, 12H), 7.00 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H). LC-MS: m/z 492.1 (M+H)+.
[00321] Compound 150: ethyl 5-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l ,5-a]pyrimidin-5-yl)amino)thiazole-4-carboxylate
Figure imgf000105_0002
[00322] 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 Cs2C03 (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 N2 atmosphere. LC-MS: m/z 578.3 (M+H)÷. [00323] Step F: A solution of ethyl 5-((7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)amino)thiazole-4-carboxylate (450 mg, 0.78mmol) in 4M HC1 in 1.4-dioxane (16 mL) was stirred at r.t. for 18hours. The mixture was concentrated, and saturated NaHC03 (10 mL) was added to obtain ethyl 5-((6-(4-methoxyphenyl)-7-oxo- 2,3-diphenyl-4,7-dihydropyrazolo[l,5-a]pyrimidin-5-yl)amino)thiazole-4-carboxylate.
[00324] 1H NMR (DMSO-d6): δ 10.03 (s, 1H), 8.30 (s, 1H), 7.50 - 7.63 (m, 4H), 7.29 -
7.45 (m, 7H), 7.14 - 7.26 (m, 1 H), 7.04 (d, J = 8.9 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 3.83 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H). LC-MS: m/z 564.3 (M+H)+.
[00325] Compound 151: 5-((1H-pyrrolo[2,3-c]pyridin-5-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l ,5-a]pyrimidin-7(4H)-one
Figure imgf000106_0001
[00326] Step E stoichiometry: Intermediate 5 (200 mg, 0.450 mmol), 7H-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 °C through microwave irradiation for 1 hour under N2 atmosphere. LC-MS: m/z 539.2 (M+H)+.
[00327] Step F: A mixture of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1H- pyrrolo[2,3-c]pyridin-5-yl)-pyrazolo [l,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) and basified with aqueous ammonia to pH 8 to afford 5-(IH- pyrrolo [2,3-c]pyridin-5-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a] pyrimidin-7(4H)-one. [00328] 1H NMR (DMSO-d6): δ 16.31 (s, 1H), 11.56 ( s., 1H), 8.61 (s, H), 8.25 (s, 1H),
7.72-7.35 (m, 14H), 7.07 (d, J = 8.8 Hz, 2H), 6.44 (s., 1H), 3.85 (s, 1 H). LC-MS: m/z 525.2 (M+H)+. [00329] 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4-methoxyphi phenylpyrazolo[ 1 ,5-a]pyrimidine
Figure imgf000107_0001
[00330] This compound was prepared according to the procedure for preparing compound 101 by using Intermediate 8 as 4-(cyclohex-l-en-l-yl)-3-phenyl-1H-pyrazol-5- amine in step B.
[00331] 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 HC1 (6N, 600 mL) were added with stirring vigorously for 0.5 h. The precipitates were collected by filtration, washed with methanol, and dried under reduced pressure to give 3-(cyclohex-l-en-l-yl)-5-hydroxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (48 g) as a yellow solid.
[00332] 1H NMR (DMSO-<&): δ 7.74 (d, J=6.98 Hz, 2 H), 7.31 - 7.49 (m, 5 H), 6.94
(d, J=8.60 Hz, 2 H), 5.80 (br. s., 1 H), 3.78 (s, 3 H), 2.15 (br. s., 2 H), 2.02 (br. s., 2 H), 1.65 (br. s., 4 H). LC-MS: m/z 414.2 (M+H) +.
[00333] Step C: A solution of 3-(cyclohex-l-en-l-yl)-5-hydroxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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. The precipitates were collected by filtration, washed with methanol, and dried under reduced pressure to give 5,7-dichloro-3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine (50 g) as a yellow solid. [00334] 1H NMR (DMSO-i/6): δ 7.82 (d, J=7.25 Hz, 2 H), 7.36 - 7.56 (m, 5 H), 7.10
(d, J=8.60 Hz, 2 H), 5.87 (br. s., 1 H), 3.84 (s, 3 H), 2.20 (br. s., 4 H), 1.70 (d, J=4.57 Hz, 4 H). LC-MS: m/z 450.2 (M+H)+. [00335] Step D: To a solution of 5,7-dichloro-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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. The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was suspended in MeOH (50 mL). The precipitates were collected by filtration, washed with MeOH, and dried under reduced pressure to give 5- chloro-3-(cyclohex-l -en-l-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[l,5- ajpyrimidine as a yellow solid.
[00336] 1H NMR (DMSO-d6): 6 7.78 - 7.91 (m, 2H), 7.42 - 7.58 (m, 3H), 7.33 - 7.42
(m, J = 8.9 Hz, 2H), 7.00 - 7.14 (m, J = 8.9 Hz, 2H), 5.83 (br. s., 1 H), 4.14 (s, 3H), 3.84 (s, 3H), 2.20 (d, J = 5.9 Hz, 4H), 1.61 - 1.77 (m, 4H). LC-MS: m/z 446.1 (M+H)+.
[00337] 6-(5-chloro-7-methoxy-2-(-diphenylpyrazolo[l,5-a]pyrimidin-6- yI)quinoline
Figure imgf000108_0001
[00338] 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. [00339] 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. After cooling to room temperature, the mixture was diluted with EtOAc (1500 mL), washed with saturated NH4CI (300 mL) and brine (250 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column (petroleum ether/ethyl acetate=3 : 1 ) to obtain dimethyl 2-(quinolin-6- yl)malonate (18.0 g) as a yellow solid. LC-MS: m/z 260.1 (M+H)+. [00340] Step B: A suspension of dimethyl 2-(quinolin-6-yl)malonate (13 g, 50 mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (1 1.8 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 NH4CI (150 ml) and brine (100 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (DCM:MeOH=15: 1) to obtain 2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione (18 g) as a yellow solid. LC-MS: m/z 431.2 (M+H)+.
[00341] Step C: The solution of 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidine-5,7(4H,6H)-dione (18 g, 42 mmol), DMAP(1 g) and PC15 (80 mg) in POCb (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. The resultant mixture was diluted with DCM (450 ml), washed with saturated NaHCOi (150 ml) and brine (100 ml), dried over anhydrous sodium sulfate, and concentrated to afford crude product of 6-(5,7-dichloro-2,3-diphenylpyrazolo[ 1 ,5-a]pyrimidin-6- yl)quinoline (13 g) which was used in the next step without further purification. LC-MS: m/z 467.1 (M+H)+.
[00342] Step D: To a solution of 6-(5,7-dichloro-2,3-diphenylpyrazolo[l,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 NH4CI (150 mL) was added to quench the reaction. The resultant mixture was extracted with DCM (500 mL), washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (DCM/MeOH= 40: 1) to obtain 6-(5-chloro-7-methoxy-2,3- diphenylpyrazolo[l,5-a]pyrimidin-6-yl)quinoline as a pale yellow solid.
[00343] 1H NMR (DMSO-d6): 6 9.01 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 - 8.52 (m, 1 H), 8.13 - 8.21 (m, 2H), 7.88 (dd, J = 8.6, 1.9 Hz, 1H), 7.59 - 7.68 (m, 3H), 7.42 - 7.48 (m, 7H), 7.34 - 7.41 (m, 1H), 4.25 (s, 3H). LC-MS: m/z 463.1 (M+H)+.
[00344] 6-(5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-2-phenyIpyrazolo[l,5- a]pyrimidin-6-yl)quinoline
Figure imgf000110_0001
[00345] 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-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine in step B. [00346] Step B: A suspension of dimethyl 2-(quinolin-6-yl)malonate (1.95 g, 7.52 mmol) and 4-(cyclohex-l-en-l-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 NH4CI (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (DCM:MeOH=l 5 : 1 ) to obtain 3-(cyclohex- l-en-l -yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[l ,5-a]pyrimidine-5,7(4H,6H)-dione (3.1 g) as a yellow solid. LC-MS: m/z 435.2 (M+H)+.
[00347] Step C : The solution of 3 -(cyclohex- 1 -en- 1 -yl)-2-phenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione (3.1 g, 7.13 mmol) in POCh (12 ml) was stirred at 1 10 °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. The resultant mixture was diluted with DCM (150 ml), washed with saturated NaHCOi (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated to afford crude product of 6-(5,7-dichloro-3-(cyclohex-l-en-l-yl)-2-phenylpyrazolo[l,5- a]pyrimidin-6-yl)quinoline ( 1.3 g) which was used in the next step without further purification. LC-MS: m/z 471.9 (M+H)+.
[00348] Step D: To a solution of 6-(5,7-dichloro-3-(cyclohex- 1 -en- 1 -yl 2- phenylpyrazolo[l,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 NH4CI (50 mL) was added to quench the reaction. The resultant mixture was extracted with DCM (150 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (DCM/MeOH=40: l) to obtain 6-(5-chloro-3- (cyclohex-l-en-l-yl)-7-methoxy-2-phenylpyrazolo[l,5-a]pyrimidin-6-yl)quinoline as a off- white solid.
1H NMR (CHLOROFORM-d): δ 9.28 (d, J = 3.8 Hz, 1H), 8.76 (d, J = 8.6 Hz, 2H), 8.1 1 (s, 1H), 7.80 - 8.03 (m, 4H), 7.36 - 7.57 (m, 3H), 5.99 (br. s., 1H), 3.75 (s, 3H), 2.20 - 2.37 (m, 4H), 1.67 - 1.87 (m, 4H). LC-MS: mlz 467.2 (M+H)+.
[00349] 6-(5-chloro-3-(cyclohex- 1 -en- 1 -yl)-7-methoxy-2-phenylpyrazolo[l ,5- a]pyrimidin-6-yl)quinoxaline
Figure imgf000111_0001
[00350] 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-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine in step B.
[00351] 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. After cooling to room temperature, the mixture was diluted with EtOAc (150 mL), washed with saturated NH4CI (80 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column (petroleum ether/ethyl acetate=3 : 1 ) to obtain dimethyl 2- (quinoxalin-6-yl)malonate (2.0 g) as a yellow solid.
[00352] 1H NMR (CHLOROFORM-d): δ 8.89 (s, 2H), 8.10 - 8.19 (m, 2H), 7.91 (dd, J = 8.7, 2.0 Hz, 1H), 4.95 (s, 1H), 3.82 (s, 6H). LC-MS: mlz 261.1 (M+H)+.
[00353] Step B: A suspension of 4-(cyclohex-l-en-l-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 NH4CI (50 ml) and brine (30 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (DCM:MeOH=15: l) to obtain 3-(cyclohex- l-en-l-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione (2.2 g) as a yellow solid.
[00354]1H NMR (DMSO-d6): δ 10.11 (br. s., 1H), 9.07 (br. s., 1H), 8.79 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.51 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.71 (d, J = 7.3 Hz, 2H), 7.27 - 7.46 (m, 3H), 5.69 (br. s., 1H), 2.14 (br. s., 2H), 2.00 (br. s., 2H), 1.60 - 1.68 (m, 4H). LC-MS: m/z 436.2 (M+H)+.
[00355] Step C: The solution of 3-(cyclohex-l -en-1 -yl)-2-phenyl-6-(quinoxalin-6- yl)pyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione (1.0 g, 2.30 mmol) in POCb (6 ml) in a sealed tube was stirred at 1 10 °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. The resultant mixture was diluted with DCM (150 ml), washed with saturated NaHC03 (50 ml) and brine (30 ml), dried over anhydrous sodium sulfate, and concentrated to afford crude product of 6-(5,7-dichloro-3-(cyclohex-l-en-l-yl)-2- phenylpyrazolo[l,5-a]pyrimidin-6-yl)quinoxaline (800 mg) which was used in the next step without further purification. LC-MS: m/z 472.1 (M+H)+.
[00356] Step D: To a solution of 6-(5,7-dichloro-3-(cyclohex-l-en-l-yl)-2- phenylpyrazolo[l,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 NH4CI (50 mL) was added to quench the reaction. The resultant mixture was extracted with DCM ( 100 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (DCM/MeOH=40: l) to obtain 6-(5-chloro- 3-(cyclohex-l-en-l-yl)-7-methoxy-2-phenylpyrazolo[l,5-a]pyrimidin-6-yl)quinoxaline as a brown solid.
[00357] 1H NMR (CHLOROFORM-d): δ 8.98 (s, 2H), 8.29 (d, J = 8.9 Hz, 1H), 8.24
(d, J = 1.6 Hz, 1H), 7.92 (dd, J = 7.9, 1.5 Hz, 2H), 7.86 (dd, J = 8.6, 1.9 Hz, 1H), 7.41 - 7.55 (m, 3H), 5.98 (dt, J = 3.6, 1.9 Hz, 1H), 4.26 - 4.37 (m, 3H), 2.33 (br. s., 2H), 2.19 - 2.30 (m, 2H), 1.71 - 1.85 (m, 4H). LC-MS: m/z 468.2 (M+H)+. [00358] The following compounds were prepared according to Example 1, step E and F, starting from 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine.
[00359] Compound 153: 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5- (pyridin-2-ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000113_0001
[00360] Step E stoichiometry: 5-chloro-3-(cyclohex-l -en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 K2C03 (265mg, 1.12mol, 2.5eq.) in dioxnae (5mL) under heating at 120 °C for 1 hour under N2 atmosphere. LC-MS: m/z 504.9 (M+H)+.
[00361] Step F: A solution of 3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenyl -N-(pyridin-2-yl)pyrazolo[l,5-a] pyrimidin-5-amine (120mg, 0.22 mol) in 4M HC1 /l .4-dioxane (3mL) was stirred at r.t. for 16 hours. The reaction mixture was basified with NaHC03 solution to pH=8 and filtered to afford the title compound.
[00362] 1H NMR (DMSO-d6): δ 9.09 (br. s., 1H), 8.20 (d, J = 4.3 Hz, 1H), 7.82 (t, J =
7.3 Hz, 1 H), 7.73 (d, J = 7.3 Hz, 2H), 7.38 - 7.51 (m, 3H), 7.28 - 7.38 (m, 3H), 7.10 - 7.17 (m, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.06 (br. s., 1H), 3.82 (s, 3H), 2.34 (br. s., 2H), 2.06 (br. s., 2H), 1.65 - 1.79 (m, 4H). LC-MS: m/z 490.2 (M+H)+.
[00363] Compound 154: 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5- (pyridin-3-ylamino)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000114_0001
[00364] Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 CS2C03 (293 mg, 0.90 mmo) in dioxane (20 mL) under heating at 1 10 °C for 4 hours under N2 atmosphere. LC-MS: m/z 504.2 (M+H)+.
[0036S] Step F : To a solution of 3 -(cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenyl-N-(pyridin-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine (60 mg,
0.12mmol) in MeOH (10 mL) was added 4N HC1 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 NaHC03 solution to give the desired product 3- (cyclohex- 1 -en-1 -yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-3-ylamino)pyrazolo[l ,5- a]pyrimidin-7(4H)-one.
[00366] 1H NMR (DMSO-d6): 6 8.69 (br. s., 1H), 8.31 (d, J = 5.4 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.71 - 7.83 (m, 3H), 7.39 - 7.52 (m, 3H), 7.24 - 7.33 (m, J = 8.6 Hz, 2H), 6.81 - 6.94 (m, J = 8.9 Hz, 2H), 5.88 (br. s., 1H), 3.73 (s, 3H), 2.14 (br. s., 2H), 2.02 - 2.12 (m, 2H), 1.56 - 1.74 (m, 4H). LC-MS: m/z 490.2 (M+H)+.
[00367] Compound 155: 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5- (pyrimidin-4-ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000115_0001
[00368] Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 Cs2C03 (285.2 mg, 2.691 mmol, 3 eq) in 1.4-dioxane (10 mL) under heating at 100 °C through microwave irradiation for 1 hour under N2 atmosphere. LC-MS: m/z 505.0 (M+H)*. [00369] Step F : A solution of 3 -(cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenyl-N-(pyrimidin-4-yl)pyrazolo[l,5-a]pyrimidin-5-amine (100 mg, 0.198mmol) in 4M HC1 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 NH3 in methanol and stirred at room temperature for 2 hours to afford the title compound. [00370] 1H NMR (DMSO-d6): δ 8.98 (s, 1 H), 8.49 (d, J=7.02 Hz, 1 H), 7.79 (d,
J=7.32 Hz, 2 H), 7.41 - 7.52 (m, 3 H), 7.27 (m, J=8.54 Hz, 2 H), 7.18 (d, J=6.41 Hz, 1 H), 6.93 (m, J=8.54 Hz, 2 H), 5.87 (br. s., 1 H), 2.18 (br. s., 2 H), 2.06 (br. s., 2 H), 1.67 (br. s., 4 H). LC-MS: m/z 491.0 (M+H) +.
[00371] Compound 156: 3-cyclohexenyl-6-(4-methoxyphenyl)- 5-(2- methoxypyrimidin-4-ylamino)-2-phenyl- pyrazolo [ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000116_0001
[00372] Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 Na2C03 (96 g, 0.904 mmol) in 1.4-dioxane (10 mL) under heating at 110 °C for 4 hours under N2 atmosphere.
[00373] 'HNMR (DMSO-d6) δ 8.46 (d, J=5.6 Hz, 1 H), 8. 14 (d, J=5.6 Hz, 1 H), 7.81 d, J=7.2 Hz, 2 H), 7.56 (s, 1 H), 7.42 - 7.51 (m, 4 H), 7.16 - 7.18 (m, 2 H), 5.88 (bs, 1 H), 4.1 1 (s, 3 H), 3.86 (s, 3 H), 3.80 (s, 3 H), 2.22 - 2.27 (m, 4 H), 1.70 -1.75 (m, 4 H). LC-MS: m/z 535.2 (M+H)+.
[00374] Step F: A mixture of 3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-N-(2- methoxy- pyrimidin-4-yl)- 2-phenyl-pyrazolo[l,5-a]pyrimidin-5-amine (55 mg, 0.103 mmol) and HC1 solution (4N in dioxane, 6 mL) was stirred at room temperature overnight. The mixture was quenched with N¾ solution (7N in methanol) to pH 7 to afford 3-cyclohexenyl- 6-(4-methoxyphenyl)- 5-(2- methoxypyrimidin-4-ylamino)-2-phenyl- pyrazolo [1,5- a]pyrimidin-7(4H)-one.
[00375] 1H NMR (DMSO-d6): δ 13.82 (s, 1 H), 9.38 (s, 1 H), 8.28 (d, J=5.80 Hz, 1 H), 7.75 (d, J=7.32 Hz, 2 H), 7.45-7.51 (m, 2 H), 7.42 (d, J=7.32 Hz, 1 H), 7.29 (m, J=8.54 Hz, 2 H), 7.02 (m, J=8.85 Hz, 2 H), 6.86 (d, J=5.80 Hz, 1 H), 5.99 (s, 1 H), 3.92 (s, 3 H), 3.81 (s, 3 H), 2.28 (bs, 2 H) 2.06 (bs, 2 H), 1.70 (bs, 4 H). LC-MS: m/z 521.5 (M+H)+. [00376] Compound 157: 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5- (pyridazin-3-ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000117_0001
[00377] Step E stoichiometry: 5-chloro-3-(cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 Cs2C03 (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) +. [00378] Step F: A solution of 3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenyl-N-(pyridazin-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine (70 mg, 0.14 mmol) in 4M HC1 in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
[00379] 1H NMR (DMSO-d6): δ 15.09 (s, 1H), 9.18 (s, 1H), 8.92 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 6.0 Hz, 2H), 7.46 - 7.53 (m, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.30 - 7.39 (m, J = 8.6 Hz, 2H), 6.98 - 7.11 (m, J = 8.6 Hz, 2H), 6.07 (br. s., 1H), 3.83 (s, 3H), 2.32 - 2.38 (m, 2H), 2.07 (br. s., 2H), 1.70 (br. s., 4H). LC-MS: m/z 491.1 (M+H)+.
[00380] Compound 158: 3-cyclohexenyl-6- (4-methoxyphenyl)-2- phenyl-5- (pyrazin-2- ylamino) pyrazolo [l,5-a]pyrimidin-7(4H)-one
Figure imgf000117_0002
[00381] Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 (lOmL) under heating at 100 °C through microwave irradiation for 1 hour under nitrogen atmosphere. LC-MS: m/z 505.2 (M+H) +. [00382] Step F: A solution of 3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2- phenyl-N- (pyrazin- 2-yl) pyrazolo [l,5-a]pyrimidin-5-amine (150 mg, 0.30 mmol) in 4M HC1/1.4-dioxane (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane: methanol = 10: 1 (10 mL) and washed with saturated sodium carbonate (5 mL) twice to pH 8. The organic layer was concentrated in vacuo to give 3-cyclohexenyl-6- (4-methoxyphenyl)-2- phenyl-5- (pyrazin-2-ylamino) pyrazolo [1,5-a] pyrimidin-7^Hj-one.
[00383] 1H NMR (DMSO-d6): 6 3.90 (s, 1 H), 9.35 (s, 1 H), 8.64 (s, 1 H), 8.25 (d,
J=2.75 Hz, 1 H), 8.20 (dd, J=2.75, 1.22 Hz, 1 H), 7.67 - 7.77 (m, 2 H) 7.44 - 7.53 (m, 2 H), 7.37 - 7.44 (m, 1 H), 7.27 - 7.36 (m, 2 H), 6.98 - 7.06 (m, 2 H), 6.04 (br. s., 1 H) 3.81 (s, 3H), 2.34 (br. s., 2 H), 2.05 (br. s., 2 H), 1.70 (d, J=4.88 Hz, 4 H). LC-MS: m/z 491.2 (M+H) +.
[00384] Compound 159: 5-(3-cyclohexenyl-6-(4-methoxyphenyl)-7-oxo-2-phenyl- 4,7-dihydropyrazolo[l,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile
N
Figure imgf000118_0001
[00385] Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 1 10 °C for 4 hours under nitrogen atmosphere. LC-MS: m/z 530.2 (M+H)". [00386] 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 to afford 5-(3-cyclohexenyl-6- (4- methoxyphenyl)- 7-oxo-2-phenyl-4,7-dihydropyrazolo[l ,5-a] pyrimidin-5-ylamino) pyrazine- 2-carbonitrile.
[00387] 1H NMR (DMSO-d6): δ 12.76 (br. s., 1 H), 10.15 (br. s., 1 H), 8.73 (s, 1 H) 8.44 (br. s., 1 H), 7.75 (d, J=7.02 Hz, 2 H), 7.36 - 7.54 (m, 3 H), 7.28 (m, J=8.54 Hz, 2 H), 6.97 (m, J=8.55 Hz, 2 H), 5.92 (br. s., 1 H), 3.78 (s, 3 H), 2.25 (br. s., 2 H), 2.04 (br. s., 2 H), 1.68 (br. s., 4 H). LC-MS: m/z 516.2 (M+H) +.
[00388] Compound 160: 5-((5-aminopyrazin-2-yl)amino)-3-(cyclohex-l-en-l-yl)-6- (4-methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000119_0001
[00389] Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 1 10 °C for 1 hour under nitrogen atmosphere. LC-MS: m/z 520.2 (M+H)+. [00390] Step F: A mixture of N?-(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 to afford 5-(5-aminopyrazin-2-ylamino)- 3-cyclohexenyl-6-(4-methoxyphenyl)-2-phenylpyrazolo [1 ,5-a] pyrimidin-7f4H,)-one.
[00391] 1H NMR (DMSO-d6): δ 13.92 (s, 1Η), 8.70 (s, 1Η), 8.08 (d, J = 1.2 Hz, 1 H),
7.71 (d, J = 7.0 Hz, 2H), 7.56 (s, 1H), 7.44 - 7.51 (m, 2H), 7.41 (d, J = 7.3 Hz, 1H), 7.27 - 7.33 (m, J = 8.9 Hz, 2H), 7.01 - 7.07 (m, J = 8.9 Hz, 2H), 6.23 (s, 2H), 6.04 (br. s., 1H), 3.83 (s, 3H), 2.33 (br. s., 2H), 2.04 (br. s., 2H), 1.71 (br. s., 4H). LC-MS: m/z 506.2 (M+Hf.
[00392] Compound 161: 5-((l,2,4-triazin-3-yl)amino)-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000120_0001
[00393] Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 Cs2C03 (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)+.
[00394] Step F : A solution of 3 -(cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenyl-N-(l ,2,4-triazin-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine (30 mg, 0.06 mmol) in 4M HC1 in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuum to obtain the title compound.
[00395] 1H NMR (DMSO-d6): δ 12.81 (s, 1H), 9.78 (s, 1H), 8.92 (s, 1H), 8.51 (s, 1H),
7.77 (d, J = 7.2 Hz, 2H), 7.39 - 7.52 (m, 3H), 7.26 (d, J =8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 3.76 (s, 3H), 2.21 (br. s., 2H), 2.06 (br. s., 2H), 1.66 (br. s., 4H). LC-MS: m/z 492.0 (M+H)+.
[00396] Compound 162: 5-((l,2,4-triazin-5-yl)amino)-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000121_0001
[00397] Step E stoichiometry: 5-chloro-3-cyclohexenyl-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo [l,5-a]pyrimidine (110 mg, 0.25 mmol), l,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) +. [00398] Step F: A mixture of 3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2- phenyl-N-( 1,2,4- triazin-5-yl) pyrazolo[l,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 to afford 5-( 1,2,4- triazin-5-ylamino)-3-cyclohexenyl-6-(4-methoxyphenyl)-2-phenylpyrazolo [ 1 ,5-a]pyrimidin- 7(4H)-one.
[00399] 1H NMR (DMSO-d6): δ 9.02 (s, 1H), 8.64 (br. s., 1H), 7.77 (d, J = 7.0 Hz, 2H), 7.38 - 7.54 (m, 3H), 7.26 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 5.85 (br. s., 1H), 3.76 (s, 3H), 2.18 (br. s., 2H), 2.05 (br. s., 2H), 1.66 (br. s., 4H). LC-MS: m/z 492.2 (M+H) +.
[00400] Compound 163: 5-((l,3,5-triazin-2-yl)amino)-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000122_0001
[00401] A suspension of 5-chloro-3-(cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidine (500mg, 1.121mmol) and 1,3,5-triazin- 2-amine (323.2mg, 3.364 mmol, 3 eq), Pd(OAc)2 (50.3 mg, 0.224 mmol,0.2 eq), Xant-phos (259.5mg, 0.453 mmol, 0.4 eq) and Cs2C03 (1.09 g, 3.364 mmol, 3 eq) in 1.4-dioxane (10 mL) was stirred and warmed up to 100 °C through microwave irradiation for 1 hour under N2 atmosphere. The reaction was then cooled to room temperature, diluted with saturated sodium hydrogen carbonate solution, and extracted with EtOAc (20X3 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the title compound.
[00402]1H NMR (CHLOROFORM-d): δ 12.85 (br. s., 1 H), 8.85 (s, 2 H), 7.88 (d, J=6.18 Hz, 2 H), 7.76 (br. s., 1 H), 7.35 - 7.48 (m, 4 H), 7.08 (d, J=8.06 Hz, 2 H), 6.09(br. s., 1 H), 3.89 (s, 2 H), 2.37 (br. s., 2 H), 2.12 (br. s., 2 H), 1.77 (br. s., 3 H), 1.68 (br. s., 1 H), 1.23 - 1.39 (m, 1 H). LC-MS : m/z 492.0 (M+H) +.
[00403] Compound 164: 5-((4-amino-l,3,5-triazin-2-yl)amino)-3-(cyclohex-l-en-l- yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[ 1 , 5-a]pyrimidin-7(4H)-one
Figure imgf000122_0002
[00404] Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l ,5-a]pyrimidine (222 g, 0.5 mmol), l ,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 Cs2C03 (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 N2 atmosphere. LC-MS: m/z 521.0 (M+H)+.
[00405] Step F: The solution of N2-(3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,3,5-triazine-2,4-diamine (80 mg, 0.15 mmol) in HC1- 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 NaHC03. The organic phase was separated and washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound.
[00406] 1H NMR (DMSO-d6): δ 8.28 (br. s., 1H), 7.74 (d, J = 7.2 Hz, 2H), 7.38 - 7.52 (m, 4H), 7.31 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 8.2 Hz, 2H), 5.96 (br. s., 1H), 3.80 (s, 3H), 2.26 (br. s., 2H), 2.04 (br. s., 2H), 1.68 (br. s., 4H). LC-MS: m/z 507.0 (M+H)+.
[00407] Compound 165: 3-(cyclohex-l-en-l-yl)-5-(isoxazol-3-ylamino)-6-(4- methoxyphenyl)-2-phenylpyrazolo[l ,5-a]pyrimidin-7(4H)-one
Figure imgf000123_0001
[00408] Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,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 1 10 °C for 12 hours under nitrogen atmosphere. LC-MS: m/z 494.2 (M+H)+.
[00409] Step F : A solution of N-(3 -(cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-5-yl)isoxazol-3-amine (450 mg,
0.91mmol) in 4M HC1 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 NaHC03 (8 mL) was added to obtain 3 -(cyclohex- 1 -en- 1 -yl)-5-(isoxazol-3 -ylamino)-6-(4-methoxyphenyl)-2-phenylpyrazolo[ 1 ,5- a]pyrimidin-7(4H)-one as.
[00410] 1H NMR (DMSO-d6): δ 1 1.97 (s, 1H), 9.40 (s, 1H), 8.79 (s, 1H), 7.72 (d, J =
7.3 Hz, 2H), 7.37 - 7.56 (m, 3H), 7.23 - 7.37 (m, J = 8.5 Hz, 2H), 6.98 - 7.13 (m, J = 8.5 Hz, 2H), 6.51 (s, 1H), 6.03 (br. s., 1H), 3.82 (s, 3H), 2.28 (br. s., 2H), 2.03 (br. s., 2H), 1.68 (br. s., 4H). LC-MS: m/z 480.2 (M+H)+.
[00411] Compound 166: 5-((l,2,4-thiadiazol-5-yl)amino)-3-(cyclohex-l-en-l-yl)-6- (4-methoxyphenyl)-2-phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000124_0001
[00412] Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l ,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 Cs2C03 (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)+.
[00413] Step F: A solution of N-(3-(cyclohex-l-en-l -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-5-yl)-l,2,4-thiadiazol-5-amine (51 mg, 0.1 mmol) in 4M HC1 in 1.4-dioxane (10 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
[00414] 1H NMR (DMSO-d6): 6 8.23 (s, 1H), 7.77 (d, J = 7.0 Hz, 2H), 7.51 (d, J = 7.2
Hz, 3H), 7.29 - 7.35 (d, J = 8.4 Hz, 2H), 7.01 - 7.09 (d, J = 8.0 Hz, 2H), 5.95 (br. s., 1H), 3.83 (s, 3H), 2.24 (br. s., 4H), 1.74 (br. s., 4H). LC-MS: m/z 497.1 (M+H)+.
[00415] Compound 167: 5-((l,3,4-thiadiazol-2-yl)amino)-3-(cyclohex-l-en-l-yl)-6- (4-methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000125_0001
[00416] Step E stoichiometry: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidine (446mg, 1 Ommol), l,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 (1 15.6mg, 0.2mmol, 0.2 eq) and Na2C03 (212mg, 2. Ommol, 2.0 eq) in toluene (40 mL)under heating at 1 10 °C for 5 hour under nitrogen atmosphere. LC-MS: m/z 51 1.2 (M+H)+.
[00417] Step F: A mixture of N-(3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-5-yl)-l ,3,4-thiadiazol-2-aminein (102mg, 0.2mmol) in 4N HC1 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 to afford the title compound.
[00418] 1H NMR (DMSO-d6): δ 13.77 (br. s.,0.5H), 10.56 (br. s., 0.5H), 9.09 (br. s., 1 H), 7.74 (d, J=7.02 Hz, 2 H), 7.40 - 7.57 (m, 3 H), 7.31 (m, J=8.24 Hz, 2 H), 7.05 (m, J=8.55 Hz, 2 H), 6.03 (br. s., 1 H), 3.83 (s, 3 H), 2.29 (br. s., 2 H), 2.08 (br. s., 2 H), 1.70 (br. s., 4 H). LC-MS: m/z 497.1 (M+H) +.
[00419] The following compounds were prepared according to the procedure preparing compound 101, steps E-F, starting from 6-(5-chloro-7-methoxy-2,3- diphenylpyrazolo[l,5-a]pyrimidin-6-yl)quinoline. [00420] Compound 168: 2,3-diphenyl-5-(pyridin-2-ylamino)-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000126_0001
[00421] A mixture of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,5-a]pyrimidin-6- yl)quinoline (250 mg, 0.541 mmol), pyridin-2-amine (102 mg, 1.08 mmol), palladium(II) acetate (121 mg, 0.541 mmol), xantphos (296 mg, 0.541 mmol) and cesium carbonate (354 mg, 1.08 mmol) in 1, 4-dioxane (10 mL) was stirred under nitrogen atmosphere in a sealed tube and heated to 1 10 °C under microwave for 1 hour to afford 2, 3-diphenyl-5-(pyridin-2- ylamino)-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin- 7(4H)-one. [00422] 1H NMR (DMSO-d6): δ 15.93 (br. s., 1 H), 9.36 (s, 1 H), 8.74 (d, J=8.06 Hz, 1
H), 8.16 - 8.34 (m, 2 H), 8.07 (d, J=3.76 Hz, 1 H), 7.99 (d, J=8.33 Hz, 1 H), 7.75 - 7.85 (m, 2 H), 7.60 (t, J=7.52 Hz, 4 H), 7.39 - 7.54 (m, 5 H), 7.21 - 7.28 (m, 1 H), 7.09 - 7.17 (m, 1 H), 6.98 (s, 1 H). LC-MS: m/z 507.2 (M+Kf .
[00423] Compound 169: 2,3-diphenyl-5-(pyrimidin-4-ylamino)-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000126_0002
[00424] Step E stoichiometry: 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,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 (1 12 mg, 0.19 mmol, 0.15 eq) and Cs2C03 (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)+. [00425] Step F: A solution of 7-methoxy-2,3-diphenyl-N-(pyrimidin-4-yl)-6-(quinolin- 6-yl)pyrazolo[l,5-a]pyrimidin-5-amine (271 mg, 0.52 mmol) in 4M HC1 in 1.4-dioxane (15 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound. [00426] 1H NMR (DMSO-d6): δ 14.65 (s, 1H), 9.64 (s, 1H), 8.92 (s, 1H), 8.43 (m, 4H),
8.12 - 7.96 (m, 2H), 7.83 (d, J= 8.0 Hz, 2H), 7.55 (m, 3H), 7.50 (d, J= 6.8 Hz, 2H), 7.37 (s, 4H), 7.19 (s, 1 H). LC-MS: m/z 507.9 (M+H)+.
[00427] Compound 170: 5-(isoxazol-3-ylamino)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000127_0001
[00428] Step E stoichiometry: 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,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 51 1.2 (M+H)+.
[00429] Step F: A mixture of N-(7-methoxy-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l ,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) and basified with aqueous ammonia to pH 8 to afford 5-(isoxazol-3- ylamino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo [l,5-a]pyrimidin- 7(4H)-one.
[00430] 1H NMR (DMSO-d6): 6 9.39 (d, J=4.03 Hz, 1 H), 9.31 (d, J=8.33 Hz, 1 H),
8.75 (d, J=l .61 Hz, 1 H), 8.51 (s, 1 H), 8.39 (d, J=8.87 Hz, 1 H), 8.25 (d, J=8.87 Hz, 1 H), 8.17 (dd, J=8.33, 5.37 Hz, 1 H), 7.47-7.58 (m, 4 H), 7.31-7.46 (m, 6 H), 6.44 (bs, 1 H). LC- MS: m/z 497.2 (M+Hf . [00431] Compound 171: ethyl 5-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)amino)-l,3,4K)xadiazole-2-carboxylate
4
Figure imgf000128_0001
[00432] A suspension of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l ,5- a]pyrimidin-6-yl)quinoline (200 mg, 0.43 mmol), ethyl 5-amino-l,3,4-oxadiazole-2- carboxylate (135 mg, 0.86 mmol, 2 eq.), Pd(OAc)2 (20 mg, 0.09 mmol, 0.2 eq.), Xantphos(75 mg, 0.13 mmol, 0.3 eq.) and Cs2C03 (282 mg, 0.87 mmol, 2.0 eq.) in 1.4-dioxane (5 mL) was stirred at 100 °C for 16 h under N2 atmosphere. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford the title compound. [00433] NMR (DMSO-d6): 6 12.55 (br. s., 1H), 9.10 (br. s., 1H), 8.85 (br. s., 1H),
8.31 (br. s., 1H), 8.15 - 8.23 (m, 1H), 8.04 - 8.15 (m, 1H), 7.84 (br. s., 1H), 7.42 - 7.60 (m, 4H), 7.38 (d, J = 6.2 Hz, 7H), 4.32 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H). LC-MS: m/z 570.0 (M+H)+.
[00434] Compound 172: N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l ,5-a]pyrimidin-5-yl)acetamide
Figure imgf000128_0002
[0043S] Step E stoichiometry: 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,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 Cs2C03 (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)+.
[00436] Step F: A solution of N-(7-methoxy-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-5-yl)acetamide (100 mg, 0.21 mmol) in 4M HC1 in 1.4-dioxane (20 mL) was stirred at 30 °C for 5 hours. The reaction mixture was concentrated in vacuo to obtain the title compound.
[00437] NMR (DMSO-d6): 6 12.96 (br. s., 1H), 10.12 (br. s., 1H), 8.92 (br. s., 1H),
8.40 (br. s., 1 H), 8.05 (br. s., 1 H), 7.99 (br. s., 1H), 7.76 (d, J = 8.6 Hz, 1 H), 7.42 - 7.64 (m, 5H), 7.30 - 7.42 (m, 5H), 1.86 - 2.03 (m, 3H). LC-MS: m/z 472.0 (M+H)÷.
[00438] Compound 173: 2-hydroxy-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a] pyrimidin-5-yl)acetamide
Figure imgf000129_0001
[00439] Step A: 2-(benzyloxy)-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[ 1 ,5-a]pyrimidin-5-yl)acetamide
Figure imgf000129_0002
[00440] A suspension of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,5- a]pyrimidin-6-yl)quinoline (200 g, 0.43 mmol), 2-(benzyloxy)acetamide (143 mg, 0.86 mmol, 2 eq.), Pd(OAc)2 (20 mg, 0.09 mmol, 0.2 eq.), Xantphos (75 mg, 0.13 mmol, 0.3 eq.) and Cs2C03 (282 mg, 0.86 mmol, 2 eq.) in 1.4-dioxane (5 mL) was stirred at 100 °C through microwave irradiation for 1 hour under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (DCM/MeOH = 10/1) to afford the desired product as a yellow solid (120 mg).
[00441] 1H NMR (DMSO-d6): δ 12.66 (br. s., 1H), 9.65 (br. s., 1H), 8.91 (br. s., 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.96 - 8.06 (m, 2H), 7.74 - 7.82 (m, 1H), 7.44 - 7.56 (m, 4H), 7.33 - 7.44 (m, 7H), 7.13 - 7.23 (m, 3H), 7.01 (d, J = 7.3 Hz, 2H), 4.32 (s, 2H), 3.97 (s, 2H). LC- MS: m/z 578.0 (M+H) +. [00442] Step B: 2-hydroxy-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a] pyrimidin-5-yl)acetamide
Figure imgf000130_0001
[00443] To a solution of 2-(benzyloxy)-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)acetamide (90 mg, 0. 156mmol) in DCM (5 mL) was added BBr3 (156 mg, 0.623 mmol, 4 eq.) at 0 °C. The mixture was stirred at r.t. for 2h. The reaction was quenched with MeOH at 0 °C to afford the title compound.
[00444] 1H NMR (DMSO-d6): δ 12.67 (br. s., 1 H), 10.91 (br. s., 1 H), 8.79 - 8.93 (m, 1H), 8.28 - 8.40 (m, 1H), 7.90 - 8.09 (m, 2H), 7.73 - 7.85 (m, 1H , 7.26 - 7.56 (m, 1 1H), 6.20 (br. s., 1 H , 3.85 (br. s., 2H). LC-MS: m/z 487.9 (M+H)+.
[00445] The following compounds were prepared according to the procedure for preparing compound 101, steps E-F, starting from 6-(5-chloro-3-(cyclohex-l-en-l-yl)-7- methoxy-2-phenylpyrazolo [l,5-a]pyrimidin-6-yl)quinoline. [00446] Compound 174: 3-cyclohexenyl-2-phenyl-5-(pyridin-2-ylamino)-6-(quinolin- 6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000131_0001
[00447] Step E stoichiometry: 6-(5-chloro-3-cyclohexenyl-7-methoxy-2- phenylpyrazolo[l,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 1 10 °C for 1 hour through microwave irradiation under nitrogen atmosphere. LC-MS: m/z 525.2 (M+H)+. [00448] Step F: A mixture of 7-methoxy -2,3 -diphenyl-N-(pyrazin-2-yl)-6-(quinolin-6- yl)pyrazolo[l,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 to afford 3-cyclohexenyl-2-phenyl-5-(pyridin-2-ylamino)-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]-pyrimidin-7(4H)-one.
[00449] 'H NMR (DMSO-d6): δ 15.37 (br. s., 1 H), 9.35 (s, 1 H), 9.18 (br. s., 1 H),
8.87 (d, J=8.24 Hz, 1 H), 8.18 - 8.36 (m, 3 H), 8.04 (d, J=8.55 Hz, 1 H), 7.88 (dd, J=7.93,
4.88 Hz, 1 H), 7.81 (t, J=7.02 Hz, 1 H), 7.75 (d, J=7.63 Hz, 2 H), 7.47 - 7.56 (m, 2 H), 7.38 - 7.46 (m, 1 H), 7.22 (d, J=8.54 Hz, 1 H), 7.10 - 7.18 (m, 1 H), 6.11 (br. s., 1 H), 2.38 (br. s., 2
H), 2.09 (s, 2 H), 1.73 (br. s., 4 H). LC-MS: m/z 51 1.2 (M+H)+.
[00450] Compound 175: 3-cyclohexenyl-2-phenyl-5-(pyrazin-2-ylamino)-6-(quinolin- 6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
[00451] Step E stoichiometry: 6-(5-chloro-3-cyclohexenyl-7-methoxy-2- phenylpyrazolo[l,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 1 10 °C for 1 hour through microwave irradiation under nitrogen atmosphere. LC-MS: m/z 526.2 (M+H)+. [00452] Step F: A mixture of 7-methoxy -2,3 -diphenyl-N-(pyrazin-2-yl)-6-(quinolin-6- yl)pyrazolo[l,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 to afford 2,3-diphenyl-5-(pyrazin- 2-ylamino)- 6-(quinolin-6-yl)pyrazolo[l ,5- a]pyrimidin-7(4H)- one.
[00453] 1H NMR (DMSO-d6): δ 14.04 (s, 1 H), 9.57 (s, 1 H), 8.94 (br. s., 1 H), 8.55 (s,
1 H), 8.41 (d, J=7.93 Hz, 1 H), 8.24 (s, 1 H), 8.26 (s, 1 H), 8.04 - 8.13 (m, 2 H), 7.81 (d, J=8.54 Hz, 1 H), 7.75 (d, J=7.32 Hz, 2 H), 7.57 (br. s., 1 H), 7.47 - 7.53 (m, 2 H), 7.44 (d, J=7.02 Hz, 2 H), 2.36 (br. s., 2H), 2.09 (br. s., 2 H), 1.72 (br. s., 4 H). LC-MS: m/z 512.2 (M+H)+.
[00454] Compound 176: 3-cyclohexenyl-5-(isoxazol-3-ylamino)-2-phenyl-6- (quinolin-6-yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000133_0001
[00455] Step E stoichiometry: 6-(5-chloro-3-cyclohexenyl-7-methoxy-2- phenylpyrazolo[l,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 (1 19 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+Hf.
[00456] Step F: A mixture of N-(3-cyclohexenyl-7-methoxy- 2-phenyl-6-(quinolin-6- yl)pyrazolo[l,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) and basified with aqueous ammonia to pH 8 to afford 3-cyclohexenyl- 5-(isoxazol-3-ylamino)-2-phenyl- 6-(quinolin-6-yl)pyrazolo[l,5-a] pyrimidin-7(4H)-one. [00457] 1H NMR (DMSO-d6): δ 9.39 (d, J=4.30 Hz, 1 H), 9.29 (d, J=8.33 Hz, 1 H),
8.78 (s, 1 H), 8.48 (s, 1 H), 8.40 (d, J=8.86 Hz, 1 H), 8.23 (d, J=8.86 Hz, 1 H), 8.16 (dd, J=8.19, 5.51 Hz, 1 H), 7.75 (d, J=7.25 Hz, 2 H) 7.38-7.59 (m, 4 H), 7.36 (bs, 1 H), 6.43 (s, 1 H), 6.06 (bs, 1 H), 2.30 (bs, 2 H), 2.06 (bs, 2 H), 1.70 (bs, 2 H) 1.23 (bs, 2 H). LC-MS: m/z 501.2 (M+H)+.
[00458] Compound 177: 3-(cyclohex-l -en-l-yl)-5-(isoxazol-3-ylamino)-2-phenyl-6- (quinoxalin-6-yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000133_0002
[00459] 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
Figure imgf000134_0001
[00460] The solution of 6-(5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-2- phenylpyrazolo[l,5-a]pyrimidin-6-yl)quinoxaline (80 mg, 0.17 mmol), isoxazol-3 -amine (43.1 mg, 0.51 mmol), palladium diacetate (19.2 mg, 0.09 mmol), Xantphos (59.4 mg, 0.10 mmol) and sodium carbonate (54.1 mg, 0.51 mmol) in 1,4-dioxane (8 mL) was refluxed for 12 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated to dryness. The residue was purified by flash column (DCM:MeOH=30: 1) to obtain 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) as yellow solid. LC-MS: m/z 516.2 (M+H)+. [00461] Step B: 3-(cyclohex-l-en-l-yl)-5-(isoxazol-3-ylamino)-2-phenyl-6- (quinoxalin-6-yl)pyrazolo [ 1 , 5-a]pyrimidin-7(4H)-one
Figure imgf000134_0002
[00462] A solution of N-(3-(cyclohex-l-en-l-yl)-7-methoxy-2-phenyl-6-(quinoxalin-6- yl)pyrazolo[l,5-a]pyrimidin-5-yl)isoxazol-3-amine (12 mg, 0.02mmol) in 4M HC1 in 1.4- dioxane (2 mL) was stirred at r.t. for 2 hours. The mixture was concentrated, and saturated NaHC03(3 mL) was added to obtain 3-(cyclohex- l-en-l-yl)-5-(isoxazol-3-ylamino)-2- phenyl-6-(quinoxalin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00463]1H NMR (TFA-d): δ 8.97 (s, 2H), 8.74 (d, J = 1.6 Hz, 1H), 8.14 - 8.22 (m,
2H), 7.91 (dd, J = 8.6, 1.9 Hz, 1H), 7.75 (d, J = 7.0 Hz, 2H), 7.36 - 7.54 (m, 3H), 6.42 (d, J = 1.9 Hz, 1H), 6.07 (br. s., 1H), 2.30 (br. s., 2H), 2.06 (d, J = 7.0 Hz, 2H), 1.70 (br. s., 4H). LC- MS: m/z 502.2 (M+Hf. [00464] Compound 178: 3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5- (pyridin-2-ylamino)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000135_0001
[0046S] Step A: 2-(3-chlorophenyl)-3-oxo-3-phenylpropanenitrile
Figure imgf000135_0002
[00466] To a solution of 2-(3-chlorophenyl)acetonitrile (6.0 g, 39.58 mmol) in THF (40 mL) cooled at-78 °C was added NaHMDS (29.7 mL, 59.37 mmol, 2.0 M in THF) dropwise. After addition, the mixture was stirred at -78 °C for 1 hour. Then benzoyl chloride (5.5 mL, 47.50 mmol) was added dropwise. The reaction was slowly warmed to room temperature and stirred for 12 hours. The reaction was quenched by saturated NH4CI (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.
[00467] Step B : 4-(3 -chlorophenyl)-3 -phenyl- 1 H-pyrazol-5 -amine
Figure imgf000136_0001
[00468] The solution of 2-(3-chlorophenyl)-3-oxo-3-phenylpropanenitrile (16 g, crude) and NH2NH2 (11.5 mL, 237.48 mmol) in EtOH/AcOH (80 mL/20 mL) was stirred at 80 °C for 6 hours. After cooling to room temperature, the mixture was concentrated by vacuum. The residue was diluted with EtOAc (200 mL), washed with saturated NaHCC (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column (petroleum ether/ethyl acetate=3 : 1 ) to obtain 4-(3-chlorophenyl)-3- phenyl-1H-pyrazol-5-amine (1.6 g) as a yellow solid.
[00469] 1H NMR (CHLOROFORM-d): δ 7.79 - 7.85 (m, 3H), 7.51 - 7.56 (m, 1H), 7.42 - 7.48 (m, 3H), 7.29 - 7.36 (m, 2H) . LC-MS: m/z 270.1 (M+H)+.
[00470] Step C: 3-<3-chlorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000136_0002
[00471] The suspension of 4-(3-chlorophenyl)-3-phenyl-1H -pyrazol-5-amine (1.6 g, 5.93 mmol) and dimethyl 2-(4-methoxyphenyl)malonate (1.7 g, 7.12 mmol) in xylene (30 mL) was stirred at 150 °C for 12 hours. After cooling to room temperature, the mixture was filtered and washed with MeOH (2 mL) to obtain 3-(3-chlorophenyl)-6-(4-methoxyphenyl)- 2-phenylpyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione (830 mg) as a white solid. LC-MS: m/z 444.1 (M+H)+.
[00472] Step D: 5,7-dichloro-3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a] pyrimidine
Figure imgf000137_0001
[00473] The solution of 3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione (800 mg, 1.80 mmol), N,N- dimethylaniline (436.8 mg, 3.60 mmol) and pentachlorophosphorane (375.3 mg, 1.80 mmol) in POC13(8 mL) in a sealed tube was stirred at 100 °C for 8 hours. After cooling to room temperature, the solvent was removed by vacuum. The residue was cooled to 0 °C and basified by adding MeOH(6 mL). The precipitate was filtered to obtain 5,7-dichloro-3-(3- chlorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidine (700 mg) as a yellow solid. LC-MS: m/z 480.1 (M+H)+. [00474] Step E: 5-chloro-3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine
Figure imgf000137_0002
[00475] To the solution of 5,7-dichloro-3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine(700 mg, 1.46 mmol) in DCM/MeOH (20 mL, 1 : 1) cooled at 0 °C was added sodium methanolate (0.9 mL, 5.0 M in methanol) dropwise. Then the mixture was stirred at 0 °C for 15 minutes. Saturated NH4CI (50 mL) was added to quench the reaction. The mixture was extracted with DCM (100 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column (petroleum ether/ethyl acetate/DCM=20: l : l) to obtain 5-chloro-3-(3-chlorophenyl)- 7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidine (520 mg) as a yellow solid.
[00476] 1H NMR (CHLOROFORM-d): δ 7.64 - 7.68 (m, 2H), 7.56 - 7.59 (m, 1H), 7.39 - 7.45 (m, 4H), 7.34 - 7.37 (m, 2H), 7.30 - 7.33 (m, 2H), 7.03 - 7.08 (m, 2H), 4.16 (s, 3H), 3.92 (s, 3H) . LC-MS: m/z 476.1 (M+H)+. [00477] Step F: 3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N- (pyridin-2-yl)pyrazolo [l,5-a]pyrimidin-5-amine
Figure imgf000138_0001
[00478] The mixture of 5-chloro-3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)- 2-phenylpyrazolo-[l,5-a]pyrimidine (120 mg, 0.25 mmol), pyridin-2-amine (47.4 mg, 0.50 mmol), palladium diacetate (28.3 mg, 0.13 mmol), Xantphos (72.9 mg, 0.13 mmol) and cesium carbonate (123.1 mg, 0.38 mmol) in 1,4-dioxane (6 mL) was reacted in microwave reactor at 120 °C for 1.5 hours under nitrogen atmosphere. After cooling to room
temperature, the mixture was filtered with celite, diluted with DCM (100 mL), washed with saturated brine (30mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by flash column (petroleum ether/ethyl acetate /DCM =6: 1 : 1 ) to obtain 3 -(3 -chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2- yl)pyrazolo[l,5-a]pyrimidin-5-amine (78 mg) as a yellow solid. LC-MS: m/z 534.2 (M+H)+.
[00479] Step G: 3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000138_0002
[00480] A solution of 3 -(3 -chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl- N-(pyridin-2-yl)pyrazolo[l,5-a]pyrimidin-5-amine (70 mg, 0.13mmol) in 4M HC1 in 1.4- dioxane (6 mL) was stirred at r.t. for 3 hours. The mixture was concentrated, and saturated NaHC03 (6 mL) was added to obtain 3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5- (pyridin-2-ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00481] 1H NMR (DMSO-d6) : δ 15.73 (s, 1H), 9.05 (s, 1H), 8.1 1 (d, J = 3.8 Hz, 1H),
7.81 (t, J = 8.1 Hz, 1H), 7.53 - 7.60 (m, 4H), 7.40 - 7.50 (m, 4H), 7.30 - 7.38 (m, 4H), 7.09 - 7.15 (m, 1H), 7.07 (d, J = 8.6 Hz, 2H), 3.85 (s, 3H). LC-MS: m/z 520.3 (M+H)+. [00482] Compound 179: 3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5- (pyridin-2-ylamino)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000139_0001
[00483] Step A: 2-(2-fluorophenyl)-3-oxo-3-phenylpropanenitrile
Figure imgf000139_0002
[00484] To a solution of 2-(2-fluorophenyl)acetonitrile (5.4 g, 40 mmol) in anhydrous THF (50 mL) was added dropwise of LDA (26 mL, 52 mmol, 1.3 eq) at -78°C. After addition, the mixture was stirred at -78°C for 0.5 h. Then methyl benzoate (6.0 g, 44 mmol, 1.1 eq) in THF (10 mL) was added slowly and stirred at RT overnight. The suspension was quenched with NH4C1 solution (30 mL) and extracted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give 2-(2-fluorophenyl)-3-oxo-3-phenylpropanenitrile (12 g, crude) which was used directly to the next step without further purification. LC-MS: m/z 240.1 (M+H)+.
[00485] Step B: 4-(2-fluorophenyl)-3-phenyl-1H-pyrazol-5-amine
Figure imgf000140_0001
[00486] To a solution of 2-(2-fluorophenyl)-3-oxo-3-phenylpropanenitrile (12 g, 40 mmol) in EtOH (80 mL) and AcOH (20 mL) was added hydrazine hydrate (4.48 g, 80 mmol, 2.0 eq). Then the reaction mixture was stirred at reflux for 4h. The solvents were removed in vacuo, and the residue was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with EtOAc, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel
(EtOAc/PE=l/l) to afford the desired product (1.3 g). LC-MS: m/z 254.1 (M+H)*.
[00487] Step C: 3-(2-fluorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000140_0002
[00488] The dimethyl 2-(4-methoxyphenyl)malonate (886 mg, 3.7 mol, 1.2 eq), 4-(2- fluorophenyl)-3-phenyl-l H-pyrazol-5-amine (780 mg, 3.1 mol, l .Oeq) and xylene (15 mL) were added into the 100 mL bottle and heated to 150°Cfor 8h. The reaction mixture was then cooled to room temperature. The mixture was filtered off, and the filter cake was washed with PE to afford the desired product 3-(2-fluorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (1 g) as a white solid. LC-MS: m/z 427.9 (M+H)+.
[00489] Step D: 5,7-dichloro-3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a] pyrimidine
Figure imgf000141_0001
[00490] A solution of 3-(2-fluorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (1.0 g, 2.3 mmol) in phosphorus oxychloride (10 mL) was heated to reflux overnight. The mixture was concentrated under reduced pressure. The residue was added slowly into MeOH (10 mL) and filtered. The filter cake was washed with MeOH to afford the desired product 5,7-dichloro-3-(2-fluorophenyl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[l ,5-a]pyrimidine (890 mg) as a white solid. LC-MS: m/z 464.1 (M+H)+.
[00491] Step E: 5-chloro-3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine
Figure imgf000141_0002
[00492] To a solution of 5,7-dichloro-3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine (463 mg, 1 mmol) in DCM (10 mL) and MeOH (10 mL) cooled at 0°C was added dropwise the sodium methoxide (1 mL, 5mol, 30% in MeOH). Then the reaction mixture was stirred at 0°C for 0.5h. The suspension was quenched with NH4C1 solution (30 mL) and extracted with EA. The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/PE=l/5) to afford the desired product. 5-chloro-3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine (390 mg). LC-MS: m/z 460.1 (M+H)+.
[00493] Step F: 3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N- (pyridin-2-yl)pyrazolo [l,5-a]pyrimidin-5-amine
Figure imgf000142_0001
[00494] A suspension of 5-chloro-3-(2-fluorophenyl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidine (230 mg, 0.5 mmol), pyridin-2-amine (94 mg, 1 mmol, 2.0 eq), Pd(OAc)2 (22 mg, 0.1 mmol, 20 mol%), Xantphos (115 mg, 0.2 mmol, 40 mol%) and Cs2C03 (325 mg, 1 mmol, 2.0 eq) in 1.4-dioxane (10 mL) in a lOmL microwave vial was heated at 100°C under microwave irradiation for lh under N2 atmosphere. The reaction was then cooled and filtered. The dark filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/PE=l/4) to afford the desired product 3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N- (pyridin-2-yl)pyrazolo[l,5-a]pyrimidin-5-amine (100 mg). LC-MS: m/z 518.2 (M+H)+.
[00495] Step G: 3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000142_0002
[00496] A solution of 3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl- N-(pyridin-2-yl)pyrazolo[l,5-a]pyrimidin-5-amine (85 mg, 0.16 mmol) in 4M HC1 in 1.4- dioxane (10 mL) was stirred at 30 °C for 18 hours. The reaction mixture was concentrated in vacuo to afford the title compound.
[00497] 1H NMR (DMSO-d6): 6 8.04 (d, J = 4.8 Hz, 1H), 7.89 (s, 1H), 7.49 - 7.59 (m,
3H), 7.31 - 7.45 (m, 9H), 7.1 1 (t, J = 6.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 3.82 (s, 3H). LC- MS: m/z 504.0 (M+H) +. [00498] Compound 180: 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)-5-(pyridin- 2-ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000143_0001
[00499] Step A: 3-oxo-2-phenyl-3-(pyridin-2-yl)propanenitrile
Figure imgf000143_0002
[00500] To a solution of methyl picolinate (20 g, 0.15mol) and 2-phenylacetonitrile(20 g, 0. 18 mol) in THF (200 mL) was added slowly NaHDMS (80 mL,2 mmol/ mL) at 0 °C. Then the reaction mixture was stirred for lh at 0 °C and allowed to room temperature overnight. The mixture was poured into water and extracted with ethyl acetate (100 mL*3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-oxo-2-phenyl-3-(pyridin-2-yl)propanenitrile (crude, 25 g). LC-MS: m/z 223.3 (M+H)+. [00501] Step B: 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine
Figure imgf000144_0001
[00502] To a solution of 3-oxo-2-phenyl-3-(pyridin-2-yl)propanenitrile (25 g, 0.126 mol) in EtOH (200 mL) was added AcOH (20 mL). The reaction mixture was heated to 60 °C for 10 minutes, and then hydrazine monohydrate (7 g,0.138 mol) was added dropwise via a syringe. Then the reaction mixture was stirred for 4h at 60 °C. The mixture was concentrated to dryness. The residue was poured into water and extracted with ethyl acetate (100 mL*3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (eluting PE/EA=2: 1) to give 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (3g). LC-MS: m/z 237.2 (M+H)+.
[00503] Step C: 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[l,5- a]pyrimidine-5,7(4H,6H)-dione
Figure imgf000144_0002
[00504] A solution of 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (1.5 g, 6.35 mmol) and dimethyl 2-(4-methoxyphenyl)malonate (1.67 g, 7.0 mmol) in toluene (50 mL) was heated to 140 °C overnight. The reaction mixture was cooled to room temperature. The precipitate was filtered off to give 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2- yl)pyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione (1.2 g). LC-MS: m/z 411.2 (M+H)+. [00505] Step D: 5,7-dichloro-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2- yl)pyrazolo[l,5-a]pyrimidine
Figure imgf000145_0001
[00506] A solution of 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[l,5- a]pyrimidine-5,7(4H,6H)-dione (lg, 2.44 mmol) in POCb (15 mL) in a sealed tube was heated to 120 °C overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was adjusted to PH=7 by adding saturated NaHC03 solution, extracted with ethyl acetate (50 mL*3), filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting PE/EA=10: 1) to give 5,7-dichloro-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[l,5-a]pyrimidine (900 mg). LC-MS: m/z 447.3 (M+H)+
[00507] Step E: 5-chloro-7-methoxy-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2- yl)pyrazolo[ 1 ,5-a]pyrimidine
Figure imgf000145_0002
[00508] To a solution of 5,7-dichloro-6-(4-methoxyphenyl)-3-phenyl-2-{pyridin-2- yl)pyrazolo[l,5-a]pyrimidine (900 mg, 2.0 mmol) in MeOH (50 mL) was added NaOMe (0.5 mL,5.0 mmol/mL) at 0 °C. The reaction mixture was stirred for 30 mins. The mixture was adjusted to PH=7 by adding 1 N HC1 solution. Then the mixture was poured into water and extracted with ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated. The resultant solid was washed with ethyl acetate to give the desired product 5-chloro-7-methoxy- 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[l,5-a]pyrimidine (500 mg). LC-MS: m/z 443.4 (M+H)+.
[00509] Step F: 7-methoxy-6-(4-methoxyphenyl)-3 -phenyl -N,2-di(pyridin-2- yl)pyrazolo[l,5-a] pyrimidin-5-amine
Figure imgf000146_0001
[00510] A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin- 2-yl)pyrazolo[l,5-a]pyrimidine (150 mg, 0.34 mmol), pyridin-2-amine (35 mg,0.37 mmol), Pd(OAc)2 (7.6 mg, 0.034 mmol), xantphos (40 mg, 0.068 mmol), and Cs2C03 (222 mg) in dioxane (5 mL) was heated to 120 °C for 2h under N2. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting DCM/MeOH=20: l) to give the desired product (crude, 80 mg), which was used directly to the next step without further purification.
[00511] Step G: 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)-5-(pyridin-2- ylamino)pyrazolo[l ,5-a]pyrimidin-7(4H)-one
Figure imgf000146_0002
[00512] To a solution of 7-methoxy-6-(4-methoxyphenyl)-3-phenyl-N,2-di(pyridin-2- yl)pyrazolo[l,5-a]pyrimidin-5-amine (crude 80 mg) in MeOH (5 mL) was added HC1 in dioxane (5 mL, 4mmol/mL). The reaction mixture was stirred for 30 mins. The reaction mixture was concentrated in vacuo. The residue was basified with saturated NaHC03 to give the desired product 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)-5-(pyridin-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00513]1H NMR (DMSO-d6): δ 15.86 (s, 1H), 9.05 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H),
7.98 - 8.10 (m, 1H), 7.92 (d, J = 3.8 Hz, 2H), 7.80 (s, 1H), 7.45 - 7.60 (m, 4H), 7.27 - 7.45 (m, 5H), 7.00 - 7.14 (m, 3H), 3.84 (s, 3H). LC-MS: m/z 487.2 (M+H)+. [00514] Compound 181: 6-(4-methoxyphenyl)-2-phenyl-3-(piperidin
(pyridin-2-ylamino)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000147_0001
[00515] Step A: 5-hydroxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000147_0002
[00516] A suspension of 3-phenyl-4-(piperidin-l -yl)-1H-pyrazol-5-amine (2g, 8.254mmol) and dimethyl 2-(4-methoxyphenyl)malonate {2.95%, 12.38mmol) in
tributylamine (25mL) was warmed up tol 80 °C for 2.5 hours under N2 protection. The mixture was cooled to the room temperature and stirred with petroleum ether. The precipitates was filtered and washed with EtOAc to afford 5-hydroxy-6-(4-methoxyphenyl)- 2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (3g) as a yellow solid. LC- MS: m/z 417.2 (M+H) ÷.
[00517] Step B: 5,7-dichloro-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l- yl)pyrazolo[ 1 ,5-a]pyrimidine
Figure imgf000148_0001
[00518] The solution of 5-hydroxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (3g, 7.203mmol) in POC (30 mL) was warmed up to 100 °C overnight. The reaction mixture was concentrated to remove POCh. The residue was basified with saturated sodium hydrogen carbonate solution at 0 °C, and extracted with EtOAc (3X30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford crude product (2.5g) as a yellow solid. LC-MS: m/z 453.1 (M+H) +.
[00519] Step C: 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l- yl)pyrazolo[l,5-a]pyrimidine
Figure imgf000148_0002
[00520] To a solution of 5,7-dichloro-6-(4-methoxyphenyl)-2-phenyl-3 -(piperidin- 1 - yl)pyrazolo[l,5-a]pyrimidine (lg, 2.4mmol) in methanol (20 mL) was added MeONa (30% wt in methanol, 1.3 mL, 7.2mmol) at 0 °C and stirred at 0 °C for 3 hours. The reaction was quenched with ice water at 0 °C, diluted with saturated sodium hydrogen carbonate solution at 0 °C, and extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column (DCM:MeOH=30: l) to afford 5-chloro-7-methoxy- 6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l-yl)pyrazolo[l ,5-a]pyrimidine (550mg) as a yellow solid. LC-MS: m/z 449.2 (M+H) +.
[00521] Step D: 7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l-yl)-N- (pyridin-2-yl)pyrazolo[l ,5-a]pyrimidin-5-amine
Figure imgf000149_0001
[00522] A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3- (piperidin-l-yl)pyrazolo[l,5-a]pyrimidine (200mg, 0.446mmol), pyridin-2-amine (125mg, 12.38 mmol, 3 eq), Pd(OAc)2 (20mg, 0.089 mmol,0.2 eq), Xant-phos (103mg, 0.178mmol, 0.4 eq) and Na2C03 (188mg, 1.782 mmol, 4 eq) in 1,4-dioxane (5 mL) was stirred and warmed up to 100 °C through microwave irradiation for 1 hour under N2 atmosphere. The reaction was cooled to room temperature, diluted with saturated sodium hydrogen carbonate solution, and extracted with EtOAc (2X30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by pre-TLC (eluting DCM/MeOH=20: 1) to obtain 7-methoxy-6-(4- methoxyphenyl)-2-phenyl-3-(piperidin-l-yl)-N-(pyridin-2-yl)pyrazolo[l,5-a]pyrimidin-5- amine (80mg) as a white solid.
[00523] 1H NMR (DMSO-d6) δ 8.49 (d, J=5.64 Hz, 1 H), 8.21 - 8.38 (m, 2 H), 8.07 (d,
J=7.25 Hz, 2 H), 7.36 - 7.60 (m,6 H), 7.16 (d, J=8.60 Hz, 2 H), 4.13 (s, 3 H), 3.86 (s, 3 H), 3.51 (br. s., 4 H), 1.80 (br. s., 4 H), 1.60 (br. s., 2 H). LC-MS: m/z 507.2 (M+H) +.
[00524] Step E: 6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-l-yl)-5-(pyridin-2- ylamino)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000149_0002
[00525] A solution of 7-methoxy-6-(4-methoxypheny l)-2-phenyl-3 -(piperidin- 1 -yl)-N- (pyridin-2-yl)pyrazolo[l,5-a]pyrimidin-5-amine (100 mg, 0.198mmol) in 4.0M HC1 in 1.4- dioxane (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrate in vacuo. The residue was dissolved in 7N NH3 in methanol and concentrated in vacuo to afford the title compound.
[00526] 'H NMR (DMSO-d6): 5 8.31 (d, J=4.88 Hz, 1 H), 8. 12 (d, J=7.63 Hz, 2 H), 7.94 (t, J=7.32 Hz, 1 H), 7.41 - 7.53 (m, 4 H), 7.34 (m, J=8.55 Hz, 2 H), 7.19 (t, J=6.26 Hz, 1 H), 7.03 (m, J=8.55 Hz, 2 H), 3.82 (s, 3 H), 3.20 (br. s., 4 H), 1.73 (br. s., 4 H), 1.53 - 1. (m, 2 H). LC-MS: m/z 493.4 (M+H) +.
[00527] Compound 182: 5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a] pyrimidin-7(4H)-one
Figure imgf000150_0001
[00528] Step A: 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(l-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine
[00529] A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (500 mg, 1.1 mmol) and l-((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (314mg, 1.47 mmol) and Pd(OAc)2 (38 mg, 0.16 mmol), Xantphos (98 mg, 0.16 mmol) and Cs2C03 (740 mg, 2.2 mmol) in 1.4- dioxane (10 mL) was stirred and heated to reflux for 16 hours under N2 atmosphere. The reaction was monitored by LC-MS until the complete conversion of the starting material. The reaction was then cooled to r.t. and filtered. The dark filtrate was concentrated in vacuo and purified by flash column chromatography eluting with DCM:MeOH = 40: 1 to obtain the Intermediate 2 (500mg) as a white solid. LC-MS: m/z 619.5 (M+H)+.
