EA042905B1 - INHIBITORS OF CELL METABOLIC PROCESSES - Google Patents

Description

The present invention relates to organic compounds that can be used for therapy and/or prevention in a mammal, and in particular to inhibitors of the enzyme methionine adenosyltransferase-2A (MAT2A), which can be used to treat certain types of cancer.

State of the art

Methionine adenosyltransferase (MAT), also known as S-adenosylmethionine synthetase, is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP and is considered a limiting factor in the methionine cycle. SAM is a donor of propylamines in the biosynthesis of polyamines and the main donor of methyl groups for DNA methylation, is involved in gene transcription and cell proliferation, as well as in the production of secondary metabolites.

Two genes, MAT1A and MAT2A, code for two different catalytic isoforms of MAT. The third gene, MAT2B, encodes the regulatory subunit of MAT2A. MAT1A is specifically expressed in the adult liver, while MAT2A is widely distributed. Since MAT isoforms differ in catalysis kinetics and regulatory properties, the SAM content in cells expressing MAT1A is significantly higher than in cells expressing MAT2A. MAT2A promoter hypomethylation and histone acetylation have been found to upregulate MAT2A expression.

In hepatocellular carcinoma (HCC), MAT1A is down-regulated and MAT2A is up-regulated, which is known as the MAT1A:MAT2A switch. The switch, accompanied by upregulation of MAT2B, leads to a decrease in SAM content, which allows better growth of hepatoma cells. Since MAT2A plays a critical role in accelerating the growth of hepatoma cells, it is a target for anticancer therapy. Recent studies have shown that silencing using a small interfering RNA significantly inhibits growth and induces apoptosis of hepatoma cells. See, for example, T. Li et al., J. Cancer, 7 (10) (2016), 1317-1327.

Marjon et al. (Cell Reports, 15 (3) (2016), 574-587) reported that MTAP-deficient cancer cell lines are particularly sensitive to MAT2A inhibition. MTAP (methylthioadenosine phosphorylase) is an enzyme widely expressed in normal tissues that catalyses the conversion of methylthioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Adenine is utilized to produce adenosine monophosphate, and 5-methylthioribose-1-phosphate is converted to methionine and formate. Through this pathway, MTA can serve as an alternative source of purine when de novo purine synthesis is blocked, for example, by antimetabolites such as L-alanosine.

Many human and mouse cancer cells lack MTAP activity. MTAP deficiency is not only found in tissue culture cells, but is also seen in primary leukemias, gliomas, melanomas, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcomas, ovarian cancer , endometrial cancer, breast cancer, soft tissue sarcomas, non-Hodgkin's lymphomas and mesothelioma. The gene encoding human MTAP is expressed in the 9p21 region on the human chromosome 9p. This region also contains the tumor suppressor genes pl6INK4A (also known as CDKN2A) and pl5INK4B. These genes encode p16 and p15, which are inhibitors of the cyclin D-dependent kinases cdk4 and cdk6, respectively.

Alternatively, the pl6INK4A transcript can be spliced using an alternate reading frame (ARF) to produce a transcript encoding pl4ARF. pl4ARF binds to MDM2 and prevents p53 degradation (Pomerantz et al. (1998) Cell, 92: 713-723). The 9p21 chromosomal region is of interest because it is often homozygously removed in a variety of cancers, including leukemias, HMPJI, pancreatic cancer, gliomas, melanomas, and mesotheliomas. These deletions often inactivate more than one gene. For example, Cairns et al. ((1995) Nat. Gen., 11: 210-212) reported that after studying over 500 primary tumors, almost all deletions identified in such tumors included a 170 kb region. containing MTAP, pl4ARF and Pl6INK4A. Carson et al. (WO 99/67634) reported that there is a correlation between tumor stage and loss of homozygosity of the gene encoding MTAP and the gene encoding p16. For example, deletion of the MTAP gene, but not pl6INK4A, has been reported to be indicative of cancer at an early stage of development, while deletion of the genes encoding p16 and MTAP is indicative of cancer at a later stage of tumor development. Garcia-Castellano et al. reported that in some patients with osteosarcoma, the MTAP gene was present at diagnosis but absent later (Garcia-Castellano et al., supra).

Brief description of the invention

For the above reasons, the present invention satisfies a strong need for safe and effective compounds and methods for the treatment, prevention and control of

- 1 042905 cancer with the reduction or absence of toxicity and/or side effects associated with conventional therapies. These cancers include cancers that are difficult to respond to conventional treatments such as surgery, radiation therapy, chemotherapy and hormone therapy.

In some embodiments, the present disclosure provides a compound of formula IA, or a pharmaceutically acceptable salt thereof.

In formula IA, RA 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-, 3-14-membered heterocycle or heterocyclo -C1C ₆ -alkyl- (wherein from 1 to 4 elements of the heterocyclic ring are heteroatoms selected from N, O and S), ( 3-14-membered heterocyclo)oxy-, C ₆ -C ₁₄ -aryl, (C ₆ -C ₁₄ -aryl) -C ₁ -C ₆ -alkyla-, C ₆ -C ₁₄ -aryloxy-, -(CH ₂ ) _0-6 NR ¹ (CH ₂ ) _0-6 C(O)R ² , -NR1R ² , -C(O)NR1R ² , NR1C(NR ² )NR1R ² , NR1C(NR2)(=NR1), SR ¹ , -CN and -OH. Each alkyl, alkenyl, alkoxy, aryl and heterocycle is optionally substituted with one or more substituents selected from the group consisting of R ¹ , OR ¹ , halogen, -N=N-R1, NR1R ² , -(C1-C6-alkyl)NR ¹ R ² , -C(O)OR1, -C(O)NR1R ² , -OC(O)R1, -CN, -OP(O)(OR1)1-2 and oxo.

R ^B is selected from the group consisting of H, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -alkyl, where R ^B is optionally substituted with one or more R ¹ .

R ^C , RD and R ^e are independently selected from the group consisting of C3-C14 carbocycle, C6-C14 aryl and 3-14 membered heterocycle (wherein 1 to 4 heterocyclic ring members are heteroatoms selected from N, O and S). R ^C , RD and R ^E are optionally substituted with one or more substituents selected from the group consisting of R ¹ , -OR ¹ , halo, -NR1R ² , -(C1-C ₆ -alkyl)-NR ¹ R ² , -C (O)OR1, -C(O)NR1R ² , -NO2, -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, NH2, 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 -C ₁₄ -aryl, 3-14-membered heterocycle or heterocyclo(C ₁ -C ₆ -alkyl)- (wherein from 1 to 4 elements of the heterocyclic ring are heteroatoms selected from N, O and S).

Each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclic, and heterocyclic moiety of R ¹ and R ² is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH2, -NHC(O)(OC ₁ -C ₆ -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)NH2, C ₁ -C ₆ -alkyl, -C(O)C ₁ -C ₆ -alkyl, -OC1C ₆ -alkyl, -Si(C ₁ -C ₆ -alkyl) ₃ , C ₆ -C ₁₄ -aryl, -(C ₁ -C ₆ -alkyl) (C ₆ -C ₁₄ -aryl), 3-14-membered heterocycle or heterocyclo(C ₁ -C ₆ -alkyl) - (where from 1 to 4 elements of the heterocyclic ring are heteroatoms selected from N, O and S) and -O(C ₆ -C ₁₄ -aryl).

In another embodiment, a pharmaceutical composition is provided comprising a compound of formula (IA), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another embodiment is a method of treating a disease or condition mediated by MAT2A overexpression in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof.

Yet another embodiment is a method of treating MTAP null cancer in a subject, comprising administering to said subject an effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present disclosure provides a method for inhibiting the synthesis of S-adenosylmethionine (SAM) from methionine and ATP by MAT2A in a cell, comprising contacting said cell with an effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt thereof.

Also in one embodiment, provided is a method of treating cancer in a subject suffering from it, wherein said cancer is characterized by decreased or absent expression of the methylthioadenosine phosphorylase (MTAP) gene, absence of the MTAP gene, or reduced function of the MTAP protein, said method comprising administering to said subject a therapeutically effective amount of a compound formula (IA) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides a compound of formula (IA), or a pharmaceutically acceptable salt thereof, for inhibiting the synthesis of S-adenosylmethionine (SAM) from methionine and ATP by MAT2A in a cell.

In yet another embodiment, a compound of formula (IA), or a pharmaceutically acceptable salt thereof, is provided for the treatment of a disease or condition in a subject suffering from it, said disease or condition being mediated by overexpression of MAT2A.

- 2 042905

In yet another embodiment, a compound of formula (IA) or a pharmaceutically acceptable salt thereof is provided for the treatment of cancer in a subject suffering from cancer, said cancer being characterized by reduced or absent expression of the methylthioadenosine phosphorylase (MTAP) gene, the absence of the MTAP gene, or reduced function of the MTAP protein.

Detailed description of the invention

Acyl means a carbonyl-containing substituent represented by the formula -C(O)-R, where R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, said alkyl, alkoxy, carbocycle, and heterocycle being as defined herein. . Acyl groups include alkanoyl (eg acetyl), aroyl (eg benzoyl) and heteroaroyl.

Alkyl means a branched or unbranched saturated or unsaturated (i.e., alkenyl, alkynyl) aliphatic hydrocarbon group, in one embodiment, containing no more than 12 carbon atoms, unless otherwise indicated, such as C ₁ -C ₆ -alkyl. When used as part of another term, such as alkylamino, the alkyl moiety may be a saturated hydrocarbon chain, but also includes unsaturated hydrocarbon chains such as alkenylamino and alkynylamino. Examples of specific alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-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, C _{1 -C} 4 -alkyl and alkyl containing from 1 to 4 carbon atoms are synonymous and are used interchangeably to refer to methyl, ethyl, 1-propyl, isopropyl, cyclopropyl, 1-butyl, sec-butyl or tert-butyl . Unless otherwise indicated, substituted alkyl groups may contain one, for example two, three or four substituents, which may be the same or different and are selected, unless otherwise indicated, from halo (F, Cl, Br, I), hydroxy, protected hydroxy , cyano, nitro, alkoxy (e.g., C ₁ -C 6 alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulfonylaminoalkyl, heterocyclylsulfonylamino , heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl or other specified groups.

Amino means primary (i.e. -NH2), secondary (i.e. -NRH), and tertiary (i.e. -NRR) amines, where R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl . Specific secondary and tertiary amines are alkylamine, dialkylamine, arylamine, diarylamine, aralkylamine and diarylkylamine, said alkyl being as defined herein and optionally substituted. Specific secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine, dimethylamine, diethylamine, dipropylamine and diisopropylamine.

Aryl, when used alone or as part of another term, means a carbocyclic aromatic group, whether or not fused, containing the specified number of carbon atoms or, if the number is not specified, not more than 14 carbon atoms, such as C ₆ -C ₁₄ -aryl . Specific aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like. (See, for example, Lang's Handbook of Chemistry (Dean, JA, ed), 13th ed., pl. 7-2 [1985]). Specific aryl is phenyl. Substituted phenyl or substituted aryl means a phenyl group or an aryl group substituted with one, two, three, four or five substituents, for example 1-2, 1-3 or 1-4 substituents selected, unless otherwise indicated, from halo (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (for example, C ₁ -C6 alkyl), alkoxy (for example, C ₁ -C6 alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulfonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl or other specified groups. One or more methane (CH) and/or methylene (CH2) groups in said substituents may, in turn, be substituted with a group similar to those mentioned above. Examples of the term substituted phenyl include, but are 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-chloro4-fluorophenyl, 2-fluorophenyl, and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, derivatives thereof containing a protected hydroxy group, 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-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like .; a mono- or di(alkoxy)phenyl group, e.g. tert-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 4-carboxyphenyl; mono or

- 3 042905 di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or mono- or du(N(methylsulfonylamino))phenyl, such as 3-(M-(methylsulfonylamino))phenyl. In addition, the term substituted phenyl means disubstituted phenyl groups where the substituents are different, for example 3-methyl-4hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 4-nitrophenyl, 2-hydroxy-4-chlorophenyl, etc., as well as trisubstituted phenyl groups, where the substituents are different, for example, 3-methoxy-4-benzyloxy-6-methylsulfonylamino, 3-methoxy-4-benzyloxy-6-phenylsulfonylamino, and tetrasubstituted phenyl groups where the substituents are different, such as 3-methoxy-4-benzyloxy-5-methyl-6-phenylsulfonylamino. Specific substituted phenyl groups include 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3,4diethoxyphenyl, 3-methoxy-4 -benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-6-methylsulfonylaminophenyl groups. Fused aryl rings may also be substituted with any number of substituents as defined herein, such as 1, 2, or 3 substituents, in the same manner as substituted alkyl groups.

Carbocyclyl, carbocyclyl, 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 containing 3 to 14 carbon atoms, such as 3 to 7 carbon atoms, which may be saturated, unsaturated, partially unsaturated, aromatic (aryl) or non-aromatic containing the indicated number of atoms, typically from 5 to about 14 ring atoms. Specific 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 groups, such as aryl groups, as previously defined, such as phenyl. Particular partially unsaturated carbocyclic groups are cyclobutene, cyclopentene, cyclohexene and cycloheptene. The terms substituted carbocyclyl, substituted carbocycle, and substituted carbocyclo mean these groups substituted with the same substituents as a substituted alkyl group, unless otherwise indicated.

The terms heterocyclic, 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 a non-aromatic ring containing the specified number of atoms, typically 5 to about 14 ring atoms, where said ring atoms are carbon and at least one heteroatom (nitrogen, sulfur or oxygen), such as 1 to 4 heteroatoms. Typically, a 5-membered ring contains 0 to 2 double bonds, and a 6- or 7-membered ring contains 0 to 3 double bonds, and nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., SO, SO ₂ ), and any nitrogen heteroatom may optionally be quaternized. Specific 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 piperidinil. A heterocycloalkyl group is a heterocyclic 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 such as 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. Specific benzo-fused 5-membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Particular 6-membered heterocycles contain from one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example, they are 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. A specific group are pyridine N-oxides and pyridazine N-oxides and pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and 1,3,4-triazin-2-yl groups. Substituents for optionally substituted heterocycles and additional examples of the 5- and 6-membered ring systems described above can be found in U.S. Patent No. 4,278,793 to W. Druckheimer et al. alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halogenated alkyl, amino,

- 4 042905 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 containing the indicated number of atoms, where at least one ring is 5-, 6-, or A 7-membered ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and in a particular embodiment, at least one heteroatom is nitrogen (Lang's Handbook of Chemistry, supra). This definition includes any bicyclic groups wherein any of the above heteroaryl rings are fused to a benzene ring. Particular heteroaryls contain a heteroatom representing nitrogen or oxygen. Examples of heteroaryl groups (whether substituted or unsubstituted) referred to by the term heteroaryl are the following ring systems: 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, fused tetrazolo[1,5b]pyridazinyl derivatives and purinyl, , for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl and indolyl. A specific heteroaryl is 1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3- sodium salt thiazol-2-yl, 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, sodium salt of 2-carboxy4-methyl-1,3,4-triazol-5-yl, 2- carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol5-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, 1 H-tetrazol-5 -yl, 1 -methyl-1 H-tetrazol-5 -yl, 1-(1 -(dimethylamino)eth-2-yl)-1 H-tetrazol5-yl, 1-(carboxymethyl)-1H-tetrazol-5- yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 2-methyl-1Htetrazol-5-yl, 1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazole -5-yl, 2-methyl-1,2,3-triazol-5-yl, 4-methyl-1,2,3triazol-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-methylasim-triazin-3-yl, 1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-asim-triazin-3-yl, 2,5-dihydro-5oxo-6-hydroxy-asim-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-asim-triazin-3-yl, 2,5- dihydro5-oxo-6-methoxy-2-methyl-asim-triazin-3-yl, 2,5-dihydro-5-oxo-asim-triazin-3-yl, 2,5-dihydro-5oxo-2-methyl- asim-triazin-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-asim-triazin-3-yl, tetrazolo[1,5b]pyridazin-6-yl and 8-aminotetrazolo[1, 5-b]-pyridazin-6-yl. An alternative heteroaryl group includes 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4triazol- 5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5yl, 1-(carboxymethyl) -1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1,2,3-triazol5-yl, 1,4,5,6-tetrahydro-5,6-dioxo- 4-methyl-asim-triazin-3-yl, 1,4,5,6-tetrahydro-4-(2-formylmethyl)5,6-dioxo-asim-triazin-3-yl, 2,5-dihydro-5 -oxo-6-hydroxy-2-methyl-asym-triazin-3-yl, tetrazolo[1,5b]pyridazin-6-yl and 8-aminotetrazolo[1,5-b]pyridazin-6-yl. Heteroaryl groups are optionally substituted as described for heterocycles.

An inhibitor means a compound that prevents or reduces the amount of S-adenosylmethionine (SAM) synthesis from methionine and ATP by MAT2A. In one embodiment, the inhibitor binds to MAT2A.

Optionally substituted, unless otherwise indicated, means that the group may be unsubstituted or substituted with one or more (eg, 2, 3 or 4) substituents listed for the specified group, where these substituents may be the same or different. In one embodiment, the optionally substituted group contains 1 substituent. In another embodiment, the optionally substituted group contains 2 substituents. In another embodiment, the optionally substituted group has 3 substituents.

Pharmaceutically acceptable salts include both acid and base addition salts. In one embodiment, the compounds of the present disclosure are in the form of a pharmaceutically acceptable salt. The term pharmaceutically acceptable acid addition salt refers to salts that retain the biological efficacy and properties of free bases and are not biologically or otherwise undesirable, prepared using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids which may be selected from organic acids of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamon

- 5 042905 acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts include salts derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In particular, base addition salts are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include 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, 2diethylaminoethanol, trimetamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. In particular, organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimetamine, dicyclohexylamine, choline and caffeine. In one embodiment, a compound as described herein is a salt. In one embodiment, the implementation of the connection according to the present description is a pharmaceutically acceptable salt. In one embodiment, a compound as described herein is an acetate. In one embodiment, a compound as described herein is a benzoate salt. In one embodiment, a compound as described herein is a besylate salt. In one embodiment, the implementation of the connection according to the present description is a bitartrate salt. In one embodiment, the implementation of the connection according to the present description is a bromide salt. In one embodiment, the implementation of the connection according to the present description is a carbonate salt. In one embodiment, the implementation of the connection according to the present description is a chloride salt. In one embodiment, the implementation of the connection according to the present description is a citrate salt. In one embodiment, the implementation of the connection according to the present description is an edetate salt. In one embodiment, a compound as described herein is an edisylate salt. In one embodiment, a compound as described herein is an estolate salt. In one embodiment, a compound as described herein is a fumarate salt. In one embodiment, a compound as described herein is a gluceptate salt. In one embodiment, the implementation of the connection according to the present description is a gluconate salt. In one embodiment, the implementation of the connection according to the present description is a hydrobromide salt. In one embodiment, the implementation of the connection according to the present description is a hydrochloride salt. In one embodiment, the implementation of the connection according to the present description is an iodide salt. In one embodiment, the implementation of the connection according to the present description is a lactate salt. In one embodiment, a compound as described herein is a lactobionate salt. In one embodiment, the implementation of the connection according to the present description is a malate salt. In one embodiment, the implementation of the connection according to the present description is a maleate salt. In one embodiment, a compound as described herein is a mandelate salt. In one embodiment, a compound as described herein is a mesylate salt. In one embodiment, a compound as described herein is a methyl bromide salt.

In one embodiment, the implementation of the connection according to the present description is a methyl sulfate salt. In one embodiment, a compound as described herein is a napsilate salt. In one embodiment, the implementation of the connection according to the present description is a nitrate salt. In one embodiment, a compound according to the present disclosure is a pamoate salt. In one embodiment, a compound as described herein is a phosphate salt. In one embodiment, the implementation of the connection according to the present description is a disphosphate salt. In one embodiment, the implementation of the connection according to the present description is a salicylate salt. In one embodiment, a compound as described herein is a disalicylate salt. In one embodiment, the implementation of the connection according to the present description is a stearate salt. In one embodiment, the implementation of the connection according to the present description is a succinate salt. In one embodiment, the implementation of the connection according to the present description is a sulfate salt. In one embodiment, the implementation of the connection according to the present description is a tartrate salt. In one embodiment, a compound as described herein is a tosylate salt. In one embodiment, a compound as described herein is a triethiodide salt. In one embodiment, the implementation of the connection according to the present description is a valerate salt. In one embodiment, a compound as described herein is an aluminum salt. In one embodiment, the connection

- 6 042905 but the present description is a benzathine salt. In one embodiment, the implementation of the connection according to the present description is a calcium salt. In one embodiment, a compound as described herein is an ethylenediamine salt. In one embodiment, the implementation of the connection according to the present description is a lysine salt. In one embodiment, the implementation of the connection according to the present description is a magnesium salt. In one embodiment, a compound as described herein is a meglumine salt. In one embodiment, the implementation of the connection according to the present description is a potassium salt. In one embodiment, the implementation of the connection according to the present description is a procaine salt. In one embodiment, the implementation of the connection according to the present description is a sodium salt. In one embodiment, a compound as described herein is a tromethamine salt. In one embodiment, the implementation of the connection according to the present description is a zinc salt.

Compounds according to the present description may exist in various tautomeric forms. In one embodiment, said compounds are in the form shown or named. In another embodiment, said compounds are in a tautomeric form other than that depicted or named. Compounds according to the present description may exist in the form of a single form or a mixture of salts and solvate forms. For example, a compound as described herein may be substantially pure and present in one particular salt or solvate form, or may be mixtures of two or more salt or solvate forms. In one embodiment, said compounds are in solvate form. In a specific embodiment, these compounds exist as hydrates.

Connections.

As generally described above, the present specification provides compounds and pharmaceutically acceptable salts thereof, said compounds having formula (IA)

In formula IA, RA 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-, 3-14-membered heterocycle or heterocyclo(C ₁ C ₆ -alkyl)- (wherein from 1 to 4 elements of the heterocyclic ring are heteroatoms selected from N, O and S ), (3-14-membered heterocyclo)oxy-, C ₆ -C ₁₄ -aryl, (C ₆ -C ₁₄ -aryl) -C ₁ -C ₆ -alkyla-, C6-C14-aryloxy-, -(C ^o^NR^C^o^C^R ² , NR1R ² , C(O)NR1R ² , NR1C(NR ² )NR1R ² , NR ¹ C(NR ² )(=NR ¹ ), SR ¹ , -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 R ¹ , OR ¹ , halogen, -N=N-R1, NR ^X R ² , -( C1-C6-alkyl)NR ¹ R ² , -C(O)OR ¹ , -C(O)NR1R ² , -OC(O)R ¹ , -CN, -OP(O)(OR ¹ )i.2 and oxo.

R ^B is selected from the group consisting of H, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -alkyl, while R ^B is optionally substituted with one or more R ¹ .

R ^C , RD and R ^e are independently selected from the group consisting of C3-C14 carbocycle, C6-C14 aryl and 3-14 membered heterocycle (wherein 1 to 4 heterocyclic ring members are heteroatoms selected from N, O and S). R ^C , RD and R ^E are optionally substituted with one or more substituents independently selected from the group consisting of R ¹ , -OR ¹ , halo, -NR1R ² , -(C1-C ₆ -alkyl)-NR ¹ R ² , - C(O)OR1, -C(O)NR1R ² , -NO2, -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 -alkynylα, -S(O) ₀ . ₂ -(C ₁ -C ₆ -alkyl), -S(O) ₀ . ₂ -(C ₆ -C ₁₄ -aryl), -C (O) (C1C ₆ -alkyl), -C (O) (C ₃ -C ₁₄ -carbocyclo), -C ₃ -C ₁₄ -carbocycle, C ₆ -C ₁₄ -aryl, 3-14-membered heterocycle or heterocyclo(C ₁ -C ₆ -alkyl)- (wherein from 1 to 4 elements of the heterocyclic ring 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(C1-C6-alkyl), -C1-C6-alkyl(C1-C6-alkoxy), -C(O)NH2, C1-C6-alkyl, -C(O )C1-C6-alkyl, -OC1C6-alkyl, -Si(C1-C6-alkyl)3, C6-C14-aryl, -(C1-C6-alkyl)(C6-C14-aryl), 3-14-membered heterocycle or heterocyclo(C1-C6-alkyl)- (wherein from 1 to 4 heterocyclic ring members are heteroatoms selected from N, O and S) and -O(C6-C14-aryl). Each alkyl, aryl and heterocyclo in R ¹ and R ² is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, -OC1-C ₆ -alkyl, halogen, -NH2, -(C ₁ -C ₆ -alkyl )NH ₂ , -C(O)OH, CN and oxo.

In some embodiments of compounds of formula IA, RD and R ^E are independently selected from C3-C14 carbocycle, C6-C14 aryl, and 3-14 membered heterocycle (wherein 1 to 4 heterocyclic ring members are heteroatoms selected from N, O, and S ). More specifically, RD and R ^E are independently selected from C3-C ₁₄ carbocycle and C ₆ -C ₁₄ aryl or C ₅ -C ₇ carbocycle and C ₆ -C ₁₀ aryl. In illustrative

- 7 042905 embodiments ^RD and R ^E are independently selected from cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and phenyl. For example, one of ^RD and R ^E is cyclohexyl or cyclohexenyl and the other is phenyl.

In other embodiments, optionally in combination with any other embodiment described herein, R ^A is selected from the group consisting of 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-, 3-14-membered heterocycle or heterocyclo(C ₁ -C ₆ -alkyl)- (where from 1 to The 4 elements of the heterocyclic ring 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)o.6NR ¹ (CH2)o.6C(0)R ² , NR1R ² , NR1C(NR ² )NR1R ² , -CN and -OH. Substituents R ¹ and R ² have the meanings described herein above for formula IA.

In various other embodiments, a compound of formula IA is provided wherein R ^A 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)R ² (where R ² is NH2, C1- C6-alkyl optionally substituted with one or more substituents independently selected from halo, hydroxy- _C1 - _C6 -alkyl-, 3-14-membered heterocycle optionally substituted with one or more of C1- _C6 -alkyl and oxo, and C ₃ -C ₁₄ carbocycle), -NHR ² (wherein R ² is a 3-14 membered heterocycle optionally substituted with one or more substituents independently selected from the group consisting of R ¹ , OR ¹ , halogen, -N= N-R1, NR1R ² , -(C1-C6-alkyl)NR ¹ R ² , -C(O)OR1, -OC(O)R1, -CN, -OP(O)(OR ¹ )1.2 and oxo) , -C(O)NR1R ² (wherein R ¹ and R ² independently represent H, C1-C ₆ -alkyl, hydroxy-C1-C ₆ -alkyl-, 3-14-membered heterocyclo-C1-C ₆ -alkyl -, C ₆ -C ₁₄ -aryloxy- or (3-14-membered heterocyclo)oxy-).

In some embodiments, R ^A is selected from the group consisting of C1-C6 alkyl, -(CH2)0.6NR1(CH2)0.6C(O)R ² , NR1R ² , and NR ¹ C(NR2)NR ¹ R ² . For example, R ^A may be C1-C ₆ alkyl or NR1R ² . In exemplary embodiments, R ^A is NR1R ² . Certain compounds of formula IA according to various embodiments contain R ^A as a secondary amino group, i. e. R ^A is NR1R ² where R ¹ is H and R ² is as defined herein above.

In various embodiments, some compounds of formula IA correspond to formula IB

R ¹ n _r d

IK^R ^E (IB)

ABOUT .

In various embodiments, in compounds of formula IB and their pharmaceutically acceptable salts, RC is a C ₃ -C ₁₄ carbocycle or a 3-14 membered heterocycle (wherein from 1 to 4 heterocyclic 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, halo, -NH2, C ₆ -C ₁₄ -aryl, (C ₆ -C ₁₄ -aryl) -C ₁ -C ₆ -alkyl-, carboxy, -CN, oxo, C1- _C6 alkyl, C1- _C6 alkoxy and -NH( _C1 - _C6 alkyl). Said C1- _C6 alkyl, C1- _C6 alkoxy and NH( _C1 - _C6 alkyl) are independently and optionally substituted with one or more of hydroxy, halo, -NH2, carboxy, -CN and oxo.

The substituents ^RD and R ^E are independently a C3-C14 carbocycle or a 3-14 membered heterocycle (wherein 1 to 4 heterocyclic ring members are heteroatoms selected from N, O and S). ^RD and R ^E are optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, -NH2, C6- _C14 -aryl, ( _C6 - _C14 -aryl)-C1- _C6 -alkyl-, carboxy, -CN, oxo, C1- _C6 alkyl, C1- _C6 alkoxy and -NH( _C1 - _C6 alkyl). Said C1- _C6 alkyl, C1- _C6 alkoxy and NH(C1- _C6 alkyl) are independently and optionally substituted with one or more of hydroxy, halo, -NH ₂ , carboxy, -CN and oxo.

The substituent R ¹ is selected from the group consisting of H, C1-C6 alkyl, C3-C14 carbocycle and 3-14 membered heterocycle (wherein from 1 to 4 heterocyclic ring elements 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, -NH2, -NO2, -CN, oxo, carboxy, -C(O)OC1-C ₆ -alkyl, (C ₁ -C ₆ -alkyl) OS ₁ C ₆ -alkyl-, -C (O) NH ₂ , C 1-C ₆ -alkyl, -C (O) H, C 1-C ₆ -alkoxy, (C ₁ -C ₆ -alkyl) N (H)-aryl-, (C ₆ -C ₁₄ -aryl) C1C ₆ -alkyl-, 5-7-membered heteroaryl, (5-7-membered heteroaryl) -C1-C ₆ -alkyl-, C ₆ -C ₁₄ -aryloxy, (C ₆ -C ₁₄ aryl) (C1-C ₆ -alkoxy) -, (5-7-membered heteroaryl) oxy- and (5-7-membered heteroaryl) (C1-C ₆ -alkoxy) - . The indicated C1-C ₆ -alkyl, C1-C ₆ -alkoxy, (C ₁ -C ₆ -alkyl) N (H) -, -C (O) OC 1 -C ₆ -alkyl, (C ₁ -C ₆ -alkyl )OC ₁ -C ₆ -alkyl-, -C (O)NH ₂ , C ₆ -C ₁₄ -aryl, (C ₆ -C ₁₄ -aryl) C1-C ₆ -alkyl-, 5-7-membered heteroaryl, (5-7-membered heteroaryl) -C1C ₆ -alkyl-, C ₆ -C ₁₄ -aryloxy, (C ₆ -C ₁₄ -aryl) (C1-C ₆ -alkoxy) -, (5-7-membered heteroaryl) hydroxy- and (5-7-membered heteroaryl)(C1- _C6 -alkoxy)- optionally substituted with one or more of hydroxy, halo, -NH2, ( _C1 - _C6 -alkyl)N(H)-, -COOH , -CN and oxo. In addition, each heteroaryl in R ¹ contains 1 to 4 heteroaryl ring elements which are heteroatoms selected from N, O and S.

In various embodiments, in certain compounds of formula IB, R ^D is a C ₃ -C ₁₄ carbocycle optionally substituted with one or more members of the group consisting of

- 8 042905 hydroxy, halogen, -NH2, -C(O)OH, -CN, oxo, alkyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and (C ₁ -C ₆ -alkyl)N (H)-.

Said C1-C6-alkyl, C1-C6-alkoxy and (C1 _- C6-alkyl)N(H)- are optionally substituted with one or more of hydroxy, halo, _-NH2 , -C(O)OH, -CN and oxo.

In some embodiments, compounds of formula IB are provided wherein ^RD is phenyl. In other embodiments, ^RD is cyclohex-1-en-1-yl.

In other embodiments, in other compounds of formula IB, R ^E is a C3-C ₁ 4-carbocycle optionally substituted with one or more members of the group consisting of hydroxy, halo, -NH2, -C(O)OH, -CN, oxo, alkyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and (C ₁ -C ₆ -alkyl)N(H)-. Said C ₁ -C6 alkyl, C ₁ -C6 alkoxy and (C ₁ -C6 alkyl)N(H)- are optionally substituted with one or more of hydroxy, halo, -NH2, -C(O)OH, -CN and oxo.

Specific examples of R ^E include, but are not limited to, an element selected from the group consisting of cyclohex-1-en-1-yl, ( ² H ₉ ) cyclohex-1-en-1-yl, cyclohexan-1,3- dien-1-yl, 4,4-difluorocyclohex-1-en-1-yl, cyclopent-1-en-1-yl, 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-1yl, 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.

For example, in some compounds of formula IB, R ^E is phenyl. Optionally, in combination with said embodiment, ^RD is cyclohex-1-en-1-yl.

In another embodiment, R ^D or R ^E is phenyl optionally substituted, for example, with one or more halo, amino, hydroxy, and alkoxy groups. For example, R ^D or R ^e 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.

In other embodiments of formula IB, ^RC is a C ₃ -C ₁₄ carbocycle or a 3-14 membered heterocycle (wherein 1 to 4 heterocyclic ring members are heteroatoms selected from N, O, and S) which optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -NH ₂ , -C(O)OH, -CN, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and ( C ₁ -C ₆ -alkyl)N(H)-. Said C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and (C ₁ -C ₆ -alkyl)N(H)- are optionally substituted with hydroxy, halogen, -NH2, -C(O)OH, -CN and oxo.

In various embodiments, ^RD is a carbocycle or a heterocycle, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, 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. Said carbocycle is optionally substituted with one or more elements 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 another embodiment, said saturated or partially unsaturated carbocycle is substituted with one or more halogens, such as one or two Fs. More specific examples of ^RD include optionally substituted cyclohex-1-enyl and a saturated or partially unsaturated ring that is deuterated. In a particular embodiment, said ring is fully deuterated. Illustrative examples of R ^D include cyclohex-1-en-1-yl (E), ( ² H9) cyclohex-1-en-1-yl, cyclohexa-E,Z-1,3-dien-1-yl, 4, 4-difluorocyclohex-1-en-1-yl, cyclopent-E1-en-1-yl and cyclopentyl.

In some embodiments, ^RD is a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, NH2, carboxy, CN, oxo, alkyl, alkoxy, and alkylamino, wherein said alkyl, alkoxy, and alkylamino are optionally substituted hydroxy, halogen, NH2, carboxy, CN and oxo. For example, said heterocycle is aromatic, i. is heteroaryl. Examples include pyridyl such as pyridin-3yl or pyridin-2-yl. Other examples include pyrazolyl, 4-methoxypyridin-3-yl, 1H-pyrazol-4-yl, N-pyrrol-3-yl, 4,4-difluoropiperidin-1-yl, 5,6-dihydro-2H-pyran-3 -yl (Z), 3,6-dihydro2H-pyran-4-yl, N-pyrrol-3-yl, N-pyrrol-1-yl, tetrahydrofuran-3-yl, 3,3-difluoropyrrolidin-1-yl and 3,6-dihydro-2H-pyran-4-yl.

In other embodiments, ^RD is a non-aromatic heterocycle that is optionally substituted with one or more halogens or alkoxy. For example, said halogen is one or two F.

In other embodiments, ^RD is a deuterated heterocycle. In one embodiment, said heterocycle is fully deuterated. In a particular embodiment, ^RD is piperidin-1-yl, such as ( ² H ₁ o)piperidin-1-yl.

In various embodiments, R ^E is a carbocycle or a heterocycle, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, 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. In a particular embodiment, ^RE is phenyl, such as 2-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-aminophenyl, and 4-hydroxyphenyl. In one embodiment, ^RE is a saturated or partially unsaturated carbocycle that is optionally substituted with one or more elements from the group consisting of hydroxy, halo, NH2, carboxy, CN, oxo, alkyl, alkoxy, and alkylamino, wherein said alkyl, alkoxy, and alkylamino is optionally substituted with hydroxy, halogen, NH ₂ , carboxy, CN or oxo. In some embodiments, said saturated or partially unsaturated carbocycle is substituted with one or more halogens, such as one or two Fs. For example, R ^e is an optionally substituted cyclohex-1-enyl, or is a saturated or partially unsaturated ring that is partially or completely deuterated. Illustrative examples of R ^E include cyclohex-1-en-1-yl (E), ( ² H9) cyclohex-1-en-1-yl, cyclohexaE,Z-1,3-dien-1-yl, 4,4- difluorocyclohex-1-en-1-yl, cyclopent-E1-en-1-yl and cyclopentyl.

In other embodiments, R ^E is a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, NH2, carboxy, CN, oxo, alkyl, alkoxy, and alkylamino, wherein said alkyl, alkoxy, and alkylamino are optionally substituted hydroxy, halogen, NH ₂ , carboxy, CN and oxo. In one embodiment, said heterocycle is aromatic, i. is heteroaryl, including pyridyl, such as pyridin-3-yl and pyridin-2-yl. In some embodiments, said heteroaryl is pyrazole, 4-methoxypyridin-3-yl, 1H-pyrazol-4-yl, or N-pyrrol-3-yl.

In one embodiment, R ^E is a non-aromatic heterocycle that is optionally substituted with one or more halogens or alkoxy. For example, in one embodiment where R ^E is substituted with halogen, said halogen is one or two Fs. In other embodiments, said heterocycle is deuterated, eg fully deuterated. Illustrative examples of R ^E include piperidin-1-yl, ( ² H ₁ o)piperidin-1-yl, 4,4-difluoropiperidin-1yl, 5,6-dihydro-2H-pyran-3-yl (Z), 3, 6-dihydro-2H-pyran-4-yl, N-pyrrol-3-yl, N-pyrrol-1-yl, tetrahydrofuran-3-yl, 3,3-difluoropyrrolidin-1-yl and 3,6-dihydro- 2H-pyran-4-yl.

In other embodiments, RD and R ^E are the same and as defined herein. In one embodiment, Ring A and Ring B are phenyl. In one embodiment, ring A and ring B are different and are as defined herein. In one 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 N-pyrrol-3yl. In one embodiment, Ring B is phenyl and Ring A is selected from the group consisting of 2-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, piperidin-1-yl, ( ^2H1o )piperidin-1-yl, 4, 4-difluoropiperidin-1-yl, cyclohex-1-en-1-yl (E), ( ² H9) cyclohex-1-en-1-yl, cyclohexa-E,Z-1,3dien-1-yl, 4 ,4-difluorocyclohex-1-en-1-yl, 5,6-dihydro-2H-pyran-3-yl (Z), 3,6-dihydro-2H-pyran-4yl, cyclopentyl, cyclopent-E1-en- 1-yl, 1H-pyrrol-3-yl, 1H-pyrrol-1-yl, tetrahydrofuran-3-yl and 3,3-difluoropyrrolidin-1-yl.

In various embodiments, ^RE is phenyl and RD is cyclohex1-en-1-yl (E). In other embodiments, other R ^E /RD combinations are contemplated, such as phenyl/2fluorophenyl, 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/( ² H9)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-3yl (Z), phenyl/3,6- dihydro-2H-pyran-4-yl, phenyl/cyclopentyl, phenyl/cyclopent-E1-en-1-yl, phenyl/Spyrrol-3-yl, phenyl/III-pyrrol-1-yl, phenyl/tetrahydrofuran-3- yl, phenyl/3,3-difluoropyrrolidin-1-yl and pyridin-2-yl/phenyl.

As described more generally above, in various embodiments, ^RC is a carbocycle or heterocycle, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, amino, carboxy, CN, oxo, alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle or heterocycle wherein said alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, NH2, carboxy, CN, oxo, carbocycle or a heterocycle, wherein said carbocycle and heterocycle are optionally substituted with one or more OH, oxo, amino, halogens and haloalkyls. In other embodiments, ^RC is a carbocycle or heterocycle, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, 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. Alternatively, ^RC is a carbocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, amino, carboxy, CN, oxo, phosphate, sulfate, alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle or heterocycle, wherein said alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, NH2,

- 10 042905 carboxy, CN, oxo, phosphate, sulfate, carbocycle or heterocycle, said carbocycle and heterocycle being optionally substituted with one or more OH, oxo, amino, halogens and haloalkyls. For example, said optionally substituted carbocycle is aromatic, i. is aryl optionally substituted with one or more substituents selected from the group consisting of OH, amino, halogen, alkyl, alkoxy and cycloalkoxy, wherein said alkyl, alkoxy, cycloalkoxy are optionally substituted with one or more OH, halogens, amino, oxo, carbocycles or heterocycles, wherein said carbocycle and heterocycle are optionally substituted with one or more hydroxy, halogen, oxo, alkyl and haloalkyl. In one embodiment, said 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.

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-4methoxyphenyl , 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, no. R ⁿ

ABOUT'

In other embodiments, ^RC is a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, amino, carboxyl, CN, oxo, phosphate, sulfate, alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy , cycloalkoxy, carbocycle, or heterocycle, wherein said alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle, and heterocycle are optionally substituted with one or more hydroxy, halogens, NH2, carboxy, CN, oxo, phosphates, sulfates, carbocycles, or heterocycles , wherein said carbocycle and heterocycle are optionally substituted with OH, oxo, amino, halogen and haloalkyl. For example, said heterocycle is aromatic, such as heteroaryl, optionally substituted with one or more substituents selected from the group consisting of OH, amino, halo, alkyl, alkoxy, and cycloalkoxy, wherein said alkyl, alkoxy, and cycloalkoxy are optionally substituted with one or more OH, halogens, amino, oxo, carbocycles or heterocycles, said carbocycle and heterocycle being 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 said alkyl is optionally substituted with OH, amino, oxo, alkoxy, heterocycle, optionally substituted oxo, and wherein said cycloalkoxy is optionally substituted with OH. Specific examples of ^RC include 6methoxypyridin-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-2methylquinolin-6-yl, 2-aminoquinazolin-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.

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-6yl, 2-hydroxymethylquinolin-6-yl, 3-hydroxy-2-methylquinolin-6-yl, 2-aminoquinazolin-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-methoxyquinoxalin6-yl, 1,8-naphthyridin-3- silt, imidazo[1,2-a]niridin-6-yl,

- 11 042905

illustrative compounds of formula IB provide R ^C in the form

As an alternative to 4-methoxyphenyl.

In various embodiments, R ¹ is H or alkyl, carbocycle, or heterocycle, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, NH2, NO2, carboxy, alkoxycarbonyl, alkoxyalkyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy and alkylamino, wherein said alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkoxyalkyl and alkylaminocarbonyl are optionally substituted with hydroxy, halogen, amino, alkylamino, carboxy, CN and oxo. In one embodiment, R1 is alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, NH2, NO2, carboxy, alkoxycarbonyl, alkylaminocarbonyl, CN, oxo, alkyl, acyl, alkoxy, and alkylamino, where said alkyl, alkoxy, alkylamino, alkoxycarbonyl, alkylaminocarbonyl are optionally substituted with hydroxy, halogen, NH ₂ , alkylamino, carboxy, CN and oxo. In another embodiment, R1 is alkyl substituted with OH and oxo. In various other embodiments, R1 is hydroxyethanoyl; 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, NH ₂ , alkylamino, carboxy, CN, and oxo; or a heterocycle optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, 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 some embodiments, said 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-triazin3-yl. In one embodiment, R1 is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, or 1,2,4-triazinyl, each optionally substituted with one or more F, Cl, CN, OH, NO2, NH2, NHMe, -C(O)NH ₂ and methoxy. In one embodiment, said substituent is F, Cl, CN, or OH. In another embodiment, said optionally substituted heterocycle is pyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, 1,3, 5-triazin-2-yl or 1,2,4-triazin-3-yl, each optionally substituted with one or more F, Cl, CN, OH, NO2, NH2, NHMe, -C(O)NH2 and methoxy . In one embodiment, said substituent is F, Cl, CN, or OH.

In various embodiments, optionally in combination with any of the other embodiments described herein, provided herein are compounds of formula IB wherein R ¹ is selected from a 3-14 membered heterocycle optionally substituted with one or more substituents selected from a group consisting of hydroxy, halogen, -NH ₂ , -NO ₂ , -C(O)OH, -C(O)OC ₁ -C ₆ -alkyl, (C ₁ -C ₆ -alkyl)N(H)C (O)-, -CN, oxo, C ₁ -C ₆ -alkyl, -C(O)H, C ₁ -C ₆ -alkoxy and (C ₁ -C ₆ -alkyl)N(H)-. Specified C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and (C ₁ -C ₆ -alkyl)N(H)-, C(O)OC ₁ -C ₆ -alkyl and (C ₁ -C ₆ -alkyl)N(H)C(O)- optionally substituted with one or more of hydroxy, halo, -NH ₂ , (C1-C6-alkyl)N(H)-, -C(O)H, -CN and oxo .

In more specific embodiments, 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-2yl, 1,2,4-triazin-3-yl, each optionally substituted with one or more of F, Cl, CN, OH,

- 12 042905

-NO2, -NH2, -NHMe, -C(O)NH ₂ and methoxy.

Illustrative fragments for R ¹ are selected from the group consisting of

In one embodiment, R ₁ is a 5-membered 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, R ¹ is imidazole, pyrazolyl, isoxazole, thiazolyl, 4,5-dihydrothiazolyl, 1H-1,2,4-triazolyl, 2H-1,2,3-triazolyl, 1,3,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1,2,4-thiadiazolyl or 1,3,4-thiadiazol-2-yl optionally substituted with OH, amino, alkyl, alkoxy, alkoxyalkyl, wherein said alkyl, alkoxy and alkoxyalkyl groups are optionally substituted with OH, oxo and amino.

Alternatively, in other embodiments, R ¹ is imidazol-2-yl, imidazol-4-yl, pyrazol-3-yl, pyrazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl , thiazol2-yl, 4,5-dihydrothiazol-2-yl, 1H-1,2,4-triazol-3-yl, 2H-1,2,3-triazol-4-yl, 1,3,4-oxadiazole -2-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-thiadiazol-5-yl or 1,3,4-thiadiazol-2-yl optionally substituted with OH, amino, alkyl, alkoxy , alkoxyalkyl, where said alkyl, alkoxy and alkoxyalkyl groups are optionally substituted with OH, oxo and amino.

- 13 042905

Specific examples of R ¹ are selected from the group consisting of

The present specification also provides compounds having the general formula I

where 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, halo, 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.

In this embodiment, ring C is a carbocycle or a heterocycle, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, amino, carboxy, CN, oxo, alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle, or heterocycle, wherein said alkyl, alkoxy, alkylamino, acyl, acylamino, acyloxy, cycloalkoxy, carbocycle, and heterocycle are optionally substituted by hydroxy, halogen, NH2, carboxy, CN, oxo, carbocycle, or heterocycle, wherein said carbocycle and heterocycle optionally substituted with OH, oxo, amino, halogen and haloalkyl.

R ₁ is H or alkyl, carbocycle or heterocycle, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, 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 is optionally substituted with hydroxy, halogen, amino, alkylamino, carboxy, CN, or oxo.

Compounds according to the present description may also contain one or more isotopic

- 14 042905 placements. 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 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 so on. For example, said compound is enriched in a particular 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 suitable for use in the treatments disclosed herein, or may be suitable for use in compound detection assays, such as competitive assays for testing other isotopically free compounds. In one embodiment, the compounds according to the present description contain an isotope. In one embodiment, said isotope is deuterium.

Specific compounds corresponding to formula IA, or their pharmaceutically acceptable salts include the compounds shown in table. 1 below.

Table 1

- 15 042905

- 16 042905

- 17 042905

- 18 042905

- 19 042905

- 20 042905

- 21 042905

- 22 042905

- 23 042905

- 24 042905

- 25 042905

- 26 042905

Specific compounds corresponding to formula IB, or their pharmaceutically acceptable salts include the compounds shown in table. 2.

- 27 042905

table 2

- 28 042905

- 29 042905

- 30 042905

- 31 042905

- 32 042905

- 33 042905

- 34 042905

- 35 042905

185 GL L Tsk ' N / - HN NJ /=4 ^xhne ⁰ 187 About cxx /4° ^8 189 ' ^N= \ ll Ύη y ΗΝ. .N. 7 .—. γ νγχο fVii ⁿ ~ ⁿ ” ⁰ 191 o Ον A IZ Uo Or VJ ² 193 ™l d) T n r ⁷ HN N ^ 7 \u003d 4 but ^ ⁰ 195 ^H GC GA NN \X 1 n HN N^7 X d) o

186 η ₂ ν X o AND ^Ν Ν /=\ - ₀ JU O 188 O R K O 190 ^<N= \ ll ⁿ u _n Q /=\ o 192 / ^S O GA X ^N \X 1 n -oo ¹ 0 194 X-o SHl YkJ ό 196 Q-.p ρχίο ^N--M 0

- 36 042905

The present description also includes prodrugs of the compounds described above. Suitable prodrugs, where applicable, contain known amino and carboxy protecting groups which are released under physiological conditions, eg, by hydrolysis, to give the parent compound. A specific class of prodrugs are compounds in which the nitrogen atom in the amino-, amidino-, aminoalkyleneamino, iminoalkyleneamino or guanidino group is replaced by a hydroxy group (OH), an alkylcarbonyl group (-CO-R'), an alkoxycarbonyl group (-CO-OR' ), an acyloxyalkyl-alkoxycarbonyl group (-CO-O-R'-O-CO-R'), where R' is a monovalent or divalent group as defined above, or a group having the formula -C(O)-OCP1P2-haloalkyl where P1 and P2 are the same or different and represent H (hydrogen), lower alkyl, lower alkoxy, cyano, halogen, lower alkyl or aryl. In a specific embodiment, the nitrogen atom is one of the nitrogen atoms of the amidino group of compounds according to the present description. Said prodrug compounds are prepared by reacting the compounds described herein above with an activated acyl compound to bond the nitrogen atom in the compound as described herein with the carbonyl of the activated acyl compound. Suitable activated carbonyl compounds contain an optimal leaving group attached to the carbonyl carbon and include acyl halides, acylamines, acyl pyridinium salts, acyl alkoxides, in particular acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and difluorophenoxy acyl. As a rule, these reactions are exothermic, and they are carried out in inert solvents at low temperatures, such as from -78°C to about 50°C. Also, these reactions are usually 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 method for producing prodrugs is described in WO 9846576, the contents of which are incorporated herein by reference in their entirety.

Compounds according to the present disclosure may exist in a variety of resonant forms, and thus all such resonant forms are within the scope of the present disclosure.

Compounds according to the present description receive using standard methods of organic synthesis from commercially available starting materials and reagents. It should be appreciated that the synthetic methods used to prepare compounds of the present disclosure will depend on the specific substituents present on the compound and that various protection and deprotection steps may be required which are standard in organic synthesis but which may not be shown on the following general diagrams.

In a specific embodiment, the compounds according to the present description, corresponding to formula IB, can be obtained according to the General scheme 1.

- 37 042905

Scheme 1

In step A of Scheme 1, acetate starting material a containing ^RC is reacted with dimethyl carbonate in the presence of a suitable strong base such as potassium tert-butoxide to give dimethyl malonate intermediate b which is reacted in a suitable solvent such as xylene with intermediate c, which is 3H-pyrazol5-amine substituted with RD and RE, to give intermediate 5-hydroxy-substituted pyrazolopyrimidone intermediate d containing rings ^RC , RD and ^RE . The 5-hydroxy group is then converted to the chloro group of intermediate e by reaction with phosphoryl chloride, which also converts the 7-keto group to a chloro group. In step D, the 7-chloro group is converted to a methoxy group by reacting intermediate e with sodium methoxide to give intermediate f, which is then aminated at position 5 of the pyrazolopyrimidone ring in step E by reacting with amine intermediate g in the presence of a palladium catalyst with obtaining intermediate h. Finally, in step F, the 7-methoxy group is hydrolyzed to a ketone to give the final product of formula (IB).

The aminopyrazole intermediate c from Scheme 1 can be prepared using standard organic synthesis techniques from commercially available starting materials and reagents. Scheme 2 shows the general method for preparing the indicated intermediate.

Scheme 2

The acetonitrile intermediate m containing RD is reacted with an ester n containing R ^E in the presence of a suitable basic catalyst such as sodium hexamethyldisilazide to form a 3-oxopropanenitrile intermediate o containing both ^RD and R ^E . This intermediate is then reacted with hydrazine hydrate to give the 5-aminopyrazole intermediate c, which can be used in Scheme 1 to prepare compounds according to the present disclosure.

In one aspect of the present description provides a method for obtaining compounds of formula IA or IB

R ¹ n _r d

HN

r ^e (IB) o

where R ^C , RD, R ^e , and R1 have the meanings defined in the present description, (method) comprising the hydrolysis of a compound of formula h

- 38 042905

Proposed is a method for obtaining a compound of formula h

comprising carrying out the reaction of a compound having the formula f

where X is a halogen, with an amine of the formula g

where R1 is a value defined in the present description.

In one embodiment, X is Cl. In one embodiment, said reaction is catalyzed by a palladium complex, such as a palladium-xanthos complex. For example, the reaction is catalyzed by a Pd(OAc) ₂ -xanthos complex. In one embodiment, the reaction is carried out in a dioxane solvent.

In another embodiment, a process is provided for preparing a compound of formula f

comprising carrying out the reaction of a compound of formula e

with sodium methoxide. In one embodiment, said reaction is carried out in methanol. In one embodiment, a process is provided for preparing a compound of formula e

comprising carrying out the reaction of a compound of formula d

- 39 042905

with phosphoryl chloride. In one embodiment, said reaction is carried out with heating.

In one embodiment, a process is provided for preparing a compound of formula d

comprising carrying out the reaction of a compound of formula c

with compound of formula b

In one embodiment, a process is provided for preparing a compound of formula b

comprising carrying out the reaction of a compound of formula a

with dimethyl carbonate.

Application methods.

The MAT2A enzyme catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and ATP in cells. Accordingly, in another aspect, the present disclosure provides a method for inhibiting the synthesis of SAM from methionine and ATP in a cell, comprising administering to said cell an effective amount of a compound of Formula IA or IB, or a salt thereof. In another aspect of the present description, the compounds of formula IA or IB can be used to identify other compounds that are inhibitors of MAT2A, for example, in a competitive assay for binding to MAT2A or inhibition of SAM production. Binding to MAT2A or inhibition of SAM production by a test compound containing a detectable label can be measured in the presence and absence of an unlabeled compound as described herein.

Overexpression of the MAT2A enzyme has been shown to mediate some cancers. Accordingly, in one aspect, the present disclosure provides a method of treating cancer mediated by MAT2A overexpression, 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, the present disclosure provides a method of treating a disease or condition mediated by MAT2A overexpression 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 one embodiment, said cancer is neuroblastoma, intestinal carcinoma such as rectal carcinoma, colon carcinoma, familial adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, lip carcinoma,

- 40 042905 laryngeal carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, renal parenchymal carcinoma, ovarian carcinoma, cervical carcinoma, uterine corpus carcinoma, carcinoma endometrium, choriocarcinoma, pancreatic carcinoma, prostate carcinoma, testicular carcinoma, breast carcinoma, bladder carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma , acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma , multiple myeloma, basalioma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In one embodiment, said cancer is lung cancer, non-small cell lung cancer (NSCLC), bronchioloalveolar lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, cancer rectal cancer, anal cancer, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma , Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer, kidney or ureter cancer , renal cell carcinoma, renal pelvis carcinoma, mesothelioma, hepatocellular carcinoma, biliary tract cancer, chronic or acute leukemia, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), tumors of the spine, brainstem glioma, glioblastoma multiforme, astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenomas, including refractory forms 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 catalyses the conversion of methylthioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Adenine is utilized with the formation of adenosine monophosphate, and 5-methylthioribose-1-phosphate is converted to methionine and formate. Due to this pathway, MTA can serve as an alternative source of purine when de novo purine synthesis is blocked, for example by antimetabolites such as L-alanosine. Many human and mouse cancer cells lack MTAP activity. MTAP deficiency is found not only in tissue culture cells, but also in primary leukemias, gliomas, melanomas, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcomas, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcomas, non-Hodgkin's lymphomas and mesotheliomas. K. Marjon et al., Cell Reports, 15 (2016) 574-587, incorporated herein by reference, report that proliferation of MTAP-null cancer cells is inhibited by suppression of MAT2A expression by small RNAs. , forming hairpins (shRNA), which was confirmed using small molecule inhibitors of MAT2A, such as inhibitors according to the present description. MTAP null cancer is a cancer in which the MTAP gene is deleted, or lost, or otherwise inactivated, or a cancer in which the MTAP protein has reduced or impaired function.

Accordingly, in one embodiment, the present disclosure provides a method of treating MTAP-null cancer in a subject, wherein said cancer is characterized by reduced or no MTAP expression, or lack of an MTAP gene, or reduced MTAP protein function, compared to cancers in which the MTAP gene is is present and fully functional, said method comprising administering to said subject a therapeutically effective amount of a compound of Formula IA or IB, or a pharmaceutically acceptable salt thereof. In another embodiment, a method for treating MTAP-nil cancer in a subject is provided, comprising administering to said subject an effective amount of a compound of Formula IA or IB, or a pharmaceutically acceptable salt thereof. In one embodiment, said MTAP-nil cancer is leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, cancer endometrium, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, or mesothelioma. In one embodiment, the MTAP-null cancer is pancreatic cancer. In one 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 B- large cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), or mantle cell lymphoma (MCL). IN

- 41 042905 one embodiment of the MTAP null cancer is pancreatic cancer. In one embodiment, the MTAP-null cancer is gastric cancer. In one embodiment, the cancer is colon cancer. In one embodiment, the MTAP-null cancer is liver cancer. In one embodiment, the MTAP-null cancer is glioblastoma multiforme (GBM). In one embodiment, the MTAP-null cancer is bladder cancer. In one embodiment, the MTAP-nil cancer is esophageal cancer. In one embodiment, the MTAP-null cancer is breast cancer. In one embodiment, the MTAP-null cancer is NSCLC. In one embodiment, the MTAP null cancer is MCL. In one embodiment, the MTAP null cancer is DLBCL. In one embodiment, the MTAP-null cancer is ALL.

Genomic analysis of MTAP-null cell lines showed that cell lines that also contain a KRAS mutation or a p53 mutation were susceptible to MAT2A inhibition. Accordingly, in one aspect of the present disclosure, there is provided a method of treating cancer in a subject, wherein said cancer is characterized by reduced or absent expression of MTAP, or absence of the MTAP gene, or reduced function of the MTAP protein, said method comprising administering to said subject a therapeutically effective amount of a compound of formula IA or IB , wherein said cancer is further characterized by the presence of a mutant KRAS or a mutant p53. In another aspect, the present disclosure provides a method of treating a subject with MTAP null cancer in the presence of a KRAS mutant or p53 mutant, comprising administering to said subject an effective amount of a compound of Formula IA or IB, or a pharmaceutically acceptable salt thereof. In one embodiment, said cancer is an MTAP null cancer with a KRAS mutant. In one embodiment, said cancer is an MTAP null cancer with a p53 mutant. In one embodiment, said cancer is an MTAP null cancer with a KRAS mutant and a p53 mutant.

The term KRAS mutant or KRAS mutation refers to a KRAS protein containing an activating mutation that alters its normal function and a gene encoding such a protein. For example, a mutant KRAS protein may contain a single amino acid substitution at position 12 or 13. In a particular embodiment, the mutant KRAS contains a G12X or G13X substitution, where X is any amino acid change at that position. In a particular embodiment, said substitution is G12V, G12R, G12C, or G13D. In another embodiment, the substituent is G13D. By mutant p53 or p53 mutation is meant a p53 protein (or a gene encoding said protein) containing a mutation that inhibits or abolishes its tumor suppression function. In one embodiment, said p53 mutation is Y126_splice, K132Q, M133K, R174fs, R175H, R196*, C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C, R282V, or R282K. In one embodiment, said cancer is non-small cell lung cancer (NSCLC), pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer, or ovarian cancer.

The compounds may be administered before, simultaneously with, or after the administration of radiation therapy or cytostatic or antitumor chemotherapy. Suitable compounds for cytostatic chemotherapy include, but are not limited to, (i) antimetabolites such as cytarabine, fludarabine, 5-fluoro-2'-deoxyuridine, gemcitabine, hydroxyurea, or methotrexate;

(ii) DNA fragmenting agents such as bleomycin;

(iii) DNA crosslinkers 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 targeting agents such as colcemid, colchicine, paclitaxel, vinblastine or vincristine;

(ix) kinase inhibitors such as flavopiridol, staurosporine, STI571 (CPG 57148B) or UCN-01 (7-hydroxystaurosporine);

(x) various experimental agents such as thioplatin, PS-341, phenylbutyrate, ET-18OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin 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 (luteinization);

- 42 042905 releasing hormone, LHRH).

In a particular embodiment, the compounds of the present disclosure are co-administered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere, and mitomycin C. In a specific embodiment, said cytostatic compound is doxorubicin.

In another embodiment, the compounds of the present disclosure may be used alone as immuno-oncological therapy or in combination with immuno-oncological therapy. In one embodiment, a compound of the present disclosure is administered prior to, simultaneously with, or after administration of an immune checkpoint inhibitor. In one embodiment, said checkpoint inhibitor is a programmed cell death protein 1 (PD-1) inhibitor. In one embodiment, said checkpoint inhibitor is a programmed cell death protein ligand 1 (PD-L1) inhibitor. In one embodiment, said checkpoint inhibitor is ipilimumab. In one embodiment, said checkpoint inhibitor is pembrolizumab, nivolumab, or atezolizumab.

Compounds according to the present description can also be used in combination with radiation therapy. The expression radiation therapy refers to the use of electromagnetic or particle radiation for the treatment of neoplasms. Radiation therapy is based on the principle that a high dose of radiation delivered to the target area leads to the death of reproducing cells in both tumor and normal tissue. The radiation dosing regimen is generally determined in terms of absorbed radiation dose (rad), time, and fractionation, and should be carefully determined by the oncologist. The amount of radiation a patient receives will depend on various aspects, but the two most important aspects are the location of the tumor in relation to other critical structures or organs in the body and the extent to which the tumor has spread.

Examples of radiotherapeutic agents are provided by radiation therapy options 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), but not limited to Recent advances in radiation therapy include 3D conformal external beam radiation therapy, intensity modulated radiation therapy (IMRT), stereotactic radiosurgery and brachytherapy (interstitial radiation therapy), in which the radiation source is placed directly into the tumor in the form implanted seeds.These new treatments deliver higher doses of radiation to the tumor, which explains their increased effectiveness compared with standard external beam radiation therapy.Ionizing radiation with beta-emitting radionuclides is considered the most suitable for use in radiotherapy due to moderate linear energy transfer (LET ) of an ionizing particle (electron) and its intermediate range (usually a few millimeters in tissue). Gamma rays deliver lower doses over much longer distances. Alpha particles have the other extreme: they provide a very high LET, but have an extremely limited range and thus must be in close contact with the cells of the tissue to be treated. In addition, sources of alpha radiation are typically heavy metals, which limits the possible process chemistry and poses an unreasonable hazard if a radionuclide escapes from the treated area. Depending on the nature of the tumor to be treated, all types of radiation sources can be included in the scope of the present description. In addition, the present description covers different types of non-ionizing radiation, such as, for example, ultraviolet (UV) radiation, high energy visible light, microwave radiation (hyperthermia therapy), infrared (IR) radiation, and lasers. In a specific embodiment of the present description, UV radiation is used.

pharmaceutical compositions.

The present description also includes pharmaceutical compositions or medicinal products containing the compounds according to the present description and a pharmaceutically acceptable carrier, as well as methods of using the compounds according to the present description for the preparation of such compositions and medicinal products. Typically, the compounds of formula IA or IB used in the methods of the present disclosure are formulated by mixing at ambient temperature at an appropriate pH and at the desired purity with physiologically acceptable carriers, i. carriers that are non-toxic to recipients at the dosages and concentrations used for galenical administration form. The pH of the resulting formulation depends primarily on the particular application and concentration of the compound, and can range from about 3 to about 8. A formulation in acetate buffer at pH 5 is a suitable implementation. In one embodiment, the inhibitory compound for use as described herein is sterile. Said compound is usually stored as a solid formulation, although lyophilized formulations or aqueous solutions are acceptable.

In another embodiment, pharmaceutical compositions according to the present disclosure may contain a compound of Formula IA or IB, or a pharmaceutically acceptable salt thereof, and one or more polymers as part of a solid dispersion (eg, an amorphous solid dispersion). In one embodiment, said solid dispersion further comprises one or more surfactants. In one embodiment, a pharmaceutical composition containing a compound of the present disclosure is a solid dispersion obtained by spray drying. Pharmaceutical compositions containing solid dispersions of a compound of the present disclosure in a matrix can provide improved chemical and physical properties and can be prepared by forming a homogeneous solution or melt of a compound of the present disclosure and a matrix material, followed by curing the resulting mixture by cooling it or removing the solvent. Such solid dispersions may exhibit increased oral bioavailability compared to oral compositions containing the undispersed compound. Dispersion refers to a dispersed system in which one substance, i.e. dispersed phase, distributed as discrete units in the volume of the second substance (continuous phase or carrier). The particle size of the dispersed phase can vary significantly (for example, the size of colloidal particles varies from nanometers to several microns). As a rule, the dispersed phases are solids, liquids or gases. In the case of a solid dispersion, both the dispersed and the continuous phase are solids. In the case of pharmaceutical applications, the solid dispersion may comprise 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). Amorphous solid dispersion generally refers to a solid dispersion of two or more components, such as a compound according to the present description and a polymer (or several polymers), but which may contain other components, such as surfactants or other pharmaceutical excipients, when this connection according to the present description is in the amorphous phase. In some embodiments, the amorphous solid dispersion comprises polymer(s) (and optionally a surfactant) constituting the dispersed phase and the compound as described herein is the continuous phase. In some embodiments, the amorphous solid dispersion comprises polymer(s) (and optionally a surfactant) constituting(s) the continuous phase, and a compound as described herein constitutes the discontinuous phase.

An exemplary solid dispersion is a co-precipitate or co-melt of a compound of the present disclosure with one or more polymers. A co-precipitate is obtained after dissolving a compound of the present disclosure and one or more polymers in a solvent or solvent mixture, followed by removal of the solvent or solvent mixture. Sometimes one or more polymers may be suspended in a solvent or mixture of solvents. Said solvent or mixture of solvents includes organic solvents and supercritical fluids. Said solvent or mixture of solvents may also include a non-volatile solvent. A co-melt is obtained by heating a compound of the present disclosure and one or more polymers to melt, optionally in the presence of a solvent or mixture of solvents, followed by stirring, removing at least a portion of the solvent, if applicable, and cooling to rt. at the selected speed. In some cases, solid dispersions are prepared by adding a solution of the therapeutically active compound and solid polymers, followed by mixing and removing the solvent or mixture of solvents. Vacuum drying, spray drying, tray drying, lyophilization and other drying methods can be used to remove said solvent or solvent mixture. The use of any of these methods using the appropriate processing parameters in accordance with the present description can provide an amorphous state of a particular therapeutically active compound in the final product, which is a solid dispersion.

The composition according to the present description can be prepared, dosed and administered in a manner consistent with good medical practice. Factors considered 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, site of delivery of the agent, route of administration, schedule of administration, and other factors known to practitioners. The effective amount of compound administered will depend on such considerations and is the minimum amount required to inhibit MAT2A activity. Such an amount may be below the amount toxic to normal cells or the mammal as a whole. Typically, an initial pharmaceutically effective amount of a parenterally administered compound of the present disclosure per dose will be in the range of about 0.01-2000 mg/kg, such as about 0.01 mg/kg to about 200 mg/kg, about 0 1 to 20 mg/kg of the patient's body weight per day, with the usual initial amount of compound used from 0.3 to 15 mg/kg/day. Oral unit dosage forms such as tablets and capsules may contain from about 25 mg to about 200 mg of a compound as described herein.

- 44 042905

The compound of the present disclosure may be administered by any suitable route, including oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and, if necessary for topical treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal or subcutaneous administration. An example of a suitable oral dosage form is a tablet containing about 1, 2, 5, 10, 15, 25, 50, 100, 250, 500, 750, 1000, 1250, 1500, 1750, or 2000 mg of a compound as described herein.

Examples

The following examples provide a more complete understanding of the present invention. However, they should not be construed as limiting the scope of the invention. Reagents and solvents were obtained from commercial sources and used without further processing.

Abbreviations and list of terms.

anz. anhydrous water. water min minute(s) ml milliliter mmol millimole(s) they say mole(moth) MS mass spectrometry NMR nuclear magnetic resonance those thin layer chromatography HPLC high performance liquid chromatography CT(k.t.) room temperature Range. Hz hertz δ chemical shift j Interaction constant S singlet d doublet t triplet q quartet m multiplet br wide qd quartet of doublets dquin doublet of quintets dd doublet of doublets dt doublet of triplets

- 45 042905

Solvents reagents.

SNS1z chloroform dhm dichloromethane DM FA dimethylformamide _Et2O diethyl ether EtOH ethanol EtOAc ethyl acetate EA(EA) Meon ethyl acetate methyl alcohol MeCN Acetonitrile RE (PE) petroleum ether THF Tetrahydrofuran ASON acetic acid HC1 hydrochloric (hydrochloric) acid _{H2SO4 _} sulfuric acid NH4CI ammonium chloride KOH potassium hydroxide NaOH sodium hydroxide K2CO3 potassium carbonate _{Na2CO3 _} sodium carbonate TFA(TFA) trifluoroacetic acid

_{Na2SO4 _} sodium sulfate _NaBH4 sodium borohydride NaHCO ₃ LiHMDS bicarbonate of soda lithium hexamethyldisylamide NaHMDS sodium hexamethyldmsilylamide LAH lithium aluminum hydride _NaBH4 sodium borohydride LDA lithium diisopropylamide Et ₃ N triethylamine DMAP 4-(dimethylamino)pyridine DIPEA ΛζΑ-diisopropylethylamine NH4OH ammonium hydroxide EDCI I-ethyl-3-(3-d-imethylaminopropyl)carbod imide HOBt I-hydroxybenzotriazole HATU О-(7-azabenzotriazol-1-yl)-ААА',А'-tetra-methyluronium Xphos BINAP 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl

Example 1. Synthesis of compounds.

General remarks about experiments.

In the examples below, 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 a silica gel column (particle size 200-300 mesh). For analytical and preparative thin layer chromatography (TLC), HSGF 254 plates (thickness 0.15-0.2 mm, Shanghai Anbang Company, China) were used. Nuclear magnetic resonance (NMR) spectra were obtained on a Brucker AMX-400 NMR device (Brucker, Switzerland). Chemical shifts were recorded in parts per million (ppm, δ) downfield from tertramethylsilane. Mass spectra were obtained with electrospray ionization (ESI) on a Waters LCT TOF mass spectrometer (Waters, USA). HPLC chromatograms were taken on an Agilent 1200 liquid chromatograph (Agilent, USA, column: Ultimate 4.6x50 mm, 5 µm, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile). Reactions

- 46 042905 under the influence of microwave radiation was carried out on an Initiator 2.5 microwave synthesizer (Biotage, Sweden).

Compound 101 6-(4-Methoxyphenyl)-2,3-diphenyl-5-(pyridazin-3-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Step A. Dimethyl-2-(4-methoxyphenyl)malonate.

t-BuOK (500 g) was added slowly to dimethyl carbonate (3.2 L) at 0° C. and the mixture was stirred for 1 h at rt. Methyl 2-(4-methoxyphenyl)acetate (400 g) was then added dropwise, added over 2 hours and stirred at rt. during the night. The reaction was quenched with water (1.5 L) and then extracted with ethyl acetate (1 Lx3). The combined organic layers were washed with brine (1L), dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate (20/1-5/1) to give the desired product as a white solid (400 g).

¹ H-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[1,5-a]pyrimidin-7(4H)-one.

Mixture of 3,4-diphenyl-1H-pirazol-5-amine 8 (470 g, 2 mol) and dimethyl-2-(4-methoxyphenyl)-malonate 2 (571 g, 2.4 mol, 1.2 eq.) in xylene (5 L) refluxed for 18 hours. The white precipitate was filtered off and washed with dichloromethane (5 L) to give the title compound as a white solid (610 g) which was used in the next step without further cleaning.

¹ H-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) ⁺ .

Step C. 5,7-dichloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine.

- 47 042905

6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine-5,7(4H, 6H)-dioxane (300 g, 0.73 mol) and phosphorus oxychloride (1200 ml, 12 90 mol) was added to a liter vial. The reaction mixture was stirred at 100° C. for 16 hours. TLC indicated completion of the reaction. The solvent and volatiles were removed under vacuum, and the residue was dissolved in DCM (500 ml). The mixture was added dropwise to MeOH (2500 ml) at 0°C. A yellow suspension formed during the addition. The mixture was stirred at rt. over 2 hours, the precipitate was collected by filtration and dried under vacuum to give the title product as a yellow solid (290 g) which was used in the next step without further purification.

LC-MS: m/z 446.1, 448.1 (M+H) ⁺ .

Step D. 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine.

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 to a 30 L reactor. This mixture was cooled to -10°C. Sodium methoxide (1.48 L, 8 mol, 30% in MeOH) was added dropwise so as to keep the internal temperature below 0°C. The reaction mixture was stirred at rt. within 2 h. TLC showed the completion of the reaction. An ice-water mixture (10 L) was added at rt. within 1 h. The organic layer was collected and the aqueous layer was extracted with dichloromethane (5lx1). The combined organic layers were dried with anhydrous Na ₂ SO ₄ and concentrated. The residue was dissolved in DCM (15 L) and MeOH (60 L) was added. The cloudy liquid was stirred at rt. over 3 hours, the precipitate was collected by filtration and dried in vacuo to give the title intermediate 5 as a yellow solid (1.35 kg).

¹ H-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) ⁺ .

Step E. 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyridazin-3-yl)pyrazolo[1,5-a]pyrimidine5-amine.

Suspension of intermediate 5, 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-pyrazolo[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 Cs ₂ CO ₃ (890 mg, 2.72 mmol, 2.0 eq.) in 1,4-dioxane (5 ml) was stirred at 120° C. (microwave heating) for 1 h under N2 atmosphere. The mixture was filtered through Celite, the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to give the desired product 6 as a yellow solid.

LC-MS: m/z 501.0 (M+H) ⁺ .

Step F. 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridazin-3-ylamino)pyrazolo[1,5-a]pyrimidin7(4H)-one.

A solution of intermediate 6 (360 mg, 0.72 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at rt. within 2 hours the Solvent and volatiles were removed under vacuum. The residue was dissolved in DCM (5 ml) and treated with aqueous saturated NaHCO3 solution. The organic phase was separated and washed with brine, dried with anhydrous Na2SO4 and concentrated in vacuo to give desired product 7.

1H-NMR (DMSO-d6): δ 15.25 (br. s., 1H), 9.21 (br. s., 1H), 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).

- 48 042905

LC-MS: m/z 486.9 (M+H)+.

The compounds below were prepared according to the procedure for compound 101, steps E and F, using intermediate 5 as starting material. Step E was performed using the appropriate amine 9, base (Cs ₂ CO ₃ , K ₂ CO ₃ , Na ₂ CO ₃ etc.) and catalyst/ligand under thermal or microwave heating, in 1,4-dioxane unless otherwise noted. Step F was performed using 5 ml of 4 HCl in dioxane unless otherwise noted. Purification was carried out using the methods described in example 101, unless otherwise indicated.

Compound 102. 6-(4-Methoxyphenyl)-2,3-diphenyl-5-(pyridin-2-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (500 mg, 1.13 mmol), pyridine-2-amine (213 mg, 2.26 mmol), Pd(OAc) ₂ (50 mg, 0.23 mmol), Xantphos (165 mg, 0.23 mmol) 28 mmol) and Na ₂ CO ₃ (240 mg, 2.26 mmol) in 1,4-dioxane (10 ml) under conditions of heating to 100° C. for 4 h under N ₂ atmosphere.

LC-MS: m/z 500.0 (M+H) ⁺ .

Step F. 7-Methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5amine (300 mg, 0.6 mmol) was dissolved in a mixture of HCl/1,4-dioxane (5 ml). The solution was stirred at rt. during the night. The precipitate was filtered off and washed with dichloromethane (CH ₂ Cl ₂ ) (3x1 ml) to give a yellow solid. Then the solid was dissolved in CH ₂ Cl ₂ /MeOH (10/1, 3 ml). After 3 ml, NH ₃ -MeOH was added, the solution was stirred at room temperature. overnight to give the title compound.

¹ H-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) ⁺ .

Compound 103 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridin-3-ylamino)pyrazolo[1,5-a]pyrimidin7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (500 mg, 1.13 mmol), pyridine-3-amine (117 mg, 1.24 mmol), Pd(OAc)2 (25 mg, 0.113 mmol), Xantphos (131 mg, 0.226 mmol), Cs2CO3 (737 mg, 2.26 mmol) in dioxane (20 ml) under heating conditions to 110° C. for 4 h under N2 atmosphere.

LC-MS: m/z 500.2 (M+H) ⁺ .

Step F. To a solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyridin-3-yl)pyrazolo[1,5a]pyrimidine-5-amine (150 mg, 0.309 mmol) in MeOH (10 ml) was added 4N. HCl solution in dioxane (10 ml). The reaction mixture was heated to 50° C. for 2 hours. The mixture was concentrated in vacuo. The residue was suspended in a saturated solution of HCO3, resulting in the desired product 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridin-3-ylamino)pyrazolo[1,5-a]pyrimidine-7(4H) -He.

1H-NMR (DMSO-d ₆ ): 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, 11H), 6.93 (d, J=8.1 Hz , 2H), 3.76 (s, 3H).

LC-MS: m/z 486.2 (M+H) ⁺ .

Compound 104 6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl)amino)nicotinonitrile.

Stage E (stoichiometry). Intermediate 5 (300 mg, 0.68 mmol), 6-aminonicotinonitrile (161.7 mg, 1.36 mmol), palladium diacetate (30.5 mg, 0.14 mmol), Xantphos (117.8 mg, 0 .20 mmol) and cesium carbo-49 042905 nat (553.0 mg, 1.70 mmol) in 1,4-dioxane (10 ml) by heating to 110° C. for 12 h under nitrogen atmosphere.

LC-MS: m/z 525.2 (M+H) ⁺ .

Step F. Solution of 6-((7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5yl)amino)nicotinonitrile (40 mg, 0.07 mmol) in solution HCl (1.0 M in 1,4-dioxane, 6 mL) was stirred at rt. over 12 h. The mixture was concentrated and NH4OH (5 mL) was added to give 6-((6-(4methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine- 5-yl)amino)nicotinonitrile.

¹ H-NMR (DMSO-d6): δ 14.21 (br. s., 1H), 9.53 (s, 1H), 8.53 (d, J=2.1 Hz, 1H), 8, 11 (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 511.3 (M+H) ⁺ .

Compound 105 5-((5-Fluoropyridin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (220 mg, 0.5 mmol), 5-fluoropyridine-2-amine (112 mg, 1.0 mmol), Pd(OAc) ₂ (56 mg, 0.25 mmol), Xantphos (173 mg, 0.3 mmol), Cs ₂ CO ₃ (117 mg, 1.1 mmol) in dioxane (20 ml) when heated to 100° C. for 4 h under N2 atmosphere.

LC-MS: m/z 518.2 (M+H)+.

Step F. To a solution of N-(5-fluoropyridin-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3diphenylpyrazolo[1,5-a]pyrimidin-5-amine (50 mg, 0. 10 mmol) in MeOH (10 ml) was added 4 N. HCl solution in dioxane (10 ml). The reaction mixture was heated to 50° C. for 2 hours. The mixture was concentrated in vacuo. The residue was suspended in a saturated solution of NaHCO ₃ , resulting in the desired product 5-((5-fluoropyridin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7 (4H)-he.

1H-NMR (DMSO-d6): δ 14.87 (br. s., 1H), 9.08 (s, 1H), 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) ⁺ .

Compound 106 5-((5-chloropyridin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

ci

Stage E (stoichiometry). Intermediate 5 (200 mg, 0.45 mmol), 5-chloropyridine-2-amine (135 mg, 0.9 mmol), Pd(OAc) ₂ (51 mg, 0.23 mmol), Xantphos (156 mg, 0.27 mmol) and Na ₂ CO ₃ (105 mg, 0.9 mmol) in 1,4-dioxane (5 ml) under heating conditions to 100° C. for 16 h under N2 atmosphere.

LC-MS: m/z 533.9, 535.9 (M+H)+.

Step F. N-(5-chloropyridin-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-5-amine (80 mg, 0.15 mmol ) was dissolved in HCl-1,4-dioxane (5 ml). The solution was stirred at rt. during the night. The precipitate was filtered off and washed with dichloromethane (CH ₂ Cl ₂ ) (3 ml) to give a yellow solid. Then the solid was dissolved in CH ₂ Cl ₂ /MeOH (10/1, 2 ml). After adding 1 ml of NH ₃ -MeOH, the solution was stirred at rt. overnight to give the title compound 7.

1H-NMR (DMSOCH): 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)+.

- 50 042905

Compound 107. 6-(4-Methoxyphenyl)-5-((5-nitropyridin-2-yl)amino)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (500 mg, 1.13 mmol), 5-nitropyridine-2-amine (472 mg, 3.39 mmol, 3 eq) and Pd(OAc) ₂ (51 mg, 0.23 mmol, 0, 2 eq.), Xantphos (262 mg, 0.45 mmol, 0.4 eq.) and Na ₂ CO ₃ (360 mg, 3.394 mmol, 3 eq.) in 1,4-dioxane (10 ml) were stirred and heated up to 100°C under the influence of microwave radiation for 1 h in an N2 atmosphere.

¹ H-NMR (DMSO-d6) δ 9.03 (d, J=2.7 Hz, 1H), 8.55-8.66 (m, 2H), 8.12 (s, 1H), 7, 58-7.65 (m, 2H), 7.437.54 (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) ⁺ .

Step F. 7-Methoxy-6-(4-methoxyphenyl)-N-(5-nitropyridin-2-yl)-2,3-diphenylpyrazolo[1,5a]pyrimidine-5-amine solution (50 mg, 0.092 mmol) in 4 M HCl in 1,4-dioxane (10 ml) was stirred at room temperature. for 3 hours. The reaction mixture was concentrated under vacuum; the residue was dissolved in 7N. amine in methanol and stirred at room temperature. over 2 h. The mixture was concentrated in vacuo to give 6-(4-methoxyphenyl)-5-((5-nitropyridin-2-yl)amino)-2,3-diphenylpyrazolo[1,5-a]pyrimidine -7(4H) he.

¹ H-NMR (DMSO-d6): δ 13.95 (br. s., 1H), 9.82-9.91 (m, 1H), 8.85 (br. s., 1H), 8, 45 (br. s., 1H), 7.54 (dd, J=6.18, 2.96 Hz, 4H), 7.37-7.45 (m, 5H), 7.33 (m, J = 8.86 Hz, 2H), 7.02 (m, J=8.60 Hz, 2H), 3.81 (s, 3H).

LC-MS: m/z 531.0 (M+H) ⁺ .

Compound 108 5-(5-Hydroxypyridin-2-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

OH % p o

Stage E (stoichiometry). Intermediate 5 (160 mg, 0.362 mmol), 5-(tert-butyldimethylsilyloxy)pyridine-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 reflux conditions for 4 h under nitrogen atmosphere.

LC-MS: m/z 630.3 (M+H) ⁺ .

Step F. Mixture of N-(5-(tert-butyldimethyl-silyloxy)pyridin-2-yl)-7-methoxy-6-(4-methoxyphenyl)2,3-diphenylpyrazolo[1,5-a]pyrimidin-5- amine (80 mg, 0.127 mmol) and HCl solution (4 N in dioxane, 10 ml) were stirred at rt. for 6 hours. Then concentrated HCl (0.5 ml) was added to the mixture. The resulting mixture was stirred at the same temperature for 4 hours. The mixture was neutralized with ammonia (7N in methanol) to pH 7 to give 5-(5-hydroxypyridin-2-ylamino)-6(4-methoxyphenyl)-2, 3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one as a white solid.

1H-NMR (TFA-d): δ 7.71-7.80 (m, 1H), 7.57 (d, J=7.32 Hz, 2H), 7.44-7.54 (m, 7H ) 7.30-7.43 (m, 4H), 7.18 (d, J=9.46 Hz, 1H), 7.13 (d, J=8.54 Hz, 2H), 3.94 ( s, 3H).

LC-MS: m/z 502. 4 (M+H) ⁺ .

Compound 109 5-((4-Hydroxypyridin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

R

HN N.7 =.

Stage E (stoichiometry). Intermediate 5 (80 mg, 0.18 mmol), 2-aminopyridin-4-ol (30 mg, 0.27 mmol, 1.5 eq.), Pd(OAc) ₂ (6.1 mg, 0.03 mmol, 0.15 eq.), Xantphos (15.7 mg, 0.03 mmol, 0.15 eq.)

- 51 042905 and Cs ₂ CO3 (120 mg, 0.36 mmol, 2.0 equiv.) in 1,4-dioxane (3 ml) at 110°C for 1 h under the influence of microwave irradiation in an N2 atmosphere.

LC-MS: m/z 516.0 (M+H) ⁺ .

Step F. 2-((7-Methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrumidin-5yl)amino)pyridin-4-ol solution (40 mg, 0.08 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was stirred at 30° C. for 2 h to give the title compound.

1I-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), 7.11 (s, 2H), 6.72 (m, 2H), 3.99 (s, 1H), 3.94 (s, 3H).

LC-MS: m/z 502.0 (M+H) ⁺ .

Compound 110 5-((6-Fluoropyridin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (200 mg, 0.45 mmol), 6-fluoropyridine-2-amine (101 mg, 0.9 mmol), Pd(OAc) ₂ (20 mg, 0.09 mmol), Xantphos (65 mg, 0.11 mmol) and Cs ₂ CO ₃ (293 mg, 0.9 mmol) in 1,4-dioxane (5 ml) under heating conditions to 100° C. for 16 h under N2 atmosphere.

LC-MS: m/z 518.1 (M+H)+.

Step F. N-(6-fluoropyrudin-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-5-amine (120 mg, 0.23 mmol ) was dissolved in HCl-1,4-dioxane (5 ml). The solution was stirred at rt. during the night. The precipitate was filtered off and washed with dichloromethane (CH ₂ Cl ₂ ) (3 ml) to give a yellow solid. Then the solid was dissolved in CH ₂ Cl ₂ /MeOH (10/1, 2 ml). After adding 1 ml of NH ₂ -MeOH, the solution was stirred at rt. overnight to give the title compound 7.

¹ H-NMR (DMSO^): δ 13.33 (s, 1H), 9.16 (s, 1H), 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)+.

Compound 111 6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin5-yl)amino)picolinonitrile.

Qt about

I h hn =,

Compound 112 6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimudin5-yl)amino)picolinamide.

Stage E (stoichiometry). Intermediate 5 (800 mg, 1.8 mmol), 6-aminopicolinonitrile (281 mg, 2.36 mmol, 1.3 eq) and Pd(OAc) ₂ (61.2 mg, 0.27 mmol, 0, 15 eq.), Xantphos (157.4 mg, 0.27 mmol, 0.15 eq.) and Cs ₂ CO ₃ (1.2 g, 3.63 mmol, 2.0 eq.) in 1.4- dioxane (15 ml) at 110°C for 1 h under the influence of microwave radiation in an N2 atmosphere.

LC-MS: m/z 524.9 (M+H)+.

Step F. Solution of 6-((7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5yl)amino)picolinonitrile (220 mg, 0.42 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was stirred at 30° C. for 5 h to give the title compounds 6-((6-(4-methoxyphenyl)-7-oxo2,3-diphenyl- 4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)amino)picolinonitrile and 6-((6-(4-methoxyphenyl)7-oxo-2,3-diphenyl-4,7-dihydropyrazolo [1 ,5-a]pyrimidin-5-yl)amino)picolinamide.

- 52 042905

6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5yl)amino)picolinonitrile.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5yl)amino)picolinamide.

¹ H-NMR (DMSO-d ₆ ): δ 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) ⁺ .

Compound 113 5-(3-hydroxypyridin-2-ylamino)-6-(4-methoxy-phenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Suspension of intermediate 5 (200 mg, 0.452 mmol), 3-(tert-butyldimethylsilyloxy)pyridine-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) were stirred and refluxed for 4 hours under nitrogen. The reaction mixture was then cooled to rt. and filtered. The filtrate was concentrated in vacuo to give 5-(3-hydroxypyridin-2-ylamino)-6-(4-methoxy-phenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)he .

1H-NMR (TFA-d): δ 8.33 (d, J=8.33 Hz, 1H), 7.99 (d, J=5.10 Hz, 1H), 7.56-7.71 ( m, 8H), 7.48-7.54 (m, 4H), 7.42 (dd, J=8.33, 5.91 Hz, 1H), 7.34 (d, J=8.60 Hz , 2H), 4.10 (s, 3H).

LC-MS: m/z 502.4 (M+H) ⁺ .

Compound 114 2-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin5-ylamino)isonicotinonitrile.

Stage E (stoichiometry). Intermediate 5 (200 mg, 0.452 mmol) and 2-aminoisonicotinonitrile (108 mg, 0.9 mmol) and Pd(OAc) ₂ (102 mg, 0.434 mmol), Xantphos (315 mg, 0.54 mmol) and Cs ₂ CO ₃ (327 mg, 1.0 mmol) in 1,4-dioxane (10 ml) under heating conditions to 110°C for 1 h by microwave radiation under N2 atmosphere.

LC-MS: m/z 525.2 (M+H) ⁺ .

Step F. A mixture of 2-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5ylamino)isonicotinonitrile (15 mg, 0.03 mmol) in HCl solution (4 M in dioxane, 1 ml) was stirred at room temperature. during the night. The mixture was neutralized with a solution of NH ₃ (7 M in methanol) to pH 7-8, resulting in 6-(4-methoxyphenyl)-5-(2-methoxypyrimidin-4-ylamino)-2,3-diphenyl pyrazolo[1, 5a]pyrimidin-7(4H)-one.

1H-NMR (DMSO-d6): δ 8.25 (d, J=5.37 Hz, 1H), 7.77 (s, 1H), 7.49-7.63 (m, 4H), 7, 37-7.47 (m, 7H), 7.34 (m, J=8.60 Hz, 2H), 7.06 (m, J=8.60 Hz, 2H), 3.84 (s, 3H ).

LC-MS: m/z 511.2 (M+H) ⁺ .

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Compound 115 2-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin5-ylamino)pyrimidine-5-carbonitrile.

A mixture of intermediate 5 (200 mg, 0.452 mmol) and 2-aminopyrimidine-5-carbonitrile (108 mg, 0.904 mmol) a Pd(OAc) ₂ (31 mg, 0.136 mmol), Xantphos (157 mg, 0.272 mmol) and Na ₂ CO ₃ (96 g, 0.904 mmol) in 1,4-dioxane (10 mL) was stirred and refluxed for 4 h under N2. The reaction mixture was then cooled to rt. and filtered. The filtrate was concentrated in vacuo to give 2-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-5-ylamino)pyrimidin-5- carbonitrile.

¹ H-NMR (DMSO-d6): δ 12.77 (bs, 1H), 10.27 (bs, 1H), 8.88 (s., 2H), 7.43-7.52 (m, 4H ), 7.35-7.40 (m, 4H), 7.32 (d, J=7.63 Hz, 2H), 7.25 (d, J=8.54 Hz, 2H), 6.93 (d, J=8.24 Hz, 2H), 3.76 (s, 3H).

LC-MS: m/z 512.2 (M+H) ⁺ .

Compound 116 6-(4-Methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-4-ylamino)pyrazolo[1,5a]pyrimidine-7(4H)-oh.

Stage E (stoichiometry). Intermediate 5 (440 mg, 1 mmol), pyrimidine-4-amine (190 mg, 2 mmol, 2 eq.), Pd(OAc) ₂ (22 mg, 0.1 mmol, 0.1 eq.), Xantphos (116 mg, 0.2 mmol, 0.2 eq.) and Cs ₂ CO ₃ (390 mg, 1.2 mmol, 1.2 eq.) in 1,4-dioxane (10 ml) under microwave heating conditions at 100°C for 1 h in an atmosphere of N ₂ .

LC-MS: m/z 501.5 (M+H) ⁺ .

Step F. 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(nirimidin-4-yl)pyrazolo[1,5a]pyrimidin-5-amine solution (260 mg, 0.52 mmol ) in 4 M HCl in 1,4-dioxane (10 ml) was stirred at room temperature. for 16 hours to give the title compound.

¹ 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) ⁺ .

Compound 117 5-((6-Aminopyrimidin-4-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-oh.

Stage E (stoichiometry). Intermediate 5 (237 mg, 0.538 mmol), pyrimidine-4,6-diamine (118.2 mg, 1.07 mmol, 2 eq.), Pd(OAc) ₂ (60 mg, 0.269 mmol, 0.5 eq. .), Xantphos (186.5 mg, 0.322 mmol, 0.6 eq.) and Na ₂ CO ₃ (125 mg, 1.184 mmol, 2.2 eq.) in 1,4-dioxane (5 ml) under heating conditions up to 100°C for 3 hours in an N ₂ atmosphere.

LC-MS: m/z 516.5 (M+H) ⁺ .

Step F. N4-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5yl)pyrimidine-4,6-diamine solution (90 mg, 0.17 mmol ) in 4 M HCl in 1,4-dioxane (3 mL) was stirred at room temperature. for 3 hours to give the title compound.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

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Compound 118 6-(4-methoxyphenyl)-5-((2-methoxypyrimidin-4-yl)amino)-2,3diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (300 mg, 0.67 mmol), 2-methoxypyrimidine-4amine (169 mg, 1.25 mmol), Pd(OAc) ₂ (48 mg, 0.067 mmol), Xantphos (72 mg, 0.13 mmol ), Cs ₂ CO ₃ (409 mg, 1.25 mmol) in dioxane (20 ml) under conditions of heating to 110° C. for 4 h under N2 atmosphere.

LC-MS: m/z 531.2 (M+H) ⁺ .

Step F. To a solution of 7-methoxy-6-(4-methoxyphenyl)-N-(2-methoxypyrimidin-4-yl)-2,3diphenylpyrazolo[1,5-a]pyrimidin-5-amine (100 mg, 0. 19 mmol) in MeOH (10 ml) was added 4N. HCl solution in dioxane (10 ml). The reaction mixture was heated to 50° C. for 2 hours. The mixture was concentrated in vacuo. The residue was suspended in a saturated solution of NaHCO ₃ , resulting in the desired product 6-(4-methoxyphenyl)-5-((2-methoxypyrimidin-4-yl)amino)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7 (4H)-he.

¹ H-NMR (TFA): δ 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) ⁺ .

Compound 119 5-(2-hydroxypyrimidin-4-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of 7-methoxy-6-(4-methoxyphenyl)-N-(2-methoxypyrimidin-4-yl)-2,3-diphenyl-pyrazolo[1,5a]pyrimidin-5-amine (126 mg, 0.244 mmol) and conc. HCl (10 ml) was heated under reflux for 2 days. The mixture was neutralized with ammonia (7N in methanol) to pH 7 and concentrated to give 5-(2-hydroxypyrimidin-4-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1.5 -a] pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d6): δ 7.52 (d, J=6.71 Hz, 3H), 7.45 (d, J=6.71 Hz, 2H), 7.20-7.40 (m, 9H), 7.05-7.19 (m, 2H), 6.99 (bs, 2H), 3.80 (s, 3H).

LC-MS: m/z 503.2 (M+H) ⁺ .

Compound 120 6-(4-Methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-5-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Suspension of intermediate 5 (500 mg, 1.13 mmol), pyrimidine-5-amine (323 mg, 3.39 mmol, 3 eq.), Pd(OAc) ₂ (51 mg, 0.23 mmol, 0.2 eq.), Xantphos (262 mg, 0.45 mmol, 0.4 eq.) and Na ₂ CO ₃ (356 mg, 3.39 mmol, 3 eq.) in 1,4-dioxane (10 ml) were stirred and heated to 100° C. (microwave heating) for 1 h under N2 atmosphere. The reaction mixture was then cooled to rt to give 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-5-ylamino)pyrazolo[1,5a]pyrimidine-7(4H)- He.

¹ H-NMR (DMSO-d ₆ ): δ 8.65 (s, 2H), 8.52 (br. s., 1H), 7.54 (d, J=8.87 Hz, 1H), 7 .34-7.49 (m, 8H), 7.31 (br. s., 3H), 6.93 (br. s., 1H), 3.68-3.84 (m, 3 H).

LC-MS: m/z 487.0 (M+H) ⁺ .

- 55 042905

Compound 121.

a]pyrimidine-7(4H)-one.

6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyrimidin-2-ylamino)pyrazolo [1,5-

Stage E (stoichiometry). Intermediate 5 (200 mg, 0.4535 mmol), pyrimidine-2-amine (86 mg, 0.91 mmol, 2 eq.), Pd(OAc) ₂ (102 mg, 0.4535 mmol, 1 eq.) , Xantphos (314.5 mg, 0.54 mmol, 1.2 eq.) and Cs ₂ CO ₃ (327 mg, 1 mmol, 2.2 eq.) in 1,4-dioxane (4 ml) under heating conditions microwave radiation at 110°C for 1 h in an N2 atmosphere.

LC-MS: m/z 501.6 (M+H) ⁺ .

Step F. 7-Methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyrimidin-2-yl)pyrazolo[1,5a]pyrimidine-5-amine solution (60 mg, 0.12 mmol ) in 4 M HCl in 1,4-dioxane (10 ml) was stirred at room temperature. within 2 hours the Solvent and volatiles were removed under vacuum. The residue was dissolved in DCM (5 ml) and treated with saturated NaHCO ₃ . The organic phase was separated and washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

¹ H-NMR (DMSOCH): δ 14.08 (br. s., 1H), 8.60 (s, 1H), 8.57 (d, J=4.84 Hz, 2H), 7.52- 7.62 (m, 4H), 7.40-7.49 (m, 6H), 7.37 (d, J=8.60 Hz, 2H), 7.18 (t, J=4.97 Hz , 1H), 7.08 (d, J=8.60 Hz, 2H), 3.84 (s, 3H).

LC-MS: m/z 487.2 (M+H) ⁺ .

Compound 122 5-((5-chloropyrimidin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Cl ifS /GA ν^ν (J

Τ η ΗΝ 7=4 ο

Stage E (stoichiometry). Intermediate 5 (220 mg, 0.5 mmol), 5-chloropyrimidin-2-amine (129 mg, 1.0 mmol), palladium diacetate (56 mg, 0.2 mmol), Xantphos (173 mg, 0.3 mmol) and sodium carbonate (117 mg, 1.1 mmol) in 1,4-dioxane (20 ml) were heated under reflux for 4 h under nitrogen atmosphere.

LC-MS: m/z 535.1 (M+H) ⁺ .

Step F. N-(5-chloropyrimidin-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3diphenylpyrazolo[1,5-a]pyrimidin-5-amine solution (50 mg, 0.1 mmol) in HCl solution (4.0 M in 1,4-dioxane, 5 ml) was stirred at room temperature. over 2 h. The mixture was concentrated and NH4OH (8 mL) was added to give 6-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[ 1,5a]pyrimidin-5-yl)amino)nicotinonitrile.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 123 5-((6-Aminopyridazin-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

_NH2

HN /=

ah o

Stage E (stoichiometry). Intermediate 5 (132 mg, 0.3 mmol) and N-(6-aminopyridazin-3yl)acetamide (93 mg, 0.2 mmol, 2 eq) and Pd(OAc) ₂ (10 mg, 0.04 mmol , 0.4 eq.), Xantphos (24 mg, 0.04 mmol, 0.4 eq.) and Cs ₂ CO ₃ (65 mg, 0.2 mmol, 2 eq.) in 1,4-dioxane (5 ml) under microwave heating at 120°C for 1 h in an N2 atmosphere.

LC-MS: m/z 558.2 (M+H) ⁺ .

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Step F. A mixture of N-(6-((7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5yl)amino)pyridazin-3-yl)acetamide (55 .7 mg, 0.1 mmol) and potassium tert-butoxide in 1,4-dioxane (5 mL) were stirred at 100° C. for 16 h. The mixture was filtered and concentrated in vacuo to give 5-((6 -aminopyridazin-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

1 H-NMR (DMSO-d ₆ ): δ 7.50 (br. s., 2H), 7.40 (br. s., 3H), 7.33 (d, J=8.86 Hz, 8H) , 7.04 (d, J=8.06 Hz, 3H), 6.89 (br. s., 1H), 3.82 (s, 4H).

LC-MS: m/z 502.1 (M+H)+.

Compound 124 6-(4-methoxyphenyl)-5-((6-methoxypyridazin-3-yl)amino)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (200 mg, 0.453 mmol) and 6-methoxypyridazine3-amine (169.8 mg, 1.358 mmol, 3 eq.), Pd(OAc) ₂ (20.3 mg, 0.091 mmol, 0.2 eq.) , Xantphos (104.7 mg, 0.181 mmol, 0.4 eq.) and Na ₂ CO ₃ (143.9 mg, 1.358 mmol, 3 eq.) in 1,4-dioxane (5 ml) under microwave heating conditions at 100°C for 1 h in an atmosphere of N ₂ .

LC-MS: m/z 531.2 (M+H)+.

Step F. 7-Methoxy-6-(4-methoxyphenyl)-N-(6-methoxypyridazin-3-yl)-2,3-diphenylpyrazolo[1,5a]pyrimidine-5-amine solution (50 mg, 0.094 mmol) in 4 M HCl in 1,4-dioxane (10 ml) was stirred at room temperature. over 3 hours. The reaction mixture was concentrated in vacuo to give the title compound.

1H-NMR (CHLOROFORM-d): δ 7.74 (d, J=9.46 Hz, 1H), 7.59 (d, J=9.46 Hz, 1H), 7.22-7.48 ( m, 12H), 7.07 (d, J=6.41 Hz, 2H), 4.07 (s, 3H), 3.88 (s, 3H).

LC-MS: m/z 517.0 (M+H)+.

Compound 125 5-((6-chloropyridazin-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (200 mg, 0.45 mmol), 6-chloropyridazine-3amine (101 mg, 0.9 mmol, 2 eq.) and Pd(OAc) ₂ (20 mg, 0.09 mmol, 0.2 eq. .), Xantphos (65 mg, 0.11 mmol, 0.3 eq.) and Cs ₂ CO ₃ (293 mg, 0.9 mmol, 2.0 eq.) in 1,4-dioxane (5 ml) in microwave heating conditions at 120°C for 1 h in an N2 atmosphere.

LC-MS: m/z 534.9, 536.9 (M+H) ⁺ .

Step F. N-(6-chloropyridazin-3-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-5-amine solution (60 mg, 0.12 mmol) in 4 M HCl in 1,4-dioxane (5 ml) was stirred at room temperature. during the night. The solvent and volatiles were removed under vacuum. The residue was dissolved in DCM (5 ml) and treated with saturated NaHCO ₃ . The organic phase was separated and washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

¹ H-NMR (DMSO-d ₆ /TRIFLUOROACETIC 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)+.

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COMPOUND 126

Stage 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 microwave heating at 100° C. for 1 hour under nitrogen.

LC-MS: m/z 501.2 (M+H) ⁺ .

Step F. Mixture of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(pyrazin-2-yl)pyrazolo[1,5a]pyrimidine-5-amine (50 mg, 0.0996 mmol ) in a solution of hydrogen chloride (4 M and dioxane, 3 ml) was stirred at room temperature. for 10 h. The mixture was evaporated to dryness. The residue was taken up in dichloromethane solution (with 10% methanol) and basified with aqueous ammonia to pH 8 to give 6-(4methoxyphenyl)-2,3-diphenyl-5-(pyrazin-2-ylamino)-pyrazolo[1, 5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d6): δ 14.27 (br. s., 1H), 9.93 (s., 1H), 9.38 (s, 1H), 8.61 (s, 1H) , 8.23 (s, 1H), 8.08 (s., 1H), 7.56 (m, 5H), 7.36 (d, J=8.60 Hz, 5H), 7.06 (d , J=8.33 Hz, 3H), 3.83 (s, 3H).

LC-MS: m/z 487.2 (M+H) ⁺ .

Compound 127 5-((3-hydroxypyrazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-oh.

Stage E (stoichiometry). Intermediate 5 (150 mg, 0.34 mmol) and 3-aminopyrazin-2-ol (49 mg, 0.44 mmol, 1.3 eq), Pd(OAc) ₂ (11 mg, 0.05 mmol, 0.15 eq.), Xantphos (29 mg, 0.05 mmol, 0.15 eq.) and Cs ₂ CO ₃ (221 mg, 0.68 mmol, 2.0 eq.) in 1,4-dioxane ( 10 ml) under microwave heating at 110°C for 1 hour under nitrogen.

LC-MS: m/z 516.9 (M+H) ⁺ .

Step F. 3-((7-Methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5yl)amino)pyrazin-2-ol solution (15 mg, 0.03 mmol) in 4 M HCl in 1,4-dioxane (5 ml) was stirred at 30° C. for 5 h. The reaction mixture was concentrated in vacuo to give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 14.12 (br. s., 1H), 12.64 (br. s., 1H), 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) ⁺ .

Compound 128 5-((3-Aminopyrazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidine-7(4H)-oh.

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 Cs ₂ CO ₃ (737 mg, 2.26 mmol, 2.0 eq.) in 1,4-dioxane (15 ml) were stirred at 120°C under microwave radiation for 1 hour under N2 atmosphere. The mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the title compound.

¹ H-NMR (TRIFLUOROACETIC 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) ⁺ .

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Compound 129 5-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrαzolo[1,5-a]pyrimidin5-ylamino)pyrazine-2-carbonitrile.

Stage E (stoichiometry). Intermediate 5 (500 mg, 1.13 mmol), 5-aminopyrazine-2carbonitrile (163 mg, 1.36 mmol), tris(dibenzylideneacetone) dipalladium (0) (311 mg, 0.34 mmol), Xantphos (216 mg , 0.374 mmol) and sodium carbonate (264 mg, 2.5 mmol) in 1,4-dioxane (20 mL) under reflux for 1 hour under N2 atmosphere.

LC-MS: m/z 526.2 (M+H) ⁺ .

Step F. To a solution of 5-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5ylamino)pyrazine-2-carbonitrile (100 mg, 0.19 mmol) in dichloromethane (6 ml) was added a solution of HCl (4 M in dioxane, 10 ml). The reaction mixture was stirred at rt. for 16 hours. The reaction mixture was neutralized with a solution of ammonia (7 M in methanol) to pH 7-8, resulting in 5-(6-(4methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo [1,5-α]pyrimidin-5-ylamino)pyrazine-2carbonitrile.

1H-NMR (DMSO-d6): δ 9.79 (s, 1H), 8.60 (s, 1H), 7.95 (s, 1H), 7.57 (d, J=6.45 Hz, 2H), 7.47 (d, J=7.25 Hz, 2H), 7.27-7.42 (m, 7H), 7.17 (d, J=6.72 Hz, 1H), 7, 01 (d, J=8.33 Hz, 2H), 3.81 (s, 3H).

LC-MS: m/z 512.2 (M+H)+.

Compound 130 5-((5-Aminopyrazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage 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 microwave heating at 110° C. for 1 h under N2 atmosphere.

LC-MS: m/z 516.2 (M+H) ⁺ .

Step F. Mixture of N ² -(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-α]pyrimidin-5-yl) pyrazin-2,5-diamine (50 mg, 0 .10 mmol) in a solution of hydrogen chloride (4 M in dioxane, 5 ml) was stirred at room temperature. within 16 hours the Mixture was evaporated to dryness. The residue was taken up in dichloromethane (with 10% methanol), basified with aqueous ammonia to pH 8 to give 5-(5-aminopyrazin-2-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[ 1,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSOCH): δ 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) ⁺ .

Compound 131 6-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrαzolo[1,5-a]pyrimidin5-ylamino)pyrazine-2-carbonitrile.

Stage E (stoichiometry). Intermediate 5 (500 mg, 1.13 mmol), 6-aminopyrazine-2carbonitrile (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 microwave heating at 110° C. for 1 hour under N ₂ atmosphere.

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LC-MS: m/z 526.2 (M+H)+.

Step F. To a solution of 6-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5ylamino)pyrazine-2-carbonitrile (100 mg, 0.19 mmol) in dichloromethane (6 ml) was added a solution of HCl (4 M in dioxane, 2 ml). The reaction mixture was stirred at rt. within 18 s. The mixture was evaporated to dryness. The residue was separated in dichloromethane solution (with 10% methanol) and washed with aqueous sodium bicarbonate to pH 8. The organic phase was dried with sodium to give 6-(6-(4-methoxyphenyl)-7oxo-2,3-diphenyl-4,7 -dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)-pyrazine-2-carbonitrile.

1H-NMR (DMSO-d6): δ 8.57-8.71 (m, 2H) 7.44-7.65 (m, 4H) 7.21-7.42 (m, 8H) 6.99 ( d, J=8.55 Hz, 2H), 3.80 (s, 3H).

LC-MS: m/z 512.2 (M+H) ⁺ .

Compound 132 5-((1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

il Ί /GA

Ν^Ν Τ η 'τ

Stage E (stoichiometry). Intermediate 5 (800 mg, 1.81 mmol), 1,3,5-triazine-2-amine (348 mg, 3.62 mmol) and Pd(OAc) ₂ (81 mg, 0.36 mmol), Xantphos (260 mg, 0.45 mmol) and Na ₂ CO ₃ (384 mg, 3.62 mmol) in 1,4-dioxane (15 ml) under heating conditions to 120° C. for 4 h under N2 atmosphere.

LC-MS: m/z 502.0 (M+H)+.

Step F. 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1,3,5-triazin-2-yl)pyrazolo[1,5-a]pyrimidine5-amine (500 mg , 1.0 mmol) was dissolved in HCl in 1,4-dioxane (10 ml). The solution was stirred at rt. within 2 hours the Precipitate was filtered and washed with dichloromethane (CH ₂ Cl ₂ , 3x1 ml), resulting in a yellow solid. Then the solid was dissolved in CH ₂ Cl ₂ /MeOH (10/1, 3 ml). After 3 ml was added NH ₃ -MeOH, the solution was stirred at room temperature. overnight to give the title compound.

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)+.

Compound 133 5-((1,2,4-triazin-5-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (220 mg, 0.5 mmol), 1,2,4-triazine-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 microwave heating at 105°C for 45 min under N ₂ atmosphere.

LC-MS: m/z 502.2 (M+H)+.

Step F. A mixture of 7-methoxu-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1,2,4-triazin-5-yl)pyrazolo[1,5a]pyrimidine-5-amine (100 mg, 0.20 mmol) in a solution of hydrogen chloride (4 M and dioxane, 15 ml) was stirred at room temperature. for 4 hours. The mixture was evaporated to dryness. The residue was taken up in dichloromethane (with 10% methanol), basified with aqueous ammonia to pH 8 to give 5-(1,2,4triazin-5-ylamino)-6-(4-methoxyphenyl)-2,3- diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

1H-NMR (DMSO-d ₆ ): δ 9.14 (s, 1H), 8.74 (s., 1H), 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)+.

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Compound 134 -He.

Stage E (stoichiometry). Intermediate 5 (500 mg, 1.13 mmol), 1,3,5-triazine-2,4diamine (189 mg, 1.7 mmol, 1.5 eq.), Pd(OAc) ₂ (38 mg, 0 .17 mmol, 0.15 eq.), Xantphos (98 mg, 0.17 mmol, 0.15 eq.) and Cs ₂ CO ₃ (360 mg, 3.34 mmol, 3.0 eq.) in 1, 4-dioxane (15 ml) under microwave heating at 105°C for 1 h under N2 atmosphere.

LC-MS: m/z 516.9 (M+H) ⁺ .

Step F. A solution of 5-((4-amino-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidine-7(4H )-one (156 mg, 0.3 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at 30° C. for 5 h. The reaction mixture was concentrated in vacuo to give the title compound .

¹ H-NMR (DMSO-d ₆ ): δ 13.80 (s, 1H), 8.17 (s, 2H), 7.66 (s, 1H), 7.51 (m, 4H), 7, 38 (dd, J=9.8, 6.1Hz, 7H), 7.33 (d, J=8.0Hz, 2H), 7.03 (d, J=8.4Hz, 2H), 3.80(s, 3H).

LC-MS: m/z 503.0 (M+H) ⁺ .

Compound 135 4H)-on.

Stage E (stoichiometry). Intermediate 5 (249 mg, 0.57 mmol), N2-methyl-1,3,5-triazine2,4-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 Cs2CO3 (370 mg, 1.13 mmol, 2.0 eq.) in 1 ,4-dioxane (10 ml) under microwave heating at 100° C. for 1 hour under N ₂ atmosphere.

LC-MS: m/z 531.0 (M+H)+.

Step F. N ² solution 2,4-diamine (100 mg, 0.19 mmol) in 4 M HCl in 1,4-dioxane (15 mL) was stirred at rt. for 6h to give the title compound.

1H-NMR (DMSO-d6 and TRIFLUOROACETIC 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) ⁺ .

Compound 136 -He.

¹ stage A 2

Step A. 5-((4-methoxy-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]n-yrimidin-7(4H) -He.

A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine (1.0 g, 2.26 mmol), 4-methoxy-1,3, 5-triazine-2-amine (424.7 mg, 3.39 mmol), palladium diacetate (253.7 mg,

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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) were refluxed for 12 h in a nitrogen atmosphere. After cooling to rt. the mixture was filtered with celite, diluted with dichloromethane (150 ml), washed with brine (50 ml), dried with anhydrous sodium sulfate and concentrated to dryness. The residue was purified to give 5-((4-methoxy-1,3,5-triazin-2-yl)amino)-6-(4methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine- 7(4H)-one as a yellow solid.

LC-MS: m/z 518.2 (M+H)+.

Step B. 5-((4-hydroxy-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidine-7(4H) -He.

5-((4-Methoxy-1,3,5-triazin-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one solution (350 mg, 0.68 mmol) in 4 M HCl in 1,4-dioxane (40 mL) was stirred at rt. over 16 h. The mixture was concentrated and saturated NaHCO ₃ (10 mL) was added to give 5-((4-hydroxy-1,3,5-triazin-2-yl)amino)-6-(4- methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-b ₆ ): δ 8.07 (br. s., 1H), 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)+.

Compound 137. 6-(4-Methoxyphenyl)-2,3-diphenyl-5-(thiazol-2-ylamino)pyrazolo[1,5-a]pyrimidin7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (220 mg, 0.5 mmol), thiazol-2-amine (100 mg, 1.0 mmol, 2 eq.), Pd(OAc) ₂ (56 mg, 0.25 mmol, 0.5 eq. .), Xantphos (174 mg, 0.3 mmol, 0.6 eq.) and Na ₂ CO ₃ (117 mg, 1.1 mmol, 2.2 eq.) in 1,4-dioxane (5 ml) in conditions of heating to 100°C for 3 h in an atmosphere of N ₂ .

LC-MS: m/z 506.1 (M+H)+.

Step F. Solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrαzolo[1,5-a]pyrimidin-5yl)thiazol-2-amine (110 mg, 0.23 mmol) in 4 M HCl in 1,4-dioxane (10 ml) was stirred at rt. for 10 hours to give the title compound.

1H-NMR (DMSO-de): 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)+.

Compound 138 5-(isoxazol-3-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (400 mg, 0.9 mmol), isoxazol-3-amine (150 mg, 1.8 mmol, 2 eq.), Pd(OAc) ₂ (20 mg, 0.09 mmol, 0.1 eq. .), Xantphos (104 mg, 0.18 mmol, 0.2 eq.) and Na ₂ CO ₃ (190 mg, 1.8 mmol, 2 eq.) in 1,4-dioxane (5 ml) under heating conditions up to 100°C for 16 h in an atmosphere of N ₂ .

LC-MS: m/z 490.5 (M+H)+.

Step F. Solution of 5-(isoxazol-3-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one (90 mg, 0.17 mmol) in 4 M HCl in 1,4-dioxane (3 ml) was stirred at rt. within 2 hours the Solvent and volatiles were removed under vacuum. The mixture was basified with NaHCO3 solution to pH 8 and concentrated in vacuo to give the title

- 62 042905 connection.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 139 5-(isoxazol-4-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (150 mg, 0.34 mmol) and isoxazol-4-amine (57 mg, 0.68 mmol, 2.0 eq.), Pd(OAc) ₂ (16 mg, 0.07 mmol, 0, 2 eq.), Xantphos (41 mg, 0.07 mmol, 0.2 eq.) and Cs ₂ CO ₃ (442 mg, 1.36 mmol, 4.0 eq.) in 1,4-dioxane (10 ml ) under microwave heating at 100°C for 1 h in an N2 atmosphere.

LC-MS: m/z 490.2 (M+H) ⁺ .

Step F. Solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5yl)isoxazol-4-amine (38 mg, 0.08 mmol) in 4 M HCl in 1,4-dioxane (5 ml) was stirred at 30° C. for 5 h. The reaction mixture was concentrated in vacuo to give the title compound.

1H-NMR (DMSO-d ₆ ): 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)+.

Compound 140 5-(isoxazol-5-ylamino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

n o \ N G HN /=4 °

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, 0.09 mmol, 0.4 eq.) and K ₂ CO ₃ (63 mg, 0.45 mmol, 2.5 eq.) in dioxane (4 ml) were stirred at heating to 100°C (heating by microwave radiation) for 1 h in an atmosphere of N ₂ . The mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the title compound.

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)+.

Compound 141 6-(4-methoxyphenyl)-5-(1-methyl-1H-imidazol-2-ylamino)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Λ

I n HN /=4 °

Stage E (stoichiometry). Intermediate 5 (100 mg, 0.226 mmol), 1-methyl-1H-imidazole2-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 microwave heating at 110° C. for 1 hour under N ₂ atmosphere.

LC-MS: m/z 503.2 (M+H)+.

Step F. 7-methoxy-6-(4-methoxyphenyl)-N-(1-methyl-1H-imidazol-2-yl)-2,3diphenylpyrazolo[1,5-c]pyrimidine-5-amine mixture (50 mg , 1 mmol) in a solution of hydrogen chloride (4 M in dioxane, 10 ml) was stirred at 70°C for 16 h. The mixture was evaporated to dryness. The residue was taken up in dichloromethane solution (with 10% methanol) and washed with aqueous sodium bicarbonate until pH 8. The organic phase was dried over sodium sulfate to give 6-(4-methoxyphenyl)-5-(1-methyl-1-nimidazol-2 -ylamino)-2,3-diphenylpyrazolo[1,5-a]nirimidin-7(4H)-one.

1 H-NMR (DMSO-d ₆ ): δ 7.49-7.31 (m, 14H), 6.99 (d, J=7.63 Hz, 2H), 3.78 (s, 3H), 3 .52 (s, 3H).

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LC-MS: m/z 489.2 (M+H) ⁺ .

Compound 142 5-((1H-imidazol-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (441 mg, 1.0 mmol), 1H-imidazol-2-amine (83 mg, 1 mmol, 2 eq.), Pd ₂ (dba) ₃ (91.5 mg, 0.1 mmol, 0 .1 eq.), Xantphos (115.6 mg, 0.2 mmol, 0.2 eq.) and Na ₂ CO ₃ (212 mg, 2 mmol, 2 eq.) in toluene (40 ml) under conditions of heating to 105°C for 5 h under N2 atmosphere.

LC-MS: m/z 489.5 (M+H) ⁺ .

Step F. N-(1H-imidazol-2-yl)-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-5-amine solution (40 mg, 0.08 mmol) in 4 M HCl in 1,4-dioxane (15 mL) was stirred at room temperature. within 16 hours the Solvent and volatiles were removed under vacuum. The resulting residue was basified with NaHCO ₃ solution to pH 8 and concentrated to give the title compound.

1H-NMR (DMSOCH): δ 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) ⁺ .

Compound 143 5-((4,5-dihydrothiazol-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (441 mg, 1.0 mmol), thiazol-2-amine (102 mg, 1 mmol, 2 eq.), Pd ₂ (dba) ₃ (91.5 mg, 0.1 mmol, 0.1 eq.), Xantphos (115.6 mg, 0.2 mmol, 0.2 eq.) and Na ₂ CO ₃ (212 mg, 2 mmol, 2 eq.) in toluene (40 ml) under conditions of heating to 105 ° C for 5 h in an N2 atmosphere.

LC-MS: m/z 506.5 (M+H) ⁺ .

Step F. Solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5yl)thiazol-2-amine (40 mg, 0.08 mmol) in 4 M HCl in 1,4-dioxane (15 ml) was stirred at rt. within 16 hours the Solvent and volatiles were removed under vacuum. The resulting residue was basified with NaHCO3 solution to pH 8 and concentrated to give the title compound.

1H-NMR (DMSO^): 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) ⁺ .

Compound 144 5-((1,3,4-thiadiazol-2-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (442 mg, 1.0 mmol) and 1,3,4-thiadiazol-2-amine (101 mg, 1.0 mmol, 1 eq) and Pd(OAc)2 (91.5 mg, 0 .1 mmol, 0.1 eq.), Xantphos (115.6 mg, 0.2 mmol, 0.2 eq.) and Na ₂ CO ₃ (212 mg, 2.0 mmol, 2.0 eq.) toluene (40 ml) under conditions of heating to 110°C for 5 h under N2 atmosphere.

LC-MS: m/z 507.1 (M+H) ⁺ .

Step F. N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,3,4thiadiazol-2-amine mixture (112 mg , 0.2 mmol) in 4 n. HCl in 1,4-dioxane (15 ml) was stirred at rt. during the night. The reaction mixture was concentrated under vacuum. The residue was stirred with methanol and saturated sodium bicarbonate solution to give the title compound.

- 64 042905

1H-NMR (DMSO-d ₆ ): δ 13.83 (br. s., 1H), 10.57 (br. s., 1H), 9.05 (br. s., 1H), 7.54 (br. s., 4H), 7.42 (br. s.,

5H), 7.34 (br. s., 3H), 7.08 (d, J=7.79 Hz, 2H), 3.85 (s, 3H).

LC-MS: m/z 493.1 (M+H)+.

Compound 145 -He.

h ₂ ns^n (/ 7 I h HN =.

-o-u o

Stage E (stoichiometry). Intermediate 5 (600 mg, 1.36 mmol) and 1,3,4-thiadiazole-2,5diamine (315 mg, 2.72 mmol, 2 eq.), Pd(OAc) ₂ (306 mg, 0.1 .36 mmol, 1 eq.), Xantphos (786 mg, 1.36 mmol, 1 eq.) and Cs ₂ CO ₃ (887 mg, 2.72 mmol, 2.0 eq.) in 1,4-dioxane ( 18 ml) under microwave heating at 120°C for 1 hour under N2 atmosphere.

LC-MS: m/z 522.0 (M+H) ⁺ .

Step F. N2-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)1,3,4-thiadiazole-2,5-diamine solution (100 mg, 0.19 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at rt. during the night. The solvent and volatiles were removed under vacuum. The residue was dissolved in DCM (5 ml) and basified with saturated NaHCO ₃ . The organic phase was separated and washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 146 -He. IO ^ ^N 's^n </ 7

I and g HN /=\

Stage E (stoichiometry). Intermediate 5 (442 mg, 1.0 mmol) and 5-methoxy-1,3,4-thiadiazol-2-amine (113 mg, 1.0 mmol, 1 eq.), Pd(OAc) ₂ (91.5 mg , 0.1 mmol, 0.1 eq.), Xantphos (115.6 mg, 0.2 mmol, 0.2 eq.) and Na ₂ CO ₃ (212 mg, 2.0 mmol, 2.0 eq. ) in toluene (40 ml) under conditions of heating to 110°C for 5 h under N2 atmosphere.

LC-MS: m/z 537.1 (M+H) ⁺ .