[00530] Step B : 7-methoxy-6-(4-methoxyphenyl)-2, 3 -diphenyl-N-( 1 -((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine
[00531] The Intermediate 2 (500mg, 0.81mmol) and sodium 2-methylpropan-2-olate (155mg, 1.62mmol) in dioxane was stirred at 1 10°C for lh under MW. The mixture was acidified to PH=7 and concentrated to give the crude product which was directly used to the next step without further purification. LC-MS: m/z 605.3 (M+H)~.
[00532] Step C: 5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a] pyrimidin-7(4H)-one
[00533] The Intermediate 3 (300 mg, 0.49mmol) in DCM (5 mL) and TFA (5 mL) was stirred at 60°C for lh. Then the mixture was concentrated to give the crude product which was added into ammonia water (5 mL) and stirred on for lh. The mixture was concentrated to give the desired product.
[00534] 1H NMR (DMSO-d6): δ 13.46 (s, 1H), 12.67 (br. s., 1H), 8.96 (br. s., 1H), 7.70 (br. s., 1H), 7.47 - 7.58 (m, 4H), 7.35 - 7.43 (m, 6H), 7.29 (s, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.00 - 6.09 (m, 1H), 3.84 (s, 3H). LC-MS: m/z 475.5 (M+H)+.
[00535] Compound 183: 5-((5-methoxy-1H-pyrazol-3-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000151_0001
[00536] This compound was prepared according to the procedure for preparing compound 182 by using Intermediate 5 as 5-methoxy-l-(4-methoxybenzyl)-1H-pyrazol-3- amine in step A.
[00537] Step A: A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (441 mg, 1 mmol), 5-methoxy-l-((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 Cs2C03 (650 mg, 2mmol, 2eq.) in 1.4-dioxane (5 mL) was stirred at 1 10 °C for 16 hour under N2 atmosphere. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The crude product was directly used in the next step without further purification. LC-MS: m/z 649.4 (M+H)+ [00538] 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[l,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. The mixture was acidified to PH=7 and concentrated to give the crude product which was purified by silica gel chromatography (DCM: MeOH = 40: 1) to afford 5-((5-methoxy-l-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3 - diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (300mg) as gray solid. LC-MS: m/z 635.3 (M+H)+. [00539] Step C: A solution of 5-((5-methoxy-l-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-3-yl)amino)-6- (4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (100 mg, 0.19 mmol) in 4M HC1 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 NaHC03. The organic phase was separated and washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo to afford the title compound.
[00540] 1H NMR (CHLOROFORM-d): δ 7.49 - 7.66 (m, 3H), 7.45 (br. s., 3H), 7.37 (br. s., 4H), 7.31 (br. s., 4H), 7.06 (br. s., 2H), 5.27 (br. s., 1 H), 3.84 (s, 3H), 3.87 (s, 3H). LC- MS: m/z 505.5 (M+H) +.
[00541] Compound 184: 5-((l H-imidazol-4-yl)amino)-6-(4-methoxyphi
diphenylpyrazolo[ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000152_0001
[00542] Step A: 6-(4-methoxyphenyl)-2,3-diphenyl-5-((l-((2-
(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000153_0001
[00543] A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (300 mg, 0.68 mmol), l-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-amine (289.7 mg, 1.36 mmol), palladium diacetate (30.5 mg, 0.14 mmol), Xantphos (117.8 mg, 0.20 mmol) and cesium carbonate (486.6 mg, 1.49 mmol) in 1,4-dioxane (8 mL) was reacted in microwave reactor at 120 °C for 45 minutes under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered with celite, diluted with DCM (100 mL), washed with saturated NH4CI (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by pre-TLC (DCM:MeOH=40: 1 ) to obtain 7-methoxy-6-(4- methoxyphenyl)-2,3-diphenyl-N-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4- yl)pyrazolo[l,5-a]pyrimidin-5-amine (1 10 mg, yellow solid) and 6-(4-methoxyphenyl)-2,3- diphenyl-5-((l-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)amino)pyrazolo[l ,5- a]pyrimidin-7(4H)-one (40 mg, yellow solid). LC-MS: m/z 605.3 (M+H)+. [00544] Step B: 5-((1H-imidazol-4-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a] pyrimidin-7(4H)-one
Figure imgf000153_0002
[00545] To the solution of 6-(4-methoxyphenyl)-2,3-diphenyl-5-(( 1 -((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)-one (40 mg, 0.1 mmol) in DCM (1.5 mL) cooled to 0 °C was added TFA (1.5 mL) dropwise. Then the mixture was stirred at room temperature for 8h. The mixture was concentrated, and NaOH (1 M) was added to pH>7 to afford pure product.
[00546] 1H NMR (TFA-d): 6 8.54 (s, 1H), 7.41 - 7.67 (m, 11H), 7.37 (d, J = 7.3 Hz,
2H), 7.22 (d, J = 8.6 Hz, 2H), 4.05 (s, 3H). LC-MS: m/z 475.4 (M+H)+. [00547] Compound 185: 5-((2H-l,2,3-triazol-4-yl)amino)-6-(4-methoxyph( diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000154_0001
[00548] 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.
[00549] Step A: A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (50 mg, 0.1 1 mmol), 2-((2-
(trimethylsilyl)ethoxy)methyl)-2H- l,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 Cs2C03 (66.7 mg, 0.283mmol, 2.5eq.) in dioxnae (6 mL) was stirred at 100 °C for 1 hour under N2 atmosphere inmicrowave. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (PE:EA = 2/1) to afford 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 (30 mg) as a white solid. LC-MS: m/z 619.9 (M+H) +.
[00550] Step B: A solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(2-((2- (trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-yl)pyrazolo[l,5-a]pyrimidin-5-amine (1 10 mg, 0.18 mmol) and KO¾u (50 mg, 0.44 mmol) in 1.4-dioxane (5 mL) was stirred at reflux for 2 hours. Solvent and volatile were removed in vacuo to afford 6-(4-methoxyphenyl)-2,3- diphenyl-5-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-yl)amino)pyrazolo[l ,5- a]pyrimidin-7(4H)-one (130 mg) which was directly used in the next step without further purification. LC-MS: m/z 605.9 (M+H)+.
[00551] Step C: A solution of 6-(4-methoxyphenyl)-2,3-diphenyl-5-((2-((2- (trimethylsilyl)ethoxy)-methyl)-2H-l,2,3-triazol-4-yl)amino)pyrazolo[l,5-a]pyrimidin-
7(4H)-one (130 mg, 0.21 mmol) in TFA (10 mL) was stirred at r.t. for 1 hours. Solvent and volatile were removed in vacuo. The residue was basified with NH3.H20 to pH=8 and concentrated to to afford the title compound. [00552] 1H NMR (DMSO-d6): δ 7.44 - 7.62 (m, 5H), 7.24 - 7.43 (m, 9H), 7.04 (d, J =
8.1 Hz, 2H), 3.81 (s, 3H). LC-MS: m z 476.3 (M+H)+.
[00553] Compound 186: 5-((5-amino-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000155_0001
[00554] Step A: N3-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5- a]pyrimidin-5-yl)-l-(4-methoxybenzyl)-1H-pyrazole-3,5-diamine
Figure imgf000155_0002
[00555] A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l ,5-a]-pyrimidine (300 mg, 0.68 mmol), l-(4-methoxybenzyl)-1H- pyrazole-3,5-diamine (296 mg, 1.36 mmol, 2 eq.), Pd(OAc)2 (30 mg, 0.14 mmol, 0.2 eq.), Xantphos (156 mg, 0.27 mmol, 0.4 eq.) and Cs2C03 (441 mg, 1.36mmol, 2eq.) in 1.4-dioxane (20 mL) was stirred at 100 °C for 16 hour under N2 atmosphere. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (DCMMeOH = 50/1) to afford N3-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)-l-(4-methoxybenzyl)-1H-pyrazole-3,5-diamine (220 mg) as a white solid. LC-MS: m/z 625.5 (M+H) +. [00556] Step B: 5-((5-amino-l-(4-methoxybenzyl)-1H-pyrazol-3-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000156_0001
[00557] A solution of N3-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5- a]pyrimidin-5-yl)-l-(4-methoxybenzyl)-1H-pyrazole-3,5-diamine (160 mg, 0.26 mmol) in MeOH (3 mL) was added 4N NaOH in MeOH (4 mL) and stirred at 80 °C for 2 hours.
Solvent and volatile were removed in vacuo. The residue was partitioned between water (30 mL) and EA (50 mL). The EA layer was dried and concentrated to give 5-((5-amino-l-(4- methoxybenzyl)-l H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo [1,5- a]pyrimidin-7(4H)-one (20 mg) as a white solid. LC-MS: m/z 610.5 (M+H)+.
[00558] Step C: 5-{(5-amino-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000156_0002
[00559] To a 5-((5-amino-l-(4-methoxybenzyl)-1H-pyrazol-3-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (20mg, 0.03 mmol) in TFA (2 mL) was added Tf20 (0.5 mL). The resultant mixture was stirred at rt for 4h. Then the mixture was concentrated below 40 °C to give the title compound.
[00560] NMR (DMSO-d6): δ 13.94 (br. s., 1H), 11.27 (br. s., 1H), 8.67 (s, 1H), 7.44
- 7.56 (m, 4H), 7.31 - 7.40 (m, 6H), 7.21 - 7.30 (m, J = 8.3 Hz, 2H), 6.95 - 7.06 (m, J = 8.6 Hz, 2H), 5.25 (br. s., 2H), 5.13 (s, 1H), 3.82 (s, 3H). LC-MS: m/z 490.1 (M+H)+. [00561] Compound 187: 5-((1H-pyrazol-3-yl)amino)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000157_0001
[00562] Step A: 2,3-diphenyl-6-(quinolin-6-yl)-5-((l-((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000157_0002
[00563] A suspension of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,5- a]pyrimidin-6-yl)quinoline (300 mg, 0.65mmol), l-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-3 -amine (166 mg, 0.78 mmol, 1.2 eq.), Pd(OAc)2 (30 mg, 0.13 mmol, 0.2 eq.),
Xantphos (28 mg, 0.13mmol, 0.2 eq.) and K2C03 (147 g, 1.30 mmol, 2.0eq.) in dioxnae (10 mL) was stirred at 90 °C for 4 hour. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (PE EA DCM = 10/1/1) to afford 2,3-diphenyl-6-(quinolin-6-yl)-5-((l-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol -3-yl)amino) pyrazolo [l,5-a]pyrimidin-7(4H)-one (90 mg) as a white solid. LC- MS: m/z 625.9 (M+H)+.
[00564] Step B: 5-((1H-pyrazol-3-yl)amino)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one
Figure imgf000158_0001
[00565] A solution of 2,3-diphenyl-6-(quinolin-6-yl)-5-((l-((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazol -3-yl)amino) pyrazolo [l,5-a]pyrimidin-7(4H)-one (90 mg, 0.14mmol) in TFA (8 mL) was stirred at rt for 1 hour. Solvent and volatile were removed in vacuo. The mixture was basified with ammonia to pH=8 and concentrated to give the crude product to afford the title compound.
[00566] 'H NIVIR (TFA-d): δ 9.32 (br. s., 1H), 9.25 (br. s., 1 H), 8.66 (br. s., 1 H), 8.57 (d, J = 8.3 Hz, 1H), 8.43 (br. s., 1H), 8.25 (br. s., 1H), 7.80 (br. s., 2H), 7.64 (s, 3H), 7.68 (s, 2H), 7.57 (br. s., 4H), 6.27 (br. s., 1H). LC-MS: m/z 496.2 (M+H)+.
[00567] Compound 188: 5-((5-methyl-l H-pyrazol-3-yl)amino)-2,3-diphenyl-6- (quinolin-6-yl)pyrazolo[ 1 , 5-a]pyrimidin-7(4H)-one
Figure imgf000158_0002
[00568] This compound was prepared according to the procedure for preparing compound 182 by using Intermediate 1 as 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l ,5- a]pyrimidin-6-yl)quinoline and Intermediate 5 as 5-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine in step A .
[00569] Step E stoichiometry: 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,5- a]pyrimidin-6-yl)quinoline (200 mg, 0.432 mmol), 5-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (147 mg,0.65 mmol), Pd(OAc)2 (10 mg, 0.043 mmol), xantphos (50 mg, 0.086 mmol), Cs2C03 (281 mg, 0.86 mmo) in dioxane (15 mL) under heating to 110 °C overnight under N2. LC-MS: m/z 640.3 (M+H)+.
[00570] Step F: To a solution of 5-((5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l H- pyrazol-3-yl)amino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (40 mg, 0.63 mmol) in DCM (90 mL) was added TFA (3 mL). The reaction mixture was stirred for 30 mins at room temperature. The mixture was concentrated in vacuo. The residue was basified with ammonia (4 mL) and concentrated to to give the desired product.
[00571] 1H NMR (DMSO-d6): δ 13.65 (br. s., 1H), 12.35 (br. s., 1H), 9.15 (br. s., 1H), 8.94 (d, J = 3.0 Hz, 1H), 8.42 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 8.02 (s, 1H), 7.77 (d, J = 7.0 Hz, 1H), 7.48 - 7.59 (m, 4H), 7.26 - 7.47 (m, 5H), 5.74 (s, 1H), 2.18 (s, 3H). LC- MS: m/z 509.9 (M+Hf.
[00572] Compound 189: 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenyl pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000159_0001
[00573] Step A: 3 -(cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N- (l-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine
Figure imgf000159_0002
[00574] A mixture of 5 -chloro-3 -(cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidine (300 mg, 0.67 mmol), l-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (430.8 mg, 2.02 mmol), palladium diacetate (30.2 mg, 0.13 mmol), Xantphos (1 16.8 mg, 0.20 mmol) and cesium carbonate (438.4 mg, 1.35 mmol) in 1,4-dioxane (6 mL) was reacted in microwave reactor at 100 °C under N2 atmosphere for 45 minutes. After cooling to room temperature, the reaction mixture was diluted with DCM (100 mL), filtered with celite, washed with aqueous NH4CI (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column (petroleum ether/ethyl acetate= 4: 1) to obtain 3- (cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-( 1 -((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine (220 mg) as a yellow solid. LC-MS: m/z 623.3 (M+H) +.
[00575] Step B: 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5-((l-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000160_0001
[00576] The solution of 3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4-methoxyphenyl)-2- phenyl-N-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5- amine (220 mg, 0.35 mmol), sodium tert-butoxide(67.9 mg, 0.71 mmol) and water (3 drops) in 1,4-dioxane (8 mL) was reacted in microwave reactor at 100 °C for 1.5 hours. After cooling to room temperature, the mixture was diluted with DCM (100 mL), washed with water(25 mL) and brine(25 mL), dried over anhydrous sodium sulfate and concentrated. MeOH (4 mL) was added to the residue, and the precipitate was filtered, washed with MeOH (4 mL) to obtain 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5-((l-((2- (trimethylsilyl)ethoxy)methyl)-l H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)-one (130 mg) as a yellow solid. LC-MS: m/z 609.3 (M+H)*.
[00577] Step C: 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenyl pyrazolo[l ,5-a]pyrimidin-7(4H)-one
Figure imgf000161_0001
[00578] The solution of 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5-((l- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)- one (130 mg, 0.21 mmol) in TFA/DCM (2 mL/1 mL) was stirred at room temperature for 4 hours to obtain 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one.
[00579] 1H NMR (DMSO-d6): 6 13.30 (s, 1H), 12.77 (br. s., 1H), 8.90 (s, 1H), 7.72 (d, J = 7.3 Hz, 2H), 7.44 - 7.53 (m, 2H), 7.37 - 7.44 (m, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.14 (s, 0.5H), 6.97 - 7.08 (m, 2.5H), 6.09 (s, 1H), 6.01 (br. s., 1H), 3.80 - 3.88 (m, 3H), 2.38 (br. s., 2H), 2.04 (br. s., 2H), 1.61 - 1.83 (m, 4H). LC-MS: m/z 479.1 (M+H)+.
[00580] Compound 190: 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-l-en-l-yl)-2- phenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000161_0002
[00581] Step A: 3-(cyclohex-l-en-l-yl)-2-phenyl-6-(quinolin-6-yl)-5-((l-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000162_0001
[00582] A suspension of 6-(5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-2- phenylpyrazolo[l,5-a]pyrimidin-6-yl)quinoline (350m g, 0.8 mmol) and l-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (356.4 mg, 1.7 mmol) and Pd(OAc)2 (206.3 mg, 0.9 mmol), Xantphos (579.9 mg, 1.0 mmol) and Cs2C03 (597.7m g, 1.8 mmol) in 1.4-dioxane (8 mL) was stirred and heated to reflux for 12 hours under N2 atmosphere. The reaction was then cooled to r.t. and filtered with celite, diluted with DCM (60 mL), washed with saturated ammonium chloride (30 mL) and brine(30 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by flash column
(DCM:MeOH=25: l) to obtain 3-(cyclohex-l-en-l-yl)-2-phenyl-6-(quinolin-6-yl)-5-((l-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)-one (160 mg) as a brown solid. LC-MS: m/z 630.3 (M+H)+.
[00583] Step B: 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-l-en-l-yl)-2-phenyl-6- (quinolin-6-yl)pyrazolo [l,5-a]pyrimidin-7(4H)-one
Figure imgf000162_0002
[00584] To the solution of 3-(cyclohex-l-en-l-yl)-2-phenyl-6-(quinolin-6-yl)-5-((l- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)- one (60 mg, 0.1 mmol) in DCM (1 mL) cooled to 0 °C was added TFA (2 mL) dropwise. The mixture was then stirred at room temperature for 2h. The mixture was concentrated, and NH4OH (5 mL) was added to obtain 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-l-en-l-yl)-2- phenyl-6-(quinolin-6-yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one.
[00585] 1H NMR (DMSO-d6): δ 13.37 (br. s., 1H), 9.13 (br. s., 1H), 8.88 - 8.98 (m, 1H), 8.41 (d, J = 8.1 Hz, 1 H), 8.09 (d, J = 8.9 Hz, 1H), 8.00 (s, 1H), 7.67 - 7.82 (m, 4H), 7.33 - 7.63 (m, 5H), 6.02 (br. s., 2H), 2.38 (br. s., 2H), 2.09 (br. s., 2H), 1.72 (br. s., 4H). LC-MS: m/z 500.2 (M+H)+. [00586] Compound 191: 3-(cyclohex-l-en-l-yl)-2-phenyl-6-(quinoxalin-6-yl)-5-((l- ((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)- one
Figure imgf000163_0001
[00587] Step A: 3 -(cyclohex- 1 -en- 1 -yl)-7-methoxy-2-phenyl-6-(quinoxalin-6-yl)-N-( 1 - ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine
Figure imgf000163_0002
[00588] A mixture of 6-(5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-2- phenylpyrazolo[l,5-a]pyrimidin-6-yl)quinoxaline (150 mg, 0.32 mmol), l-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (137.0 mg, 0.65 mmol), palladium diacetate (14.5 mg, 0.05 mmol), Xantphos (55.5 mg, 0.10 mmol) and cesium carbonate (209.5 mg, 0.65 mmol) in 1 ,4-dioxane(6 mL) was reacted in microwave reactor at 100 °C under N2 atmosphere for 45 minutes. After cooling to room temperature, the reaction mixture was diluted with DCM (100 mL), filtered with celite, washed with aqueous NH4CI (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-TLC (DCM/MeOH=30: l) to obtain 3 -(cyclohex- 1 -en- l-yl)-7- methoxy-2-phenyl-6-(quinoxalin-6-yl)-N-( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrazol- 3-yl)pyrazolo[l,5-a]pyrimidin-5-amine (80 mg) as a brown solid. LC-MS: m/z 645.3 (M+H)+.
[00589] Step B: 3-(cyclohex-l-en-l-yl)-2-phenyl-6-(quinoxalin-6-yl)-5-((l-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000164_0001
[00590] The solution of 3-(cyclohex-l-en-l-yl)-7-methoxy-2-phenyl-6-(quinoxalin-6- yl)-N-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5- amine (80 mg, 0.1 mmol) and tBυΟΚ (83.5 mg, 0.7 mmol) in dioxane H20(6 mL/1 mL) was stirred at 100 °C for 8h. After cooling to room temperature, the mixture was diluted with DCM (60 mL), washed with water (30 mL) and brine (20 mL), dried over Na2S04 and concentrated to dryness. The residue was purified by prep-TLC (DCM:MeOH=15: l) to afford yellow solid (50 mg). LC-MS: m/z 631.3 (M+H)+.
[00591] Step C: 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-l-en-l-yl)-2-phenyl-6- (quinoxalin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000164_0002
[00592] To the solution of 3-(cyclohex-l-en-l-yl)-2-phenyl-6-(quinoxalin-6-yl)-5-((l- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[l,5-a]pyrimidin-7(4H)- one (50 mg, 0.05 mmol) in DCM (1.5 mL) cooled to 0 °C was added TFA (1.5 mL) dropwise. The mixture was then stirred at room temperature for 2h. The mixture was concentrated, and NH4OH (5 mL) was added to obtain 5-((1H-pyrazol-5-yl)amino)-3- (cyclohex- 1 -en- 1 -yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one.
[00593] 1H NMR (DMSO-d6): δ 13.38 (br. s., 1H), 12.83 (br. s., 1H), 9.29 (br. s., 1H), 8.97 (s, 2H), 8.17 (d, J = 8.5 Hz, 1H), 8.1 1 (d, J = 1.5 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 7.0 Hz, 3H), 7.45 - 7.52 (m, 2H), 7.37 - 7.44 (m, 1H), 6.04 (br. s., 1H), 5.97 (br. s., 1H), 2.39 (br. s., 2H), 2.03 - 2.1 1 (m, 2H), 1.72 (d, J = 4.0 Hz, 5H). LC-MS: m/z 501.2 (M+H)+.
[00594] Compound 192: 6-(4-methoxyphenyl)-2,3-diphenyl-5-(thiazol-4- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000165_0001
[00596] A suspension of Intermediate 1 (880 mg, 2 mmol), NH3/dioxane (0.4N, 15 mL, 6.0 mmol, 3 eq) and tBuBrettphos Pd G3 (540 mg, 0.4 mmol, 0.2 eq), tBuBrettphos (98 mg, 0. 2 mmol, 0.1 eq), t-BuONa (580 mg, 6 mmol, 3.0 eq) and 1.4-dioxane (4 mL) in a 25 mL microwave vial under N2 atmosphere. The vial was sealed and heated for lh at a constant temperature of 50°C. The reaction was then cooled to r.t. and filtered. The dark filtrate was concentrated in vacuum and purified by flash column chromatography silica gel
(DCM/MeOH=20: l) to obtain the Intermediate 2 (400 mg).
[00597] 1H NMR (DMSO-d6): δ 7.47 - 7.56 (m, 2H), 7.29 - 7.43 (m, 10H), 7. 19 - 7.25
(m, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.48 - 5.96 (s, 2H), 4.03 (s, 3H), 3.82 (s, 3H). LC-MS: m/z 423.2 (M+H)+. [00598] Step B: N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5- a]pyrimidin-5-yl)thiazol-4-amine
Figure imgf000166_0001
[00599] A suspension of Intermediate 2 (84 mg, 0.2 mmol), 4-bromothiazole (164 mg, 1.0 mmol, 5 eq), tBuBrettphos Pd G3 (54 mg, 0.04 mmol, 0.2 eq), tBuBrettphos (9.8 mg, 0.02 mmol, 0.1 eq), t-BuONa (58 mg, 0.6 mmol, 3.0 eq) and 1.4-dioxane (2 mL) in a 10 mL microwave vial under N2 atmosphere. The vial was sealed and heated for lh at a constant temperature of 80°C. The reaction was then cooled to r.t. and filtered. The dark filtrate was concentrated in vacuum and purified by flash column chromatography silica gel
(DCM/MeOH=20: 1 ) to give the Intermediate 3 (40 mg) as a white solid. LC-MS: m/z 406.1 (M+H)+.
[00600] Step C: 6-{4-methoxyphenyl)-2,3-diphenyl-5-(thiazol-4-ylamino)pyrazolo[l,5- a]pyrimidin-7(4H)-one
[00601] A mixture of Intermediate 3 (40 mg, 0.08 mmol) in HC1/dioxane (5 mL, IN) was stirred at RT for 1 h. The mixture was then concentrated under reduced pressure to afford the desired product 4.
[00602] 1H NMR (DMSO-d6): δ 9.04 (d, J = 2.4 Hz, 1H), 7.48 - 7.59 (m, 4H), 7.35 -
7.44 (m, 6H), 7.28 - 7.34 (m, J = 8.8 Hz, 2H), 7.12 (d, J = 2.4 Hz, 1H), 7.01 - 7.09 (m, J = 9.2 Hz, 2H), 3.83 (s, 3H). LC-MS: m/z 492.1 (M+H)+.
[00603] Compound 152: 5-([l,2,4]triazolo[l,5-c]pyrimidin-7-ylamino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000167_0001
[00604] This compound was prepared according to the procedures for preparing compound 192, step B-C, starting from 7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-5-amine.
[00605] Step B stoichiometry: 7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-amine (210 mg, 0.5 mmol), 7-chloro-[l,2,4]triazolo[l,5- cjpyrimidine (135 mg, 0.9 mmol), Pd(OAc)2 (62 mg, 0.25 mmol, 0.5 eq.), xantphos ( 310 mg, 0.5 mmol, 1 eq.), and Cs2C03 (500 mg, 1.5 mmol, 3 eq.) in 1,4-dioxane (15 mL) under heating at 100 °C through microwave irradiation for 1 hour under N2 atmosphere. LC-MS: m/z 541.2 (M+H)+.
[00606] Step C: The solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-5-yl)-[ 1 ,2,4]triazolo[ 1 ,5-c]pyrimidin-7-amine ( 100 mg, 0.19 mmol) in HC1- 1,4-dioxane (15 mL) was stirred at r.t. for 3h. Solvent and volatile were removed in vacuo. The residue was dissolved in DCM (5 mL) and treated with saturated NaHC03. The organic phase was separated and washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound.
[00607] 1H NMR (DMSO-d6): δ 12.73 (br. s., 1H), 9.59 (br. s., 1H), 9.33 (br. s., 1H), 8.47 (s, 1H), 7.43 - 7.65 (m, 5H), 7.24 - 7.43 (m, 7H), 7.12 (s., 1H), 6.96 (d, J = 8.2 Hz, 2H), 3.76 (s, 3H). LC-MS: m/z 527.2 (M+H)+. [00608] Compound 193: 5-((1H-pyrazol-3-yl)amino)-6-(4-hydroxyphi diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000168_0001
[00609] To a solution of 5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l ,5-a]pyrimidin-7(4H)-one (Compound 182, 50 mg, 0.1 1 mmol) in anhydrous DCM (5 mL) was added a solution of BBr3 (40 mg, 0.16 mmol, 1.5eq) in DCM (0.5 mL) at -78°C. The reaction mixture was stirred at 0°C for 2h. The suspension was quenched with MeOH at -78°C and extracted with EA. The combined organic phase was washed with water and brine, dried over anhydrous Na2S0 , filtered, and concentrated under reduced pressure to afford the desired product 5-((1H-pyrazol-3-yl)amino)-6-(4- hydroxyphenyl)-2,3-diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one.
[00610] 1H NMR (DMSO-d6): δ 13.45 (s, 1H), 12.66 (s, 1H), 9.48 (s, 1H), 8.89 (s,
1H), 7.70 (s, 1H), 7.51 (d, J = 7.2 Hz, 4H), 7.38 (t, J = 7.6 Hz, 6H), 7.16 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 6.08 (s,l H). LC-MS: m/z 461.7 (M+Hf.
[00611] Compound 194: 3-cyclohexenyl-6-(4-hydroxyphenyl)-2-phenyl-5-(pyrazin-2- ylamino)pyrazolo[ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000168_0002
[00612] A mixture of 3-cyclohexenyl-6-(4-methoxyphenyl)-2-phenyl-5-(pyrazin-2- ylamino) pyrazolo[l,5-a]pyrimidin-7(4H)-one (Compoundd 158, 100 mg, 0.204 mmol) and BBr3 (1M in dichloromethane, 5 mL) was stirred at room temperature for 1 h. The mixture was quenched with methanol at 0 °C to afford 3-cyclohexenyl-6-(4-hydroxyphenyl)-2- phenyl-5-(pyrazin-2-ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one. [00613] 1H NMR (DMSO-d6): δ 13.87 (s, 1 H), 9.52 (s, 1 H), 9.28 (s, 1 H), 8.62 (s, 1
H), 8.24 (d, J=2.75 Hz, 1 H), 8.20 (s, 1 H), 7.73 (d, J=7.02 Hz, 2 H), 7.39 - 7.52 (m, 3 H), 7.20 (d, J=8.54 Hz, 2 H), 6.85 (d, J=8.24 Hz, 2 H), 6.04 (br. s., 1 H), 2.33 (br. s., 2 H), 2.04 (br. s., 2 H), 1.59 - 1.77 (m, 4 H). LC-MS: m/z 477.2 (M+H)+.
[00614] Compound 195: 5-((l H-l,2,4-triazol-3-yl)amino)-6-(4-hydroxyphenyl)-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000169_0001
[00615] Intermediate 1 was prepared according to the procedure for preparing compound 101 (step A-E) by using Intermediate 9 as l-((2-(trimethylsilyl)ethoxy)methyl)- 1H-l ,2,4-triazol-3 -amine in step E. LC-MS: m/z 620.3 (M+H)".
[00616] Step A: To the solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N- (l-((2-(trimethylsilyl)ethoxy)methyl)-1H-l,2,4-triazol-3-yl)pyrazolo[l,5-a]pyrimidin-5- amine 1 (80 mg, 0.1 mmol) in DCM (2 mL) cooled to 0 °C was added BBr3 (1.0 M in DCM, 1.5 mL) dropwise . The mixture was then stirred at 0 °C for 2h. The reaction was quenched by carefully adding MeOH and concentrated in vacuo to give the product.
[00617] 1H NMR (DMSO-d6) : δ 14.10 (br. s., 1H), 13.12 (br. s., 1H), 9.51 (br. s., 1H), 9.00 (br. s., 1 H), 8.54 (br. s., 1 H), 7.46 - 7.59 (m, 4H), 7.29 - 7.45 (m, 6H), 7.18 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H). LC-MS: m/z 462.3 (M+H)+.
[00618] Compound 196: 6-(2-methylbenzo[d]thiazol-6-yl)-2,3-diphenyl-5-(pyridin-2- ylamino)pyrazolo[l,5-a] pyrimidin-7(4H)-one
Figure imgf000170_0001
[00619] Step A: dimethyl 2-(2-methylbenzo[d]thiazol-6-yl)malonate
Figure imgf000170_0002
[00620] A mixture of 6-bromo-2-methylbenzo[d]thiazole (4.5 g, 19.7mmol), dimethyl malonate (5.2g, 39.4mmol), Pd(OAc)2 (882mg, 3.94mmol), t-BuMePhos (2.45g, 7.88mmol), and K3P04 (9.5g, 45.3mmol) in 100 mL of anhydrous toluene was stirred at 80°C under N2 atmosphere for 16h. The mixture was filtered and concentrated. The residue was purified by silica gel column (PE:EA=5: 1) to afford Intermediate 2 as white solid (3.6g).
[00621] 1H NMR (CHLOROFORM-d): δ 7.82 - 8.04 (m, 2H), 7.48 (dd, J = 8.3, 1.9 Hz, 1H), 4.79 (s, 1H), 3.79 (s, 7H), 2.86 (s, 3H). LC-MS: m/z 280.5 (M+H)+. [00622] Step B: 5-hydroxy-6-(2-methylbenzo[d]thiazol-6-yl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin -7(4H)-one
Figure imgf000171_0001
[00623] A mixture of dimethyl 2-(2-methylbenzo[d]thiazol-6-yl)malonate (3 g, 10.7mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (2.1g, 8.9mmol) in TEA (20 mL) was stirred at 150°C for 4h. The mixture was then cooled to r.t. and filtered. The precipitates were suspended in a mixed solution of 2 mL THF and 20 mL HC1 (1 M) and stirred at r.t. for 0.5h. The solid was filtered and washed with EA (10 mL) to give the desired product as a white solid (2.7g) which was directly used to the next step without further purification. LC-MS: m/z 451.2 (M+H)+.
[00624] Step C: 6-(5,7-dichloro-2,3-diphenylpyrazolo[l,5-a]pyrimidin-6-yl)-2- methylbenzo[d] thiazole
Figure imgf000171_0002
[00625] A mixture of Intermediate 3 (2.7g, 6mmol) in POC13 (20 mL) was stirred at 120°C overnight in a sealed tube. The mixture was concentrated. The residue was basified with NaHC03 solution to PH=7, extracted with DCM (10 mL X 3), dried, concentrated and purified by silica gel column (PE:EA =3: 1) to give Intermediate 4 (2.1g) as yellow solid. LC- MS: m/z 487.3 (M+H)*.
[00626] Step D: 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,5-a]pyrimidin-6-yl)-2- methylbenzo[d] thiazole
Figure imgf000171_0003
[00627] The Intermediate 4 (2. lg, 4.3mmol) was dissolved in DCM (10 mL) and MeOH (20 mL) at 0°C. NaOMe (464mg, 8.6mmol) in MeOH (5 mL) was added dropwise and stirred on for 16h at r.t. The mixture was concentrated. The residue was purified by silica gel column (PE:EA = 5: 1) to give the desired product 5 (1.6g) as white solid. [00628] 1H NMR (CHLOROFORM-d): δ 8.07 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.66 (dd, J = 7.0, 2.4 Hz, 2H), 7.54 (d, J = 7.0 Hz, 2H), 7.48 (dd, J = 8.5, 1.5 Hz, 1H), 7.35 - 7.43 (m, 5H), 7.32 (d, J = 7.3 Hz, 1H), 4.19 (s, 3H), 2.90 (s, 3H). LC-MS: m/z 483.6 (M+H)+. [00629] Step E: 6-(2-methylbenzo[d]thiazol-6-yl)-2,3-diphenyl-5-(pyridin-2- ylamino)pyrazolo[l,5-a] pyrimidin-7(4H)-one
Figure imgf000172_0001
[00630] A suspension of Intermediate 5 (482 g, 1 mmol), pyrazin-2-amine (94mg, 1 mmol), Pd(OAc)2 (42.2 mg, 0.2 mmol), Xantphos (23. lmg, 0.4 mmol) and Cs2C03 (652m g, 2 mmol) in 1.4-dioxane (10 mL) was stirred and heated to reflux for 16 hours under N2 atmosphere. The reaction was monitored by LC-MS until the complete conversion of the starting material. The reaction mixture was then cooled to r.t. and filtered. The dark filtrate was concentrated in vacuo to obtain the title compound 6. [00631] 1H NMR (CHLOROFORM-d): δ 15.25 (s, 1H), 8.05 (d, J = 4.0 Hz, 1H), 7.92 - 8.01 (m, 2H), 7.60 - 7.70 (m, 4H), 7.45 - 7.53 (m, 5H), 7.39 (dd, J = 6.1, 2.4 Hz, 1H), 7.28 (d, J = 4.0 Hz, 3H), 6.97 (dd, J = 7.2, 5.0 Hz, 2H), 2.71 (s, 3H). LC-MS: m/z 527.5 (M+H) +.
[00632] Compound 197: 6-(3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-2,3-diphenyl- 5-(pyridin-2-ylamino) pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000173_0001
[00633] Step A: 6-bromo-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine
Figure imgf000173_0002
[00634] To the mixture of 6-bromo-3,4-dihydro-2H-benzo[b][l,4]oxazine (10g, 47mmol) and K2C03 (13g, 94mmol) in DMF (100 mL). was added l-(chloromethyl)-4- methoxybenzene (8.8g, 56mmol). The mixture was stirred at r.t. for 16h. The mixture was poured into water (30 mL) and extracted with EA (30M1 X 3). The combined organic layers were dried, concentrated and purified by silica gel column (PE:EA=5: 1) to give the desired product (1 lg) as a white solid.
[00635]1H NMR (CHLOROFORM-d): δ 7.12 - 7.20 (m, J = 8.5 Hz, 2H), 6.84 - 6.90 (m, 2H), 6.80 (d, J = 2. 1 Hz, 1H), 6.61 - 6.73 (m, 2H), 4.32 (s, 2H), 4.15 - 4.20 (m, 2H), 3.76 - 3.80 (m, 3H), 3.22 - 3.30 (m, 2H). LC-MS: m/z 334.5 (M+H)+.
[00636] Step B: dimethyl 2-(4-(4-methoxybenzyl)-3,4-dihydro-2H- benzo[b][l ,4]oxazin-6-yl) malonate
Figure imgf000174_0001
[00637] A mixture of Intermediate 2 (5.5 g, 16.5mmol), dimethyl malonate (2.6g, 19.8mmol) Pd(OAc)2 (370mg, 1.65mmol), t-BuMePhos(1.96g, 3.63mmol), and K3P04(8g, 37.95mmol) in 30 mL of anhydrous toluene was stirred at 80°C under N2 atmosphere for 16h. The mixture was filtered and concentrated. The residue was purified by silica gel column (PE:EA=4: 1) to afford Intermediate 3 (5.7g) as a wihte solid. [00638] 'H NMR (CHLOROFORM-d): 6 7.18 - 7.24 (m, J = 8.9 Hz, 2H), 6.83 - 6.89
(m, J = 8.5 Hz, 2H), 6.73 - 6.79 (m, 2H), 6.62 (d, J = 10.1 Hz, 1H), 4.48 (s, 1H), 4.38 (s, 2H), 4.20 - 4.26 (m, 2H), 3.79 (s, 3H), 3.69 (s, 6H), 3.24 - 3.31 (m, 2H). LC-MS: m/z 386.5 (M+H)+.
[00639] Step C: 5-hydroxy-6-(4-(4-methoxybenzyl)-3,4-dihydro-2H- benzo[b][l,4]oxazin-6-yl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000174_0002
[00640] A mixture of Intermediate 3 (1.5 g, 3.8mmol) and 3,4-diphenyl-1H-pyrazol-5- amine (760mg, 3.2mmol) in TEA (20 mL) was stirred at 150°C for 4h. The mixture was then cooled to r.t. and filtered. The filter cake was suspended in a mixed solution of 2 mL THF and 20 mL HC1 (1M) and stirred at r.t. for 0.5h. The precipitate was filtered and washed with EA (10 mL) to give the product (1.3g) as a white solid which was directly used to the next step without further purification. LC-MS: m/z 557.2 (M+H)+.
[00641] Step D: 6-(5,7-dichloro-2,3-diphenylpyrazolo[l,5-a]pyrimidin-6-yl)-3,4- dihydro-2H-benzo[b] [l,4]oxazine
Figure imgf000175_0001
[00642] The Intermediate 4 (1.3g, 2.3mmol) was dissolved in POCh (15 mL) and stirred at 120°C overnight in a sealed tube. The mixture was concentrated and basified with NaHC03 solution to PH=7. The resultant mixture was extracted with DCM (10 mL X3), dried, and concentrated to give crude Intermediate 5 (2.1g) as a yellow solid. LC-MS: m/z 473.3 (M+H)+.
[00643] Step E: 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,5-a]pyrimidin-6-yl)- 3,4-dihydro -2H-benzo[b][ 1 ,4]oxazine
Figure imgf000175_0002
[00644] The Intermediate 5 (500mg, 1 06mmol) was dissolved in DCM (5 mL) and MeOH ( 10 mL) at 0°C. NaOMe ( 1 14mg, 2.1 1 mmol) in MeOH (5 mL) was added dropwise and stirred on for 16h at r.t. The mixture was concentrated and purified by silica gel column (PE:EA = 6: 1) to give the desired product (230mg) as a white solid.
[00645] 1H NMR (CHLOROFORM-d): δ 7.64 - 7.71 (m, 2H), 7.51 - 7.59 (m, 2H), 7.36 - 7.44 (m, 5H), 7.32 (d, J = 7.3 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.64 - 6.75 (m, 2H), 4.32 - 4.40 (m, 2H), 4.15 - 4.19 (m, 3H), 3.48 - 3.55 (m, 2H). LC-MS: m/z 469.4 (M+H) +.
[00646] Step F: 6-(3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-7-methoxy-2,3- diphenyl-N- (pyridin-2-yl)pyrazolo[l,5-a]pyrimidin-5-amine
Figure imgf000176_0001
[00647] A suspension of Intermediate 6 (200mg, 0.43 mmol), pyrazin-2-amine (48mg, 0.51 mmol), Pd(OAc)2 (9.6 mg, 0.043 mmol), Xantphos (49.6mg, 0.086 mmol) and Cs2C03 (280m g, 0.86 mmol) in 1 4-dioxane (10 mL) was heated to reflux for 16 hours under N2 atmosphere. The reaction was monitored by LC-MS until the complete conversion of the starting material. The reaction mixture was then cooled to r.t. and filtered. The dark filtrate was concentrated in vacuo and purified by flash column chromatography eluting with DCMMeOH = 40: 1 to obtain the Intermediate 7 (120mg) as a white solid.
[00648] NMR (CHLOROFORM-d): δ 8.79 (d, J = 8.5 Hz, 1H), 8.18 (dd, J = 4.9, 0.9 Hz, 1H), 7.61 - 7.71 (m, 5H), 7.48 (s, 1H), 7.30 - 7.44 (m, 6H), 6.89 - 6.97 (m, 2H), 6.63 6.75 (m, 2H), 4.34 (t, J = 4.3 Hz, 2H), 4.08 - 4.11 (m, 3H), 3.50 (d, J = 4.3 Hz, 2H). LC-MS: m/z 527.2 (M+H)+.
[00649] Step G: 6-(3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-2,3-diphenyl-5-(pyridin 2-ylamino) pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000176_0002
[00650] A solution of Intermediate 7 (50m g, 0.095 mmol) in HC1 (5 mL, 4M in 1.4- dioxane) was stirred at room temperature for 16 h. The mixture was concentrated, basified with ammonia (5 mL, 7M in MeOH) and concentrated in vacuo to give the title compound 8.
[00651] 'H NMR (DMSO-d6): δ 15.73 (s, 1H), 8.92 (s, 1H), 8.03 (d, J = 4.0 Hz, 1H),
7.78 (br. s., 1H), 7.51 - 7.60 (m, 4H), 7.32 - 7.47 (m, 7H), 7.09 (d, J = 5.8 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.62 (d, J = 1.8 Hz, 1H), 6.46 - 6.54 (m, 1H), 5.85 (br. s., 1H), 4.19 (br. s., 2H), 3.34-3.35(m, 2H). LC-MS: m/z 513.5 (M+H)+. [00652] Compound 198: 6-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-2,3- diphenyl-5-(pyridin-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000177_0001
[00653] Step A: 7-methoxy-6-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)- 2,3-diphenyl-N- (pyridin-2-yl)pyrazolo[l,5-a]pyrimidin-5-amine
Figure imgf000177_0002
[00654] 6-(3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-7-methoxy-2,3-diphenyl-N- (pyridin-2-yl)pyrazolo[l ,5-a]pyrimidin-5-amine (50mg, 0.095mmol) in THF (10 mL) was cooled to 0°C, HCOOH (5.2mg, 0.114mmol) was added and stirred for 5mins. BH3 THF (0.19 mL, 1 M) was added dropwise at 0°C, and the mixture was slowly warmed to r.t. and stirred on for 4h. The reaction was quenched by careful adding NaHC03 solution. The resultant mixture was extracted with DCM (10 mL X 3), dried, and concentrated. The residue was purified by silica gel column (PE:EA = 3: 1 ) to afford Intermediate 2 (30mg) as a light yellow solid. [00655] 1H NMR (CHLOROFORM-d): δ 8.83 (d, J = 8.2 Hz, 1 H), 8.17 (d, J = 4.3 Hz, 1H), 7.59 - 7.73 (m, 5H), 7.35 - 7.43 (m, 5H), 7.26 - 7.30 (m, 1H), 6.93 (d, J = 7.9 Hz, 2H), 6.64 - 6.75 (m, 2H), 4.39 (t, J = 4.1 Hz, 2H), 4.07 - 4.12 (m, 3H), 3.37 (d, J = 4.3 Hz, 2H), 2.90 (s, 3H). LC-MS: m/z 541.3 (M+H)÷.
[00656] Step B: 6-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-2,3-diphenyl- 5-(pyridin-2- ylamino)pyrazolo[l ,5-a]pyrimidin-7(4H)-one
Figure imgf000178_0001
[00657] The Intermediate 2 (30mg, 0.056mmol) in HC1 (10 mL, 4M in dioxane) was stirred at r.t. for 2h. The mixture was concentrated, basified with ammonia (5 mL, 7M in MeOH) and concentrated in vacuo to afford the title compound 3. [00658] 1H NMR (CHLOROFORM-d): δ 8.07 (d, J = 4.6 Hz, 1 H), 7.76 (br. s., 2H), 7.65 (br. s., 1H), 7.45 - 7.52 (m, 4H), 7.31 - 7.41 (m, 5H), 6.98 (br. s., 1H), 6.81 - 6.92 (m, 2H), 6.62 - 6.76 (m, 2H), 4.37 (br. s., 2H), 3.35 (br. s., 2H), 2.92 (s, 3H). LC-MS: m/z 527.5 (M+H)+.
[00659] Compound 199: N-ethyl-5-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)amino)-l ,3,4-oxadiazole-2-carboxamide
Figure imgf000178_0002
[00660] Step A: To a solution of 1 (20 mg, mmol) in THF (2 mL) was added ethylamine (aq. 0.1 mL ) in a sealed tube, and the mixture was stirred at 50 °C overnight to afford the desired product 2.
[00661] 1H NMR (DMSO-d6): 6 12.67 (br. s., 1H), 8.63 - 8.92 (m, 2H), 8.28 - 8.34 (m, 2H), 8.03 (s, 1H), 7.92 (s, 2H), 7.49 - 7.55 (m, 2H), 7.41 - 7.49 (m, 3H), 7.31 - 7.40 (m, 6H), 3.18 (dt, J = 13.2, 7.2 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H). LC-MS: m/z 569.0 (M+H)+. [00662] Compound 200: (E)-2-hydroxy-l-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl- 4,7-dihydropyrazolo[l,5-a]pyrimidin-5-yl)guanidine
Figure imgf000179_0001
[00664] A mixture of Intermediate 1 (441 mg, 1 mmol), NH2CN (210 mg, 5.0 mmol, 5 eq), t-BuBrettphos Pd G3 (170 mg, 0.2 mmol, 0.2 eq), t-BuBrettphos (49 mg, 0.1 mmol, 0.1 eq) and t-BuONa (288 mg, 3.0 mmol, 3.0 eq) in 1.4-dioxane (12 mL) in a sealed microwave vial (25 mL) under N2 atmosphere was heated to 80°Cfor lh. The reaction mixture was then cooled to r.t. and filtered. The dark filtrate was concentrated in vacuo and purified by flash column chromatography sillica gel (DCM/MeOH= 100: 1) to obtain Intermediate 2 (180 mg). LC-MS: m/z 448.1 (M+H)÷
[00665] Step B: (E)-2-hydroxy-l-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l ,5-a]pyrimidin-5-yl)guanidine
Figure imgf000180_0001
[00666] To a mixture of Intermediate 2 (100 mg, 0.22 mmol) and DIPEA (145 mg, 1.12 mmol, 5.0 eq) in EtOH (5 mL) was added Hydroxylamine hydrochloride (47 mg, 0.67 mmol, 3.0 eq). Then the reaction mixture was stirred at r.t. overnight. The mixture was partitioned between EA and H20. The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the desired
Intermediate 3 (30 mg). LC-MS: m/z 481.1 (M+H)+.
[00667] Step C : (E)-2-hydroxy- 1 -(6-(4-methoxyphenyl)-7-oxo-2,3 -diphenyl-4, 7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)guanidine
Figure imgf000180_0002
[00668] A mixture of Intermediate 3 (30 mg, 0.06 mmol) in HC1/dioxane (5 mL, IN) was stirred at r.t. for 1 h. The mixture was then concentrated under reduced pressure to afford the desired compound 4. [00669] 1H NMR (DMSO-d6): δ 7.23 - 7.52 (m, 12H), 7.01 (d, J = 9.2 Hz, 2H), 3.81 (s,
3H). LC-MS: m/z 467.2 (M+H)+.
[00670] Compound 201: (S)-(3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[ 1 , 5-a]pyrimidin-5-yl)amino)- 1 H-pyrazol- 1 -yl)methy 1 2-amino-3 - methylbutanoate
Figure imgf000181_0001
[00671] Step A: (S)-chloromethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate
[00672] To a solution of Intermediate 1 (1.4 g, 6.6 mmol) in DCM/H20 (10 mL/10 mL) were added chloromethyl sulfochloridate 6 (1.3 g, 7.9 mmol, 1.2 eq.), NaHC03 (4 eq) and tetrabutylammonium hydrogensulfate (0.1 eq ). The mixture was stirred at r.t. overnight. The organic phase was separated, and the water phase was extracted with DCM (3*10 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired product 2 as a colorless oil (1.5 g). LC-MS: m/z 266.2 (M+H)+.
[00673] Step B: (S)-(3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[ 1 ,5-a]pyrimidin-5-yl)amino)- 1 H-pyrazol- 1 -yl)methyl 2-((tert- butoxycarbonyl)amino)-3-methylbutanoate
[00674] To a solution of Intermediate 3 (300 mg, mmol) in DMF (20 mL) was added sodium hydride (3 eq.) at 0 °C. (S)-chloromethyl 2-((tert-butoxycarbonyl)amino)-3- methylbutanoate 2 (3 eq.) was added dropwise after the mixture was stirred at 0 °C for 30 min. Then the mixture was stirred at r.t. overnight. The mixture was poured into water (100 mL) and extracted with DCM (3* 20 mL), the combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired product 4 as a white solid. (240 mg) [00675] 1H NMR (DMSO-d6): δ 13.07 (s, 1H), 9.1 1 (s, 1H), 7.95 (s, 1H), 7.83 (d, J =
2.8 Hz, 1H), 7.49 - 7.57 (m, 4H), 7.36 - 7.42 (m, 6H), 7.28 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 6.14 (d, J = 2.8 Hz, 1H), 5.97 (d, J = 10.8 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 3.83 (s, 3H), 3.76 - 3.81 (m, 1H), 1.84 (dt, J = 13.2, 6.8 Hz, 1H), 1.35 (s, 9H), 0.74 (d, J = 6.8 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H). LC-MS: m/z 704.1 (M+H)+
[00676] Step C: (S)-(3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l ,5-a]pyrimidin-5-yl)amino)-1H-pyrazol-l -yl)methyl 2-amino-3- methylbutanoate
[00677] To a solution of Intermediate 4 (220 mg, 0.31 mmol) in DCM (1 mL) was added HC1-dixane (4 mol/L, 5 mL) at 0 °C. The mixture was stirred at r.t. for lh. The white precipitate was filtered off and mixed with DCM (5 mL) and aq. NaHC03 solution. The organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the desired product 5.
[00678] 1H NMR (DMSO-d6): δ 8.14 (s, 1H), 7.75 (br. s., 1H), 7.51 (d, J = 6.2 Hz, 2H), 7.45 (br. s., 2H), 7.34 (br. s., 6H), 7.27 (d, J = 8.4 Hz, 2H), 7.10 - 7.23 (m, 1 H), 7.03 (d, J = 8.4 Hz, 2H), 5.87 - 6.02 (m, 2H), 3.81 (s, 3H), 3.52 - 3.69 (m, 1H), 1.79 - 2.05 (m, 1H), 0.78 (br. s., 6H). LC-MS: m/z 604.0 (M+H)+.
[00679] Compound 203: 3-(cyclohex- 1 -en- 1 -yl)-6-(4-methoxyphenyl)-2-(pyridin-2- yl)-5-(pyridin-2-ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000182_0001
Figure imgf000183_0001
[00681] To a solution of methyl picolinate (13 g, 95 mmol) and acetonitrile (5.8 g, 142 mmol) in THF (150 ml) was added slowly NaHDMS (2 mol/L, 71 ml, 142 mmol) at 0 °C. Then the reaction mixture was stirred at 0 °C for 0.5h and allowed to warm up to room temperature for 2h. The reaction was quenched with water, adjusted with HC1 (2 mol/L) to pH = 7, and extracted with DCM (100 ml*3). The combined organic layers were washed with brine , dried over anhydrous sodium sulfate, and concentrated in vacuo to give 3-oxo-3- (pyridin-2-yl)propanenitrile (12 g, 87 % yield) as a dark brown solid.
[00682] 1H NMR (CHLOROFORM-d) 6 : 8.70 (dd, J = 4.8, 0.6 Hz, 1H), 8.03 - 8.17 (m, 1H), 7.92 (td, J = 7.8, 1.6 Hz, 1H), 7.58 (ddd, J = 7.6, 4.8, 1.4 Hz, 1H), 4.40 (s, 2H). LC- MS: m/z 147.1 (M+Hf. [00683] Step B: l-{4-methoxybenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine
Figure imgf000183_0002
[00684] To a solution of 3-oxo-3-(pyridin-2-yl)propanenitrile (10 g, 68 mmol) in EtOH
(80 ml) was added (4-methoxybenzyl)hydrazine hydrochloride (15.5 g, 82 mmol, 1.2 eq) and triethylamine (13.8 g, 137 mmol, 2 eq.). The reaction mixture was refluxed for 2h under N2 protection. Then the mixture was evaporated in vacuo. The residue was dissolved in EA (100 mL), washed with water, and extracted with EA (100 ml*2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product as a yellow solid. The crude product was suspended in t-BuOMe (100 mL), stirred for 0.5h and filtered off to give l-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H- pyrazol-5-amine as a pale yellow solid (15.1 g, 79% yield). [00685] 1H NMR (DMSO-d6) δ : 8.50 (d, J = 4.8 Hz, 1H), 7.77 - 7.83 (m, 1H), 7.73
(dd, J = 7.6, 1.6 Hz, 1H), 7.1 1 - 7.26 (m, 3H), 6.84 - 6.90 (m, 2H), 5.89 (s, 1H), 5.41 (s, 2H), 5.12 (s, 2H), 3.71 (s, 3H). LC-MS: m/z 281.2 (M+Hf.
[00686] Step C: 4-(cyclohex-l-en-l-yl)-l-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H- pyrazol-5-amine
Figure imgf000184_0001
[00687] To a solution of l-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine (15.0 g, 54 mmol) in acetic acid (100 mL) was added cyclohexanone (5.3 g, 54 mmol, leq.). The mixture was stirred at 90°C for lh. Then another 1 eq. of cyclohexanone was added, and the mixture was stirred at 90°C for lh. Solvent was removed in vacuo. The resultant residue was dissolved in EA (100 mL) and treated with saturated NaHC03. The organic phase was separated, and the water phase was extracted with EA ( 00 mL*2). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/DCM=l/20) to give 4-(cyclohex-l-en- l-yl)-l-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine as a brown solid (6.8 g, 35% yield).
[00688] 1H NMR (DMSO-d6) δ : 8.49 (d, J = 4.4 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.65
(d, J = 7.8 Hz, 1H), 7.07 - 7.29 (m, 3H), 6.88 (d, J = 8.8 Hz, 2H), 5.47 (br. s., 1H), 5.14 (s, 2H), 4.94 (br. s., 2H), 3.71 (s, 3H), 2.12 (br. s., 2H), 1.98 (br. s., 2H), 1.59 (br. s., 4H). LC- MS: m/z 361.2 (M+H)' [00689] Step D: 4-(cyclohex-l-en-l-yl)-3-(pyridin-2-yl)-1H -pyrazol-5-amine
Figure imgf000185_0001
[00690] The solution of 4-(cyclohex- 1 -en- 1 -yl)- 1 -(4-methoxybenzy l)-3 -(pyridin-2-yl)- 1H-pyrazol-5-amine (6.8 g, 19 mmol) in TFA/(CF3S02)20 (30 mL/10 mL) was stirred at 50°C for lh. The solvent was removed in vacuo. The residue was dissolved in EA (50 mL) and treated with saturated NaHC03. The organic phase was separated, and the water phase was extracted with EA (50 mL*2). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was dissolved in
NH3/MeOH (7 mol/L, 50 mL), and hydrazine hydrate (g, mmol, 2 eq.) was added. The mixture was stirred at r.t. overnight. Solvent was removed in vacuo and the residue was purified by flash chromatography (MeOH/DCM 1/20) to give 4-(cyclohex-l-en-l-yl)-3- (pyridin-2-yl)-1H-pyrazol-5-amine (3.6 g, 79% yield) as a brown solid. LC-MS: m/z 241.2 (M+H)+.
[00691] Step E: 3-(cyclohex-l-en-l-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-(pyridin-2- yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one
Figure imgf000185_0002
[00692] A solution of 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (3.6 g, 15 mmol) and dimethyl 2-(4-methoxyphenyl)malonate (7.2 g, 30 mmol, 2 eq.) in xylene (50 ml) was refluxed for 8h. The reaction mixture was cooled to room temperature. The precipitate was filtered off and washed with MeOH to give 3-(cyclohex-l-en-l-yl)-5-hydroxy-6-(4- methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (4.0 g, 64% yield) as a yellow solid. LC-MS: m/z 415.2 (M+H)+.
[00693] Step F: 5,7-dichloro-3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-(pyridin- 2-yl)pyrazolo[ 1 , 5-a]pyrimidine
Figure imgf000186_0001
[00694] The solution of 3-(cyclohex- 1 -en- 1 -yl)-5-hydroxy-6-(4-methoxyphenyl)-2- (pyridin-2-yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (4.0 g, 10 mmol) in POCb (30 ml) in a sealed tube was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (50 mL) and poured into ice-water (100 mL). The mixture was adjusted to PH=7 by adding saturated NaHC03 solution. The organic phase was separated, and the water phase was extracted with DCM (50 ml*2). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting PE/EA=1 : 1) to give 5,7-dichloro-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[l,5-a]pyrimidine (2.8 g, 64% yield) as a yellow solid. LC-MS: m/z 451.1, 453.1 (M+H) +.
[00695] Step G: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4-methoxyphenyl)-2- (pyridin-2-yl)pyrazolo[l,5-a]pyrimidine
Figure imgf000186_0002
[00696] To a solution of 5,7-dichloro-3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2- (pyridin-2-yl)pyrazolo[l,5-a]pyrimidine (2.8 g, 6 mmol) in DCM (50 ml) was added NaOMe (6.2 mL, 5.0 mol/L in MeOH) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and poured into ice-water (100 mL). The organic phase was separated, and the water phase was extracted with DCM (50 ml*2). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo to give 5-chloro-3-(cyclohex-l-en- l-yl)-7-methoxy-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[l,5-a]pyrimidine (2.7 g, 97% yield) as a yellow solid.
[00697] 1H NMR (DMSO-d6) δ : 8.70 (dt, J = 4.8, 1.2 Hz, 1H), 7.91 - 7.96 (m, 2H), 7.42 - 7.47 (m, 1 H), 7.39 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 5.82 (br. s., 1 H), 4.12 (s, 3H), 3.83 (s, 3H), 2.09 - 2.24 (m, 4H), 1.56 - 1.75 (m, 4H). LC-MS: m/z 447.2, 449.2 (M+H)+.
[00698] Step H: 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5- (pyridin-2-ylamino) pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000187_0001
[00699] A suspension of 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[l,5-a]pyrimidine (300 mg, 0.67 mmol), pyridine- amine (126 mg, 1.34 mmol, 2 eq ), Pd(OAc)2 (90 mg, 0.40 mmol, 0.6 eq.), Xantphos (232 mg, 0.40 mmol, 0.6 eq.) and Cs2C03 (437 mg, 1.34 mmol, 2.0 eq.) in 1.4-dioxane (10 mL) was stirred at 130 °C through microwave irradiation for 1.5 hour under N2 atmosphere. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford the title compound.
[00700] 'H NIVIR (DMSO-d6) δ : 8.67 (d, J = 8.2 Hz, 1 H), 8.42 (br. s., 1H), 8.12 (d, J = 4.4 Hz, 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.60 - 7.69 (m, 1H), 7.41 - 7.52 (m, 1H), 7.24 - 7.39 (m, 3H), 7.20 (s, 1H), 7.08 (d, J = 7.6 Hz, 2H), 6.89 - 6.98 (m, 1H), 5.97 (br. s., 1 H), 3.82 (s, 3H), 2.20 (br. s., 4H), 1.66 (br. s., 4H). LC-MS: m/z 491.2 (M+H)+.
[00701] 3,4-diphenyl-l H-pyrazol-5-amine
Figure imgf000187_0002
[00702] Step A: 3-oxo-2,3-diphenylpropanenitrile
[00703] To a solution of 2-phenylacetonitrile 1 (10 g, 85.3 mmol) and methyl benzoate 4 (12.2 g, 90 mmol) in THF (100 mL) was added sodium hydride (6.8 g, 170 mmol) at 0 °C. After addition, the mixture was stirred at room temperature overnight. The mixture was quenched with 1 M hydrochloric acid to pH 6. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was added petroleum ether (60 mL) and the turbid liquid was stirred at room temperature for 3h. The precipitate was collected by filtration and dried in vacuo to afford 3-oxo-2,3- diphenylpropanenitrile 2 (15.3 g) as a white solid. LC-MS: m/z 222.1 (M+H)+. [00704] Step B: 3,4-diphenyl-1H-pyrazol-5-amine
[00705] A mixture of 3-oxo-2, 3-diphenylpropanenitrile (15 g, 67.8 mmol), hydrazine hydrate (7.6 g, 150 mmol), acetic acid (15 mL) and the ethanol (60 mL) was heated to reflux overnight. The mixture was evaporated to remove ethanol and the residue was adjusted to pH 8 with saturated solution of sodium bicarbonate at 0 °C. The mixture was extracted with ethyl acetate (80 mL) twice, and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The resulting solid was recrystallized from 2-methoxy-2-methylpropane to give 3, 4-diphenyl-/H-pyrazol-5-amine (16 g) as a white solid. LC-MS: m/z 236.1 (M+H)*.
[00706] 3-(2-fluorophenyl)-4-phenyl- 1 H-pyrazol-5-amine
Figure imgf000188_0001
[00707] This compound was prepared according to the procedures for preparing intermediate 3,4-diphenyl-1H-pyrazol-5-amine by using compound 4 as methyl 2- fluorobenzoate. [00708] Step A stoichiometry: 2-phenylacetonitrile (5 g, 42.6 mmol), methyl 2- fluorobenzoate (6.9 g, 45 mmol) and sodium hydride (3.4 g, 85 mmol) in THF (60 mL) under cooling at 0 °C. LC-MS: m/z 240.1 (M+H)+.
[00709] Step B stoichiometry: 3-(2-fluorophenyl)-3-oxo-2-phenylpropanenitrile (3.25 g, 13.6 mmol), hydrazine hydrate (1.5 g, 30 mmol), acetic acid (3 mL) and the ethanol (15 mL) under heating to reflux overnight. LC-MS: m/z 254.2 (M+H)†.
[00710] 3-phenyl-4-((2H io)piperidin- 1 -yl)- 1 H-pyrazol-5-amine
Figure imgf000189_0001
4
[00711] Step A: 2-((2H10)piperidin-l-yl)acetonitrile
[00712] The mixture of piperidine-dio (100 mg, 1.04 mmol, 1 eq ), 2-bromoacetonitrile (150 mg, 1.2 eq.), and K2C03 (276 mg, 2 eq.) in CH3CN (5 mL) was stirred at 70 °C overnight. Then the mixture was cooled to r.t. and filtered, the filtrate was poured into water (30 mL) and extracted with EA (10 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford Intermediate 2 which was directly used to the next step without further purification. LC-MS: m/z 135.0 (M+H)+. [00713] Step B: 3-oxo-3-phenyl-2-((2H10)piperidin-l-yl)propanenitrile
[00714] To a mixture of Intermediate 2 (1 15 mg, 0.86 mmol, 1 eq.) and methyl benzoate (140 mg, 1.03 mmol, 1.2 eq.) in THF (8 mL) was added NaHMDS ( 2M in THF, 0.52 mL, 1.2 eq.) at 0 °C. The mixture was stirred at r.t. overnight. The reaction mixture was diluted with EA (10 mL) and quenched with saturated NH4CI. The organic phase was separated, washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired Intermediate 3 as a white solid. LC-MS: m/z 239.1 (M+H)+.
[00715] Step C: 3-phenyl-4-((2H10)piperidin-l-yl)-1H-pyrazol-5-amine
[00716] The mixture of Intermediate 3 (169 mg, 0.71 mmol, 1 eq.) and hydrazine (71 mg, 1.42 mmol, 2 eq.) in EtOH/AcOH (5/1,5 mL/1 mL) was refluxed for 5h. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (5 mL) and neutralized with 10% NaHC03. The organic phase was separated, and the the water phase was extracted with EA (5 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired product 4 as a white solid.
[00717] 1H NMR (DMSO-d6): δ 1 1.52 (br. s., 1 H), 7.85 (d, J = 7.6 Hz, 2H), 7.38 (t, J 7.6 Hz, 2H), 7.22 - 7.29 (m, 1H), 4.35 (br. s., 2H). LC-MS: m/z 253.1 (M+H) +.
[00718] 3-phenyl-4-(piperidin- 1 -yl)-1H-pyrazol-5-amine
Figure imgf000190_0001
[00719] This compound was prepared according to the procedure for preparing intermediate 3-phenyl-4-((2H10)piperidin-l-yl)-1H-pyrazol-5-amine, step B-C, starting from 2-(piperidin-l-yl)acetonitrile.
[00720] Step B stoichiometry: 2-(piperidin-l-yl)acetonitrile (7.8 g, 62 mmol, 1 eq.), methyl benzoate (9.4g, 68 mmol, 1.1 eq.) and NaHMDS (2 M in THF, 46 mL, 1.5 eq.) in THF (300 mL) at 0 °C-r.t..
[00721] Step C stoichiometry: 3-oxo-3-phenyl-2-(piperidin-l-yl)propanenitrile (5g, 21.902mmol) and hydrazine hydrate (3.3g, 65.706mmol) in EtOH/AcOH (5/1, 30 mL/6 mL) under heating to reflux for 16h under N2 protection.
[00722] 1H NMR (DMSO-d6): 1.52 (br. s., 1H), 7.82 (br. s., 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.25 (d, J = 7.3 Hz, 1 H), 4.28 (br. s., 2H), 2.88 (t, J = 5.0 Hz, 3H), 1.55 (br. s., 3H), 1.46 (d, J = 4.0 Hz, 2H). LC-MS: m/z 243.2 (M+H)+.
[00723] 4-(4,4-difluoropiperidin- 1 -yl)-3 -phenyl- 1 H-pyrazol-5-amine
Figure imgf000190_0002
[00724] This compound was prepared according to the procedure for preparing intermediate 3-phenyl-4-((2Hi0)piperidin-l -yl)-1H-pyrazol-5-amine, step A-C, starting from 4,4-difluoropiperidine hydrochloride salt. Step A stoichiometry: 4,4-difluoropiperidine hydrochloride salt (1.0 g, 6.3 mmol, 1 eq.), 2-bromoacetonitrile (761 mg, 6.3mmol, 1 eq.), triethylamine (2.2 g, 22.2 mmol, 3.5 eq.) in THF (30 mL) under heating at 60 °C overnight. LC-MS: m/z 161.0 (M+H)^. Step B stoichiometry: 2-(4,4-difluoropiperidin-l-yl)acetonitrile (500 mg, 3.1 mmol, 1 eq.), methyl benzoate (467 mg, 3.4 mmol, 1.1 eq.) and NaHMDS (2 M in THF, 2.3 mL, 1.5 eq.) in THF (30 mL) at 0 °C-r.t.. Step C stoichiometry: 2-(4,4- difluoropiperidin-l-yl)-3-oxo-3-phenylpropanenitrile (380 mg, 1.44 mmol,l eq.) and hydrazine hydrate (144 mg, 2.88 mmol, 2 eq.) in EtOH/AcOH (5/1, 15 mL/3 mL) under heating to reflux for 6h. LC-MS: m/z 279.1 (M+H)\
[00725] 4-(cyclohex- 1 -en- 1 -yl)-3 -phenyl- 1 H-pyrazol-5-amine
Figure imgf000191_0001
[00726] Step A: 4-(cyclohex-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine
[00727] A suspension of amino-pyrazole (10 g, 62.9 mmol) and cyclohexanone (13 mL, 126 mmol) and 4-methylbenzenesulfonic acid hydrate (1 1.4 g, 62.9 mmol) in 1.4- dioxane (50 mL) was stirred for 8 hours at 90°C. The precipitate was collected by filtration and washed with acetonitrile to afford crude product which was recrystallized from methanol to afford 4-cyclohexenyl-3-phenyl-l H-pyrazol-5-amine (4.18 g) as white solid.
[00728]1H NMR (Chloroform-d): δ 7.51 (d, J= 6.98 Hz, 2H), 7.31 - 7.43 (m, 3H), 5.81 (br. s., 1H), 2. 19 (br. s , 2H), 1.98 (d, J = 1.88 Hz, 2H), 1.59 - 1.70 (m, 4H). LC-MS: m/z 240.1 (M+H)+.