Step F. A mixture of 5-methoxy-N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin5-yl)-1,3,4-thiadiazol-2- amine (51.8 mg, 0.1 mmol) in 4N. HCl in 1,4-dioxane (15 ml) was stirred at rt. during the night. The reaction mixture was concentrated under vacuum. The residue was stirred with methanol and saturated sodium bicarbonate to give the title compound.

1H-NMR (DMSO-d6): δ 12.43 (s, 0.5H), 12.12 (s, 0.5H), 11.87 (s, 0.5H), 9.80 (s, 0 .5H), 7.50 (br. s., 3H), 7.41 (br. s., 4H), 7.30 (br. s., 4H), 7.04 (d, J=8, 55 Hz, 2H), 3.82(s, 3H).

LC-MS: m/z 509.1 (M+H) ⁺ .

Compound 147 5-((1,2,4-thiadiazol-5-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). Intermediate 5 (600 mg, 1.3 mmol) and 1,2,4-thiadiazol-5-amine (179 mg, 1.77 mmol, 1.3 eq.), Pd(OAc) ₂ (46 mg, 0 .2 mmol, 0.15 eq.), Xantphos (118 mg, 0.2 mmol, 0.15 eq.) and Cs ₂ CO ₃ (844 mg, 2.72 mmol, 2.0 eq.) in 1, 4-dioxane (15 ml) under conditions of heating to 100°C by microwave radiation for 1 h in an atmosphere of N ₂ .

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LC-MS: m/z 506.9 (M+H)+.

Step F. N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)1,2,4-thiadiazol-5-amine solution (214 mg, 0.42 mmol) in 4 M HCl in 1,4-dioxane (15 mL) was stirred at 30° C. for 5 h. The reaction mixture was concentrated in vacuo to give the title compound.

1H-NMR (DMSO-dg): 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) ⁺ .

Compound 148 -He. O-

Stage E (stoichiometry). Intermediate 5 (400 mg, 0.91 mmol) and 3-methoxy-1,2,4-thiadiazol-5-amine (155 mg, 1.18 mmol, 1.3 eq.), Pd(OAc) ₂ (11 mg , 0.14 mmol, 0.15 eq.), Xantphos (78.7 mg, 0.14 mmol, 0.15 eq.) and Cs ₂ CO ₃ (590 mg, 1.8 mmol, 2.0 eq. ) in 1,4-dioxane (10 ml) under microwave heating at 110° C. for 1 hour under N ₂ atmosphere.

LC-MS: m/z 537.0 (M+H) ⁺ .

Step F. Solution of 3-methoxy-N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-5-yl)-1,2,4-thiadiazol-5- amine (100 mg, 0.19 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at 30° C. for 5 h. The reaction mixture was concentrated in vacuo to give the title compound.

1H-NMR (DMSO): δ 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) ⁺ .

Compound 149 -He.

Stage E (stoichiometry). Intermediate 5 (220 mg, 0.5 mmol), N3-(7-mctokcu-6-(4methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1,2,5 -oxadiazole-3,4-diamine (101 mg, 1.0 mmol, 2.0 eq.), Pd(OAc) ₂ (11 mg, 0.05 mmol, 0.1 eq.), Xantphos (116 mg, 0.2 mmol, 0.4 eq.) and Cs ₂ CO ₃ (325 mg, 1.0 mmol, 2.0 eq.) in 1,4-dioxane (10 ml) under microwave heating conditions at 100°C for 1 h in an atmosphere of N ₂ .

LC-MS: m/z 506.1 (M+H) ⁺ .

Step F. N3-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)1,2,5-oxadiazol-3,4-diamine solution (237 mg, 0.47 mmol) in 4 M HCl in 1,4-dioxane (20 mL) was stirred at 30° C. for 5 h. The reaction mixture was concentrated in vacuo to give the title compound.

1H-NMR (DMSOCH): 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) ⁺ .

Compound 150 .

Stage E (stoichiometry). Intermediate 5 (500 mg, 1.13 mmol), ethyl 5-aminothiazole-4-carboxylate (292.3 mg, 1.70 mmol) and Pd(OAc) ₂ (76.2 mg, 0.34 mmol), Xantphos (196.4 mg, 0.34 mmol) and Cs ₂ CO ₃ (553.0 mg, 0.34 mmol) in 1,4-dioxane (10 ml) under microwave heating conditions

- 66 042905 at 120°C for 1.5 h in an atmosphere of N ₂ .

LC-MS: m/z 578.3 (M+H)+.

Step F. Ethyl 5-((7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpirazolo[1,5-a]n-pyrimidin-5yl)amino)thiazole-4-carboxylate solution (450 mg, 0 .78 mmol) in 4 M HCl in 1,4-dioxane (16 mL) was stirred at rt. over 18 h. The mixture was concentrated and saturated NaHCO ₃ (10 mL) was added to give ethyl 5-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo [1,5-a]pyrimidin-5yl)amino)thiazole-4-carboxylate.

¹ H-NMR (DMSO-d^: 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, 1H), 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) ⁺ .

Compound 151 -oh.

Stage E (stoichiometry). Intermediate 5 (200 mg, 0.450 mmol), 1H-pyrrolo[2,3c]pyridine-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 microwave heating at 100°C for 1 hour under N2 atmosphere.

LC-MS: m/z 539.2 (M+H)+.

Step F. 7-Methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1H-pyrrolo[2,3-c]pyridin-5-yl)pyrazolo[1,5-a]pyrimidine mixture -5-amine (80 mg, 0.148 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL) was stirred at rt. within 16 hours the Mixture was evaporated to dryness. The residue was taken up in dichloromethane solution (with 10% methanol) and basified with aqueous ammonia to pH 8 to give 5(1H-pyrrolo[2,3-c]pyridin-5-ylamino)-6-(4-methoxyphenyl) -2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)one.

¹ H-NMR (DMSOCH): 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, 1H).

LC-MS: m/z 525.2 (M+H)+.

-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine.

This compound was prepared according to the procedure for compound 101 using intermediate 8 as 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazole-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), and the resulting mixture was stirred for 1 h at 198°C. The mixture was cooled to rt. and decanted off the solvent. THF (150 mL) and HCl (6N, 600 mL) were added with vigorous stirring for 0.5 h. The precipitates were collected by filtration, washed with methanol and dried under reduced pressure to give 3-(cyclohex-1- en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (48 g) as a yellow solid.

1H-NMR (DMSO-d6): δ 7.74 (d, J=6.98 Hz, 2H), 7.31-7.49 (m, 5H), 6.94 (d, J=8.60 Hz, 2H), 5.80 (br. s., 1H), 3.78 (s, 3H), 2.15 (br. s., 2H), 2.02 (br. s., 2H), 1.65 (br. s., 4H).

LC-MS: m/z 414.2 (M+H)+.

Step C. 3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one solution (47.0 g, 104 mmol) in phosphorus oxychloride (100 ml) was stirred at reflux for 16 h. The solvent was removed in vacuo. The residue was slowly added 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-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylp-irazolo[1, 5-a]n-pyrimidine (50 g) as a yellow solid.

1 H-NMR (DMSO-d ₆ ): δ 7.82 (d, J=7.25 Hz, 2H), 7.36-7.56 (m, 5H), 7.10 (d, J=8, 60 Hz, 2H), 5.87 (br. s.,

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1H), 3.84 (s, 3H), 2.20 (br. s., 4H), 1.70 (d, J=4.57 Hz, 4H).

LC-MS: m/z 450.2 (M+H)+.

Step D. To a solution of 5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidine (40 g, 88 mmol) in dichloromethane (400 ml) at 0°C was added dropwise sodium methoxide (30% in methanol, 80 g). The resulting 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 with anhydrous sodium sulfate and concentrated in vacuo. The residue was suspended in MeOH (50 ml). The precipitates were collected by filtration, washed with methanol (MeOH) and dried under reduced pressure to give 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)- 2-phenylpyrazolo[1,5a]pyrimudine as a yellow solid.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl.

This compound was prepared according to the procedure for compound 101 using intermediate 1 as methyl-2-(quinolin-6-yl)acetate in step A.

Step A To dimethyl carbonate (150 mL) cooled at 0° C., potassium tert-butanolate (24 g, 216 mmol) was added portionwise. The resulting mixture was stirred at 0° C. for 1 h. Methyl-2(quinolin-6-yl)acetate (20 g, 100 mmol) was added. The resulting mixture was slowly heated to rt. and stirred for 1 h. The reaction mixture was heated to 80° C. with stirring overnight. After cooling to rt. the mixture was diluted with ethyl acetate (1500 ml), washed with saturated NH ₄ Cl (300 ml) and brine (250 ml), dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using a flash column (petroleum ether/ethyl acetate=3:1) to give dimethyl-2-(quinolin-6-yl)malonate (18.0 g) as a yellow solid.

LC-MS: m/z 260.1 (M+H) ⁺ .

Step B. Suspension of dimethyl-2-(quinolin-6-yl)malonate (13 g, 50 mmol) and 3,4-diphenyl-1H-pyrazol5-amine (11.8 g, 50 mmol) in tributylamine (100 ml) stirred at 185°C for 4 h. After cooling to rt. the mixture was filtered. The residue was diluted with dichloromethane (450 ml), washed with saturated NH ₄ Cl (150 ml) and brine (100 ml), dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using a flash column (DCM:MeOH=15:1) to give 2,3-diphenyl-6-(quinolin-6-ul)pyrazolo[1,5-a]pyrimidine-5,7( 4H,6H)-dione (18 g) as a yellow solid.

LC-MS: m/z 431.2 (M+H) ⁺ .

Step C. 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione solution (18 g, 42 mmol), DMAP (dimethylaminopyridine ) (1 g) and PCl ₅ (80 mg) in POCl ₃ (180 ml) were stirred at 100°C overnight. After cooling to rt. the solvent was removed under vacuum. The residue was cooled to 0°C. MeOH (60 ml) was added to stop the reaction. The resulting mixture was diluted with dichloromethane (450 ml), washed with saturated NaHCO ₃ (150 ml) and brine (100 ml), dried over anhydrous sodium sulfate and concentrated to give the crude product 6-(5,7-dichloro-2 ,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (13 g), which was used in the next step without further purification.

LC-MS: m/z 467.1 (M+n) ⁺ .

Step D. To a solution of 6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (13.0 g, crude, 27.8 mmol) in DCM/MeOH (200 ml, 1:1) cooled at 0° C., sodium methoxide (14.9 ml, 5.0 M in methanol) was added dropwise. The mixture was then stirred at 0° C. for 1 hour. Saturated NH4Cl (150 ml) was added to stop the reaction. The resulting mixture was extracted with dichloromethane (500 ml), washed with brine (150 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a flash column (DCM/MeOH=40:1) to give 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl) quinolinyl as a pale yellow solid.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

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6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl.

This compound was prepared according to the procedure for compound 101 using intermediate 1 as methyl-2-(quinolin-6-yl)acetate in step A and intermediate 8 as 4-(cyclohex-1-en-1-yl) -3-phenyl-1H-pyrazol-5-amine in step B.

Step B. Suspension of dimethyl-2-(quinolin-6-yl)malonate (1.95 g, 7.52 mmol) and 4-(cyclohex-1-en-1yl)-3-phenyl-1H-pyrazol-5- αmin (1.8 g, 7.52 mmol) in tributylamine (20 ml) was stirred at 185° C. for 4 h. the mixture was filtered. The residue was diluted with dichloromethane (150 ml), washed with saturated NH ₄ Cl (50 ml) and brine (50 ml), dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using a flash column (DCM:MeOH=15:1) to give 3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6yl)pyrazolo[1, 5-a]pyrimidine-5,7(4H,6H)-dione (3.1 g) as a yellow solid.

LC-MS: m/z 435.2 (M+H) ⁺ .

Step C. Solution of 3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine5,7(4H,6H)-dioneα ( 3.1 g, 7.13 mmol) in POCl ₃ (12 ml) was stirred at 110° C. overnight. After cooling to rt. the solvent was removed under vacuum. MeOH (60 ml) was slowly added to the residue cooled at 0°C to stop the reaction. The resulting mixture was diluted with dichloromethane (150 ml), washed with saturated NaHCO ₃ (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate and concentrated to give the crude product -6-(5,7-dichloro- 3-(cyclohex-1-en-1-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (1.3 g) which was used in the next step without further purification.

LC-MS: m/z 471.9 (M+H) ⁺ .

Step D. To a solution of 6-(5,7-dichloro-3-(cyclohex-1-en-1-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-6yl)quinolinyl (300 mg, crude, 0 .64 mmol) in DCM/MeOH (6 ml, 1:1) cooled at 0° C., sodium methoxide (0.64 ml, 5.0 M in methanol) was added dropwise. The mixture was then stirred at 0° C. for 1 hour. Saturated NH4Cl (50 ml) was added to stop the reaction. The resulting mixture was extracted with dichloromethane (150 ml), washed with brine (50 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column (DCM/MeOH=40:1) to give 6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5- a]pyrimidin-6-yl)quinolinyl as an off-white solid.

¹ H-NMR (CHLOROFORM-d): δ 9.28 (d, J=3.8 Hz, 1H), 8.76 (d, J=8.6 Hz, 2H), 8.11 (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: m/z 467.2 (M+H)+.

6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoxaline.

This compound was prepared according to the procedure for compound 101 using intermediate 1 as methyl-2-(quinoxalin-6-yl)acetate in step A and intermediate 8 as 4-(cyclohex-1-en-1-yl )-3-phenyl-1H-pyrazole-5-amine in step B.

Step A. Potassium tert-butanolate (3.8 g, 34.12 mmol) was added portionwise to dimethyl carbonate (30 ml) cooled at 0°C. The resulting mixture was stirred at 0° C. for 1 hour. Methyl-2(quinoxalin-6-yl)acetate (2.3 g, 11.37 mmol) was added. The resulting mixture was slowly heated to rt. and stirred for 1 h. The reaction mixture was heated to 90°C and stirred for 1.5 h. the mixture was diluted with ethyl acetate (150 ml), washed with saturated NH ₄ Cl (80 ml) and brine (50 ml), dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using a flash column (petroleum ether/ethyl acetate=3:1) to give dimethyl-2-(quinoxalin-6-yl)malonate (2.0 g) as a yellow solid.

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: m/z 261.1 (M+H)+.

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Step B. Suspension of 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazole-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 h. the mixture was filtered. The residue was diluted with dichloromethane (150 ml), washed with saturated NH ₄ Cl (50 ml) and brine (30 ml), dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using a flash column (DCM:MeOH=15:1) to give 3-(cyclohex-1-en-1-yl)-2-phenyl-6(quinoxalin-6-yl)pyrazolo[1.5 -a]pyrimidine-5,7(4H,6H)-dione (2.2 g) as a yellow solid.

%NMR (DMSO-d ₆ ): 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) ⁺ .

Step C. Solution of 3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidine5,7(4H,6H)-dione ( 1.0 g, 2.30 mmol) in POCl ₃ (6 ml) in a sealed tube was stirred at 110°C for 8 h. the solvent was removed under vacuum. The residue was cooled to 0°C. MeOH (6 ml) was added to stop the reaction. The resulting mixture was diluted with dichloromethane (150 ml), washed with saturated NaHCO ₃ (50 ml) and brine (30 ml), dried over anhydrous sodium sulfate and concentrated to give the crude product -6-(5,7-dichloro- 3-(cyclohex-1-en-1-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)quinoxaline (800 mg), which was used in the next step without further purification.

LC-MS: m/z 472.1 (M+n) ⁺ .

Step D. To a solution of 6-(5,7-dichloro-3-(cyclohex-1-en-1-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-6yl)quinoxaline (800 mg, crude, 2 .30 mmol) in DCM/MeOH (20 ml, 1:1) cooled at 0° C., sodium methoxide (2.3 ml, 5.0 M in methanol) was added dropwise. The mixture was then stirred at 0° C. for 1 h. Saturated NH ₄ Cl (50 ml) was added to stop the reaction. The resulting mixture was extracted with dichloromethane (100 ml), washed with brine (30 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column (DCM/MeOH=40:1) to give 6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5- a]pyrimidin-6-yl)quinoxaline as a brown solid.

¹ H-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) ⁺ .

The following compounds were prepared according to example 1, steps E and F, starting from 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2 -phenylpyrazolo[1,5a]pyrimidine.

Compound 153 -He.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (200 mg, 0.0449 mol), pyridine -2-amine (63.4 mg, 0.674 mol, 1.5 eq.), Pd(OAc) ₂ (20.2 mg, 0.0898 mol, 0.2 eq.), Xantphos (52 mg, 0, 0898 mol, 0.2 eq.) and K ₂ CO ₃ (265 mg, 1.12 mol, 2.5 eq.) in dioxane (5 ml) under conditions of heating to 120°C for 1 h under N2 atmosphere.

LC-MS: m/z 504.9 (M+H) ⁺ .

Step F. Solution of 3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2yl)pyrazolo[1,5-a]pyrimidine -5-amine (120 mg, 0.22 mol) in 4 M HCl/1,4-dioxane (3 mL) was stirred at rt. for 16 hours. The reaction mixture was basified with NaHCO ₃ solution to pH 8 and filtered to give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 9.09 (br. s., 1H), 8.20 (d, J=4.3 Hz, 1H), 7.82 (t, J=7, 3 Hz, 1H), 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) ⁺ .

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Compound 154 -He.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (200 mg, 0.45 mmol), pyridine -3-amine (85 mg, 0.90 mmol), Pd(OAc)2 (36 mg, 0.045 mmol), Xantphos (58 mg, 0.09 mmol), and Cs ₂ CO ₃ (293 mg, 0.90 mmol) in dioxane (20 ml) under conditions of heating to 110°C for 4 h under N2 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-(niridin-3yl)pyrazolo[1,5-a] pyrimidine-5-amine (60 mg, 0.12 mmol) in MeOH (10 ml) was added 4N. HCl solution in dioxane (10 ml). The reaction mixture was heated to 50° C. for 2 hours. The mixture was concentrated in vacuo. The crude product was alkalized with saturated NaHCO ₃ to give the target product 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-3ylamino)pyrazolo [1 ,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-dg): δ 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) ⁺ .

Compound 155 -oh.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (400 mg, 0.897 mmol) and pyrimidine-4 -amine (255.9 mg, 2.691 mmol, 3 eq.), Pd(OAc) ₂ (40.3 mg, 0.179 mmol, 0.2 eq.), Xantphos (578.6 mg, 0.359 mmol, 0.4 equiv.) and Cs ₂ CO ₃ (285.2 mg, 2.691 mmol, 3 equiv.) in 1,4-dioxane (10 ml) under microwave heating at 100° C. for 1 h under N ₂ atmosphere.

LC-MS: m/z 505.0 (M+H) ⁺ .

Step F. Solution of 3-(cyclohex-1-en-1-ul)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyrimidin-4yl)pyrazolo[1,5-a]pyrimidine -5-amine (100 mg, 0.198 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was stirred at rt. within 3 hours the Reaction mixture was concentrated under vacuum. The residue was dissolved in 7N. NH3 in methanol and stirred at rt. for 2 hours to give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 8.98 (s, 1H), 8.49 (d, J=7.02 Hz, 1H), 7.79 (d, J=7.32 Hz, 2H), 7.41-7.52 (m, 3H), 7.27 (m, J=8.54 Hz, 2H), 7.18 (d, J=6.41 Hz, 1H), 6, 93 (m, J=8.54 Hz, 2H), 5.87 (br. s., 1H), 2.18 (br. s., 2h), 2.06 (br. s., 2H), 1.67 (br. s., 4H).

LC-MS: m/z 491.0 (M+H) ⁺ .

Compound 156. 3-cyclohexenyl-6-(4-methoxyphenyl)-5-(2-methoxypyrimidin-4-ylamino)-2phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (200 mg, 0.452 mmol) and 2-methoxypyrimidine -4-amine (113 mg, 0.904 mmol) and Pd(OAc) ₂ (31 mg, 0.136 mmol), Xantphos (157 mg, 0.272 mmol) and Na ₂ CO ₃ (96 g, 0.904 mmol) in 1.4- dioxane (10 ml) under conditions of heating to 110°C for 4 h in an atmosphere of N ₂ .

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1H-NMR (DMSO-d) δ 8.46 (d, J=5.6 Hz, 1H), 8.14 (d, J=5.6 Hz, 1H), 7.81 (d, J=7 .2 Hz, 2H), 7.56 (s,

1H), 7.42-7.51 (m, 4H), 7.16-7.18 (m, 2H), 5.88 (bs, 1H), 4.11 (s, 3H), 3.86 (s, 3H), 3.80 (s, 3H), 2.22-2.27 (m,

4H), 1.70-1.75 (m, 4H).

LC-MS: m/z 535.2 (M+H) ⁺ .

Step F. A mixture of 3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-N-(2-methoxy-pyrimidin-4-yl)-2phenyl-pyrazolo[1,5-a]pyrimidin-5-amine ( 55 mg, 0.103 mmol) and HCl solution (4N in dioxane, 6 ml) were stirred at rt. during the night. The mixture was neutralized with NH3 solution (7N in methanol) to pH 7 to give 3-cyclohexenyl-6-(4-methoxyphenyl)-5-(2-methoxypyrimidin-4-ylamino)-2phenylpyrazolo[1.5 -a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d ₆ ): δ 13.82 (s, 1H), 9.38 (s, 1H), 8.28 (d, J=5.80 Hz, 1H), 7.75 ( d, J=7.32 Hz, 2H), 7.45-7.51 (m, 2H), 7.42 (d, J=7.32 Hz, 1H), 7.29 (m, J=8 .54 Hz, 2H), 7.02 (m, J=8.85 Hz, 2H), 6.86 (d, J=5.80 Hz, 1H), 5.99 (s, 1H), 3 .92 (s, 3H), 3.81 (s, 3H), 2.28 (bs, 2H) 2.06 (bs, 2H), 1.70 (bs, 4H).

LC-MS: m/z 521.5 (M+H) ⁺ .

Compound 157 -He.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (150 mg, 0.34 mmol) and pyridazine -3-amine (65 mg, 0.68 mmol, 2.0 eq.), Pd(OAc) ₂ (16 mg, 0.07 mmol, 0.2 eq.), Xantphos (41 mg, 0.07 mmol , 0.2 eq.) and Cs ₂ CO ₃ (442 mg, 1.36 mmol, 4.0 eq.) in 1,4-dioxane (10 ml) under microwave heating at 100°C for 1 h in a nitrogen atmosphere.

LC-MS: m/z 504.9 (M+H) ⁺ .

Step F. Solution of 3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridazin-3yl)pyrazolo[1,5-a]pyrimidine -5-amine (70 mg, 0.14 mmol) in 4 M HCl in 1,4-dioxane (15 mL) was stirred at 30° C. for 5 h. The reaction mixture was concentrated in vacuo to give the title compound.

1H-NMR (DMSO-d ₆ ): 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)+.

Compound 158. 3-cyclohexenyl-6-(4-methoxyphenyl)-2-phenyl-5-(pyrazin-2-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpirazolo[1,5-a]n-pyrimidine (200 mg, 0.450 mmol), and pyrazine- 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 (10 ml) under microwave heating at 100° C. for 1 h under nitrogen atmosphere.

LC-MS: m/z 505.2 (M+H)+.

Step F. A solution of 3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(πyrazin-2yl)pyrazolo[1,5-a]pyrimidine-5-amine (150 mg, 0. 30 mmol) in 4 M HCl/1,4-dioxane (5 ml) was stirred at rt. within 24 hours the Reaction mixture was concentrated under vacuum. The residue was dissolved in dichloromethane:methanol=10:1 (10 ml) and washed with saturated sodium carbonate (5 ml) twice until pH 8. The organic layer was concentrated in vacuo to give 3-cyclohexenyl-6-(4methoxyphenyl)-2 -phenyl-5-(pyrazin-2-ylamino)n-pyrazolo[1,5-a]pyrimidin-7(4H)-one.

1H-NMR (DMSO-d ₆ ): δ 3.90 (s, 1H), 9.35 (s, 1H), 8.64 (s, 1H), 8.25 (d, J=2.75 Hz , 1H), 8.20 (dd, J=2.75, 1.22 Hz, 1H), 7.67-7.77 (m, 2H) 7.44-7.53 (m, 2H), 7 .37-7.44 (m, 1H), 7.27-7.36 (m, 2H), 6.98-7.06 (m, 2H), 6.04 (br. s., 1H) 3 .81 (s, 3H), 2.34 (br. s., 2H), 2.05 (br. s., 2H), 1.70 (d, J=4.88 Hz, 4H).

LC-MS: m/z 491.2 (M+H)+.

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Compound 159 5-(3-cyclohexenyl-6-(4-methoxyphenyl)-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (500 mg, 1.07 mmol), 5 -aminopyrazine-2-carbonitrile (257 mg, 2.15 mmol), palladium (II) acetate (48 mg, 0.214 mmol), Xantphos (124 mg, 0.214 mmol) and sodium carbonate (230 mg, 0.215 mmol) in 1, 4-dioxane (10 ml) under conditions of heating to 110°C for 4 h under nitrogen atmosphere.

LC-MS: m/z 530.2 (M+H) ⁺ .

Step F. A mixture of 5-(3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin5-ylamino)pyrazine-2-carbonitrile (170 mg, 0.321 mmol) in a solution of hydrogen chloride (4 M in dioxane, 5 ml) was stirred at room temperature. within 16 hours the Mixture was evaporated to dryness. The residue was taken up in dichloromethane solution (with 10% methanol) and washed with aqueous sodium bicarbonate to pH 8. The organic phase was dried over sodium sulfate to give 5-(3-cyclohexenyl-6-(4-methoxyphenyl)-7-oxo -2phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-ylamino)pyrazine-2-carbonitrile.

1H-NMR (DMSO-06): δ 12.76 (br. s., 1H), 10.15 (br. s., 1H), 8.73 (s, 1H) 8.44 (br. s. , 1H), 7.75 (d, J=7.02 Hz, 2H), 7.36-7.54 (m, 3H), 7.28 (m, J=8.54 Hz, 2H), 6 .97 (m, J=8.55 Hz, 2H), 5.92 (br. s., 1H), 3.78 (s, 3H), 2.25 (br. s., 2H), 2, 04 (br. s., 2H), 1.68 (br. s., 4H).

LC-MS: m/z 516.2 (M+H)+.

Compound 160 7(4H)-oh.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (44 mg, 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 conditions of heating to 110°C for 1 h under nitrogen atmosphere.

LC-MS: m/z 520.2 (M+H) ⁺ .

Step F. Mixture of N ² -(3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidin-5-yl)pyrazin-2,5-diamine (90 mg, 0 .18 mmol) in a solution of hydrogen chloride (4 M in dioxane, 5 ml) was stirred at 50° C. for 3 h. The mixture was evaporated to dryness. The residue was taken up in dichloromethane solution (with 10% methanol), basified with aqueous ammonia to pH 8 to give 5-(5-aminopyrazin-2-ylamino)-3-cyclohexenyl-6-(4-methoxyphenyl)-2- phenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

1H-NMR (DMSO-d ₆ ): δ 13.92 (s, 1H), 8.70 (s, 1H), 8.08 (d, J=1.2 Hz, 1H), 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+H) ⁺ .

Compound 161 a] pyrimidine-7(4H)-oh.

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Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (150 mg, 0.34 mmol) and 1 ,2,4-triazine-3-amine (65 mg, 0.68 mmol,

2.0 eq.), Pd(OAc)2 (16 mg, 0.07 mmol, 0.2 eq.), Xantphos (41 mg, 0.07 mmol, 0.2 eq.) and Cs ₂ CO ₃ ( 442 mg

1.36 mmol, 4.0 eq.) in 1,4-dioxane (10 ml) under microwave heating conditions at

100°C for 1 h under nitrogen atmosphere.

LC-MS: m/z 505.9 (M+H) ⁺ .

Step F. Solution of 3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(1,2,4-triazin-3yl)pyrazolo[1 ,5-a]pyrimidine-5-amine (30 mg, 0.06 mmol) in 4 M HCl in 1,4-dioxane (15 ml) was stirred at 30°C for 5 h. The reaction mixture was concentrated in vacuo, in resulting in the title compound.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 162 a] pyrimidin-7(4H)-one.

Stage E (stoichiometry). 5-chloro-3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (110 mg, 0.25 mmol), 1,2,4-triazine-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 microwave heating at 105°C for 45 min under nitrogen.

LC-MS: m/z 506.2 (M+H)+.

Step F. Mixture of 3-cyclohexenyl-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(1,2,4-triazin-5yl)pyrazolo[1,5-a]pyrimidine-5-amine (50 mg, 0.10 mmol) in hydrogen chloride solution (4 M in dioxane, 5 mL) was stirred at rt. for 4 hours. The mixture was evaporated to dryness. The residue was taken up in dichloromethane solution (with 10% methanol), basified with aqueous ammonia to pH 8 to give 5-(1,2,4-triazin-5-ylamino)-3-cyclohexenyl-6-(4-methoxyphenyl )-2-phenylnurazolo[1,5-a]pyrimidine7(4H)-one.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 163 a] pyrimidin-7(4H)-one.

Suspension of 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidine (500 mg, 1.121 mmol) and 1, 3,5-triazine-2-amine (323.2 mg, 3.364 mmol, 3 eq.), Pd(OAc) ₂ (50.3 mg, 0.224 mmol, 0.2 eq.), Xantphos (259.5 mg , 0.453 mmol, 0.4 eq.) and Cs ₂ CO ₃ (1.09 g, 3.364 mmol, 3 eq.) in 1,4-dioxane (10 ml) were stirred and heated to 100°C (heating by microwave radiation) for 1 h in an N2 atmosphere. The reaction mixture was then cooled to rt, diluted with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (20x3 ml). The combined organic layers were washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo to give the title compound.

1H-NMR (CHLOROFORM-d): δ 12.85 (br. s., 1H), 8.85 (s, 2H), 7.88 (d, J=6.18 Hz, 2H), 7.76 (br. s., 1H), 7.35-7.48 (m, 4H), 7.08 (d, J=8.06 Hz, 2H), 6.09 (br. s., 1H), 3.89 (s, 2H), 2.37 (br. s., 2H), 2.12 (br. s., 2H), 1.77 (br. s., 3H), 1.68 (br s., 1H), 1.23-1.39 (m, 1H).

LC-MS: m/z 492.0 (M+H) ⁺ .

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Compound 164 1,5-a] pyrimidin-7(4H)-one.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (222 g, 0.5 mmol), 1 ,3,5-triazine-2,4-diamine (83 mg, 0.75 mmol, 1.5 eq.), Pd(OAc) ₂ (23 mg, 0.1 mmol, 0.2 eq.), Xantphos (115 mg, 0.2 mmol, 0.4 eq.) and Cs ₂ CO ₃ (195 mg, 0.6 mmol, 12 eq.) in 1,4-dioxane (4 ml) under microwave heating conditions at 100 °C for 1 h under N2.

LC-MS: m/z 521.0 (M+I)+.

Step F. Solution N ² -(3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidin-5-yl)-1 ,3,5-triazine-2,4-diamine (80 mg, 0.15 mmol) in HCl-1,4-dioxane (5 ml). The solution was stirred at rt. within 6 hours the Solvent and volatiles were removed under vacuum. The residue was dissolved in DCM (5 ml) and treated with saturated NaHCO ₃ . The organic phase was separated and washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 165 He.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (1.0 g, 2.24 mmol) , isoxazol-3-amine (377.1 mg, 4.48 mmol) and palladium diacetate (101.0 mg, 0.45 mmol), Xantphos (388.8 mg, 0.67 mmol) and sodium carbonate (474, 8 mg, 4.48 mmol) in 1,4-dioxane (50 ml) under heating conditions to 110° C. for 12 h under nitrogen atmosphere.

LC-MS: m/z 494.2 (M+I) ⁺ .

Step F. N-(3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidin-5-yl)isoxazol-3 solution -amine (450 mg, 0.91 mmol) in 4 M HCl in 1,4-dioxane (40 mL) was stirred at rt. within 2 hours

The mixture was concentrated at low temperature (<25°C) and saturated NaHCO ₃ (8 ml) was added, resulting in 3-(cyclohex-1-en-1-yl)-5-(isoxazol-3-ylamino)-6 -(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d ₆ ): δ 11.97 (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) ⁺ .

Compound 166 a] pyrimidin-7(4H)-one.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (220 mg, 0.5 mmol), 1 ,2,4-thiadiazol-5-amine (101 mg, 1.0 mmol, 2.0 eq.), Pd(OAc) ₂ (22 mg, 0.1 mmol, 0.2 eq.), Xantphos (57 .8 mg, 0.1 mmol, 0.2 eq.) and Cs ₂ CO ₃ (325 mg, 1.0 mmol, 2.0 eq.) in 1,4-dioxane (10 ml) under microwave heating conditions at 100°C for 1 h under nitrogen atmosphere.

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LC-MS: m/z 511.2 (M+H)+.

Step F. N-(3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-nirazolo[1,5a]pyrimidin-5-yl)-1 solution, 2,4-thiadiazol-5-amine (51 mg, 0.1 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was stirred at 30° C. for 5 h. The reaction mixture was concentrated in vacuo to give which gave the title compound.

¹ H-NMR (DMSO): δ 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) ⁺ .

Compound 167 a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]-pyrimidine (446 mg, 1.0 mmol), 1 ,3,4-thiadiazol-2-amine (101 mg, 1.0 mmol, 1 eq.) and Pd(OAc) ₂ (91.5 mg, 0.1 mmol, 0.1 eq.), xant-phos (115.6 mg, 0.2 mmol, 0.2 eq.) and Na ₂ CO ₃ (212 mg, 2.0 mmol, 2.0 eq.) in toluene (40 ml) under conditions of heating to 110°C for 5 h under nitrogen atmosphere.

LC-MS: m/z 511.2 (M+H) ⁺ .

Step F. Mixture of N-(3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-nirazolo[1,5a]pyrimidin-5-yl)-1, 3,4-thiadiazol-2-amine (102 mg, 0.2 mmol) in 4N HCl in 1,4-dioxane (15 ml) was stirred at rt. during the night. The mixture was concentrated under vacuum. The residue was basified with saturated sodium bicarbonate to give the title compound.

^-NMR (DMSO-d ₆ ): δ 13.77 (br. s., 0.5H), 10.56 (br. s., 0.5H), 9.09 (br. s., 1H) , 7.74 (d, J=7.02 Hz, 2H), 7.40-7.57 (m, 3H), 7.31 (m, J=8.24 Hz, 2H), 7.05 ( m, J=8.55 Hz, 2H), 6.03 (br. s., 1H), 3.83 (s, 3H), 2.29 (br. s., 2H), 2.08 (br. s., 2H), 1.70 (br. s., 4H).

LC-MS: m/z 497.1 (M+H)+.

The following compounds were prepared according to the procedure for preparing compound 101, steps E-F, starting from 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5a]pyrimidin-6-yl)quinolinyl.

Compound 168 2,3-diphenyl-5-(pyridin-2-ylamino)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine 7(4H)-oh.

A mixture of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (250 mg, 0.541 mmol), pyridine-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) were stirred under atmosphere nitrogen in a sealed test tube and heated to 110°C under the influence of microwave radiation for 1 h, as a result of which 2,3-diphenyl-5-(pyridin-2-ylamino)-6-(quinolin-6yl)pyrazolo[1, 5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d6): δ 15.93 (br. s., 1H), 9.36 (s, 1H), 8.74 (d, J=8.06 Hz, 1H), 8, 16-8.34 (m, 2H), 8.07 (d, J=3.76 Hz, 1H), 7.99 (d, J=8.33 Hz, 1H), 7.75-7.85 (m, 2H), 7.60 (t, J=7.52 Hz, 4H), 7.39-7.54 (m, 5H), 7.21-7.28 (m, 1H), 7, 09-7.17 (m, 1H), 6.98 (s, 1H).

LC-MS: m/z 507.2 (M+H) ⁺ .

Compound 169 2,3-diphenyl-5-(pyrimidin-4-ylamino)-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

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Stage E (stoichiometry). 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6yl)quinolinyl (600 mg, 1.3 mmol), pyrimidine-4-amine (148 mg, 1.56 mmol, 1.2 equiv.), Pd(OAc)2 (43.7 mg,

0.19 mmol, 0.15 eq.), Xantphos (112 mg, 0.19 mmol, 0.15 eq.) and Cs ₂ CO ₃ (844 mg, 2.6 mmol, 2.0 eq.)

1,4-dioxane (15 ml) under microwave heating at 110° C. for 1 hour under nitrogen.

LC-MS: m/z 521.9 (M+H) ⁺ .

Step F. 7-Methoxy-2,3-diphenyl-Ni(pyrimidin-4-yl)-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-5-amine solution (271 mg, 0.52 mmol) in 4 M HCl in 1,4-dioxane (15 mL) was stirred at 30° C. for 5 h. The reaction mixture was concentrated in vacuo to give the title compound.

1H-NMR (DMSO-d ₆ ): 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=8.0Hz, 2H), 7.55(m, 3H), 7.50(d, J=6.8Hz, 2H) , 7.37(s, 4H), 7.19(s, 1H).

LC-MS: m/z 507.9 (M+H) ⁺ .

Compound 170 5-(isoxazol-3-ylamino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine 7(4H)-oh.

Stage E (stoichiometry). 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6yl)quinolinyl (100 mg, 0.216 mmol), isoxazol-3-amine (92 mg, 0.432 mmol), acetate palladium (II) (53 mg, 0.238 mmol), Xantphos (150 mg, 0.259 mmol) and sodium carbonate (51 mg, 0.475 mmol) in 1,4-dioxane (10 ml) under microwave heating conditions at 100°C in for 1 h in a nitrogen atmosphere.

LC-MS: m/z 511.2 (M+H)+.

Step F. N-(7-methoxy-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-5-yl)isoxazol-3-amian mixture (90 mg, 0.097 mmol) in a solution of hydrogen chloride (4 M in dioxane, 4 ml) was stirred at room temperature. for 10 h. The mixture was evaporated to dryness. The residue was taken up in dichloromethane (with 10% methanol) and basified with aqueous ammonia to pH 8 to give 5-(isoxazol-3-ylamino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo [ 1,5-a]pyrimidine-7(4H)-oh.

¹ H-NMR (DMSO-d ₆ ): δ 9.39 (d, J=4.03 Hz, 1H), 9.31 (d, J=8.33 Hz, 1H), 8.75 (d, J=1.61Hz, 1H), 8.51(s, 1H), 8.39(d, J=8.87Hz, 1H), 8.25(d, J=8.87Hz, 1H) , 8.17 (dd, J=8.33, 5.37 Hz, 1H), 7.47-7.58 (m, 4H), 7.31-7.46 (m, 6H), 6.44 (bs, 1H).

LC-MS: m/z 497.2 (M+H)+.

Compound 171. ethyl-5-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl)amino)-1, 3,4-oxadiazole-2-carboxylate.

( o O=H

Suspension of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (200 mg, 0.43 mmol), ethyl-5-amino-1,3 ,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, 0.2 eq.), 13 mmol, 0.3 eq.) and Cs ₂ CO ₃ (282 mg, 0.87 mmol, 2.0 eq.) in 1,4-dioxane (5 ml) were stirred at 100°C for 16 h in an atmosphere N2. The mixture was filtered through Celite and the filtrate concentrated in vacuo to give the title compound.

1H-NMR (DMSO-d6): δ 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)+.

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Compound 172 N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]nirimidin-5yl)acetamide.

Stage E (stoichiometry). 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6yl)quinolinyl (230 mg, 0.5 mmol) and acetamide (59 mg, 1.0 mmol, 2, 0 eq.), Pd(OAc) ₂ (11 mg, 0.05 mmol, 0.1 eq.), Xantphos (116 mg, 0.2 mmol, 0.4 eq.) and Cs ₂ CO ₃ (325 mg , 1.0 mmol, 2.0 eq.) in 1,4-dioxane (10 ml) under microwave heating at 100° C. for 1 hour under nitrogen atmosphere.

LC-MS: m/z 586.2 (M+H) ⁺ .

Step F. Solution of N-(7-methoxy-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]n-pyrimidin-5yl)acetamide (100 mg, 0.21 mmol) in 4 M HCl in 1,4-dioxane (20 ml) was stirred at 30° C. for 5 hours. The reaction mixture was concentrated in vacuo to give the title compound.

¹ H-NMR (DMSO): δ 12.96 (br. s., 1H), 10.12 (br. s., 1H), 8.92 (br. s., 1H), 8.40 (br s., 1H), 8.05 (br. s., 1H), 7.99 (br. s., 1H), 7.76 (d, J=8.6 Hz, 1H), 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) ⁺ .

Compound 173 2-Hydroxy-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl)acetamide.

Step A. 2-(benzyloxy)-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl)acetamide.

Suspension of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (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 Cs ₂ CO ₃ (282 mg, 0.86 mmol, 2 eq.) in 1,4-dioxane (5 ml) was stirred at 100° C. (microwave heating) for 1 h under N ₂ atmosphere. The mixture was filtered through Celite, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH=10/1) to give the title product as a yellow solid (120 mg).

¹ H-NMR (DMSO-d6): δ 12.66 (br. s., 1H), 9.65 (br. s., 1H), 8.91 (br. s., 1H), 8.33 (d, J=8.4Hz, 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) ⁺ .

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Step B. 2-hydroxy-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin5-yl)acetamide.

To a solution of 2-(benzyloxy)-N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5а]pyrimidin-5-yl)acetamide (90 mg, 0.156 mmol) in DCM (5 ml) was added BBr ₃ (156 mg, 0.623 mmol, 4 eq.) at 0°C. The mixture was stirred at rt. for 2 hours. The reaction was quenched with methanol (MeOH) at 0° C. to give the title compound.

¹ H-NMR (DMSO-de): δ 12.67 (br. s., 1H), 10.91 (br. s., 1H), 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, 11H), 6.20 (br. s., 1H), 3.85 (br. s., 2H).

LC-MS: m/z 487.9 (M+H)+.

The following compounds were prepared according to the procedure for preparing compound 101, steps E-F, starting from 6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5- a]pyrimidin-6-yl)quinolinyl.

Compound 174. 3-cyclohexenyl-2-phenyl-5-(pyridin-2-ylamino)-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). 6-(5-chloro-3-cyclohexenyl-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6yl)quinolinyl (380 mg, 0.814 mmol), pyridine-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 microwave heating conditions at 110° C. for 1 hour under a nitrogen atmosphere.

LC-MS: m/z 525.2 (M+H) ⁺ .

Step F. 7-Methoxy-2,3-diphenyl-X-(pyrazin-2-yl)-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidine-5-amine mixture (125 mg, 0.238 mmol ) in a solution of hydrogen chloride (4 M in dioxane, 5 ml) was stirred at room temperature. within 16 hours the Mixture was evaporated to dryness. The residue was separated in dichloromethane solution (with 10% methanol) and washed with aqueous sodium bicarbonate to pH 8. The organic phase was dried with sodium sulfate, resulting in 3-cyclohexenyl-2-phenyl-5-(pyridin-2-ylamino)- 6(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

1H-NMR (DMSO-de): δ 15.37 (br. s., 1H), 9.35 (s, 1H), 9.18 (br. s., 1H), 8.87 (d, J = 8.24 Hz, 1H), 8.18-8.36 (m, 3H), 8.04 (d, J=8.55 Hz, 1H), 7.88 (dd, J=7.93, 4.88 Hz, 1H), 7.81 (t, J=7.02 Hz, 1H), 7.75 (d, J=7.63 Hz, 2H), 7.47-7.56 (m, 2H), 7.38-7.46 (m, 1H), 7.22 (d, J=8.54 Hz, 1H), 7.10-7.18 (m, 1H), 6.11 (br s., 1H), 2.38 (br. s., 2H), 2.09 (s, 2H), 1.73 (br. s., 4H).

LC-MS: m/z 511.2 (M+H) ⁺ .

Compound 175. 3-cyclohexenyl-2-phenyl-5-(pyrazin-2-ylamino)-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). 6-(5-chloro-3-cyclohexenyl-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6yl) quinolinyl (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 microwave heating conditions at 110° C for 1 h under nitrogen atmosphere.

LC-MS: m/z 526.2 (M+H) ⁺ .

Step F. 7-Methoxy-2,3-diphenyl-N-(pyrazin-2-yl)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine5-amine mixture (70 mg, 0.133 mmol ) in a solution of hydrogen chloride (4 M in dioxane, 5 ml) was stirred at room temperature. for 4 hours. The mixture was evaporated to dryness. The residue was taken up in dichloromethane solution (with 10% methanol) and washed with aqueous sodium bicarbonate to pH 8. The organic phase was dried over sodium sulfate to give 2,3-diphenyl-5-(pyrazin-2-ylamino)-6- (quinolin-6-yl)pyrazolo[1,5-79 042905

a]pyrimidine-7(4H)-one.

1H-NMR (DMSO-d ₆ ): δ 14.04 (s, 1H), 9.57 (s, 1H), 8.94 (br. s., 1H), 8.55 (s, 1H), 8.41 (d, J=7.93 Hz, 1H), 8.24 (s, 1H), 8.26 (s, 1H), 8.04-8.13 (m, 2H), 7.81 (d, J=8.54 Hz, 1H), 7.75 (d, J=7.32 Hz, 2H), 7.57 (br. s., 1H), 7.47-7.53 (m , 2H), 7.44 (d, J=7.02 Hz, 2H), 2.36 (br. s., 2H), 2.09 (br. s., 2H), 1.72 (br. s., 4H).

LC-MS: m/z 512.2 (m+H) ⁺ .

Compound 176 3-cyclohexenyl-5-(isoxazol-3-ylamino)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). 6-(5-chloro-3-cyclohexenyl-7-methoxyu-2-phenylpyrazolo[1,5-a]pyrimidin-6yl) quinolinyl (240 mg, 0.510 mmol), isoxazol-3-amine (218 mg, 1.02 mmol), palladium(II) acetate (126 mg, 0.560 mmol), Xantphos (354 mg, 0.612 mmol) and sodium carbonate (119 mg, 1.12 mmol) in 1,4-dioxane (10 mL) under heating conditions to 100°C for 16 h under nitrogen atmosphere.

LC-MS: m/z 515.2 (M+H) ⁺ .

Step F. N-(3-cyclohexenyl-7-methoxy-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin5-yl)isoxazol-3-amine mixture (50 mg, 0.097 mmol) in a solution of hydrogen chloride (4 M in dioxane, 4 ml) was stirred at room temperature. for 2 hours. The mixture was evaporated to dryness. The residue was taken up in dichloromethane (with 10% methanol) and basified with aqueous ammonia to pH 8 to give 3-cyclohexenyl-5-(isoxazol-3-ylamino)-2-phenyl-6-(quinolin-6-yl)pyrazolo [1,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d ₆ ): δ 9.39 (d, J=4.30 Hz, 1H), 9.29 (d, J=8.33 Hz, 1H), 8.78 (s, 1H), 8.48 (s, 1H), 8.40 (d, J=8.86 Hz, 1H), 8.23 (d, J=8.86 Hz, 1H), 8.16 (dd, J=8.19, 5.51Hz, 1H), 7.75(d, J=7.25Hz, 2H) 7.38-7.59(m, 4H), 7.36(bs, 1H) , 6.43 (s, 1H), 6.06 (bs, 1H), 2.30 (bs, 2H), 2.06 (bs, 2H), 1.70 (bs, 2H) 1.23 (bs , 2H).

LC-MS: m/z 501.2 (M+H) ⁺ .

Compound 177 4H)-on.

stage A

Step A. N-(3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5a]pyrimidin-5-yl)isoxazole -3-amine.

6-(5-Chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6yl)quinoxaline solution (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 heated at reflux for 12 hours under nitrogen. After cooling to rt. the mixture was concentrated to dryness. The residue was purified using a flash column (DCM:MeOH=30:1) to give N-(3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenyl-6-(quinoxaline -6-yl)pyrazolo[1,5a]pyrimudin-5-yl)uzoxazol-3-amine (12 mg) as a yellow solid.

LC-MS: m/z 516.2 (M+H) ⁺ .

Step B. 3-(cyclohex-1-en-1-yl)-5-(isoxazol-3-ylamino)-2-phenyl-6-(quinoxalin-6yl)pyrazolo[1,5-a]pyrimidine-7 ( 4H)-on.

N-(3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenyl-6-(quinoxalin-6-ul)pyrazolo[1.5-80 042905 solution

a]pyrimidin-5-yl)isoxazol-3-amine (12 mg, 0.02 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at rt. over 2 h. The mixture was concentrated and saturated NaHCO ₃ (3 mL) was added to give 3-(cyclohex-1-en-1-yl)-5-(isoxazol-3-ylamino)-2-phenyl- 6-(quinoxalin-6yl)pyrazolo[1,5-a]pyrimidin-7(4H-one.

¹ H-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+H) ⁺ .

3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[1,5 Compound 178. a] pyrimidin-7(4H)-one.

NaHMDS (29.7 ml, 59.37 mmol, 2.0 M in THF). After the addition, the mixture was stirred at -78° C. for 1 h. Then, benzoyl chloride (5.5 ml, 47.50 mmol) was added dropwise. The reaction mixture was slowly heated to rt. and stirred for 12 hours. The reaction was quenched with saturated NH ₄ Cl (150 ml), extracted with ethyl acetate (200 ml), washed with water (60 ml) and brine (60 ml), dried with anhydrous sodium sulfate and concentrated, as a result which gave the crude product (16 g), which was used in the next step without further processing without further purification.

Step B. 4-(3-chlorophenyl)-3-phenyl-1H-pyrazole-5-amine.

A solution of 2-(3-chlorophenyl)-3-oxo-3-phenylpropanenitrile (16 g, crude) and NH ₂ NH ₂ (11.5 ml, 237.48 mmol) in EtOH/AcOH (80/20 ml) was stirred at 80°C for 6 h. After cooling to rt.

- 81 042905 the mixture was concentrated under vacuum. The residue was diluted with ethyl acetate (200 ml), washed with saturated NaHCO3 (100 ml) and brine (50 ml), dried with anhydrous sodium sulfate and concentrated. The residue was purified using a flash column (petroleum ether/ethyl acetate=3:1) to give 4-(3-chlorophenyl)-3-phenyl-1H-pyrazole-5-amine (1.6 g) as yellow solid.

¹ H-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) ⁺ .

Step C. 3-(3-chlorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)one.

Suspension of 4-(3-chlorophenyl)-3-phenyl-1H-pyrazole-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 h. the mixture was filtered and washed with methanol (MeOH) (2 ml) to give 3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine-5,7(4H ,6H)-dione (830 mg) as a white solid.

LC-MS: m/z 444.1 (M+H) ⁺ .

Step F. 5,7-dichloro-3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine.

3-(3-Chlorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione solution (800 mg, 1.80 mmol), K ,K-dimethylaniline (436.8 mg, 3.60 mmol) and pentachlorophosphorane (375.3 mg, 1.80 mmol) in POCl ₃ (8 ml) in a sealed tube was stirred at 100°C for 8 h. After cooling to k.t. the solvent was removed under vacuum. The residue was cooled to 0°C and made basic by adding MeOH (6 ml). The precipitate was filtered to give 5,7-dichloro-3-(3-chlorophenyl)6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine (700 mg) as a yellow solid.

LC-MS: m/z 480.1 (M+H) ⁺ .

Step E. 5-chloro-3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine.

To a solution of 5,7-dichloro-3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine (700 mg, 1.46 mmol) in DCM/MeOH (20 ml, 1:1), cooled at 0° C., sodium methanolate (0.9 ml, 5.0 M in methanol) was added dropwise. The mixture was then stirred at 0°C for 15 min, saturated NH4Cl (50 ml) was added to stop the reaction. The mixture was extracted with dichloromethane (100 ml), washed with brine (30 ml), dried with anhydrous sodium sulfate and concentrated. The residue was purified using a flash column (petroleum ether/ethyl acetate/DCM=20:1:1) to give 5-chloro-3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)- 2-phenylpyrazolo[1,5a]pyrimidine (520 mg) as a yellow solid.

¹ H-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) ⁺ .

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Step F. 3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2-yl)pyrazolo[1,5a]pyrimidin-5-amine.

A mixture of 5-chloro-3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo-[1,5-a]pyrimidine (120 mg, 0.25 mmol), pyridine-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) in a microwave reactor at 120°C for 1.5 h under nitrogen atmosphere. After cooling to rt. the mixture was filtered with celite, diluted with dichloromethane (100 ml), washed with brine (30 ml), dried with anhydrous sodium sulfate and concentrated to dryness. The residue was purified using a flash column (petroleum ether/ethyl acetate/DCM/=6:1:1) to give 3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)2-phenyl- N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine (78 mg) as a yellow solid.

LC-MS: m/z 534.2 (M+H) ⁺ .

Step G. 3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

3-(3-chlorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2-yl)pyrazolo[1,5a]pyrimidin-5-amine solution (70 mg, 0 .13 mmol) in 4 M HCl in 1,4-dioxane (6 mL) was stirred at rt. over 3 h. The mixture was concentrated and saturated NaHCO ₃ (6 ml) was added, resulting in 3-(3-chlorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino) pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-H6): δ 15.73 (s, 1H), 9.05 (s, 1H), 8.11 (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) ⁺ .

Compound 179 3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

7

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Step A. 2-(2-fluorophenyl)-3-oxo-3-phenylpropanenitrile.

ABOUT

To a solution of 2-(2-fluorophenyl)acetonitrile (5.4 g, 40 mmol) in anhydrous THF (50 ml) was added dropwise LDA (lithium diisopropylamide) (26 ml, 52 mmol, 1.3 eq.) at -78 °C. After the 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. during the night. The suspension was neutralized with a solution of NH ₄ Cl (30 ml) and was extracted with ethyl acetate. The organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2-(2-fluorophenyl)-3-oxo-3-phenylpropanenitrile (12 g, crude), which was used directly in the next step without further purification.

LC-MS: m/z 240.1 (M+H) ⁺ .

Step B. 4-(2-fluorophenyl)-3-phenyl-1H-pyrazole-5-amine.

Hydrazine hydrate (4.48 g, 80 mmol, 2.0 equiv.). The reaction mixture was then stirred at reflux for 4 hours. The solvents were removed under vacuum, and the residue was adjusted to 8~9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether=1/1) to give the desired product (1.3 g).

LC-MS: m/z 254.1 (M+H) ⁺ .

Step C. 3-(2-fluorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)one.

Dimethyl 2-(4-methoxyphenyl)malonate (886 mg, 3.7 mol, 1.2 eq.), 4-(2-fluorophenyl)-3-phenyl-1Hpyrazole-5-amine (780 mg, 3.1 mol, 1.0 eq.) and xylene (15 ml) were added to a 100 ml vial and heated to 150°C for 8 h. Then the reaction mixture was cooled to rt. The mixture was filtered, the filter residue was washed with petroleum ether, resulting in the desired product 3-(2-fluorophenyl)5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine-7(4H )-one (1 g) as a white solid.

LC-MS: m/z 427.9 (M+H) ⁺ .

Step F. 5,7-dichloro-3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine.

A solution of 3-(2-fluorophenyl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)one (1.0 g, 2.3 mmol) in phosphorus oxychloride (10 ml) was heated under reflux overnight. The mixture was concentrated under reduced pressure. The residue was slowly added to MeOH (10 ml) and filtered. The filter cake was washed with methanol (MeOH) to give the title product 5,7-dichloro-3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine (890 mg) as a white solid.

LC-MS: m/z 464.1 (M+H) ⁺ .

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Step E. 5-chloro-3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine.

To a solution of 5,7-dichloro-3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine (463 mg, 1 mmol) in DCM (10 ml) and MeOH (10 ml) cooled at 0°C was added dropwise sodium methoxide (1 ml, 5 mol, 30% in MeOH). Then the reaction mixture was stirred at 0°C for 0.5 h, the Suspension was neutralized with a solution of NH ₄ Cl (30 ml) and was extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether=1/5) to give the desired product. 5-chloro-3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine (390 mg).

LC-MS: m/z 460.1 (M+H) ⁺ .

Step F. 3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2-yl)pyrazolo[1,5a]pyrimidine-5-amine.

Suspension of 5-chloro-3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidine (230 mg, 0.5 mmol), pyridine-2-amine ( 94 mg, 1 mmol, 2.0 eq.), Pd(OAc)2 (22 mg, 0.1 mmol, 20 mol%), Xantphos reagent (115 mg, 0.2 mmol, 40 mol%) and Cs ₂ CO ₃ (325 mg, 1 mmol, 2.0 eq.) in 1,4-dioxane (10 ml) in a 10 ml microwave treatment vessel was heated at 100°C under microwave radiation for 1 h under N2 atmosphere . Then the reaction mixture was cooled and filtered. The dark filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether=1/4) to give the desired product 3-(2-fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-( pyridin-2-yl)pyrazolo[1,5-a]pyrimidine5-amine (100 mg).

LC-MS: m/z 518.2 (M+H) ⁺ .

Step G. 3-(2-fluorophenyl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

3-(2-Fluorophenyl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-2-yl)pyrazolo[1,5a]pyrimidin-5-amine solution (85 mg, 0 .16 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was stirred at 30° C. for 18 h. The reaction mixture was concentrated in vacuo to give the title compound.

¹ H-NMR (DMSO-d6): δ 8.04 (d, J=4.8 Hz, 1H), 7.89 (s, 1H), 7.49-7.59 (m, 3H), 7 .31-7.45 (m, 9H), 7.11 (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) ⁺ .

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Compound 180 6-(4-Methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Step A. 3-oxo-2-phenyl-3-(pyridin-2-yl)propanenitrile.

To a solution of methyl picolinate (20 g, 0.15 mol) and 2-phenylacetonitrile (20 g, 0.18 mol) in THF (200 ml) was slowly added NaHDMS (80 ml, 2 mmol/ml) at 0°C. The reaction mixture was then stirred for 1 h at 0°C and allowed to reach rt. during the night. The mixture was poured into water and extracted with ethyl acetate (100 mlx3). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-oxo-2-phenyl-3-(pyridin2-yl)propanenitrile (crude, 25 g).

LC-MS: m/z 223.3 (M+H) ⁺ .

Step B. 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine.

AcOH (20 ml) was added to a solution of 3-oxo-2-phenyl-3-(pyridin-2-yl)propanenitrile (25 g, 0.126 mol) in EtOH (200 ml). The reaction mixture was heated to 60° C. for 10 min and then hydrazine monohydrate (7 g, 0.138 mol) was added dropwise via syringe. Then the reaction mixture was stirred for 4 h at 60°C. The mixture was concentrated to dryness. The residue was poured into water and extracted with ethyl acetate (100 mlx3). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (elution using petroleum ether/ethyl acetate=2:1) to give 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (3 g) .

LC-MS: m/z 237.2 (M+H) ⁺ .

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Step C. 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione.

Solution of 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (1.5 g, 6.35 mmol) and dimethyl-2-(4methoxyphenyl)malonate (1.67 g, 7 0 mmol) in toluene (50 ml) was heated to 140°C overnight. The reaction mixture was cooled to rt. The precipitate was filtered off to give 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (1 .2 g).

LC-MS: m/z 411.2 (M+H) ⁺ .

Step D. 5,7-dichloro-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine.

6-(4-Methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione solution (1 g, 2.44 mmol ) in POCl ₃ (15 ml) in a sealed tube was heated to 120°C overnight. The reaction mixture was cooled to rt. and concentrated under vacuum. The residue was brought to pH 7 by adding saturated NaHCO ₃ solution, extracted with ethyl acetate (50 mlx3), filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (elution using petroleum ether/ethyl acetate=10:1) to give 5,7-dichloro-6-(4-methoxyphenyl)-3phenyl-2-(pyridin-2-yl)pyrazolo [1,5-a]pyrimidine (900 mg).

LC-MS: m/z 447.3 (M+H) ⁺ .

Step E. 5-chloro-7-methoxy-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine.

To a solution of 5,7-dichloro-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine (900 mg, 2.0 mmol) in MeOH ( 50 ml) NaOMe (0.5 ml, 5.0 mmol/ml) was added at 0°C. The reaction mixture was stirred for 30 minutes. The mixture was adjusted to pH 7 by adding 1N. HCl solution. The mixture was then poured into water and extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting solid was washed with ethyl acetate to give the desired product -5-chloro-7-methoxy-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2yl)pyrazolo[1,5-a]pyrimidine ( 500 mg).

LC-MS: m/z 443.4 (M+H) ⁺ .

Step F. 7-methoxy-6-(4-methoxyphenyl)-3-phenyl-N,2-di(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5amine.

5-Chloro-7-methoxy-6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine mixture (150 mg, 0.34 mmol), pyridine -2-amine (35 mg, 0.37 mmol), Pd(OAc)2 (7.6 mg, 0.034 mmol), Xantphos (40 mg, 0.068 mmol) and Cs ₂ CO ₃ (222 mg) in dioxane (5 ml) was heated to 120°C for 2 h in an atmosphere of N ₂ . The mixture was cooled to rt. and concentrated under vacuum. The residue was purified by silica gel column chromatography (elution using DCM/MeOH=20:1) to give the desired product (crude, 80 mg) which was used directly in the next step without further purification.

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Step G. 6-(4-methoxyphenyl)-3-phenyl-2-(pyridin-2-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of 7-methoxy-6-(4-methoxyphenyl)-3-phenyl-N,2-di(pyridin-2-yl)pyrazolo[1,5a]pyrimidine-5-amine (crude 80 mg) in MeOH (5 ml) HCl in dioxane (5 ml, 4 mmol/ml) was added. The reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was basified with saturated NaHCO ₃ , resulting in the desired product -6-(4-methoxyphenyl)-3-phenyl-2-(nurudin-2-yl)-5-(nirudin-2-ylamino)nirazolo[1,5- a]nurumidine7(4H)-one.

¹ H-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) ⁺ .

Compound 181. 6-(4-Methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)-5-(pyridin-2ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

Step A. 5-hydroxu-6-(4-methoxyphenyl)-2-phenyl-3-(nuneridin-1-yl)pyrazolo[1,5-a]nirimudin7(4H)-one.

A suspension of 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (2 g, 8.254 mmol) and dimethyl-2-(4methoxyphenyl)malonate (2.95 g, 12.38 mmol) in tributylamine (25 ml) was heated to 180° C. for 2.5 h under N2 protection. The mixture was cooled to rt. and stirred with petroleum ether. The settled substances were filtered and washed with ethyl acetate, resulting in 5-hydroxy-6-(4methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (3 g) as a yellow solid.

LC-MS: m/z 417.2 (M+H) ⁺ .

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Step B. 5,7-dichloro-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine.

Solution of 5-hydroxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one (3 g, 7.203 mmol) in POC13 ( 30 ml) was heated to 100°C overnight. The reaction mixture was concentrated to remove POCl ₃ . The residue was made basic with saturated sodium bicarbonate solution at 0° C. and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine (30 ml), dried with anhydrous sodium sulfate and concentrated in vacuo to give the crude product (2.5 g) as a yellow solid.

LC-MS: m/z 453.1 (M+H) ⁺ .

Step C. 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidine.

To a solution of 5,7-dichloro-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine (1 g, 2.4 mmol) in methanol ( 20 ml) was added MeONa (30 wt.% in methanol, 1.3 ml, 7.2 mmol) at 0°C and stirred at 0°C for 3 hours. The reaction was quenched with ice water at 0°C, diluted with saturated solution sodium bicarbonate at 0°C and was extracted with ethyl acetate (2x20 ml). The combined organic layers were washed with brine (30 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column (DCM:MeOH=30:1) to give 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3(piperidin-1-yl)pyrazolo [1,5-a]pyrimidine (550 mg) as a yellow solid.

LC-MS: m/z 449.2 (M+H) ⁺ .

Step D. 7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)-N-(pyridin-2-yl)pyrazolo[1,5a]pyrimidin-5-amine.

Suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidine (200 mg, 0.446 mmol), pyridine-2-amine (125 mg, 12.38 mmol, 3 eq.), Pd(OAc) ₂ (20 mg, 0.089 mmol, 0.2 eq.), Xantphos (103 mg, 0.178 mmol, 0.4 eq.) and Na ₂ CO ₃ (188 mg, 1.782 mmol, 4 eq.) in 1,4-dioxane (5 mL) was stirred and heated to 100° C. (microwave heating) for 1 h under N2 atmosphere. The reaction mixture was cooled to rt, diluted with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (2x30 ml). The combined organic layers were washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (elution using DCM/MeOH=20:1) to give 7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3(piperidin-1-yl)-N-( pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine (80 mg) as a white solid.

¹ H-NMR (DMSO-d6): δ 8.49 (d, J=5.64 Hz, 1H), 8.21-8.38 (m, 2H), 8.07 (d, J=7, 25 Hz, 2H), 7.36-7.60 (m, 6H), 7.16 (d, J=8.60 Hz, 2H), 4.13 (s, 3H), 3.86 (s, 3H), 3.51 (br. s., 4H), 1.80 (br. s., 4H), 1.60 (br. s., 2H).

LC-MS: m/z 507.2 (M+H) ⁺ .

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Step E. 6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)-5-(pyridin-2-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

7-methoxy-6-(4-methoxyphenyl)-2-phenyl-3-(piperidin-1-yl)-N-(pyridin-2-yl)pyrazolo[1,5a]pyrimidin-5-amine solution (100 mg , 0.198 mmol) in 4.0 M HCl in 1,4-dioxane (10 mL) was stirred at rt. within 2 hours the Reaction mixture was concentrated under vacuum. The residue was dissolved in 7N. NH ₃ in methanol and concentrated in vacuo to give the title compound.

¹ H-NMR (DMSO-d6): δ 8.31 (d, J=4.88 Hz, 1H), 8.12 (d, J=7.63 Hz, 2H), 7.94 (t, J =7.32Hz, 1H), 7.41-7.53(m, 4H), 7.34(m, J=8.55Hz, 2H), 7.19(t, J=6.26Hz , 1H), 7.03 (m, J=8.55 Hz, 2H), 3.82 (s, 3H), 3.20 (br. s., 4H), 1.73 (br. s., 4H), 1.53-1.68 (m, 2H).

LC-MS: m/z 493.4 (M+H)+.

Compound 182 5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Step A. 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazol-3-yl)pyrazolo [1,5- a] pyrimidine-5-amine.

Suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine (500 mg, 1.1 mmol), 1-((2-(trimethylsilyl)ethoxy )methyl)-1H-pyrazol-3-amine (314 mg, 1.47 mmol), Pd(OAc) ₂ (38 mg, 0.16 mmol), Xantphos (98 mg, 0.16 mmol) and Cs ₂ CO ₃ (740 mg, 2.2 mmol) in 1,4-dioxane (10 mL) was stirred and refluxed for 16 h under N2. The course of the reaction was monitored by LC-MS until complete conversion of the starting material. The reaction mixture 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 give Intermediate 2 (500 mg) as a white solid.

LC-MS: m/z 619.5 (M+H)+.

Step B. 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazol-3-yl)pyrazolo [1,5- a] pyrimidine-5-amine.

Intermediate 2 (500 mg, 0.81 mmol) Sodium 2-methylpropan-2-olate (155 mg, 1.62 mmol) in dioxane was stirred at 110° C. for 1 h under microwave radiation. The mixture was acidified to pH 7 and concentrated to give a crude product which was used directly in the next step without further purification.

LC-MS: m/z 605.3 (M+H)+.

Step C. 5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin7(4H)-one.

Intermediate 3 (300 mg, 0.49 mmol) in DCM (5 ml) and TFA (5 ml) was stirred at 60°C for 1 h. The mixture was then concentrated to give the crude product, which was added to water with ammonia (5 ml) and stirred further for 1 h. The mixture was concentrated, resulting in the desired product.

1H-NMR (DMSO-d ₆ ): 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)+.

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Compound 183

This compound was prepared according to the procedure for compound 182 using intermediate 5 as 5-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-3-amine in step A.

Step A. Suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine (441 mg, 1 mmol), 5-methoxy-1-((2 -(trimethylsilyl)ethoxy)methyl)-III-pyrazol-3-amine (243 mg, 1 mmol, 1 eq.), Pd(OAc) ₂ (44.8 mg, 0.2 mmol, 0.2 eq.) , Xantphos (57.8 mg, 0.1 mmol, 0.1 eq.) and Cs ₂ CO ₃ (650 mg, 2 mmol, 2 eq.) in 1,4-dioxane (5 ml) were stirred at 110°C for 16 hours in an N2 atmosphere. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The crude product was used in the next step without further processing without further purification.

LC-MS: m/z 649.4 (M+H) ⁺ .

Step B. A mixture of 7-methoxy-N-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-6-(4methoxyphenyl)-3-phenyl-2- (pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-5-amine (800 mg, 1.23 mmol) and sodium 2-methylpropan-2-olate (197 mg, 4.9 mmol) in dioxane ( 10 ml) was stirred at 100° C. for 2 hours. The mixture was acidified to pH 7 and concentrated to give a crude product which was purified by silica gel chromatography (DCM:MeOH=40:1) to give 5-( (5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3diphenylpyrazolo[1,5-a]pyrimidine- 7(4H)-one (300 mg) as a gray solid.

LC-MS: m/z 635.3 (M+H) ⁺ .

Step C. Solution of 5-((5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-6-(4methoxyphenyl)-2,3-diphenylpyrazolo[1 ,5-a]pyrimidin-7(4H)-one (100 mg, 0.19 mmol) in 4 M HCl in dioxane (5 mL) was stirred at rt. within 1 h. The solvent and volatiles were removed under vacuum. The residue was dissolved in DCM (5 ml) and treated with saturated NaHCO ₃ . The organic phase was separated and washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

¹ H-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., 1H), 3.84 (s, 3H), 3.87 (s, 3H ).

LC-MS: m/z 505.5 (M+H)+.

Compound 184 5-((1H-imidazol-4-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Step A. 6-(4-methoxyphenyl)-2,3-diphenyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4yl)amino)pyrazolo [ 1,5-a ]pyrimidine-7(4H)-one.

SEM

A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimudine (300 mg, 0.68 mmol), 1-((2-(trimethylsilyl)ethoxy) was reacted )methyl)-1H-imidazole-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) in a microwave reactor at 120°C for 45 min under nitrogen atmosphere. After cooling to rt. the mixture was filtered with celite, diluted with dichloromethane (100 ml), washed with saturated NH ₄ Cl (30 ml) and brine (30 ml), dried with anhydrous sodium sulfate and concentrated to dryness. The residue was purified by preparative thin layer chromatography (DCM:MeOH=40:1) to give 7-methoxy-6-(4-methoxyphenyl)-2,3diphenyl-N-(1-((2-(trimethylsilyl )ethoxy)methyl)-1H-imidazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine (110 mg, yellow solid) and 6-(4-methoxyphenyl)-2,3-diphenyl- 5-((1-((2(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one (40 mg, yellow solid ).

LC-MS: m/z 605.3 (M+H) ⁺ .

Step B. 5-((1H-imidazol-4-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin7(4H)-one.

To a solution of 6-(4-methoxyphenyl)-2,3-diphenyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imide azol4-yl)amino)pyrazolo[1,5-a ]pyrimidin-7(4H)-one (40 mg, 0.1 mmol) in DCM (1.5 ml) cooled to 0° C. TFA (1.5 ml) was added dropwise. The mixture was then stirred at rt. over 8 h. The mixture was concentrated and NaOH (1 M) was added to pH>7, resulting in a pure product.

¹ H-NMR (FTUA-d): δ 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) ⁺ .

Compound 185 .

This compound was prepared according to the procedure for compound 182 using intermediate 5 as 2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-amine in step A.

Step A. Suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine (50 mg, 0.11 mmol), 2-((2-( trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-amine (31 mg, 0.147 mmol, 1.3 eq.), Pd(OAc) ₂ (5.1 mg, 0.027 mmol, 0, 2 eq.), Xantphos (13.1 mg, 0.027 mmol, 0.2 eq.) and Cs ₂ CO ₃ (66.7 mg, 0.283 mmol, 2.5 eq.) in dioxane (6 ml) were stirred at 100 °C for 1 h in an N2 atmosphere under the influence of microwave radiation. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether:ethyl acetate=2/1) to give 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(2-((2-(trimethylsilyl) ethoxy)methyl)-2H1,2,3-triazol-4-yl)pirazolo[1,5-a]pyrimidin-5-amine (30 mg) as a white solid.

LC-MS: m/z 619.9 (M+H) ⁺ .

Step B. Solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-Na(2-((2-(trimethylsilyl)ethoxy)methyl)2H-1,2,3-triazol-4-yl )pyrazolo[1,5-a]pyrimidine-5-amine (110 mg, 0.18 mmol) and KOtBu (50 mg, 0.44 mmol) in 1,4-dioxane (5 ml) were stirred at reflux for 2 h. The solvent and volatiles were removed under vacuum, resulting in 6-(4-methoxyphenyl)-2,3diphenyl-5-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1 ,2,3-triazol-4-yl)amino)pyrazolo[1,5-a]pyrimidin7(4H)-one (130 mg), which was used in the next step without further workup without further purification.

LC-MS: m/z 605.9 (M+H) ⁺ .

Step C. Solution of 6-(4-methoxyphenyl)-2,3-diphenyl-5-((2-((2-(trimethylsilyl)ethoxy)-methyl)-2H1,2,3-triazol-4-yl)amino )pyrazolo[1,5-a]pyrimidin-7(4H)-one (130 mg, 0.21 mmol) in TFA (10 mL) was stirred at rt. within 1 h. The solvent and volatiles were removed under vacuum. The residue was basified with NH3-H2O to pH 8 and concentrated to give the title compound.

1H-NMR (DMSO): 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) ⁺ .

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Compound 186 5-((5-Amino-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Step A. N3-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1-(4methoxybenzyl)-1 H-pyrazol-3, 5-diamine.

Suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]-pyrimidine (300 mg, 0.68 mmol), 1-(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 Cs ₂ CO ₃ (441 mg, 1.36 mmol, 2 eq.) in 1,4-dioxane (20 ml) were stirred at 100°C for 16 h under N ₂ . The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (DCM:MeOH=50/1) to give N3-(7-methoxy-6-(4-methoxyphenyl)-2,3diphenylpyrazolo[1,5-a]pyrimidin-5-yl) -1-(4-methoxybenzyl)-1H-pyrazole-3,5-diamine (220 mg) as a white solid.

LC-MS: m/z 625.5 (M+H) ⁺ .

Step B. 5 -((5-amino-1 -(4-methoxybenzyl)-1 H-pyrazol-3 -yl)amino)-6-(4-methoxyphenyl)-2,3 diphenylpyrazolo [1,5-a] pyrimidine-7(4H)-one.

rmv nh ₂ about

T n g HN /=4

To a solution of N3-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-1-(4methoxybenzyl)-1H-pyrazol-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 h. The solvent and volatiles were removed under vacuum. The residue was partitioned between water (30 ml) and ethyl acetate (50 ml). The ethyl acetate layer was dried and concentrated to give 5-((5-amino-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)amino)6-(4-methoxyphenyl)-2,3-diphenylpyrazolo [1,5-n]pyrimidin-7(4H)-one (20 mg) as a white solid.

LC-MS: m/z 610.5 (M+H)+.

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Step C. 5-((5-amino-1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

K 5-((5-amino-1-(4-methoxybenzyl)-1 H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3diphenylpyrazolo[1,5-a]pyrimidine-7 (4H)-one (20 mg, 0.03 mmol) in TFA (2 ml) was added Tf ₂ O (0.5 ml). The resulting mixture was stirred at rt. for 4 h. The mixture was then concentrated below 40° C. to give the title compound.

¹ H-NMR (DMSO-06): 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) ⁺ .

Compound 187 5-((1H-pyrazol-3-yl)amino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-oh.

Step A. 2,3-diphenyl-6-(quinolin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-n-nirazol-3yl)amino)pyrazolo[1,5 -a]pyrimidin-7(4H)-one. SEM

Suspension of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (300 mg, 0.65 mmol), 1-((2-(trimethylsilyl) ethoxy)methyl)-III-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, 0.13 mmol, 0.2 eq.) and K2CO3 (147 g, 1.30 mmol, 2.10 eq.) in dioxane (10 ml) were stirred at 90°C for 4 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether/ethyl acetate/DCM=10/1/1) to give 2,3-diphenyl-6-(quinolin-6-yl)-5-((1-((2( trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one (90 mg) as a white solid.

LC-MS: m/z 625.9 (M+H) ⁺ .

Step B. 5-((1H-pyrazol-3-yl)amino)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine 7(4H)-oh.

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A solution of 2,3-diphenyl-6-(quinolin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3yl)amino)pyrazolo[1,5-a ]pyrimidin-7(4H)-one (90 mg, 0.14 mmol) in TFA (8 mL) was stirred at rt.

within 1 h. The solvent and volatiles were removed under vacuum. The mixture was basified with ammonia to pH 8 and concentrated to give the crude product to give the title compound.

¹ H-NMR (TFA-d): δ 9.32 (br. s., 1H), 9.25 (br. s., 1H), 8.66 (br. s., 1H), 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)+.

Compound 188 He.

This compound was prepared according to the procedure for compound 182 using intermediate 1 as 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6yl)quinolinyl and intermediate 5 as 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazol-3-amine in step A.

Stage E (stoichiometry). 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (200 mg, 0.432 mmol), 5-methyl-1-((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 CO ₃ ( 281 mg, 0.86 mmol) in dioxane (15 ml) under heating to 110° C. overnight under N2 atmosphere.

LC-MS: m/z 640.3 (M+H) ⁺ .

Step F. To a solution of 5-((5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-2,3diphenyl-6-(quinolin-6-yl )pyrazolo[1,5-a]pyrimidin-7(4H)-one (40 mg, 0.63 mmol) in DCM (90 ml) was added with TFA (3 ml). The reaction mixture was stirred for 30 min at RT. The mixture was concentrated under vacuum. The residue was made basic with ammonia (4 ml) and concentrated to give the desired product.

¹ H-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+H) ⁺ .

Compound 189 ]pyrimidin-7(4H)-one.

Step A. 3 -(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-( 1 -((2(trimethylsilyl)ethoxy)methyl)-1H -pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine. SEM

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A mixture of 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine (300 mg, 0.67 mmol ), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole3-amine (430.8 mg, 2.02 mmol), palladium diacetate (30.2 mg, 0.13 mmol), Xantphos (116 .8 mg, 0.20 mmol) and cesium carbonate (438.4 mg, 1.35 mmol) in 1,4-dioxane (6 ml) in a reactor at 100° C. under N ₂ for 45 min. After cooling to rt. the reaction mixture was diluted with dichloromethane (100 ml), filtered with celite, washed with aqueous NH ₄ Cl (30 ml) and brine (30 ml), dried with anhydrous sodium sulfate and concentrated. The residue was purified using a flash column (petroleum ether/ethyl acetate=4:1) to give 3-(cyclohex-1-en1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl- N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3yl)pyrazolo[1,5-a]pyrimidin-5-amine (220 mg) as a yellow solid.

LC-MS: m/z 623.3 (M+H) ⁺ .

Step B. 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)1 H-pyrazole -3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

SEM

A solution of 3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-M-(1((2-(trimethylsilyl)ethoxy)methyl)-1H -pyrazol-3-yl)pyrazolo[1,5-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) in a microwave reactor at 100°C for 1.5 h. the mixture was diluted with dichloromethane (100 ml), washed with water (25 ml) and brine (25 ml), dried with anhydrous sodium sulfate and concentrated. MeOH (4 ml) was added to the residue, the precipitate was filtered, washed with methanol (MeOH) (4 ml) to give 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2- phenyl-5-((1((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-3 -yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one (130mg) as a yellow solid.

LC-MS: m/z 609.3 (M+H) ⁺ .

Step C. 5-(( 1 H-pyrazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine -7(4H)-he.

A solution of 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)1H-pyrazole-3- yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one (130 mg, 0.21 mmol) in TFA/DCM (2 ml/1 ml) was stirred at rt. for 4 h, which gave 5-((1H-pyrazol-5-yl)amino)3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1 ,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d6): δ 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) ⁺ .

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Compound 190 ]pyrimidin-7(4H)-one.

Step A. 3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H -pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

SEM

Suspension of 6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-6yl)quinolinyl (350 mg, 0.8 mmol) and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (356.4 mg, 1.7 mmol), Pd(OAc) ₂ (206.3 mg, 0.9 mmol) , Xantphos (579.9 mg, 1.0 mmol) and Cs ₂ CO ₃ (597.7 mg, 1.8 mmol) in 1,4-dioxane (8 mL) were stirred and refluxed for 12 h at N2 atmosphere. The reaction mixture was then cooled to rt. and filtered with celite, diluted with dichloromethane (60 ml), washed with saturated ammonium chloride (30 ml) and brine (30 ml), dried with anhydrous sodium sulfate and concentrated to dryness. The residue was purified using a flash column (DCM:MeOH=25:1) to give 3-(cyclohex-1-en-1-yl)-2-phenyl-6(quinolin-6-yl)-5- ((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazolo[1,5a]pyrimidin-7(4H)-one (160 mg) as a brown solid.

LC-MS: m/z 630.3 (M+n) ⁺ .

Step B. 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6yl)pyrazolo[1,5-a ]pyrimidin-7(4H)-one.

To a solution of 3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)-5-(( 1 -((2(trimethylsilyl)ethoxy)methyl)-1H-pyrazole -3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one (60 mg, 0.1 mmol) in DCM (1 ml) cooled to 0°C, TFA was added dropwise ( 2 ml). The mixture was then stirred at rt. over 2 h. The mixture was concentrated and NH ₄ OH (5 ml) was added, resulting in 5-((1H-pyrazol-5-yl)amino)-3-(cyclohex-1-en-1-yl)- 2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d ₆ ): δ 13.37 (br. s., 1H), 9.13 (br. s., 1H), 8.88-8.98 (m, 1H), 8 .41 (d, J=8.1 Hz, 1H), 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) ⁺ .

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Compound

191.

3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)-5-((1-((2(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3 -yl)amino)pyrazolo[1,5-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[1,5-a]pyrimidin-5-amine.

A mixture of 6-(5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-2-phenylpyrazolo[1,5a]pyrimidin-6-yl)quinoxaline (150 mg, 0.32 mmol), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3amine (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) in a microwave reactor at 100°C under N2 for 45 min. After cooling to rt. the reaction mixture was diluted with dichloromethane (100 ml), filtered with celite, washed with aqueous NH ₄ Cl (30 ml) and brine (30 ml), dried with anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC (DCM/MeOH=30:1) to give 3-(cyclohex-1-en-1-yl)-7methoxy-2-phenyl-6-(quinoxalin-6-yl)-N- (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3yl)pyrazolo[1,5-a]pyrimidin-5-amine (80 mg) as a brown solid.

LC-MS: m/z 645.3 (M+H) ⁺ .

Step B. 3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)-5-((1-((2(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

Solution 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[1,5-a]pyrimidin-5-amine (80 mg, 0.1 mmol) and tBuOK (83.5 mg, 0.7 mmol) in dioxane/H ₂ O( 6 ml/1 ml) was stirred at 100°C for 8 hours. After cooling to rt. the mixture was diluted with dichloromethane (60 ml), washed with water (30 ml) and brine (20 ml), dried with Na ₂ SO ₄ and concentrated to dryness. The residue was purified by preparative TLC (DCM:MeOH=15:1) to give a yellow solid (50 mg).

LC-MS: m/z 631.3 (M+H) ⁺ .

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Step C. 5-((1H-pyrazol-5-yl)amino)-3 -(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6yl)pyrazolo [1,5-a ] pyrimidine-7(4Н)-one.

To a solution of 3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)-5-(( 1 -((2(trimethylsilyl)ethoxy)methyl)-1H-pyrazole -3-yl)amino)pyrazolo[1,5-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) drop by drop. The mixture was then stirred at rt. over 2 h. The mixture was concentrated and NH ₄ OH (5 ml) was added, resulting in 5 -((1 H-pyrazol-5-yl)amino)-3 -(cyclohex-1 -en-1 -yl) -2-phenyl-6-(quinoxalin-6yl)pyrazolo[1,5-a]pyrimidin-7(4I)-one.

¹ H-NMR (DMSO-d ₆ ): δ 13.38 (br. s., 1I), 12.83 (br. s., 1I), 9.29 (br. s., 1I), 8, 97 (s, 2R), 8.17 (d, J=8.5Hz, 1R), 8.11 (d, J=1.5Hz, 1R), 7.89 (d, J=8.5 Hz, 1R), 7.74 (d, J=7.0 Hz, 3R), 7.45-7.52 (m, 2R), 7.37-7.44 (m, 1R), 6.04 (br. s., 1I), 5.97 (br. s., 1I), 2.39 (br. s., 2I), 2.03-2.11 (m, 2I), 1.72 ( d, J=4.0 Hz, 5R).

LC-MS: m/z 501.2 (M+I)+.

Compound 192

A suspension of intermediate 1 (880 mg, 2 mmol), NI ₃ /dioxane (0.4 N, 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 25 ml N2 microwave vial. The vessel was sealed and heated for 1 hour at a constant temperature of 50°C. The reaction mixture was then cooled to rt. and filtered. The dark filtrate was concentrated in vacuo and purified by silica gel flash column chromatography (DCM/MeOI=20:1) to give Intermediate 2 (400 mg).

1H-NMR (DMSO-d ₆ ): 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, 2I), 6.48-5.96 (s, 2I), 4.03 (s, 3I), 3.82 (s, 3I).

LC-MS: m/z 423.2 (M+I) ⁺ .

Step B. N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)thiazol-4amine.

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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 10 ml vessel for microwave processing in an atmosphere of N2. The vessel was sealed and heated for 1 hour at a constant temperature of 80°C. The reaction mixture was then cooled to rt. and filtered. The dark filtrate was concentrated in vacuo and purified by silica gel flash column chromatography (DCM/MeOH=20:1) to give Intermediate 3 (40 mg) as a white solid.

LC-MS: m/z 406.1 (M+I)+.

Step C. 6-(4-methoxyphenyl)-2,3-diphenyl-5-(thiazol-4-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of intermediate 3 (40 mg, 0.08 mmol) in HCl/dioxane (5 mL, 1N) was stirred at rt. for 1 hour. The mixture was then concentrated under reduced pressure, whereby the desired product 4 was obtained.

1H-NMR (DMSO-06): 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) ⁺ .

Compound 152 4H)-he.

/= N ρ ⁰

This compound was prepared according to the procedures for compound 192, steps B-C, starting from 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidine-5-amine.

Stage B (stoichiometry). 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine-5amine (210 mg, 0.5 mmol), 7-chloro-[1,2,4]triazolo[ 1,5-c]pyrimidine (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 CO ₃ (500 mg, 1.5 mmol, 3 eq.) in 1,4-dioxane (15 ml) under microwave heating at 100°C for 1 h under N2 atmosphere.

LC-MS: m/z 541.2 (M+H) ⁺ .

Step C. N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)[1,2,4]triazolo[1,5- c]pyrimidine-7-amine (100 mg, 0.19 mmol) in HCl-1,4-dioxane (15 mL) was stirred at rt. within 3 hours the Solvent and volatiles were removed under vacuum. The residue was dissolved in DCM (5 ml) and treated with saturated NaHCO ₃ . The organic phase was separated and washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 193 5-((1H-pyrazol-3-yl)amino)-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of 5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one (compound 182, 50 mg, 0.11 mmol) in anhydrous DCM (5 ml) was added a solution of BBr ₃ (40 mg, 0.16 mmol, 1.5 eq.) in DCM (0.5 ml) at -78°C. The reaction mixture was stirred at 0° C. for 2 hours. The suspension was neutralized with methanol (MeOH) at -78° C. and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title product 5-((1H-pyrazol-3-yl)amino)-6-(4 -hydroxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

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,

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J=7.2Hz, 4H), 7.38(t, J=7.6Hz, 6H), 7.16(d, J=8.4Hz, 2H), 6.68(d, J= 8.4 Hz, 2H), 6.08(s, 1H).

LC-MS: m/z 461.7 (M+H)+.

Compound 194. 3-cyclohexenyl-6-(4-hydroxyphenyl)-2-phenyl-5-(pyrazin-2ylamino)pyrazolo[1,5-a]pyrimidine-7(4H)-oh.

3-cyclohexenyl-6-(4-methoxyphenyl)-2-phenyl-5-(pyrazin-2-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one mixture (compound 158, 100 mg, 0.204 mmol) and BBr ₃ (1 M in dichloromethane, 5 ml) were stirred at rt. for 1 hour. The mixture was neutralized with methanol at 0°C, resulting in 3-cyclohexenyl-6-(4-hydroxyphenyl)-2-phenyl-5-(pyrazin-2-ylamino)pyrazolo[1,5-a] pyrimidine-7(4H)he.

¹ H-NMR (DMSO-d ₆ ): δ 13.87 (s, 1H), 9.52 (s, 1H), 9.28 (s, 1H), 8.62 (s, 1H), 8, 24 (d, J=2.75 Hz, 1H), 8.20 (s, 1H), 7.73 (d, J=7.02 Hz, 2H), 7.39-7.52 (m, 3H ), 7.20 (d, J=8.54 Hz, 2H), 6.85 (d, J=8.24 Hz, 2H), 6.04 (br. s., 1H), 2.33 ( br. s., 2H), 2.04 (br. s., 2H), 1.59-1.77 (m, 4H).

LC-MS: m/z 477.2 (M+H) ⁺ .

Compound 195 .

Intermediate 1 was prepared according to the procedure for compound 101 (step A-E) using intermediate 9 as 1-((2-(trimethylsilyl)ethoxy)methyl)-1H1,2,4-triazole-3-amine in step E .

LC-MS: m/z 620.3 (M+H) ⁺ .

Step A. To a solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3 -yl)pyrazolo[1,5-a]nirimidin-5-amine 1 (80 mg,

0.1 mmol) in DCM (2 ml) cooled to 0° C., BBr ₃ (1.0 M in DCM, 1.5 ml) was added dropwise. The mixture was then stirred at 0° C. for 2 hours. The reaction was quenched by careful addition of MeOH and concentrated in vacuo to give the product.

1H-NMR (DMSO-dg): δ 14.10 (br. s., 1H), 13.12 (br. s., 1H), 9.51 (br. s., 1H), 9.00 ( br. s., 1H), 8.54 (br. s., 1H), 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) ⁺ .

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Compound 196 6-(2-methylbenzo[d]thiazol-6-yl)-2,3-diphenyl-5-(pyridin-2-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Step A. dimethyl-2-(2-methylbenzo^]thiazol-6-yl)malonate.

Mixture of 6-bromo-2-methylbenzo^]thiazole (4.5 g, 19.7 mmol), dimethylmalonate (5.2 g, 39.4 mmol), Pd(OAc) ₂ (882 mg, 3.94 mmol) , t-BuMePhos (2.45 g, 7.88 mmol) and K ₃ PO ₄ (9.5 g, 45.3 mmol) in 100 ml of anhydrous toluene were stirred at 80° C. under N2 atmosphere for 16 h. filtered and concentrated. The residue was purified with a silica gel column (petroleum ether:ethyl acetate=5:1) to give Intermediate 2 as a white solid (3.6 g).

¹ H-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) ⁺ .

Step B. 5-hydroxy-6-(2-methylbenzo[d]thiazol-6-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine -7(4H)-oh.

About h ΗΟγΝΑ /= -ccr

A mixture of dimethyl-2-(2-methylbenzo[d]thiazol-6-yl)malonate (3 g, 10.7 mmol) and 3,4-diphenyl-1-Pyrazol-5-amine (2.1 g, 8.9 mmol ) in triethyl acetate (20 ml) was stirred at 150°C for 4 h. The mixture was then cooled to rt. and filtered. The settled substances were suspended in a mixed solution of 2 ml THF and 20 ml HCl (1 M) and stirred at rt. for 0.5 h. The solid was filtered and washed with ethyl acetate (10 mL) to give the title product as a white solid (2.7 g) which was used directly in the next step without further purification.

LC-MS: m/z 451.2 (M+H) ⁺ .

Step C. 6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)-2-methylbenzo[d]thiazole.

A mixture of intermediate 3 (2.7 g, 6 mmol) in POCl ₃ (20 ml) was stirred at 120°C in

- 102 042905 overnight in a sealed tube. The mixture was concentrated. The residue was alkalized with a solution

NaHCO3 to pH 7, extracted with dichloromethane (10 mlx3), dried, concentrated and purified by silica gel column (petroleum ether:ethyl acetate=3:1) to give intermediate 4 (2.1 g) as a yellow solid substances.

LC-MS: m/z 487.3 (M+H) ⁺ .

Step D. 6-(5-Chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)-2-methylbenzo[d]thiazole.

Intermediate 4 (2.1 g, 4.3 mmol) was dissolved in DCM (10 ml) and MeOH (20 ml) at 0°C. NaOMe (464 mg, 8.6 mmol) in MeOH (5 mL) was added dropwise and stirring was continued for 16 h at rt. The mixture was concentrated. The residue was purified using a silica gel column (petroleum ether:ethyl acetate=5:1) to give title product 5 (1.6 g) as a white solid.

¹ H-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, 2.4Hz, 2H), 7.54 (d, J=7.0Hz, 2H), 7.48 (dd, J=8.5, 1.5Hz, 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) ⁺ .

Step E. 6-(2-methylbenzo[d]thiazol-6-yl)-2,3-diphenyl-5-(pyridin-2-ylamino)pyrazolo[1,5a]pyrimidin-7(4H)-oh.

Suspension of intermediate 5 (482 g, 1 mmol), pyrazin-2-amine (94 mg, 1 mmol), Pd(OAc)2 (42.2 mg, 0.2 mmol), Xantphos (23.1 mg, 0 .4 mmol) and Cs ₂ CO ₃ (652 mg, 2 mmol) in 1,4-dioxane (10 ml) were stirred and heated under reflux for 16 h under N 2 atmosphere. The course of the reaction was monitored by LC-MS until complete conversion of the starting material. The reaction mixture was then cooled to rt. and filtered. The dark filtrate was concentrated in vacuo to give the title compound 6.

¹ H-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) ⁺ .

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Compound 197 ] pyrimidine-7(4Н)-one.

stage E

Step A. 6-bromo-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine.

RMV I

To a mixture of 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (10 g, 47 mmol) and K ₂ CO ₃ (13 g, 94 mmol) in DMF (100 ml) was added 1-(chloromethyl)-4-methoxybenzene (8.8 g, 56 mmol). The mixture was stirred at rt. for 16 hours. The mixture was poured into water (30 ml) and extracted with ethyl acetate (30 mlx3). The combined organic layers were dried, concentrated and purified using a silica gel column (petroleum ether:ethyl acetate=5:1) to give the title product (11 g) as a white solid.

¹ H-NMR (CHLOROFORM-d): δ 7.12-7.20 (m, J=8.5 Hz, 2H), 6.84-6.90 (m, 2H), 6.80 (d, J=2.1Hz, 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) ⁺ .

Step B. dimethyl-2-(4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl) malonate.

Mixture of intermediate 2 (5.5 g, 16.5 mmol), dimethylmalonate (2.6 g, 19.8 mmol) Pd(OAc)2 (370 mg, 1.65 mmol), t-BuMePhos (1.96 g, 3.63 mmol) and K ₃ PO ₄ (8 g, 37.95 mmol) in 30 ml of anhydrous toluene were stirred at 80° C. under N2 for 16 h. The mixture was filtered and concentrated. The residue was purified using a silica gel column (petroleum ether:ethyl acetate=4:1) to give Intermediate 3 (5.7 g) as a white solid.

¹ H-NMR (CHLOROFORM-d): δ 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)+.

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Step C. 5-hydroxy-6-(4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3diphenylpyrazolo [1,5- a] pyrimidin-7(4H)-one.

A mixture of intermediate 3 (1.5 g, 3.8 mmol) and 3,4-diphenyl-1H-pyrazole-5-amine (760 mg, 3.2 mmol) in triethyl acetate (20 ml) was stirred at 150°C in for 4 h. Then the mixture was cooled to rt. and filtered. The filter residue was suspended in a mixed solution of 2 ml THF and 20 ml HCl (1 M) and stirred at rt. for 0.5 h. The precipitate was filtered and washed with ethyl acetate (10 ml) to give the product (1.3 g) as a white solid, which was used directly in the next step without further purification.

LC-MS: m/z 557.2 (M+I)+.

Step D. 6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)-3,4-dihydro-2Hbenzo[b][1,4]oxazine.

Intermediate 4 (1.3 g, 2.3 mmol) was dissolved in POCl ₃ (15 ml) and stirred at 120° C. overnight in a sealed tube. The mixture was concentrated and basified with NaHCO ₃ solution to pH 7. The resulting mixture was extracted with dichloromethane (10 mL×3), dried and concentrated to give crude Intermediate 5 (2.1 g) as a yellow solid.

LC-MS: m/z 473.3 (M+H) ⁺ .

Step E. 6-(5-Chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)-3,4-dihydro-2Hbenzo[b][1,4]oxazine.

Intermediate 5 (500 mg, 1.06 mmol) was dissolved in DCM (5 ml) and MeOH (10 ml) at 0°C. NaOMe (114 mg, 2.11 mmol) in MeOH (5 mL) was added dropwise and stirring was continued for 16 h at rt. The mixture was concentrated and purified with a silica gel column (petroleum ether:ethyl acetate=6:1) to give the title product (230 mg) as a white solid.

¹ H-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) ⁺ .

Step F. 6-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-methoxy-2,3-diphenyl-N-(pyridin-2yl)pyrazolo [1 ,5-a] pyrimidine-5-amine.

Suspension of intermediate 6 (200 mg, 0.43 mmol), pyrazine-2-amine (48 mg, 0.51 mmol), Pd(OAc) ₂ (9.6 mg, 0.043 mmol), Xantphos (49.6 mg , 0.086 mmol) and Cs ₂ CO ₃ (280 mg, 0.86 mmol) in 1,4-dioxane (10 ml) were heated under reflux for 16 h under N2 atmosphere. The course of the reaction was monitored by LC-MS until complete conversion of the starting material. Then

- 105 042905 the reaction mixture was 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 give Intermediate 7 (120 mg) as a white solid.

¹ H-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) ⁺ .

Step G. 6-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3-diphenyl-5-(pyridin-2ylamino)pyrazolo[1,5-a ]pyrimidin-7(4H)-one.

A solution of intermediate 7 (50 mg, 0.095 mmol) in HCl (5 mL, 4 M in 1,4-dioxane) was stirred at rt. over 16 h. The mixture was concentrated, basified with ammonia (5 mL, 7 M in MeOH) and concentrated in vacuo to give the title compound 8.

¹ 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) ⁺ .

Compound 198 ,5-α]pyrimidin-7(4H)-one.

Step A. 7-methoxy-6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3-diphenyl-N-(pyridin2-yl )pyrazolo[1,5-a]pyrimidine-5-amine.

6-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-methoxy-2,3-diphenyl-N-(pyridin-2-yl)pyrazolo[1, 5a]pyrimidin-5-amine (50 mg, 0.095 mmol) in THF (10 ml) was cooled to 0°C, HCOOH (5.2 mg, 0.114 mmol) was added and stirred for 5 min. BH ₃ THF (0.19 ml, 1M) was added dropwise at 0° C. and the mixture was slowly heated to rt. and continued stirring for 4 hours. The reaction was quenched by adding NaHCO ₃ solution interday. The resulting mixture was extracted with dichloromethane (10 mlx3), dried and concentrated. The residue was purified using a silica gel column (petroleum ether:ethyl acetate=3:1) to give Intermediate 2 (30 mg) as a light yellow solid.

¹ H-NMR (CHLOROFORM-d): δ 8.83 (d, J=8.2 Hz, 1H), 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) ⁺ .

Step B. 6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2,3-diphenyl-5-(pyridin-2ylamino)pyrazolo[1 ,5-α]pyrimidin-7(4H)-one.

Intermediate 2 (30 mg, 0.056 mmol) in HCl (10 ml, 4 M in dioxane) was stirred at

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k.t. over 2 h. The mixture was concentrated, basified with ammonia (5 mL, 7 M in MeOH) and concentrated in vacuo to give the title compound 3.

1 H-NMR (CHLOROFORM-d): δ 8.07 (d, J=4.6 Hz, 1H), 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)+.

Compound 199 1,3,4-oxadiazole-2-carboxamide.

Step A To a solution of compound 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, resulting in the desired product 2 .

¹ H-NMR (DMSOCH): δ 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) ⁺ .

Compound (E)-2-hydroxy-1-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4.7200.

dihydropyrazolo[1,5-a]pyrimidin-5-yl)guanidine.

Step A. N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5yl)cyanamide.

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 microwave sealed vial. treatment (25 ml) in an atmosphere of N2 was heated to 80°C for 1 h. Then the reaction mixture was cooled to rt. and filtered. The dark filtrate was concentrated in vacuo and purified by silica gel flash column chromatography (DCM/MeOH=1O0:1) to give Intermediate 2 (180 mg).

LC-MS: m/z 448.1 (M+H) ⁺ .

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Step B. (E)-2-hydroxy-1-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5yl)guanidine.

Hydroxylamine hydrochloride (47 mg, 0.67 mmol, 3 0 equiv.). The reaction mixture was then stirred at rt. during the night. The mixture was partitioned between ethylamine and H2O. The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title intermediate 3 (30 mg).

LC-MS: m/z 481.1 (M+H) ⁺ .

Step C. (E)-2-hydroxy-1-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl)guanidine.

A mixture of intermediate 3 (30 mg, 0.06 mmol) in HCl/dioxane (5 mL, 1N) was stirred at rt. for 1 hour. The mixture was then concentrated under reduced pressure to give the title compound 4.

¹ H-NMR (DMSO^): 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) ⁺ .

Compound 201 (S)-(3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl)amino)-1H -pyrazol-1-yl)methyl-2-amino-3-methylbutanoate.

NaH/DMF /0°C - k.t.

step A n-Bu ₄ NHSO _4i flXM | /N ₂ Ok.t.

stage A

Step A. (S)-chloromethyl-2-((tert-butoxycarbonyl)amino)-3-methylbutanoate.

To a solution of intermediate 1 (1.4 g, 6.6 mmol) in DCM/H ₂ O (10/10 ml) was added chloromethylsulfochloridate 6 (1.3 g, 7.9 mmol, 1.2 eq.), NaHCO ₃ (4 eq.) and tetrabutylammonium hydrogen sulfate (0.1 eq.). The mixture was stirred at rt. during the night. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3x10 ml). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography to give desired product 2 as a colorless oil (1.5 g).

LC-MS: m/z 266.2 (M+H) ⁺ .

Step B. (S)-(3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5yl)amino)-1H -pyrazol-1-yl)methyl-2-((tert-butoxycarbonyl)amino)-3-methylbutanoate.

To a solution of intermediate 3 (300 mg, mmol) in DMF (20 ml) was added sodium hydride (3 equiv.) at 0°C. After stirring the mixture at 0° C. for 30 min, (S)-chloromethyl-2-((tert-butoxycarbonyl)amino)-3-methylbutanoate 2 (3 eq.) was added dropwise. The mixture was then stirred

- 108 042905 at room temperature during the night. The mixture was poured into water (100 ml) and extracted with dichloromethane (3x20 ml), the combined organic phase was washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography to give the desired product 4 as a white solid. (240 mg).

¹ H-NMR (DMSO-d ₆ ): δ 13.07 (s, 1H), 9.11 (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) ⁺ .

Step C. (S)-(3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5yl)amino)-1H -pyrazol-1-yl)methyl-2-amino-3-methylbutanoate.

To a solution of intermediate 4 (220 mg, 0.31 mmol) in DCM (1 ml) was added HCl-dioxane (4 mol/l, 5 ml) at 0°C. The mixture was stirred at rt. within 1 h White precipitate was filtered off and mixed with dichloromethane (5 ml) and an aqueous solution of NaHCO ₃ . The organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the desired product 5.

¹ H-NMR (DMSO-d ₆ ): 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, 1H), 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) ⁺ .

Compound 203 pyrimidine-7(4H)-one.

NC

MeCN

Et ₃ N/EtOH/Harp.c ref.cold

ABOUT

N

Ν stage B stage A

OME Stage D

ROS1 ₃

HOL.

_Tf2O /TFA/50°C

NaHMDS/ΤΓΦ /0°C - k.t.

RMV ^N

PMBNH ₂ NH ₂ conb HCI ^H 2 ^N

MeONa/MeOH

0°С - k.t.

stage H

Pd(OAc) ₂ /Xant-phos /Cz ₂ CO ₃ L ^IO| < ^san/120 ° ^s stage E stage G

Step A. 3-oxo-3-(pyridin-2-yl)propanenitrile.

To a solution of methyl picolinate (13 g, 95 mmol) and acetonitrile (5.8 g, 142 mmol) in THF (150 ml) was slowly added NaHDMS (2 mol/l, 71 ml, 142 mmol) at 0°C. The reaction mixture was then stirred at 0° C. for 0.5 h and allowed to warm to rt. for 2 hours. The reaction was quenched with water, adjusted to pH 7 with hydrochloric acid (2 mol/l) and extracted with dichloromethane (100 mlx3). The combined organic layers were washed with brine, dried with 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 substances.

¹ H-NMR (CHLOROFORM-d): δ 8.70 (dd, J=4.8, 0.6 Hz, 1H), 8.03-8.17 (m, 1H), 7.92 (td, J=7.8, 1.6Hz,

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1H), 7.58 (ddd, J=7.6, 4.8, 1.4 Hz, 1H), 4.40 (s, 2H).

LC-MS: m/z 147.1 (M+H)+.

Step B. 1-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine.

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 heated at reflux for 2 h under a protective N2 atmosphere. The mixture was then evaporated under vacuum. The residue was dissolved in ethyl acetate (100 ml), washed with water and extracted with ethyl acetate (100 mlx2). 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 0.5 h and filtered to give 1-(4-methoxybenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5- amine as a pale yellow solid (15.1 g, 79% yield).

¹ H-NMR (DMSO-d6): δ 8.50 (d, J=4.8 Hz, 1H), 7.77-7.83 (m, 1H), 7.73 (dd, J=7, 6, 1.6Hz, 1H), 7.11-7.26(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+H) ⁺ .

Step C. 4-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-3-(pyridin-2-yl)-1 H-pyrazol-5-amine.

Cyclohexanone (5.3 g , 54 mmol, 1 eq.). The mixture was stirred at 90°C for 1 h. Then another 1 eq. cyclohexanone and the mixture was stirred at 90°C for 1 h. The solvent was removed under vacuum. The resulting residue was dissolved in ethyl acetate (100 ml) and treated with saturated NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 ml x 2). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/DCM=1/20) to give 4-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-3(pyridin-2-yl)- 1H-pyrazole-5-amine as a brown solid (6.8 g, 35% yield).

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

Step D. 4-(cyclohex-1-en-1-yl)-3-(pyridin-2-yl)-1 H-pyrazol-5-amine.

4-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-3-(pyridin-2-yl)-1 H-pyrazol-5-amine solution (6.8 g, 19 mmol) in TFA/(CF ₃ SO ₂ ) ₂ O (30 ml/10 ml) was stirred at 50°C for 1 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate (50 ml) and treated with saturated NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in NH ₃ /MeOH (7 mol/l, 50 ml) and hydrazine hydrate (g, mmol, 2 eq.) was added. The mixture was stirred at rt. during the night. The solvent was removed in vacuo and the residue was purified by flash chromatography (MeOH/DCM 1/20) to give 4-(cyclohex-1-en-1yl)-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) ⁺ .

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Step E. 3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5a]pyrimidin-7(4H) -He.

Solution of 4-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (3.6 g, 15 mmol) and dimethyl-2-(4methoxyphenyl)malonate (7.2 g, 30 mmol, 2 eq.) in xylene (50 ml) was heated under reflux for 8 hours. The reaction mixture was cooled to rt. The precipitate was filtered off and washed with methanol (MeOH) to give 3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2(pyridin-2-yl)pyrazolo[1 ,5-a]pyrimidin-7(4H)-one (4.0 g, 64% yield) as a yellow solid.

LC-MS: ' m/z 415.2 (M+H) ⁺ .

Step F. 5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5a]pyrimidine.

3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one solution (4.0 g, 10 mmol) in POCl ₃ (30 ml) in a sealed tube was stirred at 120°C overnight. The reaction mixture was cooled to rt. and concentrated under vacuum. The residue was dissolved in DCM (50 ml) and poured into ice-water (100 ml). The mixture was brought to pH 7 by adding a saturated solution of NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (elution using petroleum ether/ethyl acetate=1:1) to give 5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl) )-2-(pyridin-2-yl)pyrazolo[1,5a]pyrimidine (2.8 g, 64% yield) as a yellow solid.

LC-MS: m/z 451.1, 453.1 (m+H) ⁺ .

Step G. 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-(pyridin-2ul)pyrazolo[1,5-a]pyrimidine.

To a solution of 5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-(pyridin-2-yl)pyrazolo[1,5a]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 aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4methoxyphenyl )-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine (2.7 g, 97% yield) as a yellow solid.

¹ H-NMR (DMSO-d ₆ ): δ 8.70 (dt, J=4.8, 1.2 Hz, 1H), 7.91-7.96 (m, 2H), 7.42-7 .47 (m, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.6 Hz, 2H), 5.82 (br. s., 1H ), 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) ⁺ .

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Step H. 3 -(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5-(pyridin-2ylamino)pyrazolo[1,5-a] pyrimidine-7(4H)-one.

Suspension of 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-(pyridin-2yl)pyrazolo[1,5-a]pyrimidine (300 mg , 0.67 mmol), pyridine-2-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 Cs ₂ CO ₃ (437 mg, 1.34 mmol, 2.0 eq.) in 1,4-dioxane (10 ml) were stirred at 130°C (heating microwave radiation) for 1.5 h in an N2 atmosphere. The mixture was filtered through Celite and the filtrate concentrated in vacuo to give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 8.67 (d, J=8.2 Hz, 1H), 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., 1H), 3.82 (s, 3H), 2.20 (br. s., 4H), 1.66 (br. s., 4H).

LC-MS: m/z 491.2 (M+H) ⁺ .

3,4-diphenyl-1H-pyrazole-5-amine.

Step A. 3-oxo-2,3-diphenylpropanenitrile.

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 the addition, the mixture was stirred at rt. during the night. The mixture was neutralized with 1 M hydrochloric acid to pH 6. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Petroleum ether (60 ml) was added to the residue and the resulting cloudy liquid was stirred at rt. over 3 hours. The precipitate was collected by filtration and dried under vacuum to give 3-oxo2,3-diphenylpropanenitrile 2 (15.3 g) as a white solid.

LC-MS: m/z 222.1 (M+H) ⁺ .

Step B. 3,4-diphenyl-1H-pyrazole-5-amine.

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 ethanol (60 ml) was refluxed for night. The mixture was evaporated to remove ethanol, and the residue was brought to pH 8 with saturated sodium bicarbonate solution at 0°C. The mixture was extracted with ethyl acetate (80 ml) twice, the combined organic phase was washed with brine, dried with anhydrous sodium sulfate and concentrated under vacuum to dryness. The resulting solid was recrystallized from 2-methoxy-2-methylpropane to give 3,4-diphenyl-1H-pyrazole-5-amine (16 g) as a white solid.

LC-MS: m/z 236.1 (M+H) ⁺ .

3-(2-fluorophenyl)-4-phenyl-1H-pyrazole-5-amine.

This compound was prepared according to the procedures for the preparation of intermediate 3,4-diphenyl-1H-pyrazol-5-amine using compounds 4 as methyl 2-fluorobenzoate.

Stage 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), cooled to 0 °C

LC-MS: m/z 240.1 (M+H) ⁺ .

Stage 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 ethanol (15 ml ) under reflux conditions overnight.

LC-MS: m/z 254.2 (M+H) ⁺ .

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3-phenyl-4-(( ² H ₁₀ )piperidin-1-yl)-1H-pyrazole-5-amine.

Step A. 2-(( ² H ₁₀ )piperidin-1-yl)acetonitrile.

A mixture of nunepuguHa-d ₁₀ (100 mg, 1.04 mmol, 1 eq.), 2-bromoacetonitrile (150 mg, 1.2 eq.) and K ₂ CO ₃ (276 mg, 2 eq.) in CH3CN (5 ml ) was stirred at 70°C overnight. The mixture was then cooled to rt. and filtered, the filtrate was poured into water (30 ml) and extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give intermediate 2, which was used directly in the next step without further purification.

LC-MS: m/z 135.0 (M+H) ⁺ .

Step B. 3-oxo-3-phenyl-2-(( ² H ₁₀ )piperidin-1-yl)propanenitril.

NaHMDS (2 M in THF, 0 .52 ml, 1.2 eq.) at 0°C. The mixture was stirred at rt. during the night. The reaction mixture was diluted with ethyl acetate (10 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated, washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography to give the title intermediate 3 as a white solid.

LC-MS: m/z 239.1 (M+H) ⁺ .

Step C. 3-phenyl-4-(( ² H ₁₀ )piperidin-1-yl)-1H-pyrazole-5-amine.

A 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 heated at reflux refrigerator for 5 hours Then the mixture was cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (5 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (5 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography to give the desired product 4 as a white solid.

1H-NMR (DMSO-J6): δ 11.52 (br. s., 1H), 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)+.

3-phenyl-4-(piperidin-1-yl)-1 H-pyrazol-5-amine.

This compound was obtained in accordance with the procedure for obtaining.

Intermediate 3-phenyl-4-(( ² H ₁₀ )piperidin-1-yl)-1H-pyrazol-5-amine by BC steps starting from 2-(piperidin-1-yl)acetonitrile.

Stage B (stoichiometry). 2-(piperidin-1-yl)acetonitrile (7.8 g, 62 mmol, 1 eq.), methyl benzoate (9.4 g, 68 mmol, 1.1 eq.) and NaHMDS (2 M in THF, 46 ml , 1.5 eq.) in THF (300 ml) at 0°C-rt.

Stage C (stoichiometry). 3-oxo-3-phenyl-2-(piperidin-1-yl)propanenitrile (5 g, 21.902 mmol) and hydrazine hydrate (3.3 g, 65.706 mmol) in EtOH/AcOH (5/1, 30/6 ml ) under reflux conditions for 16 hours under N ₂ protective atmosphere.

1H-NMR (DMSO-d6): δ 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) ⁺ .

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4-(4,4-difluoropiperidin-1-yl)-3-phenyl-1H-pyrazole-5-amine.

F

A-F

NH2N.J /=\

ΗΝ., /VJ/

This compound was prepared according to the procedure for preparing intermediate 3-phenyl-4-(( ² H ₁₀ )piperidin-1-yl)-1H-pyrazol-5-amine, AC steps starting from 4,4- difluoropiperidine hydrochloride.

Stage A (stoichiometry). 4,4-difluoropiperidine hydrochloride (1.0 g, 6.3 mmol, 1 eq.), 2-bromoacetonitrile (761 mg, 6.3 mmol, 1 eq.), triethylamine (2.2 g, 22.2 mmol , 3.5 eq.) in THF (30 ml) under conditions of heating to 60°C overnight.

LC-MS: m/z 161.0 (M+H) ⁺ .

Stage B (stoichiometry). 2-(4,4-difluoropiperidin-1-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-rt.

Stage C (stoichiometry). 2-(4,4-difluoropiperidin-1-yl)-3-oxo-3-phenylpropanenitrile (380 mg, 1.44 mmol, 1 eq.) and hydrazine hydrate (144 mg, 2.88 mmol, 2 eq.) in EtOH/AcOH (5/1, 15/3 ml) under reflux conditions for 6 h.

LC-MS: m/z 279.1 (M+H) ⁺ .

4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazole-5-amine.

Step A. 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazole-5-amine.

A suspension of amino-pyrazole (10 g, 62.9 mmol) and cyclohexanone (13 ml, 126 mmol) and 4-methylbenzenesulfonic acid hydrate (11.4 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 give a crude product which was recrystallized from methanol to give 4-cyclohexenyl-3-phenyl-1H-pyrazol-5-amine (4.18 g) as a white solid.

¹ H-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) ⁺ .

4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazole-5-amine.

Step A. 1-(4-methoxybenzyl)-3-phenyl-1H-pyrazole-5-amine.

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) heated to 85°C overnight. The mixture was cooled to rt. and poured into water (300 ml). The mixture was made basic by adding aqueous sodium hydroxide at 0° C. to pH 7-8. The resulting suspension was filtered. The filter cake was washed with water, dried under vacuum to give 1-(4-methoxybenzyl)-3-phenyl-III-pyrazole-5-amine (14.4 g) as a white solid.

¹ H-NMR (CHLOROFORM-d): δ 7.79 (d, J=8.8 Hz, 2H), 7.38-7.42 (m, 2H), 7.28-7.38 (m, 1H), 7.19 (d,

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J=8.8Hz, 2H), 6.89(d, J=8.8Hz, 2H), 5.91(s, 1H), 5.24(s, 2H), 3.81(s, 3H).

LC-MS: m/z 280.1 (M+H)+.

Step B. 4-(cyclohex-1-en-1-yl)-1-(4-methoxybenzyl)-3-phenyl-1H-pyrazole-5-amine.

A mixture of 1-(4-methoxybenzyl)-3-phenyl-1H-pyrazole-5-amine (9 g, 32.5 mmol) and cyclohexanone (6.4 g, 65.0 mmol) in acetic acid (50 ml) was stirred at k.t. within 16 hours the Mixture was poured into water (150 ml). To the mixture was added an aqueous solution of sodium hydroxide 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 with anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:3) to give 4-cyclohexenyl-1-(4-methoxybenzyl)-3-phenyl-1H-pyrazole-5-amine (6.5 g) as a white solid.

LC-MS: m/z 360.2 (M+H) ⁺ .

Step C. 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazole-5-amine.

Mixture of 4-cyclohexenyl-1-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-5-amine (6.0 g, 16.7 mmol) and trifluoromethanesulfonic anhydride (12 ml) in trifluoroacetic acid (36 ml) stirred at 30° C. for 2 hours. The mixture was poured into water (50 ml). To the mixture was added an aqueous solution of sodium hydroxide 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 with anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (methanol:dichloromethane=1:20) to give 4-cyclohexenyl-3-phenyl-1H-pyrazol-5-amine (2.6 g) as a white solid.

¹ H-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) ⁺ .

4-methoxy-1,3,5-triazine-2-amine.

An NH ₄ OH/-20°C nA CH ₃ ONa N^N

II Г ------------* Ϊ J * Ϊ X

CI^N^CI CI^N NH ₂ MeOH/0°C ^ON NH ₂ , ^{STAGE A} . stage B3

Step A. 4-chloro-1,3,5-triazine-2-amine.

2,4-dichloro-1,3,5-triazine (8.0 g, 53.3 mmol) was added portionwise to 200 ml NH4OH at -20°C. After the addition, the mixture was stirred at -20° C. for 10 min and then filtered, washed with water and dried to give 4-chloro-1,3,5-triazine-2-amine (5.7 g) as yellow solid, which was used in the next step without further purification.

LC-MS: m/z 131.1 (M+H) ⁺ .

Step B. 4-methoxy-1,3,5-triazine-2-amine.

CH ₃ ONa (35.2 ml, 176.1 mmol, 5.0 M). The mixture was then stirred at rt. within 1 h. Half of the solvent was removed under vacuum and the precipitate was filtered, washed with water, which gave 4-methoxy-1,3,5-triazine-2-amine as a white solid (1.0 g).

LC-MS: m/z 127.1 (M+H) ⁺ .

N2-methyl-1,3,5-triazine-2,4-diamine.

N^N /NH ₂ N^N l l ----* .ΛΑ

ΟΙ'^Ν^ΝΙ-^ MeOH/0°C λΗ stage Ao

Step A A mixture of 4-chloro-1,3,5-triazine-2-amine (200 mg, 1.5 mmol) in MeNH ₂ /THF (2 mol/l, 10 ml) was stirred at rt. within 10 min. The mixture was concentrated in vacuo and the residue purified by flash chromatography (DCM/MeOH 10/1) to give the title product as a white solid. (106 mg).

LC-MS: m/z 125.9 (M+H) ⁺ .

1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-amine.

Step A. 3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole.

A mixture of compound 1 (10 g, 0.089 mmol) and Cs ₂ CO ₃ (1.9 g, 0.116 mmol) in DMF (10 ml) was stirred at rt. for 16 hours. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (20 mlx3).

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The organic layer was dried, concentrated and purified by silica gel chromatography (petroleum ether:ethyl acetate=3:1) to give compound 2 (9 g) as a white solid.

1H-NMR (400 MHz, CHLOROFORM-d): δ 0.01-0.03 (m, 9H) 0.91-0.99 (m, 2H) 3.59-3.66 (m, 2H) 5 .53 (s,

2H) 7.01 (d, J=2.69 Hz, 1H) 7.69 (d, J=2.69 Hz, 1H).

LC-MS: m/z 244.5 (M+H) ⁺ .

Step B. 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-amine.

Compound 2 (9 g, 0.037 mmol) and Pd/C (0.9 g) in MeOH (30 ml) were stirred at RT. for 16 h in an H ₂ atmosphere. The mixture was filtered and concentrated to give a crude product which was used directly in the next step without further purification.

LC-MS: m/z 214.5 (M+H)+.

2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-amine.

SEM _VN

N^/

_NH2

This compound was prepared according to the procedures for preparing 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-amine using Intermediate 1 as 4-nitro-2H-1,2,3-triazole.

¹ H-NMR (DMSO-d ₆ ): 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)+.

1-(4-methoxybenzyl)-1H-pyrazole-3,5-diamine.

³ / _Nh2

PMBNHNH ₂ .HCI ΓΓ

NC CN -------------* H ₂ nA„N

Et |\|ethanol/load with return cold N ³ PMB Stage A

Step A. A mixture of malononitrile (1.9 g, 0.028 mmol) and (4-methoxybenzyl)hydrazine hydrochloride (5.4 g, 0.028 mmol) in EtOH (20 mL) and TFA (3 mL) was refluxed for 16 am The mixture was concentrated to dryness. The residue was suspended in water and extracted with ethyl acetate (10 mlx3). The combined organic layers were dried and concentrated to give a crude product which was used directly in the next step without further purification.

LC-MS: m/z 219.5 (M+H) ⁺ .

Methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetate.

To a solution of methyl 2-(3,4-dihydroxyphenyl)acetate (4 g, 0.022 mol) in DMF (20 ml) was added 1,2-dibromoethane (4.09 g, 0.022 mol) and K ₂ CO ₃ (6 g , 0.044 mol). The reaction mixture was heated to 80°C for 4 hours Then the reaction mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (elution using petroleum ether/ethyl acetate=10:1) to give the desired product (1.3 g).

¹ H-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) ⁺ .

3-(t-butyldimethylsilyloxy)pyridine-2-amine.

. stage A

2

Step A. To a mixture of 2-aminopyridin-3-ol (220 mg, 2 mmol), lH-imidazole (204 mg, 3 mmol) in chloroform (20 ml) slowly at rt. tert-butylchlorodimethylsilane (302 mg, 2 mmol) was added. The reaction mixture was then stirred at rt. during the night. The mixture was evaporated to dryness. The residue was purified by silica gel column chromatography (methanol:dichloromethane=1:50) to give 3-(t-butyl-dimethylsilyloxy)pyridine-2-amine (360 mg) as a white solid.

LC-MS m/z: 225.1 (M+H) ⁺ .

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This compound was prepared as 3-(tert-butyldimethylsilyloxy)pyridine-2-amine using Intermediate 1 as 6-aminopyridin-3-ol in step A.

LC-MS m/z: 225.1 (M+H) ⁺ .

General procedure 2a.