[00729] 4-(cyclohex- 1 -en- 1 -yl)-3 -phenyl- 1 H-pyrazol-5-amine
Figure imgf000192_0001
[00730] Step A: l-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-5-amine
[00731] A mixture of 3-oxo-3-phenylpropanenitrile (14.5 g, 0.1 mmol), (4- methoxybenzyl)hydrazine (15.2 g, 0.1 mmol), acetic acid (40 mL) and ethanol (150 mL) was heated to 85 °C overnight. The mixture was cooled to room temperature and poured to water (300 mL). The mixture was basified by adding aqueous sodium hydroxide at 0 °C to pH 7-8. The resulting suspension was filtrated. The filter cake was washed with water, dried in vacuo to afford l -(4- methoxybenzyl)-3-phenyl-/H-pyrazol-5-amine (14.4 g) as a white solid. [00732]1H NMR (Chloroform-d): δ 7.79 (d, J= 8.8 Hz, 2 H), 7.38 - 7.42 (m, 2 H),
7.28- 7.38 (m, 1 H), 7.19 (d, J= 8.8 Hz, 2 H), 6.89 (d, J= 8.8 Hz, 2 H), 5.91 (s, 1 H), 5.24 (s, 2 H), 3.81 (s, 3 H). LC-MS: m/z 280.1 (M+H .
[00733] Step B: 4-(cyclohex-l-en-l-yl)-l-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-5- amine [00734] A mixture of l -(4-methoxybenzyl)-3-phenyl-/H-pyrazol-5-amine (9 g, 32.5 mmol) and cyclohexanone (6.4 g, 65.0 mmol) in acetic acid (50 mL) was stirred at room temperature for 16 h. The mixture was poured to water (150 mL). Aqueous sodium hydroxide was added into the mixture at 0 °C to pH 7-8. The resulting mixture was extracted with ethyl acetate (60 mL) three times. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified with column chromatography (ethyl acetate: petroleum ether=l :3) on silica gel to afford 4-cyclohexenyl- 1 - (4- methoxybenzyl)-3-phenyl-H/-pyrazol-5-amine (6.5 g) as a white solid. LC-MS: m/z 360.2 (M+H)+.
[00735] Step C: 4-{cyclohex-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine [00736] A mixture of 4-cyclohexenyl-l-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-5- amine (6.0 g, 16.7 mmol) and trifluoromethanesulfonic anhydride (12 mL) in trifluoroacetic acid (36 mL) was stirred at 30 °C for 2 h. The mixture was poured to water (50 mL).
Aqueous sodium hydroxide was added into the mixture at 0 °C to pH 7-8. The mixture was extracted with ethyl acetate (60 mL) three times. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified with column chromatography (methanol:dichloromrthane=l :20) on silica gel to afford 4-cyclohexenyl-3-phenyl-7H- pyrazol-5- amine (2.6 g) as a white solid.
[00737] 1H NMR (Chloroform-d) 6 7.51 (d, J= 6.98 Hz, 2 H), 7.31 - 7.43 (m, 3H), 5.81 (br. s., 1H), 2.19 (br. s., 2H), 1.98 (d, J= 1.88 Hz, 2H), 1.59 - 1.70 (m, 4H). LC-MS: m/z 240.1 (M+H)+.
[00738] 4-methoxy- 1 , 3 , 5 -triazin-2-amine
Figure imgf000193_0001
[00739] Step A: 4-chloro-l,3,5-triazin-2-amine
[00740] 2,4-dichloro-l,3,5-triazine (8.0 g, 53.3 mmol) was added in portions to 200 mL of NH4OH at -20 °C. After addition, the mixture was stirred at -20 °C for l Omins, and then filtered, washed with water and dried to give 4-chloro-l,3,5-triazin-2-amine (5.7 g) as a yellow solid which was used to the next step without further purification. LC-MS: m/z 131.1 (M+H)+.
[00741] Step B: 4-methoxy- 1,3, 5 -triazin-2-amine
[00742] To the solution of 4-chloro-l,3,5-triazin-2-amine (5.7 g, 44.0 mmol) in MeOH (100 mL) cooled to 0 °C was added CH3ONa (35.2 mL, 176.1 mmol, 5.0 M) dropwise. Then the mixture was stirred at room temperature for lh. Half of the solvent was removed by vacuum, and the precipitate was filtered, washed with water to afford 4-methoxy-l,3,5- triazin-2-amine as a white solid (1.0 g). LC-MS: m/z 127.1 (M+H)+.
[00743] N2-methy 1- 1,3,5 -triazine-2, 4-di amine
Figure imgf000194_0002
[00744] Step A: The mixture of 4-chloro-l,3,5-triazin-2-amine (200 mg, 1.5 mmol) in MeNH2/THF (2mol/L, 10 mL) was stirred at r.t. for 10 min. The mixture was concentrated in vacuo, and the residue was purified by flash chromatography (DCM/MeOH 10/1) to afford the desired product as a white solid. (106 mg). LC-MS: m/z 125.9 (M+H)+.
Figure imgf000194_0001
[00746] Step A: 3-nitro-l-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [00747] A mixture of compound 1 (lOg, 0.089mmol) and Cs2C03 (1.9g, 0.116mmol) in DMF (10 mL) was stirred at r.t. for 16h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL X 3). The organic layer was dried, concentrated and purified by silica gel chromatography (PE:EA = 3: 1) to afford compound 2 (9g) as a white solid.
[00748] 1H NMR (400 MHz, CHLOROFORM-d): δ 0.01 - 0.03 (m, 9 H) 0.91 - 0.99 (m, 2 H) 3.59 - 3.66 (m, 2 H) 5.53 (s, 2 H) 7.01 (d, J=2.69 Hz, 1 H) 7.69 (d,J=2.69 Hz, 1 H). LC-MS: m/z 244.5 (M+H) +.
[00749] Step B: l-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine
[00750] The compound 2 (9g, 0.037mmol) and Pd/C (0.9g) in MeOH (30 mL) was stirred at r.t. for 16h under H2 atmosphere. The mixture was filtered and concentrated to give the crude product which was directly used to the next step without further purification. LC- MS: m/z 214.5 (M+Hf.
[00751] 2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-amine
Figure imgf000195_0001
[00752] This compound was prepared according to the procedures for preparing 1 -((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine by using intermediate 1 as 4-nitro-2H- 1,2,3-triazole.
lH NMR (DMSO-d*): δ 7.00 (s, 1H), 5.35 (s, 2H), 5.13 (s, 2H), 3.49 - 3.58 (m, 2H), 0.69 - 0.89 (m, 2H), -0.04 (s, 9H). LC-MS: m/z 215.2 (M+H)+.
[00753] 1 -(4-methoxybenzyl)- 1 H-pyrazole-3 , 5-diamine
Figure imgf000195_0002
[00754] Step A: The mixture of malononitrile (1.9g, 0.028mmol) and (4- methoxybenzyl)hydrazine hydrochloride (5.4g, 0.028mmol) in EtOH (20 mL) and TEA (3 mL) was heated to reflux for 16h. The mixture was concentrated to dryness. The residue was suspended in water and extracted with EA (10 mL X3). The combined organic layers were dried and concentrated to give the crude product which was directly used to the next step without further purification. LC-MS : m/z 219.5 (M+H)+.
[00755] Methyl 2-(2,3-dihydrobenzo[b][l ,4]dioxin-6-yl)acetate
Figure imgf000195_0003
[00756] To a solution of methyl 2-(3,4-dihydroxyphenyl)acetate (4 g, 0.022 mol) in DMF (20 mL) were added 1,2-dibromoethane (4.09 g, 0.022 mol) and K2C03 (6 g,
0.044mol). The reaction mixture was heated to 80 °C for 4h. The reaction mixture was then poured into water, extracted with ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting PE/EA=10: 1) to give the desired product (1.3 g). [00757] 1H NMR (DMSO-d6): δ 6.73 - 6.81 (m, 3H), 6.65 - 6.73 (m, 1H), 4.16 - 4.27
(m, 5H), 3.55 (s, 3H). LC-MS: m/z 223. 1 (M+H)+.
[00758] 3-(tert-butyldimethylsilyloxy)pyridin-2-amine
Figure imgf000196_0002
[00759] Step A: To a mixture of 2-aminopyridin-3-ol (220 mg, 2 mmol), /H-imidazole (204 mg, 3 mmol) in chloroform (20 mL) was added tert-butylchlorodimethylsilane (302 mg, 2 mmol) slowly at room temperature. Then the reaction mixture was stirred at room temperature overnight. The mixture was evaporated to dryness. The residue was purified by column chromatography on silica gel (methanol:dichloromethane=l :50) to afford 3-(teri- butyl- dimethylsilyloxy) pyridin-2-amine (360 mg) as a white solid. LC-MS m/z: 225.1 (M+H)+.
[00760] 5-((tert-butyldimethylsilyl)oxy)pyridin-2-amine
Figure imgf000196_0003
[00761] This compound was prepared according to 3-(tert- butyldimethylsilyloxy)pyridin-2-amine by using Intermediate 1 as 6-aminopyridin-3-ol in step A. LC-MS m/z: 225.1 (M+H)+.
[00762] General procedure
Figure imgf000196_0001
[00763] Step A: methyl 3-oxo-2-(quinolin-6-yl)butanoate
Figure imgf000197_0001
[00764] To a solution of methyl 2-(quinolin-6-yl)acetate 1 (148 g, 0.736 mol, 1.0 eq.) in THF (1 L) was added LDA (1.5 M in THF, 589 mL, 0.883 mol, 1.2 eq.) dropwise at -30 ~ -35 °C. The mixture was stirred at -30 ~ -35 °C for 30 min and acetyl chloride (56 mL, 0.788 mol, 1.05 eq.) was added dropwise. Then the mixture was stirred at rt for 6h. The mixture was poured slowly to saturated NH4CI and extracted with EA (3*350 mL). The combined organic phase was washed with brine, dried over anhydrous MgS04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired Intermediate 2 as a brown oil (150 g, 84% yield ).
[00765] Step B: Compound 204: 5-methyl-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000197_0002
[00766] The mixture of Intermediate 2 (150 g) and 4 (1.0 eq) in AcOH (700 mL) was stirred at 90 °C for 4h. A solid was filtered off and washed with E A (3 * 100 mL) to afford the desired product 3.
[00767] 1H NMR (DMSO-d6) 5 : 12.06 (s, 1H), 8.95 (dd, J = 4.2, 1.7 Hz, 1H), 8.40 (d, J = 7.5 Hz, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.76 (dd, J = 8.6, 1.9 Hz, 1H), 7.54 - 7.59 (m, 1H), 7.24 - 7.51 (m, 10H), 2.25 (s, 3H). LC-MS: m/z 429.3 (M+H)+. [00768] Compound 205: 2-(2-fluorophenyl)-5-methyl-3-phenyl-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000198_0001
[00769] This compound was prepared according to General procedure 2a by using Intermediate 4 as 3-(2-fluorophenyl)-4-phenyl-1H -pyrazol-5-amine e in step B.
[00770] Step B: The solution of 3-(2-fluorophenyl)-4-phenyl-1H-pyrazol-5-amine (50 mg, 0.20 mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (62.4 mg, 0.26 mmol) in AcOH (2 ml) was stirred at 100 °C for 1 hour. After cooling to room temperature, saturated NaHC03 was added till pH>7. The mixture was extracted with DCM (50 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by prep-TLC (DCM:MeOH=25: l) to obtain 2-(2-fluorophenyl)-5-methyl-3- phenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00771] 1H NMR (DMSO-d6) δ : 12.19 (br. s., 1H), 8.95 (dd, J = 4.2, 1.7 Hz, 1H), 8.41
(d, J = 7.5 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.76 (dd, J = 8.9, 1.9 Hz, 1H), 7.58 (dd, J = 8.2, 4.2 Hz, 1 H), 7.45 - 7.54 (m, 2H), 7.36 - 7.43 (m, 2H), 7.24 - 7.35 (m, 4H), 7.16 - 7.24 (m, 1H), 2.28 (s, 3H). LC-MS: m/z 447. 1 (M+H)+.
[00772] Compound 206: 5-methyl-2-phenyl-3-(piperidin-l -yl)-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000198_0002
[00773] This compound was prepared according to General procedure 2a by using Intermediate 4 as 3-phenyl-4-(piperidin-l-yl)-1H-pyrazol-5-amine in step B.
[00774] Step B: methyl 3-oxo-2-(quinolin-6-yl)butanoate (200 mg, 0.82 mmol) and 5- phenyl-4-(piperidin-l -yl)-1H-pyrazol-3-amine (200 mg, 0.82 mmol) were dissolved in AcOH (8 ml). The mixture was stirred at 95'C for 10 min. After cooling to room temperature, the mixture was poured into water and extracted with EA (50 ml*3). The EA layer was concentrated to dryness. The residue was basified with NaHC03 aq. solution and filtered. The filter cake was purified by prep-HPLC to give the title compound. [00775]1H NMR (DMSO-d6) δ : 1 1.52 (br. s., 1H), 8.94 (dd, J = 4.2, 1.7 Hz, 1H), 8.34 - 8.44 (m, 1H), 8.02 - 8.19 (m, 3H), 7.95 (d, J = 1.9 Hz, 1H), 7.74 (dd, J = 8.9, 1.9 Hz, 1H), 7.58 (dd, J = 8.2, 4.2 Hz, 1H), 7.31 - 7.51 (m, 3H), 3.1 1 (t, J = 4.8 Hz, 4H), 2.34 (s, 3H), 1.68 (br. s., 4H), 1.50 - 1.64 (m, 2H). LC-MS: m/z 436.4 (M+H)+.
[00776] Compound 207: 3-(4,4-difluoropiperidin-l-yl)-5-methyl-2-phenyl-6- (quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000199_0001
[00777] This compound was prepared according to General procedure 2a by using Intermediate 4 as 4-(4,4~difluoropiperidin-l-yl)-3-phenyl-1H-pyrazol-5-amine in step B.
[00778] Step B: The solution of 4-(4,4-difluoropiperidin-l-yl)-3-phenyl-1H-pyrazol-5- amine (200 mg, 0.72 mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (262.2 mg, 1.08 mmol) in AcOH (3 ml) was stirred at 100 °C for 1 hour. After cooling to room temperature, saturated NaHC03 was added till pH>7. The mixture was extracted with DCM (60 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by prep-TLC (DCM:MeOH=25: 1) to obtain 3-(4,4- difluoropiperidin-l-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)- one.
[00779] 1H NMR (DMSO-d6) δ : 11.71 (s, 1H), 8.94 (d, J = 2.7 Hz, 1H), 8.39 (d, J =
7.8 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 7.0 Hz, 2H), 7.94 (s, 1H), 7.74 (dd, J = 8.7, 2.0 Hz, 1H), 7.58 (dd, J = 8.2, 4.2 Hz, 1H), 7.52 (t, J = 7.4 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 3.24 (m, 4H), 2.33 (s, 3H), 2.04 - 2.22 (m, 4H) . LC-MS: m/z 472.2 (M+H)+. [00780] Compound 208: 3-(cyclohex-l-en-l-yl)-5-methyl-2-phenyl-6-(quinoxalin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000200_0001
[00781] This compound was prepared according to General procedure 2a by using Intermediate 1 as methyl 2-(quinoxalin-6-yl)acetate in step A and Intermediate 4 as 4- (cyclohex-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine in step B.
[00782] Step B: The solution of 4-(cyclohex-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine (60 mg, 0.25 mmol) and methyl 3-oxo-2-(quinoxalin-6-yl)butanoate (79.6 mg, 0.33 mmol) in AcOH (5 ml) was stirred at 100 °C for 1 hour. After cooling to room temperature, solvent was removed by vacuum, and saturated NaHCC was added till pH>7. The mixture was diluted with DCM (60 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by prep-TLC (DCM:MeOH=25: 1) to obtain 3-(cyclohex-l-en-l-yl)-5-methyl-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one. [00783] 1H NMR (DMSO-d6) 6 : 11.90 (br. s., 1H), 9.00 (br. s., 2H), 7.48 - 8.26 (m, 8H), 5.89 (br. s., 1H), 2.10-2.52 (m, 7H), 1.72 (br. s., 4H). LC-MS: m/z 434.1 (M+H)+.
[00784] Compound 209: 6-(4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[l ,5- a]pyrimidin-7(4H)-one
Figure imgf000200_0002
[00785] This compound was prepared according to General procedure 2a by using Intermediate 1 as methyl 2-(4-methoxyphenyl)acetate in step A and Intermediate 4 as 3, 4- diphenyl-/H-pyrazol-5-amine in step B. [00786] Step B: The mixture of methyl 2-(4-methoxyphenyl)-3-oxobutanoate (300 mg, 1.3 mmol) and 3, 4-diphenyl-/H-pyrazol-5-amine (206 mg, 0.85 mmol) in AcOH (15 mL) was stirred at 100°C for 2hto afford the title compound.
[00787]1H NMR (DMSO-d6) δ : 11.88 (s, 1H), 7.37 - 7.49 (m, 5H), 7.28 - 7.36 (m, 5H), 7.21 - 7.28 (m, 2H), 6.95 - 7.05 (m, 2H), 3.80 (s, 3H), 2.17 (s, 3H). LC-MS: m/z 408.0 (M+H)+.
[00788] Compound 210: 6-(4-ethoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000201_0001
[00789] This compound was prepared according to General procedure 2a by using Intermediate 1 as methyl 2-(4-ethoxyphenyl)acetate in step A and Intermediate 4 as 3, 4- diphenyl-/H-pyrazol-5-amine in step B.
[00790] Step B: The solution of 3,4-diphenyl-1H-pyrazol-5-amine (148 mg, 0.63 mmol) and methyl 2-(4-ethoxyphenyl)-3-oxobutanoate (150 mg, 0.63 mmol) in AcOH (5 ml) was stirred at 100 °C for 4 hour. After cooling to room temperature, the reaction mixture was filtered and washed with EA (6 mL) and MeOH (0.5 mL) to obtain title compound.
[00791] 1H NMR (DMSO-d6) δ: 1 1.88 (s, 1H), 7.36 - 7.49 (m, 5H), 7.27 - 7.36 (m,
5H), 7.19 - 7.26 (m, 2H), 6.93 - 7.02 (m , 2H), 4.07 (q, J = 7.0 Hz, 2H), 2.17 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). LC-MS: m/z 422.0 (M+H)+.
Compound 211: 6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-5-methyl-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000202_0001
[00792] This compound was prepared according to General procedure 2a, step A-B, starting from methyl 2-(2,3-dihydrobenzo[b][l ,4]dioxin-6-yl)acetate in step A.
[00793] Step A: methyl 2-(2,3-dihydrobenzo|b| [l,4]dioxin-6-yl)-3-oxobutanoate
[00794] To a solution of methyl 2-(2,3-dihydrobenzo[b][l ,4]dioxin-6-yl)acetate (1.3g, 6.3 mmol) in THF (15 ml) was added slowly LDA (3.2 ml, 2mmol/ml in THF) at -30 °C. Then acetyl chloride (730 mg, 9.5 mmol) was added slowly. The reaction mixture was stirred for 30 mins at -30 °C and allowed to room temperature for lh. The mixture was poured into water, extracted over ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated to give the crude product (1.3 g, crude) as a yellow liquid, which was used directly to the next step without further purification.
[00795] Step B: 6-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)-5-methyl-2,3- diphenyIpyrazolo[l,5-a]pyrimidin-7(4H)-one
[00796] A solution of methyl 2-(2,3-dihydrobenzo[b][l ,4]dioxin-6-yl)-3-oxobutanoate (crude 400 mg) and 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.86 mmol) in AcOH (10 ml) was heated to 120 °C overnight. The reaction mixture was cooled to room temperature to give the desired product 6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00797] 1H NMR (DMSO-d6) δ: 1 1.88 (s, 1H), 7.38 - 7.52 (m, 5H), 7.24 - 7.38 (m,
5H), 6.91 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.77 (d, J = 8.2, 2.0 Hz, 1H), 4.29 (s, 4H), 2.19 (s, 3H). LC-MS: m/z 435.9 (M+H)+. [00798] Compound 212: 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-5-methyl-2- phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000203_0001
[00799] This compound was prepared according to General procedure 2a by using Intermediate 1 as methyl 2-(4-methoxyphenyl)acetate in step A and Intermediate 4 as 4- (cyclohex-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine in step B.
[00800] Step B: The solution of 4-(cyclohex-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine (200 mg, 0.84 mmol) and methyl 2-(4-methoxyphenyl)-3-oxobutanoate (371.5 mg, 1.67 mmol) in AcOH (5 ml) was stirred at 100 °C for 1 hour. After cooling to room temperature, solvent was removed by vacuum, and saturated NaHC03 was added to pH>7 to obtain 3- (cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[l,5-a]pyrimidin- 7(4H)-one.
[00801] 1H NMR (DMSO-d6) δ : 11.62 (s, 1H), 7.72 - 7.85 (m, 2H), 7.34 - 7.55 (m,
3H), 7.19 - 7.31 (m, 2H), 6.93 - 7.07 (m, 2H), 5.84 (br. s., 1H), 3.81 (s, 3H), 2.17 - 2.32 (m, 5H), 1.98 - 2.12 (m, 2H), 1.70 (br. s., 4H). LC-MS: m/z 412.3 (M+H)+.
[00802] Compound 213: 3-(4,4-difluoropiperidin-l-yl)-6-(4-methoxyphenyl)-5- methyl-2-phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000203_0002
[00803] This compound was prepared according to General procedure 2a by using Intermediate 1 as methyl 2-(4-methoxyphenyl)acetate in step A and Intermediate 4 as 4- (4,4-difluoropiperidin-l-yl)-3-phenyl-1H-pyrazol-5-amine in step B. [00804] Step B: The mixture of 4-(4,4-difluoropiperidin-l-yl)-3-phenyl-1H-pyrazol-5- amine (321 mg, 1.4 mmol) and methyl 2-(4-methoxyphenyl)-3-oxobutanoate (200 mg, 0.72 mmol) in AcOH (20 mL) was stirred at 120°C for 2h to afford the title compound.
[00805]1H NMR (CHLOROFORM-d) δ : 7.51 (br. s., 5H), 7.24 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 3.85 (s, 3H), 3.69 (br. s., 4H), 3.18 (br. s.,2H), 2.37 (s., 3H), 2.18 (s, 2H). LC-MS: m/z 451.3 (M+H)+.
[00806] General procedure 2b:
Figure imgf000204_0001
[00807] Step A: methyl 3-oxo-2-(quinolin-6-yl)butanoate
Figure imgf000204_0002
[00808] To a solution of methyl 2-(quinolin-6-yl)acetate (14.8 g, 73.6mmol, 1.0 eq.) in THF (lOOmL) was added LDA (1.5 M in THF, 60 mL, 88.3 mmol, 1.2 eq.) dropwise at -30 ~ -35°C. The mixture was stirred at -30 ~ -35 'C for 30 min and acetyl chloride (5.6 mL, 78.8 mmol, 1.05 eq.) was added dropwise. Then the mixture was stirred at r.t. for 6h. The mixture was poured slowly to saturated NH4CI and extracted with EA (3X30 mL). The combined organic phase was washed with brine, dried over anhydrous MgS04 and concentrated in vacuo to get the title Intermediate 2 which was directly used to the next step without further purification.
[00809] Step B: 5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)- one
Figure imgf000205_0001
[00810] A suspension of methyl 3 -oxo-2-(quinolin-6-yl)butanoate (1.98g, 8.17mmol) and 3-phenyl-1H-pyrazol-5-amine (lg, 6.28mmol) in 1,4-dioxane (10ml) and AcOH (2ml) was refluxed for 16 hours under N2 protection. The mixture was cooled to the room temperature, concentrated, and neutralized with saturated sodium hydrogen carbonate solution to adjust to pH 7. The precipitates were collected by filtration, washed with petroleum ether and dried to give the Intermediate 3 (600mg, 27% yield).
[00811] 1H NMR (DMSO-d6) δ : 12.56 (br. s., 1 H), 8.94 (dd, J=4.25, 1.61 Hz, 1 H),
8.39 (d, J=7.63 Hz, 1 H), 7.99 - 8.10 (m, 3 H), 7.96 (d, J=1.76 Hz, 1 H), 7.75 (dd, J=8.66,1.91 Hz, 1 H), 7.57 (dd, J=8.36, 4.25 Hz, 1 H), 7.46 - 7.53 (m, 2 H), 7.40 - 7.46 (m, 1 H), 6.67 (s, 1 H), 2.26 (s, 3 H).
[00812] Step C: 5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2- (trimethylsilyI)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000205_0002
[00813] To a solution of Intermediate 3 (500mg, 1.42 mmol) and K2C03 (393 mg, 2.84mmol) in DMF (15 ml) at ambient temperature was added (2-
(chloromethoxy)ethyl)trimethylsilane (473 mg, 2.84mmol) dropwise. The mixture was stirred for 10 min at ambient temperature and heated to 100°C overnight. The mixture was cooled to the room temperature, washed with saturated sodium hydrogen carbonate solution, and extracted with DCM (2X30 mL). The combined organic layers were washed with brine
(3X20 ml), dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by silica gel column eluting with DCM/MeOH (30/1 to 10/1) to obtain the
Intermediate 4 as a white solid (350 g, 51% yield).
[00814] Step D: 3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000206_0001
[0081S] To a solution of Intermediate 4 (350mg, 0.725 mmol) in DCM (5 ml) at ambient temperature was added NBS (163mg, 0.92mmol). The resultant mixture was stirred for 3 hours at ambient temperature, washed with water, and extracted with DCM (20 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by prep-TLC
(DCM/MeOH=20/l) to obtain the Intermediate 5 (250mg, 61% yield). LC-MS: m/z 561.1 (M+H)+.
[00816] The following compounds were prepared according to General procedure 2b, step E and step F, starting from intermediate 5.
[00817] Compound 215: 3-(cyclopent-l-en-l-yl)-5-methyl-2-phenyl-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000206_0002
[00818] Step E stoichiometry: 3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (150 mg, 0.27 mmol), 2- (cyclopent-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (155.0 mg, 0.80 mmol), Bis(triphenylphosphine)palladium(II) chloride (19.2 mg, 0.03 mmol) and cesium carbonate (174.8 mg, 0.53 mmol) in 1 ,4-dioxane H20 (11 mL, 10: 1 ) under heating at 100 °C for 1 hour through microwave irradiation under nitrogen atmosphere. LC-MS: m/z 549.3 (M+H)+.
[00819] Step F: To the solution of 3-(cyclopent- 1 -en- 1 -yl)-5-methyl-2-phenyl-6- (quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (50 mg, 0.09 mmol) in DCM (0.5 mL)cooled at 0 °C was added TFA (1 mL) dropwise. Then the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and
NH4OH added till pH>7. The mixture was diluted with DCM (60 mL), washed with water (15 mL) and brine(15 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 3-(cyclopent- 1 -en- 1 -yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[ 1 , 5-a]pyrimidin-7(4H)- one.
[00820] 1H NMR (DMSO-d6) δ : 11.76 (br. s., 1H), 8.85 - 9.08 (m, 1 H), 8.39 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.68 - 7.79 (m, 3H), 7.57 (dd, J = 7.9, 4.2 Hz, 1H), 7.39 - 7.52 (m, 3H), 5.94 (br. s., 1H), 2.54 (br. s., 2H), 2.43 (br. s., 2H), 2.30 (s, 3H), 1.88 - 2.11 (m, 2H) . LC-MS: m z 419.2 (M+H)+.
[00821] Compound 216: 3-(cyclohex-l-en-l-yl)-5-methyl-2-phenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000207_0001
[00822] Step E stoichiometry: 3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (200 mg, 0.36 mmol), 2- (cyclohex-l -en-l -yl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (149.8 mg, 0.72 mmol), bis(triphenylphosphine)palladium(II) chloride (56.2 mg, 0.08 mmol) and cesium carbonate (234.6 mg, 0.72 mmol) in 1 ,4-dioxane/H20 (16 mL, 10: 1) under heating at 100 °C for 1 hour through microwave irradiation under nitrogen atmosphere. LC-MS: m/z 563.3 (M+H)^.
[00823] Step F: To the solution of 3-(cyclohex-l-en-l-yl)-5-methyl-2-phenyl-6- (quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (180 mg, 0.32 mmol) in DCM (0.5 mL) cooled to 0 °C was added TFA (2 mL) dropwise. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated, and NH4OH added till pH>7. The mixture was diluted with DCM (120 mL), washed with water (30 mL) and brine(30 mL), dried over anhydrous sodium sulfate and concentrated to dryness to obtain 3-(cyclohex-l-en-l-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one. [00824] 1H NMR (DMSO-d6) δ : 11.80 (s, 1H), 8.94 (dd, J = 4.0, 1.6 Hz, 1 H), 8.39 (d,
J = 7.3 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.78 - 7.84 (m, 2H), 7.74 (dd, J = 8.9, 1.9 Hz, 1H), 7.58 (dd, J = 8.3, 4.3 Hz, 1H), 7.45 - 7.52 (m, 2H), 7.39 - 7.45 (m, 1H), 5.88 (br. s., 1H), 2.31 (s, 3H), 2.23 (br. s., 2H), 2.09 (br. s., 2H), 1.72 (br. s., 4H). LC- MS: m z 433.4 (M+Hf. [00825] Compound 217: 3-(3,4-dihydro-2H-pyran-6-yl)-5-methyl-2-phenyl-6- (quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000208_0001
[00826] Step A: A mixture of 3-bromo-5-methyl-2-phenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (50 mg, 0.1 16 mmol), 2-(3,4-dihydro-2H-pyran-6- yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (49 mg, 0.232 mmol), Pd(dppf)C12 (8.4 mg, 0.012 mmol), and NaHC03 (19 mg, 0.232 mmol) in dioxane (9 ml) and H20 (3 ml) was heated to 100 °C for 4h under N2. The mixture was concentrated to dryness to give the desired product.
[00827] 1H NMR (METHANOL^) δ : 8.90 (dd, J = 4.3, 1.6 Hz, 1H), 8.42 (d, J = 8.1
Hz, 1H), 8.13 (d, J = 8.9 Hz, 1H), 7.95 - 8.02 (m, 1H), 7.79 - 7.91 (m, 3H), 7.59 (dd, J = 8.2, 4.4 Hz, 1H), 7.38 - 7.50 (m, 3H), 4.97 (t, J = 3.6 Hz, 1H), 4. 12 - 4.22 (m, 2H), 2.36 (s, 3H), 2.15 - 2.27 (m, 2H), 1.90 - 2.04 (m, 2H). LC-MS: m/z 435.0 (M+H)+.
[00828] 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000208_0002
[00829] This compound was prepared according to General procedure 2b by using Intermediate 1 as methyl 2-(4-methoxyphenyl)acetate in step A.
[00830] 1H NMR (CHLOROFORM-d) δ : 7.89 - 7.93 (m, 2H), 7.45 - 7.51 (m, 3H),
7.18 - 7.27 (m, J = 8.3 Hz, 2H), 6.95 - 7.06 (m, J = 8.3 Hz, 2H), 5.90 (br. s., 2H), 3.88 (s, 3H), 3.74 - 3.82 (m, 2H), 2.42 (s, 3H), 0.99 - 1.08 (m, 2H), 0.03 - 0.06 (m, 9H). LC-MS: m/z 468.2 (M+H)+. [00831] Compound 218: 3-(3,6-dihydro-2H-pyran-4-yl)-6-(4-methoxyphenyl)-5- methyl-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000209_0001
[00832] This compound was prepared according to General procedure 2b (step E-F) by using Intermediate 5 as 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one and Intermediate 9 as 2- (3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane in step E.
[00833] Step E: A mixture of 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (lOOmg, 0.185 mmol) , 2- (3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane ( 194.39mg,
0.925mmol), PdC12(PPh3)2 (27.07mg,0.037mmol). and Cs2C03 (180.54mg, 0.555mmol) in 1,4 dioxane (3 ml) and water (0.3 ml) was heated at 100'C for 1 hour through microwave irradiation. The mixture was cooled to the room temperature and poured into saturated sodium hydrogen carbonate solution. The resulting mixture was extracted with EtOAc
(30mL), washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by prep-TLC (DCM/MeOH=20/l) to obtain 3-(3,6-dihydro- 2H-pyran-4-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-
(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (40mg) as a white solid. LC-MS: m/z 544.2 (M+H) ÷.
[00834] Step F: To a solution of 3-(3,6-dihydro-2H-pyran-4-yl)-6-(4-methoxyphenyl)- 5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (40mg, 0.074mmol) in DCM (1ml) was added TFA (3 ml) dropwise at 0°C. The mixture was stirred for overnight at ambient temperature and concentrated to dryness. The residue was washed with saturated sodium hydrogen carbonate solution and extracted with DCM (20 ml). The organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuoto obtain the title compound. [00835] 1H NMR (DMSO-d6) δ : 11.78 (s, 1 H), 7.72 - 7.81 (m, 2 H), 7.40 - 7.51 (m, 3
H), 7.19 -7.29 (m, 2 H), 6.95 - 7.06 (m, 2 H), 5.93 (s, 1 H), 4.26 (d, J=2.42 Hz, 2 H), 3.79 - 3.86 (m, 5 H), 2.23 (s, 3 H), 2.12 - 2.18 (m, 2 H). LC-MS: m/z 414.0 (M+H)+.
[00836] Compound 219: 3-(5,6-dihydro-2H-pyran-3-yl)-6-(4-methoxyphi
methyl-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000210_0001
[00837] This compound was prepared according to General procedure 2b (step E-F) by using Intermediate 5 as 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one and Intermediate 9 as 2- (5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane in step E.
[00838] Step E: A mixture of 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (200 mg, 0.37 mmol), 2- (5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (156 mg, 0.74 mmol), Pd(dppf)C12 (27 mg, 0.037 mmol), and Cs2C03 (241 mg, 0.74 mmol) in dioxane (9 ml) and H20 (3 ml) was heated to 100 °C for 4h under N2. The mixture was concentrated to dryness. The residue was purified by prep-TLC (eluting PE/EA=1 : 1) to give the desired product (40 mg, 20% yield). LC-MS : m/z 544.3 (M+H)+.
[00839] Step F: A solution of 3-(5,6-dihydro-2H-pyran-3-yl)-6-(4-methoxyphenyl)-5- methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (40mg, 0.074 mmol) in CF C1z/TFA (V:V=3: 1 , 8 ml) was stirred for 30 mins. Then the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH (10 ml), basified with ammonia (3 ml), and concentrated in vacuo to give the desired product.
[00840] 1H NMR (METHANOLS) δ : 7.86 (br. s., 2H), 7.45 (br. s., 3H), 7.20 - 7.33 (m, J = 8.1 Hz, 2H), 6.90 - 7.11 (m, J = 7.8 Hz, 2H), 6.13 (br. s., 1H), 4.06 (br. s., 2H), 3.91 (t, J = 5.4 Hz, 2H), 3.86 (s, 3H), 2.41 (br. s., 2H . 2.30 (s, 3H). LC-MS: m/z 414.0 (M+H)+. [00841] Compound 220: 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1H-pynOl-3- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000211_0001
[00842] This compound was prepared according to General procedure 2b (step E-F) by using Intermediate 5 as 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-
(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one and compound 9 as (1- (triisopropylsilyl)-1H-pyrrol-3-yl)boronic acid in step E.
[00843] Step E: To a sealed tube charged with 3-bromo-6-(4-methoxyphenyl)-5- methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[ 1 , 5-a]pyrimidin-7(4H)-one (200mg, 0.37mmol), (l-(triisopropylsilyl)-1H-pyrrol-3-yl)boronic acid (395mg, 1.48mmol), PdC12(PPh3)2 (259mg, 0.37mmol), and Cs2C03 (482mg, 1.480mmol) was added DMF (5 ml) and water (0.5ml). The mixture was stirred for 1 hour at 120'C through microwave irradiation. The reaction mixture was cooled to the room temperature, diluted with saturated sodium hydrogen carbonate solution (30mL) , and extracted with EtOAc (30mL). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by prep-TLC (DCM/MeOH= 50/1) to obtain 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1H-pyrrol-3-yl)-4-((2-
(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (70mg) as a white solid. LC-MS: m/z 527.2 (M+H) +. [00844] Step F: A solution of 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1H-pyrrol- 3-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one(30mg, 0.057mmol) in DMSO was warmed up to 50 °C in a sealed tube through microwave irradiation for 2 hours. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution (20mL) and extracted with EtOAc (20mL). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the title compound. [00845] 1H NMR (DMSO-d6) δ : 11.63 (br. s., 1 H), 11.02 (br. s., 1 H), 7.61 - 7.71 (m, 2 H), 7.31 - 7.39 (m, 3 H), 7.24 (d, J=8.60 Hz, 2 H), 6.99 (d, J=8.87 Hz, 2 H), 6.84 - 6.92 (m, 2 H), 5.97 - 6.06 (m, 1 H), 3.80 (s, 3 H), 2.18 (s, 3 H). LC-MS: m/z 397.0 (M+H) *.
[00846] General procedure 3 :
Figure imgf000212_0001
[00847] Step A: methyl 4-(benzyloxy)-2-(4-methoxyphenyl)-3-oxobutanoate
Figure imgf000212_0002
[00848] To the solution of Intermediate 1 (36g, 0.2mol) and HMPA (7.2g, 0.02mol) in THF at -78'C was added LDA (2M in THF; 100ml, 0.2mol) over 20min. After stirring for 1 hour at -78'C, 2-(benzyloxy)acetyl chloride (36.8g, 0.2mol) was added dropwise with a funnel. The mixture was warmed up to room temperature overnight. Saturated NH4CI aqueous solution was added. The resultant mixture was extracted with DCM (3X50ml). The combined organic layers were washed with saturated NaC1 (50ml), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel column (PE / EtOAc=20/l) to give Intermediate 2 (38g, 58%) as a brown oil.
[00849] Step B: 5-((benzyloxy)methyl)-6-(4-methoxyphenyI)-2,3- diphenylpy razolo [1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000213_0001
[00850] Intermediate 2 (38g, 0.166mol) and 3 ,4-diphenyl- 1 H-pyrazol-5-amine (40g, 0.174mol) were dissolved in AcOH (300ml). The mixture was warmed up to 95°C for 4h. After cooling to room temperature, the solids were collected by filtration, wash with EtOAc, and dried under vacuum to give Intermediate 3 (28g, 47% yield) as a white solid.
[00851] 1H NMR (DMSO-d6) δ : 1 1.99 (br. s., 1H), 7.20 - 7.50 (m, 17H), 6.97 (d, J =
8.8 Hz, 2H), 4.41 (s, 2H), 4.30 (s, 2H), 3.81 (s, 3H). LC-MS: m/z 514.3 (M+H) +.
[00852] Step C: Compound 221: 5-(hydroxymethyl)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000213_0002
[00853] To a solution of Intermediate 3 (534mg, lmmol) in DCM was added BC13 (1.0M in DCM, 3ml, 3mmol) at 0"C. The mixture was stirred at 0'C for 4 hours. The reaction was quenched by careful adding MeOH and concentrated. The residue was mixed with sodium hydrogen carbonate solution and ethyl acetate with stirring for 30min. The precipitates were filtered, wash with ethyl acetate, and dried under vacuum to give
Intermediate 4 (400mg, 94% yield).
[00854] 1H NMR (DMSO-d6) δ : 11.40 (s, 1H), 7.39 - 7.54 (m, 5H), 7.21 - 7.39 (m,
7H), 6.93 - 7.06 (m, 2H), 5.59 (t, J = 5.5 Hz, 1H), 4.30 (d, J = 5.4 Hz, 2H), 3.82 (s, 3H). LC- MS: m/z 424.3 (M+Hf. [00855] Step D: 5-(chloromethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5- a] py rim id in-7(4H)-one
Figure imgf000214_0001
[00856] To a suspension of Intermediate 4 (88g, 0.208mol) in DCM (500ml) was added SOC12 (120ml) with a funnel. The mixture was stirred at room temperature for 1 hour. The precipitates were filtered, washed with ethyl acetate, and dried under vacuum to give Intermediate 5 (1 lOg) as a off-white solid which was directly used to the next step without further purification.
[00857] Step E: Compound 222: 5-(aminomethyl)-6-(4-methoxyphi
diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000214_0002
[00858] A mixture of Intermediate 5 (200g, 0.453mol) and NH3 (7.0M in MeOH, 2500ml, 17mol) in a autoclave was stirred at 60'C overnight. The precipitates were stirred in a mixed solution (50ml, DMF:MeOH=l : 1) at 45'C for 4h give the title compound 6.
[00859] 1H NMR (DMSO-d6) δ : 1 1.97 (br. s., 1 H), 8.38 (br. s., 3H), 7.29 - 7.59 (m, 12H), 7.06 (d, J = 8.9 Hz, 2H), 3.90 (br. s., 2H), 3.83 (s, 3H). LC-MS: m/z 423.1 (M+H)+.
[00860] Compound 223: 5-(aminomethyl)-6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000215_0001
[00861] This compound was prepared according to General Procedure 3 by using Intermediate 1 as methyl 2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)acetate in step A.
[00862] Step A: A solution of LDA (2M in THF; 14.1 ml, 28.1mmol) was added over 20min to the solution of methyl 2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)acetate (3.9g, 18.8mmol) and HMPA (671mg, 3.75mmol) in THF at -78'C. After stirring for 1 hour at -78'C, 2- (benzyloxy)acetyl chloride (4.14g,22.5mmol) was added dropwise with a funnel. The mixture was warmed up to room temperature overnight. Saturated aqueous NH4CI solution was added, and extracted with DCM (3X50ml), The combined organic layers were washed with saturated NaC1 (50ml) and dried over Na2S04. The residue was purified by column silica gel chromatography (PE / EtOAc=20/l) to get methyl 4-(benzyloxy)-2-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-3-oxobutanoate (2.6g) as a yellow oil. LC-MS: m/z 357.1 (M+H) +.
[00863] Step B: methyl 4-(benzyloxy)-2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-3- oxobutanoate (600mg, 1.68mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (356mg, 1.52mmol) was dissolved in AcOH (10ml). The resultant mixture was warmed up to 100°C for 16h. The reaction was then cooled to room temperature, basified with saturated sodium hydrogen carbonate solution, and extracted with EtOAc (20 mL). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo . The residue was purified by silica gel column (DCM:MeOH=30: l) to get 5-((benzyloxy)methyl)-6-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (400mg) as a white solid. LC-MS: m/z 542.2 (M+H) +. [00864] Step C: To a tube charged with 5-((benzyloxy)methyl)-6-(2,3- dihydrobenzo[o][l,4]dioxin-6-yl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (200g, 0.37mmol) was added BCI3 (5ml, 5mmol, 1.0M in DCM) at 0°C. The mixture was stirred at room temperature for 4 hours. The reaction was quenched with MeOH and concentrated. The residue was basified with sodium hydrogen carbonate solution, extracted with DCM, and concentrated under vacuum to get 6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-5- (hydroxymethyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (120g) as a white solid. LC-MS: m/z 451.2 (M+H) ÷. [0086S] Step D: To a suspension of 6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-5-
(hydroxymethyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (120mg, 0.264mmol) in DCM (5ml) was added SOC12 (63mg, 0.453mmol) dropwise at O'C. The resultant mixture was stirred at room temperature for 3 hours. The reaction was quenched by adding saturated sodium hydrogen carbonate solution and extracted with DCM (20 mL). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by silica gel column (PE:EA=1 : 1) to get 5-{chloromethyl)- 6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (90mg) as a yellow solid. LC-MS: m/z 470.1 (M+H) +.
[00866] Step E: A mixture of 5-(chloromethyl)-6-(2,3-dihydrobenzo[b][ 1 ,4]dioxin-6- yl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (20mg, 0.042mmol) in 7N NH3/MeOH (3ml) in a sealed tube was stirred at 100'C overnight to afford the title compound.
[00867] 1H NMR (DMSO-d6) δ : 8. 1 1 (br. s., 2 H), 7.44 (br. s., 4 H), 7.37 (br. s., 4 H), 6.86 - 7.00 (m, 2 H), 6.83 (br. s., 1 H), 4.30 (s, 3 H), 3.89 (br. s., 1 H). LC-MS: m/z 452.1 (M+H)+.
[00868] Compound 224: 5-(aminomethyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000216_0001
[00869] This compound was prepared according to General Procedure 3 by using Intermediate 1 as methyl 2-(quinolin-6-yl) acetate in step A.
[00870] Step B: methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (8.6g, 0.024mol) and 3,4-diphenyl-l H-pyrazol-5-amine (5.64g, 0.024mol) was dissolved in AcOH (300ml). The mixture was warmed up to 95'C for 4h. After cooling to room temperature, the precipitate was filtered, wash with EtOAc, and dried under vacuum to get 5- ((benzyloxy)memyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (lOg, 78% yield ) as a yellow solid. LC-MS: m/z 535.2 (M+H) +. [00871] Step C: To a solution of 5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (lOg, 18.7mmol) in DCM (100ml) was added BCb (25ml, 25mmol, 1.0M in DCM) at 0°C. The resultant mixture was stirred at 0°C for 4 hours. The reaction was quenched with MeOH and concentrated. The residue was stirred with sodium hydrogen carbonate solution and ethyl acetate for 30min. The solid was collected by filtration, wash with ethyl acetate, and dried under vacuum to get 5-(hydroxymethyl)-2,3- diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (8g, 96% yield). LC-MS: m/z 445.1 (M+H) +.
[00872] Step D: To a suspension of 5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (500mg, 1.126mmol,) in DCM (3ml) cooled in ice- bath was added SOC12 (670mg, 5.631mmol) dropwise. The resultant mixture was then stirred at room temperature overnight. The suspension was filtered, washed with ethyl acetate, and dried under vacuum. The residue was purified by prep-TLC (DCM:MeOH=20: l) to get 5- (chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (300mg). LC-MS: m/z 463.1 (M+H) ". [00873] Step E: To a solution of 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (150mg, 0.324mmol) in DMF was added 7N NH3 in methanol (15ml) at O'C. The reaction mixture was then warmed up to 40°C for 65 hours in a sealed tube to get the title compound.
[00874] 1H NMR (400 MHz, DMSO-ds) δ : 8.89 (dd, J=4.16, 1.75 Hz, 1 H), 8.36 (d, J=7.52 Hz, 1 H), 8.02 (d, J=8.87 Hz, 1 H), 7.91 (s, 1 H), 7.76 - 7.81 (m, 1 H), 7.52 - 7.62 (m, 5 H), 7.34 - 7.40 (m, 3 H), 7. 29 (t, J=7. 52 Hz, 2 H), 7. 15 (d, J=7.25 Hz, 1 H), 3.85 (br. s., 2 H). LC-MS: m/z 444.8 (M+H) +. [00875] Compound 225: 3-(cyclohex-l-en-l-yl)-6-(2,3-dihydrobenzo[b][l,4]dioxin- 6-yl)-5-(hydroxymethyl)-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000218_0001
[00876] This compound was prepared according to General Procedure 3 (step B-C) by using Intermediate 2 as methyl 4-(benzyloxy)-2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)- 3-oxobutanoate and Intermediate 8 as 4-(cyclohex-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine in step B.
[00877] Step B: methyl 4-(benzyloxy)-2-(2,3-dihydrobenzo[b][ 1 ,4]dioxin-6-yl)-3- oxobutanoate (662mg, 1.85mmol) and 4-(cyclohex-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine (400mg, 1.67mmol) were dissolved in AcOH (10ml). The resultant mixture was warmed up to 100'C for 16h. The reaction was then cooled to room temperature, basified with saturated sodium hydrogen carbonate solution, and extracted with DCM (20 mL). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column (DCM:MeOH=30: 1) to get 5- ((benzyloxy)methyl)-3-(cyclohex-l-en-l -yl)-6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (400mg) as a white solid. LC-MS: m/z 546.2 (M+H) +.
[00878] Step C: To a suspension of 5-((benzyloxy)methyl)-3-(cyclohex-l-en-l-yl)-6- (2,3-dihydrobenzo|¾][l,4]dioxin-6-yl)-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (260mg, 0.48mmol) in DCM (5ml) was added 1.0M BC13 in DCM (1.43ml,1.43mmol), the mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated sodium hydrogen carbonate solution and extracted with EtOAc (20 mL) to obtain the title compound.
[00879] 1H NMR (DMSO-d6) δ : 1 1.21 (s, 1 H), 7.78 (d, J=6.98 Hz, 1 H), 7.38 - 7.49 (m, 4 H), 6.85 - 6.92 (m, 2 H), 6.78 - 6.82 (m, 1 H), 5.86 (br. s., 1 H), 5.68 (s, 1 H), 4.77 (s, 1 H), 4.33 (d, J=5.10 Hz, 2 H), 4.29 (s, 3 H), 2.22 (br. s., 2 H), 2.06 (br. s., 2 H), 1.70 (br. s., 4 H). LC-MS: m/z 456.2 (M+H) +. [00880] Compound 226: 5-(aminomethyl)-3-(cyclohex-l-en-l-yl)-6-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000219_0001
[00881] This compound was prepared according to General Procedure 3 , step E-F, starting from 3-(cyclohex-l-en-l-yl)-6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-5- (hydroxymethyl)-2-phenylpyrazolo[l ,5-a]pyrimidin-7(4H)-one (Compound 225).
[00882] Step E: To a suspension of 3-(cyclohex-l-en-l-yl)-6-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-5-(hydroxymethyl)-2-phenylpyrazolo[l,5-a]pyrimidin- 7(4H)-one (Compound 225, lOOmg, 0.264mmol) in DCM (3ml) cooled in a ice-bath was added SOC12 (52mg, 0.0.44mmol) dropwise. The resultant mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated sodium hydrogen carbonate solution and extracted with DCM (20 mL). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by silica gel column (DCM:MeOH=40: 1) to get 5-(chloromethyl)-3-(cyclohex- l-en-l-yl)-6-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2-phenylpyrazolo[l ,5-a]pyrimidin- 7(4H)-one (70mg) as a yellow solid. LC-MS: m/z 474.2 (M+H) +.
[00883] Step F: A mixture of 5-(chloromethyl)-3-(cyclohex-l-en-l-yl)-6-(2,3- dihydrobenzo|¾][l,4]dioxin-6-yl)-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (70mg, 0.148mg) in 7N NH3/MeOH (5ml) in a sealed tube was stirred at 100'C overnight to get the title compound.
[00884] 1H NMR (DMSO-d6) δ : 11.74 (br. s., 1 H), 8.24 (br. s., 2 H), 7.77 (d, J=7.32 Hz, 2 H), 7.40 - 7.53 (m, 3 H), 6.86 - 7.03 (m, 2 H), 6.82 (d, J=8.24 Hz, 1 H), 5.92 (br. s., 1 H), 4.30 (s, 4 H), 3.94 (br. s., 2 H), 2.23 (br. s., 2 H), 2.05 (br. s., 2 H), 1.70 (br. s., 4 H). LC- MS: m/z 455.2 (M+H) +. [00885] Compound 227
Figure imgf000220_0001
[00886] Step A: 2-(benzyloxy)-N-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[ 1 ,5-a]pyrimidin-5-yl)methyl)acetamide
Figure imgf000220_0002
[00887] To a solution of Intermediate 1 (Compound 224, lOOmg, 0.226mmol) and Et3N (68.6mg, 0.68mmol) in DCM (3ml) was added 2-(benzyloxy)acetyl chloride (42mg, 0.45mmol) dropwise. The mixture was stirred for 2 hours at ambient temperature. The reaction was quenched by adding saturated sodium hydrogen carbonate solution and extracted with DCM (20 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by prep-TLC (DCM/MeOH=20/l) to obtain the Intermediate 2 (40mg, 30% yield).
[00888] Step B: Compound 227: 2-hydroxy-N-((7-oxo-2,3-diphenyl-6-(quinolin-6- yl)-4,7-dihydropyrazolo[l ,5-a]pyrimidin-5-yl)methyl)acetamide
Figure imgf000220_0003
[00889] To a solution of Intermediate 2 (40mg, 0.068mmol) in DCM (1ml) at 0°C was carefully added 1M BBr3 in DCM (3 ml, 3mmol), the reaction mixture was stirred for 5 min at 0°C, and then warmed up to ambient temperature for 1 hour . The reaction was quenched by careful adding MeOH. The resultant mixture was poured into saturated sodium hydrogen carbonate solution and extracted with EtOAc (3*20ml). The combined organic layers were washed with saturated NaC1 (20ml), dried over Na2S04, and concentrated in vacuo to give the title compound 3. [00890] 1H NMR (DMSO-d6) δ : 1 1.94 (s, 1 H), 8.95 (d, J=2.69 Hz, 1 H), 8.38 (d,
J=7.25 Hz, 1 H), 8.07 (d, J=8.60 Hz, 1 H), 7.98 (s, 1 H), 7.76 (dd, J=8.60, 1.88 Hz, 1 H), 7.59 (dd, J=8.33,4.30 Hz, 1 H), 7.42 - 7.53 (m, 5 H), 7.32 - 7.41 (m, 5 H), 5.59 (br. s., 1 H), 4.25 (br. s., 2 H), 3.77 (d, J=5.37 Hz, 2 H), LC-MS : m/z 502.8 (M+H) +
[00891] Compound 228: N-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)methyl)acet amide
Figure imgf000221_0001
[00892] This compound was prepared according to Compound 227 (step A) by using Intermediate 4 as acetyl chloride in step A. [00893] To a solution of 5-(aminomethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one (Compound 224, lOOmg, 0.226mmol) and DIPEA (87.3mg, 0.68mmol) in DCM (3ml) was added acetyl chloride (21.24mg, 0.271mmol) dropwise. After addition, the mixture was stirred for 2 hours at ambient temperature. The mixture was concentrated. The residue was basified with saturated sodium hydrogen carbonate solution and extracted with DCM (20 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the title compound.
[00894] 1H NMR (DMSO-d6) δ : 8.90 (br. s., 1 H), 8.35 (d, J=8.87 Hz, 1 H), 8.16 (s, 1
H), 8.02 (d, J=8.60 Hz, 1 H), 7.96 (br. s., 1 H), 7.89 (br. s., 1 H), 7.76 (d, J=7.79 Hz, l H), 7.50 - 7.56 (m, 5 H), 7.29 - 7.39 (m, 5 H), 7.20 (d, J=6.98 Hz, 1 H), 4.07 (br. s., 2 H), 1.82 (s, 3 H). LC-MS : m/z 485.9 (M+H) +. [00895] Compound 229: 3-(cyclohex-l-en-l-yl)-5-(hydroxymethyl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000222_0001
[00896] This compound was prepared according to General procedure 3, step B-C, by using Intermediate 8 as 4-(cyclohex- 1 -en- l-yl)-3 -phenyl- 1H-pyrazol-5-amine in step B.
[00897] Step B: methyl 4-(benzyloxy)-2-(4-methoxyphenyl)-3-oxobutanoate (597 mg, 1.67mmol) and 4-(cyclohex-l-en-l-yl)-3-phenyl-1H -pyrazol-5-amine(400 mg, 1.67mmol) were dissolved in AcOH (10 ml). The mixture was stirred at 100'C for 4h. After cooling to room temperature, the solids were collected by filtration, wash with EtOAc, and dried under vacuum to give 5-((benzyloxy)methyl)-3 -(cyclohex- 1 -en- 1 -yl)-6-(4-methoxypheny l)-2- phenylpyrazolo[l,5-a] pyrimidin-7(4H)-one (200 mg, 23% yield) as a white solid. LC-MS: m/z 513.9 (M+H)+.
[00898] Step C: To a solution of 5-((benzyloxy)methyl)-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a] pyrimidin-7(4H)-one (50mg, O. lmmol) in MeOH (5 ml) was added Pd/C (50 mg) and HC1 (3drops). The mixture was stirred at rt under H2 overnight. The reaction was filtered and concentrated. The residue was mixed with sodium hydrogen carbonate solution and ethyl acetate with stirring for 30min to give the title compound.
[00899]1H NMR (DMSO-d6) δ : 11.27 (br. s., 1H), 7.64 - 7.91 (m, 2H), 7.35 - 7.62 (m, 4H), 7.22 - 7.35 (m, J = 8.6 Hz, 2H), 6.90 - 7.02 (m, J = 8.9 Hz, 2H), 5.87 (br. s., 1H), 5.75 (br. s., 1H), 4.26 - 4.45 (m, 2H), 3.81 (s, 3H), 2.22 (br. s., 2H), 1.98 - 2.1 1 (m, 2H), 1.70 (br. s., 4H). LC-MS: m/z 428.3 (M+Hf. [00900] Compound 230: 3-(cyclohex-l-en-l-yl)-5-(hydroxymethyl)-2-phi
(quinolin-6-yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000223_0001
[00901] This compound was prepared according to General procedure 3 (step A-C) by using Intermediate 1 as methyl 2-(quinolin-6-yl)acetate in step A and Intermediate 8 as 4-(cyclohex-l-en-l-yl)-3-phenyl-l H-pyrazol-5-amine in step B.
[00902] Step B: methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (730 mg, 2.01mmol) and 4-(cyclohex-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine (500 mg, 2.1mmmol) were dissolved in AcOH (15ml). The mixture was warmed up to 100°C for 16h. After cooling to room temperature, the solids were collected by filtration, wash with EtOAc, and dried under vacuum to give 5-((benzyloxy)methyl)-3-(cyclohex-l-en-l -yl)-2-phenyl-6-(quinolin-6- yl) pyrazolo[l,5-a]pyrimidin-7(4H)-one (700 mg, 65% yield) as a white solid. LC-MS: m/z 538.9 (M+H)+.
[00903] Step C: To a solution of 5-((benzyloxy)methyl)-3-(cyclohex-l-en-l-yl)-2- phenyl-6-(quinolin-6-yl) pyrazolo[l,5-a]pyrimidin-7(4H)-one (700mg, 1.3mmol) in DCM was added BC13 (1.0M in DCM, 2.2ml, 2.2mmol) at O'C. The mixture was stirred at O'C for 2 hours. The reaction was quenched by careful adding MeOH and concentrated. The residue was mixed with sodium hydrogen carbonate solution and ethyl acetate with stirring for 30min give the title compound. [00904] 1H NMR (DMSO-d6) δ : 8.87 - 8.96 (m, 1H), 8.37 (d, J = 7.5 Hz, 1H), 8.03 (d,
J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.73 - 7.82 (m, 3H), 7.55 (dd, J = 8.3, 4.3 Hz, 1H), 7.43 - 7.51 (m, 2H), 7.40 (d, J = 7.3 Hz, 1H), 5.82 (br. s., 1H), 4.35 (s, 2H), 2. 19 (br. s., 4H), 1.70 (br. s., 4H). LC-MS: m/z 449.3 (M+H)+. [00905] Compound 231: 3-(cyclohex-l-en-l-yl)-5-(hydroxymethyl)-2-phi
(quinoxalin-6-yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000224_0001
[00906] This compound was prepared according to General procedure 3 (step A-C) by using Intermediate 1 as methyl 2-(quinoxalin-6-yl)acetate in step A and Intermediate 8 as 4-(cyclohex-l-en-l -yl)-3-phenyl-1H-pyrazol-5-amine in step B.
[00907] Step C: To the solution of 5-((benzyloxy)methyl)-3-(cyclohex-l-en-l-yl)-2- phenyl-6-(quinoxalin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one(170 mg, 0.32 mmol) in DCM (8 mL) cooled to 0 °C was added BC13 (1.5 mL, 1.0 M in DCM) dropwise. Then the mixture was stirred at 0°C for 2 hours. The reaction was quenched by carefully adding saturated NaHC03 (8 mL), diluted with DCM (80 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated to obtain 3-(cyclohex-l-en-l-yl)-5-(hydroxymethyl)-2- phenyl-6-(quinoxalin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00908] 1H NMR (DMSO-d6) δ : 11.57 (br. s., 1H), 8.99 (s, 2H), 8.07 - 8.22 (m, 2H), 7.89 (dd, J = 8.5, 1.8 Hz, 1H), 7.73 - 7.84 (m, 2H), 7.38 - 7.58 (m, 3H), 5.90 (br. s., 1H), 5.77 (br. s., l H), 4.42 (d, J = 3.4 Hz, 2H), 2.23 (br. s., 2H), 2.09 (s, 2H), 1.72 (br. s., 4H). LC-MS: m/z 450.3 (M+H)+.
[00909] Compound 232: 5-(aminomethyl)-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000224_0002
[00910] This compound was prepared according to General procedure 3,
starting from 3-(cyclohex-l -en-l-yl)-5-(hydroxymethyl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 229). [00911] Step D: To a suspension of 3-(cyclohex-l-en-l-yl)-5-(hydroxymethyl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 229, 140 mg, 0.32mol) in DCM (10ml) was added SOC12 dopwise (386mg, 3.2mmol) at -20°C. The mixture was stirred at -20°C for 1 hour until SM was consumed. Then the reaction was quenched by adding MeOH at -20°C. The mixture was concentrated and purified by silica gel chromatography (DMC: MeOH = 50: 1) to a 5-{chloromethyl)-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H) -one (lOOmg) as a white solid.
[00912]1H NMR (DMSO-d6) δ : 7.74 - 7.83 (m, 2H), 7.37 - 7.53 (m, 3H), 7.25 - 7.32
(m, 2H), 6.95 - 7.03 (m, 2H), 5.87 (br. s., 1H), 5.76 (s, 1H), 4.33 (br. s., 2H), 3.81 (s, 3H), 2.22 (br. s., 2H), 2.07 (br. s., 2H), 1.70 (br. s., 4H). LC-MS: m/z 446.3 (M+H)+.
[00913] Step E: A suspension of 5-(chloromethyl)-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H) -one (50 mg, 0.1 lmmol) and KI (18mg, 0.1 lmmol) in NH3 in MeOH (7M, lOmL) was stirred at 80°C for lh under microwave irradiation to get the title compound. [00914] 1H NMR (DMSO-d6) δ : 7.71 (d, J = 7.3 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.32
(br. s., 1H), 7.15 - 7.24 (m, J = 8.6 Hz, 2H), 6.93 - 7.00 (m, J = 8.6 Hz, 2H), 5.68 (br. s., 1H), 3.80 (s, 3H), 2.36 (br. s., 2H), 2.11 (d, J = 3.0 Hz, 2H), 1.58 - 1.79 (m, 4H). LC-MS: m/z 427.4 (M+H)+.
[00915] Compound 233: 5-(aminomethyl)-3-(cyclohex-l-en-l-yl)-2-phenyl-6- (quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000225_0001
[00916] This compound was prepared according to General procedure 3, step D-E, starting from 3-(cyclohex-l-en-l-yl)-5-(hydroxymethyl)-2-phenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 230)
[00917] Step D: To a suspension of 3-(cyclohex-l-en-l-yl)-5-(hydroxymethyl)-2- phenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 230, 160 mg, 0.357mol) in DCM (5ml) was added S0C12 (1ml) with a funnel. The mixture was stirred at room temperature for 1 hour. The precipitates were filtered, washed with ethyl acetate, and dried under vacuum to give 5-(chloromethyl)-3-(cyclohex-l-en-l-yl)-2-phenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin -7(4H)-one (170 mg) as a off-white solid which was directly used to the next step without further purification. LC-MS: m/z 466.9 (M+H)+
[00918] Step E: A mixture of 5-(chloromethyl)-3-(cyclohex- 1 -en- 1 -yl)-2-phenyl-6- (quinolin-6-yl)pyrazolo[l,5-a]pyrimidin -7(4H)-one (80 mg, 0.171mol) and NH3 (7.0M in MeOH, 10ml, 70mol) in autoclave was stirred at 40°C for 2days. The mixture was
concentrated in vacuo. The residue was washed with water to afford the title compound. [00919] 1H NMR (DMSO-cfo) δ : 8.84 - 8.93 (m, 1H), 8.34 (d, J = 8.1 Hz, 1 H), 8.01 (d,
J = 8.6 Hz, 1H), 7.87 (s, 1H), 7.68 - 7.78 (m, 3H), 7.52 - 7.58 (m, 1H), 7.28 - 7.47 (m, 3H), 5.71 (br. s., 1H), 3.85 (s, 2H), 2.39 (br. s., 2H), 2.11 (br. s., 2H), 1.57 - 1.79 (m, 4H). LC-MS: m/z 448.5 (M+H)+
[00920] Compound 234: 5-(aminomethyl)-3-(cyclohex-l-en-l-yl)-2-phenyl-6- (quinoxalin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000226_0001
[00921] This compound was prepared according to General procedure 3 , step D-E, starting from 3-(cyclohex- 1 -en- 1 -yl)-5-(hydroxymethyl)-2-phenyl-6-(quinoxalin-6- yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (Compound 231).
[00922] Step D: To the solution of 3-(cyclohex-l-en-l-yl)-5-(hydroxymethyl)-2- phenyl-6-(quinoxalin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 231, 100 mg, 0.22 mmol) and DMF (1 drop, cat.) in DCM was added Thionyl chloride (0.2 mL) dropwise at 0 °C. After addition, the mixture was continued to stir at 0 °C for 1 hour. The reaction was diluted with DCM (60 mL), washed with saturated NaHC03(l 5 mL) and brine(20 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by prep-TLC (DCM: MeOH: 25: 1) to obtain 5-(chloromethyl)-3-(cyclohex-l-en-l-yl)-2-phenyl- 6-(quinoxalin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one(90 mg) as yellow solid. LC-MS: m/z 468.3 (M+H)+. [00923] Step E: The solution of 5-(chloromethyl)-3-(cyclohex-l-en-l-yl)-2-phenyl-6- (quinoxalin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (85 mg, 0.18 mmol) in NH3 (4 mL, 7.0M in MeOH) was stirred at 40 °C in a sealed tube for 12 hours. After cooling to room temperature, the mixture was filtered off to obtain 5-(aminomethyl)-3-(cyclohex-l-en-l-yl)- 2-phenyl-6-(quinoxalin-6-yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one.
[00924] 1H NMR (DMSO-d6) δ : 8.92 (dd, J = 7.0, 1.9 Hz, 2H), 8.07 (d, J = 8.6 Hz,
1 H), 8.01 (d, J = 1.9 Hz, 1H), 7.91 (dd, J = 8.9, 1.9 Hz, 1 H), 7.73 (d, J = 7.0 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 5.69 (br. s., 1H), 3.88 (s, 2H), 2.40 (br. s., 2H), 2.12 (br. s., 2H), 1.60 - 1.78 (m, 4H). LC-MS: m/z 449.3 (M+H)+.
[00925] Compound 235: l-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)methyl)urea
Figure imgf000227_0001
[00926] Intermediate 1 was prepared according to General procedure 3 (step A-D) by using Intermediate 1 as methyl 2-(quinolin-6-yl)acetate.
[00927] Step A: NaH (60% dispersion in mineral oil, 28.6 mg, 0.7 mmol) was added in portions to the solution of urea (41.0 mg, 0.6 mmol) in DMF (10 mL) cooled to 0 °C and stirred at this temperature for 20 min. 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (100 mg, 0.2 mmol) was then added and stirred at 80 °C for lOh. After cooling to room temperature, water was added, and the precipitate was filtered to get l-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[l,5-a]pyrimidin 5-yl)methyl)urea.
[00928] 1H NMR (DMSO-d6) δ : 8.89 (br. s., 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.02 (d, J =
8.9 Hz, 1H), 7.89 (br. s., 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.44 - 7.59 (m, 6H), 7.24 - 7.36 (m,5H), 7.14 (d, J = 6.7 Hz, 1H), 6.10 (br. s., 1H), 5.76 (br. s., 2H), 4.02 (br. s., 2H). LC-MS m/z 487.2 (M+H)+. [00929] General procedure 4
Figure imgf000228_0001
[00931] To a solution of Intermediate 1 (Compound 222, 1 OOmg, 0.237mmol) in 1 ml DCM was carefully added 5ml BBr3 (1.0M in DCM, 5mmol) at 0'C. The mixture was stirred at 0'C for 2 hours. The reaction was quenched by careful adding ice water at 0'C. The precipitated solids were filtered to give the title compound 2.
[00932] 1H NMR (DMSO-d6) δ : 7.49 - 7.59 (m,4 H), 7.32 - 7.38 (m, 3 H), 7.26 (t,
J=7.52 Hz, 2 H), 7.06 - 7.14 (m, 3 H), 6.79 (d, J=8.33 Hz, 2 H), 3.73 (s, 2 H). LC-MS: m/z 409.0 (M+H) +.
[00933] Compound 237: 6-(4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000228_0002
[00934] This compound was prepared according to General procedure 4 by using Intermediate 1 as 6-(4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin- 7(4H)-one (Compound 209) in step A.
[00935] A mixture of 6-(4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[l ,5-a] pyrimidin- 7(4H)-one (Compound 209, 60 mg, 0.147 mmol) and BBr3 (1M in
dichloromethane, 5 mL) was stirred at room temperature for 3 h. The mixture was quenched with methanol at 0°C, and then evaporated to dryness to afford 6-(4-hydroxyphenyl)-5- methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one.
[00936] 1H NMR (DMSO-d6) δ : 1 1.84 (s, 1 H), 9.46 (s, 1 H), 7.37 - 7.58 (m, 5 H), 7.25 - 7.37 (m, 5 H), 7.12 (d, J=8.60 Hz, 2 H), 6.82 (d, J=8.60 Hz, 2 H), 2.17 (s, 3 H). LC- MS: m/z 394.1 (M+H)+.