5-((tert-butyldimethylsilyl)oxy)pyridine-2-amine.

Step A. methyl 3-oxo-2-(quinolin-6-yl)butanoate.

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 (lithium diisopropylamide) (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. The mixture was then stirred at rt. within 6 hours the Mixture was slowly poured into saturated NH ₄ Cl and was extracted with ethyl acetate (3x350 ml). The combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated in vacuo. The residue was purified by flash chromatography to give the title intermediate 2 as a brown oil (150 g, 84% yield).

Step B Compound 204 5-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of intermediate 2 (150 g) and 4 (1.0 eq.) in AcOH (700 ml) was stirred at 90°C for 4 h. The solid was filtered off and washed with ethyl acetate (3x100 ml) to give the desired product 3.

1H-NMR (DMSO^): δ 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)+.

Compound 205

This compound was prepared according to general procedure 2a using intermediate 4 as 3-(2-fluorophenyl)-4-phenyl-1H-pyrazole-5-amine in step B.

Stage B

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 h. added saturated NaHCO ₃ to pH>7. The mixture was extracted with dichloromethane (50 ml), washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated to dryness. The residue was purified by preparative TLC (DCM:MeOH=25:1) to give 2-(2-fluorophenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a ]pyrimidin-7(4H)-one.

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,

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J=8.6Hz, 1H), 7.98(d, J=1.9Hz, 1H), 7.76(dd, J=8.9, 1.9Hz, 1H), 7.58( dd, J=8.2, 4.2 Hz, 1H), 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)+.

Compound 206 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin7(4I)-one.

This compound was prepared according to general procedure 2a using intermediate 4 as 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine in step B.

Step B. Methyl 3-oxo-2-(quinolin-6-yl)butanoate (200 mg, 0.82 mmol) and 5-phenyl-4-(piperidin-1yl)-1H-pyrazol-3-amine (200 mg, 0.82 mmol) was dissolved in AcOH (8 ml). The mixture was stirred at 95°C for 10 min. After cooling to rt. the mixture was poured into water and extracted with ethyl acetate (50 mlx3). The ethyl acetate layer was concentrated to dryness. The residue was made alkaline with an aqueous solution of NaHCO ₃ and filtered. The filter cake was purified by preparative HPLC to give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 11.52 (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), 3.11 (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) ⁺ .

Compound 207 3-(4,4-difluoropiperidin-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

This compound was prepared according to general procedure 2a using intermediate 4 as 4-(4,4-difluoropiperidin-1-yl)-3-phenyl-1H-pyrazol-5-amine in step B.

Step B. A solution of 4-(4,4-difluoropiperidin-1-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 h. added saturated NaHCO ₃ to pH>7. The mixture was extracted with dichloromethane (60 ml), washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated to dryness. The residue was purified by preparative TLC (DCM:MeOH=25:1) to give 3-(4,4-difluoropiperidin-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo [1,5a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d ₆ ): 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, 2.0Hz, 1H), 7.58 (dd, J=8.2, 4.2Hz, 1H), 7.52 (t, J=7.4Hz, 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) ⁺ .

Compound 208 3-(cyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

This compound was prepared according to the general procedure 2a using Intermediate 1 as methyl-2-(quinoxalin-6-yl)acetate in Step A and Intermediate 4 as 4-(cyclohex-1-en-1-yl)-3 -phenyl-1H-pyrazole-5-amine in step B.

Step B. A solution of 4-(cyclohex-1-en-1-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 h. the solvent was removed under vacuum and saturated NaHCO3 was added to pH>7. The mixture was diluted with dichloromethane (60 ml), washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated to dryness. The residue was purified by preparative

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TLC (DCM:MeOH=25:1) gave 3-(cyclohex-1-en-1-yl)-5-methyl-2-phenyl-6(quinoxalin-6-yl)pyrazolo[1.5 -a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSOCH): δ 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) ⁺ .

Compound 209. 6-(4-Methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

ABOUT

H/ ⁷

This compound was prepared according to the general procedure 2a using intermediate 1 to methyl-2-(4-methoxyphenyl)acetate in step A and intermediate 4 as 3,4-diphenyl1H-pyrazole-5-amine in step B.

Step B. A mixture of methyl 2-(4-methoxyphenyl)-3-oxobutanoate (300 mg, 1.3 mmol) and 3,4-diphenyl-1Hpyrazol-5-amine (206 mg, 0.85 mmol) in AcOH ( 15 ml) was stirred at 100° C. for 2 hours to give the title compound.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 210. 6-(4-ethoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

Oh oh

This compound was prepared according to general procedure 2a using intermediate 1 as methyl-2-(4-ethoxyphenyl)acetate in step A and intermediate 4 as 3,4-diphenyl1H-pyrazole-5-amine in step B.

Step B. Solution of 3,4-diphenyl-1H-n-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 h. After cooling to rt. The reaction mixture was filtered and washed with ethyl acetate (6 ml) and MeOH (0.5 ml) to give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 11.88 (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][1,4]dioxin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

This compound was prepared according to the general procedure 2a, steps A-B, starting from methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetate in step A.

Step A. Methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxobutanoate.

To a solution of methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetate (1.3 g, 6.3 mmol) in THF (15 mL) was slowly added LDA ) (3.2 ml, 2 mmol/ml in THF) at -30°C. Then acetyl chloride (730 mg, 9.5 mmol) was added slowly. The reaction mixture was stirred for 30 min at -30°C and allowed to reach rt. for 1 h. The mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product (1.3 g, crude) as a yellow liquid, which was used directly on the next stage without further purification.

Step B. 6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin7(4H)-one.

A solution of methyl 2-(2,3-dihydrobenzo[b][1,4]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 rt, resulting in the desired product

6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

1H-NMR (DMSO-d ₆ ): δ 11.88 (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) ⁺ .

Compound 212 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

This compound was prepared according to general procedure 2a using intermediate 1 as methyl-2-(4-methoxyphenyl)acetate in step A and intermediate 4 as 4-(cyclohex-1-en-1-yl)-3-phenyl -1H-pyrazole-5-amine in step B.

Step B. Solution of 4-(cyclohex-1-en-1-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 h. the solvent was removed under vacuum and saturated NaHCO ₃ was added to pH>7, resulting in 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2phenylpyrazolo[1,5- a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSOCH): 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) ⁺ .

Compound 213

This compound was prepared according to the general procedure 2a using intermediate 1 as methyl-2-(4-methoxyphenyl)acetate in step A and intermediate 4 as 4-(4,4-difluoropiperidin-1-yl)-3-phenyl -1H-pyrazole-5-amine in step B.

Step B. Mixture of 4-(4,4-difluoropiperidin-1-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 2 h to give the title compound.

1I-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)+.

General procedure 2b.

SEM 'N' ? SEM-CI K2CO3/DMF

Η ₂ Ν^>=

AcOH/heating

'CI

LOA/1HF/-30°C Stage A

S

Step A. Methyl 3-oxo-2-(quinolin-6-yl)butanoate.

PdCI ₂ (PPh ₃ ) ₂ /Cs ₂ CO ₃

DMF/100°C stage E e

LDA ( lithium diisopropylamide) (1.5 M in THF, 60 ml, 88.3 mmol, 1.2 eq.).

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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. The mixture was then stirred at rt. for 6 h. The mixture was slowly poured into saturated NH4Cl and extracted with ethyl acetate (3x30 ml). The combined organic phase was washed with brine, dried with anhydrous MgSO ₄ and concentrated in vacuo to give the title intermediate 2, which was used directly in the next step without further purification.

Step B. 5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

Suspension of methyl 3-oxo-2-(quinolin-6-yl)butanoate (1.98g, 8.17mmol) and 3-phenyl-1H-pyrazole-5amine (1g, 6.28mmol) in 1.4 -dioxane (10 ml) and AcOH (2 ml) were heated under reflux for 16 h in a protective atmosphere of N ₂ . The mixture was cooled to rt, concentrated and neutralized with saturated sodium hydrogen carbonate solution to pH 7. The precipitates were collected by filtration, washed with petroleum ether and dried to give intermediate 3 (600 mg, 27% yield).

1H-NMR (DMSO-d6): δ 12.56 (br. s., 1H), 8.94 (dd, J=4.25, 1.61 Hz, 1H), 8.39 (d, J= 7.63 Hz, 1H), 7.99-8.10 (m, 3H), 7.96 (d, J=1.76 Hz, 1H), 7.75 (dd, J=8.66, 1 .91 Hz, 1H), 7.57 (dd, J=8.36, 4.25 Hz, 1H), 7.46-7.53 (m, 2H), 7.40-7.46 (m, 1H), 6.67(s, 1H), 2.26(s, 3H).

Step C. 5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of intermediate 3 (500 mg, 1.42 mmol) and K ₂ CO ₃ (393 mg, 2.84 mmol) in DMF (15 ml) at ambient temperature was added (2-(chloromethoxy)ethyl)trimethylsilane (473 mg, 2.84 mmol). The mixture was stirred for 10 min at ambient temperature and heated to 100° C. overnight. The mixture was cooled to rt, washed with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (2x30 ml). The combined organic layers were washed with brine (3x20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on a silica gel column eluting with DCM/MeOH (30/1 to 10/1) to give Intermediate 4 as a white solid (350 g, 51% yield).

Step D. 3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidine-7(4H) -He.

To a solution of intermediate 4 (350 mg, 0.725 mmol) in DCM (5 ml) at ambient temperature was added BSI (163 mg, 0.92 mmol). The resulting mixture was stirred for 3 hours at ambient temperature, washed with water and extracted with dichloromethane (20 ml). The combined organic layers were washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (DCM/McOH=20/1) to give Intermediate 5 (250 mg, 61% yield).

LC-MS: m/z 561.1 (M+H)+.

The compounds below were prepared according to general procedure 2b, step E and step F, using intermediate 5 as starting material.

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Compound 215 3-(cyclopent-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). 3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (150 mg, 0.27 mmol), 2-(cyclopent-1en-1-yl)-4,4,5,5-tetramethyl-1,3,2-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/H ₂ O (11 ml, 10 :1) under microwave heating conditions at 100°C for 1 h in a nitrogen atmosphere.

LC-MS: m/z 549.3 (M+H) ⁺ .

Step F. To a solution of 3-(cyclopent-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo [1,5-a]pyrimidin-7(4H)-one (50 mg, 0.09 mmol) in DCM (0.5 ml) cooled at 0°C was added dropwise with TFA (1 ml). The mixture was then stirred at rt. within 2 hours the Mixture was concentrated and added NH ₄ OH to pH>7. The mixture was diluted with dichloromethane (60 ml), washed with water (15 ml) and brine (15 ml), dried over anhydrous sodium sulfate and concentrated to give 3-(cyclopent-1-en-1-yl)-5 -methyl-2-phenyl-6-(quinolin-6yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d6): δ 11.76 (br. s., 1H), 8.85-9.08 (m, 1H), 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) ⁺ .

Compound 216 3-(cyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Stage E (stoichiometry). 3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200 mg, 0.36 mmol), 2-(cyclohex-1en-1-yl)-4,4,5,5-tetramethyl-1,3,2-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/H ₂ O (16 ml, 10 :1) under microwave heating conditions at 100°C for 1 h in a nitrogen atmosphere.

LC-MS: m/z 563.3 (M+H) ⁺ .

Step F. To a solution of 3-(cyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo [1,5-a]pyrimidin-7(4H)-one (180 mg, 0.32 mmol) in DCM (0.5 ml) cooled to 0° C. TFA (2 ml) was added dropwise. The mixture was then stirred at rt. within 2 hours the Mixture was concentrated and added to NH ₄ OH to pH>7. The mixture was diluted with dichloromethane (120 ml), washed with water (30 ml) and brine (30 ml), dried over anhydrous sodium sulfate and concentrated to dryness to give 3-(cyclohex-1-en-1-yl)- 5-methyl-2-phenyl-6(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

1H-NMR (DMSO-d ₆ ): δ 11.80 (s, 1H), 8.94 (dd, J=4.0, 1.6 Hz, 1H), 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+H) ⁺ .

Compound 217 -He.

stage A

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Step A. 3-Bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one mixture (50 mg, 0.116 mmol), 2 -(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (49 mg,

0.232 mmol), Pd(dppf)Cl ₂ (8.4 mg, 0.012 mmol) and NaHCO ₃ (19 mg, 0.232 mmol) in dioxane (9 ml) and H2O (3 ml) were heated to 100°C for 4 h in an N2 atmosphere. The mixture was concentrated to dryness, whereby the desired product was obtained.

¹ H-NMR (METHANOL-d): 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) ⁺ .

3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

This compound was prepared according to general procedure 2b using intermediate 1 as methyl 2-(4-methoxyphenyl)acetate in step A.

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) ⁺ .

Compound 218 3-(3,6-dihydro-2H-pyran-4-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

This compound was prepared according to general procedure 2b (step E-F) using intermediate 5 as 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2(trimethylsilyl)ethoxy)methyl )pyrazolo[1,5-a]pyrimidin-7(4H)-one and intermediate 9 as 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane in step E.

Step E. Mixture of 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7(4H) -one (100 mg, 0.185 mmol), 2-(3,6-dihydro2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (194.39 mg, 0.925 mmol), PdCl ₂ (PPh ₃ ) ₂ (27.07 mg, 0.037 mmol) and Cs ₂ CO ₃ (180.54 mg, 0.555 mmol) in 1.4 dioxane (3 ml) and water (0.3 ml) heated at 100°C for 1 h by microwave radiation. The mixture was cooled to rt. and poured into a saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (30 ml), washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH=20/1) to give 3-(3,6-dihydro2H-pyran-4-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenyl- 4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(4H)-one (40 mg) as a white solid.

LC-MS: m/z 544.2 (M+H) ⁺ .

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[1,5-a]pyrimidin-7(4H)-one (40 mg, 0.074 mmol) in DCM (1 ml) was added TFA (3 ml) dropwise at 0°C.

The mixture was stirred overnight at ambient temperature and concentrated to dryness. The residue was washed with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (20 ml). The organic layer was washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo to give the title compound.

1H-NMR (DMSO-d ₆ ): δ 11.78 (s, 1H), 7.72-7.81 (m, 2H), 7.40-7.51 (m, 3H), 7.19- 7.29 (m, 2H), 6.95-7.06 (m, 2H), 5.93 (s, 1H), 4.26 (d, J=2.42 Hz, 2H), 3.79 -3.86 (m, 5H), 2.23 (s, 3H), 2.12-2.18 (m, 2H).

LC-MS: m/z 414.0 (M+H) ⁺ .

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Compound 219 3-(5,6-dihydro-2H-pyran-3-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

This compound was prepared according to general procedure 2b (step E-F) using intermediate 5 as 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2(trimethylsilyl)ethoxy)methyl )pyrazolo[1,5-a]pyrimidin-7(4H)-one and intermediate 9 as 2-(5,6-dihydro-2H-piran-3-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane in step E.

Step E. Mixture of 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7(4H) -one (200 mg, 0.37 mmol), 2-(5,6-dihydro2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (156 mg, 0 .74 mmol), Pd(dppf)Cl ₂ (27 mg, 0.037 mmol) and Cs ₂ CO ₃ (241 mg, 0.74 mmol) in dioxane (9 ml) and H2O (3 ml) were heated to 100°C in for 4 h in an N2 atmosphere. The mixture was concentrated to dryness. The residue was purified by preparative TLC (elution using petroleum ether/ethyl acetate=1:1) to give the desired product (40 mg, 20% yield).

LC-MS: m/z 544.3 (M+H) ⁺ .

Step F. Solution of 3-(5,6-dihydro-2H-pyran-3-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2(trimethylsilyl)ethoxy)methyl) pyrazolo[1,5-a]pyrimidin-7(4H)-one (40 mg, 0.074 mmol) in CH ₂ C1 ₂ /TFA (v/v=3:1, 8 ml) was stirred for 30 min. 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.

¹ H-NMR (METHANOL-d): 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) ⁺ .

Compound 220. 6-(4-Methoxyphenyl)-5-methyl-2-phenyl-3-(1H-pyrrol-3-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

^NH

Η G

This compound was prepared according to general procedure 2b (step E-F) using intermediate 5 as 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2(trimethylsilyl)ethκoxy)methyl )pyrazolo[1,5-a]pyrimidin-7(4H)-one and compound 9 as (1-(triisopropylsilyl)-1H-pyrrol-3-yl)boronic acid in step E.

Step E. Into a sealed tube loaded with 3-bromo-6-(4-methoxyphenyl)-5-methyl-2-phenyl-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine- 7(4H)-one (200 mg, 0.37 mmol), (1-(triisopropylsilyl)-1H-pyrrol-3-yl)boronic acid (395 mg, 1.48 mmol), PdCl ₂ (PPh ₃ ) ₂ (259 mg, 0.37 mmol) and Cs ₂ CO ₃ (482 mg, 1.480 mmol), DMF (5 ml) and water (0.5 ml) were added. The mixture was stirred for 1 hour at 120° C. (microwave). The reaction mixture was cooled to rt, diluted with saturated sodium hydrogen carbonate solution (30 ml) and extracted with ethyl acetate (30 ml). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH=50/1) to give 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1H-pyrrol-3-yl)-4-( (2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(4H)-one (70 mg) as a white solid.

LC-MS: m/z 527.2 (M+H) ⁺ .

Step F. A solution of 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(1H-pyrrol-3-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5- a]pyrimidin-7(4H)-one (30 mg, 0.057 mmol) in DMSO was heated to 150°C by microwave radiation in a sealed tube for 2 h. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution (20 ml) and extracted with ethyl acetate (20 ml). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound.

1H-NMR (DMSO-d ₆ ): δ 11.63 (br. s., 1H), 11.02 (br. s., 1H), 7.61-7.71 (m, 2H), 7, 31-7.39 (m, 3H), 7.24 (d, J=8.60 Hz, 2H), 6.99 (d, J=8.87 Hz, 2H), 6.84-6.92 (m, 2H), 5.97-6.06 (m, 1H), 3.80 (s, 3H), 2.18 (s, 3H).

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LC-MS: m/z 397.0 (M+H)+.

General procedure 3.

Step A. Methyl 4-(benzyloxy)-2-(4-methoxyphenyl)-3-oxobutanoate.

To a solution of intermediate 1 (36 g, 0.2 mol) and HMPTA (hexamethylphosphorotriamide) (7.2 g, 0.02 mol) in THF at -78°C was added LDA (lithium diisopropylamide) (2M in THF; 100 ml , 0.2 mol) for 20 min. After stirring for 1 hour at -78°C, 2-(benzyloxy)acetyl chloride (36.8 g, 0.2 mol) was added dropwise via funnel. The mixture was heated to rt. during the night. A saturated aqueous solution of NH ₄ Cl was added. The resulting mixture was extracted with dichloromethane (3x50 ml). The combined organic layers were washed with saturated NaCl (50 ml), dried with Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified with a silica gel column (petroleum ether/EtOAc=20/1) to give Intermediate 2 (38 g, 58%) as a brown oil.

Step B. 5-((benzyloxy)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-α]pyrimidin-7(4H)-one.

Intermediate 2 (38 g, 0.166 mol) and 3,4-diphenyl-1H-pyrazole-5-amine (40 g, 0.174 mol) were dissolved in AcOH (300 ml). The mixture was heated to 95° C. for 4 hours. After cooling to rt. the solids were collected by filtration, washed with ethyl acetate and dried in vacuo to give Intermediate 3 (28 g, 47% yield) as a white solid.

¹ H-NMR (DMSO-d6): δ 11.99 (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) ⁺ .

Step C Compound 221 5-(hydroxymethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidine-7(4H)-oh.

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To a solution of intermediate 3 (534 mg, 1 mmol) in DCM was added BCl ₃ (1.0 M in DCM, 3 ml, 3 mmol) at 0°C. The mixture was stirred at 0° C. for 4 hours. The reaction was quenched by adding MeOH carefully and concentrated. The residue was mixed with sodium bicarbonate solution and ethyl acetate with stirring for 30 minutes. The precipitates were filtered, washed with ethyl acetate and dried in vacuo to give intermediate 4 (400 mg, 94% yield).

¹ H-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+H) ⁺ .

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Step D. 5-(chloromethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

To a suspension of intermediate 4 (88 g, 0.208 mol) in DCM (500 ml) SOCl ₂ (120 ml) was added via funnel. The mixture was stirred at rt. for 1 hour. The precipitates were filtered, washed with ethyl acetate and dried under vacuum to give Intermediate 5 (110 g) as an off-white solid which was used directly in the next step without further purification.

Step E Compound 222 5-(Aminomethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]n-pyrimidin-7(4H)-one.

A mixture of intermediate 5 (200 g, 0.453 mol) and NH ₃ (7.0 M in MeOH, 2500 ml, 17 mol) in an autoclave was stirred at 60° C. overnight. The precipitated substances were stirred in a mixed solution (50 ml, DMF:MeOH=1:1) at 45°C for 4 h, whereby the title compound 6 was obtained.

1NMR (DMSO-d ₆ ): δ 11.97 (br. s., 1H), 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) ⁺ .

Compound 223 .

This compound was prepared according to general procedure 3 using intermediate 1 as methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetate in step A.

Step A. A solution of LDA (lithium diisopropylamide) (2M in THF; 14.1 mL, 28.1 mmol) was added over 20 min to a solution of methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin -6-yl)acetate (3.9 g, 18.8 mmol) and HMPTA (671 mg, 3.75 mmol) in THF at -78°C. After stirring for 1 hour at -78° C., 2-(benzyloxy)acetyl chloride (4.14 g, 22.5 mmol) was added dropwise via funnel. The mixture was heated to rt. during the night. Saturated aqueous NH4Cl was added and extracted with dichloromethane (3x50 ml), the combined organic layers were washed with saturated NaCl (50 ml) and dried with Na ₂ SO ₄ . The residue was purified by silica gel column chromatography (petroleum ether/EtOAc=20/1) to give methyl 4-(benzyloxy)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6- yl)-3-oxobutanoate (2.6 g) as a yellow oil.

LC-MS: m/z 357.1 (M+H) ⁺ .

Step B. Methyl 4-(benzyloxy)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxobutanoate (600 mg, 1.68 mmol) and 3.4 -diphenyl-1H-pyrazol-5-amine (356 mg, 1.52 mmol) was dissolved in AcOH (10 ml). The resulting mixture was heated to 100° C. for 16 hours. The reaction mixture was then cooled to rt, basified with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (20 ml). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column (DCM:MeOH=30:1) to give 5-((benzyloxy)methyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6- yl)-2,3diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (400 mg) as a white solid.

LC-MS: m/z 542.2 (M+H) ⁺ .

Step C. Into a test tube with 5-((benzuloxu)methyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-diphenylpyrazolo[1,5 -a]pyrimidin-7(4H)-one (200 g, 0.37 mmol) was added BCl ₃ (5 ml, 5 mmol, 1.0 M in DCM) at 0°C. The mixture was stirred at rt. within 4 h. The reaction was quenched with methanol (MeOH) and concentrated. The residue was made alkaline with sodium bicarbonate solution, extracted

- 126 042905 dichloromethane and concentrated in vacuo to give 6-(2,3dihydrobenzo[b][1,4]dioxin-6-yl)-5-(hydroxymethyl)-2,3-diphenylpyrazolo[1,5- a] pyrimidin-7(4H)-one (120 g) as a white solid.

LC-MS: m/z 451.2 (M+H) ⁺ .

Step D. To a suspension of 6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-(hydroxymethyl)-2,3diphenylpyrazolo[1,5-a]pyrimidine-7(4H) -one (120 mg, 0.264 mmol) in DCM (5 ml) SOCl ₂ (63 mg, 0.453 mmol) was added dropwise at 0°C. The resulting mixture was stirred at rt. within 3 hours the Reaction was extinguished by adding a saturated solution of sodium bicarbonate and was extracted with dichloromethane (20 ml). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column (petroleum ether:ethyl acetate=1:1) to give 5-(chloromethyl)-6-(2,3dihydrobenzo[b][1,4]dioxin-6-yl)-2 ,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (90 mg) as a yellow solid.

LC-MS: m/z 470.1 (M+H) ⁺ .

Step E. A mixture of 5-(chloromethyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-diphenylpyrazolo[1,5a]pyrimidine-7(4H)- she (20 mg, 0.042 mmol) in 7 n. NH ₃ /MeOH (3 ml) in a sealed tube was stirred at 100° C. overnight to give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 8.11 (br. s., 2H), 7.44 (br. s., 4H), 7.37 (br. s., 4H), 6, 86-7.00 (m, 2H), 6.83 (br. s., 1H), 4.30 (s, 3H), 3.89 (br. s., 1H).

LC-MS: m/z 452.1 (M+H) ⁺ .

Compound 224 5-(Aminomethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

This compound was prepared according to general procedure 3 using intermediate 1 as methyl-2-(quinolin-6-yl)acetate in step A.

Step B. Methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (8.6 g, 0.024 mol) and 3,4-diphenyl1H-pyrazol-5-amine (5.64 g, 0.024 mol) was dissolved in AcOH (300 ml). The mixture was heated to 95° C. for 4 hours. After cooling to rt. the precipitate was filtered, washed with ethyl acetate and dried in vacuo to give 5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]n-pyrimidine-7(4H) -one (10 g, 78% yield) as a yellow solid.

LC-MS: m/z 535.2 (M+H)+.

Step C. To a solution of 5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one (10 g, 18.7 mmol) in DCM (100 ml) was added BCl ₃ (25 ml, 25 mmol, 1.0 M in DCM) at 0°C. The resulting mixture was stirred at 0° C. for 4 hours. The reaction was quenched with methanol (MeOH) and concentrated. The residue was stirred with a sodium bicarbonate solution of ethyl acetate for 30 minutes. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to give 5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine 7(4H)- he (8 g, 96% yield).

LC-MS: m/z 445.1 (M+H)+.

Step D. To a suspension of 5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one (500 mg, 1.126 mmol) in DCM (3 ml) cooled in an ice-water bath, SOCl ₂ (670 mg, 5.631 mmol) was added dropwise. The resulting mixture was then stirred at rt. during the night. The suspension was filtered, washed with ethyl acetate and dried under vacuum. The residue was purified by preparative TLC (DCM:MeOH=20:1) to give 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6yl)pirazolo[1,5-a]pyrimidine-7(4H )-one (300 mg).

LC-MS: m/z 463.1 (M+H)+.

Step E. To a solution of 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)one (150 mg, 0.324 mmol) in DMF added 7 n. NH3 in methanol (15 ml) at 0°C. The reaction mixture was then heated to 40° C. for 65 hours in a sealed tube to give the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.89 (dd, J=4.16, 1.75 Hz, 1H), 8.36 (d, J=7.52 Hz, 1H) , 8.02 (d, J=8.87 Hz, 1H), 7.91 (s, 1H), 7.76-7.81 (m, 1H), 7.52-7.62 (m, 5H ), 7.34-7.40 (m, 3H), 7.29 (t, J=7.52 Hz, 2H), 7.15 (d, J=7.25 Hz, 1H), 3.85 (br. s., 2H).

LC-MS: m/z 444.8 (M+H)+.

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Compound 225 ,5-a]pyrimidin-7(4H)-one.

This compound was prepared according to General Procedure 3 (Step B-C) using Intermediate 2 as methyl-4-(benzyloxy)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)- 3-oxobutanoate and intermediate 8 as 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazole-5-amine in step B.

Step B. Methyl 4-(benzyloxy)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxobutanoate (662 mg, 1.85 mmol) and 4-( cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (400 mg, 1.67 mmol) was dissolved in AcOH (10 ml). The resulting mixture was heated to 100° C. for 16 hours. The reaction mixture was then cooled to rt, basified with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (20 ml). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a silica gel column (DCM:MeOH=30:1) to give 5-((benzyloxy)methyl)-3-(cyclohex-1-en-1yl)-6-(2,3-dihydrobenzo [b][1,4]dioxin-6-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (400 mg) as a white solid.

LC-MS: m/z 546.2 (M+H)+.

Step C. To a suspension of 5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl) -2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (260 mg, 0.48 mmol) in DCM (5 mL) was added 1.0 M BC13 in DCM (1.43 mL, 1.48 mmol) 43 mmol), the mixture was stirred at rt. quenched with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (20 ml) to give the title compound.

1H-NMR (DMSO-de): δ 11.21 (s, 1H), 7.78 (d, J=6.98 Hz, 1H), 7.38-7.49 (m, 4H), 6, 85-6.92 (m, 2H), 6.78-6.82 (m, 1H), 5.86 (br. s., 1H), 5.68 (s, 1H), 4.77 (s , 1H), 4.33 (d, J=5.10 Hz, 2H), 4.29 (s, 3H), 2.22 (br. s., 2H), 2.06 (br. s., 2H), 1.70 (br. s., 4H).

LC-MS: m/z 456.2 (M+H) ⁺ .

Compound 226 ,5-a]pyrimidin-7(4H)-one.

This compound was prepared according to general procedure 3, step E-F, starting from 3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin- 6-yl)-5-(hydroxymethyl)2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (compound 225).

Step E. To a suspension of 3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5(hydroxymethyl)-2-phenylpyrazolo [1,5-a]pyrimidin-7(4H)-one (compound 225, 100 mg, 0.264 mmol) in DCM (3 ml) chilled in an ice-water bath, SOC12 (52 mg, 0.0 .44 mmol) drop by drop. The resulting mixture was stirred at rt. for 3 hours. The reaction was quenched with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (20 ml). The organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column (DCM:MeOH=40:1) to give 5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[ b][1,4]dioxin-6-yl)-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one (70 mg) as a yellow solid.

LC-MS: m/z 474.2 (M+H) ⁺ .

Step F. A mixture of 5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2phenylpyrazolo[1 ,5-a]pyrimidin-7(4H)-one (70 mg, 0.148 mg) in 7 n. NH ₃ /MeOH (5 ml) in a sealed tube was stirred at 100° C. overnight to give the title compound.

1H-NMR (DMSO-de): δ 11.74 (br. s., 1H), 8.24 (br. s., 2H), 7.77 (d, J=7.32 Hz, 2H), 7.40-7.53 (m, 3H), 6.86-7.03 (m, 2H), 6.82 (d, J=8.24 Hz, 1H), 5.92 (br. s. , 1H), 4.30 (s, 4H), 3.94 (br. s., 2H), 2.23 (br. s., 2H), 2.05 (br. s., 2H), 1 .70 (br. s., 4H).

LC-MS: m/z 455.2 (M+H) ⁺ .

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Connection 227.

Step A. 2-(benzyloxy)-N-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl)methyl )acetamide.

To a solution of intermediate 1 (compound 224, 100 mg, 0.226 mmol) and Et ₃ N (68.6 mg, 0.68 mmol) in DCM (3 ml) was added dropwise 2-(benzyloxy)acetyl chloride (42 mg, 0 .45 mmol). The mixture was stirred for 2 hours at ambient temperature. The reaction was quenched by adding saturated sodium bicarbonate solution and extracted with dichloromethane (20 ml). The combined organic layers were washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH=20/1) to give Intermediate 2 (40 mg, 30% yield).

Step B Compound 227 2-hydroxy-N-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7dihydropyrazolo[1,5-a]pyrimidin-5-yl) methyl)acetamide.

To a solution of intermediate 2 (40 mg, 0.068 mmol) in DCM (1 ml) at 0°C was carefully added 1 M BBr ₃ in DCM (3 ml, 3 mmol). The reaction mixture was stirred for 5 min at 0° C. and then warmed to ambient temperature for 1 h. The reaction was quenched by adding cautious MeOH. The resulting mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with saturated NaCl (20 ml), dried with Na ₂ SO ₄ and concentrated in vacuo to give the title compound 3.

¹ H-NMR (DMSO-de): δ 11.94 (s, 1H), 8.95 (d, J=2.69 Hz, 1H), 8.38 (d, J=7.25 Hz, 1H ), 8.07 (d, J=8.60 Hz, 1H), 7.98 (s, 1H), 7.76 (dd, J=8.60, 1.88 Hz, 1H), 7.59 (dd, J=8.33.4.30 Hz, 1H), 7.42-7.53 (m, 5H), 7.32-7.41 (m, 5H), 5.59 (br. s ., 1H), 4.25 (br. s., 2H), 3.77 (d, J=5.37 Hz, 2H).

LC-MS: m/z 502.8 (M+H)+.

Compound 228 N-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin5-yl)methyl)acetamide.

This compound was prepared as compound 227 (step A) using intermediate 4 as acetyl chloride in step A.

To a solution of 5-(aminomethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (compound 224, 100 mg, 0.226 mmol) and DIPEA (87.3 mg, 0.68 mmol) in DCM (3 mL) was added dropwise with acetyl chloride (21.24 mg, 0.271 mmol). After the addition, the mixture was stirred for 2 hours at ambient temperature. The mixture was concentrated. The residue was made basic with saturated sodium bicarbonate solution and extracted with dichloromethane (20 ml). The combined organic layers were washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo to give the title compound.

- 129 042905

1H-NMR (DMSO-d ₆ ): δ 8.90 (br. s., 1H), 8.35 (d, J=8.87 Hz, 1H), 8.16 (s, 1H), 8, 02 (d, J=8.60Hz, 1H),

7.96 (br. s., 1H), 7.89 (br. s., 1H), 7.76 (d, J=7.79 Hz, 1H), 7.50-7.56 (m, 5H), 7.29-7.39 (m, 5H), 7.20 (d,

J=6.98 Hz, 1H), 4.07 (br. s., 2H), 1.82 (s, 3H).

LC-MS: m/z 485.9 (M+H) ⁺ .

Compound 229. 3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidin-7(4H)-oh.

This compound was prepared according to general procedure 3, step B-C using intermediate 8 as 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazole-5-amine in step B.

Step B. Methyl 4-(benzyloxy)-2-(4-methoxyphenyl)-3-oxobutanoate (597 mg, 1.67 mmol) and 4(cyclohex-1-en-1-yl)-3-phenyl-1H -pyrazol-5-amine (400 mg, 1.67 mmol) was dissolved in AcOH (10 ml). The mixture was stirred at 100° C. for 4 hours. After cooling to rt. the solids were collected by filtration, washed with ethyl acetate and dried in vacuo to give 5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo [1,5-a]pyrimidine 7(4H)-oh (200 mg, 23% yield) as a white solid.

LC-MS: m/z 513.9 (M+H) ⁺ .

Step C. To a solution of 5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidine-7(4H) -one (50 mg, 0.1 mmol) in MeOH (5 ml) was added Pd/C (50 mg) and HCl (3 drops). The mixture was stirred at rt. in an H2 atmosphere during the night. The reaction mixture was filtered and concentrated. The residue was mixed with sodium bicarbonate solution and ethyl acetate with stirring for 30 minutes to give the title compound.

1H-NMR (DMSO-d ₆ ): 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 -2.11 (m, 2H), 1.70 (br. s., 4H).

LC-MS: m/z 428.3 (M+H) ⁺ .

Compound 230 .

This compound was prepared according to the general procedure 3 (step A-C) using intermediate 1 as methyl 2-(quinolin-6-yl)acetate in step A and intermediate 8 as 4-(cyclohex-1-en-1-yl )-3-phenyl-1H-pyrazole-5-amine in step B.

Step B. Methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (730 mg, 2.01 mmol) and 4-(cyclohex-1-en-1-yl)-3 -phenyl-1H-pyrazole-5-amine (500 mg, 2.1 mmol) was dissolved in AcOH (15 ml). The mixture was heated to 100° C. for 16 hours. After cooling to rt. the solids were collected by filtration, washed with ethyl acetate and dried in vacuo to give 5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoline-6- yl)pyrazolo[1,5-n]pyrimidin7(4H)-one (700 mg, 65% yield) as a white solid.

LC-MS: m/z 538.9 (M+H) ⁺ .

Step C. To a solution of 5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6yl)pyrazolo[1,5-i]pyrimidin-7 (4H)-one (700 mg, 1.3 mmol) in DCM was added BCl ₃ (1.0 M in DCM, 2.2 ml, 2.2 mmol) at 0°C. The mixture was stirred at 0° C. for 2 hours. The reaction was quenched by adding MeOH carefully and concentrated. The residue was mixed with sodium bicarbonate solution and ethyl acetate with stirring for 30 minutes to give the title compound.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

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Compound 231 .

This compound was prepared according to the general procedure 3 (step A-C) using intermediate 1 as methyl-2-(quinoxalin-6-yl)acetate in step A and intermediate 8 as 4-(cyclohex-1-en-1- yl)-3-phenyl-1H-pyrazol-5-amine in step B.

Step C. To a solution of 5-((benzyloxy)methyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6yl)pyrazolo[1,5-a]pyrimidin-7 (4H)-one (170 mg, 0.32 mmol) in DCM (8 ml) cooled to 0° C. BCl ₃ (1.5 ml, 1.0 M in DCM) was added dropwise. The mixture was then stirred at 0°C for 2 hours. The reaction was quenched by carefully adding saturated NaHCO ₃ (8 ml), diluted with dichloromethane (80 ml), washed with brine, dried with anhydrous sodium sulfate and concentrated, resulting in 3 -(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-2-phenyl-6-(quinoxalin-6yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-J6): 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., 1H), 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)+.

Compound 232 5-(Aminomethyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

This compound was prepared according to General Procedure 3, Step D-E, starting from 3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[ 1,5a]pyrimidin-7(4H)-one (compound 229).

Step D. To a suspension of 3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one ( compound 229, 140 mg, 0.32 mol) in DCM (10 ml) SOCl ₂ (386 mg, 3.2 mmol) was added dropwise at -20°C. The mixture was stirred at -20° C. for 1 hour until the starting material was consumed. The reaction was then quenched by adding MeOH at -20°C. The mixture was concentrated and purified by silica gel chromatography (DMX:MeOH=50:1) to give 5-(chloromethyl)-3(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylnurazolo[1 ,5-a]nirimidin-7(4H)-one (100 mg) as a white solid.

1H-NMR (DMSOA): 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) ⁺ .

Step E. Suspension of 5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (50 mg, 0.11 mmol) and KI (18 mg, 0.11 mmol) in NH3 in MeOH (7 M, 10 mL) were stirred at 80°C for 1 h under microwave irradiation to give the title compound.

1 H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 233 .

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-(quinoline -6-yl)pyrazolo[1,5а]pyrimidin-7(4Н)-one (compound 230)

Step D. To a suspension of 3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-2-phenyl-6-(quinolin-6yl)pyrazolo[1,5-a]pyrimidin-7(4H) -one (compound 230, 160 mg, 0.357 mol) in DCM (5 ml) SOCl ₂ (1 ml) was added via funnel. The mixture was stirred at rt. for 1 h. The precipitated substances were filtered, washed with ethyl acetate and dried under vacuum, resulting in 5-(chloromethyl)-3(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoline-6- yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (170 mg) as an off-white solid, which was used directly in the next step without further purification.

LC-MS: m/z 466.9 (M+H) ⁺ .

Step E. A mixture of 5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)- she (80 mg, 0.171 mol) and NH ₃ (7.0 M in MeOH, 10 ml, 70 mol) were stirred in an autoclave at 40° C. for 2 days. The mixture was concentrated under vacuum. The residue was washed with water to give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 8.84-8.93 (m, 1H), 8.34 (d, J=8.1 Hz, 1H), 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) ⁺ .

Compound 234 .

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-6yl )pyrazolo[1,5-a]pyrimidin-7(4H)-one (compound 231).

Step D. To a solution of 3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-2-phenyl-6-(quinoxalin-6yl)pyrazolo[1,5-a]pyrimidin-7(4H) -one (compound 231, 100 mg, 0.22 mmol) and DMF (1 drop, catalytic amount) in DCM, thionyl chloride (0.2 ml) was added dropwise at 0°C. After the addition, the mixture continued to stir at 0°C for 1 h. The reaction mixture was diluted with dichloromethane (60 ml), washed with saturated NaHCO3 (15 ml) and brine (20 ml), dried with anhydrous sodium sulfate and concentrated to dryness. The residue was purified by preparative TLC (DCM:MeOH=25:1) to give 5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6(quinoxalin-6-yl) pyrazolo[1,5-a]pyrimidin-7(4H)-one (90 mg) as a yellow solid.

LC-MS: m/z 468.3 (M+H) ⁺ .

Step E. Solution of 5-(chloromethyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)- it (85 mg, 0.18 mmol) in NH3 (4 ml, 7.0 M in MeOH) was stirred at 40°C in a sealed tube for 12 h. the mixture was filtered to give 5-(aminomethyl)-3-(cyclohex-1-en-1-yl)-2-phenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidine7( 4H)-on.

1H-NMR (DMSO-d6): δ 8.92 (dd, J=7.0, 1.9 Hz, 2H), 8.07 (d, J=8.6 Hz, 1H), 8.01 ( d, J=1.9 Hz, 1H), 7.91 (dd, J=8.9, 1.9 Hz, 1H), 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) ⁺ .

Compound 235 1-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5yl)methyl)urea.

Intermediate 1 was prepared according to the general procedure 3 (step A-D) using intermediate 1 as methyl-2-(quinolin-6-yl)acetate.

Step A. NaH (60% dispersion in mineral oil, 28.6 mg, 0.7 mmol) was added portionwise to a solution of urea (41.0 mg, 0.6 mmol) in DMF (10 mL) cooled to 0°C and stirred at this temperature for 20 minutes. Then 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.2 mmol) was added and stirred at 80 °C for 10 h.

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After cooling to rt. water was added and the precipitate was filtered to give 1-((7-oxo2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl) methyl) urea.

¹ H-NMR (DMSO-d ₆ ): 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)+.

General procedure 4.

²

Step A Compound 236 5-(aminomethyl)-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of intermediate 1 (compound 222, 100 mg, 0.237 mmol) in 1 ml DCM was carefully added 5 ml BBr ₃ (1.0 M in DCM, 5 mmol) at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction was quenched by carefully adding ice water at 0°C. The solid was filtered to give the title compound 2.

¹ H-NMR (DMSO-d ₆ ): δ 7.49-7.59 (m, 4H), 7.32-7.38 (m, 3H), 7.26 (t, J=7.52 Hz , 2H), 7.06-7.14 (m, 3H), 6.79 (d, J=8.33 Hz, 2H), 3.73 (s, 2H).

LC-MS: m/z 409.0 (M+H) ⁺ .

Compound 237. 6-(4-Hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidine-7(4H)-oh.

This compound was prepared according to general procedure 4 using intermediate 1 as 6-(4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (compound 209 ) at stage A.

A mixture of 6-(4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (compound 209, 60 mg, 0.147 mmol) and BBr ₃ (1 M in dichloromethane, 5 ml) was stirred at room temperature. for 3 hours. The mixture was neutralized with methanol at 0° C. and then evaporated to dryness to give 6-(4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidine-7( 4H)-he.

¹ H-NMR (DMSO-d ₆ ): δ 11.84 (s, 1H), 9.46 (s, 1H), 7.37-7.58 (m, 5H), 7.25-7.37 (m, 5H), 7.12 (d, J=8.60 Hz, 2H), 6.82 (d, J=8.60 Hz, 2H), 2.17 (s, 3H).

LC-MS: m/z 394.1 (M+H) ⁺ .

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6-(3-fluoro-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrαzolo[1,5-a]pyrimidine238.

Compound 7(4H)-one.

To a solution of methyl 2-(3-fluoro-4-methoxyphenyl)acetate (1 g, 5.0 mmol) in THF (15 ml) was slowly added LDA (lithium diisopropylamide) (2.5 ml, 2 mmol/ml in THF ) at -30°C. Then acetyl chloride (500 mg, 6.5 mmol) was added slowly. The reaction mixture was stirred for 30 min at -30°C and allowed to reach rt. for 1 h. The mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated, resulting in a crude product (400 mg) as a yellow liquid, which was used directly in the next step without further purification .

Step B. 6-(3-Fluoro-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

Solution of methyl 2-(3-fluoro-4-methoxyphenyl)-3-oxobutanoate (crude, 400 mg) and 3,4-diphenyl1H-pyrazole-5-amine (200 mg, 0.86 mmol) in AcOH (10 ml ) was heated to 120°C overnight. The reaction mixture was cooled to rt. The precipitate was filtered off to give the title product 6-(3-fluoro-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (200 mg, 57 % exit).

1H-NMR (DMSO-d ₆ ): δ 12.04 (s, 1H), 7.39-7.51 (m, 5H), 7.24-7.38 (m, 6H), 6.94 ( dd, J=11.7, 2.6Hz, 1H), 6.88(dd, J=8.5, 2.6Hz, 1H), 3.83(s, 3H), 2.16(s , 3H).

LC-MS: m/z 426.2 (M+H)+.

Step C Compound 238 6-(3-Fluoro-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of 6-(3-fluoro-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (200 mg, 0.47 mmol) in CH ₂ Cl ₂ (20 ml) was slowly added BBr ₃ (1 ml, 1 mmol/ml in CH ₂ Cl ₂ ). The reaction mixture was then stirred overnight. The mixture was adjusted to pH 7 with saturated NaHCO ₃ solution. The precipitate was filtered off to give the target product 6-(3-fluoro-4-hydroxyphenyl)-5methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

1H-NMR (DMSO-d ₆ ): δ 9.57 (s, 1H), 7.54 (dd, J=7.7, 1.7 Hz, 2H), 7.44-7.50 (m, 2H), 7.29-7.38 (m, 3H),

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7.26 (t, J=7.7 Hz, 2H), 7.06-7.14 (m, 1H), 7.02 (dd, J=12.8, 1.7 Hz, 1H), 6 .85-6.96 (m, 2H), 2.11 (s, 3H).

LC-MS: m/z 411.9 (M+H) ⁺ .

Compound 239

Cl

This compound was prepared according to compound 238, steps A-C using methyl 2-(3-chloro-4-methoxyphenyl)acetate as starting material.

Step A To a solution of methyl 2-(3-chloro-4-methoxyphenyl)acetate (2 g, 9.346 mmol) in THF (20 mL) was added LDA (lithium diisopropylamide) (1.5 M in THF, 8. 1 ml, 12.15 mmol) at -78°C. The mixture was stirred at -78°C for 30 min and acetyl chloride (822 mg, 10.28 mmol) was added dropwise. The mixture was then stirred at rt. within 2 hours the Mixture was slowly poured into saturated NH ₄ Cl and was extracted with ethyl acetate (3x30 ml). The combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated in vacuo. The residue was purified using a silica gel column (petroleum ether:ethyl acetate=0-30%) to give methyl 2-(3chloro-4-methoxyphenyl)-3-oxobutanoate (500 mg) as a yellow oil.

LC-MS: m/z 257.1 (M+H) ⁺ .

Step B. Suspension of methyl 2-(3-chloro-4-methoxyphenyl)-3-oxobutanoate (200 mg, 0.850 mmol) and 3,4-diphenyl-1H-pyrazole-5-amine (261 mg, 1.020 mmol) in 1,4-dioxane (5 ml) and AcOH (1 ml) were heated at reflux for 16 hours under N2 protection. The solution was cooled to rt, concentrated, basified with saturated sodium hydrogen carbonate solution to pH 7 and filtered. The filter residue was purified by preparative TLC (DCM:MeOH=20:1) to give 6-(3-chloro-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidine- 7(4H)-one (50 mg) as a white solid.

LC-MS: m/z 442.1 (M+H) ⁺ .

Step C. To a solution of 6-(3-chloro-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin7(4H)-one (50 mg, 0.113 mmol) in DCM (1 ml) was added dropwise 1.0 M BBr ₃ in DCM (3 ml, 3 mmol). This mixture was stirred for 2 hours at ambient temperature. The reaction mixture was neutralized by adding saturated sodium bicarbonate solution and extracted with dichloromethane (20 ml). The combined organic layers were washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo to give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 11.94 (br. s., 1H), 10.24 (s, 1H), 7.40-7.47 (m, 4H), 7.38 (d, J=7.25Hz, 1H), 7.34 (d, J=5.10Hz, 4H), 7.29 (d, J=1.88Hz, 1H), 7.07-7 .12 (m, 1H), 7.00-7.05 (m, 1H), 2.18 (s, 3H).

LC-MS: m/z 428.1 (M+H) ⁺ .

Compound 240 3-(cyclohex-1-en-1-yl)-6-(4-hydroxyphenyl)-5-methyl-2-phenylpyrazolo[1,5a]pyrimidine-7(4H)-oh.

This compound was prepared according to general procedure 4 using intermediate 1 as 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a ]pyrimidine7(4H)-oh (compound 212) in step A.

To a solution of 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one (compound 212, 50 mg , 0.118 mmol) in DCM (1 ml) was added dropwise 1.0 M BBr ₃ in DCM (3 ml, 3 mmol) 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 give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 7.76 (d, J=7.02 Hz, 2H), 7.30-7.52 (m, 3H), 7.09 (m, J=7 .93 Hz, 2H), 6.82 (m, J=7.93 Hz, 2H), 5.83 (br. s., 1H), 2.21 (br. s., 3H), 2.18 (br. s., 2H), 2.03 (br. s., 2H), 1.67 (br. s., 4H).

LC-MS: m/z 398.0 (M+H)+.

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Compound 241 5-(Aminomethyl)-3-(cyclohex-1-en-1-yl)-6-(4-hydroxyphenyl)-2phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

This compound was prepared according to general procedure 4 using intermediate 1 as 5-(aminomethyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a ]pyrimidin-7(4H)-one (compound 232) in step A.

To a solution of 5-(aminomethyl)-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one (compound 232, 85 mg, 0.2 mmol) in DCM (1 ml) was added dropwise to 1.0 M BBr ₃ in DCM (3 ml, 3 mmol). The mixture was stirred for 3 hours at ambient temperature. The reaction was quenched with ice water and concentrated to give the title compound.

1 H-NMR (DMSO-d ₆ ): δ 8.21 (s, 1H), 7.69 (d, J=6.72 Hz, 2H), 7.37 (d, J=6.98 Hz, 2H ), 7.31 (d, J=6.72Hz, 1H), 7.06 (m, J=8.06Hz, 2H), 6.77 (m, J=8.33Hz, 2H), 5.66 (br. s., 1H), 3.68 (br. s., 3H), 2.34 (br. s., 2H), 2.09 (br. s., 2H), 1, 53-1.74 (m, 4H).

LC-MS: m/z 413.2 (M+H) ⁺ .

Compound 242.

To a solution of 2-phenylacetonitrile (1 g, 8.536 mmol) in THF (20 mL) was added LiHMDS (2.0 M in THF, 5.1 mL, 10.2 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 30 min and heated to rt. within 15 min. 4-Methoxybenzoyl chloride (1.75 g, 10.24 mmol) was added dropwise at 0°C. The mixture was then stirred at rt. over 16 h. The mixture was slowly poured into saturated NH4Cl and extracted with ethyl acetate (3x10 ml). The combined organic phase was washed with brine, dried with anhydrous MgSO ₄ and concentrated in vacuo to give the crude product (2.5 g) as a yellow oil.

LC-MS: m/z 252.1 (M+H) ⁺ .

Step B. 3-(4-methoxyphenyl)-4-phenyl-1H-pyrazol-5-amine.

A suspension of 3-(4-methoxyphenyl)-3-oxo-2-phenylpropanenitrile (2 g, 8.761 mmol) and hydrazine hydrate (2.4 g, 43.804 mmol) in EtOH (10 mL) and AcOH (2 mL) was heated at reflux. refrigerator for 16 hours in a protective atmosphere of N2. The solution was cooled to rt. and concentrated, basified with sodium bicarbonate solution to reach pH 7 and extracted with ethyl acetate. The combined organic layers were washed with brine (30 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column (petroleum ether:ethyl acetate=3:1) to give 3-(4-methoxyphenyl)-4-phenyl-1H-pyrazole-5-amine

- 136 042905 (700 mg) as a white solid.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

Step C Compound 243 2-(4-methoxyphenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidine-7(4H)-oh.

A suspension of 3-(4-methoxyphenyl)-4-phenyl-1H-pyrazol-5-amine (250 mg, 0.942 mmol) and methyl 3-oxo2-(quinolin-6-yl)butanoate (458 mg, 1.885 mmol) in 1,4-dioxane (10 ml) and AcOH (2 ml) were heated at reflux for 16 hours under N2 protection. The solution was cooled to rt. and concentrated, basified with saturated sodium bicarbonate to pH 7 and filtered to give 2-(4-methoxyphenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a] pyrimidine-7(4H)-oh.

¹ H-NMR (DMSO-d ₆ ): δ 512.01 (s, 1H), 8.94 (d, J=2.75 Hz, 1H), 8.40 (d, J=7.93 Hz, 1H), 8.08 (d, J=8.54 Hz, 1H), 7.93-7.99 (m, 1H), 7.75 (dd, J=8.70, 1.68 Hz, 1H ), 7.58 (dd, J=8.24, 4.27 Hz, 1H), 7.41-7.51 (m, 3H), 7.34-7.40 (m, 4H), 6, 90 (d, J=8.55 Hz, 2R), 3.76 (s, 3R), 2.25 (s, 3R).

LC-MS: m/z 459.2 (M+I)+.

Step D Compound 242 2-(4-hydroxyphenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4I)-one.

To a solution of 2-(4-methoxyphenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin7(4I)-one (100 mg, 0.225 mmol) in DCM (1 ml) was added dropwise 1.0 M BBr ₃ in DCM (3 ml, 3 mmol). This mixture was stirred for 2 hours at ambient temperature. The reaction mixture was neutralized by adding saturated sodium bicarbonate solution and extracted with dichloromethane (20 ml). The combined organic layers were washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo to give the title compound.

1H-NMR (DMSO-d6): δ 11.97 (br. s., 1H), 9.63 (s, 1H), 8.93 (d, J=2.69 Hz, 1H), 8.39 (d, J=7.52 Hz, 1R), 8.07 (d, J=8.87 Hz, 1R), 7.95 (d, J=1.88 Hz, 1R), 7.75 (dd , J=8.60, 1.88 Hz, 1R), 7.57 (dd,J=8.33, 4.30 Hz, 1R), 7.42-7.49 (m, 2R), 7, 35-7.41 (m, 3R), 7.27 (m, J=8.60 Hz, 2R), 6.71 (m, J=8.60 Hz, 2R), 2.24 (s, 3R ).

LC-MS: m/z 445.2 (M+I)+.

Compound 244.

Step A. (E)-methyl-3-(dimethylamino)-2-(quinolin-6-yl)acrylate. I

A solution of methyl 2-(quinolin-6-yl)acetate (3.0 g, 14.9 mmol) and DMFDMA (dimethylformamide dimethyl acetal) (4.0 ml) in DMF was stirred at 85° C. for 12 h. After cooling to k.t. the mixture was diluted with water, extracted with ethyl acetate, dried with Na ₂ SO ₄ and concentrated to give the crude product (3.8 g) which was used directly in the next step without further purification.

LC-MS: m/z 257.3 (M+I)+.

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Step B Compound 244 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

Solution of 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.9 mmol) and (E)-methyl-3-(dimethylamino)-2(quinolin-b-yl)acrylate (283.2 mg , 1.1 mmol) in AcOH (3 ml) was stirred at 100°C for 2 h. the solvent was removed under vacuum, saturated NaHCO ₃ (6 ml) was added and the precipitate was filtered. The filter cake was washed with water (2 ml) and MeOH (2 ml) to give 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine-7(4H)- He.

¹ H-NMR (DMSO-d ₆ ): δ 12.69 (br. s., 1H), 8.91 (dd, J=4.0, 1.6 Hz, 1H), 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-.54 (m, 4H), 7.32-7.45 (m, 6H).

LC-MS: m/z 415.3 (M+H) ⁺ .

Connection 245.

5-fluoro-2-nitrobenzonitrile (5 g, 30 mmol), ethyl 3-oxobutanoate (7.8 g, 60 mmol) and K2CO3 (12.46 g, 90 mmol) in DMSO (50 ml) were stirred at 50° C for 16 hours. The mixture was acidified with hydrochloric acid (1 M) to pH 7 and extracted with ethyl acetate (50 mlx3). The organic layer was dried and concentrated to give a crude material which was purified by silica gel chromatography (petroleum ether:ethyl acetate=3:1) to give Intermediate 2 (6.15 g, 77% yield).

¹ H-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)+.

Step B. 5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]-pyrimidin-6-yl)-2-nitrobenzonitrile.

Mixture of intermediate 2 (3 g, 11 mmol), 3,4-diphenyl-1H-pyrazol-5-amine (2.7 g, 11 mmol) and TsOH (200 mg, 1.1 mmol) in toluene (20 ml ) was stirred at 120°C for 4 h. The mixture was cooled to rt. and filtered to give a crude yellow solid which was recrystallized from MeOH to give pure intermediate 3 (2.5 g, 51% yield).

1H-NMR (DMSO-d ₆ ): 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,

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10H), 2.28(s, 3H).

LC-MS: m/z 448.1 (M+H)+.

Step C. 2-Amino-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]nirimidin-6-yl)benzonitrile.

Intermediate 3 (3 g, 0.7 mmol) and 10% Pd/C (300 mg) in DMF (10 ml) and MeOH (50 ml) were stirred at RT. for 16 h in an H ₂ atmosphere. The mixture was filtered and concentrated in vacuo. The residue was purified using a silica gel column (petroleum ether:ethyl acetate=10:1~1:1) to give intermediate 4 (1.8 g, 64% yield).

¹ H-NMR (DMSO-d6): δ 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) ⁺ .

Step F. 2-amino-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzaldehyde.

Intermediate 4 (800 mg, 1.9 mmol) in dry DCM (10 ml) was cooled to 0° C. and DIBAL-H (19 mmol, 2 M) was added dropwise. The mixture was heated to rt. within 16 hours the Reaction was extinguished with methanol (MeOH) and concentrated. The residue was purified using a silica gel column (petroleum ether:ethyl acetate=1:1) to give intermediate 5 (150 mg, 19% yield).

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

Step E Compound 245 5-methyl-2,3-diphenyl-6-(quinazolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

Intermediate 5 (60 mg, 0.14 mmol) and formamidine (126 mg, 2.86 mmol) in DMF were stirred at 160° C. for 2 h. The mixture was concentrated to give the title compound 6.

1H-NMR (DMSO-d6): δ 12.13 (br. s., 1H), 9.66 (s, 1H), 9.35 (s, 1H), 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) ⁺ .

Compound 246 6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]n-pyrimidin-6yl)quinolinyl-2-carboxylic acid.

Step A. 2-amino-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydronirazolo[1,5-a]nirimudin-6yl)denzaldehyde (50 mg, 0.12 mmol) , 2-oxopropanoic acid (52 mg, 0.6 mmol) and KOH (23 mg, 0.6 mmol) in EtOH (5 mL) were stirred at rt. for 16 hours. The mixture was acidified with 1 M hydrochloric acid to pH 6 and extracted with dichloromethane (10 mlx3). The organic layer was dried and concentrated to give the desired product.

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1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 247.

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 the addition, the mixture was heated under reflux overnight. The reaction mixture was cooled to RT and diluted with ethyl acetate. The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give Intermediate 2 (6.4 g) as a yellow oil which was used in the next step without additional processing without further purification.

LC-MS: m/z 214.6 (M+H) ⁺ .

Step B. methyl 2-(3-(1,3-dioxolan-2-yl)-4-nitrophenyl)-3-oxobutanoate.

To a mixture of intermediate 2 (5.4 g, 25.4 mmol) in DMF (150 mL) was added methyl 3oxobutanoate (4.42 g, 38.0 mmol, 1.5 eq.) and K ₂ CO ₃ (5 .24 g, 38.0 mmol, 1.5 equiv.) at r.t. After the addition, the mixture was heated to 55° C. overnight. The reaction mixture was cooled to RT and diluted with ethyl acetate. The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether=1/10) to give the desired product intermediate 3 (4.23 g, 54% yield).

LC-MS: m/z 309.9 (M+H) ⁺ .

Step C. 6-(3-(1,3-dioxolan-2-yl)-4-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin7(4H)-one.

A mixture of intermediate 3 (4.23 g, 13.7 mmol) and 3,4-diphenyl-1H-pyrazole-5-amine (3.22 g, 13.7 mmol, 1.0 eq.) in CH3COOH (200 ml) was stirred at 110°C overnight and then cooled to rt. The precipitate was collected by filtration and washed with ethyl acetate to give the title intermediate 4 (4.01 g, 59% yield) as a yellow solid.

LC-MS: m/z 494.9 (M+H) ⁺ .

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Step D. 2-amino-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6yl)benzaldehyde.

Pd/C ( _0.2 g) and HCOONH ₄ (673 mg, 10.1 mmol, 5.0 eq.) at RT in an N2 atmosphere. After the addition, the mixture was heated under reflux overnight. The reaction mixture was cooled to rt, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give intermediate 5 (610 mg, 72% yield).

LC-MS: m/z 420.9 (M+H) ⁺ .

Step E Compound 247 6-(3-Hydroxy-2-methylquinolin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

KOH (40, 1 mg, 0.71 mmol, 2.0 eq.) at RT After the addition, the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure to give the title product.

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=2.0Hz, 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)+.

Compound 248.

Stage

A.

methyl-3-((2-((4-methoxybenzyl)thio)-4-(5-methyl-7-oxo-2,3-diphenyl-4,7dihydropyrazolo[1,5-a]pyrimidin-6-yl) phenyl)amino)-3-oxopropanoate

Methyl 3-chloro-3-oxopropanoate ( 24.5 mg, 0.18 mmol, 2.0 eq.). The reaction mixture was then stirred at rt. for 8 hours. The mixture was partitioned between ethyl acetate and H2O. The organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude Intermediate 2 (50 mg) which was used directly in the next step without further purification.

LC-MS: m/z 645.1 (M+H)+.

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Step B Compound 248 yl)acetate.

A mixture of intermediate 2 (50 mg, 0.08 mmol) in TFA (3 mL) was stirred at 75° C. for 3 hours. The mixture was concentrated under reduced pressure to give desired product 3.

¹ H-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) ⁺ .

Compound 249.

To a solution of methyl 2-(4-methoxyphenyl)acetate (3.0 g, 16.7 mmol) in THF (10 ml) was added dropwise LDA (lithium diisopropylamide) (10 ml, 19.98 mmol, 1.2 eq. .) and HMPTA (598 mg, 3.33 mmol, 0.2 eq.) at -78°C. After the addition, the mixture was stirred at -48°C for 0.5 h. Then the mixture was 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. during the night. The reaction was quenched with NH4Cl solution and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether=1/4) to give Intermediate 2 (2.7 g, 49% yield).

LC-MS: m/z 329.1 (M+H) ⁺ .

Step B. 5-((benzyloxy)methyl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of intermediate 2 (2.7 g, 8.23 mmol) and compound 8 (1.3 g, 8.23 mmol, 1.0 eq.) in CH ₃ COOH (10 ml) was stirred at 100°C for 3 h, and then cooled to rt. The mixture was concentrated under reduced pressure and washed with methanol (MeOH) to give the title intermediate 3 (2.4 g, 67% yield) as a white solid.

LC-MS: m/z 437.9 (M+I)+.

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Step C. 5-((benzyloxy)methyl)-6-(4-methoxyphenyl)-4-methyl-2-phenylpyrazolo[1,5-a]pyrimidin7(4H)-one.

To a mixture of intermediate 3 (2.4 g, 5.49 mmol, 1 eq.) and Cs ₂ CO ₃ (2.14 g, 6.59 mmol, 1.2 eq.) in DMF (8 ml) was added MeI (774 mg, 5.49 mmol, 1.0 eq.). The mixture was then stirred at rt. during the night. The mixture was poured into water (100 ml) and filtered. The filter cake was washed with methanol (MeOH) to give Intermediate 4 (2.9 g) as a white solid.

LC-MS: m/z 451.9 (M+H)+.

Step D. 5-((benzyloxy)methyl)-3-bromo-6-(4-methoxyphenyl)-4-methyl-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

To a mixture of intermediate 4 (2.9 g, 6.6 mmol, 1 eq.) in DMF (20 ml) was added BSI (1.37 g, 7.94 mmol, 1.2 eq.). The reaction mixture was then stirred at rt. over 2 h. The mixture was poured into water (200 mL) and filtered to give Intermediate 5 (3.1 g, 91% yield) as a white solid.

LC-MS: m/z 430.1 (M+H) ⁺ .

Step E. 5-((benzyloxy)methyl)-6-(4-methoxyphenyl)-4-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin7(4H)-one.

Suspension of intermediate 5 (1.5 g, 2.83 mmol), phenylboronic acid (414 mg,

3.40 mmol, 1.2 eq.), Pd ₁₁₈ (368 mg, 0.57 mmol, 0.2 eq.) and K ₂ CO ₃ (982 mg, 7.1 mmol, 2.5 eq.) 1,4-dioxane (30 ml) and H ₂ O (1.5 ml) were stirred at 90°C for 5 h under N2 atmosphere. The reaction mixture was then cooled to rt. and filtered. The filtrate was concentrated in vacuo and purified by silica gel flash column chromatography to give Intermediate 6 (300 mg, 20% yield).

LC-MS: m/z 527.9 (M+H) ⁺ .

Step F Compound 249 5-(hydroxymethyl)-6-(4-methoxyphenyl)-4-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of intermediate 6 (150 mg, 0.28 mmol) in dry DCM (5 ml) was added dropwise BC1 ₃ /DCM (5 ml, 1N, 2.0 eq.) at 0°C. After the addition, the mixture was stirred at rt. for 2 hours. The mixture was neutralized by carefully adding a mixture of ice-water, and was extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound 7.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

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Compound 250

LHMDS/ΤΓΦ /0°С - k.t.

stage A

hydrazine e

ASON / EUN / load with return cold

stage B ^;

Step A. 3-(4-nitrophenyl)-3-oxo-2-phenylpropanenitrile.

To a solution of 2-phenylacetonitrile (585 mg, 5 mmol) in THF (30 ml) was added n-BuLi (2.5 mol/l, ml, 1.0 eq.) at -78°C. After stirring the mixture at -78°C for 30 min, was added dropwise

4-nitrobenzoyl chloride (1.1 eq.). The mixture was stirred at -78°C for 15 min and then heated to rt. and stirred for 3 hours. The mixture was diluted with ethyl acetate (30 ml) and neutralized with saturated NH4Cl. The organic phase was separated and washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give intermediate 2, which was used in the next step without further purification.

LC-MS: m/z 267.0 (M+H) ⁺ .

Step B. 3-(4-nitrophenyl)-4-phenyl-1H-pyrazole-5-αmin.

A mixture of intermediate 2 (750 mg, 2.8 mmol, 1 eq.) and hydrazine hydrate (2 eq.) in EtOH/AcOH (5/1, 10/2 mL) was refluxed for 2 h. cooled to rt and evaporated. The residue was dissolved in ethyl acetate (10 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC to give the title intermediate 3 as a bright yellow solid.

LC-MS: m/z 281.1 (M+H) ⁺ .

Step C Compound 251 5-methyl-2-(4-nitrophenyl)-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

A mixture of intermediate 3 (95 mg, 0.34 mmol, 1 equiv.) and methyl 3-oxo-2-(quinolin-6yl)butanoate 7 (1.5 equiv.) in AcOH (5 ml) was stirred at 100° C for 1 h. The mixture was then cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (5 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (5 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC to give intermediate 4.

1H-NMR (DMSO-bb): δ 12.19 (br. s., 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H), 8.40 (d, J= 7.8 Hz, 1H), 8.21 (d, J=8.8 Hz, 2H), 8.08 (d, J=8.6 Hz, 1H), 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).

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LC-MS: m/z 474.0 (M+H)+.

Step D Compound 250 a] pyrimidin-7(4H)-one.

2-(4-aminophenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-

To a solution of intermediate 4 (35 mg, 0.07 mmol) in THF (10 ml) was added saturated NH4Cl (1 ml) and zinc powder (96 mg, 1.5 mmol, 20 eq.). The reaction mixture was stirred at rt. within 5 h. LCMS indicated completion of the reaction. The mixture was filtered through celite. The filtrate was extracted with dichloromethane (5 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the desired compound 5.

¹ H-NMR (DMSO-06): 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+H) ⁺ .

Compound 252.

Step A. methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate.

MeO n' SEM ₀ ^Z

To a solution of methyl 1H-pyrrole-3-carboxylate (2 g, 16.0 mmol) in THF (80 ml) was added sodium hydride (768 mg, 60% content, 19.2 mmol, 1.2 eq.) at 0 °C After stirring the mixture at 0° C. for 30 min, (2-(chloromethoxy)ethyl)trimethylsilane (4.0 g, 24 mmol, 1.5 eq.) was added dropwise. The mixture was then stirred at rt. during the night. The mixture was diluted with ethyl acetate (80 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated and washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography to give desired product 2 as a colorless oil. (2.1 g, 51% yield).

¹ H-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)+.

Step B. 3-oxo-2-phenyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-yl)propanenitrile.

NaHMDS (2 mol /l in THF, 4.9 ml, 1.2 equiv.) at 0°C. The mixture was then stirred at rt. during the night. The mixture was diluted with ethyl acetate (80 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated and washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography to give desired product 3 as a light yellow solid (2 g, 71% yield).

¹ H-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)+.

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Step C. 4-phenyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-yl)-1H-pyrazol-5-amine.

A mixture of intermediate 3 (2 g, 5.9 mmol, 1 eq) and hydrazine hydrate (590 mg, 11.8 mmol, 2 eq) in EtOH/AcOH (5/1, 40/8 mL) was heated at reflux refrigerator for 2 hours Then the mixture was cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (40 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography to give the title intermediate 4 as a yellow solid. (2 g, 99% yield)

1H-NMR (CHLOROFORM-d): δ 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, 1H), 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) ⁺ .

Step F. 5-methyl-3-phenyl-6-(quinolin-6-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3yl)pyrazolo[1.5 -a]pyrimidin-7(4H)-one.

A mixture of intermediate 4 (500 mg, 1.4 mmol, 1 equiv.) and methyl 3-oxo-2-(quinolin-6yl)butanoate 9 (1.5 equiv.) in AcOH (10 ml) was stirred at 100° C for 1 h. The mixture was then cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (5 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (5 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (DCM/methanol=10/1, silica gel, UV) to give Intermediate 5 (550 mg, 71% yield).

LC-MS: m/z 548.4 (M+H) ⁺ .

Step E. 2-(1 -(hydroxymethyl)-1 H-pyrrol-3-yl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine-7 (4H)-he.

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 rt. during the night. The mixture was concentrated in vacuo to give intermediate 6 which was used in the next step without further purification. (450 mg).

LC-MS: m/z 448.2 (M+H)+.

Step F. Connection 252.

a]pyrimidin-7(4H)-one.

5-methyl-3-phenyl-2-(1H-pyrrol-3-yl)-6-(quinolin-6-yl)pyrazolo[1,5-

To a solution of intermediate 6 (450 mg, 1.0 mmol) in THF (15 ml) was added aq. NaOH solution (6 mol/l, 3 ml). The mixture was stirred at rt. within 2 h, resulting in the receipt of the target product 7.

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) ⁺ .

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Compound 253.

Step A. ethyl 2-(3-chloro-4-nitrophenyl)-3-oxobutanoate.

To a mixture of 2-chloro-4-fluoro-1-nitrobenzene (10.0 g, 57.1 mmol) and Cs ₂ CO ₃ (22.3 g, 68.5 mmol, 1.2 eq.) in DMF (100 ml) ethyl 3-oxobutanoate (7.42 g, 57.1 mmol, 1.0 eq.) was added. The reaction mixture was then stirred at 60° C. for 5 hours. The mixture was partitioned between ethyl acetate and H2O. The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether=1/10) to give the title intermediate 2 (9.0 g, 55% yield).

LC-MS: m/z 285.9 (M+H) ⁺ .

Step B. 6-(3-chloro-4-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

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 5 h The reaction mixture was then cooled to rt. The mixture was filtered and the filter cake was washed with methanol (MeOH) to give the title intermediate 3 (8.9 g, 73% yield) as a white solid.

LC-MS: m/z 456.9 (M+H) ⁺ .

Step C. 6-(3-((4-Methoxybenzyl)thio)-4-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5n]pyrimidin-7(4H)-one.

Mixture of intermediate 3 (8.0 g, 17.5 mmol), K2CO3 (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 ethyl acetate and H2O. The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title intermediate 4 (8.2 g, 81% yield).

LC-MS: m/z 574.9 (M+H) ⁺ .

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Step D. 6-(4-Amino-3-((4-methoxybenzyl)thio)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Pd/C (30 mg) was added to Intermediate 4 (1.0 g, 1.74 mmol, 1 eq.) in methanol (50 ml) and THF (60 ml). The mixture was stirred at rt. in an H ₂ atmosphere during the night. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title intermediate 5 (700 mg, 74% yield).

LC-MS: m/z 544.9 (M+H) ⁺ .

Step E. 2-(1,3-dioxoisoindolin-2-yl)-N-(2-((4-methoxybenzyl)thio)-4-(5-methyl-7-oxo-2,3diphenyl-4,7- dihydropyrazolo[1,5-a]pyrimidin-6-yl)phenyl)acetamide.

To a mixture of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (452 mg, 2.20 mmol) in DCM (5 ml) was added oxalyl chloride (3 ml) and a catalytic amount of DMF (1.0 drop) at 0 °C. The reaction mixture was then stirred at rt. within 4 hours the Reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (2 ml) and added to a solution of intermediate 5 (300 mg, 0.55 mmol) in DCM (5 ml) dropwise at 0° C. under N ₂ atmosphere. The mixture was stirred at rt. during the night. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether=1/5) to give Intermediate 6 (250 mg, 62% yield).

LC-MS: m/z 731.9 (M+H) ⁺ .

Step F. 2-((6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6yl)benzo[d]thiazol-2-yl) methyl)isoindoline-1,3-dione.

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 methanol (MeOH) to give the title intermediate 7 (220 mg, 94% yield).

LC-MS: m/z 593.9 (M+H) ⁺ .

Step G Compound 253 6-(2-(aminomethyl)benzo[d]thiazol-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

To a mixture of intermediate 7 (200 mg, 0.33 mmol) in EtOH (8 ml) was added N2H4-H2O (2 ml). The reaction mixture was then stirred at rt. for 3 hours. The mixture was partitioned between ethyl acetate and H2O. The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound 8.

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) ⁺ .

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Pd/C.

HCOOMN/ethanol/30°C stage C

Compound 254.

^0N Cat.H ₂ SO ₄ methanol/ load with reverse cold stage A

Step A. Methyl 2-(4-fluoro-3-nitrophenyl)acetate.

load with return cold stage G

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 concentrated sulfuric acid at 0°C. The resulting mixture was then heated at reflux overnight. The mixture was concentrated under vacuum to 10 ml and neutralized with aqueous sodium bicarbonate to pH 7. The resulting mixture was extracted with ethyl acetate (30 mlx3). The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo to give methyl 2-(4-fluoro-3-nitrophenyl)acetate (4.1 g, 85% yield) as a yellow solid which used in the next step without further purification.

¹ H-NMR (CHLOROFORM-d): δ 8.02 (dd, J=6.98 Hz, 2.15 Hz, 1H), 7.59 (ddd, J=8.60 Hz, 4.03 Hz, 2.42 Hz, 1H), 7.21-7.38(m, 1H), 3.75(s, 3H), 3.71(s, 2H).

19F-NMR (CHLOROFORM-d): δ 119.68 (s, 1F).

Step B. Methyl 2-(4-(2-methoxy-2-oxoethyl)-2-nitrophenylamino)acetate.

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 Ν,N-dimethylformamide (50 ml) was heated to 30° C. overnight. The mixture was diluted with brine (100 ml) and extracted with ethyl acetate (30 mlx3). The combined organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo to give methyl 2-(4-(2-methoxy-2oxoethyl)-2-nitrophenyl-amino)acetate (4.6 g, 85% yield) as a yellow solid, which was used for the next steps without further purification.

LC-MS: m/z 283.1 (M+H) ⁺ .

Step C. Methyl 2-(3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)acetate.

Under an 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 charcoal, 1.73 g, 1.63 mmol), ammonium formate (15.4 g, 245 mmol) in ethanol (100 ml) was stirred at rt. during the night. The reaction mixture was filtered to remove Pd and ammonium formate. The resulting filtrate 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 give methyl 2-(3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)acetate (1.6 g, 45% yield) as a yellow solid substances.

1H-NMR (DMSO-de): δ 10.22 (bs, 1H), 6.65-6.58 (m, 3H), 5.92 (bs, 1H), 3.69 (s, 2H), 3.64(s, 3H), 3.46

- 149 042905 (s, 2H).

LC-MS: m/z 221.1 (M+H)+.

Step D. Methyl 2-(3-oxo-3,4-dihydroquinoxalin-6-yl)acetate.

A mixture of methyl 2-(3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)acetate (3.4 g, 15.5 mmol) and magnesium (IV) oxide (13.4 g, 155 mmol) in chloroform (200 ml) was heated to 50°C overnight. The mixture was filtered to remove magnesium(IV) oxide. The resulting filtrate was evaporated to dryness to give methyl 2-(3-oxo-3,4-dihydroquinoxalin-6-yl)acetate (2.9 g, 86% yield) as a gray solid.

LC-MS: m/z 219.1 (M+H) ⁺ .

Step E. Methyl 2-(3-methoxyquinoxalin-6-yl)acetate.

/ABOUT. .ABOUT.

XXI

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 at reflux for 2 h. The mixture was evaporated to remove phosphoryl trichloride . The crude oil was neutralized with methanol at rt. The mixture was then evaporated to dryness. The crude material was purified by silica gel column chromatography (methanol:dichloromethane=1:20) to give methyl 2-(3-methoxyquinoxalin-6-yl)acetate (320 mg, 38% yield) as a white solid.

LC-MS: m/z 233.1 (M+H) ⁺ .

Step F. Methyl 2-(3-methoxyquinoxalin-6-yl)-3-oxobutanoate.

XX .O.

XXdT

Under an inert atmosphere of nitrogen, 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 hexamethyldisylamide (2 N, 0.95 ml , 1.89 mmol) drop by drop. The mixture was then stirred at the same temperature for 1 hour. Acetyl chloride (89 mg, 1.14 mmol) was added to the mixture at -78°C. The reaction mixture was slowly heated to rt. The reaction was quenched with aqueous ammonium chloride and evaporated to dryness. The residue was purified by preparative TLC (methanol:dichloromethane=1:20) on silica gel to give methyl 2-(3methoxyquinoxalin-6-yl)-3-oxobutanoate (160 mg, 62% yield) as a white solid.

LC-MS: m/z 275.1 (M+H) ⁺ .

Step G Compound 254 6-(3-Methoxy-quinoxalin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of methyl 2-(3-methoxyquinoxalin-6-yl)-3-oxobutanoate (223 mg, 0.814 mmol), 3,4-diphenyl1H-pyrazol-5-amine (191 mg, 0.814 mmol) and acetic acid (2 ml ) in dioxane (8 ml) was heated to 100°C overnight. The mixture was concentrated to give 6-(3-methoxy-quinoxalin-6-yl)-5-methyl2,3-diphenylpyrazolo[1,5-a]-pyrimidin-7(4H)-one.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

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Compound 255.

_BOC2O / _Et3N

IJ ---O ₂ n^^ dmap/dxm stage A

Step A. 5-fluoro-2-nitro-(N,N)-di-tert-butyl-carbonoaniline.

Boc I

To a solution of 5-fluoro-2-nitroaniline (5 g, 32 mmol) in CH ₂ Cl ₂ was added N,N-dimethylpyridine-4amine (390 mg, 3.2 mmol) and triethylamine (6.43 g, 64 mmol). The reaction mixture was stirred for 10 min and then di-tert-butyl dicarbonate (20 g, 96 mmol) was added slowly and stirred overnight. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (elution using petroleum ether/ethyl acetate=10:1) to give the desired product (8 g, 71% yield).

¹ H-NMR (CHLOROFORM-d): δ 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).

Step B. Methyl 2-[(3-di-tert-butyldicarbo-amino-4-nitrophenyl]-3-oxobutanoate.

To a solution of 2-[(3-di-tert-butyldicarbo-amino-4-nitrophenyl]-3-oxobutanoate (8 g, 22.4 mmol) in DMF (20 ml) was added cesium carbonate (7.3 g, 8 mmol) and methyl 3-oxobutanoate (2.6 g, 22.4 mmol) The mixture was heated to 100°C for 4 hours The mixture was poured into water and extracted with ethyl acetate The organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated The residue was purified by column chromatography on silica gel (eluent using petroleum ether/ethyl acetate=10:1) to give the desired product (7 g, 69% yield).

Step C. Methyl 2-(3-amino-4-nitrophenyl)-3-oxobutanoate.

A solution of methyl 2-[(3-di-tert-butyldicarbo-amino-4-nitrophenyl]-3-oxobutanoate (2 g, 4.4 mmol) in HCl/MeOH (10 ml) was stirred for 4 hours. The reaction mixture concentrated to give the title product methyl 2-(3-amino-4-nitrophenyl)-3-oxobutanoate (1.1 g, 100% yield).

Step D. 6-(3-α-mino-4-nitrophenyl)-5-methyl-2-phenyl-3-(niperigun-1-yl)pyrazolo[1,5-a]pyrimidine 7(4H)-one.

A solution of methyl 2-(3-amino-4-nitrophenyl)-3-oxobutanoate (1.1 g, 4.3 mmol), 3-phenyl-4-(piperidin-1yl)-1H-pyrazole-5-amine ( 1.0 g, 4.3 mmol) in AcOH (10 ml) was 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-1-yl)pyrazolo[1,5-a]pyrimidine-7 (4H)-one (710 mg, 38% yield).

- 151 042905

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Step E. 6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one.

To a solution of 6-(3-amino-4-nitrophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one (710 mg, 1 .6 mmol) in MeOH (20 ml) was added Pd/C (71 mg) under H ₂ atmosphere. The reaction mixture was stirred for 4 h. The mixture was filtered and the filtrate was concentrated to give the desired product 6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-1yl)pyrazolo[1.5 -a]pyrimidin-7(4H)-one (500 mg, 75% yield).

1H-NMR (DMSOCH): 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) ⁺ .

Step F Compound 255 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(quinoxalin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of 6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one (100 mg, 0.24 mmol) in EtOH (10 ml) was added oxalaldehyde (21 mg, 0.36 mmol). The reaction mixture was then heated to 80° C. for 2 hours. The reaction mixture was concentrated to give the desired product 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(quinoxalin-6-yl) pyrazolo[1,5a]pyrimidin-7(4H)-one.

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)+.

Compound 256.

stage D

Step A. 5-fluoro-N-methyl-2-nitroaniline.

- 152 042905

To a solution of 2,4-difluoro-1-nitrobenzene (10 g, 63 mmol) in MeCN was added CH ₃ NH ₂ (63 ml, mmol/ml in MeOH) at 0°C. The reaction mixture was stirred for 4 hours. The mixture was filtered to give Intermediate 2 (10 g) as a yellow solid.

LC-MS: m/z 170.2 (M+I)+.

Step B. Dimethyl 2-(3-(methylamino)-4-nitrophenyl)malonate.

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 4 hours Then the reaction mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (elution using petroleum ether/ethyl acetate=2:1) to give the desired product (3.4 g).

¹ H-NMR (DMSO-d ₆ ): δ 8.13-8.25 (m, 1H), 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) ⁺ .

Step C. Methyl 2-(3-(methylamino)-4-nitrophenyl)acetate.

To a solution of dimethyl 2-(3-(methylamino)-4-nitrophenyl)malonate (3.4 g, 12 mmol) in DMSO (20 ml) was added saturated NaCl (5 ml). The reaction mixture was heated to 120° C. for 3 hours. The reaction mixture was then poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (elution using petroleum ether/ethyl acetate=2:1) to give the desired product (200 mg).

¹ H-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, 1.6Hz, 1H), 3.76 (s, 3H), 2.95 (d, J=4.8Hz, 4H) .

LC-MS: m/z 225.1 (M+H)+.

Step D. Methyl 2-(3-(methylamino)-4-nitrophenyl)-3-oxobutanoate.

HN^^A/OMe o ₂ nA^ ⁰

To a solution of methyl 2-(3-(methylamino)-4-nitrophenyl)acetate (200 mg, 0.89 mmol)) in THF (15 ml) was slowly added LDA (lithium diisopropylamide) (4.5 ml, 2 mmol/ ml in THF) at -30°C. Then acetyl chloride (104 mg, 1.34 mmol) was added slowly. The reaction mixture was stirred for 30 min at -30°C and allowed to reach rt. for 1 h. The mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated, resulting in a crude product (200 mg) as a yellow liquid, which was used directly in the next step without further purification .

Step E. 5-methyl-6-(3-(methylamino)-4-nitrophenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

He

X/N./ /=x

Η Ν - ^N N

Ο ₂ νΑΑ ^ο

A mixture of methyl 2-(3-(methylamino)-4-nitrophenyl)-3-oxobutanoate (crude, 200 mg) and 3,4-diphenyl-1H-pyrazole-5-aminep (100 mg, 0.43 mmol) in AcOH (10 ml) was heated to 120°C during the night. The reaction mixture was cooled to rt. The precipitate was filtered to give the title product 5-methyl-6-(3-(methylamino)-4-nitrophenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (35 mg ).

LC-MS: m/z 452.3 (M+H)+.

- 153 042905

Step F. 6-(4-amino-3-(methylamino)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

To a solution of 5-methyl-6-(3-(methylamino)-4-nitrophenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin7(4H)-one (35 mg, 0.078 mmol) in MeOH (10 ml ) was added Pd/C (5 mg) in an atmosphere of H ₂ . The reaction mixture was stirred for 4 h. 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[1,5a]pyrimidine -7(4H)-one (10 mg) as a solid.

LC-MS: m/z 422.2 (M+H)+.

Step G Compound 256 5-methyl-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

A solution of 6-(4-amino-3-(methylamino)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7 (4H)one (10 mg, 0.024 mmol) in HCOOH (5 ml) was heated to 120°C for 1 h. The reaction mixture was concentrated in vacuo to give the desired product 5-methyl-6-(1-methyl-1Hbenzo[d]imidαzol-6-yl)-2,3- diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (METHANOL-d): δ 8.21 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.27-7 .57 (m, 11H), 3.95 (s, 3H), 2.28 (s, 3H).

LC-MS: m/z 432.0 (M+H) ⁺ .

Compound 257 and Compound 258.

Step A. Methyl 2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)acetate.

A mixture of methyl 2-(4-hydroxy-3-nitrophenyl)acetate (5 g, 0.024 mol), K ₂ CO ₃ (6.5 g, 0.048 mol) and 1-(chloromethyl)-4-methoxybenzene (5.6 g 0.036 mol) was heated to 60°C for 4 h. The reaction mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered, concentrated. The residue was purified by silica gel column chromatography (elution using petroleum ether/ethyl acetate=3:1) to give the desired product (2 g, 53% yield).

LC-MS: m/z 332.2 (M+H) ⁺ .

- 154 042905

Step B. Methyl 2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)-3-oxobutanoate.

To a solution of methyl 2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)acetate (2 g, 6.0 mmol) in THF (50 ml) was slowly added LDA (lithium diisopropylamide) (3 ml, 2 mmol/ml in THF) at -30°C. Then acetyl chloride (702 mg, 9.0 mmol) was added slowly. The reaction mixture was stirred for 30 min at -30°C and allowed to reach rt. for 1 h. The mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated, resulting in a crude product (1.5 g) as a yellow liquid, which was used directly in the next step without further cleaning.

Step C. 6-(4-hydroxy-3-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

A solution of methyl 2-(4-((4-methoxybenzyl)oxy)-3-nitrophenyl)-3-oxobutanoate (crude, 1.5 g) and 3,4-diphenyl-1H-pyrazole-5-amine (1 g , 4.25 mmol) in AcOH (10 ml) was heated to 120° C. overnight. The reaction mixture was cooled to rt. The precipitate was filtered to give the title product 6-(4-hydroxy-3-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (600 mg, 32 % exit).

LC-MS: m/z 439.3 (M+I)+.

Step D. 6-(3-amino-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

To a solution of 6-(4-hydroxy-3-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (600 mg, 1.37 mmol) in MeOH ( 50 ml) was added Pd/C (60 mg) in an atmosphere of H ₂ . The reaction mixture was stirred for 4 h. The mixture was filtered, the filtrate was concentrated, resulting in the desired product 6-(3-amino-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidine- 7(4H)-one (450 mg, 80% yield).

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) ⁺ .

Step E. 2-chloro-N-(2-hydroxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-6-yl)phenyl)acetamide .

6-(3-Amino-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-α]pyrimidin-7(4H)-one (450 mg, 1.1 mmol), 2-chloroacetyl chloride mixture (136 mg, 1.2 mmol) and K ₂ CO ₃ (455 mg, 3.3 mmol) in acetone (50 ml) were heated to 80° C. overnight. The reaction mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting solid was washed with ethyl acetate to give the title product 2-chloro-N-(2-hydroxy-5(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a ]pyrimidin-6-yl)phenyl)acetamide (250 mg, 47% yield).

LC-MS: m/z 485.2 (M+H) ⁺ .

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Step F. Compound 257 ]oxazine-3(4H)-one.

A mixture of 2-chloro-N-(2-hydroxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin6-yl)phenyl)acetamide (250 mg, 0.52 mmol) and Cs ₂ CO ₃ (258 mg, 1.04 mmol) in acetone (40 ml) were heated to 100° C. overnight. The reaction mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to give the desired product 6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo [1,5-a]pyrimidin-6-yl)-2H-benzo[b][1,4]oxazin3(4H)-one.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

Step G. Compound 258 (4H)-he.

To a solution of 6-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)-2Hbenzo[b][1,4]oxazin-3 (4H)-one (110 mg, 0.25 mmol) in THF (20 ml) was added BH ₃ .THF (1 ml, 1 mmol/ml). The reaction mixture was heated to 80° C. for 4 h. The reaction mixture was then cooled to rt.

MeOH (10 ml) was added carefully and then the reaction mixture was stirred for 10 min. The mixture was concentrated to give the expected product.

1H-NMR (DMSO^): 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) ⁺ .

Compound 259.

Step A. Methyl 2-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)acetate.

K ₂ CO ₃ (1.4 g, 10.2 mmol) and PMBCl ( 795 mg, 5.1 mmol). The mixture was then heated to 80° C. for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (elution using petroleum ether/ethyl acetate=2:1) to give the desired product (900 mg, 56% yield).

LC-MS: m/z 317.3 (M+H) ⁺ .

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Step B. Methyl 2-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-3-oxobutanoate.

LDA (lithium diisopropylamide) (4.5 ml, 2 mmol/ml in THF) at -30°C. Then acetyl chloride (266 mg, 1.34 mmol) was added slowly. The reaction mixture was stirred for 30 min at -30°C and brought to rt. for 1 h. The mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated, resulting in a crude product (700 mg) as a yellow liquid, which was used directly in the next step without further purification .

Step C. 6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

A solution of methyl 2-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-3-oxobutanoate (crude, 400 mg) and 3,4-diphenyl-1H-pyrazole-5-amine (200 mg, 0.86 mmol) in AcOH (10 ml) was heated to 120° C. overnight. The reaction mixture was cooled to rt. The precipitate was filtered, resulting in the desired product 6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimudine-7(4H)- he (120 mg, 26% yield).

LC-MS: m/z 544.2 (M+n) ⁺ .

Step D Compound 259 6-(4-Hydroxy-3-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of 6-(3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one (120 mg, 0. 22 mmol) in MeOH (10 ml) was added 4N. HCl/dioxane solution (10 ml). The reaction mixture was stirred for 1 hour. After the starting material was taken up, the mixture was concentrated in vacuo to give the desired product 6-(4-hydroxy-3-methoxyphenyl)-5methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidine -7 (4H) -one.

1H-NMR (DMSO-d ₆ ): δ 11.85 (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) ⁺ .

Connection 260 and connection 261.

R= CH ₂ CH ₂ OH, AGI-0038209

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Step A. Ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate.

Mixture of ethyl 2-(3-hydroxy-4-methoxyphenyl)acetate (4.3g, 20.5mmol), ((2-bromoethoxy)methyl)benzene (7.88g, 36.8mmol), 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 rt, 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 product was purified by column chromatography (ethyl acetate:petroleum ether=1:5) to give ethyl 2-(3-(2-(benzyloxy)ethoxy)-4methoxyphenyl)acetate (3.8 g, 54% yield) in the form of a colorless oil.

Step B. Ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate.

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 (2 N, 1 ml, 2 mmol) at -78°C under nitrogen atmosphere. The mixture was stirred at the same temperature for 1 hour. Acetyl chloride (156 mg, 2 mmol) was slowly added to the mixture at -78°C. After the addition, the mixture was stirred at -78° C. for 1 h and warmed slowly to rt. during the night. The mixture was neutralized by adding an aqueous solution of ammonium chloride to pH 6-7 and was 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 product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:5) to give 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+I)+.

Step C. 6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

A mixture of ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate (280 mg, 0.725 mmol) and 3,4-diphenyl-1H-nirazol-5-amine (170 mg, 0.725 mmol) in acetic acid (5 ml) was heated under reflux for 2 h. The mixture was evaporated to remove acetic acid. The residue was purified by column chromatography (methanol:dichloromethane=1:20) to give 6-(3-(2(benzyloxu)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5- a]nirimidin-7(4H)-one (120 mg, 30% yield) as a yellow solid.

LC-MS: m/z 558.2 (M+I) ⁺ .

Step D Compound 260 and Compound 261

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6-(3-(2-(Benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenyl-pyrazolo[1,5a]pyrimidin-7(4H)-one mixture (200 mg, 0.359 mmol ) and bromine tribromide (1 M in DCM, 2 ml) were stirred at

k.t. for 1 h. The reaction was quenched with methanol at 0°C. The mixture was evaporated to dryness to give 6-(3,4-dihydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one and 6-(4-hydroxy3- (2-hydroxyethoxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

6-(3,4-dihydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (compound 260).

¹ H-NMR (DMSOCH): δ 11.82 (s, 1H), 7.37-7.52 (m, 5H), 7.20-7.37 (m, 5H), 6.78 (d, J=8.06Hz, 1H), 6.66-6.73(m, 1H), 6.55(d, J=7.79Hz, 1H), 2.17(s, 3H).

LC-MS: m/z 410.1 (M+H) ⁺ .

6-(4-hydroxy-3-(2-hydroxyethoxy)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)one (compound 261).

¹ H-NMR (DMSO-d6): δ 11.85 (s, 1H), 8.82 (s, 1H), 7.38-7.58 (m, 5H), 7.24-7.38 ( m, 5H), 6.81-6.92 (m, 2H), 6.73 (dd, J=8.06, 1.88 Hz, 1H), 4.91 (t, J=6.04 Hz , 1H), 3.97 (t, J=4.97 Hz, 2H), 3.74 (q, J=5.46 Hz, 2H), 2.06-2.22 (m, 3H).

LC-MS: m/z 454.2 (M+H) ⁺ .

Compound 262.

Step A. 5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of 3-phenyl-4-(piperidin-1-yl)-1H-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 under reflux for 2 h. The mixture was cooled to rt. The resulting suspension was filtered. The resulting solid was washed with water and cold methanol to give 5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one (7.9 g, 74% yield) as a white solid.

LC-MS: m/z 309.2 (M+H) ⁺ .

Step B. 5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

ABOUT

To a mixture of 5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrumidin-7(4H)-one (5.5 g, 17.9 mmol) in N,N -dimethylformamide (50 ml) was slowly added sodium hydride (1.4 g, 35.8 mmol) at 0°C. After the addition, the mixture was stirred at 0° C. for 1 hour. (2-(Chloromethoxy)ethyl)trimethylsilane (3.6 g, 21.7 mmol) was added. The resulting mixture was stirred at rt. during the night. The mixture was neutralized with brine and extracted with ethyl acetate (50 ml) three times. The combined organic phase was washed with brine, dried with anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (methanol:dichloromethane=1:20) to give 5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo [1,5a]n-pyrimidin-7(4H)-one (2.5 g, 35% yield) as white solid.

LC-MS: m/z 439.2 (M+H) ⁺ .

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Step C. 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidine-7 (4H) -He.

sem oh oh

To a mixture of 5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)-methyl)pyrazolo[1,5a]pyrimidin-7(4H)-one (1 .2 g, 2.74 mmol) and triethylamine (0.32 g, 3.16 mmol) in dichloromethane (20 ml) at r.t. N-bromosuccinimide (0.58 g, 3.47 mmol) was added at rt. The mixture was then stirred at rt. within 2 hours the Mixture was concentrated. The residue was purified by column chromatography (methanol:dichloromethane=1:20) to give 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) ⁺ .

Step D. 6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(mrimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine -7(4H)-he.

semO \,n.J /=\ o

To a solution of 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7(4H )-one (100 mg, 0.194 mmol) and 4-hydroxyphenylboronic acid (41 mg, 0.293 mmol) in a mixture of dioxane/H ₂ O (5/1 ml) was added a complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium ( II) dichloride with dichloromethane (28 mg, 0.0344 mmol) and sodium carbonate (42 mg, 0.396 mmol). The reaction mixture was then heated under reflux under nitrogen atmosphere overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol:dichloromethane=1/20) to give 6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(4H)-one (60 mg, 59% yield) as a white solid.

LC-MS: m/z 531.3 (M+H) ⁺ .

Step E Compound 262 6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

N VrVn ⁰

A mixture of 6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl) ethoxy)methyl)pyrazolo[1,5-a]pyrimidine- 7(4H)-one (60 mg, 0.113 mmol) in CF3COOH (2 mL) was heated to 60°C for 3 h. The mixture was cooled to rt. and concentrated in vacuo to remove the solvent. The resulting residue was washed with saturated aqueous sodium bicarbonate. The resulting suspension was filtered to give 6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (METHANOL-d): δ 8.07 (d, J=6.72 Hz, 2H), 7.45 (d, J=7.52 Hz, 3H), 7.16 (d, J = 8.33 Hz, 2H), 6.88 (d, J=8.33 Hz, 2H), 3.06-3.16 (m, 4H), 2.34 (s, 3H), 1.75 -1.73(m, 4H), 1.63-1.62(m, 2H).

LC-MS: m/z 401.2 (M+H) ⁺ .

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Connection 263.

Step A. 2,2,2-trifluoro-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)acetamide.

SEM

N-N about

And I

NN CF ₃

H

NaHMDS (14 ml, 1 mmol/ml) at -78°C. After the addition, the mixture was stirred at -78°C for 30 minutes and then allowed to warm to -30°C over 30 minutes. Trifluoroacetic anhydride (2 g, 21 mmol) was added slowly and the mixture was stirred at -30° C. for 20 min. The reaction mixture was allowed to warm up to rt. during the night. The mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (elution using petroleum ether/ethyl acetate=1:1) to give the desired product 2,2,2-trifluoro-X-(1-((2(trimethylsilyl)ethoxy)methyl)- 1H-1,2,4-triazol-3-yl)acetamide (2 g, 46% yield).

¹ H-NMR (DMSO-d ₆ ): 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 311.2 (M+H)+.

Step B. Compound 263 5-yl)methyl)acetamide.

To a solution of 2,2,2-trifluoro-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)acetamide (200 mg, 0.65 mmol ) in NMP (N-methylpyrrolidone)(N-methylpyrrolidone) (10 ml) was added t-BuOk (1 ml, 1 mmol/ml in THF). The reaction mixture was stirred for 30 min, and then 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.22 mmol). The reaction mixture was stirred at rt. for 1 h. The mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain the target product 2,2,2-trifluoro-N-((7-oxo-2,3-diphenyl -6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5yl)methyl)acetamide.

1H-NMR (DMSO-d ₆ ): δ 12.23 (s, 1H), 9.65 (br. s., 1H), 8.95 (br. s., 1H), 8.35 (d, J=8.1Hz, 1H), 8.06(d, J=8.3Hz, 1H), 7.92(s, 1H), 7.71(d, J=8.6Hz, 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) ⁺ .

Connection 264.

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Step A. N-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimudin-5yl)methyl)hydrazinecarboximidamide.

A mixture of 5-(aminomethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (compound 222, 200 mg, 0.47 mmol) and methylhydrazinecarbimidothioate ( 100 mg, 0.94 mmol) in EtOH (20 ml) in a sealed tube was heated to 120° C. overnight. The reaction mixture was concentrated to dryness. The resulting solid was washed with ethyl acetate to give the desired product (170 mg, 75% yield).

¹ H-NMR (DMSOCH): 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) ⁺ .

Step B Compound 264 7(4H)-he.

HN- _n ^N Γ Η V

UV ⁰

A solution of N-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5yl)methyl)hydrazinecarboximidamide (170 mg, 0.355 mmol) in HCOOH (5 ml) and trimethoxymethane (5 ml) were heated to 150° C. for 4 h. After the reaction mixture was taken up, the mixture was concentrated to dryness. The residue was suspended in DMSO (10 ml) and stirred for 30 min at 5°C, resulting in the desired product 5-(((1H-1,2,4-triazol-3-yl)amino)methyl)-6 -(4-methoxyphenyl)-2,3diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO^): δ 8.44 (s, 1H), 7.28-7.49 (m, 11H), 7.11-7.24 (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) ⁺ .

Compound 265.

Step A. 4-(4,4-Difluorocyclohex-1-en-1-yl)-3-phenyl-1H-pyrazole-5-amine.

A solution of 3-phenyl-1H-pyrazole-5-amine (1 g, 6.3 mmol) and 4,4-difluorocyclohexanone (844 mg, 6.3 mmol) in AcOH (10 ml) was heated to 80°C for 3 h. The reaction mixture was concentrated, resulting in a crude product, which was used directly in the next step without further purification.

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Step B. Compound 265 (4H)-he.

F

A mixture of methyl 3-oxo-2-(quinolin-6-yl)butanoate (200 mg, 0.82 mmol) and 4-(4,4-difluorocyclohex-1en-1-yl)-3-phenyl-1H-pyrazole -5-amine (100 mg, crude) in AcOH (10 ml) was heated to 120° C. for 2 hours. The reaction mixture was cooled to rt, resulting in the desired product.

¹ H-NMR (DMSOCH): δ 11.86 (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, 1H), 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), 2.11-2.23 (m, 2H).

LC-MS: m/z 469.8 (M+H)+.

Compound 266.

Step A. tert-butyl 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)4,7-dihydropyrazolo [ 1,5-a]pyrimidin-6-yl)-1 H-pyrazole-1-carboxylate.

Vos

Suspension of 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7(4H)- she (synthesized according to the scheme for compound 305, 200 mg, 0.39 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazol-1 -carboxylate (341 mg, 1.16 mmol), PdCl ₂ (dppf) (28 mg, 0.04 mmol) and Na ₂ CO ₃ (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 mixture was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1) to give the title product (40 mg, 18% yield) as a white solid.

LC-MS: m/z 605.3 (M+H)+.

Step B. 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]n-pyrimidin-7(4H)-one.

A mixture of tert-butyl 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)4,7-dihydropyrazolo[1, 5-a]pyrimidin-6-yl)-1H-pyrazole-1-carboxylate (40 mg, 0.07 mmol) and HCl in MeOH (0.5 mol, 10 ml, 5 mmol) were stirred at rt. for 1 h. The mixture was then concentrated to dryness. The residue was dissolved in concentrated hydrochloric acid (10 ml) and stirred at 100° C. for 24 hours to give the desired product.

1H-NMR (DMSO-06): δ 12.90 (br. s., 1H), 11.34 (br. s., 1H), 8.13 (d, J=7.2 Hz, 2H), 7.99-7.51 (m, 2H), 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)+.

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Compound 267.

stage D

_BOC2O / _Et3N

O^ ^ DMAFflXM stage A

sz ₂ sodmfa stage B

stage C

HCI/MeOH

Step F Compound 267 )-He.

A mixture of 6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)one (synthesized according to the scheme for compound 255 , 100 mg, 0.24 mmol) in HCOOH (10 ml) was stirred at 100°C for 2 h. The reaction mixture was concentrated and washed with water. NaHCO ₃ solution, resulting in the target product 6-(1H-benzo[d]imidazol-5-yl)-5-methyl-2-phenyl-3(piperidin-1-yl)pyrazolo[1,5-a] pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d6): δ 12.47 (br. s., 1H), 11.47 (br. s., 1H), 8.25 (s, 1H), 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)+.

Compound 268.

Step A. 6-(2-Amino-1H-benzo[d]imidazol-5-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidin-7 ( 4H)-oh.

To a solution of 6-(3,4-diaminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one (100 mg, 0.24 mmol) in CH3CN (10 ml) and H ₂ O (5 ml) cyanogen bromide (28 mg, 0.256 mmol) was added. The mixture was stirred at rt. over 1 hour. The mixture was concentrated to give a crude product which was washed with water. NaHCO ₃ solution and filtered, resulting in the target product 6-(2-amino-1H-benzo[d]imidazol-5-yl)-5-methyl-2-phenyl-3-(piperidin-1yl)pyrazolo [ 1 ,5-a]pyrimidine-7 (4H)-oh.

¹ H-NMR (DMSOCH): 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)+.

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Compound 269.

CH ₃ 1/DMF/Cs ₂ COs step C

Step A. Ethyl 2-(4-methoxyphenyl)-3-oxobutanoate.

To a solution of ethyl 2-(4-methoxyphenyl)acetate (5 g, 25.7 mmol) in THF (100 ml) was added LDA (lithium diisopropylamide) (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. The mixture was then stirred at rt. within 6 hours the Mixture was poured into saturated NH ₄ Cl and was extracted with ethyl acetate (3x100 ml). The combined organic phase was washed with brine, dried with anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the title ethyl 2-(4-methoxyphenyl)-3-oxobutanoate as a brown oil (5.2 g, 86% yield).

Step B. 6-(4-Methoxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of ethyl 2-(4-methoxyphenyl)-3-oxobutanoate (292 mg, 1.24 mmol) and 3-phenyl-4-(piperidin-1yl)-1H-pyrazole-5-amine (300 mg, 1.24 mmol) in AcOH (10 ml) was stirred at 95°C for 4 h. the solids were collected by filtration, washed with ethyl acetate and dried in vacuo to give 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1yl)-n-pyrazolo[1,5-a]-nyrimidine-7 (4H)-one (210 mg, 41% yield) as a white solid.

LC-MS: m/z 415.1 (M+I)+.

Step C Compound 269 6-(4-methoxyphenyl)-4,5-dimethyl-2-phenyl-3-(piperidin-1yl)-pirazolo[1,5-a]-pyrimidin-7(4H)-one.

To a mixture of 6-(4-methoxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)one (210 mg, 0.49 mmol ) and Cs ₂ CO ₃ (320 mg, 0.98 mmol) in DMF (10 ml) was added MeI (103 mg, 0.735 mmol). The mixture was then stirred at rt. overnight to give the title compound.

1H-NMR (400 MHz, CHLOROFORM-d): δ 7.62 (br. s., 2H), 7.45 (d, J=2.15 Hz, 3H), 7.23 (m, J=8 .33Hz, 2H), 6.98(m, J=8.33Hz, 2H), 4.26(s, 3H), 3.86(s, 3H), 3.00(d, J=11 .55 Hz, 4H), 2.31 (s, 3H), 1.78 (br. s., 4H), l.66 (br. s., 2H).

LC-MS: m/z 429.0 (M+H) ⁺ .

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Compound 271.

Step A. Methyl 2-(4-((4-methoxybenzyl)oxy)phenyl)acetate.

To a solution of methyl 2-(4-hydroxyphenyl)acetate (5.0 g, 30 mmol) in DMF (25 ml) was added K ₂ CO ₃ (8.3 g, 60 mmol) at rt. in an N2 atmosphere. After stirring the mixture at rt. 1-(Bromomethyl)-4-methoxybenzene (7.2 g, 36 mmol) was added dropwise over 30 min and the mixture was stirred at rt. over 2 hours. The mixture was poured into H2O (100 ml) and extracted with ethyl acetate (3x50 ml). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was recrystallized from EtOH to give the title compound 2 as a white solid (5.6 g, 65% yield).

LC-MS: m/z 287.1 (M+I)+.

Step B. Methyl 2-(4-((4-methoxybenzyl)oxy)phenyl)-3-oxobutanoate.

To a solution of intermediate 2 (4.6 g, 16 mmol) in THF (50 ml) was added LDA (lithium diisopropylamide) (2 mol/l in THF, 16 ml) dropwise at -60°C. The mixture was stirred at -60°C for 30 minutes. Then acetyl chloride (1.5 g, 19.2 mmol) was added dropwise. The mixture was stirred at -60°C for 30 min and at rt. for 1 h. The mixture was diluted with ethyl acetate (50 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated and washed with water and brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 3 as a yellow oil which was used in the next step without purification (5.2 g, 99% yield).

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Step C. 6-(4-((4-Methoxybenzyl)oxCi)phenyl)-5-methyl-2-phenylpyrαzolo[1,5-α]pyrimidin-7(4H)-one.

A solution of intermediate 3 (5.3 g, 16 mmol) and 3-phenyl-1H-pyrazol-5-amine (1.9 g, 12 mmol) in AcOH (10 ml) was refluxed for 1 h. the mixture was cooled to rt. The precipitate was filtered off and washed with ethyl acetate (3x5 ml) to give the title compound 4 (3.0 g, 43% yield).

LC-MS: m/z 438.1 (M+I)+.

Step D. 6-(4-((4-methoxybenzyl)oxy)phenyl)-4,5-dimethyl-2-phenylpyrazolo[1,5-α]pyrimidin-7(4H)-one.

To a solution of intermediate 4 (3.0 g, 6.9 mmol) in DMF (50 ml) was added Cs ₂ CO ₃ (6.8 g, 20.7 mmol) and iodomethane (2.9 g, 20.7 mmol ). The mixture was then stirred at rt. during the night. The mixture was poured into water (200 ml). The white precipitate was filtered off, washed with water (H2O) (3x5 ml) and ethyl acetate (3x5 ml) to give the title compound 5 as a white solid (2.8 g, 88% yield).

LC-MS: m/z 452.1 (M+H) ⁺ .

Step E. 3-bromo-6-(4-((4-methoxybenzyl)oxy)phenyl)-4,5-dimethyl-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

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 rt. during the night. The mixture was poured into water (200 ml). The organic phase was separated, washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 6 (3.1 g, 94% yield) as a white solid.

LC-MS: m/z 530.1/532.1 (M+H)+.

Step F. 6-(4-((4-methoxybenzyl)oxy)phenyl)-4,5-dimethyl-2-phenyl-3-(thiophen-2-yl)pyrazolo[1,5

a]pyrimidin-7(4H)-one.

SJ G X/N./ /=x

PMBO

Suspension of intermediate 6 (200 mg, 0.38 mmol), thiophen-2-ylboronic acid (242 mg, 1.89 mmol), Pd(dppf)Cl ₂ (100 mg, 0.12 mmol) and Cs ₂ CO ₃ (246 mg, 0.76 mmol) in 1,4-dioxane (16 ml) and H2O (2 ml) was stirred at 90° C. overnight under N2 atmosphere. The reaction mixture was then cooled to rt, diluted with dichloromethane (50 ml) and filtered through celite. The filtrate was washed with water and brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC to give compound 7 (70 mg, 35% yield).

LC-MS: m/z 534.1 (M+H)+.

Step G. 6-(4-hydroxyphenyl)-4,5-dimethyl-2-phenyl-3-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one.

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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 rt. for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in DCM (5 ml), washed with saturated NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 8.

¹ H-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) ⁺ .

Compound 272.

Step A. 2-(3,3-difluoropyrrolidin-1-yl)acetonitrile.

A mixture of 3,3-difluoropyrrolidine hydrochloride (3.6 g, 24.8 mmol), 2-bromoacetonitrile (3.0 g, 24.8 mmol) and K ₂ CO ₃ (10.3 g, 74.4 mmol) in CH3CN (50 ml) was stirred at 80°C overnight. The mixture was then cooled to rt. and filtered. The filtrate was poured into water (100 ml) and extracted with ethyl acetate (30 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 2 (2.9 g, 80% yield) which was used directly in the next step without further purification. .

LC-MS: m/z 147.0 (M+H) ⁺ .

Step B. 2-(3,3-difluoropyrrolidin-1-yl)-3-oxo-3-phenylpropanenitrile.

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 rt. during the night. The reaction mixture was diluted with ethyl acetate (50 ml) and neutralized with saturated NH4Cl. The organic phase was separated, washed with brine, dried with anhydrous Na2SO4 and concentrated in vacuo to give the title compound 3 as a white solid (4.9 g, 97% yield) which was used in the next step without purification. .

LC-MS: m/z 251.0 (M+H) ⁺ .

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Step C. 4-(3,3-difluoropyrrolidin-1-yl)-3-phenyl-1H-pyrazole-5-amine.

A 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 at during the night. The mixture was then cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (50 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (25 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 4 as a yellow solid (5.1 g, 98%) which was used in the next step without cleaning.

LC-MS: m/z 265.1 (M+H) ⁺ .

Step D. 3-(3,3-difluoropyrrolidin-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

A 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 1 h The mixture was then cooled to rt to give the title compound 5.

¹ H-NMR (DMSO-d ₆ ): δ 11.80 (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) ⁺ .

Compound 273.

To a solution of methyl 2-(4-methoxyphenyl)acetate (5.0 g, 27.7 mmol) in THF (50 ml) was added LDA (lithium diisopropylamide) (2 mol/l in THF, 16.6 ml) dropwise at -60°C. The mixture was stirred at -60°C for 30 minutes. Then ethyl chloroformate (3.6 g, 33.2 mmol) was added dropwise. The mixture was stirred at -60°C for 30 min and then stirred at rt. within 2 hours the Mixture was diluted with ethyl acetate (50 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated and washed with water and brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether/ethyl acetate=20:1) to give the title compound 2 as a colorless oil (3.0 g, 43% yield).

LC-MS: m/z 253.1 (M+H) ⁺ .

Step B. 5-Hydroxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

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Mixture of intermediate 2 (1.0 g, 4.0 mmol) and 3,4-diphenyl-1H-pyrazole-5-amine (933 mg,

4.0 mmol) in tributylamine (10 ml) was stirred at 185°C for 1 h and then cooled to rt.

The precipitate was collected by filtration, washed with methanol (MeOH) (3x10 mL) to give the title compound 3 as a white solid (1.1 g, 67% yield).

¹ H-NMR (DMSO-d ₆ ): 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+n)+.

Step C. 5-hydroxy-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

Boron tribromide (0.2 ml) was added dropwise to a solution of intermediate 3 (80 mg, 0.2 mmol) in DCM (3 ml) at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction was quenched with methanol (MeOH) at 0°C and concentrated in vacuo to give the title compound 4.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 274.

Step A. N-(3,4-diphenyl-1H-pyrazol-5-yl)formamide.

A mixture of 3,4-diphenyl-1H-pyrazole-5-amine (5.0 g, 21.3 mmol) in formic acid (30 ml) was heated at reflux for 1 h. The mixture was evaporated, the residue was dissolved in ethyl acetate (50 ml), washed with 10% aqueous NaHCO ₃ , water and brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether/ethyl acetate 1:1) to give the title compound 2 as a light yellow solid (4.0 g, 72% yield).

LC-MS: m/z 264.1 (M+H)+.

Step B. N-methyl-3,4-diphenyl-1H-pyrazole-5-amine.

To a solution of intermediate 2 (4.0 g, 15.2 mmol) in THF (30 mL) was added borane-THF (1 mol/L in THF, 15.2 mL) dropwise at 0°C. The mixture was stirred at rt. during the night. The reaction was quenched by careful addition of MeOH and concentrated in vacuo. The residue was purified by flash chromatography to give the title compound 3 as a white solid (2.1 g, 56%).

LC-MS: m/z 250.1 (M+H)+.

Step C. 5-Hydroxy-6-(4-methoxyphenyl)-4-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of intermediate 3 (200 mg, 0.8 mmol) and 1-ethyl-3-methyl-2-(4methoxyphenyl)malonate (200 mg, 0.8 mmol) in AcOH (5 ml) was stirred at 160°C (heating microwave radiation) for 1 h and cooled to rt to give the title compound 4.

¹ H-NMR (DMSO-de): 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) ⁺ .

Compound 275.

Step A. dimethyl-2-(quinolin-6-yl)malonate.

To a solution of methyl 2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) in THF (30 mL) was added LDA (lithium diisopropylamide) (2 mol/L in THF, 7.4 ml) at -60°C. The mixture was stirred at -60°C for 30 minutes. Then methyl chloroformate (1.0 g, 10.9 mmol) was added dropwise. The mixture was stirred at -60°C for 30 min and stirred at RT. for 2 hours. The mixture was diluted with ethyl acetate (30 ml) and neutralized with saturated NH4Cl. The organic phase was separated and washed with water and brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether/ethyl acetate=20:1) to give the title compound 2 as a colorless oil (1.0 g, 39% yield).

LC-MS: m/z 260.0 (M+H) ⁺ .

Step B. 5-Hydroxy-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

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 rt. The precipitate was collected by filtration to give the title compound 3.

¹ H-NMR (DMSO-de): 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) ⁺ .

Compound 276.

Step A. N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)acetamide.

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A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidine (synthesized according to the scheme for 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 Cs ₂ CO ₃ (650 mg, 1.99 mmol) in 1,4-dioxane (30 ml) in a microwave reactor at 100°C for 45 min under N ₂ atmosphere. The reaction mixture 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 give the title product as a yellow solid (100 mg, 23% yield).

LC-MS: m/z 464.2 (M+H)+.

Step B. N-(7-hydroxy-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)acetamide.

To a solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrαzolo[1,5-a]pyrimidin-5yl)acetamide (70 mg, 0.15 mmol) in DCM (2 ml) carefully added BBr ₃ (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 carefully adding ice water at 0°C. The precipitated solids were filtered and purified by preparative HPLC to give the title product as a yellow solid (50 mg, 75% yield).

LC-MS: m/z 437.2 (M+I)+.

Step C. 5-αmino-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

N-(7-hydroxy-6-(4-hydroxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)acetamide (50 mg, 0.11 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 hours. The mixture was then concentrated to give the desired product.

¹ H-NMR (DMSO-d ₆ ): δ 9.20 (br. s., 1H), 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)+.

Compound 277.

stage A stage B

2 3

Step A. 2-cyclohexylacetonitrile.

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A mixture of 2-cyclohexenylacetonitrile (2.0 g, 16.5 mmol) and Pd(OH) ₂ /C (200 mg, 10%) in MeOH (100 ml) was stirred at rt. under H2 atmosphere for 10 h. The mixture was filtered and concentrated to give the title product as a yellow solid (1.8 g, 90% yield).

LC-MS: m/z 124.2 (M+H) ⁺ .

Step B. 2-cyclohexyl-3-oxo-3-phenylpropanenitrile.

To a solution of 2-cyclohexylacetonitrile (1.8 g, 14.6 mmol) in THF (100 ml) was added LDA (lithium diisopropylamide) (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, benzoyl chloride (0.17 ml, 2.33 mmol) was added dropwise. The mixture was then slowly heated to RT and stirred for 10 h. The mixture was slowly poured into saturated water. NH ₄ Cl and extracted with ethyl acetate (30 mlx3). The combined organic phase was washed with brine, dried with anhydrous MgSO ₄ and concentrated in vacuo to give the desired product as a yellow oil (2.9 g, 88% yield).

LC-MS: m/z 228.2 (M+H) ⁺ .

Step C. 4-cyclohexyl-3-phenyl-1H-pyrazole-5-amine.

A 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 with reflux condenser for 16 h under N2 protective atmosphere. The reaction mixture was concentrated, filtered, washed with Et ₂ O diethyl ether and dried to give the desired product as a yellow oil (2.9 g, 96% yield).

LC-MS: m/z 242.1 (M+I)+.

Step F. 3-cyclohexyl-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of 4-cyclohexyl-3-phenyl-1H-pyrαzol-5-amine (230 mg, 0.96 mmol) and methyl 3-oxo-2-(quinolin6-yl)butanoate (300 mg, 1.24 mmol) in AcOH (5 ml) was stirred at 100° C. for 1 h. After removal of AcOH, 10% NaHCO ₃ was added. The precipitate was filtered, washed with methanol (MeOH) and dried to give the expected product.

¹ H-NMR (DMSO-d6): δ 11.56 (br. s., 1H), 8.94 (d, J=2.4 Hz, 1H), 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, 1.6Hz, 1H), 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)+.

Compound 278.

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To a suspension of 5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (compound 319, 500 mg, 1.126 mmol) in DCM (3 mL) chilled in an ice-water bath) SOCl ₂ (670 mg, 5.631 mmol) was added dropwise. The resulting mixture was then stirred at rt. during the night. The suspension was filtered, washed with ethyl acetate and dried under vacuum. The residue was purified by preparative TLC (DCM:MeOH=20:1) to give 5-(chloromethyl)-2,3-diphenyl-6-(quinolin6-yl)pyrazolo[1,5-a]pyrimidin-7(4H )-one (300 mg).

LC-MS: m/z 463.1 (M+H) ⁺ .

Step B Compound 278 5-((methylamino)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

A solution of 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-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 stop the reaction. The resulting mixture was concentrated to give the title compound.

¹ H-NMR (400 MHz, TFA): δ 9.26-9.48 (m, 2H), 8.57-8.76 (m, 2H), 8.42 (d, J=8.60 Hz , 1H), 8.35 (dd, J=8.33, 5.64 Hz, 1H), 7.64-7.81 (m, 6H), 7.55-7.62 (m, 2H), 7.51 (d, J=7.25 Hz, 2H), 4.80 (br. s., 2H), 2.95 (s, 3H).

LC-MS: m/z 458.1 (M+H) ⁺ .

Compound 279.

Step A. 3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

A suspension of 4-cyclohexenyl-3-phenyl-1H-pyrazol-5-amine (200 mg, 0.84 mmol) and dimethyl-2-(4methoxyphenyl)malonate (240 mg, 1.00 mmol) in tributylamine (5 ml) was heated up to 180°C for 1 h in N2 protective atmosphere. The mixture was cooled to rt. and stirred with petroleum ether, resulting in the desired product.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 280.

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Step A. Methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate.

To a solution of methyl 1H-pyrazole-3-carboxylate (1 g, 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 stirring the mixture at 0° C. for 30 min, (2-(chloromethoxy)ethyl)trimethylsilane (1.6 g, 9.5 mmol) was added dropwise. The mixture was then stirred at rt. during the night. The mixture was diluted with ethyl acetate (30 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated and washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography to give Intermediate 2 as a white solid (1.1 g, 54% yield).

¹ H-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+H) ⁺ .

Step B. 3-oxo-2-phenyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propanenitrile.

To a 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) drop by drop at 0°C. The mixture was kept at 0°C for 30 min and then stirred at rt. during the night. The mixture was diluted with ethyl acetate (20 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated and washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography to give intermediate 3 as a light yellow solid (200 mg, 25% yield).

1H-NMR (DMSO-d6): δ 12.41 (br. s., 1H), 7.73-7.78 (m, 2H), 7.66 (d, J=1.8 Hz, 1H) , 7.43 (t, J=7.8 Hz, 2H), 7.30 (t, J=7.4 Hz, 1H), 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) ⁺ .

Step C. 4-phenyl-1'-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-[3,3'-bipyrazole]-5-amine.

A 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 2 h. Then the mixture was cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (20 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give Intermediate 4 as a yellow solid (200 mg, 96% yield) which was used in the next step without purification.

LC-MS: m/z 356.1 (M+I)+.