[00937] Compound 238: 6-(3-fluoro-4-hydroxyphenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000229_0001
[00938] Step A: methyl 2-(3-fluoro-4-methoxyphenyl)-3-oxobutanoate
Figure imgf000229_0002
[00939] To a solution of methyl 2-(3-fluoro-4-methoxyphenyl)acetate (lg, 5.0 mmol) in THF (15 ml) was added slowly LDA (2.5 ml, 2mmol/ml in THF) at -30 °C. Then acetyl chloride (500mg, 6.5 mmol) was added slowly. The reaction mixture was stirred for 30mins at -30 °C and allowed to room temperature for lh. The mixture was poured into water, extracted over ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated to give the crude product (400 mg) as a yellow liquid, which was used directly to the next step without further purification.
[00940] Step B: 6-(3-fluoro-4-methoxyphenyI)-5-methyl-2,3-diphenyIpyrazoIo[l,5- a] py rim id in-7(4H)-one
Figure imgf000230_0001
[00941] A solution of methyl 2-(3-fluoro-4-methoxyphenyl)-3-oxobutanoate (crude, 400 mg) and 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.86 mmol) in AcOH (10 ml) was heated to 120 °C overnight. The reaction mixture was cooled to room temperature. The precipitate was filtered off to give the desired product 6-(3-fiuoro-4-methoxyphenyl)-5- methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (200 mg, 57% yield).
[00942] 1H NMR (DMSO-d6) δ : 12.04 (s, 1H), 7.39 - 7.51 (m, 5H), 7.24 - 7.38 (m,
6H), 6.94 (dd, J = 1 1.7, 2.6 Hz, 1H), 6.88 (dd, J = 8.5, 2.6 Hz, 1H), 3.83 (s, 3H), 2.16 (s, 3H). LC-MS: m/z 426.2 (M+Hf.
[00943] Step C: Compound 238: 6-(3-fluoro-4-hydroxyphenyl)-5-methyl-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000231_0001
[00944] To a solution of 6-(3-fluoro-4-methoxyphenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (200 mg, 0.47 mmol) in CH2C12 (20 ml) was added slowly BBr3 (1 ml, 1 mmol/ml in CH2C12). And then the reaction mixture was stirred overnight. The mixture was adjusted to pH=7 with saturated NaHC03 solution. The precipitate was filtered off to give the desired product 6-(3-fluoro-4-hydroxyphenyl)-5- methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one. [00945] 1H NMR (DMSO-d6) δ : 9.57 (s, 1 H), 7.54 (dd, J=7.7, 1.7 Hz, 2 H), 7.44 -
7.50 (m, 2 H), 7.29 - 7.38 (m, 3 H), 7.26 (t, J=7.7 Hz, 2 H), 7.06 - 7.14 (m, 1 H), 7.02 (dd, J=12.8, 1.7 Hz, 1 H), 6.85 - 6.96 (m, 2 H), 2.11 (s, 3 H). LC-MS: m/z 411.9 (M+H)+.
[00946] Compound 239: 6-(3-chloro-4-hydroxyphenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000231_0002
[00947] This compound was prepared according to Compound 238, step A-C, starting from methyl 2-(3-chloro-4-methoxyphenyl)acetate.
[00948] Step A: To a solution of methyl 2-(3-chloro-4-methoxyphenyl)acetate (2g, 9.346 mmol) in THF (20 ml) was added LDA ( 1.5 M in THF, 8. 1 mL, 12.15mmol) dropwise at -78'C. The mixture was stirred at -78 'C for 30 min., and acetyl chloride (822mg,
10.28mmol) was added dropwise. Then the mixture was stirred at rt for 2 hours. The mixture was poured slowly into saturated NH4CI and extracted with EA (3X30 mL). The combined organic phase was washed with brine, dried over anhydrous MgS04 and concentrated in vacuo. The residue was purified by silica gel column (PE:EA=0-30%) to get methyl 2-(3- chloro-4-methoxyphenyl)-3-oxobutanoate (500mg) as a yellow oil. LC-MS: m/z 257.1 (M+H)+.
[00949] Step B: A suspension of methyl 2-(3-chloro-4-methoxyphenyl)-3- oxobutanoate (200mg, 0.850mmol) and 3,4-diphenyl-l H-pyrazol-5-amine (261 mg,
1.020mmol) in 1,4-dioxane (5ml) and AcOH (1ml) was refluxed for 16 hours under N2 protection. The solution was cooled to room temperature, concentrated, basified with saturated sodium hydrogen carbonate solution to adjust pH equal to 7, and filtered. The filter cake was purified by prep-TLC (DCM:MeOH=20: 1) to get 6-(3-chloro-4-methoxyphenyl)-5- methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (50mg) as a white solid. LC-MS: m/z 442.1 (M+H) +.
[00950] Step C: To a solution of 6-(3-chloro-4-methoxyphenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (50mg, 0.113mmol) in DCM (1ml) was added 1.0M BBr3 in DCM (3ml, 3mmol) dropwise. The mixture was stirred for 2 hours at ambient temperature. The reaction mixture was quenched by adding saturated sodium hydrogen carbonate solution and extracted with DCM (20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the title compound.
[00951] 1H NMR (DMSO-d6) 5 : 11.94 (br. s., 1 H), 10.24 (s, 1 H), 7.40 - 7.47 (m, 4 H), 7.38 (d,J=7.25 Hz, 1 H), 7.34 (d, J=5.10 Hz, 4 H), 7.29 (d, J=1.88 Hz, 1 H), 7.07 - 7.12 (m, 1 H), 7.00 - 7.05 (m, 1 H), 2.18 (s, 3 H). LC-MS: m/z 428.1 (M+H) +.
[00952] Compound 240: 3-(cyclohex-l-en-l-yl)-6-(4-hydroxyphenyl)-5-methyl-2- phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000233_0001
[00953] This compound was prepared according to General procedure 4 by using Intermediate 1 as 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-5-methyl-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 212) in step A.
[00954] To a solution of 3 -(cyclohex- 1 -en- 1 -yl)-6-(4-methoxyphenyl)-5-methyl-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 212, 50mg, 0.118mmol) in DCM (lml) was added 1.0M BBr3 in DCM (3ml, 3mmol) dropwise at 0 °C. The mixture was stirred for 3 hours at ambient temperature. The reaction was quenched with ice water at -10°C and concentrated to obtain the title compound.
[00955] 1H NMR (DMSO-d6) δ : 7.76 (d, J=7.02 Hz, 2 H), 7.30 - 7.52 (m, 3 H), 7.09
(m, J=7.93 Hz, 2 H), 6.82 (m, J=7.93 Hz, 2 H), 5.83 (br. s., 1 H), 2.21 (br. s., 3 H), 2.18 (br. s., 2 H), 2.03 (br. s., 2 H), 1.67 (br. s., 4 H). LC-MS: m/z 398.0 (M+H) +.
[00956] Compound 241: 5-(aminomethyl)-3 -(cyclohex- 1 -en- l-yl)-6-(4- hydroxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000233_0002
[00957] This compound was prepared according to General procedure 4 by using Intermediate 1 as 5-(aminomethyl)-3-(cyclohex-l -en-l -yl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 232) in step A.
[00958] To a solution of 5-(aminomethyl)-3-(cyclohex-l-en-l-yl)-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 232, 85mg, 0.2mmol) in DCM (1ml) was added 1.0M BBr3 in DCM (3ml, 3mmol) dropwise. The mixture were stirred for 3 hours at ambient temperature, The reaction was quenched with ice water and concentrated to obtain the title compound.
[00959]1H NMR (DMSO-d6) δ : 8.21 (s, 1 H), 7.69 (d, J=6.72 Hz, 2 H), 7.37 (d, J=6.98 Hz, 2 H), 7.31 (d, J=6.72 Hz, 1 H), 7.06 (m, J=8.06 Hz, 2 H), 6.77 (m, J=8.33 Hz, 2 H), 5.66 (br. s., 1 H), 3.68 (br. s., 3 H), 2.34 (br. s., 2 H), 2.09 (br. s., 2 H), 1.53 - 1.74 (m, 4 H). LC-MS: m/z 413.2 (M+H) +.
[00960] Compound 242
Figure imgf000234_0001
[00961] Step A: 3-(4-methoxyphenyl)-3-oxo-2-phenylpropanenitrile
Figure imgf000234_0002
[00962] To a solution of 2-phenylacetonitrile (lg, 8.536 mmol) in THF (20 ml) was added LiHMDS ( 2.0 M in THF, 5.1 mL, 10.2mmol) dropwise at 0°C. The mixture was stirred at 0 'C for 30 min and warmed up to room temperature for 15min. 4-methoxybenzoyl chloride (1.75g, 10.24mmol) was added dropwise at 0"C. Then the mixture was stirred at room temperature for 16 hours. The mixture was poured slowly into saturated NH4CI and extracted with EA (3X10 mL). The combined organic phase was washed with brine, dried over anhydrous MgS04 and concentrated in vacuo to get crude product (2.5g) as a yellow oil. LC-MS: m/z 252.1 (M+H) +.
[00963] Step B: 3-(4-methoxyphenyl)-4-phenyl-l H-pyrazol-5-amine
Figure imgf000235_0001
[00964] A suspension of 3-(4-methoxyphenyl)-3-oxo-2-phenylpropanenitrile (2g,
8.761mmol) and hydrazine hydrate (2.4g, 43.804mmol) in EtOH (10ml) and AcOH(2ml) was refluxed for 16 hours under N2 protection. The solution was cooled to the room temperature and concentrated, basified with sodium hydrogen carbonate solution to adjust pH equal to 7, and extracted with EtOAc. The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column (PE:EA=3: 1) to get 3-(4-methoxyphenyl)-4-phenyl-1H-pyrazol-5-amine (700mg) as a white solid .
[00965] 1H NMR (DMSO-d6) δ 11.76 - 11.92 (m, 1H), 7.27 - 7.35 (m, 2H), 7.15 - 7.24
(m, 5H), 6.88 (d, J = 8.3 Hz, 2H), 4.33 - 4.63 (m, 2H), 3.74 (s, 3H). LC-MS: m/z 266.1 (M+H) +.
[00966] Step C: Compound 243: 2-(4-methoxyphenyl)-5-methyl-3-phenyl-6- (quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000235_0002
[00967] A suspension of 3-(4-methoxyphenyl)-4-phenyl-1H-pyrazol-5-amine (250mg, 0.942mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (458mg, 1.885mmol) in 1,4- dioxane (10ml) and AcOH (2ml) was refluxed for 16 hours under N2 protection. The solution was cooled to the room temperature and concentrated, basified with saturated sodium hydrogen carbonate solution to adjust pH equal to 7, and filtered to afford 2-(4- methoxyphenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one. [00968] 1H NMR (DMSO-d6) 612.01 (s, 1 H), 8.94 (d, J=2.75 Hz, 1 H), 8.40 (d, J=7.93
Hz, 1 H), 8.08 (d, J=8.54 Hz, 1 H), 7.93 - 7.99 (m, 1 H), 7.75 (dd, J=8.70, 1.68 Hz, 1 H), 7.58 (dd, J=8.24, 4.27 Ηζ,Ι H), 7.41 - 7.51 (m, 3 H), 7.34 - 7.40 (m, 4 H), 6.90 (d, J=8.55 Hz, 2 H), 3.76 (s, 3 H), 2.25 (s, 3 H). LC-MS: m/z 459.2 (M+H) +.
[00969] Step D: Compound 242: 2-(4-hydroxyphenyl)-5-methyl-3-phenyl-6- (quinolin-6-yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000236_0001
[00970] To a solution of 2-(4-methoxyphenyl)-5-methyl-3-phenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (lOOmg, 0.225mmol) in DCM (1ml) was added 1.0 M BBr3 in DCM (3ml, 3mmol) dropwise. The mixture was stirred for 2 hours at ambient temperature. The reaction mixture was quenched by adding saturated sodium hydrogen carbonate solution and extracted with DCM (20 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the title compound.
[00971] 1H NMR (DMSO-d6) δ : 1 1.97 (br. s., 1 H), 9.63 (s, 1 H), 8.93 (d, J=2.69 Hz,
1 H), 8.39 (d, J=7.52 Hz, 1 H), 8.07 (d, J=8.87 Hz, 1 H), 7.95 (d, J=1.88 Hz, 1 H), 7.75 (dd, J=8.60, 1.88 Hz, 1 H), 7.57 (dd,J=8.33, 4.30 Hz, 1 H , 7.42 - 7.49 (m, 2 H), 7.35 - 7.41 (m, 3 H), 7.27 (m, J=8.60 Hz, 2 H), 6.71 (m, J=8.60 Hz, 2 H), 2.24 (s, 3 H). LC-MS: m/z 445.2 (M+H) +.
[00972] Compound 244
Figure imgf000236_0002
[00973] Step A: (E)-methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate It
Figure imgf000237_0001
[00974] The solution of methyl 2-(quinolin-6-yl)acetate (3.0 g, 14.9 mmol) and DMF- DMA (4.0 mL) in DMF was stirred at 85 °C for 12h. After cooling to room temperature, the mixture was diluted with water, extracted with EtOAc, dried over Na2S0 , and concentrated to get the crude product (3.8 g) which was directly used to the next step without further purification. LC-MS: m/z 257.3 (M+H)+.
[00975] Step B: Compound 244: 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000237_0002
[00976] The solution of 3,4-diphenyl-1H-pyrazol-5-amine(200 mg, 0.9 mmol) and (E)- methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate (283.2 mg, 1.1 mmol) in AcOH (3 mL) was stirred at 100 °C for 2h. After cooling to room temperature, the solvent was removed by vacuum, saturated NaHC03 (6 mL) was added, and the precipitate was filtered. The filter cake was washed with water (2 mL) and MeOH (2 mL) to afford 2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one.
[00977] NMR (DMSO-d6) δ : 12.69 (br. s., 1H), 8.91 (dd, J = 4.0, 1.6 Hz, 1H), 8.37
- 8.47 (m, 1 H), 8.32 (d, J = 1.9 Hz, 1H), 8.10 - 8.16 (m, 2H), 8.03 - 8.10 (m, 1H), 7.56 (dd, J = 8.3, 4.0 Hz, 1H), 7.45 - 7.54 (m, 4H), 7.32 - 7.45 (m, 6H). LC-MS: m/z 415.3 (M+H)+.
[00978] Compound 245
Figure imgf000238_0001
[00979] Step A: ethyl 2-(3-cyano-4-nitrophenyl)-3-oxobutanoate
Figure imgf000238_0002
[00980] 5-fluoro-2-nitrobenzonitrile (5g, 30mmol), ethyl 3-oxobutanoate (7.8g, 60mmol) and K2C03 (12.46g, 90mmol) in DMSO (50mL) was stirred at 50°C for 16h. The mixture was acidified with HC1 (1M) to pH=7 and extracted with EA (50mL X 3). The organic layer was dried and concentrated to give the crude which was purified by silica gel chromatography (PE:EA = 3 : 1 ) to get Intermediate 2 (6. 15g, 77% yield).
[00981] 1H NMR (CHLOROFORM-d) δ : 8.33 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.63 (dd, J = 8.6, 1.9 Hz, 1H), 3.84 (s, 1H), 3.76 (s, 3H), 1.95 (s, 3H). LC-MS: m/z 277.2 (M+H)+.
[00982] Step B: 5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5-a]pyrimidin- 6-yl)-2- nitrobenzonitrile
Figure imgf000238_0003
[00983] A mixture of Intermediate 2 (3g, 1 lmmol), 3,4-diphenyl-1H-pyrazol-5-amine (2.7g, 1 lmmol), and TsOH (200mg, 1. lmmol) in toluene (20 mL) was stirred at 120°C for 4h. The mixture was cooled to r.t. and filtered to give the crude yellow solid which was recystallized from MeOH to give the pure Intermediate 3 (2.5g, 51% yield). [00984] NMR (DMSO-d6) δ : 8.45 (d, J = 8.6 Hz, 1H), 8. 14 - 8.30 (m, 1H), 8.01 (d,
J = 8.6 Hz, 1H), 7.20 - 7.50 (m, 10H), 2.28 (s, 3H). LC-MS: m/z 448.1(M+H)+.
[00985] Step C: 2-amino-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5- a]pyrimidin-6-yl) benzonitrile
Figure imgf000239_0001
[00986] The Intermediate 3 (3g, 0.7mmol) and 10% Pd/C (300 mg) in DMF (lOmL) and MeOH (50mL) was stirred at r.t. for 16h under H2 atmosphere. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column (PE:EA=10: 1-1 : 1) to give Intermediate 4 (1.8g, 64% yield).
[00987] 1H NMR (DMSO-d6) 6 : 11.91 (s, 1H), 7.38 - 7.52 (m, 5H), 7.21 - 7.38 (m, 7H), 6.85 (d, J = 8.9 Hz, 1H), 6.16 (s, 2H), 2.20 (s, 3H). LC-MS: m/z 418.3(M+H)+.
[00988] Step D: 2-amino-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[ 1,5- a]pyrimidin-6-yl) benzaldehyde
Figure imgf000239_0002
[00989] The Intermediate 4 (800mg, 1.9mmol) in dry DCM (lOmL) was cooled to 0°C and DIBAL-H (19mmol, 2M) was added dropwise. The mixture was warmed up to r.t. for 16h. The reaction was quenched with MeOH and concentrated. The residue was purified by silica gel column (PE;EA=1 : 1) to get Intermediate 5 (150mg, 19% yield). [00990] 1H NMR (DMSO-d6) δ : 11.90 (br. s., 1H), 9.85 (s, 1H), 7.38 - 7.51 (m, 6H),
7.22 - 7.38 (m, 8H), 6.84 (d, J = 8.6 Hz, 1H), 2.23 (s, 3H). LC-MS: m/z 421.5 (M+H)+.
[00991] Step E: Compound 245: 5-methyl-2,3-diphenyl-6-(quinazolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000240_0001
[00992] The Intermediate 5 (60mg, 0.14mmol) and formamidine (126mg, 2.86mmol) in DMF was stirred at 160°C for 2h. The mixture was concentrated to get the title compound 6.
[00993] 1H NMR (DMSO-d6) δ : 12.13 (br. s., 1H), 9.66 (s, 1H), 9.35 (s, 1 H), 8.17 (s, 1H), 8.08 (d, J = 12.1 Hz, 1H), 7.95 - 8.05 (m, 1H), 7.41 - 7.52 (m, 6H), 7.34 - 7.41 (m, 5H), 2.27 (s, 3H). LC-MS: m/z 430.2 (M+H) +.
[00994] Compound 246: 6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5- a]pyrimidin-6-yl) quinoline-2-carboxylic acid
Figure imgf000240_0002
[00995] Step A: 2-amino-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5- a]pyrimidin-6-yl)benzalde-hyde (50mg, 0.12mmol), 2-oxopropanoic acid (52mg, 0.6mmol), and KOH (23 mg, 0.6mmol) in EtOH (5mL) was stirred at r.t. for 16h. The mixture was acidified with 1 M HC1 to pH=6 and extracted with DCM (10ml X 3). The organic layer was dried and concentrated to afford the desired product. [00996] 1H NMR (DMSO-d6) δ : 12.12 (br. s., 1H), 8.58 (d, J = 8.3 Hz, 1H), 8.15 -
8.24 (m, 2H), 8.09 (br. s., 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.42 - 7.50 (m, 5H), 7.33 - 7.42 (m, 6H), 2.28 (s, 3H). LC-MS: m/z 473.5 (M+H)+.
[00997] Compound 247
Figure imgf000241_0001
[00998] Step A: 2-(5-fluoro-2-nitrophenyl)-l,3-dioxolane
Figure imgf000241_0002
[00999] To a solution of 5-fluoro-2-nitrobenzaldehyde (5.0 g, 29.6 mmol) in toluene (150 mL) was added ethylene glycol (2.75 g, 44.4 mmol) and p-TSOH (500 mg). After addition, the mixture was heated to reflux overnight. The reaction mixture was cooled to RT and diluted with EtOAc. The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give Intermediate 2 (6.4 g) as a yellow oil which was directly used in the next step without further purification. LC-MS: m/z 214.6 (M+H)+.
[001000] Step B: methyl 2-(3-(l,3-dioxolan-2 yl)-4-nitrophenyl)-3-oxobutanoatc
Figure imgf000241_0003
[001001] To a mixture of Intermediate 2 (5.4 g, 25.4 mmol) in DMF (150 mL) was added methyl 3-oxobutanoate (4.42 g, 38.0 mmol, 1.5 eq) and K2C03 (5.24 g, 38.0 mmol, 1.5 eq) at RT. After addition, the mixture was heated to 55°C overnight. The reaction mixture was cooled to RT and diluted with EtOAc. The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/PE=l/10) to afford the desired product Intermediate 3 (4.23 g, 54 % yield). LC-MS: m/z 309.9 (M+H)+.
[001002] Step C: 6-(3-(13-dioxolan-2-yl)-4-nitrophenyl)-5-methyl-2,3- diphenylpyrazolo [1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000242_0001
[001003J A mixture of Intermediate 3 (4.23 g, 13.7 mmol) and 3,4-diphenyl-l H- pyrazol-5-amine (3.22 g, 13.7 mmol, 1.0 eq) in CH3COOH (200 mL) was stirred at 1 10 °C overnight, and then cooled to room temperature. The precipitate was collected by filtration and washed with EA to afford the desired product Intermediate 4 (4.01 g, yield 59%) as a yellow solid. LC-MS: m/z 494.9 (M+H)+. [001004J Step D: 2-amino-5-(5-methyI-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5- a] pyrimidin-6-yl)benzaldehyde
Figure imgf000242_0002
[001005] To a solution of Intermediate 4 (1.0 g, 2.02 mmol) in a mixed solution of MeOH (50 mL)/DCM (5 mL)/H20 (5 mL) was added Pd/C (0.2 g) and HCOONH4 (673 mg, 10.1 mmol, 5.0 eq) at RT under N2. After addition, the mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford Intermediate 5 (610 mg, 72% yield). LC-MS: m/z 420.9 (M+H)+. [001006] Step E: Compound 247
6-(3-hydroxy-2-methylquinolin-6-yl)-5-methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)- one
Figure imgf000243_0001
[001007] To a mixture of Intermediate 5 (150 mg, 0.36 mmol) and 1-hydroxypropan- 2-one (52.9 mg, 0.71 mmol, 2.0 eq) in EtOH (5 mL) was added KOH (40.1 mg, 0.71 mmol, 2.0 eq) at RT. After addition, the mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure to afford the title product.
[001008]1H NMR (DMSO-d6) δ: 12.00 (s, 1H), 10.32 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.50 - 7.39 (m, 7H), 7.38 - 7.30 (m, 5H), 2.56 (s, 3H), 2.22 (s, 3H). LC-MS: m/z 459.0 (M+H) +.
[001009] Compound 248
PWBS.
Figure imgf000243_0002
[001010] Step A: methyl 3-((2-((4-methoxybenzyl)thio)-4-(5-methyl-7-oxo-2,3- diphenyl-4,7-dihydropyrazolo[l,5-a]pyrimidin-6-yl)phenyl)amino)-3-oxopropanoate
Figure imgf000243_0003
[001011] To a mixture of Intermediate 1 (50 mg, 0.09 mmol) and DIPEA (23.2 mg, 0.18 mmol, 2.0 eq) in THF (5 mL) was added methyl 3-chloro-3-oxopropanoate (24.5 mg, 0.18 mmol, 2.0 eq). The reaction mixture was then stirred at rt for 8 h. The mixture was partitioned between EA and H20. The organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give crude Intermediate 2 (50 mg) which was directly used to the next step without further purification. LC-MS: m/z 645.1 (M+H) +.
[001012] Step B: Compound 248: 2-(6-(5-methyl-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l ,5-a]pyrimidin-6-yl)benzo[d]thiazol-2-yl)acetate
Figure imgf000244_0001
[001013] A mixture of Intermediate 2 (50 mg, 0.08 mmol) in TFA (3 mL) was stirred at 75°C for 3 h. The mixture was concentrated under reduced pressuren to afford the desired product 3.
[001014] 1H NMR (DMSO-d6) δ : 12.01 (s, 1H), 7.44 (m, 6H), 7.34 (m, 5H), 4.37 (s, 2H), 3.71 (s, 3H), 2.20 (s, 3H). LC-MS: m/z 507.0 (M+H)+.
Figure imgf000244_0002
[001016] Step A: methyl 4-(benzyloxy)-2-(4-methoxyphenyl)-3-oxobutanoate
OBn
Figure imgf000245_0001
[001017] To a solution of methyl 2-(4-methoxyphenyl)acetate (3.0 g, 16.7 mmol) in THF (10 mL) was added dropwise LDA (10 mL, 19.98 mmol, 1.2 eq) and HMPA (598 mg, 3.33 mmol, 0.2 eq) at -78°C. After addition, the mixture was stirred at -48°C for 0.5 h. The mixture was then cooled to -78°C, 2-(benzyloxy)acetyl chloride (3.69 g, 17 mmol) in dry THF (3 mL) was added slowly and stirred at RT overnight. The reaction was quenched with NH4CI solution, extracted with EA. The combined organic phase was washed with water and brine, dried over anhydrous Na2S0 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/PE=l/4) to afford Intermediate 2 (2.7 g, 49% yield). LC-MS: m/z 329.1 (M+Hf.
[001018] Step B: 5-((benzyloxy)methyl)-6-(4-methoxyphenyl)-2- phenylpy razolo [1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000245_0002
[001019] A mixture of Intermediate 2 (2.7 g, 8.23 mmol) and compound 8 (1.3 g, 8.23 mmol, 1.0 eq) in CH3COOH (10 mL) was stirred at 100 °C for 3h and then cooled to room temperature. The mixture was concentrated under reduced pressure and washed with MeOH to afford the desired Intermediate 3 (2.4 g, yield 67%) as a white solid. LC-MS: m/z 437.9 (M+H)+. [001020] Step C: 5-((benzyloxy)methyl)-6-(4-methoxyphenyl)-4-methyl-2- phenylpy razolo [1,5-a] py rimid in-7(4H)-one
Figure imgf000246_0001
[001021 J To a mixture of Intermediate 3 (2.4 g, 5.49 mmol, leq.) and Cs2C03 (2.14 g, 6.59 mmol, 1.2 eq.), in DMF (8 ml) was added Mel (774mg, 5.49 mmol, 1.0 eq). The mixture was then stirred at rt overnight. The mixture was poured into water (100 ml) and filtered. The filter cake was washed with MeOH to give Intermediate 4 (2.9 g) as a white solid. LC-MS: m/z 451.9 (M+H)+.
[001022] Step D: 5-((benzyloxy)methyl)-3-bromo-6-(4-methoxyphenyl)-4-methyl-2- phenylpyrazolo[l,S-a]pyrimidin-7(4H)-one
Figure imgf000246_0002
[001023] To a mixture of Intermediate 4 (2.9 g, 6.6 mmol, leq) in DMF (20 ml) was added NBS (1.37 g, 7.94 mmol, 1.2 eq). The reaction mixture was then stirred at rt for 2h. The mixture was poured into water (200 ml) and filtered to give Intermediate 5 (3.1 g, yield 91%) as a white solid. LC-MS: m/z 430.1 (M+H)+.
[001024] Step E: 5-((benzyloxy)methyl)-6-(4-methoxyphenyl)-4-methyl-2,3- diphenylpy razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000246_0003
[001025] A suspension of Intermediate 5 (1.5 g, 2.83 mmol), phenylboronic acid (414 mg, 3.40 mmol, 1.2 eq), Pdng (368 mg, 0.57 mmol, 0.2 eq) and K2C03 (982 mg, 7.1 mmol, 2.5 eq) in 1.4-dioxane (30 ml) and H20 (1.5 ml) was stirred at 90°C for 5h under N2 atmosphere. The reaction mixture was then cooled to r.t. and filtered. The filtrate was concentrated in vacuo and purified by flash column chromatography silica gel to obtain Intermediate 6 (300 mg, 20% yield). LC-MS: m/z 527.9 (M+H)+
[001026] Step F: Compound 249: 5-(hydroxymethyl)-6-(4-methoxyphenyl)-4-methyl- 2,3 -diphenylpyrazolo [1,5 -a]pyrimidin-7(4H)-one
Figure imgf000247_0001
[001027] To a solution of Intermediate 6 (150 mg, 0.28 mmol) in dry DCM (5 mL) was added dropwise BCh DCM (5 mL, IN, 2.0 eq) at 0°C. After addition, the mixture was stirred at rt for 2 h. The mixture was quenchedby careful adding ice-water and extracted with EA. The combined organic phase was washed with water and brine, dried over anhydrous Na2S0 , filtered, and concentrated under reduced pressure to give the title compound 7.
[001028] 1H NMR (DMSO-d6) δ: 7.42 - 7.50 (m, 5H), 7.34 - 7.40 (m, 2H), 7.22 - 7.32 (m, 5H), 6.98 - 7.07 (m, 2H), 5.63 (t, J = 4.8 Hz, 1H), 4.34 (d, J = 4.8 Hz, 2H), 3.82 (s, 3H), 3.44 (s, 3H). LC-MS: m/z 438.0 (M+H) +.
[001029] Compound 250
Figure imgf000247_0002
[001030] Step A: 3-(4-nitrophenyl)-3-oxo-2-phenylpropanenitrile
Figure imgf000248_0001
[001031] To a solution of 2-phenylacetonitrile (585 mg, 5 mmol) in THF (30 mL) was added n-BuLi (2.5 mol/L, 2 mL, 1.0 eq.) at -78°C. 4-nitrobenzoyl chloride (1.1 eq) was added dropwise after the mixture was stirred at -78°C for 30 min. The mixture was stirred at -78°C for 15 min, and then warmed to r.t. and stirred for 3h. The mixture was diluted with EA (30 mL) and quenched with saturated NH4CI. The organic phase was separated and washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to get Intermediate 2 which was used to the next step without further purification. LC-MS: m/z 267.0 (M+H)+.
[001032J Step B: 3-(4-nitrophenyl)-4-phenyl-1H -pyrazoI-5-amine
Figure imgf000248_0002
[001033] The mixture of Intermediate 2 (750 mg, 2.8 mmol, 1 eq.) and hydrazine hydrate (2 eq.) in EtOH/AcOH (5/1,10 mL/2 mL) was refluxed for 2h. The mixture was then cooled to r.t. and evaporated. The residue was dissolved in EA (10 mL) and neutralized with 10% NaHC03. The organic phase was separated and the water phase was extracted with EA (10 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by prep-TLC to afford the desired Intermediate 3 as a bright yellow solid. LC-MS: m/z 281.1 (M+H)+.
[001034] Step C: Compound 251: 5-methyl-2-(4-nitrophenyl)-3-phenyl-6-(quinolin- 6-yI)py razo lo [ 1 ,5-a] pyrimidin-7(4 H)-one
Figure imgf000248_0003
[001035] The mixture of Intermediate 3 (95 mg, 0.34mmol, leq.) and methyl 3-oxo-2- (quinolin-6-yl)butanoate 7 (1.5 eq.) in AcOH (5 mL) was stirred at 100 °C for lh. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (5 mL) and neutralized with 10% NaHC03. The organic phase was separated and the water phase was extracted with EA (5 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by prep-TLC to afford Intermediate 4.
[001036] 1H NMR (DMSO-d6) δ : 12.19 (br. s., 1H), 8.94 (dd, J = 4.2, 1.6 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1 H), 8.21 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.6 Hz, 1 H), 7.97 (d, J = 1.6 Hz, 1H), 7.75 (dd, J = 8.6, 1.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.58 (dd, J = 8.4, 4.4 Hz, 1H), 7.46 - 7.54 (m, 3H), 7.36 - 7.42 (m, 2H), 2.26 (s, 3H). LC-MS: m/z 474.0 (Μ+ΗΓ [001037] Step D: Compound 250: 2-(4-aminophenyl)-5-methyl-3-phenyl-6-(quinolin- 6-yl)pyrazolo[ 1 , 5-a]pyrimidin-7(4H)-one
Figure imgf000249_0001
[001038] To a solution of Intermediate 4 (35 mg, 0.07 mmol) in THF (10 mL) was added saturated NH4CI (1 mL) and zinc powder (96 mg, 1.5 mmol, 20 eq.). The reaction was stirred at r.t. for 5h. LCMS indicated that the reaction was completed. The mixture was filtered through celite. The filtrate was extracted with DCM (5 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the desired product compound 5.
[001039]1H NMR (DMSO-d6) δ : 8.82 - 8.94 (m, 1H), 8.22 - 8.43 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 7.89 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 8.2, 4.2 Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 6.49 (d, J = 8.2 Hz, 2H), 2.19 (s, 3H). LC-MS: m/z 444.9 (M+Hf. [001040] Compound 252
Figure imgf000250_0001
[001041] Step A: methyl l-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate
Figure imgf000250_0002
[001042] To a solution of methyl 1H-pyrrole-3-carboxylate (2g, 16.0 mmol) in THF (80 mL) was added sodium hydride (768 mg, 60% content, 19.2 mmol, 1.2 eq.) at 0°C. (2- (chloromethoxy)ethyl)trimethylsilane (4.0 g, 24 mmol, 1.5 eq.) was added dropwise after the mixture was stirred at 0°C for 30 min. Then the mixture was stirred at r.t. overnight. The mixture was diluted with EA (80 mL) and quenched with saturated NH4CI. The organic phase was separated and washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired product 2 as a colorless oil. (2.1 g, 51% yield)
[001043] 1H NMR (CHLOROFORM-d) δ : 7.40 (t, J = 2.0 Hz, 1H), 6.72 - 6.75 (m, 1H), 6.62 (dd, J = 3.0, 1.6 Hz, 1H), 5.19 (s, 2H), 3.82 (s, 3H), 3.45 (dd, J = 8.8, 7.8 Hz, 2H), 0.86 - 0.93 (m, 2H), -0.02 (s, 9H). LC-MS: m/z 256.0 (M+H)+
[001044] Step B: 3-oxo-2-phenyl-3-(l-((2-(trimethyls-lyl)ethoxy)methyl)-1H -pyrrol- 3-yl)propanenitrile
Figure imgf000250_0003
[001045] To the mixture of Intermediate 2 (2.1 g, 8.2 mmol) and 2-phenylacetonitrile (1.16 g, 9.9 mmol, 1.2 eq.) in THF (80 mL) was added NaHMDS (2mol/L in THF, 4.9 mL, 1.2 eq.) dropwise at 0°C. The mixture was then stirred at r.t. overnight. The mixture was diluted with EA (80 mL) and quenched with saturated NH4CI. The organic phase was separated and washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired product 3 as a light yellow solid (2 g, 7\% yield).
[001046]1H NMR (CHLOROFORM-d) δ : 7.45 - 7.50 (m, 3H), 7.35 - 7.42 (m, 3H), 6.76 (dd, J = 3.0, 2.2 Hz, 1H), 6.66 (dd, J = 3.0, 1.8 Hz, 1H), 5.21 (s, 1H), 5.18 (s, 2H), 3.40 - 3.47 (m, 2H), 0.85 - 0.92 (m, 2H), -0.03 (s, 9H). LC-MS: m/z 341.2 (M+H)+
[001047] Step C: 4-phenyl-3-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H -pyrrol-3-yl)- 1 H-py razol-5-amine
Figure imgf000251_0001
[001048] The mixture of Intermediate 3 (2 g, 5.9 mmol, 1 eq.) and hydrazine hydrate (590 mg, 1 1.8 mmol, 2 eq.) in EtOH/AcOH (5/1, 40 mL/8 mL) was refluxed for 2h. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (40 mL) and neutralized with 10% NaHC03. The organic phase was separated and the the water phase was extracted with EA (10 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired Intermediate 4 as a yellow solid. (2 g, 99% yield)
[001049] 1H NMR (CHLOROFORM-d) 6 : 7.37 - 7.42 (m, 4H), 7.28 - 7.31 (m, 1H), 6.77 (t, J = 1.8 Hz, 1H), 6.72 (t, J = 2.4 Hz, 1 H), 6.20 (dd, J = 2.8, 1.8 Hz, 1H), 5.10 (s, 2H), 3.37 - 3.44 (m, 2H), 0.83 - 0.90 (m, 2H), -0.05 - -0.01 (m, 9H). LC-MS: m z 355.3 (M+H)+
[001050] Step D: 5-methyl-3-phenyl-6-(quinolin-6-yl)-2-(l-((2- (trimethylsilyI)ethoxy)methyl)-1H -pyrrol-3-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one SEM
Figure imgf000252_0001
[001051] The mixture of Intermediate 4 (500 mg, 1.4mmol, leq.) and methyl 3-oxo-2- (quinolin-6-yl)butanoate 9 (1.5 eq.) in AcOH (10 mL) was stirred at 100 °C for lh. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (5 mL) and neutralized with 10% NaHC03. The organic phase was separated and the water phase was extracted with EA (5 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash
chromatography (DCM/Methanol=10/1, silica gel, uv) to get Intermediate 5 (550 mg, 71% yield). LC-MS: m/z 548.4 (M+H)+ [001052] Step E: 2-(l-(hydroxymethyI)-l H-pyrrol-3-yl)-5-methyl-3-phenyl-6- (quinolin-6-yl)pyrazolo[l,5-a]-pyrimidin-7(4H)-one
Figure imgf000252_0002
[001053] To a solution of Intermediate 5 (550 mg, 1.0 mmol) in DCM (15 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at r.t. overnight. The mixture was concentrated in vacuo to get Intermediate 6 which was used to the next step without further purification. (450 mg). LC-MS: m/z 448.2 (M+H)*
[001054] Step F: Compound 252: 5-methyl-3-phenyl-2-(1H-pyrrol-3-yl)-6-(quinolin- 6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000253_0001
[001055] To a solution of Intermediate 6 (450 mg, 1.0 mmol) in THF (15 mL) was added aq. NaOH solution (6mol/L,3 mL). The mixture was stirred at r.t. for 2h to give the desired product 7.
[001056] 1H NMR (DMSO-d6) δ : 10.78 (br. s., 1H), 8.74 - 8.91 (m, 1H), 8.32 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 7.4 Hz, 2H), 7.49 (dd, J = 8.2, 4.4 Hz, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.14 - 7.24 (m, 1H), 6.97 (br. s., 1H), 6.68 (br. s., 1H), 6.24 (br. s., 1H), 2.16 (s, 3H). LC-MS: m/z 418.0 (M+H)+.
[001057] Compound 253
Figure imgf000253_0002
[001058] Step A: ethyl 2-(3-chloro-4-nitrophenyl)-3-oxobutanoate 02N
CI
Figure imgf000254_0001
[0010591 To a mixture of 2-chloro-4-fluoro-l -nitrobenzene (10.0 g, 57. 1 mmol) and Cs2C03 (22.3 g, 68.5 mmol, 1.2 eq) in DMF (100 mL) was added ethyl 3-oxobutanoate (7.42 g, 57.1 mmol, 1.0 eq). Then the reaction mixture was stirred at 60°C for 5 h. The mixture was partitioned between EA and H20. The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/PE=l/10) to afford the desired Intermediate 2 (9.0 g, 55% yield). LC-MS: m/z 285.9 (M+H)+.
[001060] Step B: 6-(3-chloro-4-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000254_0002
[001061] A mixture of Intermediate 2 (7.6 g, 26.7 mmol) and compound 9 (6.27 g, 26.7 mmol, 1.0 eq) in CH3COOH (30 mL) was stirred at 100 °C for 5h. The reaction was then cooled to room temperature. The mixture was filtered and the filter cake was washed with MeOH to afford the desired Intermediate 3 (8.9 g, yield 73%) as a white solid. LC-MS: m/z 456.9 (M+H)+.
[001062] Step C: 6-(3-((4-methoxybenzyl)thio)-4-nitrophenyl)-5-methyl-2,3- dipheny Ipyrazolo [1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000254_0003
[001063] A mixture of Intermediate 3 (8.0 g, 17.5 mmol), K2C03 (6.1 g, 43.75 mmol, 2.5 eq) and (4-methoxyphenyl)methanethiol (5.4 g, 35.08 mmol, 1.0 eq) in DMF (35 mL) was stirred at 110°C overnight. The mixture was partitioned between EA and H20. The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the desired Intermediate 4 (8.2 g, 81% yield). LC- MS: m/z 574.9 (M+H) +.
[001064] Step D: 6-(4-amino-3-((4-methoxybenzyl)thio)phenyl)-5-methyl-2,3- diphenylpy razolo [1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000255_0001
[001065] To Intermediate 4 (1.0 g, 1.74 mmol, 1 eq.) in methanol (50 ml) and THF (60 ml) was added Pd/C (30 mg). The mixture was stirred rt under H2 atmosphere overnight. The mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford the desired
Intermediate 5 (700 mg, 74% yield). LC-MS: m/z 544.9 (M+H)+.
[001066] Step E: 2-(l,3-dioxoisoindolin-2-yl)-N-(2-((4-methoxybenzyl)thio)-4-(S- methyI-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5-a]pyrimidin-6-yl)phenyl)acetamide
Figure imgf000255_0002
[001067] To a mixture of 2-(l,3-dioxoisoindolin-2-yl)acetic acid (452 mg, 2.20 mmol) in DCM (5 mL) was added oxalyl chloride (3 ml) and cat. DMF (1.0 drop) at 0°C. Then the reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (2ml) and added to a solution of
Intermediate 5 (300 mg, 0.55 mmol) in DCM (5 ml) dropwise at 0°C under N2 atmosphere. The mixture was stirred rt overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/PE=l/5) to afford Intermediate 6 (250 mg, 62% yield). LC-MS: m/z 731.9 (M+H)+.
[001068] Step F: 2-((6-(5-methyl-7-oxo-2rJ-diphenyl-4,7-dihydropyrazolo[l,5- a]pyrimidin-6-yl)benzo[d]thiazoI-2-yl)methyl)isoindoline-l,3-dione
Figure imgf000256_0001
[001069] A mixture of Intermediate 6 (250 mg, 0.34 mmol) in TFA (5 mL) was stirred at 75°C for 3 h. The mixture was concentrated under reduced pressure. The residue was washed with MeOH to afford the desired Intermediate 7 (220 mg, 94% yield). LC-MS: m/z 593.9 (M+H)+.
[001070] Step G: Compound 253: 6-(2-(aminomethyl)benzo[d]thiazol-6-yl)-5-methyl- 2, 3 -diphenylpyrazolo [1,5 -a]pyrimidin-7(4H)-one
Figure imgf000256_0002
[001071] To a mixture of Intermediate 7 (200 mg, 0.33 mmol) in EtOH (8 mL) was added N2H4-H20 (2 ml). Then the reaction mixture was stirred at rt for 3 h. The mixture was partitioned between EA and H20. The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to afford the title Compound 8.
[001072] 1H NMR (DMSO-d6) δ: 8.18 (s., 1H), 8.01 (s., 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.36 - 7.52 (m, 7H), 7.33 (m, 4H), 4.26 (s, 2H), 2.18 (s, 3H). LC-MS: m/z 464.1 (M+H)+. [001073] Compound 254
Figure imgf000257_0001
[0010741 Step A: methyl 2-(4-fluoro-3-nitrophenyl) acetate
[001075] To a solution of 2-(4-fluoro-3-nitrophenyl) acetic acid (4.5 g, 22.6 mmol) in 50 mL of methanol was added 1 mL of cone, sulfuric acid at 0°C. The resulting mixture was then heated to reflux overnight. The mixture was concentrated in vacuo to 10 mL and quenched with aqueous sodium bicarbonate to pH 7. The resultant mixture was extracted with ethyl acetate (30 mL*3). The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo to afford methyl 2-(4-fluoro-3-nitrophenyl) acetate (4.1 g, 85% yield) as a yellow solid which was used for next step without further purification.
[001076] 1H NMR (Chloroform -d) δ : 8.02 (dd, J=6.98 Hz, 2.15 Hz, 1 H), 7.59 (ddd, J=8.60 Hz, 4.03 Hz, 2.42 Hz, 1 H), 7.21 - 7.38 (m, 1 H), 3.75 (s, 3 H), 3.71 (s, 2 H). 19F NMR (Chloroform-d) 6 -: 119.68 (s, 1 F). [001077] Step B: methyl 2- (4-(2-methoxy-2-oxoethyl)-2-nitrophenyl- amino) acetate
Figure imgf000258_0001
[001078] A mixture of methyl 2-(4-fluoro-3-nitrophenyl) acetate (4.1 g, 19.2 mmol), methyl 2-aminoacetate hydrochloride (2.67 g, 21.2 mmol), and N, N-diisopropylethylamine (5.4 g, 42.2 mmol) in N, N- dimethylformamide (50 mL) was heated to 30°C overnight. The mixture was diluted with brine (100 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo to afford methyl 2- (4-(2-methoxy-2-oxoethyl)-2-nitrophenyl- amino) acetate (4.6 g, 85% yield) as yellow solid which was used for next steps without further purification. LC- MS: m/z 283.1 (M+H)-.
[001079] Step C: methyl 2-(3-oxo-l, 2, 3, 4-tetrahydro- quinoxalin-6-yl) acetate
Figure imgf000258_0002
[001080] Under inert nitrogen atmosphere, a mixture of methyl 2- (4-(2-methoxy-2- oxoethyl)-2- nitrophenyl- amino) acetate (4.6 g, 16.3 mmol), Pd (w/w 10% on carbon, 1.73 g, 1.63 mmol), ammonium formate (15.4 g, 245 mmol) in ethanol (100 mL) was stirred at room temperature overnight. The reaction mixture was filtrated to remove Pd and ammonium formate. The filtrate obtained was evaporated to dryness. The solid was dissolved in ethyl acetate (100 mL) and washed with brine. The organic phase was then evaporated to dryness to afford methyl 2-(3-oxo-l, 2, 3, 4-tetrahydro- quinoxalin-6-yl) acetate (1.6 g, 45% yield) as yellow solid.
[001081] 1H NMR (DMSO- d) δ 10.22 (bs, 1 H), 6.65- 6.58 (m, 3 H), 5.92 (bs, 1 H), 3.69 (s, 2 H), 3.64 (s, 3 H), 3.46 (s, 2 H). LC-MS: m/z 221.1 (M+H)+.
[001082] Step D: methyl 2-(3-oxo-3, 4-dihydroquinoxalin-6-yl) acetate
Figure imgf000258_0003
[001083] A mixture of methyl 2-(3-oxo-l, 2, 3, 4-tetrahydro- quinoxalin-6-yl) acetate (3.4 g, 15.5 mmol) and manganese (IV) oxide (13.4 g, 155 mmol) in chloroform (200 mL) was heated to 50°C overnight. The mixture was filtrated to remove manganese (IV) oxide. The filtrate obtained was evaporated to dryness to afford methyl 2-(3-oxo-3, 4- dihydroquinoxalin-6-yl) acetate (2.9 g, 86% yield) as grey solid. LC-MS: m/z 219.1 (M+H)+.
[001084] Step E: methyl 2-(3-methoxyquinoxalin-6-yl) acetate
Figure imgf000259_0001
[001085] A mixture of 2-(3-oxo-3, 4-dihydroquinoxalin-6-yl) acetate (0.8 g, 3.67 mmol) in phosphoryl trichloride (6 mL) was heated to reflux for 2 h. The mixture was evaporated to remove phosphoryl trichloride. The crude oil was quenched with methanol at room temperature. The mixture was then evaporated to dryness. The crude was purified with column chromatography (methanol: dichloromethane = 1 : 20) on silica gel to afford methyl 2-(3-methoxyquinoxalin-6-yl) acetate (320 mg, 38% yield) as white solid. LC-MS: m/z 233.1
(M+H)+. [001086] Step F: methyl 2-(3-methoxyquinosalin- 6-yl)-3-oxobutanoate
Figure imgf000259_0002
[001087] Under inert nitrogen atmosphere, to a mixture of methyl 2-(3- methoxyquinoxalin-6-yl) acetate (220 mg, 0.948 mmol) in tetrahydrofuran (10 mL) at -78°C was added lithium hexamethyldisilylamide (2N, 0.95 mL, 1.89 mmol) dropwise. The mixture was then stirred at the same temperature for 1 h. Acetyl chloride (89 mg, 1.14mmol) was added into the mixture at -78°C. The reaction mixture was warmed slowly to room
temperature. The reaction was quenched with aqueous ammonium chloride and evaporated to dryness. The residue was purified with prep-TLC (methanol: dichloromethane = 1 : 20) on silica gel to afford methyl 2-(3-methoxyquinoxalin- 6-yl)-3-oxobutanoate (160 mg, 62% yield) as white solid. LC-MS: m/z 275.1 (M+H)+. [001088] Step G: Compound 254: 6-(3-methoxy- quinoxalin-6-yl)-5-methyl-2, 3- diphenylpyrazolo [1, 5-a]- pyrimidin-7^-/Hj-one
Figure imgf000260_0001
[001089] A mixture of methyl 2-(3-methoxyquinoxalin- 6-yl)-3-oxobutanoate (223 mg, 0.814mmol), 3,4-diphenyl-/H-pyrazol-5-amine (191 mg, 0.814 mmol) and acetate acid (2 mL) in dioxane (8 mL) was heated to 100°C overnight. The mixture was concentrated to to afford 6-(3-methoxy- quinoxalin-6-yl)-5-methyl-2, 3-diphenylpyrazolo [1, 5-a]- pyrimidin- l(4H)-ox\Q.
[001090] 1H NMR (DMSO-d6) δ : 12.07 (s, 1H), 8.64 (s, 1H), 8.07 (d, J=8Hz, 1H), 7.84 (d, J=2Hz, 1H), 7.64 (dd, J=8Hz, 2Hz, 1H), 7.43-7.50 (m, 5H), 7.34-7.38 (m, 5H), 4.08 (s, 3H), 2.27 (s, 3H). LC-MS: m/z 460.2 (M+H)+.
[001091] Compound 255
Figure imgf000260_0002
[001092] Step A: 5-fluoro-2-nitro-(N,N)-di-tert-butyl-carbonoaniline
Figure imgf000260_0003
[001093] To a solution of 5-fluoro-2-nitroaniline (5 g, 32 mmol) in CH2C12 was added N,N-dimethylpyridin-4-amine (390 mg, 3.2 mmol) and triethylamine (6.43 g, 64 mmol). The reaction mixture was stirred for 10 mins and then di-tert-butyl dicarbonate (20 g, 96 mmol) was added slowly and stirred overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting PE/EA=10: 1) to give the desired product (8 g, 71% yield). [001094] lU NMR (CHLOROFORM-d) 6 : 8.16 (dd, J = 9.1, 5.4 Hz, 1H), 7.16 - 7.24 (m, 1H), 7.07 (dd, J = 8.3, 2.7 Hz, 1H), 1.41 - 1.44 (m, 18H).
[001095] Step B: methyl 2-[(3-di-tert-butyldicarbo-amino-4-nitrophenyl]-3- oxobutanoate
Figure imgf000261_0001
[001096] To a solution of 2-[(3-di-tert-butyldicarbo-amino-4-nitrophenyl]-3- oxobutanoate (8 g, 22.4mmol) in DMF (20 ml) was added cesium carbonate (7.3 g, 44.8 mmol) and methyl 3-oxobutanoate (2.6 g, 22.4 mmol). The mixture was heated to 100 °C for 4h. The mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluting PE/EA=10: 1) to give the desired product (7 g, 69% yield).
[001097] Step C: methyl 2-(3-amino-4-nitrophenyl)-3-oxobutanoate
Figure imgf000261_0002
[001098] A solution of methyl 2-[(3-di-tert-butyldicarbo-amino-4-nitrophenyl]-3- oxobutanoate (2 g, 4.4 mmol) in HC1/MeOH (10 ml) was stirred for 4h. The reaction mixture was concentrated to give the desired product methyl 2-(3-amino-4-nitrophenyl)-3- oxobutanoate (1.1 g, 100% yield). [001099] Step D: 6-(3-amino-4-nitrophenyl)-5-methyI-2-phenyl-3-(piperidin-l- yl)py razolo f 1 ,5-a] py rimidin-7(4H)-one
Figure imgf000262_0001
[001100] A solution of methyl 2-(3-amino-4-nitrophenyl)-3-oxobutanoate (1.1 g, 4.3 mmol), 3-phenyl-4-(piperidin-l-yl)-1H-pyrazol-5-amine (1. 0 g, 4.3 mmol) in AcOH (10 ml) were heated to 120 °C overnight. The reaction mixture was concentrated. The residue was washed with ethyl acetate to give the desired product 6-(3-amino-4-nitrophenyl)-5-methyl-2- phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (710 mg, 38% yield).
[001101]1H NMR (DMSO-d6) δ : 7.98 - 8.10 (m, 3H), 7.66 (br. s., 2H), 7.43 - 7.52 (m, 3H), 6.99 (d, J = 1.6 Hz, 1H), 6.60 (dd, J = 8.9, 1.9 Hz, 1H), 3.07 - 3.21 (m, 4H), 2.33 (s, 3H), 1.71 (br. s., 4H), 1.51 - 1.63 (m, 2H). LC-MS : m/z 445.2 (M+H)".
[001102] Step £: 6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-l- yl)py razolo [ 1 ,5-a] py rimidin-7(4H)-one
Figure imgf000262_0002
[001103] To a solution of 6-(3-amino-4-nitrophenyl)-5-methyl-2-phenyl-3-(piperidin-l- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (710 mg, 1.6 mmol) in MeOH (20 ml) was added Pd/C (71 mg) under H2. The reaction mixture was stirred for 4h. The mixture was filtered and the filtrate was concentrated to give the desired product 6-(3,4-diaminophenyl)-5-methyl-2- phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (500 mg, 75% yield). [001104]1H NMR (DMSO-d6) δ : 11.21 (br. s., 1H), 8.05 - 8.17 (m, 2H), 7.46 (t, J = 7.4 Hz, 2H), 7.35 - 7.42 (m, 1H), 6.54 (d, J = 7.8 Hz, 1H), 6.43 (d, J = 1.9 Hz, 1H), 6.29 (dd, J = 7.8, 1.9 Hz, 1H), 4.49 (br. s., 4H), 3.07 (d, J = 5.1 Hz, 4H), 2.22 - 2.29 (m, 3H), 1.66 (br. s., 4H), 1.51 - 1.61 (m, 2H). LC-MS: m/z 415.2 (M+H)+. [001105] Step F: Compound 255: 5-methyl-2-phenyl-3-(piperidin-l-yl)-6-(quinoxalin- 6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000263_0001
[001106] To a solution of 6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-l- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (100 mg, 0.24 mmol) in EtOH (10 ml) was added oxalaldehyde (21 mg, 0.36 mmol). Then the reaction mixture was heated to 80 °C for 2h. The reaction mixture was concentrated to give the desired product 5-methyl-2-phenyl-3- (piperidin-l-yl)-6-(quinoxalin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[001107] 1H NMR (CHLOROFORM-d) δ : 8.86 - 8.93 (m, 2H), 8.21 (d, J = 8.6 Hz, 1H), 8.07 (s, 1H), 8.02 (br. s., 1H), 7.81 - 7.88 (m, 1H), 7.54 (br. s., 1H), 7.47 (br. s., 3H), 3.06 (br. s., 4H), 2.44 (br. s., 3H), 1.77 (br. s., 2H), 1.71 (br. s., 3H), 1.65 (br. s., 2H). LC- MS: m/z 437.4 (M+H)+.
[001108] Compound 256
Figure imgf000263_0002
[001109] Step A: 5-fluoro-N-methyl-2-nitroaniline
Figure imgf000264_0001
[001110] To a solution of 2,4-difluoro-l -nitrobenzene (10 g, 63 mmol) in MeCN was added CH3NH2 (63 ml, lmmol/ml in MeOH) at 0 °C. The reaction mixture was stirred for 4h. The mixture was filtered to give Intermediate 2 (10 g) as a yellow solid. LC-MS: m/z 170.2 (M+H)+.
[001111] Step B: dimethyl 2-(3-(methylamino)-4-nitrophenyl)malonate
Figure imgf000264_0002
[001112] To a solution of Intermediate 2 (5 g, 29.4 mmol) in DMSO (20 ml) was added dimethyl malonate (3.88 g, 29.4 mmol) and cesium carbonate (19.2 g, 58.8 mmol). The reaction mixture was heated to 120 °C for 4h. The reaction mixture was then poured into water, extracted with ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluting PE/EA=2: 1) to give the desired product (3.4 g).
[001113] 1H NMR (DMSO-d6) δ : 8.13 - 8.25 (m, 1 H), 8.07 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.67 (dd, J = 8.9, 1.6 Hz, 1H), 5.16 (s, 1H),3.71 (s, 6H) 2.92 - 2.98 (m, 3H). LC-MS: m/z 283.3 (M+H) +.
[001114] Step C: methyl
Figure imgf000264_0003
2-(3-(methylamino)-4-nitrophenyl)acetate
Figure imgf000264_0004
[001115] To a solution of dimethyl 2-(3-(methylamino)-4-nitrophenyl)malonate (3.4 g, 12 mmol) in DMSO (20 ml) was added saturated NaC1 (5 ml). The reaction mixture was heated to 120 °C for 3h. The reaction mixture was then poured into water, extracted with ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluting PE/EA=2: 1) to give the desired product (200 mg). [001116] 1H NMR (DMSO-d6) δ : 8.19 (d, J = 4.3 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 6.87 - 6.96 (m, 1H), 6.59 (dd, J = 8.9, 1.6 Hz, 1H), 3.76 (s, 3H), 2.95 (d, J = 4.8 Hz, 4H). LC- MS: m/z 225.1 (M+H) +.
[001117] Step D: methyl 2-(3-(methyIamino)-4-nitrophenyl)-3-oxobutanoate
Figure imgf000265_0001
[001118] To a solution of methyl 2-(3-(methylamino)-4-nitrophenyl)acetate (200 mg, 0.89 mmol)) in THF (15 ml) was added slowly LDA (4.5 ml, 2mmol/ml in THF) at -30 °C. Then acetyl chloride (104 mg, 1.34 mmol) was added slowly. The reaction mixture was stirred for 30mins at -30 °C and allowed to room temperature for lh. The mixture was poured into water, extracted by ethyl acetate, dried over anhydrous Na2S04, filtered, and
concentrated to give the crude product (200 mg) as a yellow liquid, which was used directly to the next step without further purification.
[001119] Step E: 5-methyl-6-(3-(methylamino)-4-nitrophen>l)-2,3- diphenylpy razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000265_0002
[001120] A mixture of methyl 2-(3-(methylamino)-4-nitrophenyl)-3-oxobutanoate (crude, 200 mg) and 3,4-diphenyl-1H-pyrazol-5-amine (100 mg, 0.43 mmol) in AcOH (10 ml) was heated to 120 °C overnight. The reaction mixture was cooled to room temperature. The precipitate was filtered to give the desired product 5-methyl-6-(3-(methylamino)-4- nitrophenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (35 mg). LC-MS: m/z 452.3 (M+H)+.
[001121] Step F: 6-(4-amino-3-(methylamino)phenyl)-S-methyl-2,3- d ipheny Ipy razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000266_0001
[001122] To a solution of 5-methyl-6-(3-(methylamino)-4-nitrophenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (35 mg, 0.078 mmol) in MeOH (10 ml) was added Pd/C (5 mg) under H2. The reaction mixture was stirred for 4h. The mixture was filtered and the filtrate was concentrated to give the desired product 6-(4-amino-3-
(methylamino)phenyl)-5-methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (10 mg) as a solid. LC-MS: m/z 422.2 (M+H)+.
[001123] Step G: Compound 256: 5-methyl-6-(l -methyl- 1 H-benzo[d]imidazol-6-yl)- 2, 3 -dipheny lpyrazolo [ 1 , 5 -a] pyrimidin-7(4H)-one
Figure imgf000266_0002
[001124] A solution of 6-(4-amino-3-(methylamino)phenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (10 mg, 0.024 mmol) in HCOOH (5 ml) was heated to 120 °C for lh. The reaction mixture was concentrated in vacuo to give the desired product 5-methyl-6-( 1 -methyl- 1 H-benzo[d]imidazol-6-yl)-2,3-diphenylpyrazolo[ 1 ,5- a]pyrimidin-7(4H)-one.
[001125] 1H NMR (METHANOL^) δ : 8.21 (s, 1 H), 7.77 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.27 - 7.57 (m, 1 1H), 3.95 (s, 3H), 2.28 (s, 3H). LC-MS: m/z 432.0 (M+H)+. [001126] Compound 257 and Compound 258
Figure imgf000267_0001
[001127] Step A: methyl 2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)acetate
Figure imgf000267_0002
[001128] A mixture of methyl 2-(4-hydroxy-3-nitrophenyl)acetate (5 g, 0.024 mol), K2C03 (6.5 g, 0.048 mol), and l-(chloromethyl)-4-methoxybenzene (5.6 g 0.036 mol) was heated to 60°C for 4h. The reaction mixture was poured into water, extracted with ethyl acetate, dried over anhydrous Na2S04, filtered, concentrated. The residue was purified by column chromatography on silica gel (eluting PE/EA=3: 1) to give the desired product (2 g, 53% yield). LC-MS: m/z 332.2 (M+H)+.
[001129] Step B: methyl 2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)-3- oxobutanoate
Figure imgf000267_0003
[001130] To a solution of methyl 2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)acetate (2 g, 6.0 mmol) in THF (50 ml) was added slowly LDA (3 ml, 2mmol/ml in THF) at -30 °C. Then acetyl chloride (702 mg, 9.0 mmol) was added slowly. The reaction mixture was stirred for 30mins at -30 °C and allowed to room temperature for lh. The mixture was poured into water, extracted with ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated to give the crude product (1.5 g) as a yellow liquid, which was used directly to next step without further purification.
[001131] Step C: 6-(4-hydroxy-3-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[l,5- a] pyrimidin-7(4H)-one
Figure imgf000268_0001
[001132] A solution of methyl 2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)-3- oxobutanoate (crude, 1.5 g) and 3,4-diphenyl-1H-pyrazol-5-amine (1 g, 4.25 mmol) in AcOH (10 ml) was heated to 120 °C overnight. The reaction mixture was cooled to room
temperature. The precipitate was filtered to give the desired product 6-(4-hydroxy-3- nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[l ,5-a]pyrimidin-7(4H)-one (600mg, 32% yield). LC-MS: m/z 439.3 (M+H)÷. [001133] Step D: 6-(3-amino-4-hydroxyphenyl)-5-methyl-2-(-diphenylpyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000268_0002
[001134] To a solution of 6-(4-hydroxy-3-nitrophenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (600mg, 1.37 mmol) in MeOH (50 ml) was added Pd/C (60 mg) under H2. The reaction mixture was stirred for 4h. The mixture was filtered and the filtrate was concentrated to give the desired product 6-(3-amino-4- hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (450 mg, 80% yield). [001135] 1H NMR (DMSO-d6) δ : 11.96 (s, 1H), 10.84 (br. s., 1H), 9.88 (br. s., 2H), 7.37 - 7.51 (m, 5H), 7.24 - 7.37 (m, 6H), 7.19 (dd, J = 8.3, 1.9 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 2.20 (s, 3H). LC-MS: m/z 409.2 (M+H)+.
[001136J Step E: 2-chIoro-N-(2-hydroxy-5-(5-methyl-7-oxo-2 3-diphenyI-4,7- dihy dropy razolo [ 1 ,5-a] pyrimidin-6-yl)phenyl)acetamide
Figure imgf000269_0001
[001137] A mixture of 6-(3-amino-4-hydroxyphenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (450mg, 1.1 mmol), 2-chloroacetyl chloride (136 mg, 1.2 mmol), and K2C03 (455 mg, 3.3 mmol) in acetone (50 ml) was heated to 80 °C overnight . The reaction mixture was poured into water, extracted with ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated. The resultant solid was washed with ethyl acetate to give the desired product 2-chloro-N-(2-hydroxy-5-(5-methyl-7-oxo-2,3-diphenyl- 4,7-dihydropyrazolo[l ,5-a]pyrimidin-6-yl)phenyl)acetamide (250 mg, 47% yield). LC-MS: m/z 485.2 (M+H)+. [001138] Step F: Compound 257: 6-(5-methyl-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-6-yl)-2H-benzo[b][l,4]oxazin-3(4H)-one
Figure imgf000269_0002
[001139] A mixture of 2-chloro-N-(2-hydroxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l ,5-a]pyrimidin-6-yl)phenyl)acetamide (250 mg, 0.52 mmol), and Cs2C0 (258 mg, 1.04 mmol) in acetone (40 ml) was heated to 100 °C overnight. The reaction mixture was poured into water, extracted with ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated to give the desired product 6-(5-methyl-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-6-yl)-2H-benzo[b][l,4]oxazin-3(4H)-one. [001140] 1H NMR (DMSO-d6) δ : 11.93 (s, 1H), 10.79 (s, 1H), 7.38 - 7.56 (m, 5H), 7.24 - 7.38 (m, 4H), 7.01 (d, J = 8.9 Hz, 1H), 6.81 - 6.92 (m, 2H), 4.63 (s, 2H), 2.18 (s, 3H). LC- MS: m/z 449.0 (M+H) +.
[001141] Step G: Compound 258: 6-(3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)-5- methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000270_0001
[001142] To a solution of 6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5- a]pyrimidin-6-yl)-2H-benzo[b][l,4]oxazin-3(4H)-one (110 mg, 0.25 mmol) in THF (20 ml) was added BH3.THF (1 ml, lmmol/ml). The reaction mixture was heated to 80 °C for 4h. The reaction mixture was then cooled to room temperature. MeOH (10ml) was added carefully, and then the reaction mixture was stirred for 10 mins. The mixture was concentrated to give the desired product.
[001143] NMR (DMSO-d6) δ : 11.82 (br. s., 1H), 7.39 - 7.51 (m, 5H), 7.33 (br. s.,
5H), 6.68 (d, J = 7.9 Hz, 1H), 6.50 (s, 1H), 6.38 (d, J = 8.2 Hz, 1H), 5.80 (br. s., 1H), 4.16 (br. s., 2H), 3.31 (br. s., 2H), 2.17 (s, 3H). LC-MS: m/z 435.0 (M+H)+.
[001144] Compound 259
Figure imgf000271_0001
[001145] Step A: methyl 2-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)acetate
Figure imgf000271_0002
[001146] To a solution of methyl 2-(4-hydroxy-3-methoxyphenyl)acetate (1 g, 5.1 mmol) in CH3CN (50 ml) was added K2C03 (1.4 g, 10.2 mmol) and PMBCI (795 mg, 5.1 mmol). Then the mixture was heated to 80 °C for 2h. The reaction mixture was poured into water, extracted with ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluting PE/EA=2: 1) to give the desired product (900 mg, 56% yield). LC-MS: m/z 317.3 (M+H)+.
[001147] Step B: methyl 2-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-3- oxobutanoate
Figure imgf000271_0003
[001148] To a solution of methyl 2-(3 -methoxy-4-((4- methoxybenzyl)oxy)phenyl)acetate (900 mg, 2.85mmol) in THF (15 ml) was added slowly LDA (4.5 ml, 2mmol/ml in THF) at -30 °C. Then acetyl chloride (266 mg, 1.34 mmol) was added slowly. The reaction mixture was stirred for 30 mins at -30 °C and allowed to room temperature for lh. The mixture was poured into water, extracted with ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated to give the crude product (700 mg) as a yellow liquid, which was used directly to the next step without further purification.
[001149] Step C: 6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-5-methyl-2 - diphenyIpyrazoIo[l,5-a]pyriniidin-7(4H)-one
Figure imgf000272_0001
[001150] A solution of methyl 2-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-3- oxobutanoate (crude, 400 mg) and 3,4-diphenyl-1H -pyrazol-5-amine (200 mg, 0.86 mmol) in AcOH (10 ml) was heated to 120 °C overnight. The reaction mixture was cooled to room temperature. The precipitate was filtered to give the desired product 6-(3-methoxy-4-((4- methoxybenzyl)oxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one ( 120 mg, 26% yield). LC-MS: m/z 544.2 (M+H)+.
[001151] Step D: Compound 259: 6-(4-hydroxy-3-methoxyphenyl)-5-methyl-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000272_0002
[001152] To a solution 6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (120 mg, 0.22 mmol) in MeOH (10 ml) was added 4N HC1/dioxane solution (10 ml). The reaction mixture was stirred for lh. When the starting material was consumed, the mixture was concentrated in vacuo to give the desired product 6-(4-hydroxy-3-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin- 7(4H)-one.
[001153] NMR (DMSO-d6) δ : 1 1.85 (s, 1H), 9.04 (s, 1H), 7.37 - 7.52 (m, 6H), 7.27
- 7.37 (m, 6H), 6.79 - 6.90 (m, 2H), 6.72 (dd, J = 8.1, 1.9 Hz, 1H), 2.19 (s, 3H). LC-MS: m/z 424.1 (M+H)+. [001154] Compound 260 & Compound 261
Figure imgf000273_0001
[001155] Step A: ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate
Figure imgf000273_0002
[001156] A mixture of ethyl 2-(3-hydroxy-4-methoxyphenyl) acetate (4.3 g, 20.5 mmol), ((2-bromoethoxy)methyl)benzene (7.88 g, 36.8 mmol), potassium carbonate (5.66 g, 41 mmol) in N,N-dimethylformamide (50 mL) was heated to 80 °C for 18 h. The mixture was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (100 mL) three times. The combined organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by column chromatography (ethyl acetate:petroleum ether=l :5) to afford ethyl 2-(3-(2-(benzyloxy)ethoxy)-4- methoxyphenyl)acetate (3.8 g, 54% yield) as a colorless oil. [001157] Step B: ethyl 2-(3-(2-(benzyloxy)ethoxy)-4- methoxyphenyl)-3- oxobutanoate
Figure imgf000273_0003
[001158] To a mixture of ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate (690 mg, 2 mmol) in tetrahydrofuran (10 mL) was added lithium diisopropylamide (2N, 1 mL, 2 mmol) at -78°C under nitrogen atmosphere. The mixture was stirred at the same temperature for 1 h. Acetyl chloride (156 mg, 2 mmol) was added into the mixture at -78°C slowly. After addition, the mixture was stirred at -78°C for 1 h and warmed slowly to room temperature overnight. The mixture was quenched by adding aqueous ammonium chloride to pH 6-7 and extracted with ethyl acetate (20 mL) three times. The combined organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=l :5) to afford ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate (280 mg, 38 % yield) as a colorless oil. LC-MS: m/z 387.2 (M+H)+.
[001159] Step C: 6-(3-(2-(benz loxy)ethoxy)-4-methoxyphenyl)-5-methyl-2^3- diphenylp razolo [ 1 ,5-a] yrimidin-7(4H)-one
Figure imgf000274_0001
[001160] A mixture of ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3- oxobutanoate (280 mg, 0.725 mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (170 mg, 0.725 mmol) in acetic acid (5 mL) was heated to reflux for 2 h. The mixture was evaporated to remove acetic acid. The residue was purified with column chromatography (methanol:
dichloromethane=l :20) to afford 6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (120 mg, 30% yield) as a yellow solid. LC- MS: m/z 558.2 (M+H)+.
[001161] Step D: Compound 260 & Compound 261: 6-(3,4-dihydroxyphi methyl-2,3-diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000275_0001
[001162] 6-(4-hydroxy-3-(2-hydroxyethoxy)phenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a] pyrimidin- 7(4H)-one
Figure imgf000275_0002
[001163] A mixture of 6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3- diphenyl- pyrazolo[l,5-a] yrimidin-7(4H)-one (200 mg, 0.359 mmol) and tribromoborane (1M in DCM, 2 mL) was stirred at room temperature for 1 h. The reaction was quenched with methanol at 0 °C. The mixture was evaporated to dryness to afford 6-(3,4-dihydroxyphenyl)- 5-methyl-2,3-diphenylpyrazolo[l ,5-a]pyrimidin-7(4H)-one and 6-(4-hydroxy-3-(2- hydroxyethoxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[l,5-a] pyrimidin-7(4H)-one.
[001164] 6-(3,4-dihydroxy phenyl)-5-methyl-2,3-diphenylpy razolo [ 1 ,5-a] pyrimidin- 7(4H)-one (Compound 260)
[001165] 1H NMR (DMSO-d6) δ : 11.82 (s, 1 H), 7.37 - 7.52 (m, 5 H), 7.20 - 7.37 (m, 5 H), 6.78 (d, J=8.06 Hz, 1 H), 6.66 - 6.73 (m, 1 H), 6.55 (d, J=7.79 Hz, 1 H), 2.17 (s, 3 H). LC-MS: m/z 410.1 (M+Hf.
[001166] 6-(4-hydroxy-3-(2-hydroxyethoxy)phenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a] pyrimidin- 7(4H)-one (Compound 261) [001167] 1H NMR (DMSO-d6) δ : 11.85 (s, 1 H), 8.82 (s, 1 H), 7.38 - 7.58 (m, 5 H),
7.24 - 7.38 (m, 5 H), 6.81 - 6.92 (m, 2 H), 6.73 (dd, J=8.06, 1.88 Hz, 1 H), 4.91 (t, J=6.04 Hz, 1 H), 3.97 (t, J=4.97 Hz, 2 H), 3.74 (q, J=5.46 Hz, 2 H), 2.06 - 2.22 (m, 3 H). LC-MS: m/z 454.2 (M+H)+. [001168] Compound 262
Figure imgf000276_0001
[001169] Step A: 5-methyl-2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin-7(4H)- one
Figure imgf000276_0002
[001170] A mixture of 3-phenyl-4-(piperidin-l-yl)-/H-pyrazol-5-amine (8.43 g, 34.8 mmol) and methyl 3-oxobutanoate (9 g, 69.2 mmol) in acetic acid (5 mL) was heated to reflux for 2h. The mixture was cooled to room temperature. The suspension obtained was filtered. The resulting solid was washed with water and cold methanol to afford 5-methyl-2- phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (7.9 g, 74% yield) as a white solid. LC-MS: m/z 309.2 (M+H)+.
[001171] Step B: 5-methyl-2-phenyl-3-(piperidin-l-yl)-4- ((2- (trimethy Isily I)ethoxy)methy 1) pyrazolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000276_0003
[001172] To a mixture of 5-methyl-2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a] pyrimidin-7(4H)-one (5.5 g, 17.9 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (1.4 g, 35.8 mmol) slowly at 0 °C. After addition, the mixture was stirred at 0 °C for 1 h. (2-(Chloromethoxy)ethyl)trimethylsilane (3.6 g, 21.7 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was quenched with brine and extracted with ethyl acetate (50 mL) three times. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was purified by column chromatography (methanol :dichloromethane= 1 :20) to afford 5-methyl-2-phenyl-3-(piperidin-l -yl)-4- ((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (2.5 g, 35% yield) as a white solid. LC-MS: m/z 439.2 (M+H)+.
[001173] Step C: 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)- 4-((2- (trimethylsily l)ethoxy)methyl) pyrazolo [1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000277_0001
[001174] To a mixture of 5-methyl-2-phenyl-3-(piperidin-l-yl)-4- ((2-
(trimethylsilyl)ethoxy)- methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (1.2 g, 2.74 mmol) and triethylamine (0.32 g, 3.16 mmol) in dichloromethane (20 mL) at room temperature was added N-bromosuccinimide (0.58 g, 3.47 mmol) at room temperature. Then the mixture was stirred at room temperature for 2 h. The mixture was concentrated. The residue was purified by column chromatography (methanol:dichloromethane=l :20) to afford 6-bromo-5-methyl-2- phenyl-3-(piperidin- 1 -yl)- 4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[ 1 ,5-a]pyrimidin- 7(4H)-one (1.3 g, 80 % yield) as a white solid. LC-MS: m/z 519.2, 517.2 (M+H)+.
[001175] Step D: 6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3- (piperidin-l-yl)-4-((2- (trimethylsily l)ethoxy) methyl)py razolo [1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000277_0002
[001176] To a solution of 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)- 4-((2- (trimethylsilyl)- ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (100 mg, 0.194 mmol) and 4-hydroxyphenylboronic acid (41 mg, 0.293 mmol) in dioxane/H20 (5 mlJl mL) was added 1, l'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (28 mg, 0.0344 mmol) and sodium carbonate (42 mg, 0.396 mmol). The reaction mixture was then refluxed under nitrogen atmosphere overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol: dichloromethane=l/20) to afford 6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3- (piperidin-1 -yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (60 mg, 59% yield) as a white solid. LC-MS: m/z 531.3 (M+H)+.
[001177] Step E: Compound 262: 6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3- (piperidin-l-yl)pyrazolo[l,5-a] pyrimidin- 7(4H)-one
Figure imgf000278_0001
[001178] A mixture of 6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3- (piperidin-l-yl)-4- ((2- (trimethylsilyl) ethoxy)methyl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (60 mg, 0.1 13 mmol) in CF3COOH (2 mL) was heated to 60 °C for 3 h. The mixture was cooled to room temperature and concentrated in vacuo to remove solvent. The resulting residue was washed with saturated aqueous sodium bicarbonate. The suspension obtained was filtered to afford 6- (4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a] pyrimidin-7(4H)- one.
[001179] 1H NMR (Methanol-d4) δ : 8.07 (d, J=6.72 Hz, 2 H), 7.45 (d, J=7.52 Hz, 3 H), 7.16 (d, J=8.33 Hz, 2 H), 6.88 (d, J=8.33 Hz, 2 H), 3.06 - 3.16 (m, 4 H), 2.34 (s, 3 H), 1.75- 1.73 (m, 4 H), 1.63-1.62 (m, 2 H). LC-MS: m/z 401.2 (M+H) +. [001180] Compound 263
Figure imgf000279_0001
[001181] Step A: 2,2,2-trifluoro-N-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H-l,2,4- triazol-3-yl)acetamide
SEM
Figure imgf000279_0002
[001182] To a solution of l-((2-(trimethylsilyl)ethoxy)methyl)-1H-l,2,4-triazol-3-amine (3 g, 14 mmol) in THF (50 ml) was added slowly NaHMDS (14 ml,l mmol/ml) at -78 °C. After addition, the mixture was stirred at -78 °C for 30 mins, and then allowed to -30 °C for 30 mins. TFAA (2 g, 21 mmol) was added slowly, and the mixture was stirred at -30 °C for 20 mins. The reaction mixture was allowed to warm to room temperature overnight. The mixture was poured into water, extracted with ethyl acetate, dried over anhydrous Na2S04, and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting PE/EA=1 : 1) to give the desired product 2,2,2-trifluoro-N-(l-((2- (trimethylsilyl)ethoxy)methyl)-l H-l,2,4-triazol-3-yl)acetamide (2 g, 46% yield).
[001183] 1H NMR (DMSO-d6) δ : 12.14 (s, 1H), 8.76 (s, 1H), 5.52 (s, 2H), 3.63 - 3.71 (m, 2H), 3.51 - 3.61 (m, 2H), 0.80 - 0.98 (m, 9H). LC-MS: m/z 31 1.2 (M+H) +.
[001184] Step B: Compound 263: 2,2,2-trifluoro-N-((7-oxo-2,3-diphenyl-6-(quinolin- 6-yl)-4,7-dihydropyrazolo[l,5-a]pyrimidin-5-yl)methyl)acetamide
Figure imgf000280_0001
[001185] To a solution of 2,2,2-trifluoro-N-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H- l,2,4-triazol-3-yl)acetamide (200 mg, 0.65 mmol) in NMP (10 ml) was added t-BuOk (1 ml, lmmol/ml in THF). The reaction mixture was stirred for 30 mins, and then 5-(chloromethyl)- 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (100 mg, 0.22 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was poured into water, extracted with ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated to to give the desired product 2,2,2-trifluoro-N-((7-oxo-2,3-diphenyl-6- (quinolin-6-yl)-4,7-dihydropyrazolo[l,5-a]pyrimidin-5-yl)methyl)acetamide.
[001186] 1H NMR (DMSO-d6) δ : 12.23 (s, 1H), 9.65 (br. s., 1H), 8.95 (br. s., 1H), 8.35 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.92 (s, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 7.9, 4.2 Hz, 2H), 7.46 (br. s., 4H), 7.19 - 7.42 (m, 6H), 4.32 (br. s., 2H). LC-MS: m/z 540.0 (M+H)+.
[001187] Compound 264
Figure imgf000280_0002
[001188] Step A: N-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)methyl)hydrazinecarboximidamide
Figure imgf000281_0001
[001189] A mixture of 5-(aminomethyl)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 222, 200 mg, 0.47 mmol) and methyl hydrazinecarbimidothioate (100 mg, 0.94 mmol) in EtOH (20 ml) in a seal tube were heated to 120 °C overnight. The reaction mixture was concentrated to dryness. The resultant solid was washed with ethyl acetate to give the desired product (170 mg, 75% yield);
[001190] 1H NMR (DMSO-d6) δ : 8.62 (br. s., 1H), 7.49 - 7.58 (m, 4H), 7.31 - 7.42 (m, 4H), 7.17 - 7.30 (m, 4H), 7.04 - 7.14 (m, 1H), 6.96 (d, J = 8.6 Hz, 2H), 4.72 (br. s., 2H), 4.07 (br. s., 2H), 3.80 (s, 3H). LC-MS: m/z 480.2 (M+H)+. [001191] Step B: Compound 264: 5-(((1H-l,2,4-triazol-3-yl)amino)methyl)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000281_0002
[001192] A solution of N-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)methyl)hydrazinecarboximidamide (170 mg, 0.355 mmol) in HCOOH (5 ml) and trimethoxymethane (5 ml) was heated to 150 °C for 4h. When the reaction mixture was consumed, the mixture was concentrated to dryness. The residue was suspended in DMSO (10 ml) and stirred for 30 mins at 5 °C to give the desired product 5-((( 1 H- 1 ,2,4-triazol-3-yl)amino)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[ 1 , 5- a]pyrimidin-7(4H)-one. [001193] 1H NMR (DMSO-d6) δ : 8.44 (s, 1H), 7.28 - 7.49 (m, 1 1 H), 7. 1 - 7.24 (m, J = 8.6 Hz, 2H), 6.87 - 7.04 (m, J = 8.6 Hz, 2H), 4.90 (s, 2H), 3.74 - 3.86 (m, 3H). LC-MS: m/z 490.0 (M+H)+. [001194] Compound 265
Figure imgf000282_0001
[001195] Step A: 4-(4,4-difluorocyclohex- 1 -en- 1 -yl)-3 -phenyl- 1 H-pyrazol-5-amine
F
H2N
Figure imgf000282_0002
[001196] To a solution of 3-phenyl-1H-pyrazol-5-amine (1 g, 6.3 mmol) and 4,4- difluorocyclohexanone (844 mg, 6.3 mmol) in AcOH (10 ml) were heated to 80 °C for 3h. The reaction mixture was concentrated to give the crude product, which was used directly to the next step without further purification.
[001197] Step B: Compound 265: 3-(4,4-difluorocyclohex-l-en-l -yl)-5-methyl-2- phenyl-6-(quinolin-6-yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
F
Figure imgf000282_0003
[001198] A mixture of methyl 3-oxo-2-(quinolin-6-yl)butanoate (200 mg, 0.82 mmol) and 4-(4,4-difluorocyclohex-l-en-l-yl)-3-phenyl-1H-pyrazol-5-amine (100 mg, crude) in AcOH ( 10 ml) was heated to 120 °C for 2 h. The reaction mixture was cooled to room temperature to give the desired product.
[001199] 1H NMR (DMSO-d6) 5 : 1 1.86 (s, 1H), 8.95 (dd, J = 4.2, 1.7 Hz, 1H), 8.40 (d, J = 7.3 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1 H), 7.96 (d, J = 1.9 Hz, 1H), 7.67 - 7.81 (m, 3H), 7.58 (dd, J = 8.3, 4.3 Hz, 1H), 7.38 - 7.52 (m, 3H), 5.78 (br. s., 1H), 2.78 (t, J = 15.0 Hz, 2H), 2.37 (br. s., 2H), 2.31 (s, 3H), 2. 1 1 - 2.23 (m, 2H). LC-MS: m/z 469.8 (M+Hf.
[001200] Compound 266
Figure imgf000283_0001
[001201] Step A: tert-butyl 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-l-yl)-4-((2-
(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[l,5-a]pyrimidin-6-yl)-1H-pyrazole-l- carboxylate
Figure imgf000283_0002
[001202] A suspension of 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2-
(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 305, 200 mg, 0.39 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-1H-pyrazole-l-carboxylate (341 mg, 1.16 mmol), PdC12(dppf) (28 mg, 0.04 mmol) and Na2C03 (82 mg, 0.78 mmol) in 1.4-dioxane/water (10 mL/1 mL) was stirred and heated to 85 °C for 16 h under N2 atmosphere. The reaction was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo. The residue was purified by flash column chromatography, eluting with PE/EA (4/1 ), to desired product (40 mg, 18% yield) as a white solid. LC-MS: m/z 605.3 (M+H)+.
[001203] Step B: 5-methyl-2-phenyl-3-(piperidin-l-yl)-6-(1H -pyrazol-4- yI)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000284_0001
[001204] The mixture of tert-butyl 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)-4,7-dihy
carboxylate (40 mg, 0.07 mmol) and HC1 in MeOH (0.5 mol, 10 mL, 5 mmol) was stirred at RT for 1 h. The mixture was then concentrated to dryness. The residue was dissolved into cone, hydrochloric acid (10 mL), and stirred at 100 °C for 24 h to get the desired product.
[001205] 1H NMR (DMSO-<&) δ: 12.90 (br. s., 1H), 1 1.34 (br. s., 1H), 8.13 (d, J=7.2 Hz, 2H), 7.99-7.51 (m, 2 H), 7.49-7.37 (m, 3H), 3.08 (br. s., 4H), 2.45 (s, 3H), 1.66 (br. s., 4H), 1.59 (br. s., 2H). LC-MS: m/z 375.2 (M+H) +.
[001206] Compound 267
Figure imgf000284_0002
[001207] Step F: Compound 267: 6-(1H-benzo[d]imidazol-5-yl)-5-methyl-2-phi (piperidin- 1 -yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000284_0003
[001208] A mixture of 6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-l- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 255, 100 mg, 0.24 mmol) in HCOOH (10 ml) was stirred at 100 °C for 2h. The reaction mixture was concentrated and washed with aq. NaHC03 solution to give the desired product 6-(1H- benzo[d]imidazol-5-yl)-5-methyl-2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin- 7(4H)-one.
[001209J 1H NMR (DMSO-d6) δ : 12.47 (br. s., 1H), 11.47 (br. s., 1H), 8.25 (s, 1 H), 8.08 - 8.17 (m, 2H), 7.57 (br. s., 2H), 7.44 - 7.50 (m, 2H), 7.34 - 7.42 (m, 1H), 7.12 (br. s., 1H), 3.11 (br. s., 4H), 2.26 (s, 3H), 1.67 (br. s., 4H), 1.59 (br. s., 2H). LC-MS: m/z 425.3 (M+H)+.
[001210] Compound 268
Figure imgf000285_0001
[001211] Step A: 6-(2-amino-l H-benzo[d]imidazol-5-yl)-5-methyl-2-phi
(piperidin- 1 -yl)pyrazolo [ 1 , 5 -a] pyri midin-7(4H)-one
Figure imgf000285_0002
[001212] To the solution of 6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-l- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (lOOmg, 0.24mmol) in CH3CN (lOmL) and H20 (5mL) was added cyanic bromide (28mg, 0.256mmol). The mixture was stirred at r.t. for lh. The mixture was concentrated to give the crude product, which was washed with aq.
NaHC03 solution and filtered to give the desired product 6-(2-amino-1H-benzo[d]imidazol- 5-yl)-5-methyl-2-phenyl-3-(piperidin-l-yl)pyrazolo [l,5-a]pyrimidin-7(4H)-one. [001213] 1H NMR (DMSO-d6) δ : 10.64 (br. s., 1H), 8.31-8.33(d, 2H), 7.35-8.39 (m, 2H), 7.24-7.28 (m, 1H), 6.98-7.04 (m, 2H), 6.74 (m, 1H), 5.99 (br. s., 1H), 3.23 (br. s., 4H), 2.08 (s, 3H), 1.66 (br. s., 4H), 1.54 (br. s., 2H). LC-MS: m/z 440.3 (M+H)+.
[0012141 Compound 269
Figure imgf000286_0001
4
[001215] Step A: ethyl 2-(4-methoxyphenyl)-3-oxobutanoate
Figure imgf000286_0002
[001216] To a solution of ethyl 2-(4-methoxyphenyl)acetate (5 g, 25.7 mmol) in THF (100 mL) was added LDA (1.5 M in THF, 20 mL, 30.84 mmol) dropwise at -30 ~ -35°C. The mixture was stirred at -30 ~ -35°C for 30 min, and acetyl chloride (2.1 g, 27 mmol) was added dropwise. Then the mixture was stirred at rt for 6h. The mixture was poured into saturated NH4C1 and extracted with EA (3* 100 mL). The combined organic phase was washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired ethyl 2-(4- methoxyphenyl)-3-oxobutanoate as a brown oil (5.2 g, 86% yield ).
[001217] Step B: 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(piperidiii-l- yl)py razolo [ 1 ,5-a] py rimidin-7(4H)-one
Figure imgf000287_0001
[001218] A mixture of ethyl 2-(4-methoxyphenyl)-3-oxobutanoate (292 mg, 1.24 mmol) and 3-phenyl-4-(piperidin-l-yl)-l H-pyrazol-5-amine (300 mg, 1.24 mmol) in AcOH (lOmL) was stirred at 95'C for 4h. After cooling to room temperature, the solids were collected by filtration, wash with ethyl acetate, and dried under vacuum to give 6-(4-methoxyphenyl)-5- methyl-2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (210 mg, 4\% yield) as a white solid. LC-MS: m/z 415. 1 (M+H)+.
[001219] Step C: Compound 269: 6-(4-methoxyphenyl)-4,S-dimethyl-2-phenyl-3- (piperid in- 1 -yl)py razolo [ 1 ,5-a] py rimidin-7(4H)-one
Figure imgf000287_0002
[001220] To a mixture of 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(piperidin- 1 - yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (210 mg, 0.49 mmol) and Cs2C03 (320 mg, 0.98 mmol) in DMF (10 mL) was added Mel (103 mg, 0.735 mmol). The mixture was then stirred at rt overnight to give the title compound. [001221] 1H NMR (400 MHz, CHLOROFORM-^ δ : 7.62 (br. s., 2 H), 7.45 (d, J=2.15 Hz, 3 H), 7.23 (m, J=8.33 Hz, 2 H), 6.98 (m, J=8.33 Hz, 2 H), 4.26 (s, 3 H), 3.86 (s, 3 H), 3.00 (d, J=11.55 Hz, 4 H), 2.31 (s, 3 H), 1.78 (br. s., 4 H), 1.66(br. s., 2 H). LC-MS: m/z 429.0 (M+H)+. [001222] Compound 271
Figure imgf000288_0001
[001223] Step A: methyl 2-(4-((4-methoxybenzyl)oxy)phenyl)acetate
PMB
Figure imgf000288_0002
C
[001224] To a solution of methyl 2-(4-hydroxyphenyl)acetate (5.0 g, 30 mmol) in DMF (25 ml) was added K2C03 (8.3 g, 60 mmol) at r.t. under N2 atmosphere. After the mixture was stirred at r.t. for 30 min, l-(bromomethyl)-4-methoxybenzene (7.2 g, 36 mmol) was added dropwise, and the mixture was stirred at r.t. for 2h. The mixture was poured into H20 (100 mL) and extracted with EA (3*50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was recrystalized from EtOH to afford the title compound 2 as a white solid (5.6 g, 65% yield). LC-MS: m/z 287.1 (M+H)+. [001225] Step B: methyl 2-(4-((4-methoxybenzyl)oxy)phenyl)-3-oxobutanoate
Figure imgf000289_0001
[001226] To a solution of Intermediate 2 (4.6 g, 16 mmol) in THF (50 mL) was added LDA (2mol/l in THF, 16 ml) dropwise at -60 °C. The mixture was stirred at -60 °C for 30 min. Then acetyl chloride (1.5 g, 19.2 mmol) was added dropwise. The mixture was stirred at -60 °C for 30 min and stirred at r.t. for lh. The mixture was diluted with EA (50 mL) and quenched with saturated NH4CI. The organic phase was separated and washed with water and brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 3 as a yellow oil which was used to the next step without purification (5.2g, 99% yield). [001227] Step C: 6-(4-((4-methoxybenzyl)oxy)phenyl)-5-methyl-2- phenylpy razolo [ 1 ,5-a] pyrimidin-7(4H)-o
Figure imgf000289_0004
ne
Figure imgf000289_0002
[001228] A solution of Intermediate 3 (5.3 g, 16 mmol) and 3-phenyl-l H-pyrazol-5- amine (1.9 g, 12 mmol) in AcOH (10 ml) was refluxed for lh. The reaction mixture was cooled to room temperature. The precipitate was filtered off and washed with EA (3*5 mL) to afford the title compound 4 (3.0 g, 43% yield). LC-MS: m/z 438.1 (M+H)+.
[001229] Step D: 6-<4-((4-methoxybenzyl)oxy)phenyl)-4,5-dimethyl-2- phenylpy razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000289_0003
[001230] To a solution of Intermediate 4 (3.0 g, 6.9 mmol) in DMF (50 mL) were added Cs2C03 (6.8 g, 20.7 mmol) and iodomethane (2.9 g, 20.7 mmol). The mixture was then stirred at r.t. overnight. The mixture was poured into water (200 mL). The white precipitate was filtered off, washed with H20 (3*5 mL) and EA (3*5 mL) to afford the title compound 5 as a white solid (2.8 g, 88% yield). LC-MS: m/z 452.1 (M+H)+.
[001231] Step E: 3-bromo-6-(4-((4-methoxybenzyl)oxy)phenyl)-4,S-dimethyl-2- phenylpy razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000290_0001
[001232] To a mixture of Intermediate 5 (2.8 g, 6.1 mmol) in DCM (50 ml) was added N-Bromosuccinimide (1.2 g, 6.7 mmol). The reaction mixture was then stirred at r.t.
overnight. The mixture was poured into water (200 mL). The organic phase was separated, washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 6 (3.1 g, 94% yield) as a white solid. LC-MS: m/z 530.1/532.1 (M+H)+.
[001233] Step F: 6-(4-((4-methoxybenzyl)oxy)phenyl)-4,5-dimethyl-2-phenyl-3- (thiophen-2-yl)py razolo [ 1 ,5-a] py rimidin-7(4H)-one
Figure imgf000290_0002
[001234] A suspension of Intermediate 6 (200 mg, 0.38 mmol), thiophen-2-ylboronic acid (242 mg, 1.89 mmol), Pd(dppf)C12 (100 mg, 0.12 mmol) and Cs2C03 (246 mg, 0.76 mmol) in 1 4-dioxane (16 mL) and H20 (2 ml) was stirred at 90°C overnight under N2 atmosphere. The reaction mixture was then cooled to r.t., diluted with DCM (50 mL) and filtered through celite. The filtrate was washed with water and brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by prep-TLC to afford
compound 7 (70 mg, 35% yield). LC-MS: m/z 534.1 (M+H)+.
[001235] Step G: 6-(4-hydroxyphenyI)-4,5-dimethyl-2-phenyl-3-(thiophen-2- yl)py razolo [ 1 ,5-a] pyrimid in-7(4H)-one
Figure imgf000291_0001
[001236] To a solution of Intermediate 7 (25 mg, 0.05 mmol) in DCM (5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at r.t. for 2h. The mixture was concentrated in vacuo. The residue was dissolved in DCM (5 mL), washed with saturated NaHCOi solution and brine, dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound 8.
[001237] 1H NMR (CHLOROFORM-d) δ: 7.54 - 7.63 (m, 2H), 7.43 - 7.48 (m, 1H), 7.21-7.33 (m, 3H), 7.08-7.15 (m, 2H), 6.90 - 7.05 (m, 2H), 6.72 - 6.81 (m, 2H), 3.54 (br. s., 3H), 2.24 (br. s., 3H). LC-MS: m/z 414.1 (M+H)+.
[001238] Compound 272
Figure imgf000291_0002
[001239] Step A: 2-(3,3-difluoropyrrolidin-l-yl)acetonitrile NC
Figure imgf000292_0001
[001240] The mixture of 3,3-difluoropyrrolidine hydrochloride (3.6 g, 24.8 mmol), 2- bromoacetonitrile (3.0 g, 24.8 mmol), and K2C03 (10.3 g, 74.4 mmol) in CH3CN (50 mL) was stirred at 80 °C overnight. Then the mixture was cooled to r.t. and filtered. The filtrate was poured into water (100 mL) and extracted with EA (30 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 2 (2.9 g, 80% yield) which was directly used to the next step without further purification. LC-MS: m/z 147.0 (M+H)+.
[001241] Step B: 2-(3,3-difluoropyrrolidin-l-yI)-3-oxo-3-phenyIpropanenitrile
Figure imgf000292_0002
[001242] To a mixture of Intermediate 2 (2.9 g, 20 mmol) and methyl benzoate (2.7 g, 20 mmol) in THF (40 mL) was added NaHMDS ( 2 mol/L in THF, 20 mL) at 0 °C. The mixture was stirred at r.t. overnight. The reaction mixture was diluted with EA (50 mL) and quenched with saturated NHiC1. The organic phase was separated, washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 3 as a white solid (4.9 g, 97% yield) which was used to the next step without purification. LC-MS: m/z 251.0 (M+H)+.
[001243] Step C: 4-(3 3-difluoropyrrolidin-l-yl)-3-phenyl-1H -pyrazol-5-amine
Figure imgf000292_0003
[001244] The mixture of Intermediate 3 (4.9 g, 19.6 mmol) and hydrazine hydrate (1.5 g, 29.4 mmol,) in EtOH/AcOH (4/1,40 mL/10 mL) was refluxed overnight. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (50 mL) and neutralized with 10% NaHCOj. The organic phase was separated, and the the water phase was extracted with EA (25 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 4 as a yellow solid (5.1 g, 98%) which was used to the next step without purification. LC-MS: m/z 265.1 (M+H)+.
[001245] Step D: 3-(3,3-difluoropyrrolidin-l-yl)-6-(4-methoxyphenyl)-5-methyI-2- phenylpy razolo [1 ,5-a] py rim idin-7(4H)~one
Figure imgf000293_0001
[001246J The mixture of Intermediate 4 (500 mg, 1.1 mmol) and methyl 2-(4- methoxyphenyl)-3-oxobutanoate (359 mg, 1.6 mmol) in AcOH (10 mL) was stirred at 100 °C for lh. Then the mixture was cooled to r.t. to afford the title compound 5.
[001247] 1H NMR (DMSO-d6) δ: 1 1.80 (br. s., 1H), 7.96 - 8.00 (m, 2H), 7.38 - 7.50 (m, 3H), 7.23 (d, J = 8.6 Hz, 9H), 6.99 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.59 (t, J = 12.8 Hz, 2H), 3.42 (t, J = 7.0 Hz, 2H), 2.43 - 2.56 (m, 2H), 2.25 (s, 3H). LC-MS: m/z 437.7 (M+H) +.
[001248] Compound 273
Figure imgf000293_0002
[001249] Step A: 1 -ethyl 3-methyl 2-(4-methoxyphenyl)malonate
Figure imgf000293_0003
[001250] To a solution of methyl 2-(4-methoxyphenyl)acetate (5.0 g, 27.7 mmol) in THF (50 ml) was added LDA (2mol/L in THF, 16.6 ml) dropwise at -60 °C. The mixture was stirred at -60 °C for 30 min. Then ethyl carbonochloridate (3.6 g, 33.2 mmol) was added dropwise. The mixture was stirred at -60 °C for 30 min and then stirred at r.t. for 2h. The mixture was diluted with EA (50 mL) and quenched with saturated NH4C1. The organic phase was separated and washed with water and brine, dried over anhydrous Na2S04 and
concentrated in vacuo. The residue was purified by flash chromatography (PE/EA=20: 1) to afford the title compound 2 as a colorless oil (3.0 g, 43% yield). LC-MS: m/z 253.1 (M+H) +.
[001251] Step B: 5-hydroxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000294_0001
[001252] A mixture of Intermediate 2 (1.0 g, 4.0 mmol) and 3,4-diphenyl-1H-pyrazol- 5-amine (933 mg, 4.0 mmol) in tributylamine (10 mL) was stirred at 185 °C for 1 h and then cooled to room temperature. The precipitate was collected by filtration, washed with MeOH (3* 10 mL) to afford the title compound 3 as a white solid (1.1 g, 67% yield).
[001253] 1H NMR (DMSO-d6) δ : 11.57 (br. s, 1H), 7.26 - 7.49 (m, 12H), 6.90 - 6.99 (m, 2H), 3.78 (s, 3H). LC-MS: m/z 410. 1 (M+H)+.
[001254] Step C: 5-hydroxy-6-(4-hydroxyphenyl)-2^3-diphenylpyrazolo[l,5- a] pyrimidin-7(4H)-one
Figure imgf000294_0002
[001255] To a solution of Intermediate 3 (80 mg, 0.2 mmol) in DCM (3 mL) was added borontribromide (0.2 mL) at 0 °C dropwise. The mixture was stirred at 0 °C for 2h. The reaction was quenched with MeOH at 0 °C and concentrated in vacuo to afford the desired compound 4. [001256] 1H NMR (DMSO-d6) δ: 9.66 (br. s., 1H), 8.93 (br. s., 1H), 7.39 - 7.50 (m, 4H), 7.17 - 7.36 (m, 8H), 6.62 (d, J = 8.6 Hz, 2H). LC-MS: m/z 396.1 (M+H)+.
[001257] Compound 274
Figure imgf000295_0001
[001258] Step A: N-(3,4-diphenyl-1H-pyrazol-5-yl)formamide
Figure imgf000295_0002
[001259] The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (5.0 g, 21.3 mmol) in formic acid (30 mL) was refluxed for lh. The mixture was evaporated, and the residue was dissolved in EA (50 mL), washed with 10% NaHC03 aqueous solution, water and brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash
chromatography (PE/EA 1 : 1) to afford the title compound 2 as a light yellow solid (4.0 g, 72% yield). LC-MS: m/z 264.1 (M+H)+. [001260] Step B: N-methyl-3,4-diphenyl-1H -pyrazol-5-amine
Figure imgf000295_0003
[001261] To a solution of Intermediate 2 (4.0 g, 15.2 mmol) in THF (30 mL) was added borane-THF (lmol/L in THF, 15.2 mL) dropwise at 0 °C. The mixture was stirred at r.t. overnight. The reaction was quenched by careful adding MeOH and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound 3 as a white solid (2.1 g, 56%). LC-MS: m/z 250.1 (M+Hf [001262] Step C: 5-hydroxy-6-(4-methoxyphenyl)-4-methyl-2,3- d ipheny Ipy razolo [ 1 ,5-a] py rimidin-7(4H)-one
Figure imgf000296_0001
[001263] A mixture of Intermediate 3 (200 mg, 0.8 mmol) and 1-ethyl 3-methyl 2-(4- methoxyphenyl)malonate (200 mg, 0.8 mmol) in AcOH (5 mL) was stirred at 160 °C through microwave irradiation for 1 h and cooled to room temperature to afford the title compound 4.
[001264] 1H NMR (DMSO-d6) δ: 7.33 - 7.49 (m, 9H), 7.22 - 7.33 (m, 3H), 6.94 (d, J = 8.6 Hz, 2H), 3.78 (s, 3H), 3.05 (s, 3H). LC-MS: m/z 424.7 (M+H)+.
[001265] Compound 275
Figure imgf000296_0002
[001266] Step A: dimethyl 2-(quinolin-6-yl)malonate
Figure imgf000296_0003
[001267] To a solution of methyl 2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) in THF (30 ml) was added LDA (2mol/L in THF, 7.4 ml) dropwise at -60 °C. The mixture was stirred at - 60 °C for 30 min. Then methyl carbonochloridate (1.0 g, 10.9 mmol) was added dropwise. The mixture was stirred at -60 °C for 30 min and stirred at r.t. for 2h. The mixture was diluted with EA (30 mL) and quenched with saturated NH4CI. The organic phase was separated and washed with water and brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography (PE/EA=20: 1) to afford the title compound 2 as a colorless oil (1.0 g, 39% yield). LC-MS: m/z 260.0 (M+H) +.
[001268] Step B: 5-hydroxy-2-(-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a] pyrimidin-7(4H)-one
Figure imgf000297_0001
[001269] A mixture of Intermediate 2 (260 mg, 1.0 mmol) and 3,4-diphenyl-1H - pyrazol-5-amine (212 mg, 0.9 mmol) in tributylamine (10 mL) was stirred at 185 °C for 1 h and cooled to room temperature. The precipitate was collected by filtration to afford the title compound 3.
[001270] 1H NMR (DMSO-d6) δ: 9.95 (br. s., 1H), 8.75 (d, J = 3.8 Hz, 1H), 8.30 - 8.39 (m, 2H), 8.26 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.39 - 7.48 (m, 3H), 7.19 - 7.37 (m, 8H). LC-MS: m/z 431.1 (M+H)+.
[001271] Compound 276
Figure imgf000297_0002
[001272] Step A: N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5- a]pyrimidin-5-yl)acetamide
Figure imgf000298_0001
[001273] A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (Synthesized in Scheme of Compound 101, 400 mg, 0.91 mmol), acetamide (230 mg, 1.81 mmol), Pd(OAc)2 (40.5 mg, 0.18 mmol), Xantphos (158 mg, 0.27 mmol) and Cs2C0 (650 mg, 1.99 mmol) in 1.4-dioxane (30 ml) was reacted in microware reactor at 100 °C for 45 min under N2 atmosphere. The reaction was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo and purified by flash column chromatography, eluting with DCM/MeOH (40/1), to get the desired product as a yellow solid (100 mg, 23% yield). LC-MS: m/z 464.2 (M+H)+. [001274] Step B: N-(7-hydroxy-6-(4-hydroxyphenyl)-2-3-diphenylpyrazolo[l,5- a] pyrimidin-5-yl)acetamide
Figure imgf000298_0002
[001275] To a solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-5-yl)acetamide (70 mg, 0.15 mmol) in DCM (2 mL) was carefully added BBr3 ( 1.0 M in DCM, 0.5 ml, 5 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched by careful adding ice water at 0 °C. The precipitated solids were filtered and purified by prep-HPLC to get the desired product as a yellow solid (50 mg, 75% yield). LC-MS: m/z 437.2 (M+H)+.
[001276] Step C: 5-amino-6-(4-hydroxyphenyI)-2,3-diphenylpyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000299_0001
[001277] The N-(7-hydroxy-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[ 1,5- a]pyrimidin-5-yl)acetamide (50 mg, 0.1 1 mmol) and NaOH (17.8 mg, 0.44 mmoL) in EtOH (10 mL) and water (0.5 mL) was stirred at 40 °C for 14 h. Then the mixture was concentrated to get the desired product.
[001278] 1H NMR (OMSO-d6) δ: 9.20 (br. s., 1 H), 7.53 (d, J=6.0 Hz, 2H), 7.42 (d, J=6.8 Hz, 2H), 7.35-7.30 (m, 3H), 7.20 (t, J=7.6 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 4.71 (br. s., 2H). LC-MS: m/z 395.6 (M+H)+.
[001279] Compound 277
Figure imgf000299_0002
[001280] Step A: 2-cyclohexylacetonitrile
Figure imgf000299_0003
A mixture of 2-cyclohexenylacetonitrile (2.0 g, 16.5 mmol) and Pd(OH)2/C (200 mg, 10%) MeOH (100 mL) was stirred at RT under H2 atmosphere for 10 h. The mixture was filtered and concentrated to get the desired product as a yellow solid (1.8 g, 90% yield). LC-MS: m/z 124.2 (M+H)+.
[001281] Step B: 2-cyclohexyl-3-oxo-3-phenylpropanenitrile
Figure imgf000300_0001
[001282J To a solution of 2-cyclohexylacetonitrile (1.8 g, 14.6 mmol) in THF (100 mL) was added LDA (2.0 M in THF, 8.8 mL, 17.5 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 30 min, and benzoyl chloride (0.17 mL, 2.33 mmolo) was added dropwise. Then the mixture was slowly warmed to RT and stirred for 10 h. The mixture was poured slowly to saturated aq.NH.jC1 and extracted with EA (30 mL*3). The combined organic phase was washed with brine, dried over anhydrous MgS04 and concentrated in vacuo to get the desired product as a yellow oil (2.9 g, 88% yield). LC-MS: m/z 228.2 (M+H)+.
[001283] Step C: 4-cyclohexyl-3-phenyl-1H-pyrazol-5-amine
Figure imgf000300_0002
[001284] The solution of 2-cyclohexyl-3-oxo-3-phenylpropanenitrile (2.9 g, 12.8 mmol) and hydrazine hydrate (1.9 g, 38.6 mmol) in EtOH/AcOH (30 mL/6 mL) was heated to reflux for 16 h under N2 protection. The reaction mixture was concentrated, filtered, washed with Et20, and dried to get the desired product as a yellow oil (2.9 g, 96% yield). LC-MS: m/z 242.1 (M+H)+. [001285] Step D: 3-cyclohexyl-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazoIo[l,5- a] pyrimidin-7(4H)-one
Figure imgf000301_0001
[001286] The mixture of 4-cyclohexyl-3-phenyl-1H-pyrazol-5-amine (230 mg, 0.96 mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (300 mg, 1.24 mmol) in AcOH (5 mL) was stirred at 100 °C for 1 h. After removal of AcOH, 10% of NaHC03 was added. The precipitate was filtered, washed with MeOH, and dried to get the desired product.
[001287] 1H NMR (DMSO-^) δ: 1 1.56 (br. s., 1H), 8.94 (d, J = 2.4 Hz, 1 H), 8.39 (d, J = 8.0 Hz, 1H), 8.07 (d, J= 8.8 Hz, 1H), 7.95 (d, J= 0.8 Hz, 1H), 7.74 (dd, J= 1.6 Hz, 1.6 Hz, 1 H), 7.58-7.40 (m, 6H), 2.80 (m, 1H ), 2.34 (s, 3H), 1.81-1.60 (m, 8H), 1.30-1.23 (m, 2H). LC-MS: m/z 435.2 (M+H)÷.
[001288] Compound 278
Figure imgf000301_0002
[001289] Step A: 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000301_0003
[001290] To a suspension of 5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (Compound 319, 500mg, 1.126mmol,) in DCM (3mL) cooled in ice-bath was added SOC12 (670mg, 5.631mmol) dropwise. The resultant mixture was then stirred at room temperature overnight. The suspension was filtered, washed with ethyl acetate, and dried under vacuum. The residue was purified by prep-TLC (DCM:MeOH=20: l) to get 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one (300mg). LC-MS: m/z 463. 1 (M+H) +.
[001291] Step B: Compound 278: 5-((methylamino)methyl)-2,3-diphenyl-6- (quinolin-6-yI)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000302_0001
[001292] A solution of 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one (150 mg, 0.324 mmol) in methylamine (2.0 M in MeOH, 5 mL) was stirred at 50 °C overnight. Water (10 mL) was added to quench the reaction. The resultant mixture was concentrated to to get the title compound.
[001293]1H NMR (400 MHz, TFA)5 : 9.26 - 9.48 (m, 2 H), 8.57 - 8.76 (m, 2 H), 8.42 (d, J=8.60 Hz, 1 H), 8.35 (dd, J=8.33, 5.64 Hz, 1 H), 7.64 - 7.81 (m, 6 H), 7.55 - 7.62 (m, 2 H), 7.51 (d, J=7.25 Hz, 2 H), 4.80 (br. s., 2 H), 2.95 (s, 3 H). LC-MS: m/z 458.1 (M+H) +.
[001294] Compound 279
Figure imgf000302_0002
[001295] Step A: 3-(cyclohex-l-en-l-yl)-5-hydroxy-6-(4-methoxyphi
phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000302_0003
[001296] A suspension of 4-cyclohexenyl-3-phenyl-1H-pyrazol-5-amine (200 mg, 0.84 mmol) and dimethyl 2-(4-methoxyphenyl)malonate (240 mg, 1.00 mmol) in tributylamine (5 ml) was heated to 180 °C for 1 h under N2 protection. The mixture was cooled to the RT and stirred with petroleum ether to get the desired product. [001297] 1H NMR (DMSO-<&) δ: 12.05 (br. s., 1H), 7.56-6.50 (m, 9H), 5.67 (s, 1H), 3.73 (s, 3H), 2.09 (br. s., 2H), 1.91 (br. s., 2H), 1.58 (br. s., 4H). LC-MS: m/z 414.0 (M+H) +.
[001298] Compound 280
Figure imgf000303_0001
[001299] Step A: methyl l-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3- carboxylate
Figure imgf000303_0002
[001300] To a solution of methyl 1H-pyrazole-3-carboxylate (lg, 7.9 mmol) in THF (30 mL) was added sodium hydride (380 mg, 60% dispersion in mineral oil, 9.5 mmol) at 0°C. After the mixture was stirred at 0°C for 30 min, (2-(chloromethoxy)ethyl)trimethylsilane (1.6 g, 9.5 mmol) was added dropwise. Then the mixture was stirred at r.t. overnight. The mixture was diluted with EA (30 mL) and quenched with saturated NH4C1. The organic phase was separated and washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by flash chromatography to afford the intermediate 2 as a white solid (1.1 g, 54% yield).
[001301] 1H NMR (CHLOROFORM-d) δ: 7.55 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 1.8 Hz, 1H), 5.86 (s, 2H), 3.90 (s, 3H), 3.59 (t, J = 8.0 Hz, 2H), 0.90 (t, J = 8.0 Hz, 2H), -0.04 (s, 9H). LC-MS: m/z 257.1 (M+Hf. [001302] Step B: 3-oxo-2-phenyl-3-(l-((2-(trimethylsilyl)ethoxy)methyl)-l H- pyrazol-3-yl)propanenitrile
Figure imgf000304_0001
[001303] To the mixture of Intermediate 2 (600 mg, 2.3 mmol) and 2- phenylacetonitrile (330 mg, 2.8 mmol) in THF (20 mL) was added NaHMDS (2.0 mol/L in THF, 1.4 mL) dropwise at 0°C. The mixture was kept at 0°C for 30 min, and then stirred at r.t. overnight. The mixture was diluted with EA (20 mL) and quenched with saturated NH4CI. The organic phase was separated and washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by flash chromatography to afford the intermediate 3 as a light yellow solid (200 mg, 25% yield).
[001304] 1H NMR (DMSO-d6) δ: 12.41 (br. s., 1H), 7.73 - 7.78 (m, 2H), 7.66 (d, J = 1.8 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1 H), 6.77 (d, J = 1.8 Hz, 1H), 5.49 (s, 2H), 3.45 (t, J = 8.0 Hz, 2H), 0.81 (t, J = 8.0 Hz, 2H), -0.10 (s, 9H) . LC-MS: m/z 342.1 (M+H)+. [001305] Step C: 4-phenyl-l,-((2-(trimethylsilyl)ethoxy)methyl)-1H ,l,H-[3^,- bipyrazol]-5-amine
Figure imgf000304_0002
[001306] The mixture of Intermediate 3 (200 mg, 0.6 mmol) and hydrazine hydrate (59 mg, 1.2 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2h. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (20 mL) and neutralized with 10% NaHCO?. The organic phase was separated and the the water phase was extracted with EA (10 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo to afford the intermediate 4 as a yellow solid (200 mg, 96% yield) which was used to the next step without purification. LC-MS: m/z 356.1 (M+H)+. [001307] Step D: 5-methyl-3-phenyl-6-(quinolin-6-yl)-2-(l-((2-
(trimethy Isily I)ethoxy)methy 1)- 1 H-pyrazol-3-yl)pyrazolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000305_0001
[001308] The mixture of Intermediate 4 (200 mg, 0.56 mmol) and methyl 3-oxo-2- (quinolin-6-yl)butanoate 8 (205 mg, 0.85 mmol) in AcOH (8 mL) was stirred at 100 °C for lh. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (15 mL) and neutralized with 10% NaHC03. The organic phase was separated and the water phase was extracted with EA (15 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo to afford the intermediate 5 as a yellow solid (200 mg, 65% yield) which was used to the next step without purification. LC-MS: m/z 549.2 (M+H) +. [001309] Step E: 5-methyl-3-phenyl-2-(1H -pyrazol-3-yl)-6-(quinolin-6- yl)pyrazoIo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000305_0002
[001310] To a solution of Intermediate 5 (200 mg, 0.4 mmol) in DCM (10 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at r.t. overnight. The mixture was concentrated in vacuo and then dissolved in DCM (10 mL), washed with 10% NaHC03 and brined, dried over anhydrous Na2S04, and concentrated in vacuo to afford the desired product 6.
[001311] 1H NMR (DMSO-d6) δ: 12.84 (br. s., 1H), 8.91 (d, J = 2.6 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.17 (br. s., 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.40 - 7.63 (m, 6H), 7.36 (d, J = 7.2 Hz, 1H), 6. 18 (br. s., 1H), 2.22 (s, 3H). LC-MS: m/z 419.0 (M+H)+. [001312] Compound 281
Figure imgf000306_0001
[001314] To a mixture of methyl 2-(quinolin-6-yl)acetate (40.2 g, 0.2mol) and HMPA (7.2g, 0.02mol) in THF was added LDA (2M in THF; lOOmL, 0.2mol) over 20min at -78'C. The mixture was stirring for 1 hour at -78"C, 2-(benzyloxy)acetyl chloride (36.8g, 0.2 mol) was added dropwise with a funnel. The mixture was warmed up to room temperature overnight. Saturated NH4C1 aqueous solution was added. The resultant mixture was extracted with DCM (3*50mL). The combined organic layers were washed with saturated NaC1 (50mL), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel column (PE / EtOAc=20/l) to give the title compound (38g, 58° ) as a brown oil.
[001315] Step B: methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate
Figure imgf000306_0002
[001316] Methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (1.2 g, 3.4 mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (545 mg, 3.4 mmol) were dissolved in AcOH (lOmL). The mixture was warmed up to 95°C for 4h. After cooling to room temperature, the solids were collected by filtration, wash with EtOAc, and dried under vacuum to give methyl 4- (benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (1.05 g, 67% yield) as a white solid. LC-MS: m/z 459.1 (M+H)+.
[001317] Step C: 5-(benzyloxymethyl)-4-methyl-2-phenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000307_0001
[001318] To a mixture of methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (900 mg, 1.97 mmol) and Cs2C03 (1.38 g, 4.25 mmol) in DMF (10 mL) was added Mel (416 mg, 2.95 mmol). The mixture was then stirred at rt overnight. The mixture was poured into water (100 mL) and filtered. The filter cake was washed with MeOH to give 5-(benzyloxymethyl)- 4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (900 mg) as a white solid. LC-MS: m/z 473.0 (M+H)+.
[001319] Step D: 5-(benzyloxymethyl)-3-bromo-4-methyl-2-phenyl-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
ΟΒΠ
Figure imgf000307_0002
[001320] To a solution of 5-(benzyloxymethyl)-4-methyl-2-phenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (900 mg, 1.9 mmol) in DMF (10 mL) was added NBS (374 mg, 2.1 mmol). The reaction mixture was then stirred at room temperature for 2h. The mixture was poured into water (50 mL) and filtered to give 5-(benzyloxymethyl)-3- bromo-4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (900 mg, yield 86%) as a white solid. LC-MS: m/z 551.0 (M+H)+. [001321] Step E: 5-(benzyloxymethyl)-4-methyl-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000308_0001
[001322] A mixture of 5-(benzyloxymethyl)-3-bromo-4-methyl-2-phenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (800 mg, 1.45 mmol), phenylboronic acid (230 mg, 1.89 mmol), Pd118 (188 mg, 0.29 mmol) and K2C03 (496 mg, 3.64 mmol) in 1.4-dioxane (6 mL) and H20 (0.5 mL) was stirred at 100°C for 12 h under N2 atmosphere. The reaction mixture was then cooled to r.t. and filtered. The filtrate was concentrated in vacuo and purified by flash column chromatography silica gel to obtain 5-(benzyloxymethyl)-4-methyl- 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (700 mg, 88% yield). LC- MS: m/z 549.0 (M+H) +.
[001323] Step F: Compound 281 : 5-(hydroxymethyl)-4-methyl-2,3-diphenyl-6- (quinolin-6-yl)pyrazolo[ 1 , 5-a]pyrimidin-7(4H)-one
Figure imgf000308_0002
[001324] To a solution of 5-(benzyloxymethyl)-4-methyl-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (700 mg, 1.28 mmol) in dry DCM (5 mL) was added dropwise BBr3 (1 M in DCM, 2.56 mL, 2.56 mmol) at 0°C. After addition, the mixture was stirred at rt for 2 h. The mixture was quenched by careful adding of ice-water and extracted with EA. The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give the title compound.
[001325] 1H NMR (400 MHz, DMSC &)6 : 8.97 (br. s., 1 H), 8.42 (d, J=7.79 Hz, 1 H), 8.10 (d, J=8.87 Hz, 1 H), 7.99 (d, J=1.88 Hz, 1 H), 7.76 (dd, J=8.60, 1.88 Hz, 1 H), 7.60 (dd, J=8.33, 4.03 Hz, 1 H), 7.48 (s, 5 H), 7.36 - 7.42 (m, 2 H), 7.25 - 7.33 (m, 3 H), 4.37 (br. s., 2 H), 3.49 (s, 3 H). LC-MS: m/z 459.0 (M+H)+
[001326] Compound 282
Figure imgf000309_0001
[001328] A mixture of PPh3 (25 g, 96.5 mmol) and I2 (24 g, 94.8 mmol) in acetonitrile (400 mL) was stirred at r.t. for 2h, then Et3N (14.4 mL, 98.3 mmol) and cyclohexane-1,3- dione (10.0 g, 86.2 mmol) were added. The mixture was stirred at r.t. overnight. The mixture was concentrated in vacuo, and the residue was purified by chromatography to afford the title compound 2 as a yellow solid (4.0 g, 21%yield). LC-MS: m/z 222.9 (M+H)+.
[001329] Step B: 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-2-enone
Figure imgf000310_0001
[001330] A suspension of Intermediate 2 (2.0 g, 9 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (4.6 g, 18 mmol), KOAc (2.7 g, 27 mmol) and Pd(dppf)C12 (0.6 g, 0.9 mmol) in 1,4-dioxane (50 mL) was stirred at 90'C overnight. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound 3 as a yellow solid (1.0 g, 50%yield). LC-MS: m/z 223.1 (M+H)+.
[001331] Step C: 5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-
7(4H)-one
Figure imgf000310_0002
[001332] A suspension of methyl 3-oxo-2-(quinolin-6-yl)butanoate (2.0 g, 8.2 mmol) and 3-phenyl-1H-pyrazol-5-amine (1.0 g, 6.3 mmol) in 1,4-dioxane (10 mL) and AcOH (2 mL) was refluxed for 16 hours under N2 protection. The mixture was cooled to the room temperature, concentrated, and neutralized with saturated NaHC03 solution until pH = 7. The precipitate was collected by filtration, washed with petroleum ether and dried to afford the title compound 5 as a white solid (600mg, 27% yield).
[001333] 1H NMR (DMSO-d6) δ : 12.56 (br. s., 1 H), 8.94 (dd, J=4.25, 1.61 Hz, 1 H), 8.39 (d, J=7.63 Hz, 1 H), 7.99 - 8.10 (m, 3 H), 7.96 (d, J=1.76 Hz, 1 H), 7.75 (dd, J=8.66,1.91 Hz, 1 H), 7.57 (dd, J=8.36, 4.25 Hz, 1 H), 7.46 - 7.53 (m, 2 H), 7.40 - 7.46 (m, 1 H), 6.67 (s, 1 H), 2.26 (s, 3 H). LC-MS: m/z 353.1 (M+Hf.
[001334] Step D: 5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2- (trimethylsily l)ethoxy)methyl)pyrazolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000310_0003
[001335] To a solution of Intermediate 5 (500 mg, 1.42 mmol) and K2C03 (393 mg, 2.84mmol) in DMF (15 ml) at ambient temperature was added (2-
(chloromethoxy)ethyl)trimethylsilane (473 mg, 2.84mmol) dropwise. The mixture was stirred for 10 min at ambient temperature and heated to 100'C overnight. The mixture was cooled to the room temperature, washed with saturated sodium hydrogen carbonate solution, and extracted with DCM (2*30 mL). The combined organic layers were washed with brine (3*20 ml), dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by silica gel column, eluting with DCM/MeOH (30/1 to 10/1), to obtain the title compound 6 as a white solid (350 mg, 51% yield). LC-MS: m/z 483.1 (M+H)+. [001336] Step £: 3-bromo-S-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2- (trimethylsilyI)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000311_0001
[001337] To a solution of Intermediate 6 (350mg, 0.725 mmol) in DCM (5 ml) at ambient temperature was added N-Bromosuccinimide (163mg, 0.92mmol). The resultant mixture was stirred for 3 hours at ambient temperature, washed with water, and extracted with DCM (20 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by prep-TLC (DCM/MeOH=20/l) to obtain the title compound 7 as a yellow solid (250mg, 61% yield). LC-MS: m/z 561.1 (M+H) +. [001338] Step F: 5-methyl-3-(3-oxocyclohex-l-en-l-yl)-2-phenyl-6-(quinolin-6-yl)-4- ((2-(trimethy Isily l)ethoxy)methy l)py razolo [ 1 ,5-a] py rimid in-7(4H)-one
Figure imgf000311_0002
[001339] A suspension of Intermediate 7 (600mg, 1.1 mmol), 3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)cyclohex-2-enone (800mg, 3.6 mmol), Pd(dppf)C12 (80 mg,
O. lmmol) and Cs2C03 (1.4 g, 4.3 mmol) in l,4-dioxane/H20 (30 mL/5 mL) was refluxed for 4h. The mixture was cooled to r.t. and filtered through celite, the filtrate was diluted with H20 (10 mL) and extracted with EA (3*30 mL). The extracts was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography (DCM/MeOH=20/l) to afford the title compound 8 as a yellow solid (300 mg, 49% yield). LC-MS: m/z 577.2 (M+H)+.
[001340] Step G: 5-methyl-3-(3-oxocyclohex-l-en-l-yl)-2-phenyl-6-(quinolin-6- y I)py razolo [ 1 ,5-a] py rimid in-7(4H)-one
Figure imgf000312_0001
[001341] To a solution of intermediate 8 (100 mg, 0.2 mmol) in DCM (10 mL) was added TFA (1 mL). The mixture was stirred at r.t. overnight. The mixture was concentrated in vacuo. The residue was dissolved in EA ( 0 mL) and neutralized with 10% NaHC03. The organic phase was separated and the water phase was extracted with EA (3*5 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by prep-TLC to get the title compound 9 as an orange solid (30 mg, 39% yield). LC-MS: m/z 447.1 (M+H)+.
[001342] Step H: 3-(3-hydroxycycIohex-l-en-l-yl)-5-methyI-2-phenyl-6-(quinoIin-6- yl)py razolo [ 1 ,5-a] py rimidin-7(4H)-one
Figure imgf000312_0002
[001343] To a solution of intermediate 9 (30 mg, 0.07 mmol) and Cerium(III) chloride heptahydrate (43 mg, 0.1 mmol) in MeOH (3 mL) was added Sodium borohydride (5 mg, 0.1 mmol). The mixture was stirred at r.t. for 2h and quenched with H20 (0.5 mL). The mixture was evaporated. The residue was dissolved in EA (10 mL), washed with water and brine, dried over anhydrous Na2S04 and concentrated in vacuo to get the title compound 10. [001344] 1H NMR (METHANOL-d,) δ: 8.83 (d, J = 3.2 Hz, 1H), 8.39 (d, J = 7.4 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.95 (br. s., 1H), 7.81 (br. s., 3H), 7.55 (dd, J = 8.2, 4.4 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 7.4 Hz, 2H), 5.97 (d, J = 2.4 Hz, 1H), 4.32-4.38 (m, 1H), 2.29 (s, 3H), 2.05 - 2.15 (m, 2H), 1.92 - 1.98 (m, 1H), 1.80 - 1.89 (m, 1H), 1.62 - 1.75 (m, 2H). LC-MS: m/z 449.1 (M+H)+.
[001345] Compound 283
Figure imgf000313_0001
[001346] Step A: 5-((4-methoxybenzyl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l ,5-a] pyrimidin-7(4H)-one
Figure imgf000313_0002
[001347] A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a] pyrimidine (Synthesized in Scheme of Compound 101, 300 mg, 0.7 mmol) and (4-methoxyphenyl)methanamine (3mL) was stirred at 180 °C for 40mins in a microwave reactor. The mixture was cooled and derectly purified by reverse phase column (MeOH/H2O=0~50% 30mins, 50%~50% 30mins, 50%~100% 30mins) to get crude product (600mg) which was directly used to the next step without further purification. LC-MS 529.2 (M+H)+.
[001348] Step B: 5-amino-6-(4-methoxyphenyl)-2,3-diphenyIpyrazoIo[l,5- a] py rimidin-7(4H)-one
Figure imgf000314_0001
[001349] The solution of 5-((4-methoxybenzyl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo l,5-a]pyrimidin-7(4H)-one (600mg, 1.07mmol) in DCM (5mL) and TFA (5 mL) was stirred at 60 °C for 2h. The mixture was concentrated, basified with aq.Na2C03 solution to pH=8, and extracted with DCM (10mL*3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was purified by reverse phase column (MeOH/H2O=0~100% 50mins) to afford the desired product 5-amino- 6-(4-methoxyphenyl) -2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (480mg, 80% purity) as a brown solid. LC-MS: m/z 409.2 (M+H)+.
[001350] Step C: tert-butyl (2-((6-(4-methoxyphenyl)-7-oxo-2^-diphenyl-4,7- dihydropyrazolo[l,5-a] pyrimidin-5-yl)amino)-2-oxoethyl)carbamate
Figure imgf000314_0002
[001351] To a solution of 5 -amino-6-(4-methoxyphenyl)-2, 3 -diphenylpyrazolo [1,5- a]pyrimidin-7(4H)-one (lOOmg, 0.245mmol) in pyridine (3mL) was added 2,5- dioxopyrrolidin- 1 -yl 2-((tert-butoxycarbonyl)amino)acetate (333mg, 1.22mmol) and DMAP (cat.). The mixture was stirred at 120 °C for 45 mins through microwave irradiation. The mixture was concentrated in vacuo to dryness. The residue was separated between HC1 (1M, lOmL) and DCM (30mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was purified by Prep-TLC
(DCM/MeOH=50/l) to afford the desired product tert-butyl (2-((6-(4-methoxyphenyl)-7-oxo- 2,3-diphenyl-4,7-dihydropyrazolo[l,5-a]pyrimidin-5-yl)amio)-2-oxoethyl)carbamate (20mg, 14.5% yield) as a white solid. LC-MS: m/z 565.2 (M+H)+.
[001352] Step D: Compound 283: 2-amino-N-(6-(4-methoxyphenyl)-7-oxo-2,3- diphenyI-4,7-dihydropyrazolo[l,5-a]pyrimidin-5-yl)acetamide
Figure imgf000315_0001
[001353] The solution of tert-butyl (2-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo [l,5-a]pyrimidin-5-yl)amino)-2-oxoethyl)carbamate (20 mg, 0.035 mmol) i 4M HC1 in 1.4-dioxane was stirred r.t. for 2h. The mixture was concentrated to obtain 2- amino-N-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5-a]pyrimidin-5- yl)acetamide.
[001354] 1H NMR (DMSO-d6) δ : 7.61 - 7.42 (m, 5 H), 7.42 - 7.25 (m, 9 H), 7.00 (d, J 8.3 Hz, 2 H), 3.82 (s, 3 H), 3.62 - 3.59 (m, 2 H). LC-MS: m/z 466.0 (M+H)+.
[001355] Compound 285
Figure imgf000315_0002
[001356] Step A : N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5- a]pyrimidin-5-yl) -5-methyl-l,3,4-thiadiazol-2-amine
Figure imgf000315_0003
[001357] A mixture of Intermediate 1 (Synthesized in Scheme of Compound 101,
200 mg, 0.45 mmol), 5-methyl-l,3,4-thiadiazol-2-amine (102 mg, 0.9 mmol, 2 eq.), Pd(OAc)2 (10 mg, 0.045 mmol, 0.1 eq.), Xantphos(52 mg, 0.09 mmol, 0.2 eq.) and Cs2C03 (293 mg, 0.9 mmol, 2 eq.) in 1.4-dioxane (3 mL) was heated at 100 °C for 3 h under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford the Intermediate 2 as a yellow solid (200mg, 85% yield). LC-MS: m/z 520.7 (M+H)+.
[001358] Step B: Compound 285: 6-(4-methoxyphenyl)-5-((5-methyl- 1,3,4- thiadiazol-2-yl)amino)-2,3-diphenylpyrazolo[l,5-alpyrimidin-7(4H)-one
Figure imgf000316_0001
[001359] The solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a] pyrimidin-5-yl)-5-methyl-l,3,4-thiadiazol-2-amine (180 mg, 0.346 mmol) in 4M HC1 in 1.4-dioxane (10 mL) was stirred at r.t. for 10 h to afford the title compound 3. [001360] 1H NMR (DMSO-d6) δ : 7.53 (br. s., 3 H), 7.49 - 7.37 (m, 7 H), 7.32 (d, J = 8.3 Hz, 3 H), 7.06 (d, J = 8.3 Hz, 2 H), 3.83 (s, 3 H), 2.55 (br. s., 3 H). LC-MS: m/z 507.2 (M+H)+.
Figure imgf000316_0002
Step A: 5-chloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin
Figure imgf000317_0001
[001363] A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a] pyrimidine (Synthesized in Scheme of Compound 101, 200 mg, 0.45 mmol), potassium t-butoxide (50mg, 0.45mmol) in dioxane was stirred at 100 °C for 2h. The mixture was concentrated to give the crude product (200mg) which was used to the next step without further purification. LC-MS: m/z 428.1 (M+H)+.
[001364] Step B: Compound 286: 5-((2-hydroxyethyl)amino)-6-(4-methoxyphenyl)- 2^-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000317_0002
[001365] The mixture of 5-chloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo [1,5- a]pyrimidin-7(4H)-one (lOOmg, 0.23mmol) and 2-aminoethanol (3mL) was stirred at 170 °C for 4h under microwave irradiation in a sealed tube to get 5-((2-hydroxyethyl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one.
[001366] 1H NMR (DMSO-d6) δ : 7.28 (br. s., 5H), 7.22 (d, J = 7.25 Hz, 5H), 7.06 - 7.17 (m, 3H), 6.96 (d, J = 7.79 Hz, 2H), 3.81 (s, 3H), 3.66 (br. s., 2H), 3.43 (br. s., 2H). LC- MS: m/z 453.2 (M+H) +.
[001367] Compound 287
Figure imgf000318_0001
[001368] Step A: ethyl 3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)amino)-l H-pyrazole-l-carboxylate
Figure imgf000318_0002
[001369] To a solution of 5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 182, 50 mg, 0.1 mmol) in DMF (5 mL) was added sodium hydride (13 mg, 60% dispersion in mineral oil, 0.3 mmol) at 0°C. Ethyl chloroformate (24 mg, 0.2 mmol) was added dropwise after the mixture was stirred at 0°C for 30 min. Then the mixture was stirred at r.t. overnight. The mixture was poured into water (10 mL) and extracted with DCM (3* 5 mL), the combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo to afford the desired product.
[001370] 1H NMR (DMSO-d6 & TFA-d) δ: 8.22 (d, J = 3.0 Hz, 1H), 7.43 - 7.50 (m, 4H), 7.34 - 7.41 (m, 6H), 7.31 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.36 - 6.45 (m, 1H), 4.35 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.0 Hz, 3H). LC-MS: m/z 547.1 (M+H)+. [001371] Compound 288
Figure imgf000319_0001
[001372] Step E: 5-((benzyloxy)methyl)-3-(cyclohex- 1 -en- 1 -yl)-6-(4-methoxyphenyl)- 4-methyl-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000319_0002
[001373] A suspension of Intermediate 5 (200 mg, 0.4 mmol, synthesized in scheme of Compound 249), 2-(cyclohex-l-en-l -yl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (94 mg, 0.5 mmol, 1.2 eq), Pdns (48 mg, 0.07 mmol, 0.2 eq) and K2C03 (103 mg, 0.7 mmol, 2.0 eq) in 1.4-dioxane (5 ml) and H20 (0.3 ml) was stirred at 90°C for 4h under N2 atmosphere. The reaction mixture was then cooled to r.t. and filtered. The filtrate was concentrated in vacuo and purified by flash column chromatography silica gel (PE/EA 2: 1- 1 :2) to obtain
Intermediate 6 (39 mg, 20% yield). LC-MS: m/z 532.0 (M+H)+
[001374] Step F: 3-(cyclohex-l-en-l-yl)-5-(hydroxymethyl)-6-(4-methoxyphenyl)-4- methyi-2-phenylpy razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000320_0001
[001375] To a solution of Intermediate 6 (29 mg, 0.05 mmol) in dry DCM (3 mL) was added dropwise BC13 (lmol/L in DCM, 0.5 mL) at 0°C. After addition, the mixture was stirred at r.t. for 3 h. The mixture was quenched by ice-water (3 mL) and extracted with DCM (3*5 mL). The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo to give the title compound 7.
[001376] 1H NMR (DMSO-d6) δ: 7.82 (d, J = 7.0 Hz, 2H), 7.39 - 7.50 (m, 3H), 7.25 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 5.92 (br. s., 1 H), 5.69 (t, J = 4.8 Hz, 1 H), 4.36 (d, J = 4.6 Hz, 2H), 3.90 (s, 3H), 3.81 (s, 3H), 2.20 (br. s., 2H), 2.12 (br. s., 2H), 1.66 (br. s., 4H). LC-MS: m/z 442.2 (M+H)*.
[001377] Compound 290
Figure imgf000320_0002
[001378] Step A: Dimethyl 2-(4-methoxyphenyl)malonate
Figure imgf000320_0003
[001379] To a solution of t-BuOK (7.4 g, 0.066 mol) in dimethyl carbonate ( 60 mL) was added dropwise methyl 2-(4-methoxyphenyl)acetate (6 g, 0.033 mol) at 0°C. After addition, the mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was then heated to 80°C overnight. The suspension was diluted with EtOAc
(200mL), washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: EtOAc/PE=l/10) to afford the desired product (5.7 g, 0.024 mol, yield 72.7%).