Step D. 5-methyl-3-phenyl-6-(quinolin-6-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3- 175 042905

0.56 mmol) and methyl-3-oxo-2-(quinolin-6yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of intermediate 4 (200 mg, yl)butanoate 8 (205 mg, 0.85 mmol) in AcOH (8 mL) was stirred at 100° C. for 1 h. The mixture was then cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (15 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (15 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give Intermediate 5 as a yellow solid (200 mg, 65% yield) which was used in the next step without purification.

LC-MS: m/z 549.2 (M+I)+.

Step E. 5-methyl-3-phenyl-2-(1H-n-pyrazol-3-yl)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

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 rt. during the night. The mixture was concentrated in vacuo and then dissolved in DCM (10 ml), washed with 10% NaHCO ₃ and brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give desired product 6.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 281.

To a mixture of methyl 2-(quinolin-6-yl)acetate (40.2 g, 0.2 mol) and HMPTA (7.2 g, 0.02 mol) in THF was added LDA (lithium diisopropylamide) (2 M in THF; 100 ml, 0.2 mol) for 20 min at -78°C. The mixture was stirred for 1 h at -78° C., 2-(benzyloxy)acetyl chloride (36.8 g, 0.2 mol) was added dropwise via funnel. The mixture was heated to rt. during the night. A saturated aqueous solution of NH ₄ Cl was added. The resulting mixture was extracted with dichloromethane (3x50 ml). The combined organic layers were washed with saturated NaCl (50 ml), dried with Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified using a silica gel column (petroleum ether/EtOAc=20/1) to give the title compound (38 g, 58%) as a brown oil.

Step B. Methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate.

Methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (1.2 g, 3.4 mmol) and 3,4-diphenyl-1Hpyrazol-5-amine (545 mg, 3.4 mmol) 4 mmol) was dissolved in AcOH (10 ml). The mixture was heated to 95° C. for 4 hours. After cooling to rt. the solids were collected by filtration, washed with ethyl acetate and dried in vacuo to give methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (1.05 g, 67% yield) as white solid.

LC-MS: m/z 459.1 (M+H) ⁺ .

Step C. 5-(benzyloxymethyl)-4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

To a mixture of methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (900 mg, 1.97 mmol) and Cs ₂ CO ₃ (1.38 g, 4.25 mmol) in DMF (10 ml) MeI (416 mg, 2.95 mmol) was added. The mixture was then stirred at rt. during the night. The mixture was poured into water (100 ml) and filtered. The filter cake was washed with methanol (MeOH) to give 5-(benzyloxymethyl)-4-methyl-2-phenyl-6-(quinolin-6yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (900 mg) as a white solid.

LC-MS: m/z 473.0 (M+H) ⁺ .

Step D. 5-(benzyloxymethyl)-3-bromo-4-methyl-2-phenyl-6-(quinolin-6-ul)nirazolo[1,5-a]pyrimidin7(4H)-one.

OVp । _Vg about

To a solution of 5-(benzyloxymethyl)-4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one (900 mg, 1.9 mmol) in DMF (10 ml) BSI (374 mg, 2.1 mmol) was added. The reaction mixture was then stirred at rt. over 2 h. The mixture was poured into water (50 ml) and filtered, resulting in 5-(benzyloxymethyl)-3-bromo-4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1 ,5a]pyrimidin-7(4H)-one (900 mg, 86% yield) as a white solid.

LC-MS: m/z 551.0 (M+H) ⁺ .

Step E. 5-(benzyloxymethyl)-4-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one.

OVp । /=\ k o

5-(Benzyloxymethyl)-3-bromo-4-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one mixture (800 mg, 1.45 mmol ), phenylboronic acid (230 mg, 1.89 mmol), Pd ₁₁₈ (188 mg, 0.29 mmol) and K2CO3 (496 mg, 3.64 mmol) in 1,4-dioxane (6 ml) and H2O (0 .5 ml) was stirred at 100°C for 12 h under N2 atmosphere. The reaction mixture was then cooled to rt. and filtered. The filtrate was concentrated in vacuo and purified by flash silica gel column chromatography to give 5-(benzyloxymethyl)-4-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a] nirimidin-7(4H)-one (700 mg, 88% yield).

LC-MS: m/z 549.0 (M+H) ⁺ .

- 177 042905

Step F Compound 281 5-(hydroxymethyl)-4-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of 5-(benzyloxymethyl)-4-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one (700 mg, 1.28 mmol) in dry DCM (5 ml) was added dropwise BBr ₃ (1M in DCM, 2.56 ml, 2.56 mmol) at 0°C. After the addition, the mixture was stirred at rt. for 2 hours. The mixture was neutralized by carefully adding a mixture of ice-water, and was extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound.

¹ H-NMR (400 MHz, DMSO-d6): δ 8.97 (br. s., 1H), 8.42 (d, J=7.79 Hz, 1H), 8.10 (d, J= 8.87 Hz, 1H), 7.99 (d, J=1.88 Hz, 1H), 7.76 (dd, J=8.60, 1.88 Hz, 1H), 7.60 (dd, J=8.33, 4.03 Hz, 1H), 7.48 (s, 5H), 7.36-7.42 (m, 2H), 7.25-7.33 (m, 3H), 4 .37 (br. s., 2H), 3.49 (s, 3H).

LC-MS: m/z 459.0 (M+H) ⁺ .

Compound 282.

l ₂ /PPh ₃

Et ₃ N/MeCNK.T. stage A

SEM-CI _ k ₂ co ₃ dmfa /100°C stage D

NBS/DXM

TFA/DXM stage G

Step A. 3-iodocyclohex-2-enone.

O

Η ₂ Ν^

ΗΝ ₄

Pd(dppf)CI ₂ /KOAc O 1,4-dioxane/90°C ¹ 1,4-dioxane/AcOH/ load. with arr. cold

Pd (dppf) CI ₂ /Cs ₂ CO ₃ 1,4-dioxane / H ₂ 0 / load. with arr. cold

SEM

A mixture of PPh ₃ (25 g, 96.5 mmol) and I2 (24 g, 94.8 mmol) in acetonitrile (400 ml) was stirred at rt. over 2 hours. Et ₃ N (14.4 ml, 98.3 mmol) and cyclohexane-1,3-dione (10.0 g, 86.2 mmol) were then added. The mixture was stirred at rt. during the night. The mixture was concentrated in vacuo and the residue purified by chromatography to give the title compound 2 as a yellow solid (4.0 g, 21% yield).

LC-MS: m/z 222.9 (M+H) ⁺ .

Step B. 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone.

- 178 042905

A suspension of intermediate 2 (2.0 g, 9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2dioxaborolane) ( 4.6 g, 18 mmol), KOAc (2.7 g, 27 mmol) and Pd(dppf)Cl ₂ (0.6 g, 0.9 mmol) in 1,4-dioxane (50 ml) were stirred at 90 °C during the night. The mixture was filtered through Celite, the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to give the title compound 3 as a yellow solid (1.0 g, 50% yield).

LC-MS: m/z 223.1 (M+H) ⁺ .

Step C. 5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A suspension of methyl 3-oxo-2-(quinolin-6-yl)butanoate (2.0 g, 8.2 mmol) and 3-phenyl-1H-pyrazol-5amine (1.0 g, 6.3 mmol) in 1,4-dioxane (10 ml) and AcOH (2 ml) were heated at reflux for 16 hours under N2 protection. The mixture was cooled to rt, concentrated and neutralized with saturated NaHCO ₃ solution to pH 7. The precipitate was collected by filtration, washed with petroleum ether and dried to give the title compound 5 as a white solid (600 mg, 27% yield ).

1H-NMR (DMSOCH): δ 12.56 (br. s., 1H), 8.94 (dd, J=4.25, 1.61 Hz, 1H), 8.39 (d, J=7, 63 Hz, 1H), 7.99-8.10 (m, 3H), 7.96 (d, J=1.76 Hz, 1H), 7.75 (dd, J=8.66, 1.91 Hz, 1H), 7.57 (dd, J=8.36, 4.25 Hz, 1H), 7.46-7.53 (m, 2H), 7.40-7.46 (m, 1H) , 6.67 (s, 1H), 2.26 (s, 3H).

LC-MS: m/z 353.1 (M+H) ⁺ .

Step D. 5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

SEM

(2-(chloromethoxy)ethyl)trimethylsilane (473 mg , 2.84 mmol). The mixture was stirred for 10 min at ambient temperature and heated to 100° C. overnight. The mixture was cooled to rt, washed with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (2x30 ml). The combined organic layers were washed with brine (3x20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column eluting with DCM/MeOH (30/1 to 10/1) to give the title compound 6 as a white solid (350 mg, 51% yield).

LC-MS: m/z 483.1 (M+H) ⁺ .

Step E. 3-bromo-5-methyl-2-phenyl-6-(quinolin-6-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidine-7 (4H) -He.

SEM _Vg

CH AA o

To a solution of intermediate 6 (350 mg, 0.725 mmol) in DCM (5 ml) at ambient temperature was added N-bromosuccinimide (163 mg, 0.92 mmol). The resulting mixture was stirred for 3 hours at ambient temperature, washed with water and extracted with dichloromethane (20 ml). The combined organic layers were washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH=20/1) to give the title compound 7 as a yellow solid (250 mg, 61% yield).

LC-MS: m/z 561.1 (M+H) ⁺ .

Step F. 5-methyl-3-(3-oxocyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)-4-((2

- 179 042905 (trimethylsilyl)ethoxy)methyl)pyrazolo [ 1,5-a]pyrimidin-7 (4H)-one.

Suspension of intermediate 7 (600 mg, 1.1 mmol), 3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)cyclohex-2-enone (800 mg, 3.6 mmol ), Pd(dppf)Cl ₂ (80 mg, 0.1 mmol) and Cs ₂ CO ₃ (1.4 g, 4.3 mmol) in 1,4-dioxane/H ₂ O (30 ml/5 ml ) was heated at reflux for 4 hours. The mixture was cooled to rt. and filtered through Celite, the filtrate was diluted with water (10 ml) and extracted with ethyl acetate (3x30 ml). The extracts were washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (DCM/MeOH=20/1) to give the title compound 8 as a yellow solid (300 mg, 49% yield).

LC-MS: m/z 577.2 (M+H) ⁺ .

Step G. 5-methyl-3-(3-oxocyclohex-1-en-1-yl)-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one .

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 rt. during the night. The mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate (10 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3x5 ml). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC to give the title compound 9 as an orange solid (30 mg, 39% yield).

LC-MS: m/z 447.1 (M+H) ⁺ .

Step H. 3-(3-Hydroxycyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one .

To a solution of intermediate 9 (30 mg, 0.07 mmol) and cerium (III) heptrahydrate (43 mg, 0.1 mmol) in MeOH (3 ml) was added sodium borohydride (5 mg, 0.1 mmol). The mixture was stirred at rt. for 2 h and neutralized with water (H2O) (0.5 ml). The mixture was evaporated. The residue was dissolved in ethyl acetate (10 ml), washed with water and brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 10.

¹ H-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=7.2Hz, 1H), 7.38 (d, J=7.4Hz, 2H), 5.97 (d, J=2.4Hz, 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)+.

- 180 042905

Compound 283.

Step A. 5-((4-methoxybenzyl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimudin7(4H)-one.

A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine (synthesized according to the scheme for compound 101, 300 mg, 0.7 mmol) and (4- methoxyphenyl)methanamine (3 ml) was stirred at 180°C for 40 min in a microwave reactor. The mixture was cooled and immediately purified using a reverse phase column (MeOH/H ₂ O=0~50% 30 min, 50~50% 30 min, 50~100% 30 min) to give a crude product (600 mg) , which was used directly in the next step without further purification.

LC-MS: m/z 529.2 (M+H) ⁺ .

Step B. 5-amino-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

Solution of 5-((4-methoxybenzyl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo 1,5-a]pyrimidin7(4H)-one (600 mg, 1.07 mmol) in DCM (5 ml) and TFA (5 ml) were stirred at 60°C for 2 h. The mixture was concentrated, basified with an aqueous solution of Na ₂ CO ₃ to pH 8, and extracted with dichloromethane (10 ml×3). The organic layer was dried with anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified using a reverse phase column (MeOH/H ₂ O=0~100% 50 min) to give the title product 5-amino-6-(4-methoxyphenyl)2,3-diphenylpyrazolo[1,5- a]pyrimidin-7(4H)-one (480 mg, 80% purity) as a brown solid.

LC-MS: m/z 409.2 (M+H) ⁺ .

Step C. tert-butyl (2-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl)amino)-2- oxoethyl) carbamate.

To a solution of 5-amino-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg,

- 181 042905

0.245 mmol) in pyridine (3 ml) was added 2,5-dioxopyrrolidin-1-yl 2-((tert-butoxycarbonyl)amino)acetate (333 mg, 1.22 mmol) and DMAP (dimethylaminopyridine) (cat.). The mixture was stirred at 120° C. (microwave heating) for 45 minutes. The mixture was concentrated under vacuum to dryness. The residue was separated between HCl (1 M, 10 ml) and DCM (30 ml). The organic layer was dried with anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by preparative TLC (DCM/MeOH=50/1) to give the desired product tert-butyl (2-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[ 1,5-a]pyrimidin-5-yl)amino)-2oxoethyl)carbamate (20 mg, 14.5% yield) as a white solid.

LC-MS: m/z 565.2 (M+I)+.

Step D Compound 283 2-amino-N-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetamide.

O

HN /=4 o

Solution of tert-butyl-(2-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl)amino)-2-oxoethyl )carbamate (20 mg, 0.035 mmol) in 4 M HCl in 1,4-dioxane was stirred at rt. over 2 h. The mixture was concentrated to give 2-amino-N-(6-(4methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5 -ul)acetamide.

¹ H-NMR (DMSO-de): δ 7.61-7.42 (m, 5H), 7.42-7.25 (m, 9H), 7.00 (d, J=8.3 Hz, 2H), 3.82 (s, 3H), 3.62-3.59 (m, 2H).

LC-MS: m/z 466.0 (M+H) ⁺ .

Compound 285.

Step A. N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-5-yl)-5-methyl1,3,4-thiadiazol-2-amine .

A mixture of intermediate 1 (synthesized according to the scheme for compound 101, 200 mg, 0.45 mmol), 5-methyl-1,3,4-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 Cs ₂ CO ₃ (293 mg, 0.9 mmol, 2 equiv.) in 1,4-dioxane (3 mL) was heated at 100°C for 3 h under N2 atmosphere. The mixture was filtered through Celite, the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to give Intermediate 2 as a yellow solid (200 mg, 85% yield).

LC-MS: m/z 520.7 (M+H) ⁺ .

Step B Compound 285 6-(4-methoxyphenyl)-5-((5-methyl-1,3,4-thiadiazol-2-yl)amino)-2,3diphenylpyrazolo[1,5-a]pyrimidine-7 (4H)-he.

Solution of N-(7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]n-yrimidin-5-yl)-5-methyl1,3,4-thiadiazol-2-amine (180 mg, 0.346 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was stirred at rt. for 10 hours to give the title compound 3.

- 182 042905 ¹ H-NMR (DMSO-d ₆ ): δ 7.53 (br. s., 3H), 7.49-7.37 (m, 7H), 7.32 (d, J=8, 3 Hz, 3H), 7.06 (d, J=8.3 Hz, 2H),

3.83 (s, 3H), 2.55 (br. s., 3H).

LC-MS: m/z 507.2 (M+H) ⁺ .

Compound 286.

A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine (synthesized according to the scheme for compound 101, 200 mg, 0.45 mmol), t-butoxide potassium (50 mg, 0.45 mmol) in dioxane was stirred at 100° C. for 2 h. The mixture was concentrated to give a crude product (200 mg) which was used in the next step without further purification.

LC-MS: m/z 428.1 (M+H) ⁺ .

Step B Compound 286 5-((2-hydroxyethyl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

A mixture of 5-chloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.23 mmol) and 2-aminoethanol (3 ml) stirred at 170° C. for 4 h under microwave radiation in a sealed tube to give 5-((2-hydroxyethyl)amino)-6-(4methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a] pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 287.

Step A. Ethyl 3-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-α]pyrimidin-5yl)amino)-1 H-pyrazole -1 -carboxylate.

To a solution of 5-((1H-pyrazol-3-yl)amino)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-183 042905

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. After the mixture was stirred at 0° C. for 30 min, ethyl chloroformate (24 mg, 0.2 mmol) was added dropwise. The mixture was then stirred at rt. during the night. The mixture was poured into water (10 ml) and extracted with dichloromethane (3x5 ml), the combined organic phase was washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum, resulting in the desired product.

¹ H-NMR (DMSO-d6 and 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) ⁺ .

Compound 288.

Step E. 5-((benzyloxy)methyl)-3 -(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-4-methyl-2phenylpyrazolo[1,5-a]pyrimidine-7 ( 4H)-on.

Suspension of intermediate 5 (200 mg, 0.4 mmol, synthesized according to scheme 249), 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (94 mg, 0.5 mmol, 1.2 eq.), Pd ₁₁₈ (48 mg, 0.07 mmol, 0.2 eq.) and K ₂ CO ₃ (103 mg, 0.7 mmol, 2, 0 eq.) in 1,4-dioxane (5 ml) and H2O (0.3 ml) was stirred at 90°C for 4 h under N ₂ atmosphere. The reaction mixture was then cooled to rt. and filtered. The filtrate was concentrated in vacuo and purified by silica gel flash column chromatography (petroleum ether/ethyl acetate 2:1~1:2) to give intermediate 6 (39 mg, 20% yield).

LC-MS: m/z 532.0 (M+H)+.

Step F. 3-(cyclohex-1-en-1-yl)-5-(hydroxymethyl)-6-(4-methoxyphenyl)-4-methyl-2phenylpyrazolo[1,5-a]pyrimidin-7(4H)- He.

To a solution of intermediate 6 (29 mg, 0.05 mmol) in dry DCM (3 ml) was added dropwise BCl ₃ (1 mol/l in DCM, 0.5 ml) at 0°C. After the addition, the mixture was stirred at rt. within 3 hours the Mixture was neutralized with a mixture of ice water (3 ml) and was extracted with dichloromethane (3x5 ml). The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound 7.

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., 1H), 5.69 (t, J=4.8 Hz, 1H), 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)+.

- 184 042905

Compound 290.

To a solution of t-BuOK (7.4 g, 0.066 mol) in dimethyl carbonate (60 ml) was added dropwise methyl-2-(4methoxyphenyl)acetate (6 g, 0.033 mol) at 0°C. After the addition, the mixture was allowed to warm to rt. and stirred for 0.5 h. The mixture was then heated to 80° C. overnight. The suspension was diluted with ethyl acetate (200 ml), washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc/petroleum ether=1/10) to give the desired product (5.7 g, 0.024 mol, 72.7% yield).

¹ H-NMR (CDCl ₃ ): 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).

Step B. 5-Hydroxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-α]pyrimidin-7(4H)-one.

Mixture of 3,4-diphenyl-1H-pyrazole-5-amine (5.64 g, 0.024 mol) and dimethyl-2-(4-methoxyphenyl)malonate 2 (5.7 g, 0.024 mol) in xylene (350 ml) refluxed for 18 hours to give the title compound.

¹ H-NMR (DMSOCH): 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) ⁺ .

Compound 291.

Step A Compound 291 3-cyclohexenyl-1-(methoxymethyl)-6-(4-methoxyphenyl)-5-methyl-2phenylpyrazolo[1,5-α]pyrimidin-7(1H)-one.

3-cyclohexenyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one mixture (compound 212, 100 mg, 0.243 mmol), chloro(methoxy) methane (21.4 mg, 0.268 mmol) and Cs ₂ CO ₃ (159 mg, 0.486 mmol) in DMSO (5 ml) were stirred at rt. within 5 days. The mixture was poured into water (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine, dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound.

¹ H-NMR (400 MHz, DMSO-de): δ 7.54-7.64 (m, 5H), 7.21-7.27 (m, 2H), 6.99 (m, J=8, 85 Hz, 2H), 5.88 (br. s., 1H), 5.65 (s, 2H), 3.80 (s, 3H), 2.96 (s, 3H), 2.21 (s , 3H), 2.14 (br. s., 2H), 2.01-2.08 (m, 2H), 1.51-1.64 (m, 4H).

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LC-MS: m/z 456.1 (M+H)+.

Compound 292.

Step A. Ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)acetate.

Mixture of ethyl 2-(3-hydroxy-4-methoxyphenyl)acetate (4.3g, 20.5mmol), ((2-bromoethoxy)methyl)benzene (7.88g, 36.8mmol), potassium carbonate (5.66 g, 41 mmol) in X,X-dimethylformamide (50 ml) was heated to 80°C for 18 h. The mixture was cooled to rt, 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:petroleum ether=1:5) to give ethyl 2-(3-(2-(benzyloxy)ethoxy)-4methoxyphenyl)acetate (3.8 g, 54% yield) in the form of a colorless oil.

Step B. Ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate.

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 (2 N, 1 ml, 2 mmol) dropwise at -78°C under nitrogen. The mixture was stirred at the same temperature for 1 hour. Acetyl chloride (156 mg, 2 mmol) was slowly added to the mixture at -78°C. After the addition, the mixture was stirred at -78° C. for 1 hour and then heated slowly to rt. during the night. The mixture was neutralized by adding ammonium chloride to pH 6-7 and was 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 product was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:5) to give 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) ⁺ .

Step C. 6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

A mixture of ethyl 2-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-3-oxobutanoate (280 mg, 0.725 mmol) and 3,4-diphenyl-1H-pyrazole-5-amine (170 mg, 0.725 mmol) in acetic acid (5 ml) was heated under reflux for 2 h. The mixture was evaporated to remove acetic acid. The residue was purified by column chromatography (methanol:dichloromethane=1:20) to give 6-(3-(2(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5- a]pyrimidin-7(4H)-one (120 mg,

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30% yield) as a yellow solid.

LC-MS: m/z 558.2 (M+H) ⁺ .

Step D. 6-(3-(2-hydroxyethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin7(4H)-one.

To a solution of 6-(3-(2-(benzyloxy)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one (100 mg, 0.18 mmol) in DCM (10 ml) was added dropwise 1 M BBr ₃ (0.5 ml) in DCM at 0°C, after addition the mixture was stirred at rt. for 1 h. MeOH (5 ml) was added carefully to stop the reaction. The mixture was then evaporated and the residue was purified by preparative TLC (DCM/MeOH=100:10) to give 6-(3-(2-hydroxyethoxy)-4-methoxyphenyl)-5-methyl-2,3diphenylpyrazolo[1,5- a]pyrimidin-7(4H)-one (60 mg) as a white solid.

LC-MS: m/z 468.2 (M+H) ⁺ .

Step E. 2-(2-methoxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6yl)phenoxy)ethyl 4-methylbenzenesulfonate.

6-(3-(2-hydroxyethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin7(4H)-one mixture (200 mg, 0.427 mmol), TsCl (97 mg, 0.512 mmol), DMAP (dimethylaminopyridine) (52 mg, 0.427 mmol), Et ₃ N (130 mg, 1.281 mmol) in DCM (5 ml) was stirred at 50°C for 18 h. The mixture was neutralized by adding water and was extracted with dichloromethane (2x20 ml). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH=100:5) to give 2-(2-methoxy-5-(5-methyl7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5- a]pyrimidin-6-yl)phenoxy)ethyl 4-methylbenzenesulfonate (150 mg) as a white solid.

LC-MS: m/z 622.1 (M+H) ⁺ .

Step F. 6-(3-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Mixture

2-(2-methoxy-5-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6 yl)phenoxy)ethyl-4-methylbenzenesulfonate (150 mg, 0.241 mmol) and dimethylamine (30% in H2O, 1 ml) in THF (5 ml) in a sealed tube was stirred at 70°C overnight. The reaction mixture was cooled to rt. and evaporated under reduced pressure to give crude 6-(3-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidine-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) ⁺ .

Step G Compound 292 6-(3-(2-(dimethylamino)ethoxy)-4-hydroxyphenyl)-5-methyl-2,3diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

To a solution of 6-(3-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one (140 mg, 0.225 mmol) in DCM (4 ml) was added dropwise BBr ₃ (1 M in DCM, 1 ml). The mixture was then stirred at rt. for 2 h. The mixture was neutralized by adding MeOH

- 187 042905 and concentrated under reduced pressure, resulting in 6-(3-(2(dimethylamino)ethoxy)-4-hydroxyphenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidine-7 (4H)-he.

¹ H-NMR (400 MHz, CHLOROFORM-d): δ 7.38-7.62 (m, 10H), 7.17 (br. s., 1H), 7.02 (br. s., 2H) , 4.44 (br. s., 2H), 3.66 (br. s., 2H), 3.07 (s, 6H), 2.33 (s, 3H).

LC-MS: m/z 481.1 (M+H)+.

Compound 294.

Step A. (S)-chloromethyl-2-(tert-butoxycarbonylamino)-3-methylbutanoate.

ABOUT

BocHN.

About Cl

A mixture of (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (1 g, 4.6 mmol), chloromethyl sulfochloridate (912 mg, 5.53 mmol), NaHCO ₃ (1.54 g, 18.4 mmol ) in DCM (5 ml) and H2O (5 ml) were stirred at RT. during the night. Water (20 ml) was added. The mixture was extracted with dichloromethane (3x20 ml). The combined organic layers were washed with brine, dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (800 mg) as a colorless oil.

¹ H-NMR (400 MHz, CHLOROFORM-d): δ 5.90 (d, J=5.91 Hz, 1H), 5.64 (d, J=6.18 Hz, 1H), 5.00 ( d, J=8.06Hz, 1H), 4.29 (dd, J=8.87, 4.57Hz, 1H), 2.21 (dd, J=12.09, 6.45Hz, 1H ), 1.02 (d, J=6.98 Hz, 3H), 0.94 (d, J=6.98 Hz, 3H).

Step B. (S)-4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6yl)phenyl 2-(tert-butoxycarbonylamino) -3-methylbutanoate.

To a mixture of 3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)one (compound 240, 200 mg, 0.504 mmol), NaI (76 mg , 0.504 mmol), Cs ₂ CO ₃ (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 rt. for 1 h. Then the mixture was neutralized by adding water (20 ml) and was extracted with ethyl acetate (2x20 ml). The combined organic layers were concentrated. The residue was purified by silica gel column chromatography (elution using petroleum ether/ethyl acetate=2:1) to give the desired product (150 mg) as a white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.71 (s, 1H), 7.78 (d, J=7.25 Hz, 2H), 7.44-7.53 (m, 3H), 7.35-7.44 (m, 3H), 7.14 (d, J=8.33 Hz, 2H), 5.85 (br. s., 1H), 4.05-4, 11 (m, 1H), 2.25 (s, 3H), 2.19-2.23 (m, 3H), 2.06 (br. s., 2H), 1.71 (br. s., 4H), 1.44 (s, 9H), 1.03 (d, J=6.72 Hz, 6H).

LC-MS: m/z 597.2 (M+H) ⁺ .

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Step C Compound 294 3-methylbutanoate.

To a solution of (S)-4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin6-yl)phenyl-2-(tert-butoxycarbonylamino) -3-methylbutanoate (150 mg, 0.251 mmol) in DCM (5 ml) TFA (2 ml) was added. The mixture was then stirred at rt. for 2 hours and evaporated under reduced pressure to give the title compound.

¹ H-NMR (DMSO-d ₆ + TFA): δ 11.79 (s, 1H), 8.59 (br. s., 3H), 7.75-7.82 (m, 2H), 7, 39-7.51 (m, 5H), 7.23-7.29 (m, 2H), 5.86 (br. s., 1H), 4.29 (br. s., 1H), 2, 32-2.42 (m, 1H), 2.26 (s, 3H), 2.22 (br. s., 2H), 2.07 (br. s., 2H), 1.71 (br. s., 4H), 1.15 (d, J=6.98 Hz, 3H), 1.12 (d, J=6.98 Hz, 3H).

LC-MS: m/z 497.1 (M+H)+.

Compound 295.

To a solution of methyl 2-(4-methoxyphenyl)acetate (900 mg, 5.0 mmol)) in THF (15 ml) was slowly added LDA (lithium diisopropylamide) (2.5 ml, 2 mmol/ml in THF) at - 30°C. Then acetyl chloride (500 mg, 6.5 mmol) was added slowly. The reaction mixture was stirred for 30 min at -30°C and allowed to reach rt. for 1 h. The mixture was poured into water, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated, resulting in a crude product (800 mg) as a yellow liquid, which was used directly in the next step without further refinement. stitches.

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Step B. 3-cyclohexenyl-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

A solution of 4-(cyclohex-1-en-1-yl)-3-phenyl-1H-pyrazol-5-amine (200 mg, 0.84 mmol) and methyl 2-(4methoxyphenyl)-3-oxobutanoate (371, 5 mg, 1.67 mmol) in AcOH (5 ml) was stirred at 100° C. for 1 h. the solvent was removed under vacuum and saturated NaHCO ₃ was added until pH>7. The precipitate was filtered, washed with water (6 ml) and MeOH (0.5 ml) to give 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2- phenylpyrazolo[1,5-a]pyrimidin-7(4H)one (260 mg) as a white solid.

¹ H-NMR (DMSO-d ₆ ): 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)+.

Step C. 3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2-phenylpyrαzolo[1,5-a]pyrimidin-7(4H)-one.

To a solution of 3-cyclohexenyl-6-(4-methokCiphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (50 mg, 0.118 mmol) in CH ₂ Cl ₂ (1 ml) was slowly added BBr ₃ (3 ml, 1 mmol/ml in CH ₂ Cl ₂ ) at 0°C. The reaction mixture was then stirred overnight. The reaction was quenched with ice water at -10° C. and concentrated. The residue was purified by preparative HPLC to give the title compound (15 mg) as a white solid.

1H-NMR (DMSO-66): δ 7.76 (d, J=7.02 Hz, 2H), 7.30-7.52 (m, 3H), 7.09 (m, J=7.93 Hz, 2H), 6.82 (m, J=7.93 Hz, 2H), 5.83 (br. s., 1H), 2.21 (br. s., 3H), 2.18 (br s., 2H), 2.03 (br. s., 2H), 1.67 (br. s., 4H).

LC-MS: m/z 398.0 (M+H) ⁺ .

Step D. Dibenzyl 4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-6-yl)phenyl phosphate.

To a solution of 3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin7(4H)-one (40 mg, 0.1 mmol) in DMF (5 ml) was added dibenzylchloromethyl phosphate (50 mg, 0.15 mmol) in DMF (1 ml) and Cs ₂ CO ₃ (100 mg, 0.31 mmol) at RT The mixture was heated to 80°C and stirred overnight. The reaction mixture was cooled to rt, then poured into water (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with water (2x20 ml) and brine (20 ml) and then concentrated under reduced pressure. The residue was purified by preparative TLC eluting with 2:3 ethyl acetate/DCM to give the title compound (20 mg) as a white solid.

LC-MS: m/z 658.1 (M+H) ⁺ .

Step E. Compound 295 )phenyl dihydrogen phosphate.

To a solution of dibenzyl-4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-6-yl)phenyl phosphate (20 mg, 0.03 mmol) in MeOH (2 ml) was added with Pd/C (3 mg). The mixture was stirred at rt. under H ₂ atmosphere for 10 min and filtered. The filtrate was concentrated, in re

- 190 042905 whereby the title compound (12 mg) was obtained.

1H-NMR (400 MHz, DMSO-d6): δ 11.70 (br. s., 1H), 7.78 (d, J=7.25 Hz, 2H), 7.42-7.49 (m , 2H), 7.36-7.42 (m, 1H), 7.19 (br. s., 2H), 7.11 (d, J=8.06 Hz, 2H), 5.82 (br s., 1H), 2.21 (br. s., 5H), 2.08 (br. s., 2H), 1.69 (br. s., 4H).

LC-MS: m/z 477.9 (M+H)+.

Compound 296.

Step A. Di-t-butyl (4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-6-yl)phenoxy)methyl phosphate.

To a solution of 3-cyclohexenyl-6-(4-hydroxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin7(4H)-one (compound 240, 300 mg, 0.75 mmol) in DMF (10 ml) NaH (60% dispersion in mineral oil, 75.6 mg, 1.89 mmol) and TBAB (36 mg, 0.15 mmol) were added at 0°C for 5 min. Then di-tert-butylchloromethyl phosphate (250 mg, 1.13 mmol) in DMF (5 ml) was added. The mixture was heated to rt. and stirred for 2 hours. The reaction mixture was poured into water (20 ml), extracted with dichloromethane (3x20 ml). The combined organic layers were washed with water (2x20 ml) and brine (20 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:DCM=1:3) to give the title compound (120 mg) as a white solid.

¹ H-NMR (400 MHz, DMSO-d6): δ 11.66 (s, 1H), 7.77 (d, J=7.02 Hz, 2H), 7.44-7.50 (m, 2H ), 7.41 (d, J=7.32Hz, 1H), 7.29 (m, J=8.54Hz, 2H), 7.13 (m, J=8.54Hz, 2H), 5.84 (br. s., 1H), 5.67 (d, J=12.21 Hz, 2H), 2.22 (s, 5H), 2.06 (br. s., 2H), 1 .70 (br. s., 4H), 1.41 (s, 18H).

LC-MS: m/z 620.1 (M+H) ⁺ .

Step B Compound 296 (4-(3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-6-yl)phenoxy)methyl dihydrogen phosphate.

To a solution of di-tert-butyl (4- (3-cyclohexenyl-5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5a] pyrimidin-6-yl) phenoxy) methyl phosphate (110 mg, 0.177 mmol) in DCM (2 ml) was added TFA (1 ml). The mixture was stirred at rt. in an N2 atmosphere for 30 min. The reaction mixture was filtered. The filter cake was washed with ether and dried to give the title compound.

¹ H-NMR (400 MHz, DMSO-d6): δ 11.65 (s, 1H), 7.73-7.83 (m, 2H), 7.44-7.50 (m, 2H), 7 .38-7.44 (m, 1H), 7.25-7.31 (m, 2H), 7.14 (m, J=8.86 Hz, 2H), 5.85 (br. s., 1H), 5.62 (d, J=11.28 Hz, 2H), 2.24 (s, 3H), 2.22 (br. s., 2H), 2.06 (br. s., 2H ), 1.71 (br. s., 4H).

LC-MS: m/z 508.2 (M+H) ⁺ .

Compound 297.

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Stage A ₁ . 5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidine.

A solution of 3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one (synthesized according to the scheme for compound 279 , 47.0 g, 104 mmol) in phosphorus oxychloride (100 ml) was stirred at reflux for 16 h. The solvent was removed under vacuum. The residue was slowly added 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-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1 ,5a]pyrimidine (50 g) as a yellow solid.

¹ H-NMR (DMSO-d6): δ 1.70 (d, J=4.57 Hz, 4H), 2.20 (br. s., 4H), 3.84 (s, 4H), 5, 87 (br. s., 1H), 7.10 (d, J=8.60 Hz, 2H), 7.36-7.56 (m, 5H) 7.82 (d, J=7.25 Hz , 2H).

LC-MS: m/z 450.2 (M+H) ⁺ .

Stage B1. 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidine.

To a solution of 5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidine (40 g, 88 mmol) in dichloromethane ( 400 ml) at 0°C was added dropwise sodium methoxide (30% in methanol, 80 g). The resulting 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 with anhydrous sodium sulfate and concentrated in vacuo. The residue was suspended in MeOH (50 ml). The precipitates were collected by filtration, washed with methanol (MeOH) and dried under reduced pressure to give 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)- 2-phenylpyrazolo[1,5a]pyrimidine (36 g) as a yellow solid.

¹ H-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) ⁺ .

Step A. 3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(pyridin-4yl)pyrazolo[1,5-a]pyrimidine- 5-amine.

A mixture of 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidine (300 mg, 0.68 mmol), pyridine-4-amine (70 mg, 0.75 mmol), palladium diacetate (15 mg, 0.068 mmol), Xantphos (79 mg, 0.136 mmol) and Cs ₂ CO ₃ (443 mg, 1.36 mmol) in 1, 4-dioxane (20 ml) was heated at 110° C. for 2 h under nitrogen with microwave radiation. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to give title product 2 (40 mg, 11.7% yield) as a light yellow solid.

LC-MS: m/z 504.2 (M+H) ⁺ .

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Step B Compound 297 (4H)-he.

A solution of 3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenyl-N-(niridin-4yl)pyrazolo[1,5-d]pyrimidine-5- amine (40 mg, 0.0.8 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at rt. within 2 hours the Mixture was concentrated at low temperature (<25°C) was added saturated NaHCO ₃ (8 ml). The precipitate was filtered. The filter cake was suspended in DCM/MeOH (14 ml, 1:6), filtered and washed with methanol (MeOH) (2 ml) to give 3-(cyclohex-1-en1-yl)-6-(4- methoxyphenyl)-2-phenyl-5-(pyridin-4-ylamino)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹ H-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., 1H), 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)+.

Compound 298.

Step A. Isobutyl-2-cyclopropyl acetate.

A mixture of 2-cyclopropylacetic acid (1 g, 10 mmol), 1-iodo-2-methylpropane (1.65 g, 12 mmol) and Cs ₂ CO ₃ (6.5 g, 20 mmol) in DMF (50 ml) was stirred at 80°C for 16 hours the Mixture was slowly poured into saturated NH ₄ Cl and was extracted with ethyl acetate (3x100 ml). The combined organic phase was washed with brine, dried with anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the title ethyl isobutyl-2-cyclopropyl acetate (500 mg) as a colorless oil.

1H-NMR (400 MHz, DMSO-d ₆ ): δ 3.82 (d, J=6.72 Hz, 2H), 2.23 (d, J=6.98 Hz, 2H), 1.81- 1.93 (m, 1H), 0.92-1.02 (m, 1H), 0.89 (d, J=6.72 Hz, 6H), 0.43-0.51 (m, 2H) , 0.11-0.17(m, 2H).

Step B. Isobutyl 2-cyclopropyl-3-oxobutanoate.

To a solution of 2-cyclopropyl acetate (500 mg, 3.2 mmol) in THF (10 ml) was added LDA (lithium diisopropylamide) (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. The mixture was then stirred at rt. within 4 hours the Mixture was slowly poured into saturated NH ₄ Cl and was extracted with ethyl acetate (3x20 ml). The combined organic phase was washed with brine, dried with anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the desired isobutyl 2-cyclopropyl-3-oxobutanoate (380 mg) as a brown oil.

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Step C Compound 298 6-cyclopropyl-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Mixture of 2-cyclopropyl-3-oxobutanoate (327 mg, 1.65 mmol) and 3-phenyl-4-(n-piperidin-1-yl)-1Hpyrazol-5-amine (200 mg, 0.825 mmol) in dioxane (5 ml) and water (1 ml) were stirred at 115°C under microwave radiation for 2 hours. The solvent was removed under reduced pressure, resulting in 6-cyclopropyl-5-methyl-2-phenyl-3-(piperidin-1-yl )pyrazolo[1,5-a]pyrimidine7(4H)-one.

¹ H-NMR (400 MHz, DMSO-4 ₆ ): δ 11.13 (br. s., 1H), 8.10 (d, J=7.25 Hz, 2H), 7.41-7.48 (m, 2H), 7.37 (d, J=7.25 Hz, 1H), 3.00-3.11 (m, 4H), 2.50 (s, 3H), 1.63 (br. s., 4H), 1.56 (br. s., 2H), 1.42-1.50 (m, 1H), 0.80-0.89 (m, 2H), 0.57-0, 67(m, 2H).

LC-MS: m/z 349.6 (M+H) ⁺ .

Compound 299.

Suspension of 3-phenyl-4-(piperidin-1-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 heated at reflux for 30 min under a protective atmosphere of N2. The mixture was cooled to RT, concentrated and neutralized with saturated sodium hydrogen carbonate solution to pH 7, resulting in the desired product.

¹ H-NMR (DMSO-d6): δ 11.40 (s, 1H), 8.12 (t, J=4.0 Hz, 2H), 7.49-7.31 (m, 8H), 3 .08 (br. s., 4H), 2.26 (s, 3H), 1.67-1.50 (m, 6H).

LC-MS: m/z 485.2(M+H)+.

Connection 300.

Step A. Isobutyl-2-cyclopentyl acetate.

A mixture of 2-cyclopentylacetic acid (1 g, 7.8 mmol), 1-iodo-2-methylpropane (1.7 g, 9.36 mmol) and Cs ₂ CO ₃ (5.1 g, 15.6 mmol) in DMF (40 ml) was stirred at 80° C. for 16 h. The mixture was slowly poured into saturated NH ₄ Cl and extracted with ethyl acetate (3x100 ml). The combined organic phase was washed with brine, dried with anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the desired isobutyl-2-cyclopentyl acetate (988 mg) as a colorless oil.

Step B. Isobutyl 2-cyclopentyl-3-oxobutanoate.

To a solution of 2-cyclopropyl acetate (988 mg, 6.33 mmol) in THF (10 ml) was added LDA (lithium diisopropylamide) (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. The mixture was then stirred at rt. within 4 hours the Mixture was slowly poured into saturated NH ₄ Cl and was extracted with ethyl acetate (3x20 ml). The combined organic phase was washed with brine, dried with anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the desired isobutyl 2-cyclopentyl-3-oxobutanoate (700 mg) as a colorless oil.

Step C Compound 300 6-cyclopentyl-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

2-cyclopentyl-3-oxobutanoate (467 mg, 2.06 mmol) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (250 mg, 1.03 mmol) were dissolved in AcOH (10 ml). The mixture was heated to 95° C. for 4 hours. After cooling to rt. the solids were collected by filtration and washed with ethyl acetate to give 6-cyclopentyl-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one ( 120 mg).

1H-NMR (400 MHz, DMSO-d ₆ ): δ 10.98 (br. s., 1H), 8.06-8.17 (m, 2H), 7.43-7.49 (m, 2H ), 7.36-7.41 (m, 1H), 3.03-3.07 (m, 4H), 2.46 (s, 3H), 1.92-2.05 (m, 3H), 1.84 (br. s., 2H), 1.54-1.74 (m, 10H).

LC-MS: m/z 377.6 (M+H) ⁺ .

Connection 301.

Step A. 6-(3-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyr imidine-7(4H)-oh.

To a solution of 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7(4H) -one (synthesized according to the scheme for compound 305, 100 mg, 0.194 mmol) and (3-aminophenyl)boronic acid (53 mg, 0.386 mmol) in dioxane/H ₂ O (5 ml/1 ml) were added complex 1.1 '-bis(diphenylphosphino)ferrocene-palladium(II) dichloride with dichloromethane (28 mg, 0.0344 mmol) and sodium carbonate (42 mg, 0.396 mmol). The reaction mixture was then heated under reflux under nitrogen atmosphere overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol:dichloromethane=1/20) to give 5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3(piperidin-1-yl)-4-(( 2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (35 mg, 34.3% yield) as a white solid.

LC-MS: m/z 530.1 (m+H) ⁺ .

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Step B Compound 301 6-(3-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

^H 2 ^N / ^N - V / o

A mixture of 6-(3-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7 (4H)-one (35 mg, 0.1 mmol) in CF3COOH (2 mL) was heated to 60°C for 3 h. The mixture was cooled to rt. and concentrated in vacuo to give 6-(3-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)one.

1H-NMR (DMSO-0 ₆ ): δ 11.33 (br. s., 1H), 8.12 (d, J=7.25 Hz, 2H), 7.44-7.50 (m, 2H ), 7.41 (d, J=7.25Hz, 1H), 7.06 (t, J=7.66Hz, 1H), 6.55 (d, J=8.60Hz, 1H), 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)+.

Connection 302.

Step A. Ethyl 2-morpholino-3-oxobutanoate.

Oh Oh

To a solution of morpholine (0.95 g, 27 mmol) in CH3CN (20 ml) and K2CO3 (3.01 g, 54 mmol) was added dropwise ethyl 2-chloro-3-oxobutanoate (2 g, 27 mmol) over 2 hours After the addition, the mixture was concentrated and purified by silica gel chromatography (petroleum ether/ethyl acetate=5/1) to give ethyl 2-morpholino-3-oxobutanoate (1.5 g).

LC-MS: m/z 216.3 (M+H) ⁺ .

Step B Compound 302 5-methyl-6-morpholino-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

A solution of methyl ethyl 2-morpholino-3-oxobutanoate (500 mg, 2.3 mmol), 3-phenyl-4-(piperidin-1yl)-1H-pyrazol-5-amine (565 mg, 2.3 mmol) in AcOH (20 ml) and xylene (20 ml) were heated to 140° C. for 16 h. The reaction mixture was concentrated to give 5-methyl-6-morpholino-2-phenyl-3-(piperidin-1-yl)-pyrazolo [ 1,5-a]pyrimidin-7(4H)-one.

1 H-NMR (DMSO-d ₆ ): δ 7.97 (br. s., 2H), 7.43 (d, J=6.7 Hz, 2H), 3.87 (br. s., 2H) , 3.81 (br. s., 2H), 3.74 (br. s., 2H), 3.00 (br. s., 4H), 2.54 (s, 5H), 1.68 ( br. s., 4H), 1.54 (br. s., 2H).

LC-MS: m/z 394.3 (M+H)+.

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Connection 303.

Step A. 6-(2-methoxypyridin-4-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5 -a]pyrimidine-7(4H)-one.

Suspension of 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7(4H)- she (synthesized according to the scheme for compound 305, 200 mg, 0.39 mmol) and 2-methoxypyridin-4-ylboronic acid (178 mg, 1.16 mmol), PdCl ₂ (dppf) (28 mg, 0.04 mmol) and Na ₂ CO ₃ (82 mg, 0.78 mmol) in a mixture of 1,4-dioxane/water (10/1 ml) was stirred and heated to 85°C for 16 h under N ₂ atmosphere. The reaction mixture was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1) to give the title product (40 mg, 18% yield) as a white solid.

LC-MS: m/z 546.3 (M+I)+.

Step B. 5-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenyl-3-(piperidin-1-yl)pyrazolo [1,5-

a] pyrimidin-7(4H)-one.

A mixture of 6-(2-methoxypyridin-4-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a ]pyrimidin-7(4H)-one (40 mg, 0.07 mmol) and HCl in MeOH (0.5 mol, 1 ml, 0.5 mmol) were stirred at room temperature. for 1 h. The mixture was then concentrated to dryness. The residue was dissolved in concentrated hydrochloric acid (10 ml) and stirred at 100° C. for 72 hours. The reaction mixture was concentrated to give the expected product.

¹ H-NMR (DMSO-de): δ 11.20 (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)+.

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Connection 304.

stage D

Step A. 5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

ABOUT

A mixture of ethyl 3-oxobutanoate (18.7 g, 0.143 mol) and 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine (synthesized according to scheme 305, 17.5 g, 0.072 mmol) in AcOH (100 ml) was stirred at 95°C for 4 h. the solids were collected by filtration, washed with ethyl acetate and dried in vacuo to give 5-methyl-2-phenyl-3-(piperidin-1yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (15 g , 68% yield) as a white solid.

LC-MS: m/z 309.1 (M+H) ⁺ .

Step B. 5-methyl-2-phenyl-3-(piperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(1H)-one.

To a solution of 5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (synthesized according to the scheme of compound 305, 6.5 g, 21.1 mmol) in dry DMF (50 ml) was added portionwise with NaH (60% dispersion in mineral oil, 1.7 g, 42.5 mmol) at 0°C. After the addition, the mixture was stirred at 0° C. for 1 h. SEM-Cl (5.3 g, 31.7 mmol) was then added and the mixture was heated to rt. and stirred overnight. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (3x200 ml). The combined organic layers were washed with water (2x300 ml) and brine (300 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=2:1) to give the title compound (3.8 g, 41% yield) as a white solid.

LC-MS: m/z 439.1 (M+H) ⁺ .

Step C. 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidine-7 (1 H )-He.

To a solution of 5-methyl-2-phenyl-3-(piperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(1H)-one (3, 4 g, 7.76 mmol) in DCM (30 ml) were added BSI (1.3 g, 7.76 mmol) and Et ₃ N (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), the aqueous layer was extracted with dichloromethane (30 ml). The combined organic layers were washed with brine (30 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on

- 198 042905 silica gel (ethyl acetate:petroleum ether = 2:1) to obtain the title compound (3.1 g,

78% yield) as a white solid.

LC-MS: m/z 517.2 (M+H) ⁺ .

Step D. 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(pyridin-4-yl)-1-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a ]pyrimidin-7(1H)-one.

6-Bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(1H)-one mixture (100 mg, 0.19 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (59 mg, 0.288 mmol), Pd(dppf)Cl ₂ (21 mg, 0.029 mmol) and Na ₂ CO ₃ (41 mg, 0.386 mmol) in 1,4-dioxane (5 ml) and H 2 O (0.5 ml) were stirred at 100°C for 2 h under N 2 atmosphere. The reaction mixture was then cooled to rt. and filtered. The filtrate was concentrated in vacuo and purified by preparative TLC to give 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(pyridin-4-yl)-1-((2(m-rimethylsilyl)ethoxy )methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one (50 mg) as a white solid.

LC-MS: m/z 516.0 (M+H) ⁺ .

Step E Compound 304 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(pyridin-4-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(pyridin-4-yl)-1-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a] pyrimidin-7(1H)-oneα (50 mg, 0.097 mmol) in DCM (3 ml) TFA (1 ml) was added. The mixture was stirred at ambient temperature for 2 hours. The mixture was then concentrated to dryness. The residue was stirred with saturated sodium hydrogen carbonate solution to give the title compound.

¹ H-NMR (400 MHz, DMSO-b6): δ 8.50 (br. s., 2H), 8.26 (d, J=7.25 Hz, 2H), 7.39-7.45 ( m, 2H), 7.35-7.38 (m, 2H), 7.28-7.34 (m, 1H), 3.18 (br. s., 4H), 2.22 (s, 3H ), 1.61-1.66 (m, 4H), 1.52-1.57 (m, 2H).

LC-MS: m/z 386.1 (m+H) ⁺ .

Connection 305.

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Step A. 3-oxo-3-phenyl-2-(piperidin-1-yl)propanenitrile.

NaHMDS (2 M in THF, 46 ml, 1 .2 equiv.) at 0°C. The mixture was stirred at rt. during the night. The reaction mixture was diluted with ethyl acetate (300 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated, washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography to give the title 3-oxo-3-phenyl-2-(piperidin-1-yl)propanenitrile as a white solid.

LC-MS: m/z 229.1 (M+H) ⁺ .

Step B. 3-phenyl-4-(piperidin-1-yl)-1H-pyrazol-5-amine.

Mixture of 3-oxo-3-phenyl-2-(piperidin-1-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 heated under reflux for 16 h. The mixture was then cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (50 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (petroleum ether/ethyl acetate=1/3) to give 3-phenyl-4-(piperidin-1-yl)-1Hpyrazol-5-amine (2.2 g) as white solid.

¹ H-NMR (DMSO-d ₆ ): δ 11.52 (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) ⁺ .

Step C. 5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of 3-phenyl-4-(piperidin-1-yl)-1H-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 under reflux for 2 hours. The mixture was cooled to rt. The suspension was filtered. The resulting solid was washed with water and cold methanol to give 5-methyl-2-phenyl-3-(piperidin-1yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (7.9 g, 74% yield) as a white solid.

LC-MS: m/z 309.2 (M+H) ⁺ .

Step D. 5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

To a mixture of 5-methyl-2-phenyl-3-(piperidin-1-yl)-pyrazolo[1,5-a]pyrimidin-7(4H)-one (5.5 g, 17.9 mmol) in N,N -dimethylformamide (50 ml) was slowly added sodium hydride (1.4 g, 35.8 mmol) at 0°C. After the addition, the mixture was stirred at 0° C. for 1 hour. (2-(Chloromethoxy)ethyl)trimethylsilane (3.6 g, 21.7 mmol) was added. The resulting mixture was stirred at rt. during the night. The mixture was neutralized with brine and extracted with ethyl acetate (50 ml) three times. The combined organic phase was washed with brine, dried with anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by column chromatography (methanol:dichloromethane=1:20) to give 5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[ 1,5-a]pyrimidin-7(4H)-one (2.5 g, 35% yield) as a white solid.

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LC-MS: m/z 439.2 (M+H)+.

Step E. 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidine-7 (4H) -He.

To a mixture of 5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)-methyl)pyrazolo[1,5a]pyrimidin-7(4H)-one (1 .2 g, 2.74 mmol) and triethylamine (0.32 g, 3.16 mmol) in dichloromethane (20 ml) at r.t. N-bromosuccinimide (0.58 g, 3.47 mmol) was added at rt. The mixture was then stirred at rt. within 2 hours the Mixture was concentrated. The residue was purified by column chromatography (methanol:dichloromethane=1:20) to give 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) ⁺ .

Step F. 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7dihydropyrazolo [1,5- a] pyrimidin-6-yl)benzamide.

To a solution of 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7(4H) -one (100 mg, 0.194 mmol) and (4-carbamoylphenyl)boronic acid (48.3 mg, 0.293 mmol) in dioxane/H ₂ O (5 mL/1 mL) was added 1,1'-bis(diphenylphosphino ) ferrocene-palladium (II) dichloride - dichloromethane (28 mg, 0.0344 mmol) and sodium carbonate (42 mg, 0.396 mmol). The reaction mixture was then heated under reflux under nitrogen atmosphere overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol:dichloromethane=1/20) to give 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-( trimethylsilyl)ethoxy)methyl)-4,7dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzamide (60 mg, 55% yield) as a white solid.

LC-MS: m/z 558.3 (M+H) ⁺ .

Step G Compound 305 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5a]pyrimidin-6-yl)beschamide.

A mixture of 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7dihydropyrazolo[1,5-a] pyrimidin-6-yl)benzamide (60 mg, 0.11 mmol) in CF3COOH (2 mL) was heated to 60°C for 3 h. The mixture was cooled to rt. and concentrated in vacuo to remove the solvent. The resulting residue was washed with saturated aqueous sodium bicarbonate to give 6-(4-hydroxyphenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine 7(4H) -He.

1 H-NMR (DMSO-dg): 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) ⁺ .

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Connection 306.

Step A. 5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5- a]pyrimidine-7(4H)-one.

To a solution of 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7(4H) -one (synthesized according to the scheme for compound 305, 100 mg, 0.194 mmol) and (4-(methylsulfonyl)phenyl)boronic acid (78 mg, 0.386 mmol) in dioxane/H ₂ O (5/1 ml) was added complex 1 ,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride - dichloromethane (28 mg, 0.0344 mmol) and sodium carbonate (42 mg, 0.396 mmol). The reaction mixture was then heated at reflux under nitrogen atmosphere overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (methanol:dichloromethane=1/20) to give 5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3(piperidin-1-yl)-4-(( 2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (60 mg, 52.6% yield) as a white solid.

LC-MS: m/z 593.3 (M+H) ⁺ .

Step B Compound 306 5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-1yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

5-Methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a] mixture 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 rt. and concentrated in vacuo to remove the solvent. The resulting residue was washed with saturated aqueous sodium bicarbonate to give 5-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidine-7 (4H)-he.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

Connection 307.

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Step A. 6-(4-aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine -7(4H)-one.

Suspension of 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7(4H)- she (synthesized according to the scheme for compound 305, 100 mg, 0.19 mmol), 4-aminophenylboronic acid as hydrochloric acid salt (60 mg, 0.58 mmol), PdCl ₂ (dppf) (8.4 mg, 0. 02 mmol) and Na ₂ CO ₃ (55 mg, 0.78 mmol) in 1,4-dioxane/water (10 ml/1 ml) were stirred and heated to 85°C for 16 h under N2 atmosphere. The reaction mixture was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1) to give the title product (30 mg, 29% yield) as a white solid.

LC-MS: m/z 530.3 (M+H) ⁺ .

Step B. 6-(4-Aminophenyl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]nirimidin-7(4H)-one.

A mixture of tert-butyl 4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)4,7-dihydropyrazolo[1, 5-a]pyrimidin-6-yl)-1H-pyrazole-1-carboxylate (40 mg, 0.07 mmol) and HCl in MeOH (0.5 mol, 10 ml, 5 mmol) were stirred at rt. within 1 h. The mixture was concentrated, resulting in the desired product.

1H-NMR (DMSO-d4): δ 11.27 (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) ⁺ .

Connection 308.

Step A. N-(4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7dihydropyrazolo [1 ,5-a] pyrimidin-6-yl)phenyl)acetamide.

Suspension of 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7(4H)- she (synthesized according to the scheme for compound 305, 100 mg, 0.19 mmol) and 4-acetamidophenylboronic acid (100 mg, 0.58 mmol), PdCl ₂ (dppf) (8.4 mg, 0.02 mmol) and Na ₂ CO ₃ (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 N ₂ atmosphere. The reaction mixture was then cooled to RT and filtered. The dark filtrate was concentrated in vacuo. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1) to give the title product (20 mg, 18% yield) as a white solid.

LC-MS: m/z 572.3 (M+H) ⁺ .

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Step B. N-(4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin6-yl)phenyl)acetamide .

A mixture of N-(4-(5-methyl-7-oxo-2-phenyl-3-(piperidin-1-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4,7dihydropyrazolo[1,5 -a]pyrimidin-6-yl)phenyl)acetamide (20 mg, 0.03 mmol) and HCl in MeOH (0.5 mol, 10 ml, 5 mmol) were stirred at room temperature. for 1 h, whereby the target product was obtained.

¹ H-NMR (DMSOCH): δ 11.35 (br. s., 1H), 10.02 (br. s., 1H), 8.12 (d, J=7.2 Hz, 2H), 7 .62 (d, J=7.2Hz, 2H), 7.47 (d, J=7.2Hz, 1H), 7.40 (t, J=7.2Hz, 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)+. Connection 309.

Step A. 6-(6-hydroxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one mixture (compound 358, 40 mg , 0.10 mmol) in conc. hydrochloric acid (10 ml) was stirred at 100° C. for 48 hours to give the expected product.

1 H-NMR (DMSO-d6): 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) ⁺ .

Connection 310.

Step A. Ethyl 3-oxo-2-(thiazol-4-yl)butanoate.

To a solution of ethyl 2-(thiazol-4-yl)acetate (500 mg, 2.92 mmol) in THF (10 ml) was added LDA (lithium diisopropylamide) (1.5 M in THF, 2.3 ml, 3.5 mmol) 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. The mixture was then heated to rt. and stirred for 6 h. The mixture was poured into saturated NH ₄ Cl and extracted with ethyl acetate (3x10 ml). The combined organic phase was washed with brine, dried with anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the desired ethyl 3-oxo-2-(thiazol-4-yl)butanoate as a brown oil (500 mg, 80% yield).

Step B Compound 310 5-methyl-2-phenyl-3-(piperidin-1-yl)-6-(thiazol-4-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

A mixture of 3-oxo-2-(thiazol-4-yl)butanoate (200 mg, 0.94 mmol) and 3-phenyl-4-(piperidin-1-yl)-1Hpyrazol-5-amine (227 mg, 0.94 mmol) 94 mmol) in AcOH (5 mL) was stirred at 95° C. for 2 h to give the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.52 (br. s., 1H), 9.17 (d, J=1.88 Hz, 1H), 8.13 (d, 7 =6.98Hz, 2H), 7.82(d, 7=1.88Hz, 1H), 7.45-7.51(m, 2H), 7.37-7.44(m, 1H) , 3.08-3.11 (m, 4H), 2.42 (s, 3H), 1.67 (br. s., 4H), 1.56-1.61 (m, 2H).

LC-MS: m/z 392.3 (M+H)+.

Connection 311.

H

Step A. Ethyl 2-(4-hydroxypiperidin-1-yl)-3-oxobutanoate.

Ethyl 2-chloro-3-oxobutanoate (442 mg , 2.4 mmol) at 0°C. The mixture was stirred at 40° C. for 18 hours. The mixture was concentrated and purified by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1) to give the title product as a yellow solid (120 mg, 26% exit).

LC-MS: m/z 230.2 (M+H)+.

Step B. 6-(4-hydroxypiperidin-1-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

A mixture of 3,4-diphenyl-1H-pyrazol-5-amine (116 mg, 0.66 mmol) and ethyl 2-(4-hydroxypiperidin-1-yl)3-oxobutanoate (120 mg, 0.66 mmol) in AcOH (5 ml) was stirred at 100° C. for 1 hour. After removal of AcOH, 10% NaHCO ₃ was added to give the expected product.

1H-NMR (DMSO-d ₆ ): δ 11.16 (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, 6H), 1.21 (br. s ., 2H).

LC-MS: m/z 408.6 (M+H)+.

Connection 312.

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Step A. Methyl 2-(4-methoxyphenyl)-3-oxopentanoate.

To a solution of methyl 2-(4-methoxyphenyl)-3-oxopentanoate (2.0 g, 11.10 mmol) in THF (20 ml) was added LDA (lithium diisopropylamide) (2.0 M in THF, 6 .6 ml, 13.32 mmol) 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. The mixture was then slowly heated to RT and stirred for 10 min. The mixture was slowly poured into saturated aq. NH ₄ Cl and extracted with ethyl acetate (30 ml x 3) The combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated in vacuo to give the title product as a yellow oil (4.0 g, crude) which was used directly on next step without further purification.

LC-MS: m/z 237.2 (M+H) ⁺ .

Step B. 5-ethyl-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

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) stirred at 100° C. for 1 h. After removal of AcOH, 10% NaHCO ₃ was added, resulting in the desired product.

1H-NMR (DMSO): 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=7.2 Hz, 3H).

LC-MS: m/z 422.7 (M+H) ⁺ .

Connection 313.

Step A. 2-(6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5yl)acetonitrile.

Solution of 5-(chloromethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]-pyrimidin-7(4H)-one (synthesized according to the scheme for compound 340, 230 mg, 0.52 mmol ), TMSCN (77.4 mg, 0.78 mmol) and Cs ₂ CO ₃ (338.8 mg, 1.04 mmol) in acetonitrile (30 ml) were stirred at reflux for 8 h. Then the reaction mixture cooled to RT and filtered. The dark filtrate was concentrated in vacuo to give the title product as a brown solid.