[001380J 1H NMR (CDCb) δ : 7.33 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H) , 4.62 (s, 1H), 3.82 (s, 3H), 3.77 (s, 6H). [001381] Step B: 5-hydroxy-6-(4-methoxyphenyl)-2^-diphenylpyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000321_0002
[001382] The mixture of 3, 4-diphenyl-1H-pyrazol-5-amine (5.64g, 0.024 mol) and dimethyl-2-(4-methoxyphenyl)-malonate 2 (5.7 g, 0.024 mol) in xylene (350mL) was refluxed for 18h to afford the title compound.
[001383] 1H NMR (DMSO-d6) δ : 1 1.57 (br. s, 1H), 7.26 - 7.49 (m, 12H), 6.90 - 6.99 (m, 2H), 3.78 (s, 3H). LC-MS: m/z 410.2 (M+H)+.
[001384] Compound 291
Figure imgf000321_0001
[001385] Step A: Compound 291 : 3-cyclohexenyl-l-(methoxymethyl)-6-(4- methoxyphenyl)-5-methyl-2-phenylpyrazolo[l,5-a]pyrimidin-7(1H)-one
Figure imgf000321_0003
[001386] A mixture of 3-cyclohexenyl-6-(4-methoxyphenyl)-5-methyl-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 212, 100 mg, 0.243 mmol), chloro(methoxy)methane (21.4 mg, 0.268mmol) and Cs2C03 (159 mg, 0.486 mmol) in DMSO (5 mL) was stirred at room temperature for 5 days. The mixture was poured into water (20 mL) and extracted with EtOAc (3*20 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure to obtain the title compound.
[001387] 1H NMR (400 MHz, DMSO-^) δ : 7.54 - 7.64 (m, 5 H), 7.21 - 7.27 (m, 2 H), 6.99 (m, J=8.85 Hz, 2 H), 5.88 (br. s., 1 H), 5.65 (s, 2 H), 3.80 (s, 3 H), 2.96 (s, 3 H), 2.21 (s, 3 H), 2.14 (br. s., 2 H), 2.01 - 2.08 (m, 2 H), 1.51 - 1.64 (m, 4 H). LC-MS: m/z 456.1 (M+H)
[001388] Compound 292
Figure imgf000322_0001
[001389] Step A: ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate
Figure imgf000322_0002
[001390] A mixture of ethyl 2-(3-hydroxy-4-methoxyphenyl) acetate (4.3 g, 20.5 mmol), ((2-bromoethoxy)methyl)benzene (7.88 g, 36.8 mmol), potassium carbonate (5.66 g, 41 mmol) in N,N-dimethylformamide (50 mL) was heated to 80°C for 18 h. The mixture was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (100 mL) three times. The combined organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude mixture was purified by column chromatography (ethyl acetate: petroleumether= 1 :5) to afford ethyl 2-(3-(2- (benzyloxy)ethoxy)-4-methoxyphenyl)acetate (3.8 g, 54% yield) as a colorless oil. [001391] Step B: ethyl 2-(3-(2-(beiizyloxy)ethoxy)-4-methoxyphenyl)-3- oxobutanoate
Figure imgf000323_0001
[001392] To a solution of ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate (690 mg, 2 mmol) in tetrahydrofuran (10 mL) was added lithium diisopropylamide (2N, 1 mL, 2 mmol) at -78°C under nitrogen atmosphere dropwise. The mixture was stirred at the same temperature for 1 h. Acetyl chloride (156 mg, 2 mmol) was added into the mixture at - 78°C slowly. After addition, the mixture was stirred at -78°C for 1 h and then warmed slowly to room temperature overnight. The mixture was quenched by adding aqueous ammonium chloride to pH 6-7 and extracted with ethyl acetate (20 mL) three times. The combined organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=l :5) to afford ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate (280 mg, 38 % yield) as a colorless oil. LC-MS: m/z 387.2 (M+H) +.
[001393] Step C: 6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2^3- diphenylpyrazolo[l,5-a] yrimidin-7(4H)-one
Figure imgf000323_0002
[001394] A mixture of ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3- oxobutanoate (280 mg, 0.725 mmol) and 3,4-diphenyl-l H-pyrazol-5-amine (170 mg, 0.725 mmol) in acetic acid (5 mL) was heated to reflux for 2 h. The mixture was evaporated to remove acetic acid. The residue was purified by column chromatography (methanol:
dichloromethane=l :20) to afford 6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl- 2,3-diphenylpyrazolo[l,5-a] yrimidin-7(4H)-one (120 mg, 30% yield) as a yellow solid. MS: m/z 558.2 (M+H)+.
[001395] Step D: 6-(3-(2-hydroxyethoxy)-4-methoxyphenyl)-5-methyl-2^- diphenyIpyrazoIo[l,5-a]pyriniidin-7(4H)-one
Figure imgf000324_0001
[001396] To a solution of 6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one(100 mg, 0.18 mmol) in DCM(10 mL) was added 1M BBr3(0.5 mL) in DCM dropwise at 0 °C, after addition, the mixture was stirred at room temperature for lh. MeOH(5 mL) was added carefully to quench the reaction. Then the mixture was evaporated, the residue was purified by prep-TLC (DCM/MeOH=100: 10) to obtain the 6-(3-(2-hydroxyethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[l,5- a]pyrimidin-7(4H)-one(60 mg) as a white solid. LC-MS: m/z 468.2 (M+H) +.
[001397] Step E: 2-(2-methoxy-5-(5-methyl-7-oxo-2^-diphenyl-4,7- dihydropyrazolo [1 ,5-a] pyrimidin-6-yl)phenoxy)ethyl 4-methylbenzenesulfonate
Figure imgf000324_0002
[001398] A mixture of 6-(3-(2-hydroxyethoxy)-4-methoxyphenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (200 mg, 0.427 mmol), TsC1 (97 mg, 0.512 mmol), DMAP (52 mg, 0.427 mmol), Et3N (130 mg, 1.281 mmol) in DCM (5 mL) was stirred at 50°C for 18 h. The mixture was quenched by addition of water and extracted with DCM (2*20 mL). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=100:5) to obtain the 2-(2-methoxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5- a]pyrimidin-6-yl)phenoxy)ethyl 4-methylbenzenesulfonate (150 mg) as a white solid. LC- MS: m/z 622.1 (M+H)+. [001399] Step F: 6-(3-(2-(dimethylaniino)ethoxy)-4-methoxyphenyl)-5-methyl-2,3- d ipheny Ipy razolo [ 1 ,5-a] py rimidin-7(4H)-one
Figure imgf000325_0001
[001400] A mixture of 2-(2-methoxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-6-yl)phenoxy)ethyl 4-methylbenzenesulfonate (150 mg, 0.241 mmol) and dimethylamine (30% in H20, 1 mL) in THF (5 mL) in a seal tube was stirred at 70 °C overnight. The reaction mixture was cooled to room temperature and evaporated under reduced pressure to get the crude 6-(3-(2-(dimethylamino)ethoxy)-4- methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[l ,5-a]pyrimidin-7(4H)-one (140 mg) as an oil, which was used in the next step without further purification. LC-MS: m/z 495.0 (M+H)+.
[001401] Step G: Compound 292: 6-(3-(2-(dimethylamino)ethoxy)-4- hy droxy phenyl)~5-methyl-2,3-diphenylpyrazolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000325_0002
[001402] To a solution of 6-(3-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)-5-methyl- 2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (140 mg, 0.225 mmol) in DCM (4 mL) was added BBr3 (1M in DCM, 1 mL) dropwise. The mixture was then stirred at room temperature for 2h. The mixture was quenched by addition of MeOH and concentrated under reduced pressure to obtain 6-(3-(2-(dimethylamino)ethoxy)-4-hydroxyphenyl)-5-methyl-2,3- diphenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one. [001403] 1H NMR (400 MHz, CHLOROFORM-i/) δ : 7.38 - 7.62 (m, 10 H), 7.17 (br. s., 1 H), 7.02 (br. s., 2 H), 4.44 (br. s., 2 H), 3.66 (br. s., 2 H), 3.07 (s, 6 H), 2.33 (s, 3 H). LC- MS: m/z 481.1 (M+H)÷. [001404] Compound 294
Figure imgf000326_0001
4
[001405] Step A: (S)-chloromethyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate
Figure imgf000326_0002
[001406] A mixture of (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (1 g, 4.6 mmol), chloromethyl sulfochloridate (912 mg, 5.53 mmol), NaHC03 (1.54 g, 18.4 mmol) in DCM (5 mL) and H20 (5 mL) was stirred at room temperature overnight. Water (20 mL) was added. The mixture was extracted with DCM (3*20 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure to get the title compound (800 mg) as a colorless oil.
[001407] 1H NMR (400 MHz, CHLOROFORM-d) 6 : 5.90 (d, J=5.91 Hz, 1 H), 5.64 (d, J=6.18 Hz, 1 H), 5.00 (d, J=8.06 Hz, 1 H), 4.29 (dd, J=8.87, 4.57 Hz, 1 H), 2.21 (dd,
J=12.09, 6.45 Hz, 1 H), 1.02 (d, J=6.98 Hz, 3 H), 0.94 (d, J=6.98 Hz, 3 H).
[001408] Step B: (S)-4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7- dihydropyrazolo[l,S-a]pyrimidin-6-yl)phenyl 2-(tert-butoxycarbonylamino)-3- methylbutanoate
Figure imgf000327_0001
[001409] To a mixture of 3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 240, 200 mg, 0.504 mmol), Nal (76 mg, 0.504 mmol), Cs2C03 (330 mg, 1.0 mmol) in DMF (5 mL) was added (S)-chloromethyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (200 mg, 0.755 mmol). The mixture was stirred at room temperature for 1 h. Then the mixture was quenched by addition of water (20 mL) and extracted with EtOAc (2*20 mL). The combined organic layers were concentrated. The residue was purified by column chromatography on silica gel (eluting PE/EA=2: 1) to give the desired product (150 mg) as a white solid. [001410] 1H NMR (400 MHz, DMSO-<&) 6 : 11.71 (s, 1 H), 7.78 (d, J=7.25 Hz, 2 H), 7.44 - 7.53 (m, 3 H), 7.35 - 7.44 (m, 3 H), 7.14 (d, J=8.33 Hz, 2 H), 5.85 (br. s., 1 H), 4.05 - 4.11 (m, 1 H), 2.25 (s, 3 H), 2.19 - 2.23 (m, 3 H), 2.06 (br. s., 2 H), 1.71 (br. s., 4 H), 1.44 (s, 9 H), 1.03 (d, J=6.72 Hz, 6 H). LC-MS: m/z 597.2 (M+H)+.
[001411] Step C: Compound 294: (S)-4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl- 4,7-dihydropyrazolo[l,5-a]pyrimidin-6-yi)phenyi 2-amino-3-methylbutanoate
[001412] To a solution of (S)-4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7- dihydropyrazolo[ 1 ,5-a]pyrimidin-6-yl)phenyl 2-(tert-butoxycarbonylamino)-3- methylbutanoate (150 mg, 0.251 mmol) in DCM (5 mL) was added TFA (2 mL). Then the mixture was stirred at room temperature for 2 h, and evaporated under reduced pressure to get the title compound.
[001413] 1H NMR (DMSO-^+TFA) δ : 1 1.79 (s, 1 H), 8.59 (br. s., 3 H), 7.75 - 7.82 (m, 2 H), 7.39 - 7.51 (m, 5 H), 7.23 - 7.29 (m, 2 H), 5.86 (br. s., 1 H), 4.29 (br. s., 1 H), 2.32 - 2.42 (m, 1 H), 2.26 (s, 3 H), 2.22 (br. s., 2 H), 2.07 (br. s., 2 H), 1.71 (br. s., 4 H), 1.15 (d, J=6.98 Hz, 3 H), 1.12 (d, J=6.98 Hz, 3 H). LC-MS: m/z 497.1 (M+H)+.
[001414] Compound 295
Figure imgf000328_0001
[001416] To a solution of methyl 2-(4-methoxyphenyl)acetate (900 mg, 5.0 mmol)) in THF (15 mL) was added slowly LDA (2.5 mL, 2mmol/mL in THF) at -30°C. Then acetyl chloride (500 mg, 6.5 mmol) was added slowly. The reaction mixture was stirred for 30mins at -30 °C and allowed to room temperature for lh. The mixture was poured into water, extracted over ethyl acetate, dried over anhydrous Na2S04, filtered, and concentrated to give the crude product (800 mg) as a yellow liquid, which was used directly to the next step without further purification. [001417] Step B: 3-cyclohexenyl-6-(4-methoxyphenyI)-5-inethyl-2- phenylpy razolo [1,5-a] py rimid in-7(4H)-one
Figure imgf000329_0001
[001418] The solution of 4-(cyclohex-l-en-l-yl)-3-phenyl-1H -pyrazol-5-amine (200 mg, 0.84 mmol) and methyl 2-(4-methoxyphenyl)-3-oxobutanoate (371.5 mg, 1.67 mmol) in AcOH (5 mL) was stirred at 100 °C for 1 hour. After cooling to room temperature, solvent was removed by vacuum, and saturated NaHC03 was added till pH>7. The precipitate was filtered, washed with water (6 mL) and MeOH (0.5 mL) to obtain 3-(cyclohex-l -en-l-yl)-6- (4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (260 mg) as a white solid.
[001419] 1H NMR (DMSO-d6) δ : 1 1.62 (s, 1 H), 7.72 - 7.85 (m, 2H), 7.34 - 7.55 (m, 3H), 7.19 - 7.31 (m, 2H), 6.93 - 7.07 (m, 2H), 5.84 (br. s., 1H), 3.81 (s, 3H), 2.17 - 2.32 (m, 5H), 1.98 - 2.12 (m, 2H), 1.70 (br. s., 4H). LC-MS: m/z 412.3 (M+H)+.
[001420] Step C: 3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2- phenylpyrazolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000329_0002
[001421] To a solution of 3-cyclohexenyl-6-(4-methoxyphenyl)-5-methyl-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (50 mg, 0.1 18 mmol) in CH2C12 (1 mL) was added slowly BBr3 (3 mL, 1 mmol/mL in CH2C12) at 0°C. And then the reaction mixture was stirred overnight. The reaction was quenched with ice water at -10°C and concentrated. The residue was purified by prep-HPLC to obtain the title compound (15mg) as a white solid.
[001422] 1H NMR (DMSO-d6) δ : 7.76 (d, J=7.02 Hz, 2 H), 7.30 - 7.52 (m, 3 H), 7.09 (m, J=7.93 Hz, 2 H), 6.82 (m, J=7.93 Hz, 2 H), 5.83 (br. s., 1 H), 2.21 (br. s., 3 H), 2.18 (br. s., 2 H), 2.03 (br. s., 2 H), 1.67 (br. s., 4 H). LC-MS: m/z 398.0 (M+H) [001423] Step D: dibenzyl 4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7- dihydropy razolo [ 1 ,5-a] py rimidin-6-yl)phenyl phosphate
Figure imgf000330_0001
[001424] To a solution of 3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one(40 mg, 0.1 mmol) in DMF(5 mL) was added dibenzyl chloromethyl phosphate (50 mg,0.15 mmol) in DMF (1 mL) and Cs2C03 (100 mg, 0.31 mmol) at room temperature. The mixture was warmed to 80°C and stirred overnight. The reaction mixture was cooled to room temperature, then poured into water (20 mL), and extracted with EtOAc (3*20 mL). The combined organic layers were washed with water (2*20mL) and brine (20 mL), and then concentrated under reduced pressure. The residue was purified by prep TLC, eluting with EA/DCM=2:3, to get the title compound (20 mg) as a white solid. LC-MS: m/z 658.1 (M+H)+.
[001425] Step E: Compound 295: 4-(3-(cyclohex-l-en-l-yl)-5-methyl-7-oxo-2- phenyl-4,7-dihydropy razolo [1 ,5-a] pyrimidin-6-yl)phenyl dihydrogen phosphate
Figure imgf000330_0002
[001426] To a solution of dibenzyl 4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7- dihydropyrazolo[l ,5-a]pyrimidin-6-yl)phenyl phosphate (20 mg, 0.03 mmol) in MeOH (2 mL) was added Pd/C (3 mg). The mixture was stirred at room temperature under H2 for 10 min and filtered. The filtrate was concentrated to afford the title compound (12 mg).
[001427] 1H NMR (400 MHz, OMSO-de) 5 : 1 1.70 (br. s., 1 H), 7.78 (d, J=7.25 Hz, 2 H), 7.42 - 7.49 (m, 2 H), 7.36 - 7.42 (m, 1 H), 7.19 (br. s., 2 H), 7.11 (d, J=8.06 Hz, 2 H), 5.82 (br. s., 1 H), 2.21 (br. s., 5 H), 2.08 (br. s., 2 H), 1.69 (br. s., 4 H). LC-MS: m/z 477.9 (M+H)+. [001428] Compound 296
Figure imgf000331_0001
Step A: di-tert-butyl (4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[l,5- a]pyrimidin-6-yl)phenoxy)methyl phosphate
Figure imgf000331_0003
[001429] To a solution of 3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 240, 300 mg, 0.75 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil, 75.6 mg, 1.89 mmol) and TBAB (36 mg, 0.15mmol) at 0°C for 5 min. Then di-tert-butyl chloromethyl phosphate (250 mg, 1.13 mmol) in DMF (5 mL) was added. The mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was poured into water (20 mL), extracted with DCM (3*20 mL). The combined organic layers were washed with water (2*20mL) and brine (20 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate :DCM=1 :3) to get the title compound (120 mg) as a white solid. [001430] 1H NMR (400 MHz, OMSO-de) δ : 1 1.66 (s, 1 H), 7.77 (d, J=7.02 Hz, 2 H), 7.44 - 7.50 (m, 2 H), 7.41 (d, J=7.32 Hz, 1 H), 7.29 (m, J=8.54 Hz, 2 H), 7.13 (m, J=8.54 Hz, 2 H), 5.84 (br. s., 1 H), 5.67 (d, J=12.21 Hz, 2 H), 2.22 (s, 5 H), 2.06 (br. s., 2 H), 1.70 (br. s., 4 H), 1.41 (s, 18 H). LC-MS: m/z 620.1 (M+H)+.
[001431] Step B: Compound 296: (4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7- dihydropyrazolo[l ,5-a]pyrimidin-6-yl)phenoxy)methyl dihydrogen phosphate
Figure imgf000331_0002
[001432] To a solution of di-tert-butyl (4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl- 4,7-dihydropyrazolo[l,5-a]pyrimidin-6-yl)phenoxy)methyl phosphate (1 10 mg, 0.177 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at room temperature under N2 for 30 min. The reaction mixture was filtered off. The filter cake was washed with ether and dried to get the title compound.
[001433] 1H NMR (400 MHz, DMSO-d6) δ : 11.65 (s, 1 H), 7.73 - 7.83 (m, 2 H), 7.44 - 7.50 (m, 2 H), 7.38 - 7.44 (m, 1 H), 7.25 - 7.31 (m, 2 H), 7.14 (m, J=8.86 Hz, 2 H), 5.85 (br. s., 1 H), 5.62 (d, J=11.28 Hz, 2 H), 2.24 (s, 3 H), 2.22 (br. s., 2 H), 2.06 (br. s., 2 H), 1.71 (br. s., 4 H). LC-MS: m/z 508.2 (M+H)+.
Figure imgf000332_0001
[001435] Step Ai: 5,7-dichloro-3-(cyclohex-l-en-l-yl)-6-(4-methoxyphi
phenylpyrazolo[l,5-a]pyrimidine
Figure imgf000332_0002
[001436] A solution of 3-(cyclohex-l-en-l-yl)-5-hydroxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 279, 47.0 g, 104 mmol) in phosphorus oxychloride (100 mL) was stirred at reflux for 16 hrs. The solvent was removed invacuo. The residue was added slowly to methanol (100 mL) cooled at 0°C. The precipitates were collected by filtration, washed with methanol, and dried under reduced pressure to give 5,7-dichloro-3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine (50 g) as a yellow solid.
[001437] 1H NMR (DMSO-d6): δ 1.70 (d, J=4.57 Hz, 4 H) 2.20 (br. s., 4 H) 3.84 (s, 4 H) 5.87 (br. s., 1 H) 7.10 (d, J=8.60 Hz, 2 H) 7.36 - 7.56 (m, 5 H) 7.82 (d, J=7.25 Hz, 2 H). LC-MS: m/z 450.2 (M+H) +. [001438] Step 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4-methoxyphi phenylpyrazolo[ 1 ,5-a]pyrimidine
Figure imgf000333_0001
[001439] To a solution of 5,7-dichloro-3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l ,5-a]pyrimidine (40 g, 88 mmol) in dichloromethane (400 ml) at 0 °C was added sodium methoxide {301% 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. The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was suspended in MeOH (50 mL). The precipitates were collected by filtration, washed with MeOH, and dried under reduced pressure to give 5-chloro-3-(cyclohex-l-en-l- yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[l ,5-a]pyrimidine (36 g) as a yellow solid.
[001440] 1H NMR (DMSO-d6): 6 7.78 - 7.91 (m, 2H), 7.42 - 7.58 (m, 3H), 7.33 - 7.42 (m, J = 8.9 Hz, 2H), 7.00 - 7.14 (m, J = 8.9 Hz, 2H), 5.83 (br. s., 1H), 4.14 (s, 3H), 3.84 (s, 3H), 2.20 (d, J = 5.9 Hz, 4H), 1.61 - 1.77 (m, 4H). LC-MS: m/z 446.1 (M+H)+.
Figure imgf000333_0002
[001441] Step A : 3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N- (pyridin-4-yl)pyrazolo[ 1 ,5-a]pyrimidin-5-amine
Figure imgf000334_0001
[001442] A mixture of 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l ,5-a]pyrimidine (300 mg, 0.68 mmol), pyridin-4-amine (70 mg, 0.75 mmol), and palladium diacetate (15mg, 0.068 mmol), Xantphos (79 mg, 0.136 mmol) and Cs2C03 (443 mg, 1.36 mmol) in 1,4-dioxane (20 mL) was heated at 110 °C for 2 hours under nitrogen atmosphere through microwave irradiation. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford the desired product 2 (40mg, 1 1.7% yield) as a light yellow solid. LC-MS: m/z 504.2 (M+H)÷. [001443] Step B: Compound 297: 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2- phenyI-5-(pyridin-4-yIamino)pyrazoIo[l,5-a]pyrimidin-7(4H)-one
I
Figure imgf000334_0002
[001444] A solution of 3-(cyclohex- 1 -en- 1 -yl)-7-methoxy-6-(4-methoxyphenyl)-2- phenyl-N-(pyridin-4-yl)pyrazolo[l,5-a]pyrimidin-5-amine (40 mg, 0.0.8mmol) in 4M HC1 in 1.4-dioxane (5 mL) was stirred at r.t. for 2 hours. The mixture was concentrated at low temperature (<25°C), and saturated NaHC03 (8 mL) was added. The precipitate was filtered. The filter cake was suspended in DCM/MeOH (14 mL, 1 :6), filtered and washed with MeOH (2 mL) to obtain 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-4- ylamino)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one. [001445] 1H NMR (DMSO-d6) δ : 8.32 (d, J = 7.02 Hz, 2H), 7.81 (d, J = 7.02 Hz, 2H), 7.38 - 7.56 (m, 4H), 7.20 - 7.36 (m, 5H), 6.91 (d, J = 8.85 Hz, 2H), 5.89 (br. s., 1 H), 3.75 (s, 3H), 2.18 (br. s., 2H), 2.10 (br. s., 2H), 1.69 (br. s., 4H). LC-MS: m/z 490.1 (M+H)+. [001446] Compound 298
Figure imgf000335_0001
[001447] Step A: isobutyl 2-cyclopropylacetate
Figure imgf000335_0002
[001448] A mixture of 2-cyclopropylacetic acid (1 g, 10 mmol), l-iodo-2- methylpropane(1.65g, 12 mmol) and Cs2C03 (6.5 g, 20 mmol)in DMF (50 mL) was stirred at 80°C for 16 h. The mixture was poured slowly into saturated NH4CI and extracted with EA (3* 100 mL). The combined organic phase was washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The residue was purified by flash
chromatography to afford the desired ethyl isobutyl 2-cyclopropylacetate (500 mg) as a colorless oil.
[001449] lK NMR (400 MHz, DMSCMs) δ : 3.82 (d, J=6.72 Hz, 2 H), 2.23 (d, J=6.98 Hz, 2 H), 1.81 - 1.93 (m, 1 H), 0.92-1.02 (m, 1 H) , 0.89 (d, J=6.72 Hz, 6 H), 0.43 - 0.51 (m, 2 H), 0.1 1 - 0.17 (m, 2 H).
[0014S0] Step B: isobutyl 2-cyclopropyl-3-oxobutanoate
Figure imgf000335_0003
[001451] To a solution of 2-cyclopropylacetate (500 mg, 3.2 mmol) in THF (10 mL) was added LDA (1.5 M in THF, 2.5 mL, 3.84 mmol) dropwise at -78 °C. The mixture was stirred at -78°C for 30 min, and acetyl chloride (326 mg, 4.2 mmol) was added dropwise. Then the mixture was stirred at rt for 4 h. The mixture was poured slowly into saturated NLUC1 and extracted with EA (3*20 mL). The combined organic phase was washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired isobutyl 2-cyclopropyl-3- oxobutanoate (380 mg) as a brown oil.
[001452] Step C: Compound 298: 6-cyclopropyl-5-methyl-2-phenyl-3-(piperidin-l- yl)py razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000336_0001
[0014S3] A mixture of 2-cyclopropyl-3-oxobutanoate (327 mg, 1.65 mmol) and 3- phenyl-4-(piperidin-l-yl)-1H-pyrazol-5-amine (200 mg, 0.825 mmol) in dioxane (5 mL) and water (lmL) was stirred at 1 15"C under microwave irradiation for 2h. The solvent was removed under reduced pressure to give 6-cyclopropyl-5-methyl-2-phenyl-3-(piperidin-l - yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one.
[001454] 1H NMR (400 MHz, DMSCMs) δ : 11.13 (br. s., 1 H), 8.10 (d, J=7.25 Hz, 2 H), 7.41 - 7.48 (m, 2 H), 7.37 (d, J=7.25 Hz, 1 H), 3.00 - 3.11 (m, 4 H), 2.50(s, 3 H), 1.63 (br. s., 4 H), 1.56 (br. s., 2 H), 1.42 - 1.50 (m, 1 H), 0.80 - 0.89 (m, 2 H), 0.57 - 0.67 (m, 2 H). LC-MS: m/z 349.6 (M+Hf.
[001455] Compound 299
Figure imgf000336_0002
2
Step A: 5-methyl-2,6-diphenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin
Figure imgf000337_0001
[001457] A suspension of 3-phenyl-4-(piperidin-l-yl)-1H-pyrazol-5-amine (70 mg, 0.29 mmol) and methyl 3-oxo-2-phenylbutanoate (120 mg, 0.58 mmol) in AcOH (2 ml) was refluxed for 30 min under N2 protection. The mixture was cooled to the RT, concentrated, and neutralized with saturated sodium hydrogen carbonate solution to adjust to pH=7 to obtain the desired product.
[001458] 1H NMR (DMSO-<&) δ: 1 1.40 (s, 1H), 8.12 (t, J= 4.0 Hz, 2H), 7.49 - 7.31 (rn, 8H), 3.08 (br. s., 4H), 2.26 (s, 3H), 1.67-1.50 (m, 6H). LC-MS: m/z 485.2(M+H)+.
[001459] Compound 300
Figure imgf000337_0002
Figure imgf000337_0003
[001460] Step A: isobutyl 2-cyclopentylacetate
Figure imgf000337_0004
[001461] A mixture of 2-cyclopentylacetic acid (1 g, 7.8 mmol), l-iodo-2- methylpropane (1.7 g, 9.36 mmol) and Cs2C03 (5.1 g, 15.6 mmol) in DMF (40 mL) was stirred at 80°C. for 16 h. The mixture was poured slowly into saturated NH4CI and extracted with EA (3* 100 mL). The combined organic phase was washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired isobutyl 2-cyclopentylacetate (988 mg) as a colorless oil. [001462] Step B: isobutyl 2-cyclopentyl-3-oxobutanoate
O
Figure imgf000338_0001
[001463] To a solution of 2-cyclopropylacetate (988 mg, 6.33 mmol) in THF (10 mL) was added LDA (1.5 M in THF, 4.6 mL, 6.96 mmol) dropwise at -78°C. The mixture was stirred at -78°C for 30 min, and acetyl chloride (1.86 g, 23.72 mmol) was added dropwise. Then the mixture was stirred at rt for 4 h. The mixture was poured slowly into saturated
NH4CI and extracted with EA (3*20 mL). The combined organic phase was washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired isobutyl 2-cyclopentyl-3-oxobutanoate (700 mg) as a colorless oil.
[001464] Step C: Compound 300: 6-cyclopentyl-5-methyl-2-phenyl-3-(piperidin-l- yl)py razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000338_0002
[001465] 2-cyclopentyl-3-oxobutanoate(467 mg, 2.06 mmol) and 3-phenyl-4-(piperidin- l-yl)-1H-pyrazol-5-amine (250 mg, 1.03 mmol) were dissolved in AcOH (lOmL). The mixture was warmed to 95°C for 4h. After cooling to room temperature, the solids were collected by filtration and washed with EtOAc to afford 6-cyclopentyl-5-methyl-2-phenyl-3- (piperidin-l -yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (120 mg).
[001466] 1H NMR (400 MHz, OMSO-de) δ : 10.98 (br. s., 1 H), 8.06 - 8.17 (m, 2 H), 7.43 - 7.49 (m, 2 H), 7.36 - 7.41 (m, 1 H), 3.03 - 3.07 (m, 4 H), 2.46 (s, 3 H), 1.92 - 2.05 (m, 3 H) ,1.84 (br. s., 2 H), 1.54 - 1.74 (m, 10 H). LC-MS: m/z 377.6 (M+H)+.
Figure imgf000339_0001
[001468] Step A: 6-(3-aminophenyl)-5-methyl-2-phenyl-3-(piperidin
(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000339_0002
[001469] To a solution of 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 305, 100 mg, 0.194 mmol) and (3-aminophenyl)boronic acid (53 mg, 0.386 mmol) in dioxane/H20 (5 mL/1 mL) was added l, l'-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (28 mg, 0.0344 mmol) and sodium carbonate (42 mg, 0.396 mmol). The reaction mixture was then refluxed under nitrogen atmosphere overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol: dichloromethane=l/20) to afford 5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-l-yl)-4-((2-
(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (35 mg, 34.3% yield) as a white solid. LC-MS: m/z 530.1 (M+H)+.
[001470] Step B: Compound 301: 6-(3-aminophenyl)-5-methyl-2-phenyl-3- (piperidin- 1 -yl)pyrazolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000339_0003
[001471] A mixture of 6-(3-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-on (35 mg, 0.1 mmol) in CF3COOH (2 mL) was heated to 60 °C for 3 h. The mixture was cooled to room temperature and concentrated in vacuo to afford 6-(3-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-l- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[001472] 1H NMR (DMSO-d6) δ : 11.33 (br. s., 1H), 8.12 (d, J = 7.25 Hz, 2H), 7.44 - 7.50 (m, 2H), 7.41 (d, J = 7.25 Hz, 1 H), 7.06 (t, J = 7.66 Hz, 1H), 6.55 (d, J = 8.60 Hz, 1 H), 6.48 (s, 1H), 6.41 (d, J = 7.52 Hz, 1H), 5.08 (br. s., 2H), 3.09 (br. s., 4H), 2.25 (s, 3H), 1.66 (br. s., 4H), 1.59 (br. s., 2H). LC-MS: m/z 400.5 (M+H)+.
[001473] Compound 302
Figure imgf000340_0001
[001474] Step A: ethyl 2-morpholino-3-oxobutanoate
O O
Figure imgf000340_0002
[001475] To the solution of morpholine (0.95g, 27mmol) in CH3CN (20mL) and K2C03 (3.01g, 54mmol ) and added dropwise ethyl 2-chloro-3-oxobutanoate (2g, 27mmol) over 2h. After addition, The mixture was concentrated and purified by silica gel chromatography (PE/EA=5/1 ) to get ethyl 2-morpholino-3-oxobutanoate (1.5g). LC-MS: m/z 216.3 (M+H)+. [001476] Step B: Compound 302: 5-methyI-6-morphoIino-2-phenyl-3-(piperidin-l- yl)py razolo f 1 ,5-a] py rimidin-7(4H)-one
Figure imgf000341_0001
[001477] A solution of methyl ethyl 2-morpholino-3-oxobutanoate (500mg, 2.3mmol), 3-phenyl-4-(piperidin-l-yl)-1H-pyrazol-5-amine (565mg, 2.3 mmol) in AcOH (20 ml) and xylene (20mL) was heated to 140 °C for 16h. The reaction mixture was concentrated to afford 5-methyl-6-moφholino-2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[001478] 1H NMR (DMSO-d6) δ : 7.97 (br. s., 2 H), 7.43 (d, J = 6.7 Hz, 2 H), 3.87 (br. s., 2 H), 3.81 (br. s., 2 H), 3.74 (br. s., 2 H), 3.00 (br. s., 4 H), 2.54 (s, 5 H), 1.68 (br. s., 4 H), 1.54 (br. s., 2 H). LC-MS: m/z 394.3 (M+H)+.
[001479] Compound 303
Figure imgf000341_0002
[001480] Step A: 6-(2-methoxypyridin-4-yl)-5-methyl-2-phenyl-3-(piperidin-l-yl)-4- ((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000341_0003
[001481] A suspension of 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 305, 200 mg, 0.39 mmol) and 2-methoxypyridin-4-ylboronic acid (178 mg, 1.16 mmol), PdCb(dppf) (28 mg, 0.04 mmol) and Na2C03 (82 mg, 0.78 mmol) in 1,4- dioxane/water (10 mL/1 mL) was stirred and heated to 85 °C for 16 h under N2 atmosphere. The reaction was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo. The residue was purified by flash column chromatography, eluting with PE/EA (4/1 ), to get desired product (40 mg, 18% yield) as a white solid. LC-MS: m/z 546.3 (M+H)+.
[001482] Step B: 5-methyl-6-(2-oxo-l,2-dihydropyridin-4-yl)-2-pheny]-3-(piperidin- 1 -yl)pyrazolo [ 1 ,5-a] py rimidin-7(4H )-one
Figure imgf000342_0001
[001483] The mixture of 6-(2-methoxypyridin-4-yl)-5-methyl-2-phenyl-3-(piperidin-l- yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (40 mg, 0.07 mmol) and HC1 in MeOH (0.5 mol, 1 mL, 0.5 mmol) was stirred at RT for 1 h. The mixture was then concentrated to dryness. The residue was dissolved into con. hydrochloric acid (10 mL) and stirred at 100 °C for 72 h. The reaction mixture was concentrated to afford the desired product.
[001484] 1H NMR (DMSO-i/e) δ: 1 1.20 (br. s., 1H), 8.30 (d, J=7.2 Hz, 2H), 7.41-7.37 (m, 2H), 7.30-7.22 (m, 2H), 6.21 (t, J=2.0 Hz, 2H), 3.19 (br. s., 4H), 2.33 (s, 3H), 1.62-1.50 (m, 6H). LC-MS: m/z 402.2 (M+H) +.
[001485] Compound 304
Figure imgf000343_0001
[001486] Step A: 5-methyl-2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin-7(4H)- one
Figure imgf000343_0002
[001487] A mixture of ethyl 3-oxobutanoate (18.7 g, 0.143 mol) and 3-phenyl-4- (piperidin-l-yl)-1H-pyrazol-5-amine (synthesized in scheme of Compound 305, 17.5 g, 0.072 mol) in AcOH (100 mL) was stirred at 95'C for 4h. After cooling to room temperature, the solids were collected by filtration, washed with ethyl acetate, and dried under vacuum to give 5-methyl-2-phenyl-3-(piperidin-l-yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (15 g, 68% yield) as a white solid. LC-MS: m/z 309.1 (M+H) +.
[001488] Step B: 5-methyl-2-phenyl-3-(piperidin-l-yl)-l-((2- (trimethy Isily I)ethoxy)methy l)py razolo [1 ,5-a] pyrimidin-7( 1 H)-one
Figure imgf000343_0003
Figure imgf000343_0004
[001489] To a solution of 5-methyl-2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one (synthesized in scheme of Compound 305, 6.5 g, 21.1 mmol) in dry DMF (50 mL) was added NaH (60% dispersion in mineral oil, 1.7 g, 42.5 mmol) in portion at O'C. After addition, the mixture was stirred at 0'C for 1 h. Then the SEM-C1 (5.3 g, 31.7 mmol) was added, and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into water (200 mL) and extract with EtOAc (3*200 mL). The combined organic layers were washed with water (2*300 mL) and brine (300 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate :PE=2: 1) to get the title compound (3.8 g, 41% yield) as a white solid. LC-MS: m/z 439.1 (M+H)+.
[001490] Step C: 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l ,5-a]pyrimidin-7(1H)-one
Figure imgf000344_0001
[001491] To a solution of 5-methyl-2-phenyl-3-(piperidin-l-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(1H)-one (3.4 g, 7.76 mmol) in DCM (30 mL) were added NBS (1.3 g, 7.76 mmol) and Et3N (0.82 g, 7.76 mmol). The resulting mixture was stirred at ambient temperature for 3 hours. Then the mixture was washed with water (30 mL), and the aqueous layer was extracted with DCM (30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was purified by column chromatography on silica gel (ethyl acetate :PE=2: 1) to get the title compound (3.1 g, 78% yield) as a white solid. LC-MS: m/z 517.2 (M+H)+.
[001492] Step D: 5-methyl-2-phenyl-3-(piperidin-l-yl)-6-(pyridin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,S-a]pyrimidin-7(1H )-one
Figure imgf000344_0002
[001493] A mixture of 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(1H)-one (100 mg, 0. 19 mmol), 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (59 mg, 0.288 mmol), Pd(dppf)C12 (21 mg, 0.029 mmol) and Na2C03 (41 mg, 0.386 mmol) in 1.4-dioxane (5 mL) and H20 (0.5 mL) was stirred at 100°C for 2 h under N2. The reaction mixture was then cooled to r.t. and filtered. The filtrate was concentrated in vacuo and purified by prep TLC to obtain 5-methyl- 2-phenyl-3-(piperidin- 1 -yl)-6-(pyridin-4-yl)- 1 -((2-
(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(1H)-one (50 mg) as a white solid. LC-MS: m/z 516.0 (M+H) +. [001494] Step E: Compound 304: 5-methyl-2-phenyl-3-(piperidin-l-yl)-6-(pyridin- 4-yI)py razo lo [ 1 ,5-a] pyrimidin-7(4 H)-one
Figure imgf000345_0001
[001495] To a solution of 5-methyl-2-phenyl-3-(piperidin-l-yl)-6-(pyridin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l ,5-a]pyrimidin-7(1H)-one (50mg, 0.097 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at ambient temperature for 2 h. Then the mixture was concentrated to dryness. The residue was stirred with saturated sodium hydrogen carbonate solution to get the title compound.
[001496] 1H NMR (400 MHz, DMSO-^) δ : 8.50 (br. s., 2 H), 8.26 (d, J=7.25 Hz, 2 H), 7.39 - 7.45 (m, 2 H), 7.35 - 7.38 (m, 2 H), 7.28 - 7.34 (m, 1 H), 3.18 (br. s., 4 H), 2.22 (s, 3 H), 1.61-1.66 (m, 4 H), 1.52-1.57 (m, 2 H). LC-MS: m/z 386.1 (M+H)+.
[001497] Compound 305
Figure imgf000346_0001
[001498J Step A: 3-oxo-3-phenyl-2-(piperidin-l-yl)propanenitrile
Figure imgf000346_0002
[001499J To a mixture of 2-(piperidin-l-yl)acetonitrile (7.8 g, 62 mmol) and methyl benzoate (9.4 g, 68 mmol) in THF (200 mL) was added NaHMDS (2M in THF, 46 mL, 1.2 eq.) at 0 °C. The mixture was stirred at r.t. overnight. The reaction mixture was diluted with EA (300 mL) and quenched with saturated NH4CI. The organic phase was separated, washed with brine, dried over anhydrous Na2S04 and concentrated in vaaio. The residue was purified by flash chromatography to afford the desired 3-oxo-3-phenyl-2-(piperidin-l- yl)propanenitrile as a white solid. LC-MS: m/z 229.1 (M+H)+.
[001500] Step B: 3-phenyl-4-(piperidin-l-yl)-1H -pyrazoI-5-aniine
O
Figure imgf000346_0003
The mixture of 3-oxo-3-phenyl-2-(piperidin-l-yl)propanenitrile (5 g, 21.902 mmol) and hydrazine (3.3 g, 65.706 mmol) in EtOH/AcOH (5/1, 30 mL/6 mL) was refluxed for 16h. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (50 mL) and neutralized with 10% NaHC03. The organic phase was separated, and the the water phase was extracted with EA (50 mL*2). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE/EA=l/3) to afford 3-phenyl-4-(piperidin-l-yl)-1H- pyrazol-5-amine (2.2g) as a white solid.
[001501] NMR (DMSO-d6) δ : 1 1.52 (br. s., 1H), 7.82 (br. s., 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.25 (d, J = 7.3 Hz, 1H), 4.28 (br. s., 2H), 2.88 (t, J = 5.0 Hz, 3H), 1.55 (br. s., 3H), 1.46 (d, J = 4.0 Hz, 2H). LC-MS: m/z 243.2 (M+H) +.
[001502] Step C: 5-methyl-2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a]pyrimidin-7(4H)- one
Figure imgf000347_0001
[001503] A mixture of 3-phenyl-4-(piperidin-l-yl)-H/-pyrazol-5-amine (8.43 g, 34.8 mmol) and methyl 3-oxobutanoate (9 g, 69.2 mmol) in acetic acid (5 mL) was heated to reflux for 2h. The mixture was cooled to room temperature. The suspension was filtered off. The resulting solid was washed with water and cold methanol to afford 5-methyl-2-phenyl-3- (piperidin-l-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (7.9 g, 74% yield) as a white solid. LC- MS: m/z 309.2 (M+H) +.
[001504] Step D: 5-methyl-2-phenyl-3-(piperidin-l-yl)-4- ((2- (trimethylsilyl)ethoxy)methyl) pyrazolo [l,5-a]pyrimidin-7(4H)-one
Figure imgf000347_0002
[001505] To a mixture of 5-methyl-2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a] pyrimidin-7(4H)-one (5.5 g, 17.9 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (1.4 g, 35.8 mmol) slowly at 0 °C. After addition, the mixture was stirred at 0 °C for 1 h. (2-(Chloromethoxy)ethyl)trimethylsilane (3.6 g, 21.7 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was quenched with brine and extracted with ethyl acetate (50 mL) three times. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was purified by column chromatography
(methanol:dichloromethane=l :20) to afford 5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (2.5 g, 35% yield) as a white solid. LC-MS: m/z 439.2 (M+H)+.
[001506J Step E: 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsily l)ethoxy)methyl) pyrazolo [1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000348_0001
[0015071 To a mixture of 5-methyl-2-phenyl-3-(piperidin-l-yl)-4- ((2-
(trimethylsilyl)ethoxy)- methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (1.2 g, 2.74 mmol) and triethylamine (0.32 g, 3.16 mmol) in dichloromethane (20 mL) at room temperature was added N-bromosuccinimide (0.58 g, 3.47 mmol) at room temperature. Then the mixture was stirred at room temperature for 2 h. The mixture was concentrated. The residue was purified by column chromatography (methanol:dichloromethane=l :20) to afford 6-bromo-5-methyl-2- phenyl-3-(piperidin-l-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin- 7(4H)-one (1.3 g, 80 % yield) as a white solid. LC-MS: m/z 519.2, 517.2 (M+H)+.
[001508] Step F: 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy) methyl)-4,7-dihydropyrazolo[ 1 ,5-a]pyrimidin-6-yl)benzamide
Figure imgf000349_0001
[001509] To a solution of 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (100 mg, 0.194 mmol) and (4-carbamoylphenyl)boronic acid (48.3 mg, 0.293 mmol) in dioxane/H20 (5 mL/1 mL) was added 1 , 1 '-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (28 mg, 0.0344 mmol) and sodium carbonate (42 mg, 0.396 mmol). The reaction mixture was then refluxed under nitrogen atmosphere overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol: dichloromethane=l/20) to afford 4-(5-methyl-7-oxo-2-phenyl-3 -(piped din- 1-yl)- 4-((2-(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[l ,5-a]pyrimidin-6-yl)benzamide (60 mg, 55% yield) as a white solid. LC-MS: m/z 558.3 (M+H)+.
[001510] Step G: Compound 305: 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-l-yl)- 4,7-dihydropy razolo [ 1 ,5-a] pyrimidin-6-yl)benzamide
Figure imgf000349_0002
[001511] A mixture of 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-l-yl)-4-((2-
(trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[l,5-a]pyrimidin-6-yl)benzamide (60 mg, 0.1 1 mmol) in CF3COOH (2 mL) was heated to 60 °C for 3 h. The mixture was cooled to room temperature and concentrated in vacuo to remove solvent. The resulting residue was washed with saturated aqueous sodium bicarbonate to afford 6-(4-hydroxyphenyl)-5-methyl- 2-phenyl-3-(piperidin-l-yl)pyrazolo[l,5-a] pyrimidin- 7(4H)-one.
[001512] 1H NMR (DMSO-d6) δ : 7.96 - 8.06 (m, J = 8.06 Hz, 2H), 7.68 (br. s., 2H), 7.59 (br. s., 3H), 7.46 - 7.54 (m, J = 7.79 Hz, 2H), 3.55 (br. s., 4H), 2.42 (s, 3H), 1.94 - 2.10 (m, 4H), 1.59 (br. s., 2H). LC-MS: m/z 428.3 (M+H)+.
Figure imgf000350_0001
[001514] Step A: 5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-l-yl)-4- ((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[ 1 , 5-a]pyrimidin-7(4H)-one
Figure imgf000350_0002
[001515] To a solution of 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 305, 100 mg, 0.194 mmol) and (4-(methylsulfonyl)phenyl)boronic acid (78 mg, 0.386 mmol) in dioxane/H20 (5 mL/1 mL) was added Ι, Γ-
Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (28 mg, 0.0344 mmol) and sodium carbonate (42 mg, 0.3% mmol). The reaction mixture was then refluxed under nitrogen atmosphere overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol: dichloromethane=l/20) to afford 5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3- (piperidin-1 -yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (60 mg, 52.6% yield) as a white solid. LC-MS: m/z 593.3 (M+H)+. [001516] Step B: Compound 306: 5-methyl-6-(4-(methylsuIfonyl)phenyl)-2-phenyI- 3-(piperidin-l-yl)pyrazolofl,5-alpyrimidin-7(4H)-one
Figure imgf000351_0001
[001517] A mixture of 5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-l- yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (60 mg, 0. 1 mmol) in CF3COOH (2 mL) was heated to 60 °C for 3 h. The mixture was cooled to room temperature and concentrated in vacuo to remove solvent. The resulting residue was washed with saturated aqueous sodium bicarbonate to afford 5-methyl-6-(4-(methylsulfonyl)phenyl)- 2-phenyl-3-(piperidin-l -yl)pyrazolo[ 1 ,5-a] pyrimidin-7(4H)-one. [001518] 1H NMR (DMSO-d6) δ : 8.05 (d, J = 7.52 Hz, 2H), 7.44 - 7.69 (m, 7H), 3.70 (br. s., 2H), 3.33 (d, J = 8.33 Hz, 2H), 3.13 (s, 3H), 2.58 (d, J = 12.09 Hz, 2H), 2.44 (s, 3H), 1.73 - 1.97 (m, 3H). LC-MS: m/z 463.2 (M+H)+.
[001519] Compound 307
OH
Figure imgf000351_0002
[001520] Step A: 6-(4-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000351_0003
[001521] A suspension of 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 305, 100 mg, 0.19 mmol), 4-aminophenylboronic acid hydrochloric salt (60 mg, 0.58 mmol), PdCb(dppf) (8.4 mg, 0.02 mmol) and Na2C03 (55 mg, 0.78 mmol) in 1.4- dioxane/water (10 mL/1 mL) was stirred and heated to 85 °C for 16 h under N2 atmosphere. The reaction was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo. The residue was purified by flash column chromatography, eluting with PE/EA (4/1), to give desired product (30 mg, 29% yield) as a white solid. LC-MS: m/z 530.3 (M+H)+.
[001522] Step B: 6-(4-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-l- yl)pyrazoIo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000352_0001
[001523] The mixture of tert-butyl 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin- 1 -yl)-4-((2- (trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[l,5-a]pyrimidin-6-yl)-l H-pyrazole-l- carboxylate (40 mg, 0.07 mmol) and HC1 in MeOH (0.5 mol, 10 mL, 5 mmol) was stirred at RT for 1 h. The mixture was concentrated to afford the desired product.
[001524] 1H NMR (DMSO-i/e) δ: 1 1.27 (br. s., 1H), 8.12 (d, J=7.2 Hz, 2H), 7.47 (t, J=7.2 Hz, 2H), 7.40 (d, J=7.2 Hz, 1H), 6.93 (t, J=8.4 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 5.12 (s, 2H), 3.08 (d, J=4.2 Hz, 4H), 2.26 (s, 3H), 1.62-1.50 (m, 6H). LC-MS: m/z 400.2 (M+H) *.
[001525] Compound 308
Figure imgf000353_0001
[001526] Step A: N-(4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[l,5-a]pyrimidin-6-yl)phenyl)acetamide
Figure imgf000353_0002
[001527] A suspension of 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 305, 100 mg, 0.19 mmol) and 4-acetamidophenylboronic acid (100 mg, 0.58 mmol), PdC12(dppf) (8.4 mg, 0.02 mmol) and Na2C03 (55 mg, 0.78 mmol) in 1.4- dioxane/water (10 mL/1 mL) was stirred and heated to 85 °C for 16 h under N2 atmosphere. The reaction was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo The residue was purified by flash column chromatography, eluting with PE/EA (4/1), to give desired product (20 mg, 18% yield) as a white solid. LC-MS: m/z 572.3 (M+H)+. [001528] Step B: N-(4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-l-yl)-4,7- dihydropyrazolo [1 ,5-a] pyrimidin-6-yl)phenyl)acetamide
Figure imgf000353_0003
[001529] The mixture of N-(4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)-4,7-dihydropyrazolo[l,5-a]pyrimidin-6-yl)phenyl)acetamide (20 mg, 0.03 mmol) and HC1 in MeOH (0.5 mol, 10 mL, 5 mmol) was stirred at RT for 1 h to afford the desired product.
[001530J 1H NMR (DMSO-d6) δ: 1 1.35 (br. s., 1 H), 10.02 (br. s., 1 H), 8.12 (d, J=7.2 Hz, 2H), 7.62 (d, J=7.2 Hz, 2H), 7.47 (d, J=7.2 Hz, 1H), 7.40 (t, J=7.2 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 3.08 (d, J=4.8 Hz, 4H), 2.26 (s, 3H), 2.07 (s, 3H), 1.67-1.50 (m, 6H). LC-MS: m/z 442.3 (M+H) +.
[001531] Compound 309
Figure imgf000354_0001
1 2 [001532] Step A: 6-(6-hydroxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-l- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000354_0002
[001533] The mixture of 6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-l- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 358, 40 mg, 0.10 mmol) in con.
hydrochloric acid (10 mL) was stirred at 100 °C for 48 h to afford the desired product.
[001534] 1H NMR (DMSO-rfe) δ: 8.29 (d, J=7.2 Hz, 2H), 7.39 (t, J=8.0 Hz, 3H), 7.26 (d, J=7.2 Hz, 1H), 7.14 (s, 1H), 6.30 (d, J=9.6 Hz, 1H), 3.19 (br. s., 4H), 2.12 (s, 3H), 1.62- 1.50 (m, 6H). LC-MS: m/z 402.3 (M+H) +. [001535] Compound 310
Figure imgf000355_0001
[001536] Step A: ethyl 3-oxo-2-(thiazol-4-yl)butanoate
Figure imgf000355_0002
[001537] To a solution of ethyl 2-(thiazol-4-yl)acetate (500 mg, 2.92 mmol) in THF (10 mL) was added LDA (1.5 M in THF, 2.3 mL, 3.5 mmol) dropwise at -30 ~ -35°C. The mixture was stirred at -30 ~ -35°C for 30 min, and acetic anhydride (360 mg, 3.5 mmol) was added dropwise. Then the mixture was warmed to room temperature and stirred for 6h. The mixture was poured into saturated NH4CI and extracted with EA (3* 10 mL). The combined organic phase was washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired ethyl 3-oxo- 2-(thiazol-4-yl)butanoate as a brown oil (500 mg, 80% yield ).
[001538] Step B: Compound 310: 5-methyl-2-phenyl-3-(piperidin-l-yl)-6-(thiazol-4- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000355_0003
[001539] A mixture of 3-oxo-2-(thiazol-4-yl)butanoate (200 mg, 0.94 mmol) and 3- phenyl-4-(piperidin-l-yl)-l H-pyrazol-5-amine (227 mg, 0.94 mmol) in AcOH (5 mL) was stirred at 95'C for 2 h to give title compound.
[001540] 1H NMR (400 MHz, DMSC s) δ : 1 1.52 (br. s., 1 H), 9. 17 (d, J=1.88 Hz, 1 H), 8.13 (d, J=6.98 Hz, 2 H), 7.82 (d, J=1.88 Hz, 1 H), 7.45 - 7.51 (m, 2 H), 7.37 - 7.44 (m, 1 H), 3.08-3.1 1 (m, 4 H), 2.42 (s, 3 H), 1.67 (br. s., 4 H), 1.56-1.61 (m, 2 H). LC-MS: m/z 392.3 (M+H)+.
[001541] Compound 311
Figure imgf000356_0001
[001542] Step A: ethyl 2-(4-hydroxypiperidin-l-yl)-3-oxobutanoate
Figure imgf000356_0002
[001543] To a solution of piperidin-4-ol (200 mg, 2.0 mmol) and TEA (0.3 mL, 2.4 mmoL) in EtOH (10 mL) was added ethyl 2-chloro-3-oxobutanoate (442 mg, 2.4 mmol) dropwise at 0 °C. The mixture was stirred at 40 °C for 18 h. The mixture was concentrated and purified by flash column chromatography, eluting with PE/EA (4/1), to get the desired product as a yellow solid (120 mg, 26% yield). LC-MS: m/z 230.2 (M+H) +.
[001544] Step B: 6-(4-hydroxypiperidin-l-yl)-5-methyl-2-phenyl-3-(piperidin-l- yl)py razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000356_0003
[001545] The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (116 mg, 0.66 mmol) and ethyl 2-(4-hydroxypiperidin-l-yl)-3-oxobutanoate (120 mg, 0.66 mmol) in AcOH (5 mL) was stirred at 100 °C for 1 h. After removal of AcOH, 10% of NaHC03 was added to afford the desired product. [001546] 1H NMR (DMSO-i/e) δ: 1 1.16 (br. s., 1H), 8.08 (d, J= 7.2 Hz, 2H), 7.46 (t, J = 7.2 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 3.42-3.17 (m, 3H), 3.03 (br. s., 4H), 2.68 (br. s., 2H), 2.51 (s, 3H), 1.82-1.79 (m, 2H), 1.64-1.56 (m, 6 H), 1.21 (br. s., 2H). LC-MS: m/z 408.6 (M+H)+.
[001547] Compound 312
Figure imgf000357_0001
[001548] Step A: methyl 2-(4-methoxyphenyl)-3-oxopentanoate
Figure imgf000357_0002
[001549] To a solution of methyl 2-(4-methoxyphenyl)-3-oxopentanoate (2.0 g, 11.10 mmol.) in THF (20 mL) was added LDA (2.0 M in THF, 6.6 mL, 13.32 mmol) dropwise at - 78*C. The mixture was stirred at -78"C for 30 min, and propionyl chloride (1.1 mL, 13.32 mmol) was added dropwise. Then the mixture was slowly warmed to RT and stirred for 10 min. The mixture was poured slowly to saturated aq. NH4CI and extracted with EA (30 mL*3). The combined organic phase was washed with brine, dried over anhydrous MgS04, and concentrated in vacuo to get the desired product as a yellow oil (4.0 g, crude) which was directly used to the next step without further purification. LC-MS: m/z 237.2 (M+H)+.
[001550] Step B: 5-ethyl-6-(4-methoxyphenyl)-2,3-diphenyIpyrazoIo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000357_0003
[001551] The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (1.3 g, 4.25 mmol) and methyl 2-(4-methoxyphenyl)-3-oxopentanoate (1.3 eq.) in AcOH (10 mL) was stirred at 100 °C for 1 h. After removal of AcOH, 10% of NaHC03 was added to afford the desired product.
[001552]1H NMR (DMSO-d6) δ: 11.84 (br. s., 1H), 7.46-7.33 (m, 10H), 7.22 (d, J = 8.4 Hz, 2H), 6.99 (d, J= 8.4 Hz, 2H), 3.81 (s, 3H), 2.43 (dd, J= 7.2 Hz, 7.2 Hz, 2H), 1.05 (t, J = 12 Hz, 3H). LC-MS: m/z 422.7 (M+H)+.
[001553] Compound 313
Figure imgf000358_0001
[001555] The solution of 5-(chloromethyl)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 340, 230 mg, 0.52 mmol), TMSCN (77.4 mg, 0.78 mmol) and Cs2C03 (338.8 mg, 1.04 mmol) in acetonitrile (30 mL) was stirred at reflux for 8 h. The reaction was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo to afford the desired product as a brown solid.
[001556] 1H NMR (DMSO-<&) δ: 7.55 (m, 4H), 7.37 (dd, J=6.0 Hz, 7.2 Hz, 3H), 7.27- 7.20 (m, 4H), 7.1 1 (d, J=7.2 Hz, 1H), 6.97 (dd, J=2.0 Hz, 2.0 Hz, 2H), 3.80 (s, 3H), 3.62 (s, 2H). LC-MS: m/z 433.8 (M+H) +. [001557] Compound 314
Figure imgf000359_0001
[001559] A mixture of 5-(hydroxymethyl)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (900 mg, 2.12 mmol) and PCC (synthesized in scheme of Compound 338, 688 mg, 3.18 mmol) in DCM (100 mL) was stirred at RT overnight. The mixture was filtered, washed with DCM, and concentrated in vacuo to get the desired product as a yellow solid (900 mg, 100%). LC-MS: m/z 422.2 (M+H) +.
[001560] Step B: (E)-6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo [ 1 ,5-a] pyrimidine-5-carbaldehyde oxime
Figure imgf000359_0002
[001561] The solution of 6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidine-5-carbaldehyde (1.0 g, 2.37 mmol), hydroxylamine hydrochloride (1.8 g, 26.1 mmol) and sodium hydroxide (104 mg, 2.61 mmol) in EtOH/H20 (90 ml/ 10 mL) was stirred at RT overnight. The reaction mixture was concentrated in vacuo and purified by flash column chromatography, eluting with DCM/MeOH (30/1), to get the desired product as a yellow solid (330 mg, 32% yield). LC-MS: m/z 437.2 (M+H)+.
[001562] Step C: 6-(4-methoxyphenyl)-7-oxo-2rJ-diphenyl-4,7-dihydropyrazolo[l,5- a] pyrimidine-5-carbonitrile
Figure imgf000360_0001
[001563] The solution of (E)-6-(4~methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidine-5-carbaldehyde oxime (150 mg, 0.34 mmol) in DCM (10 mL) was added thionyl chloride (0.2 mL, 3.44 mmol) dropwise at RT for 3 h. The reaction mixture was diluted with DCM, washed with saturated NaHC03 and extracted with DCM (30 mL*3). The combined organic phase was washed with brine, dried over anhydrous MgS04 and concentrated to afford the desired product.
[001564] 1H NMR (DMSO-i/e) δ: 7.51-7.01 (m, 12H), 7.7.01-6.99 (m, 2H), 3.81 (s, 3H), 3.18 (s, 1H). LC-MS: m/z 418.9 (M+H) +.
[001565] Compound 315
Figure imgf000360_0002
[001566] Step A: 6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[l,5- a]pyrimidine-5-carboxamide
Figure imgf000361_0001
[001567] A solution of 6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l ,5-a]pyrimidine-5-carbonitrile (Compound 314, 40 mg, 0.10 mmol) in MeOH (10 ml) were added hydrogen peroxide (30%, 32.5 mg, 0.96 mmol) and sodium hydroxide (IN, 38.4 mg, 0.96 mmol). The resultant mixture was stirred at 40 °C for 1 h. The saturated sodium sulfite was added to afford the desired product.
[001568] 1H NMR (DMSO-<&) δ: 7.55-7.46 (m, 4H), 7.34-7.02 (m, 8H), 6.86-.83 (m, 2H), 3.77 (s, 3H). LC-MS: m/z 436.9 (M+H) +.
[001569] Compound 316
Figure imgf000361_0002
[001570] Step A: 3-(3,3-difluoropyrrolidin-l-yl)-5-methyl-2-phenyl-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000361_0003
[001571] The mixture of methyl 3-oxo-2-(quinolin-6-yl)butanoate (184 mg, 0.76 mmol) and 4-(3,3-difluoropyrrolidin-l-yl)-3-phenyl-1H-pyrazol-5-amine (200 mg, 0.76 mmol, synthesized in the scheme of Compound 272) in AcOH (50 mL) was stirred at 100 °C for lh to afford the title compound 2.
[001572J 1H NMR (DMSO-d6) δ: 1 1.99 (s, 1 H), 8.94 (dd, J = 4.2, 1.6 Hz, 1H), 8.29 - 8.44 (m, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.99 (dd, J = 8.2, 1.2 Hz, 2H), 7.94 (d, J = 1.8 Hz, 1H), 7.73 (dd, J = 8.6, 2.0 Hz, 1H), 7.57 (dd, J = 8.2, 4.2 Hz, 1H), 7.40 - 7.52 (m, 3H), 3.62 (t, J = 12.8 Hz, 2H), 3.45 (t, J = 7.0 Hz, 2H), 2.42 - 2.59 (m, 2H), 2.32 (s, 3H). LC-MS: m/z 458.0 (M+H)+.
[001573J Compound 317
Figure imgf000362_0001
[001574] Step A: methyl 2-(6-nitropyridin-3-yl)-3-oxobutanoate
Figure imgf000362_0002
[0015751 To a solution of 5-chloro-2-nitropyridine (3.2 g, 20 mmol) in DMSO (20 mL) were added methyl 3-oxobutanoate (3.5 g, 30 mmol) and K2C03 (5.5 g, 40 mmol). The mixture was stirred at 110'C for 8h. The mixture was cooled to r.t. and poured into H2O (60 mL) and extracted with EA (3*50 mL). The extract was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound 2 as a yellow solid (470 mg, 10% yield). LC- MS: m/z 239.0 (M+H)+.
[001576J Step B: 3-(3,3-difluoropyrrolidin-l-yl)-5-methyl-6-(6-nitropyridin-3-yl)-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000363_0001
[001577] The mixture of intermediate 2 (470 mg, 2.0 mmol) and 4-(3,3- difluoropyrrolidin-l-yl)-3-phenyl-1H-pyrazol-5-amine (521 mg, 2.0 mmol, synthesized in the scheme of Compound 272) in AcOH (8 mL) was stirred at 100 °C for lh. Then the mixture was cooled to r.t, concentrated, and neutralized with saturated NaHC03 solution until pH = 7. The precipitate was filtered off and washed with EA (3*2 mL) to afford the title compound 3 as a yellow solid (400 mg, 45% yield).
[001578] 1H NMR (DMSO-d6) δ: 12.17 (s, 1H), 8.63 - 8.73 (m, 1H), 8.41 (d, J = 8.2 Hz, 1H), 8.25 (dd, J = 8.2, 2.0 Hz, 1H), 7.98 (d, J = 6.6 Hz, 2H), 7.38 - 7.55 (m, 3H), 3.61 (t, J = 12.8 Hz, 2H), 3.44 (t, J = 6.8 Hz, 2H), 2.44-2.58 (m, 2H), 2.37 (s, 3H). LC-MS: m/z 452.9 (M+H)+.
[001579] Step C: 6-(6-aminopyridin-3-yl)-3-(3,3-difluoropyrrolidin-l-yl)-5-methyl-2- phenylpyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
F
Figure imgf000363_0002
[001580] To a solution of intermediate 3 (390 mg, 0.09 mmol) in MeOH (8 mL) was added Pd/C (10 mg). The mixture was stirred at r.t. under H2 atmosphere overnight. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (DCM/MeOH 20: 1) to afford the title compound 4 as a yellow solid (270 mg, 74% yield). LC-MS: m/z 422.9 (M+H) +.
[0015811 Step D: 3-(3,3-difluoropyrrolidin-l -yl)-6-(imidazo[l,2-a]pyridin-6-yl)-5- methyl-2-phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000364_0001
[001582] To a solution of intermediate 4 (270 mg, 0.6 mmol) in EtOH (5 mL) was added 2-chloroacetaldehyde (40% in water, 0.3 mL) and NaHC03 (161 mg, 1.9 mmol). The mixture was refluxed for 2h. The mixture was cooled to r.t. and evaporated. The residue was dissolved in DCM (10 mL), washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 5.
[001583] 1H NMR (DMSO-d6) δ: 12.38 (br. s., 1H), 8.94 (s, 1H), 8.38 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 9.4 Hz, 1H), 7.96 - 8.01 (m, 2H), 7.90 - 7.95 (m, 1H), 7.44 - 7.52 (m, 3H), 3.64 (t, J = 12.8 Hz, 2H), 3.47 (t, J = 7.0 Hz, 2H), 2.47 - 2.60 (m, 2H), 2.40 (s, 3H). LC-MS: m/z 446.9 (M+H)+.
[001584] Compound 318
Figure imgf000364_0002
[001585] Step A: 5-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin- 7(4H)-one
Figure imgf000365_0001
[001586] A suspension of methyl 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.8 mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (200 mg, 0.85 mmol) in AcOH (2 ml) was refluxed for 30 min under N2 protection. The mixture was cooled to the RT, concentrated, and neutralized with saturated sodium hydrogen carbonate solution to adjust to pH=7. The precipitates were collected by filtration, washed with petroleum ether, and dried to obtain the desired product as a yellow solid (50 mg, 62% yield). LC-MS: m/z 429.2 (M+H)+
[001587] Step B: 4,5-dimethyl-2^diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a] pyrimidin-7(4H)-one
Figure imgf000365_0002
[001588] To a solution of 5-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l ,5- a]pyrimidin-7(4H)-one (34 mg, 0.08 mmol) and Cs2C03 (26 mg, 0.08 mmol) in DMF (2 ml) at ambient temperature was added Mel (22 mg, 0.16 mmol) dropwise. The mixture was stirred for 4 h at ambient temperature. The mixture was cooled to the RT, washed with saturated sodium hydrogen carbonate solution, and extracted with DCM (3*30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the desired product.
[001589] 1H NMR (DMSO-i/(5) 6: 8.95 (dd, J= 1.6 Hz, 1.6 Hz, 1H), 8.42 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.70 (dd, J= 2.0 Hz, 2.0 Hz, 1H), 7.59 (dd, J = 4.4 Hz, 4.0 Hz, 1H), 7.47 (s, 5H), 7.39 - 7.37 (m, 2H), 7.32 - 7.28 (m, 3H), 3.37 (s, 3H), 2.27 (s, 3H). LC-MS: m/z 443.3 (M+H)+.
Figure imgf000366_0001
Figure imgf000366_0002
[001592] To a solution of methyl 2-(quinolin-6-yl)acetate (10 g, 49.7mmol) in THF (300mL) was added dropwise LDA (1.5 M in THF, 39.8mL, 59.7mmol) at -30 ~ -35 °C. The mixture was stirred at -30 ~ -35 °C for 30 min and 2-(benzyloxy)acetyl chloride (9. 15g, 49.7mol) was added dropwise. Then the mixture was stirred at r.t. for 6h. The mixture was poured slowly to saturated NH4CI and extracted with EA (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous MgS04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired methyl 4-(benzyloxy)-3- oxo-2-(quinolin-6-yl)butanoate as a brown oil (13.6 g, 80% yield ). LC-MS: m/z 350.2 (M+H)+.
[001593] Step B: 5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000367_0001
[001594] A mixture of methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (8.6g,
0.024mol) and 3,4-diphenyl-1H-pyrazol-5-amine (5.64g, 0.024mol) was dissolved in AcOH (300ml). The mixture was warmed up to 95 °C for 4h. After cooling to room temperature, the precipitate was filtered, wash with EtOAc, and dried under vacuum to get 5-
((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (lOg, 78% yield ) as a yellow solid. LC-MS: m/z 535.2 (M+H)+.
[001595] Step C : Compound 319: 5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one
Figure imgf000367_0002
[001596] To a solution of 5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a] pyrimidin-7(4H)-one (lOg, 18.7mmol) in DCM (100ml) was added BCb (25ml, 25mmol, 1.0M in DCM) at 0 °C. The resultant mixture was stirred at 0°C for 4 hours. The reaction was quenched with MeOH and concentrated. The residue was stirred with sodium hydrogen carbonate solution and ethyl acetate for 30min to afford 5-
(hydroxymethyl)-2,3-diphenyl-6- (quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[001597]1H NMR (DMSO-d6) δ : 11.65 (br. s., 1H), 8.96 (d, J = 2.69 Hz, 1H), 8.40 (d, J = 7.79 Hz, 1H), 8.08 (d, J = 8.60 Hz, 1H), 8.01 (s, 1H), 7.79 (d, J = 8.87 Hz, 1H), 7.59 (dd, J = 4.03, 8.06 Hz, 1H), 7.36 - 7.51 (m, 9H), 5.64 (br. s., 1H), 4.36 (br. s., 2H). LC-MS: m/z 445.8 (M+H)+. [001598] Compound 320
Figure imgf000368_0001
[001599] Step A: 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000368_0002
[001600] To a suspension of 5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a] pyrimidin-7(4H)-one (Compound 319, 500mg, 1.126mmol,) in DCM (3ml) was added dropwise S0C12 (670mg, 5.631mmol) at 0 °C. The resultant mixture was then stirred at room temperature overnight. The suspension was filtered, washed with ethyl acetate, and dried under vacuum. The residue was purified by prep-TLC (DCM:MeOH=20: l) to get 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (300mg). LC-MS: m/z 463.1 (M+H)+.
[001601] Step B: Compound 320: 5-((1H-pyrazol-l-yl)methyl)-2,3-diphenyl-6- (quinolin-6-yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one
Figure imgf000368_0003
[001602] To a solution of 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one (lOOmg, 0.22mmol) in DMF (lOmL) were added 1H-pyrazole (30mg, 0.433mmol), K2C03 (60mg. 0.433mmol) and KI (5mg, 0.03mmol). The mixture was stirred at 80 °C for 2h to afford 5-((1H-pyrazol-l-yl)methyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one. [001603] 1H NMR (DMSO-d6) δ : 12.45 (br. s., 1H), 8.93 (d, J = 2.96 Hz, 1H), 8.27 (d, J = 8.06 Hz, 1H), 8.00 (d, J = 8.33 Hz, 1H), 7.75 (br. s., 1H), 7.64 (br. s., 1H), 7.56 (dd, J = 4.03, 8.33 Hz, 1H), 7.26 - 7.52 (m, 10H), 6.15 (s, 1H), 5.22 (br. s., 2H). LC-MS: m/z 494.8 (M+H)+.
[001604] Compound 321
Figure imgf000369_0001
[001606] To a solution of 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 320, lg, 22mmol) in CH3CN (lOmL) were added K2C03 (600mg. 4.33mmol) and NaCN (lOOmg, 22 mmol). The mixture was stirred at r.t. for 2h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography
(methanol :dichloromethane= 1 : 10) to afford 2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)acetonitrile (600mg, 61% yield). LC-MS: m/z 454.2 (M+H)+. [001607] Step B: Compound 321 : 5-((l H-l,2,4-triazol-5-yl)methyl)-2,3-diphenyl-6- (quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000370_0001
[001608] To a solution of 2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)acetonitrile (170mg, 0.375mmol) in butan-l-ol (lOmL) were added 2C03 (60mg. 0.433mmol) and formohydrazide (225mg, 3.75mmol). The mixture was stirred at 160 °C under microwave irradiation for 2h to afford 5-(( 1H- 1,2,4- triazol-5-yl)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[001609] 1H NMR (DMSO-d6) δ : 9.20 (br. s., 1H), 9.03 (d, J = 7.79 Hz, 1H), 8.32 (br. s., 1H), 8.24 (br. s., 2H), 7.95 - 8.10 (m, 2H), 7.56 (br. s., 3H), 7.25 - 7.51 (m, 9H), 4.17 (br. s., 2H). LC-MS: m/z 495.8 (M+H) +.
[001610] Compound 322
Figure imgf000370_0002
[001611] Step E: Compound 322: 3-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidin-5-yl)methyl)imidazolidine-2,4-dione
Figure imgf000370_0003
[001612] To a mixture of hydantoin (324 mg, 3.24 mmol) in DMF (6 mL) was added NaH (60% dispersion in mineral oil, 143 mg, 3.56 mmol) in portionse at 0°C. After addition, the mixture was stirred at 0°C for 30 min. Then the 5-(chloromethyl)-2,3-diphenyl-6- (quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (150 mg, 0.324 mmol, synthesized in scheme of Compound 278) was added into the mixture. The reaction mixture was warmed to 80°C and stirred overnight. The reaction was quenched with brine and mixed with EA to afford the title compound.
[001613] 1H NMR (400 MHz, TFA) δ : 9.37 (d, J=8.06 Hz, 1 H), 9.29 (d, J=5.37 Hz, 1 H), 8.61 (br. s., 2 H), 8.20 - 8.42 (m, 2 H), 7.47 - 7.66 (m, 7 H), 7.13-7.35 (m, 3 H), 5.00 (br. s., 1 H), 4.35 (br. s., 1 H), 3.22 (br. s., 2 H). LC-MS: m/z 527.0 (M+H)+.
Figure imgf000371_0001
[001615] Step A: 3-(4-methoxybenzyl)imidazolidine-2,4-dione
O
Figure imgf000371_0002
[001616] To a solution of imidazolidine-2,4-dione (500 mg, 5 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil, 240 mg, 6 mmol) in portions at 0°C. After addition, the mixture was stirred at 0°C for 40 min. Then PMBBr (1.0 g, 5mmol) was added dropwise. The resultant mixture was warmed to 80°C and stirred overnight. The reaction was quenched with brine (30 mL). The suspension was filtered off. The filter cake was washed with brine and EA, and then dried in vacuo to get the title compound (430 mg) as a white solid. LC-MS: m/z 221.1 (M+H)+.
[001617] Step B: 3-(4-methoxybenzyl)-l-((7-oxo-23-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazoIo[l,5-a]pyriniidin-5-yl)methyI)iniidazolidine-2,4-dione
Figure imgf000372_0001
[001618] To a mixture of hydantoin (124 mg, 0.562 mmol) in DMF (6 mL) was added NaH (60% dispersion in mineral oil, 27 mg, 0.674 mmol) in portions at 0°C. After addition, the mixture was stirred at 0°C for 30 min. Then the 5-(chloromethyl)-2,3-diphenyl-6- (quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (130 mg, 0.281 mmol, Synthesized in scheme of Compound 278) was added into the mixture. The reaction mixture was warmed to 80°C and stirred overnight. The reaction was quenched with brine and then mixed with EA. The mixture was filtered off. The filter cake was purified by prep HPLC to get the title compound (100 mg) as a yellow solid. LC-MS: m/z 647.0 (M+H) +.
[001619] Step C: Compound 323: l-((7-oxo-2,3-diphenyl-6-<quinolin-6-yl)-4,7- dihydropyrazolo [ 1 ,5-a] pyrimidin-5-yl)methyi)imidazolidine-2,4-dione
Figure imgf000372_0002
[001620] A mixture of 3-(4-methoxybenzyl)-l-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)- 4,7-dihydropyrazolo[l,5-a]pyrimidin-5-yl)methyl)imidazolidine-2,4-dione and CF3SO3H (0.5 mL) in TFA (2 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature, quenched with aq. NaHCCb to pH=7-8 to afford the title compound.
[001621] 1H NMR (400 MHz, TFA) δ : 9.34 (d, J=8.33 Hz, 1 H), 9.25 (d, J=5.10 Hz, 1 H), 8.49 - 8.64 (m, 2 H), 8.34 (d, J=8.06 Hz, 1 H), 8.24 (dd, J=8.06, 5.64 Hz, 1 H), 7.55 - 7.71 (m, 6 H), 7.46 - 7.53 (m, 2 H), 7.43 (d, J=6.72 Hz, 2 H), 4.88 (br. s., 2 H), 4.27 (br. s., 2 H). LC-MS: m/z 527.0 (M+H)+. [001622] Compound 324
Figure imgf000373_0001
[001623J Step A: Compound 324: 5-((2-oxoimidazolidin-l-yl)methyl)-2,3-diphi (quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000373_0002
[001624] A mixture of 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one (100 mg, 0.216 mmol, Synthesized in scheme of Compound 278), imidazolidin-2-one (93 mg, 1.08 mmol) and K2C03 (136 mg, 0.259 mmol) in DMF (3 mL) was heated to 80°C and stirred overnight. The reaction mixture was quenched with brine and then mixed with EA to get the title compound.
[001625] 1H NMR (400 MHz, DMSCMs) δ : 8.88 (br. s., 1 H), 8.36 (d, J=7.52 Hz, 1 H), 8.00 (d, J=8.06 Hz, 1 H), 7.89 (br. s., 1 H), 7.78 (d, J=8.33 Hz, 1 H), 6.95 - 7.68 (m, 11 H), 6.19 (br. s., 1 H), 4.09 - 4.33 (m, 2 H), 3.58 (br. s., 2 H), 3.21 (br. s., 2 H). LC-MS: m/z 513.0 (M+H)+.
[001626] Compound 325
Figure imgf000374_0001
[001627J Step A: 3-(3-hydroxycyclohex-l-en-l-yl)-5-methyl-2-phenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000374_0002
[001628] To a solution of 7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid (Synthesized in scheme of Compound 329, 100 mg, 0.2 mmol) in DMF (5 mL) were added methanamine hydrochloride (16 mg, 0.2 mmol), 0-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (91 mg, 0.2 mmol) and N,N-diisopropylethylamine (65 mg, 0.5 mmol). The mixture was stirred at r.t. for 30 min. The mixture was diluted with H20 (15 mL) and extracted with DCM (3* 15 mL). The extracts were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 2.
[001629] 1H NMR (DMSO-d6) δ: 13.00 (br. s., 1H), 8.92 - 9.12 (m, 1H), 8.65 (d, J = 4.6 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.07 - 8.15 (m, 1H), 8.05 (br. s., 1H), 7.86 (d, J = 7.4 Hz, 1H), 7.68 (d, J = 3.8 Hz, 1 H), 7.40 - 7.52 (m, 5H), 7.28 - 7.39 (m, 5H), 2.44 (d, J = 4.6 Hz, 3H). LC-MS: m/z 472.2 (M+H)+. [001630] Compound 326
Figure imgf000375_0001
[001632] The solution of 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidine- 5,7(4H,6H)-dione (18 g, 42 mmol, Compound 275), DMAP (1 g) and PC15 (80 mg) in POCb (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. The resultant mixture was diluted with DCM (450 ml), washed with saturated NaHCC (150 ml) and brine (100 ml), dried over anhydrous sodium sulfate, and concentrated to get crude product of 6-(5,7-dichloro-2,3-diphenylpyrazolo[l,5-a]pyrimidin-6-yl)quinoline (13 g) which was used in the next step without further purification. LC-MS: m/z 467.1 (M+H)+ [001633] Step D: 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,5-a]pyrimidin-6- yl)quinoline
Figure imgf000375_0002
[001634] To a solution of 6-(5,7-dichloro-2,3-diphenylpyrazolo[l,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 NH4CI (150 mL) was added to quench the reaction. The resultant mixture was extracted with DCM (500 mL), washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (DCM/MeOH= 40: 1) to obtain 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,5- a]pyrimidin-6-yl)quinoline (9.0 g) as a pale yellow solid.
[001635] 1H NMR (DMSO-d6): δ 9.01 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 - 8.52 (m, 1H), 8.13 - 8.21 (m, 2H), 7.88 (dd, J = 8.6, 1.9 Hz, 1H), 7.59 - 7.68 (m, 3H), 7.42 - 7.48 (m, 7H), 7.34 - 7.41 (m, 1H), 4.25 (s, 3H). LC-MS: m/z 463.1 (M+H)+.
[001636] Step E: N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[ 1,5- a]pyrimidin-5-yl)cyclopropanecarboxamide
Figure imgf000376_0001
[001637] A mixture of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l,5-a]pyrimidin-6- yl)quinoline (100 mg, 0.216 mmol), cyclopropanecarboxamide (55.2 mg, 0.65 mmol), palladium(II) acetate (9.7 mg, 0.04 mmol), xantphos (37.5 mg, 0.06 mmol) and sodium carbonate (140.8 mg, 0.43 mmol) in 1, 4-dioxane (10 mL) was stirred at 100 °C under N2 for 12 h to afford the desired product. [001638] 1H NMR (DMSO-<&) δ: 9.41-9.31 (m, 2H), 8.73-8.72 (m, 1H), 8.47-8.32 (m, 1H), 7.80-7.38 (m, 14H), 1.15-1.32 (m., 5H). LC-MS: m/z 498.2 (M+H)+. [001639] Compound 327
Figure imgf000377_0001
[001640] Step A: N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[l,5- a]pyrimidin-5-yl)propionamide
Figure imgf000377_0002
[001641] A mixture of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[l ,5-a]pyrimidin-6- yl)quinoline (Synthesized in scheme of Compound 326, 100 mg, 0.216 mmol),
propionamide (47.4 mg, 0.65 mmol), palladium(II) acetate (9.7 mg, 0.04 mmol), xantphos (37.5 mg, 0.06 mmol) and sodium carbonate (140.8 mg, 0.43 mmol) in 1, 4-dioxane (10 mL) was stirred at 100 °C under N2 for 12 h to afford the desired product.
[001642] 1H NMR (DMSO-i/e) δ: 12.92 (br. s., 1H), 10.08 (s, 1H), 8.94 (d, J=2.8 Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.75 (dd, J=1.6 Hz, 1.6 Hz, 1H), 7.55 (dd, J=4.4 Hz, 4.0 Hz, 4H), 7.51-7.41 (m, 4H), 7.39-7.35 (m, 6H), 2.28 (dd, J=7.6 Hz, 7.2 Hz, 2H), 0.94 (t, J=7.6 Hz, 3H). LC-MS: m/z 486.8 (M+H)+.
[001643] Compound 328
Figure imgf000378_0001
1 2
[001644J Step A: N-((1H-pyrazol-3-yl)methyl)-7-oxo-2,3-diphenyl-6-(quinolin-6-yl)- 4,7-dihydropyrazolo[ 1 ,5-a]pyrimidine-5-carboxamide
Figure imgf000378_0002
[001645] To a solution of 7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid (Synthesized in scheme of Compound 329, 100 mg, 0.2 mmol) in DMF (5 mL) were added (1H-pyrazol-3-yl)methanamine (23 mg, 0.2 mmol), 0-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (91 mg, 0.2 mmol) and N,N-diisopropylethylamine (65 mg, 0.5 mmol). The mixture was stirred at r.t. for 30 min. The mixture was diluted with H20 (15 mL) and extracted with DCM (3*15 mL). The extracts were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 2.
[001646] 1H NMR (DMSO-d6) δ: 12.51 (br. s., 1 H), 8.85 (br. s., 1H), 8.54 - 8.94 (m, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.82 - 7.94 (m, 2H), 7.78 (d, J = 9.0 Hz, 1H), 7.40 - 7.66 (m, 6H), 7.1 1 - 7.40 (m, 7H), 5.85 (br. s., 1 H), 4.22 (br. s., 2H). LC-MS: m/z 538.3 (M+H)". [001647] Compound 329
Figure imgf000379_0001
[001649] To a solution of methyl 2-(quinolin-6-yl)acetate (10.0 g, 49.7 mmol) in THF (60 mL) was added dropwise LDA (2.0 mol/L in THF, 29.8 mL) and HMPA (1.8 g, 9.9 mmol) at -78°C. After addition, the mixture was stirred at -78°C for 0.5 h. The mixture was then cooled to -78°C. 2-(benzyloxy)acetyl chloride (11.0 g, 59.6 mmol) in dry THF (10 mL) was added slowly and stirred at r.t. overnight. The reaction mixture was diluted with EA (60 mL), quenched with NH4CI solution, extracted with EA (3*60 mL). The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/PE=l/4) to afford the title compound 2 (8.6 g, 48% yield). LC-MS: m/z 350. 1 (M+H)+. [001650] Step B: 5-((benzyloxy)methyl)-2^3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a] pyrimidin-7(4H)-one
Figure imgf000380_0001
[001651] A mixture methyl 4-(benzyloxy)-3-oxo-2-{quinolin-6-yl)butanoate (8.6 g, 24.6 mmol) and 3,4-diphenyl-1H-pyrazol-5-amine (5.8 g, 24.6 mol) in AcOH (100 mL) was stirred at 100'C for 4h. After cooling to room temperature, the precipitate was filtered, wash with EA (3 * 10 mL), and dried under vacuum to afford the title compound 3 as a yellow solid (10.0 g, 78% yield). LC-MS: m/z 535.2 (M+H) +.
[001652] Step C: 5-(hydroxymethyl)-2,3-diphenyl-6-(quuiolin-6-yl)pyrazolo[l,5- a] pyrimidin-7(4H)-one
Figure imgf000380_0002
[001653] To a solution of Intermediate 3 (10.0 g, 18.7 mmol) in DCM (100 mL) was added BCb (1.0 mol/L in DCM, 25 mL) at 0"C. The resultant mixture was stirred at 0"C for 4 h. The reaction was quenched with MeOH and evaporated. The residue was stirred with 10% NaHCCh (10 mL) aqueous solution and EA (10 mL) for 30 min. The precipitate was filtered off, washed with EA (3*2 mL) and dried under vacuum to afford the title compound 4 (8.0 g, 96% yield). LC-MS: m/z 445.1 (M+H) +.
[001654] Step D: 7-oxo-2rJ-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[l,5- a] py rimidine-5-carbaldehy de
Figure imgf000380_0003
[001655] To a solution of Intermediate 4 (4.4 g, 10 mmol) in 1 ,2-dichloroethane (50 mL) was added Mn02 (8.7 g, 100 mmol). The mixture was refluxed for 2 days. The reaction was cooled to r.t. and filtered through celite. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound 5 as a brown solid (1.5 g, 34% yield). LC-MS: m/z 443.1 (M+H) +.
[001656J Step E: 7-oxo-2r3-diphenyl-6-(quinoIin-6-yl)-4,7-dihydropyrazolo[l,5- a]pyrimidine-5-carboxylic acid
Figure imgf000381_0001
[001657] To a solution of Intermediate 5 ( 415 mg, 0.9 mmol) and NaH2P04 (702 mg, 4.5 mmol) in DMSO/H20 (5 mL/5 mL) was added sodium chlorite (203 mg in 1 mL H20, 2.3 mmol) at O'C. After addition, the mixture was stirred at r.t. for lh and poured into H20 (10 mL). The precipitate was filtered off, washed with MeOH (3* 1 mL) and dried in vacuo to afford the title compound 6 as a brown solid (300 mg, 73%). LC-MS: m/z 459.1 (M+H)+
[001658] Step F: N-(2-hydroxyethyl)-7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7- dihydropy razolo [1 ,5-a] pyrimidine-5-carboxamide
HO
Figure imgf000381_0002
[001659] To a solution of Intermediate 6 (140 mg, 0.3 mmol) in DMF (5 mL) were added 2-aminoethanol (22 mg, 0.4 mmol), 0-(7-Azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (137 mg, 0.4 mmol) and N,N- diisopropylethylamine (97 mg, 0.8 mmol). The mixture was stirred at r.t. for 30 min. The mixture was diluted with H20 (15 mL) and extracted with DCM (3* 15 mL). The extracts were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 7. [001660] 1H NMR (DMSO-d6) δ: 8.81 (br. s., 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.18 (br. s., 1H), 7.75 - 7.94 (m, 3H), 7.44 - 7.57 (m, 5H), 7.35 (br. s., 3H), 7.29 (t, J = 7.4 Hz, 2H), 7.12 - 7.17 (m, 1H), 3.25 - 3.30 (m, 2H), 3.10 (d, J = 5.6 Hz, 2H). LC-MS: m/z 502.2 (M+H)+.
[001661] Compound 330
Figure imgf000382_0001
[001663] A mixture of Intermediate 5 (170mg, 0.41mmol, synthesized in scheme of Compound 245) and formamide (5mL) was stirred at 180°C for 2h. under microwave irradiation. The mixture was concentrated under vacuum to afford the title compound 6.
[001664] 1H NMR (DMSO-d6) δ : 8.40 (s, 1 H), 8.18 (d, J = 1.6 Hz, 1 H), 7.90 - 7.63 (m, 4 H), 7.53 - 7.24 (m, 1 1 H), 2.23 (s, 3 H). LC-MS: m/z 445.1 (M+H)+. [001665] Compound 331
Figure imgf000383_0001
[001666] Step A: methyl 2-(quinoxalin-6-yl)acetate
Figure imgf000383_0002
[001667] To 2-(quinoxalin-6-yl)acetic acid (1.0 g, 5.31 mmol) in methanol (20 mL) was added slowly cone. H2S04 (1.0 mL) at 0 °C, and the mixture was refluxed overnight. The reaction mixture was concentrated in vacuo, and the residue dissolved in EA. The organic solution was washed with saturated aqueous NaHC03 and brine, dried over Na2S04, and concentrated in vacuo. The residue was purified by flash chromatography, eluting with PE/ EA=4/1, to obtain the desired product as a yellow oil (0.47 g, 43% yield). LC-MS: m/z 203.2 (M+H)+.
[001668] Step B: methyl 3-oxo-2-(quinoxaIin-6-yl)butanoate
Figure imgf000383_0003
[001669] To a solution of methyl methyl 2-(quinoxalin-6-yl)acetate (0.45 g, 2.23 mmol) in THF (20 mL) was added LDA (2.0 M in THF, 1.4 mL, 2.90 mmol) dropwise at -40 °C. The mixture was stirred at -78 °C for 30 min and acetyl chloride (0.17 mL, 2.33 mmolo) was added dropwise. Then the mixture was slowly warmed to RT and stirred for 10 h. The mixture was poured slowly to saturated aq. NLUC1 and extracted with EA (30 mL*3). The combined organic phase was washed with brine, dried over anhydrous MgS04 and concentrated in vacuo to get the desired product as a yellow oil (0.40 g, 88% yield). LC-MS: m/z 245.2 (M+H)+.
[001670] Step C: 5-methyl-2^-diphenyI-6-(quinoxalin-6-yl)pyrazoIo[l,5- a] pyrimidin-7(4H)-one
Figure imgf000384_0001
[001671] The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (100 mg, 0.42 mmol) and methyl methyl 3-oxo-2-(quinoxalin-6-yl)butanoate (135 mg, 0.55 mmol) in AcOH (5 mL) was stirred at 100 °C for 1 h. After removal of AcOH, 10% of NaHC03 was added to afford the desired product.
[001672]1H NMR (DMSO-d6) δ: 12.05 (br. s., 1H), 8.95 (dd, J = 1.6 Hz, 2.0 Hz, 2H), 8.12 (d, J= 8.8 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 1.6 Hz, 2.0 Hz, 1H), 7.51 (dd, J= 3.6 Hz, 2.4 Hz, 2H), 7.44-7.28 (m, 8H), 2.26 (s, 3H). LC-MS: m/z 430.0 (M+H)+.
[001673] Compound 332
Figure imgf000384_0002
[001674] Step D: N,N-dimethyl-2-(4-(5-methyl-7-oxo-2,3-diphenyl-4,7- dihydropyrazolo[l,5-a]pyrimidin-6-yl)phenoxy)acetamide
Figure imgf000385_0001
[001675] To a solution of Intermediate 4 (80 mg, 0.2 mmol, Compound 237) in DMF (5 mL) were added 2-bromo-N,N-dimethylacetamide (34 mg, 0.2 mmol) and K2CO3 (56 mg, 0.4 mmol). The mixture was stirred at 60 °C for 3h. The mixture was poured into H20 (15 mL) and extracted with DCM (3* 10 mL). The combined extracts were washed with brine and dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 5.
[001676] 1H NMR (DMSO-d6) δ: 1 1.88 (br. s., 1H), 7.39 - 7.49 (m, 5H), 7.28 - 7.38 (m, 5H), 7.23 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.84 (s, 2H), 3.03 (s, 3H), 2.87 (s, 3H), 2.18 (s, 3H). LC-MS: m/z 480.0 (M+H)+.
[001677] Compound 333
Figure imgf000385_0002
[001678] Step A: methyl 2-(6-methoxypyridin-3-yl)acetate
Figure imgf000385_0003
[001679] To 2-(6-methoxypyridin-3-yl)acetic acid (1.0 g, 5.98 mmol) in MeOH (20 mL) was slowly added thionyl chloride (4.0 mL, 55.1 mmol) at -10 °C, and the mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in DCM. The solution was washed with saturated aqueous NaHC03 and brine, dried over Na2S04, and concentrated in vacuo. The residue was purified by flash
chromatography, eluting with PE/ EA =4/1, to obtain the desired product as yellow oil (1.0 g, 92% yield). LC-MS: m/z 182.2 (M+H)+. [001680] Step B: methyl 2-(6-methoxypyridin-3-yl)-3-oxobutanoate
Figure imgf000386_0001
[001681] To a solution of methyl 2-(6-methoxypyridin-3-yl)acetate (0.5 g, 2.76 mmol) in THF (20 mL) was added LDA (2.0 M in THF, 1.8 mL, 3.58 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 30 min and acetyl chloride (0.2 mL, 3.31 mmol) was added dropwise. Then the mixture was slowly warmed to RT and stirred for 10 min. The mixture was poured slowly to saturated aq. NHiC1 and extracted with EA (30 mL*3). The combined organic phase was washed with brine, dried over anhydrous MgS04 and concentrated in vacuo to get the desired product as a yellow oil (0.76 g, crude) which was directly used to the next step without further purification. LC-MS: m/z 224.2 (M+H)+. [001682] Step C: 6-(6-methoxypyridin-3-yl)-5-methyl-2^-diphenylpyrazolo[l,5- a] pyrimidin-7(4H)-one
Figure imgf000386_0002
[001683] The mixture of 3,4-diphenyl-1H-pyrazol-5-amine (150 mg, 1.06 mmol) and methyl 2-(6-methoxypyridin-3-yl)-3-oxobutanoate (309 mg, 1.38 mmol) in AcOH (5 mL) was stirred at 100 °C for 1 h. After removal of AcOH under reduced pressure, 10% of NaHC03 was added to afford the desired product.
[001684]1H NMR (DMSO-d6) δ: 12.01 (br. s., 1H), 8.13 (d, J= 2.4 Hz, 1H), 7.70 (dd, J = 2.4 Hz, 2.4 Hz, 1H), 7.47-7.42 (m, 5H), 7.33 (dd, J = 1.6 Hz, 1.6 Hz, 5H), 6.91 (dd, J = 0.4 Hz, 0.4 Hz, 1H), 3.91 (s, 3H), 2.22 (s, 3H). LC-MS: m/z 409.4 (M+Hf . [001685] Compound 334
Figure imgf000387_0001
[001686] Step A: methyl 2-(benzofuran-5-yl)acetate
Figure imgf000387_0002
[001687] To a solution of 2-(benzofuran-5-yl)acetic acid (350 mg, 2 mmol) in MeOH (40 mL) was added one drop of concentrated H2S04. The mixture was refluxed for 3h. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (30 mL), washed with 10% NaHC03 aqueous solution and brine, dried over anhydrous MgS04, and concentrated in vacuo to afford the intermediate 2 as a colorless oil (340 mg, 90% yield) which was used to the next step without purification. LC-MS: m/z 191.0 (M+H)~.
[001688] Step B: methyl 2-(benzofuran-5-yl)-3-oxobutanoate
Figure imgf000387_0003
[001689] To a solution of Intermediate 2 (340 mg, 1.8 mmol) in THF (20 mL) was added LD A (2 mol/L in THF, 1.1 mL) at -40'C dropwise. After the mixture was stirred at - 40'C for 30 min, acetyl chloride (173 mg, 2.2 mmol) was added dropwise. The mixture was then stirred at r.t. for 3h. The mixture was diluted with EA (20 mL) and quenched with saturated NHiC1 aqueous solution. The organic phase was separated and washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo to afford the crude intermediate 3 as a yellow oil (250 mg, 60% yield) which was used to the next step without purification. LC- MS: m/z 233.0 (M+Hy.
[001690] Step C: 6-(benzofuran-5-yI)-5-methyl-2^-diphenyIpyrazoIo[l,5- a] py rim id in-7(4H)-one
Figure imgf000388_0001
[001691] The mixture of Intermediate 3 (110 mg, 0.47 mmol) and 3,4-diphenyl-1H - pyrazol-5-amine (120 mg, 0.51 mmol) in AcOH (10 mL) was stirred at 100 °C for lh. Then the mixture was cooled to r.t. to afford the desired product 4. [001692] 1H NMR (DMSO-d6) 6: 11.94 (br. s., 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.38 - 7.48 (m, 5H), 7.31 - 7.37 (m, 5H), 7.25 (dd, J = 8.4, 1.6 Hz, 1H), 7.00 (d, J = 1.2 Hz, 1H), 2.17 (s, 3H). LC-MS: m/z 418.0 (M+H)+.
[001693] Compound 335
Figure imgf000388_0002
[001694] Step A: ethyl 2-(3-bromo-4-nitrophenyl)-3-oxobutanoate
Figure imgf000388_0003
[001695] 2-bromo-4-fluoro-l -nitrobenzene (6.6 g, 30 mmol), ethyl 3-oxobutanoate (7.8 g, 60 mmol) and K2C03 (12.46 g, 90 mmol) in DMSO (50 mL) was stirred at 60 °C for 16 h. The mixture was acidified with 1M HC1 to pH=7 and extracted with EA (50mL*3). The organic layer was dried and concentrated to give the crude product, which was purified by silica gel chromatography (PE/EA=3/1) to obtain the desired product as yellow solid (7.6 g, 77% yield). LC-MS: m/z 331.2 (M+H)+. [0016961 Step B: 6-(3-bromo-4-nitrophenyl)-5-methyl-2^-diphenylpyrazolo[l,5- a] pyrimidin-7(4H)-one
Figure imgf000389_0001
[001697] A suspension of 3,4-diphenyl-1H-pyrazol-5-amine (4.6 g, 19.6 mmol) and ethyl 2-(3-bromo-4-nitrophenyl)-3-oxobutanoate (7.2 g, 21.8 mmol) in AcOH (20 mL) was refluxed for 30 min under N2 protection. The mixture was cooled to the RT, concentrated and neutralized with saturated sodium hydrogen carbonate solution to adjust to pH=7. The precipitates were collected by filtration, washed with petroleum ether and dried to obtain the desired product as a yellow solid (9.0 g, 92% yield). LC-MS: m/z 502.2 (M+H)".
[001698J Step C: 5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2,3- diphenyIpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000389_0002
[001699] A suspension of 6-(3-bromo-4-nitrophenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (3.0 g, 6.0 mmol), ethynyltrimethylsilane (1.18 g, 12.0 mmol), Pd(PPh3)2C12 (42 mg, 0.6 mmol), Cul (228 mg, 1.2 mmol) and TEA (15 mL, 18.0 mmol) in THF (50 ml) was heated to 50 °C for 6 h under an atomosphere of N2. The mixture was cooled to the RT, diluted with water, and extracted with EA (30 mL*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column, eluting with DCM/MeOH (40/1), to obtain the desired product as a yellow solid (2.3 g, 74% yield). LC- MS: m/z 519.2 (M+H)+.
[001700] Step D: 6-(4-ainino-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-2,3- diphenyIpyrazoIo[l,5-a]pyriniidin-7(4H)-one
Figure imgf000390_0001
[001701] To a suspension of 5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (2.3 g, 4.4 mmol) in DMF/MeOH (20 mL/30 mL) was added sat. ammonium chloride aqueous solution (20 mL) and zinc powder (2.88 g, 44.4 mmol). The resultant mixture was stirred at RT overnight. The reaction mixture was filtered and concentrated. The residue was purified by flash column chromatography, eluting with DCM/MeOH (20/1), to obtain the desired product as a yellow solid (600 mg, 28% yield). LC-MS: m/z 489.2 (M+H)+.
[001702] Step E: 5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2-3- diphenyIpyrazoIo[l,5-a]pyriniidin-7(4H)-one
Figure imgf000390_0002
[001703] A suspension of 6-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (120 mg, 0.24 mmol) in acetonitrile/water (1.4 mL/0.7 mL) was added con. hydrochloric acid (0.2 mL, 2.4 mmol) at 0 °C. Then a solution of sodium nitrite (25 mg, 0.37 mmol) in water (2 mL) was introduced slowly while keeping the temperature below 0 °C. After the addition, the resultant mixture was stirred at 0 °C for 30 min. Then the mixture was added slowly to a stirred solution of piperidine (137 mg, 1.62 mmol) and potassium carbonate (260 mg, 1.88 mmol) in acetonitrile/water (2 mL/1 mL) at 0 °C. The resultant mixture was allowed to warm to RT for 1 h. The reaction was quenched with water, extracted with EA (30 mL*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column, eluting with DCM/MeOH (20/1), to obtain the desired product as a yellow solid (140 mg, 99% yield). LC-MS: m/z 585.3 (M+H)+.
[001704] Step F: 6-(3-ethynyl-4-(piperidin-l-yldiazenyI)phenyl)-5-methyl-2,3- diphenylpy razolo [1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000391_0001
[001705] To a mixture of 5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (50 mg, 0.08 mmol) in THF/MeOH (0.85 ml/0.17 mL) was added potassium carbonate (1 17 mg, 0.85 mmol) and potassium hydroxide (50 mg, 0.09 mmol). Then the mixture was stirred at RT for 2 h, The reaction mixture was diluted with water, extracted with EA (30 mL*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column, eluting with DCM/MeOH (25/1 ), to obtain the desired product as a yellow solid (30 mg, 50% yield). LC-MS: m/z 513.2 (M+H)+.
[001706] Step G: 6-(cinnolin-6-yl)-5-methyl-2^-diphenylpyrazolo[l,5-a]pyrimidin- 7(4H)-one
Figure imgf000391_0002
[001707] A mixture of 6-(3-ethynyl-4-(piperidin-l-yldiazenyl)phenyl)-5-methyl-2,3- diphenylpyrazolo[l ,5-a]pyrimidin-7(4H)-one (30 mg, 0.006 mmol) in 1,2-dichlorobenzen (2 mL) was heated at 200 °C for 16 h to obtain the desired product. [001708] 1H NMR (DMSO-i/e) δ: 12.05 (br. s., 1H), 9.38 (d, J= 5.6 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.23 (d, J= 6.0 Hz, 1H), 8.05 (s, 1H), 7.98 (dd, J = 2.0 Hz, 1.6 Hz, 1H), 7.48- 7.31 (m, 10H), 2.27 (s, 3H). LC-MS: m/z 430.2 (M+H)+.
[001709] Compound 336
Figure imgf000392_0001
St*p D St»p E
[001710] Step A: 5-methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000392_0002
[001711] The mixture of 3, 4-diphenyl-l H-pyrazol-5-amine (3g, 12.8mmol, leq.) and methyl 3-oxobutanoate (2.96g, 25.5mmol) in AcOH (20 mL) was stirred at 120 °C for 4h. Then the mixture was cooled to r.t. and filtered to give the crude solid which was washed with EA to afford the desired product 5-methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)- one (3.5g) LC-MS: m/z 302.1 (M+H)+. [001712] Step B: 5-methyl-2-3-diphenyl-l-((2-
(trimethy Isily I)ethoxy)methy l)py razolo [ 1 ,5-a] pyrimidin-7( 1 H)-one
Figure imgf000393_0001
[001713] To the mixture of 5-methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (3.5g, 11.6 mmol), Cs2C03 (7.58g, 23.2mmol) in DMF (50mL) was added l-(chloromethyl)- 4-methoxybenzene (2.3g,13.9mmol). The reaction was stirred at r.t. for 16h. The mixture was diluted with H20 (30mL) and extracted with DCM (10mL*3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The resulting solid was purified by silica gel chromatography (PE/EA=10: 1) to give the desired product (3.19g). LC- MS: m/z 432.3 (M+Hf.
[001714] Step C: 6-bromo-5-methyl-2,3-diphenyl-l-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(1H )-one
Figure imgf000393_0002
[001715] To a solution of 5-methyl-2,3-diphenyl-l-((2-
(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(1H)-one (3.1g, 7.2 mmol) in DCM (50 mL) and TEA (1.45g, 14.58mmol) was added dropwise NBS (1.4g, 7.9mmol) in DCM (5mL). The resultant mixture was stirred for 3 hours at ambient temperature and washed with water. The aqueous phase was extracted with DCM (20 mL). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EA=10/1) to obtain the 6- bromo-5-methyl-2,3-diphenyl-l-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin- 7(1H)-one (3g, 82% yield). LC-MS: m/z 510.1 (M+H)+.
[001716] Step D: 5-methyl-2^-diphenyl-6-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l-((2- (trimethy Isily I)ethoxy)methy l)py razolo [1 ,5-a] pyrimidin-7( 1 H)-one
Figure imgf000394_0001
[001717] To a solution of 6-bromo-5-methyl-2,3-diphenyl-l-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l ,5-a]pyrimidin-7(1H)-one (400 mg, 0.786 mmol) and l,4-dioxaspiro[4.5]dec-7-en-8-ylboronic acid (251 mg, 0.943 mmol) in dioxane/H20 (26 mL/9 mL) was added l,l '-bis(diphenylphosphino)fenOcene-palladium(II)dichloride dichloromethane complex (57 mg, 0.078 mmol) and sodium carbonate (166 mg, 1.57 mmol). The reaction mixture was then refluxed under nitrogen atmosphere overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=l/20) to afford 5-methyl-2,3-diphenyl-6-(l,4-dioxaspiro[4.5]dec-7- en-8-yl)-l-((2-(trimethylsilyl) ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(1H)-one (100 mg, 22.3% yield) as a white solid. LC-MS: m/z 570.2 (M+H)+.
[001718] Step E: Compound 336: 5-methyl-6-(4-oxocyclohex-l-en-l-yl)-2,3- diphenylpyrazolo[l,S-a]pyrimidin-7(4H)-one
Figure imgf000394_0002
[001719] A mixture of 5-methyl-2,3-diphenyl-6-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l- ((2-(trimethylsilyl) ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(1H)-one 100 mg, 0.176 mmol) in HC1/dioxane (1.5 mL, 4M) was stirred at r.t. for 1 h. The mixture was concentrated in vacuo to dryness. The resulting residue was dissolved in 4N HC1 and THF (lOmL) and stirred at r.t. for lh to afford 5-methyl-6-(4-oxocyclohex- l-en-l-yl)-2,3-diphenylpyrazolo[l,5- a]pyrimidin-7(4H)-one.
[001720] 1H NMR (DMSO-d6) δ : 11.81 (br. s., 1H), 7.39 - 7.48 (m, 5H), 7.28 - 7.35 5H), 5.65 - 5.74 (m, 1H), 3.02 (br. s., 2H), 2.53 - 2.70 (m, 4H), 2.33 (s, 3H). LC-MS: m/z 396.1 (M+H)+. [001721] Compound 337
Figure imgf000395_0001
2
[001722J Step A: 6-(4-hydroxycyclohex-l-en-l-yl)-5-methyl-2,3-diphenylpyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000395_0002
[001723] To a solution of 5-methyl-6-(4-oxocyclohex-l-en-l-yl)-2,3- diphenylpyrazolo[l ,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 336, 20mg, 0.05mmol) in MeOH (lOmL) was added NaBH4 (2.3mg, 0.06mmol). The reaction mixture was stirred at r.t. for lh. The mixture was poured into water and extracted with EA (lOmL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 6-(4-hydroxycyclohex-l-en-l-yl)-5- methyl-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one.
[001724] 1H NMR (DMSO-d6) 5 : 11.71 (br. s., 1H), 7.37 - 7.46 (m, 5H), 7.24 - 7.35 (m, 6H), 5.48 (br. s., 1H), 4.69 (d, J = 4.03 Hz, 1H), 3.82 (br. s., 1H), 2.29 - 2.43 (m, 2H), 2.27 (s, 4H), 1.96 - 2.08 (m, 1H), 1.82 - 1.93 (m, 1H), 1.55 - 1.68 (m, 1H). LC-MS: m/z 398.2 (M+H)+. [001725] Compound 338 and Compound 339
Figure imgf000396_0001
[001727] To a suspension of 5-(hydroxymethyl)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (88g, 0.208mol, Compound 221) in DCM (500mL) was added SOC12 (120mL) with a funnel. The mixture was stirred at room temperature for 1 hour. The precipitates were filtered, washed with ethyl acetate, and dried under vacuum to give 5-(chloromethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l ,5- a]pyrimidin-7(4H)-one (1 lOg) as an off-white solid which was directly used to the next step without further purification. [001728] Step E: Compound 338 and Compound 339: 5-((1H -tetrazol-l-yl)methyl)- 6-(4-met hoxy pheny l)-2,3-d ipheny Ipy razolo [ 1 ,5-a] py rim id in-7(4H)-on e and 5-((2H- tetrazol-2-yI)methy l)-6-(4-methoxy phenyI)-2,3-diphenylpyrazolo [ 1 ,5-a] pyrimidin-7(4H)- one
Figure imgf000397_0001
[001729] A mixture of 5-(chloromethyl)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (200 mg, 0.453 mmol), 1H-tetrazole (63.4 mg, 0.905 mmol), and TEA (229 mg, 2.263 mmol) in DMF (5 mL) was stirred at 40"C overnight. The mixture was concentrated under reduced pressure to afford 5-((1H-tetrazol-l-yl)methyl)- 6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one and 5-((2H-tetrazol- 2-yl)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[l,5-a]pyrimidin-7(4H)-one.
[001730] Compound 338: S-((l H-tetrazol-l-yl)methyl)-6-(4-methoxyphenyl)-2,3- d ipheny Ipy razolo [ 1 ,5-a] py rimidin-7(4H)-one
[001731] 'H NMR (400 MHz, OMSO-de) δ : 8.97 (br. s., 1 H), 7.19-7.44 (m, 4 H), 7.07 - 7.18 (m, 5 H) 6.85 - 7.07 (m, 5 H), 6.36-6.82 (m, 1 H), 5.74 - 5.93 (m, 2 H), 3.80 (s, 3 H). LC-MS: m/z 476.1 (M+H) +.
[001732] Compound 339: 5-((2H-tetrazol-2-yl)methyI)-6-(4-methoxyphenyl)-2,3- d ipheny ipy razolo [ 1 ,5-a] py rimidin-7(4H)-one
[001733] 1H NMR (400 MHz, TFA) δ : 9.32 (br. s., 1 H), 7.61 (br. s., 6 H), 7.51 (br. s., 2 H), 7.32 - 7.47 (m, 4 H), 7.25 (br. s., 2 H), 5.99 (br. s., 2 H), 4.08 (br. s., 3 H). LC-MS: m/z 476.0 (M+H)+. [001734] Compound 340
Figure imgf000398_0001
[001736] To a solution of Intermediate 6 (Compound 222, 200 mg, 0.45 mmol) in DMF (8 mL) were added (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (117 mg, 0.54 mmol), 0-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (258 mg, 0.68 mmol) and Ν,Ν-diisopropylethylamine (116 mg, 0.9 mmol). The mixture was stirred at r.t. overnight. The mixture was diluted with H20 (30 ml) and extracted with DCM (3*30 mL). The extracts were washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by prep-TLC (DCM/MeOH=20: l) to affored the title compound 7 as a white solid (230 mg, 82% yield). LC-MS: m/z 622.2 (M+H) +. [001737] Step G: (S)-2-amino-N-((6-(4-methoxyphenyl)-7-oxo-2^-diphenyl-4,7- d ihy d ropy razolo [ 1 ,5-a] py rimidin-5-yl)methyl)-3-methylbutanamide
Figure imgf000399_0001
[0017381 A solution of Intermediate 7 (180 mg, 0.29 mmol) in 4M HC1 in 1,4-dioxane (8 mL) was stirred at 0°C r.t. for lh and then at r.t. for 3h. Solvent and other volatiles were removed in vacuo. The residue was dissolved in MeOH (10 mL) and treated with NaHC03 (2mol/L, 10 mL) to afford the title compound 8.
[001739J 1H NMR (DMSO-d6) δ: 8.45 (br. s., 1H), 7.50 (t, J = 8.2 Hz, 4H), 7.31 (br. s., 3H), 7.18 - 7.27 (m, 4H), 7.07 - 7.12 (m, 1H), 6.94 (d, J = 8.6 Hz, 2H), 4.18 (d, J = 15.6 Hz, 1H), 3.91 (d, J = 15.6 Hz, 1H), 3.79 (s, 3H), 3.52 (d, J = 5.0 Hz, 1H), 2.06 (dd, J = 12.4, 6.6 Hz, 1H), 0.91 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H). LC-MS: m/z 522.2 (M+H)+.
[001740] Compound 341
Figure imgf000399_0002
[001741] Step A: 5,7-dichloro-3-(cyclohex-l-en-l-yl)-6-(4-methoxyph<
phenylpyrazolo[l,5-a]pyrimidine
Figure imgf000400_0001
[001742] A solution of 3-(cyclohex-l-en-l-yl)-5-hydroxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 279, 47.0 g, 104 mmol) in phosphorus oxychloride (100 mL) was stirred at reflux for 16 hrs. The solvent was removed invacuo. The residue was added slowly to methanol (100 mL) cooled at 0°C. The precipitates were collected by filtration, washed with methanol, and dried under reduced pressure to give 5,7-dichloro-3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine (50 g) as a yellow solid.
[001743] NMR (DMSO-d6): 6 1.70 (d, J=4.57 Hz, 4 H) 2.20 (br. s., 4 H) 3.84 (s, 4 H) 5.87 (br. s., 1 H) 7.10 (d, J=8.60 Hz, 2 H) 7.36 - 7.56 (m, 5 H) 7.82 (d, J=7.25 Hz, 2 H). LC-MS: m/z 450.2 (M+H) +.
[001744] Step B: 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidine
Figure imgf000400_0002
[001745] To a solution of 5,7-dichloro-3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,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. The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was suspended in MeOH (50 mL). The precipitates were collected by filtration, washed with MeOH, and dried under reduced pressure to give 5-chloro-3-(cyclohex-l-en-l- yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidine (36 g) as a yellow solid. [001746] 1H NMR (DMSO-d6): δ 7.78 - 7.91 (m, 2H), 7.42 - 7.58 (m, 3H), 7.33 - 7.42 (m, J = 8.9 Hz, 2H), 7.00 - 7.14 (m, J = 8.9 Hz, 2H), 5.83 (br. s., 1H), 4.14 (s, 3H), 3.84 (s, 3H), 2.20 (d, J = 5.9 Hz, 4H), 1.61 - 1.77 (m, 4H). LC-MS: m/z 446.1 (M+H)+.
[001747] Step C: N-(3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4-methoxyphenyl)-2- phenylpyrazolo [l,5-alpyrimidin-5-yl)isoxazol-3-amine
Figure imgf000401_0001
[001748] A mixture of 5-chloro-3-(cyclohex-l-en-l-yl)-7-methoxy-6-(4- methoxyphenyl)-2-phenylpyrazolo[l,5-a]pyrimidine (200 mg, 0.45 mmol), isoxazol-3 -amine (1 13.4 mg, 1.35 mmol), and palladium diacetate (10.1 mg, 0.045 mmol), Xantphos (52 mg, 0.09 mmol) and sodium carbonate (143 mg, 1.35 mmol) in 1,4-dioxane (50 mL) was heated at 1 10 °C for 12 hours under nitrogen atmosphere. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford the desired product N-(3-(cyclohex-l -en-l-yl)-7-methoxy-6-(4-methoxyphenyl)-2- phenylpyrazolo[l,5-a]pyrimidin-5-yl)isoxazol-3-amine.
[001749] 1H NMR (DMSO-d6) δ : 8.84 (d, J = 1.61 Hz, 1H), 8.30 (s, 1H), 7.74 - 7.82 (m, 2H), 7.35 - 7.55 (m, 5H), 7.28 (d, J = 1.61 Hz, 1H), 7.07 - 7.16 (m, 2H), 5.83 (s, 1H), 4.08 (s, 3H), 3.86 (s, 3H), 2.25 (br. s., 2H), 2.19 (br. s., 2H), 1.70 (d, J = 4.84 Hz, 4H). LC- MS: m/z 493.9 (M+H)'
[001750] Compound 342
Figure imgf000401_0002
[001751] Step A: 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(l-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrazolo[l,5-a]pyrimidin-5-amine
Figure imgf000402_0001
[001752] A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (Synthesized in Scheme of Compound 101, 300 mg, 0.68 mmol), l-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-amine (230 mg, 1.36 mmol), Pd(OAc)2 (30.5 mg, 0.14 mmol), Xantphos (1 18 mg, 0.20 mmol) and Cs2C03 (487 mg, 1.49 mmol) in 1,4-dioxane (10 ml) was reacted at 100 °C for 45 min under N2 atmosphere in a microwave reactor. The reaction was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo and purified by flash column chromatography, eluting with DCM/ MeOH=40: l, to get the desired product as a yellow solid (110 mg, 26% yield). LC-MS : m/z 619.5 (M+H) +.
[001753] Step B: 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(l-((2- (trimethy Isily I)ethoxy)methy 1)- 1 H-imidazol-4-yl)py razolo [ 1 ,5-a] py rimidin-5-amine
Figure imgf000402_0002
[001754] The 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(l-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrazolo[l,5-a]pyrimidin-5-amine (1 10 mg, 0.18 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at 60 °C for 1 h. Then the mixture was concentrated to give the crude product, which was added into ammonia water (5 mL) and stirred on for lh to afford the desired product.
[001755] 1H NMR (DMSO-<&) δ: 8.20 (s, 1H), 7.44-7.30 (m, 14H), 7.15 (d, J= 8.0 Hz, 2H), 3.88 (s, 3H), 3.74 (s, 3H). LC-MS: m/z 489.0 (M+H)+. [001756] Compound 343
Figure imgf000403_0001
[001757] Step E: 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(l-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine
Figure imgf000403_0002
[001758] A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidine (600 mg, 1.36 mmol, Synthesized in Scheme of Compound 101), l-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (580 mg, 2.72 mmol), Pd(OAc). (61 mg, 0.27 mmol), xantphos(197 mg, 0.34 mmol) and Cs2C03 (890 mg, 2.72 mmol) in 1,4-dioxane (5 mL) was stirred at 120 °C through microwave irradiation for 1 hour under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford the 7- methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(l-((2-(trimethylsilyl)ethoxy)methyl)-l H- pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine (150 mg) as a yellow solid. LC-MS: m/z 619.0 (M+H)+. [001759] Step F: Compound 343: 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N- ( 1 H-pyrazol-3-yl)py razolo [ 1 ,5-a] py rim id in-5-am ine
Figure imgf000404_0001
[001760J To a solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(l-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-5-amine(150 mg, 0.243 mmol) in DCM (5 mL) was added TFA (2 mL), the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was dissolved in ammonium hydroxide (3 mL) and stirred at room temperature overnight. The mixture was then concentrated to afford the title compound. [001761] 1H NMR (400 MHz, DMSO-^) δ : 12.34 (br. s., 1 H), 7.63 (br. s., 1 H), 7.58 (d, J=3.49 Hz, 2 H), 7.47 (d, J=8.33 Hz, 2 H), 7.51 (d, J=7.52 Hz, 2 H), 7.34 - 7.44 (m, 5 H), 7.12 - 7.32 (m, 4 H), 6.88 (br. s., 1 H), 4.09 (s, 3 H), 3.87 (s, 3 H). LC-MS: m/z 488.9 (M+H)+.
Figure imgf000404_0002
[001763] Step A: chloromethyl dimethylcarbamate
Figure imgf000404_0003
[001764] To a solution of chloromethyl carbonochloridate (500 mg, 3.9 mmol) in THF (30 mL) was added dimethylamine (2 mol/L in THF, 3.9 mL) dropwise at 0 °C under vigorous stirring. Then the mixture was stirred at r.t. overnight. The mixture was evaporated. The residue was stirred in toluene (5 mL) and filtered. The filtrate was washed with 10% NaHCOi aqueous solution, water and brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 2 as a yellow oil (400 mg, 75 yield) which was used to the next step without further purification.
[001765]1H NMR (DMSO-d6) δ: 5.79 (s, 2H), 2.98 (s, 3H), 2.96 (s, 3H).
[001766] Step B: ((3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-5-methyI-2- phenylpyrazolo[l,5-a]pyrimidin-7-yl)oxy)methyl dimethylcarbamate
Figure imgf000405_0001
[001767] To a solution of 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-5-methyl-2- phenylpyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound 212, 50 mg, 0.12 mmol) in DMF (3 mL) were added chloromethyl dimethylcarbamate (54 mg, 0.36 mmol) and K2C03 (50 mg, 0.36 mmol). The mixture was stirred at 60 °C for 10 h. The mixture was poured into H20 (15 mL) and extracted with DCM (3*10 mL). The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound 3.
[001768] 1H NMR (DMSO-d6) δ: 7.79 - 7.85 (m, 2H), 7.45 - 7.52 (m, 2H), 7.39 - 7.45 (m, 1H), 7.19 - 7.25 (m, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.04 (s, 2H), 5.79 (dt, J = 3.4, 2.0 Hz, 1H), 3.82 (s, 3H), 2.71 (s, 3H), 2.63 (s, 3H), 2.29 (s, 3H), 2.23-2.28 (m, 2H), 2.13 - 2.19 (m, 2H), 1.62 - 1.76 (m, 4H). LC-MS: m/z 513.1 (M+H)+. [001769] Compound 345
Figure imgf000406_0001
[001770J Step A: 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(l,3,5-triazin-2- yl)pyrazolo[l,5-a]pyrimidin-5-amine
Figure imgf000406_0002
[001771] A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l ,5-a]pyrimidine (800 mg, 1.81 mmol), ethyl l ,3,5-triazin-2-amine
(Synthesized in Scheme of Compound 101, 348 mg, 3.62 mmol), and Pd(OAc)2 (81 mg, 0.36 mmol), Xantphos (260 mg, 0.45 mmol) and Na2C03 (384 mg, 3.62 mmol) in 1.4- dioxane (15 mL) was heated at 110 °C for 4 hours under N2 atmosphere. The mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford the title product.
[001772] 1H NMR (DMSO-d6) δ: 10.42 (s, 1H), 8.51 (s, 2H), 7.57 - 7.63 (m, 2H), 7.36 - 7.49 (m, 7H), 7.28 - 7.33 (m, 3H), 6.87 - 6.95 (m, 2H), 4.20 (s, 3H), 3.74 (s, 3H). LC-MS: m/z 502.0 (M+H)+.
[001773] Compound 346
Figure imgf000406_0003
[001774] Step A: 3-(3-chlorophenyl)-3-oxo-2-phenylpropanenitrile
Figure imgf000407_0001
[001775] To a solution of 2-phenylacetonitrile (975 mg, 8.3 mmol) in THF (40 mL) was added lithium diisopropylamide (2.0 mol/L in THF, 5 mL, 10.0 mmol) at -78°C. After the mixture was stirred at -78°C for 30 min, 3-chlorobenzoyl chloride (1.8 g, 10.0 mmol) was added dropwise. Then the mixture was stirred at r.t. for 2h. The mixture was diluted with EA (30 mL) and quenched with saturated NH4CI. The organic phase was separated and washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was washed with PE to afford the desired intermediate 2 as a white solid (1.2 g, 57% yield). LC-MS: m/z 256.0/258.0 (M+H)+. [0017761 Step B: 3-(3-chlorophenyl)-4-phenyl-l H-pyrazoI-5-amine
Figure imgf000407_0002
[001777] The mixture of Intermediate 2 (500 mg, 2.0 mmol) and hydrazine hydrate (200 mg, 4.0 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2h. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (20 mL) and neutralized with 10% NaHC03. The organic phase was separated and the water phase was extracted with EA (10 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the crude desired intermediate 3 as a yellow oil (500 mg, 95% yield) which was used to the next step without purification. LC- MS: m/z 270.0/272.0 (M+H)+. [001778] Step C: 2-(3-chlorophenyl)-5-methyI-3-phenyl-6-(quinolin-6- yl)py razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000408_0001
[001779] The mixture of Intermediate 3 (200 mg, 0.7 mmol) and methyl 3-oxo-2- (quinolin-6-yl)butanoate (270 mg, 1.1 mmol) in AcOH (10 mL) was stirred at 100 °C for lh. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (15 mL) and neutralized with 10% NaHC03. The organic phase was separated, and the water phase was extracted with EA (15 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vaaio to afford the desired product 4.
[001780J 1H NMR (DMSO-d6) δ: 12.15 (s, 1 H), 8.94 (dd, J = 4.2, 1.6 Hz, 1H), 8.40 (d, J = 7.4 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.75 (dd, J = 8.6, 1.8 Hz, 1H), 7.57 (dd, J = 8.2, 4.2 Hz, 1 H), 7.40 - 7.53 (m, 5H), 7.33 - 7.40 (m, 4H), 2.25 (s, 3H). LC-MS: m/z 463.0/465.0 (M+H)+.
[001781] Compound 347
Figure imgf000408_0002
[001782] Step A: 3-(4-chlorophenyl)-3-oxo-2-phenylpropanenitrile
Figure imgf000408_0003
[001783] To a solution of 2-phenylacetonitrile (975 mg, 8.3 mmol) in THF (40 mL) was added lithium diisopropylamide (2.0 mol/L in THF, 5 mL, 10.0 mmol) at -78°C. After the mixture was stirred at -78°C for 30 min, 4-chlorobenzoyl chloride (1.8 g, 10.0 mmol) was added dropwise. Then the mixture was stirred at r.t. for 2h. The mixture was diluted with EA (30 mL) and quenched with saturated NH4C1. The organic phase was separated and washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was washed with PE to afford the desired intermediate 2 as a white solid (1.3 g, 61% yield). LC-MS: m/z 256.0/258.0 (M+Hf .
[001784J Step B: 3-(4-chlorophenyl)-4-phenyI-1H -pyrazoI-5-amine
Figure imgf000409_0001
[001785] The mixture of Intermediate 2 (500 mg, 2.0 mmol) and hydrazine hydrate (200 mg, 4.0 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2h. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (20 mL) and neutralized with 10% NaHC03. The organic phase was separated and the the water phase was extracted with EA (10 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the crude desired intermediate 3 as a yellow oil (500 mg, 95% yield) which was used to the next step without purification. LC- MS: m/z 270.0/272.0 (M+H)+.
[001786] Step C: 2-(4-chlorophenyl)-5-methyl-3-phenyl-6-(quinolin-6- yI)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000409_0002
[001787] The mixture of Intermediate 3 (80 mg, 0.3 mmol) and methyl 3-oxo-2- (quinolin-6-yl)butanoate (108 mg, 0.5 mmol) in AcOH (5 mL) was stirred at 100 °C for lh. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (10 mL) and neutralized with 10% NaHC03. The organic phase was separated and the water phase was extracted with EA (10 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the desired product 4.
[001788] lH NMR (DMSO-C!G) δ: 12.10 (s, 1H), 8.94 (dd, J = 4.2, 1.6 Hz, 1 H), 8.39 (d, J = 7.4 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.74 (dd, J = 8.6, 1.8 Hz, 1H), 7.57 (dd, J = 8.2, 4.2 Hz, 1H), 7.44 - 7.52 (m, 3H), 7.40 - 7.44 (m, 4H), 7.34 - 7.38 (m, 2H), 2.24 (s, 3H). LC-MS: m/z 463.0/465.0 (M+H)+.
Figure imgf000410_0001
[0017901 Step A: 3-oxo-2-phenyl-3-(pyridin-4-yl)propanenitrile
Figure imgf000410_0002
[001791] To the mixture of methyl isonicotinate (1.4 g, 10 mmol) and 2- phenylacetonitrile (1.2 g, 10 mmol) in THF (50 mL) was added sodium hydride (480 mg, 60% content, 12 mmol) at r.t.. The mixture was refluxed overnight. The mixture was diluted with EA (50 mL) and quenched with saturated NH4CI. The organic phase was separated and washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the desired intermediate 2 as a light yellow solid (800 mg, 36% yield). LC-MS: m/z 223.1 (M+H)+.
[001792] Step B: 4-phenyl-3-(pyridiii-4-yl)-1H -pyrazol-5-amine
Figure imgf000410_0003
[001793] The mixture of Intermediate 2 (500 mg, 2.3 mmol) and hydrazine hydrate (230 mg, 4.6 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2h. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (15 mL) and neutralized with 10% NaHC03. The organic phase was separated and the the water phase was extracted with EA (15 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the desired intermediate 3 as a yellow solid (250 mg, 46% yield) which was used to the next step without purification. LC- MS: m/z 237.1 (M+H)+.
[001794] Step C: 5-methyl-3-phenyl-2-(pyridin-4-yl)-6-(quinolin-6-yl)pyrazolo[l,5- a] pyrimidin-7(4H)-one
Figure imgf000411_0001
[001795] The mixture of Intermediate 3 (100 mg, 0.42 mmol) and methyl 3-oxo-2- (quinolin-6-yl)butanoate (150 mg, 0.64 mmol) in AcOH (10 mL) was stirred at 100 °C for lh. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (10 mL) and neutralized with 10% NaHC03. The organic phase was separated and the water phase was extracted with EA (10 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the desired product 4.
[001796] 1H NMR (DMSO-d6) δ: 12.22 (s, 1H), 8.94 (dd, J = 4.2, 1.6 Hz, 1H), 8.54 (d, J = 4.6 Hz, 2H), 8.36 - 8.43 (m, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.75 (dd, J = 8.6, 2.0 Hz, 1H), 7.58 (dd, J = 8.2, 4.2 Hz, 1H), 7.44 - 7.54 (m, 3H), 7.36 - 7.42 (m, 4H), 2.25 (s, 3H). LC-MS: m/z 430.1 (M+H)+.
[001797] Compound 349
Figure imgf000412_0001
[001798] Step A: 3-(6-methoxypyridin-3-yl)-3-oxo-2-phenylpropanenitrile
Figure imgf000412_0002
[001799] To a solution of 2-phenylacetonitrile (1.0 g, 8.54 mmol) in THF (20 mL) was added LiHMDS (5.1 mL, 10.2 mmol, 2.0 M in THF) at -78°C dropwise. After addition, the mixture was stirred at -78 °C for 1 hour. Then methyl 6-methoxynicotinate (1.43 g, 8.54 mmol) was added dropwise. The reaction was slowly warmed to room temperature and stirred for 12 hours. The reaction was quenched by adding saturated NH4CI (50 mL), extracted with ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (crude, 2 g) which was directly used in the next step without further purification.
[001800] Step B: 3-(6-methoxypyridin-3-yl)-4-phenyl-l H-pyrazol-5-amine
Figure imgf000412_0003
[001801] A mixture of 3-(6-methoxypyridin-3-yl)-3-oxo-2-phenylpropanenitrile (2 g, crude) and NH2NH2 (2.37 g, 43.8 mmol) in EtOH/AcOH (20 mL 15 mL) was stirred at 100 °C for 8 hours. After cooling to room temperature, the mixture was concentrated by vacuum. The residue was diluted with EtOAc (20 mL), washed with saturated NaHC03 (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column (petroleum ether/ethyl acetate=3: l) to obtain 3-(6-methoxypyridin- 3-yl)-4-phenyl-1H-pyrazol-5-amine (150 mg) as a yellow solid. LC-MS: m/z 267.0 (M+H)+.
[001802J Step C: Compound 349: 2-(6-methoxypyridin-3-yl)-5-methyl-3-phenyl-6- (quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000413_0001
[001803] A mixture of 3-(6-methoxypyridin-3-yl)-4-phenyl- 1H-pyrazol-5-amine (150 mg, 0.564 mmol) and methyl 3-oxo-2-(quinolin-6-yl)butanoate (137 mg, 0.564 mmol) in AcOH (5 mL) and dioxane (1 mL) was stirred at 100 °C overnight to obtain the title compound. [001804]1H NMR (DMSO-dk) δ : 12.1 1 (s, 1 H), 8.95 (dd, J=4.16, 1.75 Hz, 1 H), 8.37 - 8.44 (m, 1 H), 8.1 1 - 8.15 (m, 1 H), 8.08 (d, J=8.60 Hz, 1 H), 7.97 (d, J=1.61 Hz, 1 H) ,7.77 - 7.80 (m, 1 H), 7.75 (dd, J=8.73, 2.01 Hz, 1 H), 7.58 (dd, J=8.19, 4.16 Hz, 1 H), 7.49 - 7.54 (m, 2 H), 7.43 - 7.48 (m, 1 H), 7.37 - 7.42 (m, 2 H), 6.84 (d, J=8.60 Hz, 1 H), 3.85 (s, 3 H), 2.25 (s, 3 H). LC-MS: m/z 460.1 (M+Hf .
[001805] Compound 350
Figure imgf000413_0002
[001806] Step A: 3-(2-chloropyridin-4-yl)-3-oxo-2-phenylpropanenitrile
Figure imgf000414_0001
[001807] To a solution of 2-phenylacetonitrile (1.2 g, 10 mmol) and methyl 2- chloroisonicotinate (1.7 g, 10.0 mmol) in THF (50 mL) was added sodium hydride (480 mg, 60% content, 12 mmol) at r.t. The mixture was refluxed for 5h. The mixture was diluted with EA (50 mL) and quenched with saturated NH4CI. The organic phase was separated and washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by flash chromatography to afford the intermediate 2 as a yellow solid (800 mg, 31% yield). LC-MS: m/z 257.0/259.0 (M+H)+.
[001808J Step B: 3-(2-chloropyridin-4-yl)-4-phenyl-1H -pyrazoI-5-amine
Figure imgf000414_0002
[001809] The mixture of Intermediate 2 (350 mg, 1.4 mmol) and hydrazine hydrate (140 mg, 2.8 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2h. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (10 mL) and neutralized with 10% NaHCCh. The organic phase was separated and the the water phase was extracted with EA (10 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by flash chromatography (PE/EA=3: 1) to afford the crude intermediate 3 as a yellow solid (40 mg, 1 1% yield). LC-MS: m/z 271.0/273.0 (M+H)÷.
[001810] Step C: 2-(2-chloropyridin-4-yl)-5-methyl-3-phenyl-6-(quinolin-6- yl)py razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000414_0003
[001811] The mixture of Intermediate 3 (40 mg, 0.15 mmol) and methyl 3-oxo-2- (quinolin-6-yl)butanoate (54 mg, 0.22 mmol) in AcOH (5 mL) was stirred at 100 °C for lh. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (10 mL) and neutralized with 10% NaHC03. The organic phase was separated and the water phase was extracted with EA (10 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo to afford the desired product 4.
[001812] 'H NMR (DMSO-d6) δ: 12.26 (s, 1 H), 8.95 (br. s., 1H), 8.35 - 8.43 (m, 2H), 8.09 (d, J = 8.6 Hz, 1H), 7.93 - 8.00 (m, 1H), 7.75 (dd, J = 8.6, 1.6 Hz, 1H), 7.47 - 7.62 (m, 4H), 7.36 - 7.46 (m, 4H), 2.25 (s, 3H). LC-MS: m/z 464.0/466.0 (M+H)+.
[001813] Compound 351
Figure imgf000415_0001
[001814] Step A: methyl 2-methoxyisonicotinate
Figure imgf000415_0002
[001815] To a solution of methyl 2-chloroisonicotinate (1.7 g, 10 mmol) in MeOH (30 mL) was added Sodium methoxide (1.1 g, 20 mmol). The resultant mixture was refluxed overnight. The mixture was then treated with HC1 (2 mol/L) until pH=7 and evaporated. The residue was dissolved in EA (50 mL), washed with H20 and brine, dried over anhydrous MgS04 and concentrated in vacuo. The residue was purified by flash chromatography to afford the intermediate 2 as a white solid (1.2 g, 72% yield). [001816] 1H NMR (CHLOROFORM-d) δ: 8.26 - 8.30 (m, 1H), 7.40 (dd, J = 5.1, 1.2 Hz, 1H), 7.30 - 7.33 (m, 1H), 3.97 (s, 3H), 3.94 (s, 3H). LC-MS: m/z 168.0 (M+H)+.
[001817] Step B: 3-(2-methoxypyridin-4-yl)-3-oxo~2-phenylpropanenitrile
Figure imgf000416_0001
[001818] To the mixture of Intermediate 2 (860 mg, 5.1 mmol) and 2- phenylacetonitrile (730 mg, 6.2 mmol) in THF (20 mL) was added NaHMDS (2.0 mol/L in THF, 3.1 mL) dropwise at 0°C. The mixture was at 0°C for 30 min and then stirred at r.t. overnight. The mixture was diluted with EA (30 mL) and quenched with saturated NH4CI. The organic phase was separated and washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by flash chromatography to afford the intermediate 3 as a light yellow solid (640 mg, 50% yield).
[001819] 1H NMR (METHANOL- L,) δ: 8.08 - 8.1 1 (m, 1 H), 7.88 - 7.92 (m, 2H), 7.23 (t, J = 7.8 Hz, 2H), 7.15 (dd, J = 5.0, 1.2 Hz, 1H), 6.97 - 7.02 (m, 2H), 3.92 (s, 3H). LC-MS: m/z 253.1 (M+H)+. [001820] Step C: 3-(2-methoxypyridin-4-yl)-4-phenyl-1H -pyrazoI-5-amine
Figure imgf000416_0002
[001821] The mixture of Intermediate 3 (320 mg, 1.3 mmol) and hydrazine hydrate (130 mg, 2.6 mmol) in EtOH/AcOH (5/1, 10 mL/2 mL) was refluxed for 2h. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (10 mL) and neutralized with 10% NaHC03. The organic phase was separated and the the water phase was extracted with EA (10 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by flash chromatography (PE/EA 3: 1) to afford the crude intermediate 4 as a yellow solid (250 mg, 74% yield). LC-MS: m/z 267.1 (M+H)+. [001822] Step D: 2-(2-methoxypyridin-4-yl)-5-methyl-3-phcnyl-6-(quinolin-6- yl)py razolo f 1 ,5-a] py rimidin-7(4H)-one
Figure imgf000417_0001
[001823] The mixture of Intermediate 4 (250 mg, 0.94 mmol) and methyl 3-oxo-2- (quinolin-6-yl)butanoate (340 mg, 1.4 mmol) in AcOH (8 mL) was stirred at 100 °C for lh. Then the mixture was cooled to r.t. and evaporated. The residue was dissolved in EA (15 mL) and neutralized with 10% NaHC03. The organic phase was separated and the water phase was extracted with EA (15 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo to afford the desired product 5. [001824] lU NMR (DMSO-d6) δ: 12.18 (s, 1H), 8.94 (dd, J = 4.2, 1.6 Hz, 1H), 8.39 (d, J = 7.4 Hz, 1H), 8.14 (d, J = 5.6 Hz, 1 H), 8.08 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1 H), 7.74 (dd, J = 8.6, 2.0 Hz, 1H), 7.57 (dd, J = 8.2, 4.2 Hz, 1H), 7.45 - 7.55 (m, 3H), 7.37 - 7.42 (m, 2H), 7.08 (dd, J = 5.2, 1.4 Hz, 1H), 6.70 (s, 1H), 3.80 (s, 3H), 2.24 (s, 3H). LC-MS: m/z 460.0 (M+H)+.
[001825] Compound 352
Figure imgf000418_0001
[001826] Step A: (E)-methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate
Figure imgf000418_0002
[001827] A mixture of methyl 2-(quinolin-6-yl)acetate (3.0 g, 14.9 mmol) and DMF- DMA (4.0 mL) in DMF was stirred at 85 °C for 12h. After cooling to room temperature, the mixture was poured into water, extracted with ethyl acetate, dried over Na2S04, filtered and concentrated to get the crude product (3.8 g) which was directly used to the next step without further purification. LC-MS: m/z 257.3 (M+H)+.
[001828] Step B: 2^-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000418_0003
[001829] A mixture of 3,4-diphenyl-1H-pyrazol-5-amine(200 mg, 0.9 mmol) and (E)- methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate (283.2 mg, 1.1 mmol) in AcOH (3 mL) was stirred at 100°C for 2h. After cooling to room temperature, the solvent was removed by vacuum, saturated NaHC03 (6 mL) was added, and the precipitate was filtered. The filter cake was washed with water (2 mL) and MeOH (2 mL) to get 2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one as yellow solid (300 mg, 85% yield).
[001830J 1H NMR (DMSO-d6) δ : 12.69 (br. s., 1H), 8.91 (dd, J = 4.0, 1.6 Hz, 1 H), 8.37 - 8.47 (m, 1H), 8.32 (d, J = 1.9 Hz, 1H), 8.10 - 8.16 (m, 2H), 8.03 - 8.10 (m, 1H), 7.56 (dd, J = 8.3, 4.0 Hz, 1H), 7.45 - 7.54 (m, 4H), 7.32 - 7.45 (m, 6H). LC-MS: m/z 415.3 (M+H)+. [001831] Step C: 4-(2-(tert-butyldimethylsUyloxy)ethyl)-2,3-diphenyl-6-(quinolin-6- yl)py razolo [1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000419_0001
[001832] A mixture of 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)- one (200 mg, 0.483 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (173 mg, 0.724 mmol) and Cs2C03 (471 mg, 1.448 mmol) in DMF (10 mL) was stirred at 80 °C overnight. After cooling to room temperature, the mixture was poured into water (20 mL), and extract with EtOAc (3*30 mL). The combined organic layers were washed with water (2*30 mL) and brine (30 mL), and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel (MeOH :DCM=5: 100) to get the title compound (130 mg, 47% yield). LC-MS: m/z 573.2 (M+H)+.
[001833] Step D: 4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a] py rimidin-7(4H)-one
Figure imgf000419_0002
[001834] A mixture of 4-(2-(tert-butyldimethylsilyloxy)ethyl)-2,3-diphenyl-6-(quinolin- 6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (130 mg, 0.227 mmol) and TBAF (59 mg, 0.227 mmol) in DCM (5 mL) was stirred at room temperature for 3h. The mixture was poured into water (20 mL), and the precipitate was filtered. The filter cake was washed with water (2 mL) and dried to get the title compound (90 mg) as a white solid which was used directly in the next step without further purification. LC-MS: m/z 459.1 (M+H)+. [001835] Step E: 4-(2-chloroethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a] py rimidin-7(4H)-one
Figure imgf000420_0001
[001836] To a solution of 4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (90 mg, 0.2 mol) in DCM (5 mL) was added SOC12 (0.5 mL) dropwise. The mixture was stirred at room temperature for 4 hours. The precipitates were filtered, washed with ethyl acetate, and dried under vacuum to give 4-(2-chloroethyl)- 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (80 mg) as a off-white solid which was used directly in the next step without further purification. LC-MS: m/z 477.0 (M+H)+. [001837] Step F: Compound 352: 4-(2-(1H -tetrazol-l-yI)ethyl)-2,3-diphenyl-6- (quinolin-6-yl)pyrazolo [ 1 ,5-a] py rimid in-7(4H)-one
Figure imgf000420_0002
[001838] To a solution of 1H-tetrazole (29.4 mg, 0.42 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil, 12.6 mg, 0.524 mmol) in portions at 0°C. The resulting mixture was stirred at 0°C for 25 min. 4-(2-chloroethyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (50 mg, 0.105 mmol) was then added. The mixture was warmed to 80°C and stirred for lOh. After cooling to room temperature, water was added to get the title compound. [001839] 1H NMR (DMSO-i/6) δ : 8.99 (s, 1 H), 8.92 (dd, J=4.30, 1.61 Hz, 1 H), 8.41 (d, J=8.33 Hz, 1 H), 8.21 (d, J=1.88 Hz, 1 H), 8.17 (s, 1 H), 8.09 (d, J=8.87 Hz, 1 H), 8.00 (dd, J=8.87, 2.15 Hz, 1 H), 7.59 (dd, J=8.19, 4.16 Hz, 1 H), 7.48 (s, 5 H), 7.39 - 7.43 (m, 2 H), 7.30 - 7.35 (m, 3 H), 4.84 (t, J=6.04 Hz, 2 H), 4.45 (t, J=5.78 Hz, 2 H). LC-MS: m/z 511.1 (M+H)+.
[001840] Compound 353
Figure imgf000421_0001
d
[001841] Step Al : (E)-methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate
Figure imgf000421_0002
[001842] A mixture of methyl 2-(quinolin-6-yl)acetate (3.0 g, 14.9 mmol) and DMF- DMA (4.0 mL) in DMF was stirred at 85 °C for 12h. After cooling to room temperature, the mixture was poured into water, extracted with ethyl acetate, dried over Na2S04, filtered and concentrated to get the crude product (3.8 g) which was directly used to the next step without further purification. LC-MS: m/z 257.3 (M+H)+.
[001843] Step Bl : 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000421_0003
[001844] A mixture of 3,4-diphenyl-1H-pyrazol-5-amine(200 mg, 0.9 mmol) and (E)- methyl 3-(dimethylamino)-2-(quinolin-6-yl)acrylate (283.2 mg, 1.1 mmol) in AcOH (3 mL) was stirred at 100°C for 2h. After cooling to room temperature, the solvent was removed by vacuum, saturated NaHC03 (6 mL) was added, and the precipitate was filtered. The filter cake was washed with water (2 mL) and MeOH (2 mL) to get 2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one as yellow solid (300 mg, 85% yield).
[001845J 1H NMR (DMSO-d6) δ : 12.69 (br. s., 1H), 8.91 (dd, J = 4.0, 1.6 Hz, 1 H), 8.37 - 8.47 (m, 1H), 8.32 (d, J = 1.9 Hz, 1H), 8.10 - 8.16 (m, 2H), 8.03 - 8.10 (m, 1H), 7.56 (dd, J = 8.3, 4.0 Hz, 1H), 7.45 - 7.54 (m, 4H), 7.32 - 7.45 (m, 6H). LC-MS: m/z 415.3 (M+H)+. [001846] Step CI : 4-(2-(tert-butyldimethylsilyloxy)ethyl)-2,3-diphenyl-6-(quinolin-6- yl)pyrazolo[ 1 ,5-a]pyrimidin-7(4H)-one
Figure imgf000422_0001
[001847] A mixture of 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)- one (200 mg, 0.483 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (173 mg, 0.724 mmol) and Cs2C03 (471 mg, 1.448 mmol) in DMF (10 mL) was stirred at 80 °C overnight. After cooling to room temperature, the mixture was poured into water (20 mL), and extract with EtOAc (3*30 mL). The combined organic layers were washed with water (2*30 mL) and brine (30 mL), and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel (MeOH :DCM=5: 100) to get the title compound (130 mg, 47% yield). LC-MS: m/z 573.2 (M+H)+.
[001848] Step Dl : 4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000422_0002
[001849] A mixture of 4-(2-(tert-butyldimethylsilyloxy)ethyl)-2,3-diphenyl-6-(quinolin- 6-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (130 mg, 0.227 mmol) and TBAF (59 mg, 0.227 mmol) in DCM (5 mL) was stirred at room temperature for 3h. The mixture was poured into water (20 mL), and the precipitate was filtered. The filter cake was washed with water (2 mL) and dried to get the title compound (90 mg) as a white solid which was used directly in the next step without further purification. LC-MS: m/z 459.1 (M+H)+.
Figure imgf000423_0001
[001850] Step A: 2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin- 4(7H)-yl)ethyl methanesulfonate
Figure imgf000423_0002
[001851] A mixture of 4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-7(4H)-one (250 mg, 0.545 mmol), MsC1 (187 mg, 1.636 mmol) and Et3N (165 mg, 1.636 mmol) in DCM (10 mL) was stirred at room temperature for 3 h. The mixture was concentrated in vacuo, and the residue was purified by flash chromatography to afford 2-(7- oxo-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5-a]pyrimidin-4(7H)-yl)ethyl
methanesulfonate (200 mg) as a white solid. LC-MS: m/z 537.1 (M+H)+.
[001852] Step B: Compound 353: 4-(2-aminoethyl)-2^-diphenyl-6-(quinolin-6- y l)py razolo [ 1 ,5-a] py rimidin-7(4H)-one
Figure imgf000423_0003
[001853] A solution of 2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[l,5- a]pyrimidin-4(7H)-yl)ethyl methanesulfonate (75 mg, 0.14 mmol) in ammonia (7.0 M in MeOH, 10 mL) was stirred at 75 °C in a seal tube for 2 days to afford the title compound. [001854] 1H NMR (400 MHz, DMSO-i/6) δ : 8.92 (dd, J=4.03, 1.34 Hz, 1 H), 8.34 - 8.49 (m, 3 H), 8.18 (dd, J=9.00, 1.75 Hz, 1 H), 8.10 (d, J=8.87 Hz, 1 H), 7.58 (dd, J=8.19, 4.16 Hz, 1 H), 7.50 (s, 5 H), 7.40 (d, J=2.15 Hz, 2 H), 7.28 - 7.35 (m, 3 H), 4.01 (br. s., 2 H), 2.56 (br. s., 2 H). LC-MS: m/z 458.0 (M+H) +.
[001855] Compound 354
Figure imgf000424_0001
[001856] Step A: 5-chloro-l-(4-methoxybenzyl)-6-(4-methoxyphi
diphenylpyrazolo[ 1 ,5-a] pyrimidin-7( 1H)-one
Figure imgf000424_0002
[001857] To a mixture of 5 -chloro-6-(4-methoxypheny l)-2, 3 -dipheny lpyrazolo [1,5- a]pyrimidin-7(1H)-one (Synthesized in scheme of Compound 286, 2.29g, 5.36 mmol), Cs2C03 (3.49g, 10.7mmol) in DMF (30mL) was added l-(chloromethyl)-4-methoxybenzene (0.728mL). The resultant mixture was stirred at 60 °C for 16h. The mixture was added into H20 (30mL) and extracted with DCM (10mL*3 ). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The resulting solid was washed with MeOH (5mL) to get 5-chloro-l-(4~methoxybenzyl)-6-(4-methoxyphenyl)-2,3 - diphenylpyrazolo[l,5-a]pyrimidin-7(1H)-one (1.6g) as a white solid. LC-MS: m/z 548.3 (M+H)+. [001858] Step B: Compound 354: 6-(4-methoxyphenyl)-2r3-diphenyl-5-(pyridazin- 3-yloxy)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000425_0001
[001859] The mixture of 5-chloro-l-(4-methoxybenzyl)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l,5-a]pyrimidin-7(1H)-one (200mg, 0.365mmol), KF (1.7g, 29mmol) and 18-Crown-6 (481mg, 1.825mmol) in NMP (3mL) was stirred at 180 °C for 4h under microwave irradiation in a sealed tube to afford 6-(4-methoxyphenyl)-2,3-diphenyl-5- (pyridazin-3-yloxy)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[001860] 1H NMR (DMSO-d6) δ : 7.76 (br. s., 1H), 7.53 (d, J = 6.98 Hz, 2H), 7.26 - 7.38 (m, 8H), 7.13 - 7.24 (m, 3H), 6.80 (d, J = 8.60 Hz, 3H), 3.76 (s, 3H). LC-MS: m/z 488.1 (M+H)+.
[001861] Compound 355
Figure imgf000425_0002
[001862] Step A: 6-(4-methoxyphenyl)-5-phenoxy-2,3-diphenylpyrazolo[l,5- a]pyrimidin-7(4H)-one
Figure imgf000425_0003
[001863] The mixture of 5-chloro-6-(4~methoxyphenyl)-2,3-diphenylpyrazolo [1,5- a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 286, 200mg, 0.45mmol) and sodium phenolate (105mg, 0.9mmol) in NMP (3mL) was stirred at 170 °C for 2h under microwave irradiation in a sealed tube to afford 6-(4-methoxyphenyl)-5-phenoxy-2,3- dipheny lpyrazolo [ 1 , 5 -a] pyri midin -7(4H)-one .
[001864J 1H NMR (DMSO-d6) δ : 7.48 (br. s., 2H), 7.42 (br. s., 4H), 7.26 - 7.37 ( 5H), 7.23 (br. s., 2H), 7.10 (d, J = 6.45 Hz, 3H), 6.92 (d, J = 7.52 Hz, 2H), 3.76 (br. s., LC-MS: m/z 485.9 (M+H) +.
[001865] Compound 356
Figure imgf000426_0001
[001866] Step A : 7-methoxy-6-(4-methoxyphenyl)-N,2,3-triphenylpyrazolo[l,5- a]pyrimidin-5-amine
Figure imgf000426_0002
[001867] A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[l ,5-a]pyrimidine (Synthesized in Scheme of Compound 101, 100 mg, 0.22 mmol), aniline (45 mg, 0.48 mmol, 2 eq.), Pd(OAc)2 (20 mg, 0.09 mmol, 0.1 eq.),
Xantphos (26 mg, 0.05mmol, 0.2 eq.) and Cs2C03 (150 mg, 0.46mmol, 2eq.) in 1,4-dioxane (5 mL) was stirred at 100°C for 16 hours under N2 atmosphere. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound 2 (70mg, 64.2% yield) as a yellow solid. LC- MS: m/z 520.7 (M+H)+.LC-MS: m/z 499.1 (M+H)\
[001868] Step B: Compound 356: 6-(4-mcthoxyphenyl)-2,3-diphcnyl-5- (phenylamino)py razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000427_0001
[001869] A solution of 7 7-methoxy-6-(4-methoxyphenyl)-N,2,3-triphenylpyrazolo[ 1,5- a]pyrimidin-5-amine (70 mg, 0.14 mmol) in 4M HC1 in 1.4-dioxane (3 mL) was stirred at r.t. for 2 hours. Solvent and volatile were removed in vacuo. The mixture was basified with NaHC03 solution to pH=8 and concentrated in vacuo to give the the title compound 6-(4- methoxyphenyl)-2,3-diphenyl-5-(phenylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one.
[001870] 1H NMR (DMSO-d6) δ : 7.41 - 7.68 (m, 14H), 7.22 - 7.36 (m, 6H), 4.06 (s, 3H). LC-MS: m/z 484.9 (M+H)+.
[001871] Compound 358
OH
Figure imgf000427_0002
[001872] Step A: 6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-l-yl)-4- ((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one
Figure imgf000427_0003
[001873] A suspension of 6-bromo-5-methyl-2-phenyl-3-(piperidin-l-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[l ,5-a]pyrimidin-7(4H)-one (Synthesized in scheme of Compound 305, 150 mg, 0.29 mmol) and 6-methoxypyridin-3-ylboronic acid (133 mg, 0.87 mmol), PdC12(dppf) (21 mg, 0.03 mmol) and Na2C03 (61 mg, 0.58 mmol) in 1.4- dioxane/water (10 mL/1 mL) was stirred and heated to 85 °C for 16 h under N2 atmosphere. The reaction was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo. The residue was purified by flash column chromatography, eluting with PE/EA (4/1), to get desired product (40 mg, 25% yield) as a white solid. LC-MS: m/z 546.3 (M+H)+.
[001874J Step B: 6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyI-3-(piperidin-l- yl)py razolo [ 1 ,5-a] pyrimidin-7(4H)-one
Figure imgf000428_0001
[001875] The mixture of 6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-l- yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one (40 mg, 0.07 mmol) and HC1 in MeOH (0.5 mol, 10 mL, 5 mmol) was stirred at RT for 1 h to get the desired product.
[001876] NMR (DMSO-ί/δ) δ: 11.47 (br. s., 1H), 8. 12 (dd, J=1.6 Hz, 2.8 Hz, 3H),
7.67 (dd, J=2.4 Hz, 2.4 Hz, 1H), 7.50-7.40 (m, 3H), 6.90 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 3.08 (t, J=4.8 Hz, 4H), 2.29 (s, 3H), 1.67-1.50 (m, 6H). LC-MS: m/z 416.2 (M+H)+.
[001877] Example 2 Biochemical Assay
[001878] In the reaction catalyzed by MAT2A enzyme, L-Met and ATP were converted to SAM, inorganic phosphate, and inorganic diphosphate. Measurement of MAT2A enzymatic activity was made by direct chemical detection of the inorganic phosphate upon the addition of sulfuric acid and ammonium molybdate to the enzymatic reaction mixture, which stochiometrically formed highly chromogenic malachite green phosphomolybdate with an absorption maxima at 620 to 650 nM. The concentration of malachite green
phosphomolybddate produced in the detection reaction is thus directly related to the quantity of product produced by the MAT2A enzyme. Multiple commercial kits exist for this method of phosphate detection and quantification, such as PiColorLock Gold (Innova Biosciences). [001879] Typical reaction was performed in 50 μΐ final volume, containing buffer (Tris, pH 8.0, 50 mM KC1, 15 mM MgC12, 300 uM EDTA, bovine serum albumin at 0.005% w/v) and ^g/ml MAT2A. Compounds were added in 1 μΐ of DMSO at the desired concentration; a typical dose response curve contained ten points with three-fold dilution between compound concentrations. The mixture of MAT2a enzyme and inhibitor was preincubated for 60 minutes at 25 °C; the enzymatic reaction was started with the addition of L-Met and ATP to a final concentration of 80 μΜ and 100 μΜ respectively. The reaction was allowed to proceed for 60 minutes at room temperature then halted by the addition of 13 μΐ of PiColor Lock reagent. After a further 5 minutes of incubation at room temperature, 5 μΐ of PiColor Stabilizer was added and the reactions were further incubated at 25 °C for 25 minutes.
Quantitative measurement of product produced was determined by spectrophotometric analysis at 623 nM and comparison to a phosphate standard curve. [001880] Recombinant MAT2A protein was expressed in SF9 insect cells and purified by metal chelate affinity chromatography, using methods well known in the art. After expression of His6-tagged MAT2A cells were disrupted by 4 passes through an M-Yl 10 Micro fluidizer (Microfluidics) set to 500 psi, and then centrifuged at 22,000 rcf for 20 min at 4°C. The supernatant was harvested and loaded at 15cm/h on a Histrap FF 5* lml column (GE) which was equilibrated with 50mM Tris, 500mM NaC1, pH7.4. Host cell contaminants were removed by washing the column with equilibration buffer followed by equilibration buffer containing 20mM imidazole and 60mM imidazole to baseline. MAT2A protein was eluted by the addition of buffer containing 250 mM imidazole, dialized into 50 mM NaC1, 50 mM Tris, pH 7.4, flash frozen in liquid nitrogen, and stored at -80 °C until use. [001881] Compounds that are shown in Tables 1 and 2 were tested in the foregoing assay and they were determined to inhibit MAT2A with an IC50 according to the following scores: (A) less than lOOnM, (B) between 100 nm and 1 μΜ, and (C) between 1 μΜ and 10 μΜ, as shown in Table 3 below.
TABLE 3
Figure imgf000429_0001
Figure imgf000430_0001
Figure imgf000431_0001
Figure imgf000432_0001
Figure imgf000433_0001
Figure imgf000434_0001
Figure imgf000435_0001
[001882] Example 3 Cellular Assay of target engagement (SAM) [001883] Measurement of MAT2A activity in cells was made by direct quantitation of the abundance of the product of its enzymatic activity, SAM. Cancer cells were treated with candidate MAT2A inhibitors for a suitable incubation period, and the cells were then lysed using a reagent which quenched any further enzyme activity. Soluble metabolites including SAM were collected and SAM itself was directly measured from the lysate using quantitative LC/MS. [001884] A typical assay was performed using an HCT116 human colon carcinoma cell line which was genetically engineered to delete the MTAP gene (commercially available from Horizon Discovery). This cell line was utilized because it was determined that loss of the MTAP gene predicts sensitivity to MAT2A inhibitors. Cells were plated in 96-well dishes at appropriate cell density. Following 24 hours, cells were then treated with the candidate MAT2A inhibitor. Prior to addition to cells, the compound was first serially diluted in DMSO, typically as a 3-fold serial dilution with 10 dose points. Compound was then transferred to a working stock plate in cell culture media by adding 5 µl of compound in DMSO to 495 µl of cell culture media. This working stock was then added to cells via a further 5-fold dilution, by adding 25 µl of working stock to 100 µl of cells in culture media. Following compound addition, cells were incubated at 37qC / 5% CO2 for 4 hrs. [001885] To quantitate SAM levels following compound treatment, cells were gently washed once in Ammonium Carbonate buffer (75mM at pH 7.4), placed on dry ice, and lysed with metabolite extraction buffer (80% cold methanol and 20% acetic acid containing 50 ng/ml of deuterated d3SAM). Following centrifugation at 4qC at 3200 rpm for 30 minutes, the supernatant was collected and stored at -80qC until analysis by Liquid Chromatography- Mass Spectrometry (LC/MS). LC/MS analysis was performed using an Xevo TQS (Milford, MA) operating in positive electrospray mode, with chromatographic separation using a Waters Acquity BEH Amide column. Multiple Reaction Monitoring data was acquired for SAM and the d3SAM standard, using MRM transitions of 399.2/250.1 amu and 402.2/250.1 amu, respectively. In a typical LC/MS analysis, the initial flow rate was 0.5ml/min of 25% H2O:ACN(95/5,v/v)-1% FA -10mM NH4OAc (Mobile Phase A), 75% H2O:ACN(5/95,v/v)- 1% FA -10mM NH4OAc (Mobile Phase B), at 0.2 min 25 % MA , at 0.5 min 65% MA, at 1.1min 25% MA with a total run time of 2.5 minutes
[001886] Example 4 Assay for Inhibition of Cellular Proliferation [001887] Test compound impact on cancer cell growth was assessed by treating cancer cells with compound for 4 days and then measuring proliferation using an ATP-based cell proliferation readout (Cell Titer Glo, Promega Corporation). [001888] In a typical assay an isogenic pair of HCT116 human colon carcinoma cell lines which vary only in MTAP deletion status (HCT116 MTAP+/+ and HCT116 MTAP-/-) were plated in 96-well dishes at appropriate cell density. Following 24 hours, cells were then treated with the candidate MAT2A inhibitor. Prior to addition to cells, the compound was first serially diluted in DMSO, typically as a 3-fold serial dilution with 10 dose points.
Compound was then transferred to a working stock plate in cell culture media by adding 5 µl of compound in DMSO to 495 µl of cell culture media. This working stock was then added to cells via a further 5-fold dilution, by adding 25 µl of working stock to 100 µl of cells in culture media. Following compound addition, cells were incubated at 37qC / 5% CO2 for 4 days. [001889] To measure inhibition of cellular proliferation, cells were allowed to equilibrate to room temperature for 30 minutes, and were then treated with 125 µl of Cell Titer Glo reagent. The plate was then shaken for 15 minutes to ensure complete mixing and full cell lysis. Luminescent signal of the Cell Titer Glo reagent was then measured using a plate-based luminometer and normalized via an ATP standard curve. This luminescence measure was converted to a proliferation index by subtracting from each datapoint the ATP luminescence measured from a control cell plate that was measured at the time of compound treatment (i.e., day 0). Compound activity was then represented as a % change in
proliferation relative to a within-plate DMSO control.

Claims

WE CLAIM:
1. A compound according to formula IA or a pharmaceutically acceptable salt
thereof:
Figure imgf000438_0001
wherein
RA is selected from the group consisting of H, C1-C6-alkyl, C2-C6-alkenyl, d-C6-alkoxy, C3-C14-carbocycle, (C3-C14-carbocyclo)-C1-C6-alkyl-, 3- to 14-membered heterocycle or heterocyclo-C1-C6-alkyl- (wherein 1 to 4 heterocycle ring members are
heteroatoms selected from N, O, and S), (3- to 14-membered heterocyclo)oxy-, C6-
C14-aryl, (C6-C14-aryl)-C1-C6-alkyl-, C6-C14-aryloxy-, -(CH^NR1CCH^C(O)R2, NR1R2, C(O)NR1R2, NR1C(NR2)NR1R2, NR1C(NR2)(=NR1), SR1, -CN, and -OH; wherein each alkyl, alkenyl, alkoxy, aryl, and heterocycle is optionally substituted with one or more substituents selected from the group consisting of R1, OR1, halo, -N=N-R1, NR1R2, -(C1-C6-alkyONR1R2, -CCOJOR1, -C(0)NR1R2, -
OC(O)R1, -CN, -OP(0)(OR1)1-2, and oxo;
RB is selected from the group consisting of H, C2-C6-alkenyl, and d-C6-alkyl, wherein
RB is optionally substituted by one or more R1;
Rc, RD, and RE are independently selected from the group consisting of C3-G4- carbocycle, C6-C14-aryl, and 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S),
wherein Rc, RD, and RE are optionally substituted with one or more substituents selected from the group consisting of R1, -OR1, halo, -NR1R2, -(d-C6-alkyO-NR1R2, - C(0)OR1, -C(0)NR1R2, -N02, -CN, and oxo; and
R1 and R2 are independently selected from the group consisting of H, D (2H), -CN, -OH, C1-C6-alkyl, G-Cc-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, NH2, -S(0)o-2-(C1-C6- alkyl), -S(0)o-2-(C6-C14-aryl), -C(0)(C1-C6-alkyl), -C(0)(C3-C14-carbocyclo), -C3-G4- carbocycle, C6-C14-aryl, 3- to 14-membered heterocycle or heterocyclo(C1-C6-alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), wherein each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocycle, and heterocycle moiety of R1 and R2 is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, -NH2, -NHC(0)(0C1-C6 alkyl), -N02, -CN, oxo, -C(0)OH, -C(0)0(C1-C6-alkyl), -C1-C6-alkyKC1-C6- alkoxy), -C(0)NH2, C1-C6-alkyl, -C(0)C1-C6-alkyl, -OC1-C6-alkyl, -Si(C1-C6- alkyl)3, C6-C14-aryl, -(C1-C6-alkyl)( C6-Cn-aryl), 3- to 14-membered heterocycle or heterocyclo(C1-C6-alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), and -CXC6-Cn-aryl), wherein each alkyl, aryl, and heterocyclo in R1 and R2 is optionally
substituted with one or more substituents selected from the group consisting of hydroxy, -0C1-C6-alkyl, halo, -NH2, -(C1-C6-alkytyNH2, C(0)OH, CN, and oxo. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein RD and RE are independently selected from C3-C14-carbocycle, C6-C14- aryl, and 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S). 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein RD and RE are independently selected from C3-C14-carbocycle and C6-C14-aryl. 4. The compound according to any one of claims 1 - 3, or a pharmaceutically
acceptable salt thereof, wherein RD and RE are independently selected from C5-C7 carbocycle and C6-C1o-aryl. 5. The compound according to any one of claims 1 - 4, or a pharmaceutically
acceptable salt thereof, wherein RD and RE are independently selected from cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and phenyl. 6. The compound according to any one of claims 1 - 5, or a pharmaceutically
acceptable salt thereof, wherein one of RD and RE is cyclohexyl or cyclohexen and the other is phenyl.
7. The compound according to any one of claims 1 - 6, or a pharmaceutically
acceptable salt thereof, wherein RA is selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, Ci-Ce- alkoxy, C3-C14-carbocycle, (C3-C14-carbocyclo)-C1-C6-alkyl-, 3- to 14- membered heterocycle or heterocycloCd-C6-alkyl)- (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), C6-C14- aryl, (C6-C14-aryl)-C1-C6-alkyl-, C6-C14-aryloxy, -(CH2)o^NR1(CH2)0-6C(0)R2, NR1R2, NR1C(NR2)NR1R2, -CN, and -OH. 8. The compound according to any one of claims 1 - 7, or a pharmaceutically
acceptable salt thereof, wherein RA is selected from the group consisting of G-C6- alkyl, -(CH2)0-6)NR1(CH2)0-5)C(O)R2, NR1R2, and NR1C(NR2)NR1R2. 9. The compound according any one of claims 1 - 8, or a pharmaceutically
acceptable salt thereof, wherein RA is G-C6-alkyl or NR1R2. 10. The compound according any one of claims 1 - 9, or a pharmaceutically
acceptable salt thereof, wherein RA is NR1R2.
1 1. The compound according to claim 10, or a pharmaceutically acceptable salt
thereof, wherein R1 is H.
12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is one according to formula IB:
Figure imgf000440_0001
Rc is a C3-C14-carbocycle or a 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S),
each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, C6-C14-aryl, (C6-C14-aryl)-C1-C6-alkyl-, carboxy, -CN, oxo, C1-C6-alkyl, C1-C6-alkoxy, and -NH(C1-C6-alkyl), wherein the d-C6-alkyl, d-C6-alkoxy, and NH(d-C6-alkyl) are independently and optionally substituted with one or more of hydroxy, halogen, -NH2, carboxy, -CN, and oxo;
RD and RE are independently a C3-C14-carbocycle or a 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S), each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, C6-C14-aryl, (C6-C14-aryty-d-C6-alkyl-, carboxy, -CN, oxo, d-C6-alkyl, d-C6-alkoxy, and -NH(C1-C6-alkyl),
wherein the C1-C6-alkyl, C1-C6-alkoxy, and NH(d-C6-alkyl) are
independently and optionally substituted with one or more of hydroxy, halogen, -NH2, carboxy, -CN, and oxo; and
R1 is selected from the group consisting of H, C1-C6-alkyl, C3-C14-carbocycle, and 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S),
each optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, -N02, -CN, oxo, carboxy, -C(0)OC1- C6-alkyl, (C1-C6-alkylJOC1-C6-alk l-, -C(0)NH2, C1-C6-alkyl, -C(0)H, C1-C6- alkoxy, (C1-C6-alkyl)N(H)-aryl-, (C6-C14-aryl)Ct-C6-alkyl-, 5- to 7-membered heteroaryl, (5- to 7-membered heteroaryl)-d-C6-alkyl-, C6-C14-aryloxy, (C6- C14-aryl)(C1-C6-alkoxy)-, (5- to 7-membered heteroaryl)oxy-, and (5- to 7- membered heteroaryl)(C1-C6-alkoxy)-,
wherein the C1-C6-alkyl, Ct-C6-alkoxy, (d-C6-alkyl)N(H)-, -C(0)OCt-C6- alkyl, (d-C6-alkyl)Od-C6-alkyl-, -C(0)NH2, C6-C14-aryl, (C6-C14- aryl)C1-C6-alkyl-, 5- to 7-membered heteroaryl, (5- to 7-membered heteroaryl)-d-C6-alkyl-, C6-C14-aryloxy, (C6-C14-aryl)(d-C6-alkoxy)-, (5- to 7-membered heteroaryl)oxy-, and (5- to 7-membered heteroaryl)(C1-C6- alkoxy)-, are optionally substituted with one or more of hydroxy, halogen, -NH2, (C1-C6-alkyl)N(H)-, -COOH, -CN, and oxo,
wherein each heteroaryl in R1 has 1 to 4 heteroaryl ring members that are heteroatoms selected from N, O, and S.
13. The compound according to claim 12, or a pharmaceutically acceptable salt
thereof, wherein RD is C3-C14-carbocycle optionally substituted with one or more members of the group consisting of hydroxy, halogen, -NH2, -C(0)OH, -CN, oxo, alkyl, C1-C6-alkyl, G-C6-alkoxy, and (G-C6-alkyONCH)-,
wherein the G-C6-alkyl, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)- are optionally substituted with one or more of hydroxy, halogen, -NH2, -C(0)OH, -CN, and oxo. 14. The compound according to claim 12, or a pharmaceutically acceptable salt
thereof, wherein RD is phenyl. 15. The compound according claim 12, or a pharmaceutically acceptable salt thereof, wherein RD is cyclohex-l-en-l-yl. 16. The compound according claim 12, or a pharmaceutically acceptable salt thereof, wherein RE is C3-C14-carbocycle optionally substituted with one or more members of the group consisting of hydroxy, halogen, -NH2, -C(0)OH, -CN, oxo, alkyl, C1- C6-alkyl, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)-,
wherein the C1-C6-alkyl, G-C6-alkoxy, and (G-C6-alkytyNiH)- are
optionally substituted with one or more of hydroxy, halogen, -NH2, -
C(0)OH, -CN, and oxo. 17. The compound according to claim 12, or a pharmaceutically acceptable salt
thereof, wherein RE is selected from the group consisting of cyclohex-l-en-l-yl, (2H9)cyclohex- 1 -en- 1 -yl, cyclohexan- 1 , 3 -dien- 1 -yl , 4,4-difluorocy clohex- 1 -en- 1 - yl, cyclopent-l-en-lyl, cyclopentyl, pyridin-3-yl, pyridin-2-yl, 4-methoxypyridin- 3-yl, pyridin-2-yl, 1H-pyrazol-4-yl, 1H-pyrrol-3-yl, 4,4-difluoropiperidin-l-yl, 5,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 1H-pyrrol-3-yl, 1H- pyrrol-l-yl, tetrahydrofuran-3-yl, 3,3-difluoropyrrolidin-l-yl, and 3,6-dihydro-2H- pyran-4-yl. 18. The compound according to claim 12, or a pharmaceutically acceptable salt
thereof, wherein RE is phenyl.
19. The compound according to claim 18, or a pharmaceutically acceptable salt
thereof, wherein RD is cyclohex-l-en-l-yl.
20. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein Rc is C3-C14-carbocycle or 3- to 14-membered heterocycle (wherein 1 to 4 heterocycle ring members are heteroatoms selected from N, O, and S) and that is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, -C(0)OH, -CN, oxo, C1-C6- alkyl, C1-C6-alkoxy, (C1-C6-alkyl)N(H)-,
wherein the 0-C6-alkyl, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)- are optionally substituted with hydroxy, halogen, -NH2, -C(0)OH, -CN and oxo. 21. The compound according to claim 12, or a pharmaceutically acceptable salt
thereof, wherein Rc is selected from the group consisting of 4-hydroxyphenyl, 4- chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4- trifluoromethoxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-2- methoxyphenyl,3,4-dihydroxyphenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(2- (dimethylamino)ethoxy)phenyl, 3-fluoro-4-hydroxyphenyl, 3-fluoro-4- methoxyphenyl, 2-chloro-4-hydroxyphenyl, 2-fluoro-4-methoxyphenyl, 3- amino-4-hydroxyphenyl, 3-amino-4-fluorophenyl, 3-(N,N-dimethylaminoethoxy)- 4-hydroxyphenyl, 3 -chloro-2-hydroxyphenyl, 3 -hydroxyethoxy-4-hydroxyphenyl
Figure imgf000443_0001
22. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein Rc is selected from the group consisting of 6-methoxypyridin-3-yl, 2- methoxypyridin-4-yl, 1H-pyrazol-4-yl, quinolin-6-yl, 2-methylquinolin-6-yl, 2- methoxyquinolin-6-yl, 2-hydroxymethylquinolin-6-yl, 3-hydroxy-2-methylquinolin-6- yl, 2-aminoquniazolin-6-yl,4-aminoquinazolin-6-yl, cinnolin-6-yl, quinoxalin-6-yl, 2- chloroquinoxalin-6-yl, 3-chloroquinoxalin-6-yl, 3-aminoquinoxalin-6-yl, 3- hydroxyquinoxalin-6-yl,3-methoxyquinoxalin-6-yl, l,8-naphthyridin-3-yl, imidazo[ 1 ,2-a]pyridin-6-yl,
Figure imgf000444_0001
23. The compound according claim 12, or a pharmaceutically acceptable salt thereof, wherein Rc is 4-methoxyphenyl. 24. The compound according claim 12, or a pharmaceutically acceptable salt thereof, wherein R1 is a 3- to 14-membered heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy,
halogen, -NH2, -N02, -C(0)OH, -C(0)OC1-C6-alkyl, (C1-C6-alkyl)N(H)C(0)-, - CN, oxo, d-C6-alkyl, -C(0)H, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)-, wherein the C1-C6-alkyl, C1-C6-alkoxy, and (C1-C6-alkyl)N(H)-, C(0)OC1-C6- alkyl, and (C1-C6-alkyl)N(H)C(0)- are optionally substituted with one or more of hydroxy, halogen, -NH2, (C1-C6-alkyl)N(H)-, -C(0)H, -CN, and oxo. 25. The compound according claim 12, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of pyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, l,3,5-triazin-2-yl, l,2,4-triazin-3-yl, each of which is optionally substituted with one or more of F, CI, CN, OH, -NCh, -NH2 , -NHMe, -C(O)NIt., and methoxy.
26. The compound according claim 12, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of:
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000446_0002
27. The compound according claim 12, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of:
Figure imgf000446_0003
Figure imgf000447_0001
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
Ri 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, N02, 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.
29. A compound according to claim 1 or claim 28, or a pharmaceutically acceptable salt thereof, that is selected from the following table:
Figure imgf000448_0001
Figure imgf000449_0001
Figure imgf000450_0001
Figure imgf000451_0001
Figure imgf000452_0001
Figure imgf000453_0001
Figure imgf000454_0001
Figure imgf000455_0001
Figure imgf000456_0001
Figure imgf000457_0002
30. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, that is selected from the following table:
204
Figure imgf000457_0001
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001
Figure imgf000463_0001
Figure imgf000464_0001
Figure imgf000465_0001
Figure imgf000466_0001
Figure imgf000467_0001
Figure imgf000468_0001
Figure imgf000469_0001
Figure imgf000470_0001
3 1. A method for inhibiting the synthesis of S-adenosyl methionine (SAM) from methionine and ATP by MAT2A in a cell, comprising introducing into the cell effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 28. 32. A method for treating a disease or condition in a subject suffering therefrom, wherein the disease or condition is mediated by the overexpression of MAT2A, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 28. 33. The method according to claim 32, wherein said disease or condition is cancer.
34. The method according to claim 33, wherein the cancer is selected from the group consisting of neuroblastoma, 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 lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma. 35. A method for treating a cancer in a subject suffering therefrom, wherein the
cancer is characterized by a reduction or absence of methylthioadenosine phosphorylase (MTAP) gene expression, the absence of the MTAP gene, or reduced function of MTAP protein, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 30. 36. The method of claim 35, wherein the cancer is MTAP null. 37. The method of claim 35 or 36, wherein the cancer has a KRAS mutation. 38. The method of claim 37, wherein the KRAS mutation is an amino acid
substitution at residue 12 or 13.
39. The method of claim 37, wherein said KRAS mutation is G12C, G12R, G12V or G13D.
40. The method of claim 35 or 36, wherein the cancer has a p53 mutation.
41. The method of claim 40, wherein the p53 mutation is Y126_splice, 132Q, M133K, R174fs, R175H, R196*, C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C, R282W, A159V or R280K.
42. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 30, and a
pharmaceutically acceptable carrier.
43. A compound according to any one of claims 1 - 30, or a pharmaceutically
acceptable salt thereof, for inhibiting the synthesis of S-adenosyl methionine (SAM) from methionine and ATP by MAT2A in a cell.
44. A compound according to any one of claims 1 - 30, or a pharmaceutically
acceptable salt thereof, for treating a disease or condition in a subject suffering therefrom, wherein the disease or condition is mediated by the overexpression of MAT2A.
45. A compound according to any one of claims 1 - 30, or a pharmaceutically
acceptable salt thereof, for treating a cancer in a subject suffering therefrom, wherein the cancer is characterized by a reduction or absence of
methylthioadenosine phosphorylase (MT AP) expression, the absence of the MTAP gene, or reduced function of MTAP protein.
PCT/US2017/049439 2016-08-31 2017-08-30 Inhibitors of cellular metabolic processes WO2018045071A1 (en)

Priority Applications (19)

Application Number Priority Date Filing Date Title
EP17764997.7A EP3507290A1 (en) 2016-08-31 2017-08-30 Inhibitors of cellular metabolic processes
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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019191470A1 (en) * 2018-03-30 2019-10-03 Agios Pharmaceuticals, Inc. Heterobicyclic inhibitors of mat2a and methods of use for treating cancer
WO2020123395A1 (en) * 2018-12-10 2020-06-18 Ideaya Biosciences, Inc. 2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors
WO2020139992A1 (en) * 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Aza-heterobicyclic inhibitors of mat2a and methods of use for treating cancer
WO2020139991A1 (en) * 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Aza-heterobicyclic inhibitors of mat2a and methods of use for treating cancer
US10738056B2 (en) 2017-09-15 2020-08-11 Aduro Biotech Inc. Pyrazolopyrimidinone compounds and uses thereof
WO2020168032A1 (en) 2019-02-13 2020-08-20 Agios Pharmaceuticals, Inc. Combination therapies for use in treating cancer
WO2020167952A1 (en) * 2019-02-12 2020-08-20 Mirati Therapeutics, Inc. Mat2a inhibitors
US10800782B2 (en) 2016-08-31 2020-10-13 Agios Pharmaceutical, Inc. Inhibitors of cellular metabolic processes
WO2021023609A1 (en) 2019-08-02 2021-02-11 Glaxosmithkline Intellectual Property Development Limited Combination of a type i protein arginine methyltransferase (type i prmt) inhibitor and a methionine adenosyltransferase ii alpha (mat2a) inhibitor
EP3672597A4 (en) * 2017-08-21 2021-09-22 Navigen, Inc. Arf6 inhibitors and related methods
CN113999232A (en) * 2020-07-28 2022-02-01 南京正大天晴制药有限公司 MAT2A inhibitors
WO2022036067A1 (en) * 2020-08-12 2022-02-17 Servier Pharmaceuticals, Llc Combination therapies for use in treating cancer
WO2022036033A2 (en) 2020-08-12 2022-02-17 Servier Pharmaceuticals, Llc Solid state forms of an organic compound
WO2022063128A1 (en) * 2020-09-24 2022-03-31 上海凌达生物医药有限公司 Aromatic ring or arylheterocyclic pyridone compound, pharmaceutical compositions, and use thereof
WO2022078403A1 (en) * 2020-10-15 2022-04-21 江苏先声药业有限公司 Substituted pyridone compound and application
WO2022115521A1 (en) * 2020-11-25 2022-06-02 Servier Pharmaceuticals, Llc (heteo)aryl substituted pyrrolo-, pyrazolo- and triazolopyridazine derivates as mat2a inhibitors
WO2022143864A1 (en) 2020-12-31 2022-07-07 江苏先声药业有限公司 Tricyclic compound and use thereof
WO2022189379A1 (en) 2021-03-08 2022-09-15 Technische Universität München Treatment of coronavirus infections using sam cycle inhibitors
WO2022204481A1 (en) * 2021-03-26 2022-09-29 Orphagen Pharmaceuticals, Inc. Pyrazolopyrimidinone compounds
US11512097B2 (en) 2019-11-25 2022-11-29 Amgen Inc. Heterocyclic compounds as Delta-5 desaturase inhibitors and methods of use
WO2023194708A1 (en) 2022-04-04 2023-10-12 Cambridge Enterprise Limited Mat2a inhibitor and/or tsg101 inhibitor for use in antiviral therapy
RU2809987C2 (en) * 2018-12-27 2023-12-20 Ле Лаборатуар Сервье Heterocyclic mat2a inhibitors and methods of their use for cancer treatment
WO2024105553A1 (en) * 2022-11-16 2024-05-23 Novartis Ag Bicyclic heterocycles and their use as wrn inhibitors

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114901664B (en) * 2020-01-10 2024-07-02 南京再明医药有限公司 Pyridone compounds and uses thereof
WO2021158792A1 (en) * 2020-02-04 2021-08-12 Agios Pharmaceuticals, Inc. Methods of treating autoimmune or inflammatory diseases or disorders
WO2021254529A1 (en) * 2020-07-14 2021-12-23 江苏先声药业有限公司 Bicyclic compound
JP2024116429A (en) * 2021-07-06 2024-08-28 国立研究開発法人産業技術総合研究所 Composition for preventing or treating tissue aging
CN115716831B (en) * 2021-08-25 2024-07-02 中国科学院分子细胞科学卓越创新中心 MAT2A inhibitor and application thereof in antiviral
WO2023083210A1 (en) * 2021-11-09 2023-05-19 上海海雁医药科技有限公司 Substituted naphthyridinone derivative, and pharmaceutical composition thereof and use thereof
WO2023086934A1 (en) * 2021-11-12 2023-05-19 Ideaya Biosciences, Inc. Combination therapy comprising a mat2a inhibitor and a taxane
CN116283994A (en) * 2021-12-20 2023-06-23 艾立康药业股份有限公司 Heterocyclic compounds as MAT2A inhibitors
EP4434989A1 (en) 2021-12-21 2024-09-25 Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd. Methionine adenosyltransferase 2a heterocyclic inhibitor
TW202415370A (en) 2022-10-13 2024-04-16 南韓商韓美藥品股份有限公司 Novel tricycle derivative compounds and uses thereof
CN116425721B (en) * 2022-12-19 2024-02-02 艾立康药业股份有限公司 Bicyclic compounds as MAT2A inhibitors
WO2024153244A1 (en) * 2023-01-20 2024-07-25 南京再明医药有限公司 Nitrogen-containing compound

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278793A (en) 1977-04-02 1981-07-14 Hoechst Aktiengesellschaft Cephem derivative
WO1998046576A2 (en) 1997-04-15 1998-10-22 Genentech, Inc. Halo-alkoxycarbonyl prodrugs
WO1999067634A1 (en) 1998-06-23 1999-12-29 The Regents Of The University Of California Method for early diagnosis of, and determination of prognosis in, cancer
US20120178915A1 (en) * 2009-09-23 2012-07-12 Lifeng Xu Pyrimidine derivatives and analogs, preparation method and use thereof
WO2012103457A2 (en) * 2011-01-28 2012-08-02 University Of Kentucky Stilbene analogs and methods of treating cancer

Family Cites Families (109)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3686228T3 (en) 1985-09-17 1997-08-28 Konishiroku Photo Ind Heat-developable photosensitive material.
US4950585A (en) 1987-08-18 1990-08-21 Konica Corporation Coupler for photographic use
JPH01271751A (en) 1988-04-23 1989-10-30 Konica Corp Silver halide color photographic sensitive material containing novel photographic coupler
JPH03172839A (en) 1989-12-01 1991-07-26 Konica Corp Novel photographing coupler
JPH04133055A (en) 1990-09-25 1992-05-07 Konica Corp Silver halide color photographic sensitive material improved in color reproducibility
US5356897A (en) 1991-09-09 1994-10-18 Fujisawa Pharmaceutical Co., Ltd. 3-(heteroaryl)-pyrazololi[1,5-a]pyrimidines
JPH05125079A (en) 1991-11-05 1993-05-21 Otsuka Pharmaceut Factory Inc Pyrazolo(1,5-a)pyrimidine derivative
JPH07253630A (en) 1994-03-15 1995-10-03 Konica Corp Direct positive silver halide color photographic sensitive material and formation of direct positive color image
KR19990008451A (en) 1995-05-09 1999-01-25 페라스타르크 Pyrazolo- (1,5a) -pyrimidine, its preparation method and its use
JPH08325248A (en) 1995-05-26 1996-12-10 Chugoku Kayaku Kk New reagent for synthesizing tetrazole compound and production of tetrazole compound using the same
JPH095630A (en) 1995-06-15 1997-01-10 Nikon Corp Optical scanning method
FR2746309B1 (en) 1996-03-22 1998-04-17 Oreal COMPOSITION FOR DYEING KERATIN FIBERS CONTAINING PYRAZOLOPYRIMIDINEOXO; THEIR USE FOR DYEING AS COUPLER, DYEING PROCESSES
FR2750048B1 (en) 1996-06-21 1998-08-14 Oreal KERATIN FIBER DYEING COMPOSITIONS CONTAINING PYRAZOLO- (1, 5-A) -PYRIMIDINE DERIVATIVES, DYEING PROCESS, NOVEL PYRAZOLO- (1, 5-A) -PYRIMIDINE DERIVATIVES AND THEIR PREPARATION METHOD
US6191131B1 (en) 1997-07-23 2001-02-20 Dupont Pharmaceuticals Company Azolo triazines and pyrimidines
US6060478A (en) 1996-07-24 2000-05-09 Dupont Pharmaceuticals Azolo triazines and pyrimidines
US6313124B1 (en) 1997-07-23 2001-11-06 Dupont Pharmaceuticals Company Tetrazine bicyclic compounds
US6124289A (en) 1996-07-24 2000-09-26 Dupont Pharmaceuticals Co. Azolo triazines and pyrimidines
US5817663A (en) 1996-10-07 1998-10-06 American Cyanamid Company Pentafluorophenylazolopyrimidines
FR2767685B1 (en) 1997-09-01 2004-12-17 Oreal COMPOSITION FOR OXIDATION DYEING OF KERATINIC FIBERS COMPRISING 2-CHLORO 6-METHYL 3-AMINOPHENOL AND AN OXIDATION BASE, AND DYEING METHOD
FR2779952B1 (en) 1998-06-19 2000-08-04 Oreal TINCTORIAL COMPOSITION CONTAINING PYRAZOLO- [1,5-A] - PYRIMIDINE AS OXIDATION BASE AND PYRIDINIC COUPLER, AND DYEING METHODS
US20020062529A1 (en) 1998-06-19 2002-05-30 L'oreal S.A. Dye composition containing 1,8-bis(2,5-diaminophenoxy)-3,6-dioxaoctane, an additional oxidation base and a coupler, and dyeing processes
FR2779951B1 (en) 1998-06-19 2004-05-21 Oreal TINCTORIAL COMPOSITION CONTAINING PYRAZOLO- [1,5-A] - PYRIMIDINE AS AN OXIDATION BASE AND A NAPHTHALENIC COUPLER, AND DYEING METHODS
FR2779950B1 (en) 1998-06-19 2004-05-21 Oreal KERATINIC FIBER OXIDATION DYE COMPOSITION AND DYEING METHOD USING THE SAME
FR2779949B1 (en) 1998-06-19 2004-05-21 Oreal KERATINIC FIBER OXIDATION DYE COMPOSITION AND DYEING METHOD USING THE SAME
FR2779948B1 (en) 1998-06-19 2004-04-23 Oreal TINCTORIAL COMPOSITION CONTAINING 1,8-BIS- (2,5-DIAMINOPHENOXY) -3,5-DIOXAOCTANE, AN ADDITIONAL OXIDATION BASE AND A COUPLER, AND DYEING METHODS
JP2000089418A (en) 1998-09-08 2000-03-31 Konica Corp Image recording material, direct positive type silver halide photographic sensitive material and image forming method
US6277857B1 (en) 1998-09-25 2001-08-21 American Cyanamid Company Fungicidal 7-oxy-and 7-thio-substituted-triazolopyrimidines
FR2784380B1 (en) 1998-09-25 2002-09-06 American Cyanamid Co TRIAZOLOPYRIMIDINES 7-OXY- AND 7-THIO-SUBSTITUTED FUNGICIDES
US6531477B1 (en) 1998-10-13 2003-03-11 Dupont Pharmaceuticals Company 6-substituted pyrazolo [3,4-d] pyrimidin-4-ones useful as cyclin dependent kinase inhibitors
FR2785183B1 (en) 1998-11-04 2002-04-05 Oreal TINCTORIAL COMPOSITION CONTAINING CATIONIC DIRECT DYE AND PYRAZOLO- [1,5-a] - PYRIMIDINE AS OXIDATION BASE, AND DYEING METHODS
JP2000153671A (en) 1998-11-20 2000-06-06 Fuji Photo Film Co Ltd Heat-sensitive recording material
FR2791562B1 (en) 1999-03-29 2004-03-05 Oreal TINCTORIAL COMPOSITION CONTAINING PYRAZOLO- [1,5-A] - PYRIMIDINE AND A MONOCYCLIC POLYAMINOPYRIMIDINE AS OXIDATION BASES AND A COUPLER, AND DYEING METHODS
FR2791563A1 (en) 1999-03-29 2000-10-06 Oreal KERATIN FIBER OXIDATION DYEING COMPOSITION AND DYEING METHOD USING THE SAME
JP4193285B2 (en) 1999-06-04 2008-12-10 コニカミノルタホールディングス株式会社 Color toner
EP1067165A3 (en) 1999-07-05 2001-03-14 Konica Corporation Organic electroluminescent element
IL148905A0 (en) 1999-09-30 2002-09-12 Neurogen Corp Pfizer Inc Certain alkylene diamine-substituted pyrazolo{1,5,-a}-1,5-pyrimidines and pyrazolo{1,5,-a}-1,3,5-triazines
OA12049A (en) 1999-09-30 2006-05-02 Neurogen Corp Amino substituted pyrazoloÄ1,5,-aÜ-1,5-pyrimidinesand pyrazoloÄ1,5,-aÜ-1,3,5-triazines.
US20020041880A1 (en) 2000-07-05 2002-04-11 Defeo-Jones Deborah Method of treating cancer
JP2002326462A (en) 2001-04-27 2002-11-12 Fuji Photo Film Co Ltd Heat-sensitive recording material
FR2831055B1 (en) 2001-10-24 2004-05-28 Oreal TINCTORIAL COMPOSITION COMPRISING AT LEAST ONE HETEROCYCLIC BASE AND 1-N- (B-HYDROXYETHYL) 4-HYDROXY INDOLE AS A COUPLER; DYEING PROCESSES
DE50214170D1 (en) 2001-11-17 2010-03-04 Henkel Ag & Co Kgaa OXIDATION STAINING AGENT BASED ON TWO-CORE DEVELOPER COMPONENTS
GB0130416D0 (en) 2001-12-20 2002-02-06 Eastman Kodak Co Photographic elements containing a de-aggregating compound dye-forming coupler and stabilizer
GB0130418D0 (en) 2001-12-20 2002-02-06 Eastman Kodak Co Photographic elements containing a deaggregating compound and dye forming coupler
JP2003301009A (en) 2002-04-10 2003-10-21 Konica Minolta Holdings Inc Photopolymerization initiator, radical generation process, photopolymerizing composition, photosensitive material for preparing lithographic printing plate and preparation method of lithographic printing plate
WO2003101993A1 (en) 2002-06-04 2003-12-11 Neogenesis Pharmaceuticals, Inc. Pyrazolo` 1,5a! pyrimidine compounds as antiviral agents
EP1572113B1 (en) 2002-08-26 2017-05-17 Takeda Pharmaceutical Company Limited Calcium receptor modulating compound and use thereof
AU2003299651A1 (en) 2002-12-11 2004-06-30 Merck And Co., Inc. Tyrosine kinase inhibitors
WO2004065542A2 (en) * 2002-12-30 2004-08-05 Exelixis, Inc. MAT2As AS MODIFIERS OF THE p53 PATHWAY AND METHODS OF USE
JP4564485B2 (en) 2003-02-28 2010-10-20 帝人ファーマ株式会社 Pyrazolo [1,5-a] pyrimidine derivatives
ES2423800T3 (en) 2003-03-28 2013-09-24 Novartis Vaccines And Diagnostics, Inc. Use of organic compounds for immunopotentiation
EP1633756B1 (en) 2003-04-09 2008-12-24 Biogen Idec MA Inc. A2a adenosine receptor antagonists
JP4795634B2 (en) 2003-10-31 2011-10-19 出光興産株式会社 Organic thin film transistor
DE10356579A1 (en) 2003-12-04 2005-07-07 Merck Patent Gmbh amine derivatives
WO2005103052A1 (en) 2004-04-21 2005-11-03 Pfizer Products Inc. Pyrazolo [1,5-a] pyrimidin-7-one compounds and uses thereof
GB0516378D0 (en) 2005-08-09 2005-09-14 Eirx Therapeutics Ltd Compound
JP5066516B2 (en) 2005-09-01 2012-11-07 アステラス製薬株式会社 Pyridazinone derivatives used for the treatment of pain
WO2007071688A1 (en) 2005-12-22 2007-06-28 L'oréal Composition for dyeing keratin fibres with a tetraazapentamethine cationic direct dye, a particular oxidation base and a coupler
US20090304821A1 (en) 2006-03-08 2009-12-10 Takeda Pharmaceutical Company Limited Pharmaceutical Combination
BRPI0708813A2 (en) 2006-03-17 2011-05-24 Wyeth Corp compound; composition; method of treatment, growth inhibition or eradication of neoplasms in a mammal in need; method of treating cancer in a needy mammal; and mix
EP2233472B1 (en) 2006-03-28 2014-01-15 Atir Holding S.A. Heterocyclic compounds and uses thereof in the treatment of sexual disorders
WO2007118844A1 (en) 2006-04-13 2007-10-25 Basf Se Substituted pyrazolopyrimidines, process for their preparation and their use for controlling harmful fungi and compositions comprising them
JP2009544625A (en) 2006-07-20 2009-12-17 メーメット・カーラマン Benzothiophene inhibitors of RHO kinase
WO2008019309A1 (en) 2006-08-04 2008-02-14 Metabasis Therapeutics, Inc. Novel inhibitors of fructose 1,6-bisphosphatase
WO2008046856A2 (en) 2006-10-18 2008-04-24 Basf Se Fungicidal compositions
US20080176870A1 (en) 2006-11-20 2008-07-24 Bert Nolte Heterobicyclic metalloprotease inhibitors
WO2008062026A1 (en) 2006-11-23 2008-05-29 Novartis Ag 5-sulfanylmethyl-pyrazolo [1,5-a] pyrimidin-7-ol derivatives as cxcr2 antagonists
WO2008079028A1 (en) * 2006-12-22 2008-07-03 Industrial Research Limited Azetidine analogues of nucleosidase and phosphorylase inhibitors
JP5205794B2 (en) 2007-04-26 2013-06-05 コニカミノルタホールディングス株式会社 Optical filter composition, optical filter, front filter for display and squarylium compound
WO2009017954A1 (en) 2007-08-01 2009-02-05 Phenomix Corporation Inhibitors of jak2 kinase
DE102007048447A1 (en) 2007-10-10 2009-04-16 Bayer Healthcare Ag New substituted dihydropyrazole-3-thione compounds are hypoxia inducible factor-prolyl-4-hydroxylase inhibitor, useful for preparing medicament to treat and/or prevent e.g. cardiovascular diseases, wound healing and anemia
DE102007049157A1 (en) 2007-10-13 2009-04-16 Bayer Healthcare Ag New substituted 2,3-dihydro-(1,2,3)triazol-4-one compounds are hypoxia inducible factor-prolyl-4-hydroxylase inhibitor, useful for preparing medicament to treat and/or prevent e.g. cardiovascular diseases, inflammatory disease and anemia
US20100029657A1 (en) 2008-02-29 2010-02-04 Wyeth Bridged, Bicyclic Heterocyclic or Spiro Bicyclic Heterocyclic Derivatives of Pyrazolo[1, 5-A]Pyrimidines, Methods for Preparation and Uses Thereof
US8507501B2 (en) 2008-03-13 2013-08-13 The Brigham And Women's Hospital, Inc. Inhibitors of the BMP signaling pathway
US20100204265A1 (en) 2009-02-09 2010-08-12 Genelabs Technologies, Inc. Certain Nitrogen Containing Bicyclic Chemical Entities for Treating Viral Infections
WO2010114780A1 (en) 2009-04-01 2010-10-07 Merck Sharp & Dohme Corp. Inhibitors of akt activity
GB0908957D0 (en) 2009-05-22 2009-07-01 Ucb Pharma Sa Therapeutic agents
WO2011050245A1 (en) 2009-10-23 2011-04-28 Yangbo Feng Bicyclic heteroaryls as kinase inhibitors
MX2012006994A (en) 2009-12-18 2012-07-03 Mitsubishi Tanabe Pharma Corp Novel anti-platelet agent.
EP2566333A4 (en) 2010-05-07 2014-04-02 Univ Leland Stanford Junior Identification of stabilizers of multimeric proteins
SG185675A1 (en) 2010-06-01 2012-12-28 Exxonmobil Res & Eng Co Hydroprocessing catalysts and their production
EP2585467B1 (en) 2010-06-24 2016-03-02 Gilead Sciences, Inc. Pyrazolo[1,5-a]pyrimidines and -triazines as antiviral agents
EP2402343A1 (en) 2010-06-29 2012-01-04 Basf Se Pyrazole-fused bicyclic compounds
EP2402345A1 (en) 2010-06-29 2012-01-04 Basf Se Pyrazole fused bicyclic compounds
EP2402344A1 (en) 2010-06-29 2012-01-04 Basf Se Pyrazole fused bicyclic compounds
EP2402337A1 (en) 2010-06-29 2012-01-04 Basf Se Pyrazolopyridine compounds
MX2013001970A (en) 2010-08-20 2013-08-09 Hutchison Medipharma Ltd Pyrrolopyrimidine compounds and uses thereof.
EP2665726A4 (en) 2011-01-21 2014-09-03 Gen Hospital Corp Compositions and methods for cardiovascular disease
WO2012149157A2 (en) * 2011-04-26 2012-11-01 Bioenergenix Heterocyclic compounds for the inhibition of pask
WO2012147890A1 (en) 2011-04-27 2012-11-01 持田製薬株式会社 Novel azole derivative
WO2012154610A1 (en) 2011-05-06 2012-11-15 Intellikine, Llc Reactive pi3k kinase inhibitors and uses thereof
EP2768834B1 (en) 2011-10-20 2016-04-27 Glaxosmithkline LLC Substituted bicyclic aza-heterocycles and analogues as sirtuin modulators
US9474779B2 (en) 2012-01-19 2016-10-25 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
JP6133907B2 (en) 2013-01-31 2017-05-24 三井化学アグロ株式会社 Fused ring pyrimidine compound and pest control agent containing the same
US9718816B2 (en) 2013-03-15 2017-08-01 Epizyme, Inc. 1-phenoxy-3-(alkylamino)-propan-2-ol derivatives as CARM1 inhibitors and uses thereof
EP3026051A4 (en) 2013-07-24 2017-03-08 Takeda Pharmaceutical Company Limited Heterocyclic compound
RU2016112568A (en) 2013-09-05 2017-10-06 Дженентек, Инк. ANTIPROLIFERATIVE COMPOUNDS
GB201403093D0 (en) 2014-02-21 2014-04-09 Cancer Rec Tech Ltd Therapeutic compounds and their use
JP6492101B2 (en) 2014-03-04 2019-03-27 シンジェンタ パーティシペーションズ アーゲー Biocidal bicyclic heterocyclic derivative
US10179111B2 (en) 2014-03-07 2019-01-15 University of Pittsburgh—of the Commonwealth System of Higher Education Treating soft tissue via controlled drug release
FR3022455B1 (en) 2014-06-20 2017-09-01 Oreal PROCESS FOR COLORING KERATIN FIBERS COMPRISING THE APPLICATION OF A PARTICULAR CYCLIC OXIDATION BASE (HETERO) IN THE ABSENCE OF OXIDANT AND IN A RICH BODY
FR3022454B1 (en) 2014-06-20 2017-10-06 Oreal METHOD FOR COLORING KERATINIC FIBERS COMPRISING THE APPLICATION OF A SELF-OXIDABLE COLORANT AND A PARTICULAR CYCLIC OXIDATION BASE (HETERO) IN THE ABSENCE OF OXIDIZER
WO2016044650A1 (en) 2014-09-17 2016-03-24 Epizyme, Inc. Carm1 inhibitors and uses thereof
JP2018076234A (en) 2015-03-16 2018-05-17 大正製薬株式会社 Pyrazolo[1,5-a]pyrimidine compound
US9796722B1 (en) 2015-10-15 2017-10-24 Indiana University Research And Technology Corporation Hepatitis B viral assembly effectors
WO2017210678A1 (en) 2016-06-03 2017-12-07 An2H Discovery Limited Pyrazolopyrimidine derivatives and the compositions and methods of treatment regarding the same
KR102411150B1 (en) 2016-08-31 2022-06-21 아지오스 파마슈티컬스 아이엔씨. inhibitors of cellular metabolic processes
WO2018039972A1 (en) 2016-08-31 2018-03-08 Agios Pharmaceuticals, Inc. Inhibitors of cellular metabolic processes
EP3449918A1 (en) 2017-09-01 2019-03-06 Technische Universität Dortmund Bmp-mimetics
CR20200114A (en) 2017-09-15 2020-06-01 Aduro Biotech Inc Pyrazolopyrimidinone compounds and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278793A (en) 1977-04-02 1981-07-14 Hoechst Aktiengesellschaft Cephem derivative
WO1998046576A2 (en) 1997-04-15 1998-10-22 Genentech, Inc. Halo-alkoxycarbonyl prodrugs
WO1999067634A1 (en) 1998-06-23 1999-12-29 The Regents Of The University Of California Method for early diagnosis of, and determination of prognosis in, cancer
US20120178915A1 (en) * 2009-09-23 2012-07-12 Lifeng Xu Pyrimidine derivatives and analogs, preparation method and use thereof
WO2012103457A2 (en) * 2011-01-28 2012-08-02 University Of Kentucky Stilbene analogs and methods of treating cancer

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CAIRNS ET AL., NAT. GEN., vol. 11, 1995, pages 210 - 212
DEAN, J. A.,: "Ixing's Handbook of Chemistry 13th ed.", 1985, article "Table 7-2"
K. MARJON ET AL., CELL REPORTS, vol. 15, 2016, pages 574 - 587
MARJON ET AL., CELL REPORTS, vol. 15, no. 3, 2016, pages 574 - 587
POMERANTZ ET AL., CELL, vol. 92, 1998, pages 713 - 723
T. LI, J. CANCER, vol. 7, no. 10, 2016, pages 1317 - 1327

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2019191470A1 (en) * 2018-03-30 2019-10-03 Agios Pharmaceuticals, Inc. Heterobicyclic inhibitors of mat2a and methods of use for treating cancer
JP2021519783A (en) * 2018-03-30 2021-08-12 アジオス ファーマシューティカルズ， インコーポレイテッド Complex bicyclic inhibitors of MAT2A and how to use them for the treatment of cancer
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US11046691B1 (en) 2018-12-10 2021-06-29 Ideaya Biosciences, Inc. 2-oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors
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US11130759B1 (en) 2018-12-10 2021-09-28 Ideaya Bioscience, Inc. 2-oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors
US11084798B1 (en) 2018-12-10 2021-08-10 Ideaya Biosciences, Inc. 2-oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors
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WO2020123395A1 (en) * 2018-12-10 2020-06-18 Ideaya Biosciences, Inc. 2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors
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WO2020139992A1 (en) * 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Aza-heterobicyclic inhibitors of mat2a and methods of use for treating cancer
WO2020139991A1 (en) * 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Aza-heterobicyclic inhibitors of mat2a and methods of use for treating cancer
WO2020167952A1 (en) * 2019-02-12 2020-08-20 Mirati Therapeutics, Inc. Mat2a inhibitors
CN113453687A (en) * 2019-02-13 2021-09-28 法国施维雅药厂 Combination therapy for the treatment of cancer
WO2020168032A1 (en) 2019-02-13 2020-08-20 Agios Pharmaceuticals, Inc. Combination therapies for use in treating cancer
WO2021023609A1 (en) 2019-08-02 2021-02-11 Glaxosmithkline Intellectual Property Development Limited Combination of a type i protein arginine methyltransferase (type i prmt) inhibitor and a methionine adenosyltransferase ii alpha (mat2a) inhibitor
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