¹ H-NMR (DMSO-d ₆ ): δ 7.55 (m, 4H), 7.37 (dd, J=6.0 Hz, 7.2 Hz, 3H), 7.27-7.20 ( m, 4H), 7.11 (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)+.

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Connection 314.

6-(4-Methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrαzolo[1,5-a]pyrimidine-5A.

stage carbaldehyde.

Mixture

-(hydroxymethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (900 mg, 2.12 mmol) and PCC (synthesized according to scheme 338 , 688 mg, 3.18 mmol) in DCM (100 mL) was stirred at rt. during the night. The mixture was filtered, washed with dichloromethane and concentrated in vacuo to give the desired product as a yellow solid (900 mg, 100%).

LC-MS: m/z 422.2 (M+H) ⁺ .

Step B. (E)-6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5carbaldehyde oxime.

Solution

6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-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/H ₂ O (90 ml/10 ml) were stirred at rt. during the night. The reaction mixture was concentrated in vacuo and purified by flash column chromatography eluting with DCM/MeOH (30/1) to give the title product as a yellow solid (330 mg, 32% yield).

LC-MS: m/z 437.2 (M+I)+.

Step C. 6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5carbonitrile.

Solution of (E)-6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carbaldehyde oxime (150 mg, 0.34 mmol) in Thionyl chloride (0.2 ml, 3.44 mmol) was added dropwise with DCM (10 ml) at rt. for 3 hours. The reaction mixture was diluted with dichloromethane, washed with saturated NaHCO ₃ and extracted with dichloromethane (30 mlx3). The combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated to give the desired product.

- 207 042905

1H-NMR (DMSO-d6): 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)+.

Connection 315.

2

Step A. 6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5carboxamide.

Solution of 6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-5carbonitrile (compound 314, 40 mg, 0.10 mmol) in MeOH (10 ml) hydrogen peroxide (30%, 32.5 mg, 0.96 mmol) and sodium hydroxide (1N, 38.4 mg, 0.96 mmol) were added. The resulting mixture was stirred at 40° C. for 1 hour. Saturated sodium sulfite was added to give the expected product.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

Connection 316.

Step A. 3-(3,3-difluoropyrrolidin-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

Mixture of methyl 3-oxo-2-(quinolin-6-yl)butanoate (184 mg, 0.76 mmol) and 4-(3,3-difluoropyrrolidin-1yl)-3-phenyl-1H-pyrazole-5-amine (200 mg, 0.76 mmol, synthesized according to scheme 272) in AcOH (50 ml) was stirred at 100° C. for 1 h to give the title compound 2.

1H-NMR (DMSO-06): δ 11.99 (s, 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H), 8.29-8.44 (m, 1H ), 8.07 (d, J=8.8Hz, 1H), 7.99 (dd, J=8.2, 1.2Hz, 2H), 7.94 (d, J=1.8Hz , 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) ⁺ .

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Connection 317.

Cl

AsOH/100 C h ₂ n

Step A. Methyl 2-(6-nitropyridin-3-yl)-3-oxobutanoate.

stage

Pd/C

Meon stage C

G,

To a solution of 5-chloro-2-nitropyridine (3.2 mmol) in DMSO (20 methyl-3 ml) was added oxobutanoate (3.5 g, 30 mmol) and K2CO3 (5.5 g, 40 mmol). The mixture was stirred at 110° C. for 8 h. The mixture was cooled to rt, poured into H2O (60 ml) and extracted with ethyl acetate (3x50 ml). The extract was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography to give the title compound 2 as a yellow solid (470 mg, 10% yield).

LC-MS: m/z 239.0 (M+H) ⁺ .

Step B. 3-(3,3-Difluoropyrrolidin-1-yl)-5-methyl-6-(6-nitropyridin-3-yl)-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Mixture of intermediate 2 (470 mg, 2.0 mmol) and 4-(3,3-difluoropyrrolidin-1-yl)-3phenyl-1H-pyrazol-5-amine (521 mg, 2.0 mmol, synthesized according to the scheme 272) in AcOH (8 ml) was stirred at 100°C for 1 h. The mixture was then cooled to rt, concentrated and neutralized with saturated NaHCO ₃ solution to pH 7. The precipitate was filtered off and washed with ethyl acetate (3x2 ml), as a result which gave the title compound 3 as a yellow solid (400 mg, 45% yield).

¹ H-NMR (DMSO-06): 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)+.

Step C. 6-(6-Aminopyridin-3-yl)-3-(3,3-difluoropyrrolidin-1-yl)-5-methyl-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of intermediate 3 (390 mg, 0.09 mmol) in MeOH (8 mL) was added Pd/C

- 209 042905 (10 mg). The mixture was stirred at rt. in an H2 atmosphere during the night. 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 give the title compound 4 as a yellow solid (270 mg,

74% yield).

LC-MS: m/z 422.9 (M+I)+.

Step D. 3-(3,3-difluoropyrrolidin-1-yl)-6-(imidazo[1,2-a]pyridin-6-yl)-5-methyl-2phenylpyrazolo[1,5-a]pyrimidine-7 (4H)-he.

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 NaHCO ₃ (161 mg, 1.9 mmol). The mixture was heated at reflux for 2 hours. The mixture was cooled to rt. and evaporated. The residue was dissolved in DCM (10 ml), washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 5.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Connection 318.

Suspension of methyl 3,4-diphenyl-1H-pyrazol-5-amine (200 mg, 0.8 mmol) and methyl 3-oxo-2-(quinolin6-yl)butanoate (200 mg, 0.85 mmol) in AcOH (2 ml) was heated at reflux for 30 min under N2 protective atmosphere. The mixture was cooled to rt, concentrated and neutralized with saturated sodium bicarbonate solution until pH 7 was reached. The precipitates were collected by filtration, washed with petroleum ether and dried to give the desired product as a yellow solid (50 mg, 62% yield) .

LC-MS: m/z 429.2 (M+H) ⁺ .

Step B. 4,5-dimethyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

To a solution of 5-methyl-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (34 mg, 0.08 mmol) and Cs ₂ CO ₃ (26 mg, 0.08 mmol) in DMF (2 ml) MeI (22 mg, 0.16 mmol) was added dropwise at ambient temperature. The mixture was stirred for 4 hours at ambient temperature. The mixture was cooled to rt, washed with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (3x30 ml). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate and concentrated in vacuo to give the desired product.

¹ H-NMR (DMSO-d ₆ ): δ 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),

- 210 042905

7.93 (d, J=2.0Hz, 1H), 7.70 (dd, J=2.0Hz, 2.0Hz, 1H), 7.59 (dd, J=4.4Hz, 4.0Hz, 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)+.

Connection 319.

To a solution of methyl 2-(quinolin-6-yl)acetate (10 g, 49.7 mmol) in THF (300 ml) was added dropwise LDA (lithium diisopropylamide) (1.5 M in THF, 39.8 ml, 59.7 mmol) at -30-35°C. The mixture was stirred at -30-35°C for 30 min and 2-(benzyloxy)acetyl chloride (9.15 g, 49.7 mol) was added dropwise. The mixture was then stirred at rt. for 6 hours. The mixture was slowly poured into saturated NH ₄ Cl and extracted with ethyl acetate (50 mlx3). The combined organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated in vacuo. The residue was purified by flash chromatography to give the desired methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6yl)butanoate as a brown oil (13.6 g, 80% yield).

LC-MS: m/z 350.2 (M+H) ⁺ .

Step B. 5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (8.6 g, 0.024 mol) and 3,4-diphenyl1H-pyrazol-5-amine (5.64 g, 0.024 mol) was dissolved in AcOH (300 ml). The mixture was heated to 95° C. for 4 hours. After cooling to rt. the precipitate was filtered, washed with ethyl acetate and dried in vacuo to give 5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidine-7(4H) -one (10 g, 78% yield) as a yellow solid.

LC-MS: m/z 535.2 (M+H) ⁺ .

Step C Compound 319 5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

To a solution of 5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)one (10 g, 18.7 mmol) in DCM (100 ml) was added BCl ₃ (25 ml, 25 mmol, 1.0 M in DCM) at 0°C. The resulting mixture was stirred at 0° C. for 4 hours. The reaction was quenched with methanol (MeOH) and concentrated. The residue was stirred with a solution of sodium bicarbonate and ethyl acetate for 30 minutes to give 5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a] pyrimidine-7(4H)he.

1H-NMR (DMSOCH): 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) ⁺ .

Connection 320.

To a suspension of 5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (compound 319, 500 mg, 1.126 mmol) in DCM (3 ml) was added dropwise SOCl ₂ (670 mg, 5.631 mmol) at 0°C. The resulting mixture was then stirred at rt. during the night. The suspension was filtered, washed with ethyl acetate and dried under vacuum. The residue was purified by preparative TLC (DCM:MeOH=20:1) to give 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6yl)pyrazolo[1,5-a]pyrimidine-7(4H )-one (300 mg).

LC-MS: m/z 463.1 (M+H)+.

Step B Compound 320 .

To a solution of 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.22 mmol) in DMF (10 ml) was added N-pyrazole (30 mg, 0.433 mmol), K ₂ CO ₃ (60 mg, 0.433 mmol) and KI (5 mg, 0.03 mmol). The mixture was stirred at 80° C. for 2 hours to give 5-((1H-pyrazol-1-yl)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1, 5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

Connection 321.

2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5Step A. yl)acetonitrile.

To a solution of 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (syn

- 212 042905 tested according to the scheme for compound 320, 1 g, 22 mmol) in CH ₃ CN (10 ml) was added K ₂ CO ₃ (600 mg, 4.33 mmol) and NaCN (100 mg, 22 mmol). The mixture was stirred at rt. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (methanol:dichloromethane=1:10) to give 2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)4,7-dihydropyrazolo[1.5 -a]pyrimidin-5-yl)acetonitrile (600 mg, 61% yield).

LC-MS: m/z 454.2 (M+H) ⁺ .

Step B Compounds 321 7(4H)-he.

To a solution of 2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5yl)acetonitrile (170 mg, 0.375 mmol) in buten-1-ole (10 ml) was added K ₂ CO ₃ (60 mg, 0.433 mmol) and formohydrazide (225 mg, 3.75 mmol). The mixture was stirred at 160° C. under microwave irradiation for 2 hours to give 5-((1H-1,2,4-triazol-5-yl)methyl)-2,3-diphenyl-6(quinolin- 6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-66): 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) ⁺ .

Connection 322.

5

Step E. Compound 322 2,4-dione.

To a mixture of hydantoin (324 mg, 3.24 mmol) in DMF (6 mL) NaH (60% dispersion in mineral oil, 143 mg, 3.56 mmol) was added portionwise at 0°C. After the addition, the mixture was stirred at 0° C. for 30 min. Then 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one (150 mg, 0.324 mmol, synthesized according to the scheme of the compound 278). The reaction mixture was heated to 80°C and stirred overnight. The reaction was quenched with brine and mixed with ethyl acetate to give the title compound.

¹ H-NMR (400 MHz, TFA): δ 9.37 (d, J=8.06 Hz, 1H), 9.29 (d, J=5.37 Hz, 1H), 8.61 (br. s., 2H), 8.20-8.42 (m, 2H), 7.47-7.66 (m, 7H), 7.13-7.35 (m, 3H), 5.00 (br s., 1H), 4.35 (br. s., 1H), 3.22 (br. s., 2H).

LC-MS: m/z 527.0 (M+H) ⁺ .

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Connection 323.

Step A. 3-(4-methoxybenzyl)imidazolidine-2,4-dione.

To a solution of imidazolidine-2,4-dione (500 mg, 5 mmol) in DMF (10 ml) NaH (60% dispersion in mineral oil, 240 mg, 6 mmol) was added in portions at 0°C. After the addition, the mixture was stirred at 0° C. for 40 minutes. PMBBr (1.0 g, 5 mmol) was then added dropwise. The resulting mixture was heated to 80°C and stirred overnight. The reaction was quenched with brine (30 ml).

The suspension was filtered. The filter cake was washed with brine and ethyl acetate and then dried under vacuum to give the title compound (430 mg) as a white solid.

LC-MS: m/z 221.1 (M+H) ⁺ .

Step B. 3-(4-methoxybenzyl)-1-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl )methyl)imidazolidine-2,4-dione.

To a mixture of hydantoin (124 mg, 0.562 mmol) in DMF (6 ml) NaH (60% dispersion in mineral oil, 27 mg, 0.674 mmol) was added portionwise at 0°C. After the addition, the mixture was stirred at 0° C. for 30 min. Then 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one (130 mg, 0.281 mmol, synthesized according to the scheme of the compound 278). The reaction mixture was heated to 80°C and stirred overnight. The reaction was quenched with brine and then mixed with ethyl acetate. The mixture was filtered. The filter residue was purified by preparative HPLC to give the title compound (100 mg) as a yellow solid.

LC-MS: m/z 647.0 (M+H) ⁺ .

Step C Compound 323 2,4-dione.

3-(4-Methoxybenzyl)-1-((7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl)methyl mixture )imidazolidine-2,4-dione and CF3SO3H (0.5 ml) in TFA (2 ml) were heated at reflux overnight. The reaction mixture was cooled to rt, neutralized with aqueous NaHCO ₃ to pH 7-8, resulting in the title compound.

¹ H-NMR (400 MHz, TFA): δ 9.34 (d, J=8.33 Hz, 1H), 9.25 (d, J=5.10 Hz, 1H), 8.49-8, 64 (m, 2H), 8.34 (d, J=8.06 Hz, 1H), 8.24 (dd, J=8.06, 5.64 Hz, 1H), 7.55-7.71 (m, 6H), 7.46-7.53 (m, 2H), 7.43 (d, J=6.72 Hz, 2H), 4.88 (br. s., 2H), 4.27 (br. s., 2H).

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LC-MS: m/z 527.0 (M+H)+.

Connection 324.

324.

5-((2-oxoimidazolidin-1-yl)methyl)-2,3-diphenyl-6-(quinoline-6) Step A. Compound

A mixture of 5-(chloromethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.216 mmol, synthesized according to scheme 278 ), imidazolidin-2-one (93 mg, 1.08 mmol) and K2CO3 (136 mg, 0.259 mmol) in DMF (3 mL) were heated to 80°C and stirred overnight. The reaction mixture was neutralized with brine and then mixed with ethyl acetate to give the title compound.

¹ H-NMR (400 MHz, DMSO-O6): δ 8.88 (br. s., 1H), 8.36 (d, J=7.52 Hz, 1H), 8.00 (d, J= 8.06 Hz, 1H), 7.89 (br. s., 1H), 7.78 (d, J=8.33 Hz, 1H), 6.95-7.68 (m, 11H), 6 .19 (br. s., 3.21 (br. s., 2H).

LC-MS: m/z 513.0 (M+H) ⁺ .

Connection 325.

1H), 4.09-4.33 (m, 2H), 3.58 (br. s., 2H),

3-(3-Hydroxycyclohex-1-en-1-yl)-5-methyl-2-phenyl-6-(quinolin-6-yl)pyrazolo[1,5Step A.

a]pyrimidin-7(4H)-one.

To a solution of 7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid (synthesized according to the scheme for compound 329, 100 mg, 0 .2 mmol) in DMF (5 ml) was added methanamine hydrochloride (16 mg, 0.2 mmol), O-(7-Azabenzotriazol-1-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 rt. within 30 min. The mixture was diluted with water (15 ml) and extracted with dichloromethane (3x15 ml). The extracts were washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 2.

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, 1H), 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) ⁺ .

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Connection 326.

stage C

Step C. 6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl.

2,3-diphenyl-6-(quinolin-6-yl)-nirazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione solution (18 g, 42 mmol, compound 275), DMAP (dimethylaminopyridine ) (1 g) and PCl5 (80 mg) in POCl ₃ (180 ml) were stirred at 100°C overnight. After cooling to rt. the solvent was removed under vacuum. The residue was cooled to 0°C. MeOH (60 ml) was added to stop the reaction. The resulting mixture was diluted with dichloromethane (450 ml), washed with saturated NaHCO ₃ (150 ml) and brine (100 ml), dried over anhydrous sodium sulfate and concentrated to give the crude product -6-(5,7-dichloro- 2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (13 g), which was used in the next step without further purification.

LC-MS: m/z 467.1 (M+H) ⁺ .

Step D. 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl.

To a solution of 6-(5,7-dichloro-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (13.0 g, crude, 27.8 mmol) in DCM/MeOH (200 ml , 1:1) cooled at 0° C., sodium methoxide (14.9 ml, 5.0 M in methanol) was added dropwise. The mixture was then stirred at 0° C. for 1 h. Saturated NH ₄ Cl (150 ml) was added to stop the reaction. The resulting mixture was extracted with dichloromethane (500 ml), washed with brine (150 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a flash column (DCM/MeOH=40:1) to give 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]n-pyrimidin-6-yl) quinolinyl (9.0 g) as a pale yellow solid.

¹ H-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) ⁺ .

Step E. N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]nirimidin-5yl)cyclopropanecarboxamide.

A mixture of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (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, whereby the expected product was obtained.

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1H-NMR (DMSO-d ₆ ): 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 (t., 5H).

LC-MS: m/z 498.2 (M+H)+.

Connection 327.

2

Step A. N-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5yl)propionamide.

A mixture of 6-(5-chloro-7-methoxy-2,3-diphenylpyrazolo[1,5-a]pyrimidin-6-yl)quinolinyl (synthesized according to the scheme for 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 give the expected product.

1H-NMR (DMSO-06): δ 12.92 (br. s., 1H), 10.08 (s, 1H), 8.94 (d, J=2.8 Hz, 1H), 8.40 (d, J=8.0Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 8.00 (s, 1H), 7.75 (dd, J=1.6Hz , 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=7.6Hz, 7.2Hz, 2H), 0.94 (t, J=7.6Hz, 3H).

LC-MS: m/z 486.8 (M+H) ⁺ .

Connection 328.

2

Step A. N-((1H-pyrazol-3-yl)methyl)-7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7dihydropyrazolo[1,5-a]pyrimidin- 5-carboxamide.

To a solution of 7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]nirimidine-5carboxylic acid (synthesized according to the scheme for compound 329, 100 mg, 0 .2 mmol) in DMF (5 ml) was added (1H-pyrazol-3-yl)methanamine (23 mg, 0.2 mmol), O-(7-azabenzotriazol-1-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 rt. within 30 min. The mixture was diluted with water (15 ml) and extracted with dichloromethane (3x15 ml). The extracts were washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 2.

1H-NMR (DMSO-d6): δ 12.51 (br. s., 1H), 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), 7.11-7.40 (m, 7H), 5.85 (br. s., 1H), 4.22 (br. s., 2H).

LC-MS: m/z 538.3 (M+H) ⁺ .

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Connection 329.

Step A. Methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate.

ORp

To a solution of methyl 2-(quinolin-6-yl)acetate (10.0 g, 49.7 mmol) in THF (60 mL) was added dropwise LDA (lithium diisopropylamide) (2.0 mol/L in THF, 29 .8 ml) and HMPTA (1.8 g, 9.9 mmol) at -78°C. After the addition, the mixture was stirred at -78°C for 0.5 h. Then the mixture was 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 rt. during the night. The reaction mixture was diluted with ethyl acetate (60 ml), neutralized with NH ₄ Cl solution, extracted with ethyl acetate (3x60 ml). The combined organic phase was washed with water and brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether=1/4) to give the title compound 2 (8.6 g, 48% yield).

LC-MS: m/z 350.1 (M+H) ⁺ .

Step B. 5-((benzyloxy)methyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of methyl 4-(benzyloxy)-3-oxo-2-(quinolin-6-yl)butanoate (8.6 g, 24.6 mmol) and 3,4-diphenyl1H-pyrazole-5-amine (5.8 g, 24.6 mol) in AcOH (100 ml) was stirred at 100°C for 4 h. After cooling to rt, the precipitate was filtered, washed with ethyl acetate (3x10 ml) and dried under vacuum, resulting in title compound 3 as a yellow solid (10.0 g, 78% yield).

LC-MS: m/z 535.2 (M+H) ⁺ .

Step C. 5-(hydroxymethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

To a solution of intermediate 3 (10.0 g, 18.7 mmol) in DCM (100 mL) was added BCl ₃ (1.0 mol/L in DCM, 25 mL) at 0°C. The resulting mixture was stirred at 0° C. for 4 hours. The reaction was quenched with methanol (MeOH) and evaporated. The residue was stirred with 10% aqueous NaHCO ₃ (10 ml) and ethyl acetate (10 ml) for 30 minutes. The precipitate was filtered off, washed with ethyl acetate (3x2 ml) and dried in vacuo to give the title compound 4 (8.0 g,

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96% yield).

LC-MS: m/z 445.1 (M+H)+.

Step D. 7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5carbaldehyde.

To a solution of intermediate 4 (4.4 g, 10 mmol) in 1,2-dichloroethane (50 ml) was added MnO ₂ (8.7 g, 100 mmol). The mixture was heated under reflux for 2 days. The reaction mixture was cooled to rt. and filtered through celite. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography to give the title compound 5 as a brown solid (1.5 g, 34% yield).

LC-MS: m/z 443.1 (M+H) ⁺ .

Step E. 7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid.

_Sodium chlorite (203 _mg in 1 _ml H2O , 2.3 mmol) at 0°C. After the addition, the mixture was stirred at rt. for 1 h and poured into H2O (10 ml). The precipitate was filtered off, washed with methanol (MeOH) (3x1 ml) and dried under vacuum to give the title compound 6 as a brown solid (300 mg, 73%).

LC-MS: m/z 459.1 (M+H) ⁺ .

Step F. N-(2-hydroxyethyl)-7-oxo-2,3-diphenyl-6-(quinolin-6-yl)-4,7-dihydropyrazolo[1,5a]pyrimidine-5-carboxyamide.

But

To a solution of intermediate 6 (140 mg, 0.3 mmol) in DMF (5 ml) was added 2-aminoethanol (22 mg, 0.4 mmol), O-(7-azabenzotriazol-1-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 rt. within 30 min. The mixture was diluted with water (15 ml) and extracted with dichloromethane (3x15 ml). The extracts were washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 7.

¹ H-NMR (DMSO^): 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)+.

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Connection 330.

Step E Compound 330 6-(4-aminoquinazolin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

A mixture of intermediate 5 (170 mg, 0.41 mmol, synthesized according to the scheme of compound 245) and formamide (5 ml) was stirred at 180°C for 2 h under microwave radiation. The mixture was concentrated in vacuo to give the title compound 6.

¹ H-NMR (DMSO-06): δ 8.40 (s, 1H), 8.18 (d, J=1.6 Hz, 1H), 7.90-7.63 (m, 4H), 7 .53-7.24 (m, 11H), 2.23 (s, 3H).

LC-MS: m/z 445.1 (M+H) ⁺ .

Connection 331.

Step A. Methyl 2-(quinoxalin-6-yl)acetate.

To 2-(quinoxalin-6-yl)acetic acid (1.0 g, 5.31 mmol) in methanol (20 ml) was added slowly conc. H2SO4 (1.0 ml) at 0°C and heated the mixture under reflux overnight. The reaction mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate. The organic solution was washed with saturated aqueous NaHCO ₃ and brine, dried with Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=4/1 to give the desired product as a yellow oil (0.47 g, 43% yield).

LC-MS: m/z 203.2 (M+H) ⁺ .

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Step B. Methyl 3-oxo-2-(quinoxalin-6-yl)butanoate.

To a solution of methylmethyl-2-(quinoxalin-6-yl)acetate (0.45 g, 2.23 mmol) in THF (20 mL) was added LDA (lithium diisopropylamide) (2.0 M in THF, 1.4 ml, 2.90 mmol) at -40°C. The mixture was stirred at -78° C. for 30 min and acetyl chloride (0.17 ml, 2.33 mmol) was added dropwise. The mixture was then slowly heated to RT and stirred for 10 h. The mixture was slowly poured into saturated water.

NH ₄ Cl and extracted with ethyl acetate (30 mlx3). The combined organic phase was washed with brine, dried with anhydrous MgSO ₄ and concentrated in vacuo to give the title product as a yellow oil (0.40 g, 88% yield).

LC-MS: m/z 245.2 (M+H) ⁺ .

Step C. 5-methyl-2,3-diphenyl-6-(quinoxalin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

Mixture of 3,4-diphenyl-1H-pyrazole-5-amine (100 mg, 0.42 mmol) and methylmethyl 3-oxo-2-(quinoxalin-6yl)butanoate (135 mg, 0.55 mmol) in AcOH (5 ml) was stirred at 100°C for 1 hour After removal of AcOH was added 10% NaHCO ₃ , resulting in the desired product.

¹ H-NMR (DMSOCH): δ 12.05 (br. s., 1H), 8.95 (dd, J=1.6 Hz, 2.0 Hz, 2H), 8.12 (d, J= 8.8Hz, 1H), 8.06(d, J=1.6Hz, 1H), 7.90(dd, J=1.6Hz, 2.0Hz, 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) ⁺ .

Connection 332.

Step D. N,N-dimethyl-2-(4-(5-methyl-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6yl)phenoxy)acetamide.

To a solution of intermediate 4 (80 mg, 0.2 mmol, compound 237) in DMF (5 ml) was added 2-bromo-N,N-dimethylacetamide (34 mg, 0.2 mmol) m K ₂ CO ₃ (56 mg , 0.4 mmol). The mixture was stirred at 60°C for 3 h. The mixture was poured into H2O (15 ml) and extracted with dichloromethane (3x10 ml). The combined extracts were washed with brine and dried with anhydrous Na2SO4 and concentrated in vacuo to give the title compound 5.

¹ H-NMR (DMSO-d ₆ ): δ 11.88 (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) ⁺ .

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Connection 333.

Step A. Methyl 2-(6-methoxypyridin-3-yl)acetate.

To 2-(6-methoxypyridin-3-yl)acetic acid (1.0 g, 5.98 mmol) in MeOH (20 mL) was added thionyl chloride (4.0 mL, 55.1 mmol) slowly at -10°C and the mixture was stirred at rt. during the night. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM. The solution was washed with saturated aqueous NaHCO ₃ and brine, dried with Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=4/1 to give the desired product as a yellow oil (1.0 g, 92% yield).

LC-MS: m/z 182.2 (M+H) ⁺ .

Step B. Methyl 2-(6-methoxypyridin-3-yl)-3-oxobutanoate.

To a solution of methyl 2-(6-methoxypyridin-3-yl)acetate (0.5 g, 2.76 mmol) in THF (20 mL) was added LDA (lithium diisopropylamide) (2.0 M in THF, 1 .8 ml, 3.58 mmol) 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. The mixture was then slowly heated to RT and stirred for 10 minutes. The mixture was slowly poured into saturated water. NH ₄ Cl and extracted with ethyl acetate (30 mlx3). The combined organic phase was washed with brine, dried with anhydrous MgSO ₄ and concentrated in vacuo to give the title product as a yellow oil (0.76 g, crude) which was used directly in the next step without further purification.

LC-MS: m/z 224.2 (M+H) ⁺ .

Step C. 6-(6-methoxy-pyridin-3-yl)-5-methyl-2,3-diphenyl-pyrazolo[1,5-a]pyrimidin-7(4H)-one.

Mixture of 3,4-diphenyl-1H-pyrazol-5-amine (150 mg, 1.06 mmol) and methyl 2-(6-methoxypyridin-3-yl)-3oxobutanoate (309 mg, 1.38 mmol) in AcOH (5 ml) was stirred at 100°C for 1 hour After removal of AcOH under reduced pressure was added 10% NaHCO ₃ , resulting in the desired product.

¹ H-NMR (DMSO-d ₆ ): δ 12.01 (br. s., 1H), 8.13 (d, J=2.4 Hz, 1H), 7.70 (dd, J=2, 4Hz, 2.4Hz, 1H), 7.47-7.42(m, 5H), 7.33(dd, J=1.6Hz, 1.6Hz, 5H), 6.91(dd , J=0.4Hz, 0.4Hz, 1H), 3.91(s, 3H), 2.22(s, 3H).

LC-MS: m/z 409.4 (M+H) ⁺ .

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Connection 334.

Step A. Methyl 2-(benzofuran-5-yl)acetate.

One drop of concentrated H2SO4 was added to a solution of 2-(benzofuran-5-yl)acetic acid (350 mg, 2 mmol) in MeOH (40 ml). The mixture was heated at reflux for 3 hours. The mixture was then cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (30 ml), washed with 10% aq. NaHCO ₃ and brine, dried over anhydrous MgSO ₄ and concentrated in vacuo to give intermediate 2 as a colorless oil (340 mg, 90% yield) , which was used in the next step without purification.

LC-MS: m/z 191.0 (M+H) ⁺ .

Step B. Methyl 2-(benzofuran-5-yl)-3-oxobutanoate.

To a solution of intermediate 2 (340 mg, 1.8 mmol) in THF (20 ml) was added LDA (lithium diisopropylamide) (2 mol/l in THF, 1.1 ml) dropwise at -40°C. After stirring the mixture at -40° C. for 30 min, acetyl chloride (173 mg, 2.2 mmol) was added dropwise. The mixture was then stirred at rt. for 3 h. The mixture was diluted with ethyl acetate (20 ml) and neutralized with saturated aqueous NH4Cl. The organic phase was separated and washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude intermediate 3 as a yellow oil (250 mg, 60% yield) which was used in the next step without purification.

LC-MS: m/z 233.0 (M+H) ⁺ .

Step C. 6-(benzofuran-5-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

A 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 1 h. Then the mixture was cooled to rt, resulting in the receipt of the target product 4.

1H-NMR (DMSO-d6): δ 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) ⁺ .

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Connection 335.

Step A. Ethyl 2-(3-bromo-4-nitrophenyl)-3-oxobutanoate.

2-bromo-4-fluoro-1-nitrobenzene (6.6 g, 30 mmol), ethyl 3-oxobutanoate (7.8 g, 60 mmol) and K ₂ CO ₃ (12.46 g, 90 mmol) in DMSO (50 ml) was stirred at 60° C. for 16 hours. The mixture was acidified with 1M hydrochloric acid to pH 7 and extracted with ethyl acetate (50 mlx3). The organic layer was dried and concentrated to give a crude product which was purified by silica gel chromatography (petroleum ether/ethyl acetate=3/1) to give the title product as a yellow solid (7.6 g, 77% yield) .

LC-MS: m/z 331.2 (M+H) ⁺ .

Step B. 6-(3-bromo-4-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

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 heated at reflux for 30 min under a protective N2 atmosphere. The mixture was cooled to rt, concentrated and neutralized with saturated sodium hydrogen carbonate solution until pH 7 was reached. The precipitates were collected by filtration, washed with petroleum ether and dried to give the title product as a yellow solid (9.0 g, 92% exit).

LC-MS: m/z 502.2 (M+H)+.

Step C. 5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

Suspension of 6-(3-bromo-4-nitrophenyl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (3.0 g, 6.0 mmol), ethynyltrimethylsilane (1.18 g, 12.0 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (42 mg, 0.6 mmol), CuI (228 mg, 1.2 mmol) and triethylamine (15 ml, 18.0 mmol ) in THF (50 mL) was heated to 50°C for 6 h under N2 atmosphere. The mixture was cooled to rt, diluted with water and extracted with ethyl acetate (30 mlx3). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on a silica gel column eluting with DCM/MeOH (40/1) to give the desired product as a yellow solid (2.3 g, 74% yield).

LC-MS: m/z 519.2 (M+H) ⁺ .

Step D. 6-(4-Amino-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

To a suspension of 5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one (2.3 g, 4, 4 mmol) in DMF/MeOH (20 ml/30 ml) were added saturated aqueous ammonium chloride solution (20 ml) and zinc powder (2.88 g, 44.4 mmol). The resulting mixture was stirred at rt. during the night. The reaction mixture was filtered and concentrated. The residue was purified by flash column chromatography eluting with DCM/MeOH (20/1) to give the desired product as a yellow solid (600 mg, 28% yield).

LC-MS: m/z 489.2 (M+H) ⁺ .

Step E. 5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

To a suspension of 6-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one (120 mg, 0.24 mmol ) in acetonitrile/water (1.4/0.7 ml) was added conc. 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 slowly introduced, keeping the temperature below 0°C. After the addition, the resulting mixture was stirred at 0° C. for 30 minutes. The mixture was then slowly added 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 resulting mixture was allowed to warm up to rt. within 1 h. The reaction was quenched with water, extracted with ethyl acetate (30 mlx3). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on a silica gel column eluting with DCM/MeOH (20/1) to give the title product as a yellow solid (140 mg, 99% yield).

LC-MS: m/z 585.3 (M+H)+.

Step F. 6-(3-ethynyl-4-(piperidin-1-yldiazenyl)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

To a mixture of 5-methyl-6-(4-nitro-3-((trimethylsilyl)ethynyl)phenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one (50 mg, 0.08 mmol ) in THF/MeOH (0.85 ml/0.17 ml) was added potassium carbonate (117 mg, 0.85 mmol) and potassium hydroxide (50 mg, 0.09 mmol). The mixture was then stirred at rt. within 2 h, the reaction mixture was diluted with water, extracted with ethyl acetate (30 mlx3). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on a silica gel column eluting with DCM/MeOH (25/1) to give the title product as a yellow solid (30 mg, 50% yield).

LC-MS: m/z 513.2 (M+H)+.

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Step G. 6-(cinnolin-6-yl)-5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of 6-(3-ethynyl-4-(piperidin-1-yldiazenyl)phenyl)-5-methyl-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one (30 mg, 0.006 mmol) in 1,2-dichlorobenzene (2 ml) was heated at 200° C. for 16 hours to give the expected product.

1H-NMR (DMSO-d ₆ ): 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=6.0Hz, 1H), 8.05 (s, 1H), 7.98 (dd, J=2.0Hz, 1.6Hz, 1H) , 7.48-7.31 (m, 10H), 2.27 (s, 3H).

LC-MS: m/z 430.2 (m+H) ⁺ .

Connection 336.

Mixture of 3,4-diphenyl-1H-pyrazole-5-amine (3 g, 12.8 mmol, 1 eq.) and methyl 3-oxobutanoate (2.96 g, 25.5 mmol) in AcOH (20 ml) stirred at 120° C. for 4 h. The mixture was then cooled to rt. and filtered to give a crude solid which was washed with ethyl acetate to give the title product 5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)one (3.5 g) .

LC-MS: m/z 302.1 (M+H) ⁺ .

Step B. 5-methyl-2,3-diphenyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one.

To a mixture of 5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (3.5 g, 11.6 mmol), Cs ₂ CO ₃ (7.58 g, 23, 2 mmol) in DMF (50 ml) was added 1-(chloromethyl)-4-methoxybenzene (2.3 g, 13.9 mmol). The reaction mixture was stirred at rt. for 16 hours. The mixture was diluted with water (H2O) (30 ml) and extracted with dichloromethane (10 mlx3). The organic layer was dried with anhydrous sodium sulfate and concentrated to dryness in vacuo. The resulting solid was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1) to give the desired product (3.19 g).

LC-MS: m/z 432.3 (M+H) ⁺ .

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Step C. 6-bromo-5-methyl-2,3-diphenyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(1H)-one.

O_N-V

Br N -O SEM

To a solution of 5-methyl-2,3-diphenyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin7(1H)-one (3.1 g, 7.2 mmol) in DCM (50 ml) and triethylamine (1.45 g, 14.58 mmol) was added dropwise BSI (1.4 g, 7.9 mmol) in DCM (5 ml). The resulting mixture was stirred for 3 hours at ambient temperature and washed with water. The aqueous phase was extracted with dichloromethane (20 ml). The combined organic layers were washed with brine (20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10/1) to give 6-bromo-5-methyl-2,3-diphenyl-1-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1, 5-a]pyrimidin-7(1H)-one (3 g, 82% yield).

LC-MS: m/z 510.1 (M+I)+.

Step D. 5-methyl-2,3-diphenyl-6-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)-1-((2(trimethylsilyl)ethoxy)methyl)pyrazolo [1,5-a]pyrimidin-7(1H)-one.

To a solution of 6-bromo-5-methyl-2,3-diphenyl-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5a]pyrimidin-7(1H)-one (400 mg, 0.786 mmol) and 1,4-dioxaspiro[4,5]dec-7-en-8-ylboronic acid (251 mg, 0.943 mmol) in a mixture of dioxαn/H ₂ O (26/9 ml) complex 1,1'-bis( diphenylphosphino) ferrocene-palladium (II) dichloride - dichloromethane (57 mg, 0.078 mmol) and sodium carbonate (166 mg, 1.57 mmol). The reaction mixture was then heated at reflux under nitrogen atmosphere overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1/20) to give 5-methyl-2,3-diphenyl-6-(1,4-dioxaspiro[4,5]dec-7-en-8- yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7(1H)-one (100 mg, 22.3% yield) as a white solid.

LC-MS: m/z 570.2 (M+H) ⁺ .

Step E Compound 336 5-methyl-6-(4-oxocyclohex-1-en-1-yl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

A mixture of 5-methyl-2,3-diphenyl-6-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)-1-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1 ,5-a]pyrimidin-7(1H)-one (100 mg, 0.176 mmol) in HCl/dioxane (1.5 mL, 4 M) was stirred at rt. for 1 h. The mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in 4N. HCl and THF (10 ml) and stirred at rt. for 1 hour to give 5-methyl-6-(4-oxocyclohex-1-en-1-yl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

1H-NMR (DMSO-d ₆ ): δ 11.81 (br. s., 1H), 7.39-7.48 (m, 5H), 7.28-7.35 (m, 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) ⁺ .

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Compound 337.

To a solution of 5-methyl-6-(4-oxocyclohex-1-en-1-yl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)one (synthesized according to the scheme for compound 336, 20 mg, 0.05 mmol) in MeOH (10 ml) was added NaBH ₄ (2.3 mg, 0.06 mmol). The reaction mixture was stirred at rt. for 1 h. The mixture was poured into water and extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous sodium sulfate and concentrated in vacuo to give 6-(4-hydroxycyclohex-1-en-1-yl)-5-methyl-2,3-diphenylpyrazolo[1, 5-a]pyrimidine 7(4B)-one.

¹ H-NMR (DMSO-d ₆ ): δ 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)+.

Connection 338 and connection 339.

7

Step D. 5-(chloromethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

To a suspension of 5-(hydroxymethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)one (88 g, 0.208 mol, compound 221) in DCM (500 ml ) was added via funnel SOCl ₂ (120 ml). The mixture was stirred at rt. for 1 h. The settled substances were filtered, washed with ethyl acetate and dried under vacuum, as a result of which 5-(chloromethyl)-6-(4-methoxyphenyl)-2,3diphenylpyrazolo[1,5-a]pyrimidine- 7(4H)-one (110 g) as an off-white solid which was used directly in the next step without further purification.

Step E Compound 338 and Compound 339 and 5-((2H-tetrazol-2-yl)methyl)-6-(4-methoxyphenyl)-2,3diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

A mixture of 5-(chloromethyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-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) were stirred at 40° C. overnight. The mixture was concentrated under reduced pressure to give 5-((1H-tetrazol-1-yl)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine-7(4H )one and 5-((2H-tetrazol-2-yl)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

Compound 338 5-((1H-tetrazol-1-yl)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpirazolo[1,5a]pyrimidin-7(4H)-one.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ 8.97 (br. s., 1H), 7.19-7.44 (m, 4H), 7.07-7.18 (m, 5H ) 6.85-7.07 (m, 5H), 6.36-6.82 (m, 1H), 5.74-5.93 (m, 2H), 3.80 (s, 3H).

LC-MS: m/z 476.1 (M+H) ⁺ .

Compound 339 5-((2H-tetrazol-2-yl)methyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidin-7(4H)-one.

¹ H-NMR (400 MHz, TFA): δ 9.32 (br. s., 1H), 7.61 (br. s., 6H), 7.51 (br. s., 2H), 7, 32-7.47 (m, 4H), 7.25 (br. s., 2H), 5.99 (br. s., 2H), 4.08 (br. s., 3H).

LC-MS: m/z 476.0 (M+H)+.

Connection 340.

8

Step F. (S)-tert-butyl-(1-(((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl )methyl)amino)-3-methyl-1-oxobuten-2-yl)carbamate.

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To a solution of intermediate 6 (compound 222, 200 mg, 0.45 mmol) in DMF (8 mL) was added (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutyric acid (117 mg, 0.54 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (258 mg, 0.68 mmol) and N,N-diisopropylethylamine (116 mg, 0.9 mmol ). The mixture was stirred at rt. during the night. The mixture was diluted with water (30 ml) and extracted with dichloromethane (3x30 ml). The extracts were washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC (DCM/MeOH=20:1) to give the title compound 7 as a white solid (230 mg, 82% yield).

LC-MS: m/z 622.2 (M+H) ⁺ .

Step G. (S)-2-amino-N-((6-(4-methoxyphenyl)-7-oxo-2,3-diphenyl-4,7-dihydropyrazolo[1,5a]pyrimidin-5-yl)methyl )-3-methylbutanamide.

A solution of intermediate 7 (180 mg, 0.29 mmol) in 4 M HCl in 1,4-dioxane (8 ml) was stirred at 0° C. rt. within 1 h, and then at k.t. within 3 hours the Solvent and other volatiles were removed under vacuum. The residue was dissolved in MeOH (10 ml) and treated with NaHCO ₃ (2 mol/l, 10 ml) to give the title compound 8.

¹ H-NMR (DMSO-d ₆ ): 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=15.6Hz, 1H), 3.91(d, J=15.6Hz, 1H), 3.79(s, 3H), 3.52(d, J=5.0Hz, 1H) , 2.06 (dd, J=12.4, 6.6Hz, 1H), 0.91 (d, J=6.8Hz, 3H), 0.85 (d, J=6.8Hz, 3H).

LC-MS: m/z 522.2 (M+H) ⁺ .

Compound 341.

Solution of 3-(cyclohex-1-en-1-yl)-5-hydroxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5-a]pyrimidin7(4H)-one (synthesized according to the scheme for compound 279 , 47.0 g, 104 mmol) in phosphorus oxychloride (100 ml) was stirred at reflux for 16 h. The solvent was removed under vacuum. The residue was slowly added 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-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1 ,5-a]pyrimidine (50 g) as a yellow solid.

1H-NMR (DMSO-d ₆ ): δ 1.70 (d, J=4.57 Hz, 4H) 2.20 (br. s., 4H) 3.84 (s, 4H) 5.87 (br s., 1H) 7.10 (d, J=8.60 Hz, 2H) 7.36-7.56 (m, 5H) 7.82 (d, J=7.25 Hz, 2H).

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LC-MS: m/z 450.2 (M+H)+.

Step B. 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidine.

To a solution of 5,7-dichloro-3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidine (40 g, 88 mmol) in dichloromethane (400 ml) sodium methoxide (30% in methanol, 80 g) was added dropwise at 0°C. The resulting mixture was stirred for 10 min at 0°C. The reaction mixture was quenched with ice water (100 ml) and extracted with dichloromethane (200 ml) three times. The combined organic layers were washed with brine (200 ml), dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was suspended in MeOH (50 ml). The precipitates were collected by filtration, washed with methanol (MeOH) and dried under reduced pressure to give 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)- 2-phenylpyrazolo[1,5a]pyrimidine (36 g) as a yellow solid.

1H-NMR (DMSOCH): 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) ⁺ .

Step C. N-(3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidin-5-yl)isoxazol-3 - amine.

A mixture of 5-chloro-3-(cyclohex-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidine (200 mg, 0.45 mmol), isoxazol-3-amine (113.4 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 110°C for 12 h under nitrogen. The mixture was filtered through Celite, the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to give the desired product N-(3-(cyclohekC-1-en-1-yl)-7-methoxy-6-(4-methoxyphenyl)-2-phenylpyrazolo[1,5a]pyrimidine -5-yl)isoxazol-3-amine.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

Connection 342.

Step A. 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-( 1 -((2-(trimethylsilyl)ethoxy)methyl)-1Himidazol-4-yl)pyrazolo [1,5- a] pyrimidine-5-amine.

SEM

A suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5a]pyrimidine (synthesized according to the scheme for compound 101, 300 mg, 0.68 mmol) was reacted, 1-( (2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-amine (230 mg, 1.36 mmol), Pd(OAc) ₂ (30.5 mg,

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0.14 mmol), Xantphos (118 mg, 0.20 mmol) and Cs ₂ CO3 (487 mg, 1.49 mmol) in 1,4-dioxane (10 ml) at

100°C for 45 min under N2 in a microwave reactor. The reaction mixture 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 give the title product as a yellow solid (110 mg, 26% yield).

LC-MS: m/z 619.5 (M+H) ⁺ .

Step B. 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1Himidazol-4-yl)pyrazolo[1,5- a] pyrimidine-5-amine.

^H / ^N ^O) w su

ΗΝ /O

7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-imidazol4-yl)pyrazolo[1,5-a] pyrimidine-5-amine (110 mg, 0.18 mmol) in DCM (5 ml) and TFA (5 ml) was stirred at 60° C. for 1 h. The mixture was then concentrated to give a crude product which was added to water with ammonia (5 ml) and continued stirring for 1 h, resulting in the desired product.

¹ H-NMR (DMSO-d6): 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) ⁺ .

Compound 343.

Step E. 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazol-3 -yl)pyrazolo [1,5- a] pyrimidine-5-amine.

SEM

A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine (600 mg, 1.36 mmol, synthesized according to the scheme for compound 101), 1-( (2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazol-3-amine (580mg, 2.72mmol), Pd(OAc)2 (61mg, 0.27mmol), Xantphos (197mg, 0.34mmol ) and Cs ₂ CO ₃ (890 mg, 2.72 mmol) in 1,4-dioxane (5 ml) were stirred at 120° C. (microwave heating) for 1 h under N ₂ atmosphere. The mixture was filtered through Celite, the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to give 7-methoxy-6-(4methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3- yl)pyrazolo[1,5a]pyrimidin-5-amine (150 mg) as a yellow solid.

LC-MS: m/z 619.0 (M+H) ⁺ .

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Step F Compound 343 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1H-pyrazol-3yl)pyrazolo[1,5-a]pyrimidine-5-amine.

To a solution of 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1Hpyrazol-3-yl)pyrazolo[1,5-a ]pyrimidine-5-amine (150 mg, 0.243 mmol) in DCM (5 ml) was added with TFA (2 ml), the mixture was stirred at rt. over 3 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in ammonium hydroxide (3 ml) and stirred at rt. during the night. The mixture was then concentrated to give the title compound.

¹ H-NMR (400 MHz, DMSOCH): δ 12.34 (br. s., 1H), 7.63 (br. s., 1H), 7.58 (d, J=3.49 Hz, 2H ), 7.47 (d, J=8.33 Hz, 2H), 7.51 (d, J=7.52 Hz, 2H), 7.34-7.44 (m, 5H), 7.12 -7.32 (m, 4H), 6.88 (br. s., 1H), 4.09 (s, 3H), 3.87 (s, 3H).

LC-MS: m/z 488.9 (M+H)+.

Compound 344.

Step A. Chloromethyl dimethylcarbamate.

O and SG O Ν I

To a solution of chloromethyl chloroformate (500 mg, 3.9 mmol) in THF (30 ml) was added dropwise dimethylamine (2 mol/l in THF, 3.9 ml) at 0° C. with vigorous stirring. The mixture was then stirred at rt. during the night. The mixture was evaporated. The residue was stirred in toluene (5 ml) and filtered. The filtrate was washed with 10% aqueous NaHCO ₃ , water and brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 2 as a yellow oil (400 mg, 75 yield) which was used in the next step without further purification.

¹ H-NMR (DMSO-d ₆ ): δ 5.79 (s, 2H), 2.98 (s, 3H), 2.96 (s, 3H).

Step B. ((3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin7-yl)oxy)methyl dimethylcarbamate.

To a solution of 3-(cyclohex-1-en-1-yl)-6-(4-methoxyphenyl)-5-methyl-2-phenylpyrazolo[1,5a]pyrimidin-7(4H)-one (compound 212, 50 mg , 0.12 mmol) in DMF (3 ml) was added chloromethyldimethylcarbamate (54 mg, 0.36 mmol) and K2CO3 (50 mg, 0.36 mmol). The mixture was stirred at 60°C for 10 h. The mixture was poured into H2O (15 ml) and extracted with dichloromethane (3x10 ml). The combined extracts were washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound 3.

¹ H-NMR (DMSO-d ₆ ): 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) ⁺ .

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Compound 345.

Step A. 7-methoxy-6-(4-methoxyphenyl)-2,3-diphenyl-N-(1,3,5-triazin-2-yl)pyrazolo[1,5a]pyrimidine-5-amine.

A mixture of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine (800 mg, 1.81 mmol), ethyl-1,3,5-triazine- 2-amine (synthesized according to the scheme for compound 101, 348 mg, 3.62 mmol) and Pd(OAc) ₂ (81 mg, 0.36 mmol), Xantphos (260 mg, 0.45 mmol) and Na ₂ CO ₃ (384 mg, 3.62 mmol) in 1,4-dioxane (15 mL) was heated at 110° C. for 4 h under N2. The mixture was filtered through celite and the filtrate concentrated in vacuo to give the title product.

1H-NMR (DMSO-d ₆ ): 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) ⁺ .

Compound 346.

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 stirring the mixture at -78° C. for 30 min, 3-chlorobenzoyl chloride (1.8 g, 10.0 mmol) was added dropwise. The mixture was then stirred at rt. within 2 hours the Mixture was diluted with ethyl acetate (30 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated and washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was washed with petroleum ether to give the title intermediate 2 as a white solid (1.2 g, 57% yield).

LC-MS: m/z 256.0/258.0 (M+H) ⁺ .

Step B. 3-(3-chlorophenyl)-4-phenyl-1H-pyrazole-5-amine.

A mixture of intermediate 2 (500 mg, 2.0 mmol) and hydrazine hydrate (200 mg, 4.0 mmol) in EtOH/AcOH (5/1, 10/2 mL) was refluxed for 2 h. cooled to rt and evaporated. The residue was dissolved in ethyl acetate (20 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude title intermediate 3 as a yellow oil (500 mg, 95% yield) which was used in the next step. stage without cleaning.

LC-MS: m/z 270.0/272.0 (M+H) ⁺ .

Step C. 2-(3-chlorophenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A 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 1 h. Then the mixture was cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (15 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (15 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give desired product 4.

¹ H-NMR (DMSOCH): δ 12.15 (s, 1H), 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, 1H), 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) ⁺ .

Compound 347.

Step A. 3-(4-chlorophenyl)-3-oxo-2-phenylpropanenitrile.

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 stirring the mixture at -78° C. for 30 min, 4-chlorobenzoyl chloride (1.8 g, 10.0 mmol) was added dropwise. The mixture was then stirred at rt. for 2 h. The mixture was diluted with ethyl acetate (30 ml) and neutralized with saturated NH4CL. The organic phase was separated and washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was washed with petroleum ether to give the title intermediate 2 as a white solid (1.3 g, 61% yield).

LC-MS: m/z 256.0/258.0 (M+H) ⁺ .

Step B. 3-(4-chlorophenyl)-4-phenyl-1H-pyrazole-5-amine.

A 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 2 h. Then the mixture was cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (20 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na2SO4 and concentrated in vacuo to give the crude title intermediate 3 as a yellow oil (500 mg, 95% yield) which was used in the next step without purification.

LC-MS: m/z 270.0/272.0 (M+H) ⁺ .

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Step C. 2-(4-chlorophenyl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

A 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 1 h. Then the mixture was cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (10 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give desired product 4.

¹ H-NMR (DMSOCH): δ 12.10 (s, 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H), 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)+.

Compound 348.

To a 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 room temperature. The mixture was heated under reflux overnight. The mixture was diluted with ethyl acetate (50 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated and washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography to give the title intermediate 2 as a light yellow solid (800 mg, 36% yield).

LC-MS: m/z 223.1 (M+H) ⁺ .

Step B. 4-phenyl-3-(pyridin-4-yl)-1H-pyrazol-5-amine.

A mixture of intermediate 2 (500 mg, 2.3 mmol) and hydrazine hydrate (230 mg, 4.6 mmol) in EtOH/AcOH (5/1, 10/2 mL) was refluxed for 2 h. cooled to rt and evaporated. The residue was dissolved in ethyl acetate (15 ml) and neutralized with 10% NaHCO3.

The organic phase was separated and the aqueous phase was extracted with ethyl acetate (15 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title intermediate 3 as a yellow solid (250 mg, 46% yield) which was used in the next step without purification.

LC-MS: m/z 237.1 (M+H) ⁺ .

Step C. 5-methyl-3-phenyl-2-(pyridin-4-yl)-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

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A mixture of intermediate 3 (100 mg, 0.42 mmol) and methyl 3-oxo-2-(quinolin-6yl)butanoate (150 mg, 0.64 mmol) in AcOH (10 mL) was stirred at 100°C for 1 h. The mixture was then cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (10 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give desired product 4.

¹ H-NMR (DMSO-d ₆ ): 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)+.

Compound 349.

Step A. 3-(6-methoxypyridin-3-yl)-3-oxo-2-phenylpropanenitrile.

ABOUT

To a solution of 2-phenylacetonitrile (1.0 g, 8.54 mmol) in THF (20 mL) at -78°C was added LiHMDS (5.1 mL, 10.2 mmol, 2.0 M in THF) dropwise. After the addition, the mixture was stirred at -78° C. for 1 hour. Methyl 6-methoxynicotinate (1.43 g, 8.54 mmol) was then added dropwise. The reaction mixture was slowly heated to rt. and stirred for 12 hours. The reaction was quenched by adding saturated NH ₄ Cl (50 ml), extracted with ethyl acetate (50 ml), washed with water (50 ml) and brine (50 ml), dried with anhydrous sodium sulfate, filtered and concentrated to give the title compound (crude, 2 g) which was used in the next step without further workup without further purification.

Step B. 3-(6-methoxypyridin-3-yl)-4-phenyl-1H-pyrazol-5-amine.

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 (20/5 mL) was stirred at 100°C for 8 hours. After cooling to rt. the mixture was concentrated under vacuum. The residue was diluted with ethyl acetate (20 ml), washed with saturated NaHCO3 (20 ml) and brine (20 ml), dried with anhydrous sodium sulfate and concentrated. The residue was purified using a flash column (petroleum ether/ethyl acetate=3:1) to give 3-(6-methoxypyridin-3-yl)-4-phenyl-1H-pyrazol-5-amine (150 mg) in form of a yellow solid.

LC-MS: m/z 267.0 (M+H) ⁺ .

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Step C. Compound 349. yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

2-(6-methoxypyridin-3-yl)-5-methyl-3-phenyl-6-(quinoline-6-

A mixture of 3-(6-methoxypyridin-3-yl)-4-phenyl-1H-pyrazol-5-amine (150 mg, 0.564 mmol) and methyl 3oxo-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 give the title compound.

1H-NMR (DMSO): δ 12.11 (s, 1H), 8.95 (dd, J=4.16, 1.75 Hz, 1H), 8.37-8.44 (m, 1H), 8.11-8.15 (m, 1H), 8.08 (d, J=8.60 Hz, 1H), 7.97 (d, J=1.61 Hz, 1H), 7.77-7 .80 (m, 1H), 7.75 (dd, J=8.73, 2.01Hz, 1H), 7.58 (dd, J=8.19, 4.16Hz, 1H), 7, 49-7.54 (m, 2H), 7.43-7.48 (m, 1H), 7.37-7.42 (m, 2H), 6.84 (d, J=8.60 Hz, 1H), 3.85(s, 3H), 2.25(s, 3H).

LC-MS: m/z 460.1 (M+H) ⁺ .

Connection 350.

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 at rt. sodium hydride (480 mg, content 60%, 12 mmol). The mixture was heated under reflux for 5 hours, the Mixture was diluted with ethyl acetate (50 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated and washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography to give Intermediate 2 as a yellow solid (800 mg, 31% yield).

LC-MS: m/z 257.0/259.0 (M+H) ⁺ .

Step B. 3-(2-chloropyridin-4-yl)-4-phenyl-1H-pyrazol-5-amine.

A 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 2 h. Then the mixture was cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (10 ml) and neutralized with 10% NaHCO ₃ . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether/ethyl acetate=3:1) to give crude Intermediate 3 as a yellow solid (40 mg, 11% yield).

LC-MS: m/z 271.0/273.0 (M+H)+.

Step C. 2-(2-chloropyridin-4-yl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one.

A 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 1 h. Then the mixture was cooled to rt.

- 238 042905 and evaporated. The residue was dissolved in ethyl acetate (10 ml) and neutralized with 10% NaHCO3.

The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give desired product 4.

¹ H-NMR (DMSO-d ₆ ): δ 12.26 (s, 1H), 8.95 (br. s., 1H), 8.35-8.43 (m, 2H), 8.09 ( d, J=8.6Hz, 1H), 7.93-8.00 (m, 1H), 7.75 (dd, J=8.6, 1.6Hz, 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) ⁺ .

Compound 351.

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 resulting mixture was heated at reflux overnight. The mixture was then treated with hydrochloric acid (2 mol/l) to pH 7 and evaporated. The residue was dissolved in ethyl acetate (50 ml), washed with water (H2O) and brine, dried with anhydrous MgSO ₄ and concentrated in vacuo. The residue was purified by flash chromatography to give Intermediate 2 as a white solid (1.2 g, 72% yield).

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) ⁺ .

Step B. 3-(2-methoxypyridin-4-yl)-3-oxo-2-phenylpropanenitrile.

w

ome

NaHMDS (2.0 mol/l in THF, 3.1 ml) at 0°C. The mixture was kept at 0°C for 30 min and then stirred at rt. during the night. The mixture was diluted with ethyl acetate (30 ml) and neutralized with saturated NH ₄ Cl. The organic phase was separated and washed with saline, dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by flash chromatography to give intermediate 3 as a light yellow solid (640 mg, 50% yield).

1H-NMR (METHANOL-d): δ 8.08-8.11 (m, 1H), 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) ⁺ .

Step C. 3-(2-methoxypyridin-4-yl)-4-phenyl-1H-pyrazol-5-amine.

Mixture of intermediate 3 (320 mg, 1.3 mmol) and hydrazine hydrate (130 mg, 2.6 mmol) in

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EtOH/AcOH (5/1, 10/2 ml) was heated at reflux for 2 h. The mixture was then cooled to

k.t. and evaporated. The residue was dissolved in ethyl acetate (10 ml) and neutralized with 10%

NaHCO3. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether/ethyl acetate 3:1) to give crude intermediate 4 as a yellow solid (250 mg, 74% yield).

LC-MS: m/z 267.1 (M+H) ⁺ .

Step D. 2-(2-methoxypyridin-4-yl)-5-methyl-3-phenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin7(4H)-one.

A mixture of intermediate 4 (250 mg, 0.94 mmol) and methyl 3-oxo-2-(quinolin-6yl)butanoate (340 mg, 1.4 mmol) in AcOH (8 ml) was stirred at 100°C for 1 h. The mixture was then cooled to rt. and evaporated. The residue was dissolved in ethyl acetate (15 ml) and neutralized with

10% _NaHCO3 . The organic phase was separated and the aqueous phase was extracted with ethyl acetate (15 mlx3). The combined organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated in vacuo to give desired product 5.

¹ H-NMR (DMSO-d ₆ ): 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, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H), 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) ⁺ .

Compound 352.

DMFDMA = N N-dimethylformamide dimethyl acetal

Step A. (E)-methyl-3-(dimethylamino)-2-(quinolin-6-yl)acrylate.

A mixture of methyl 2-(quinolin-6-yl)acetate (3.0 g, 14.9 mmol) and N,N-dimethylformamide dimethyl acetal (DMFDMA) (4.0 ml) in DMF was stirred at 85° C. for 12 h. After cooling to rt. the mixture was poured into water, extracted with ethyl acetate, dried with Na ₂ SO ₄ , filtered and concentrated to give a crude product (3.8 g) which was used directly in the next step without further purification.

LC-MS: m/z 257.3 (M+H) ⁺ .

Step B. 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

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 2 h. the solvent was removed under vacuum, saturated NaHCO ₃ (6 ml) was added and the residue was filtered. The filter residue was washed with water (2 ml) and MeOH (2 ml) to give 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one as yellow solid (300 mg, 85% yield).

¹ H-NMR (DMSO-de): δ 12.69 (br. s., 1H), 8.91 (dd, J=4.0, 1.6 Hz, 1H), 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) ⁺ .

Step C. 4-(2-(tert-Butyldimethylsilyloxy)ethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

2,3-Diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]πyrimidin-7(4H)-oneα (200mg, 0.483mmol), (2-bromoethoxy)(tert-butyl) mixture dimethylsilane (173 mg, 0.724 mmol) and Cs ₂ CO ₃ (471 mg, 1.448 mmol) in DMF (10 ml) was stirred at 80°C overnight. After cooling to rt. the mixture was poured into water (20 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with water (2x30 ml) and brine (30 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM=5:100) to give the title compound (130 mg, 47% yield).

LC-MS: m/z 573.2 (M+H) ⁺ .

Step D. 4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

4-(2-(tert-Butyldimethylsilyloxy)ethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one mixture (130 mg, 0.227 mmol) and TBAF (tetrabutylammonium fluoride) (59 mg, 0.227 mmol) in DCM (5 mL) was stirred at rt. for 3 hours. 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 give 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) ⁺ .

Step E. 4-(2-chloroethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

To a solution of 4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6-yl)πirazolo[1,5-a]pyrimidin-7(4H)-one (90 mg, 0.2 mol) SOCl ₂ (0.5 ml) was added dropwise in DCM (5 ml). The mixture was stirred at rt. for 4 hours. The precipitated substances were filtered, washed with ethyl acetate and dried under vacuum, as a result

- 241 042905 which gave 4-(2-chloroethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (80 mg) as an off-white solid which was used directly in the next step without further purification.

LC-MS: m/z 477.0 (M+H) ⁺ .

Step F: Compound 352 -He.

To a solution of 1H-tetrazole (29.4 mg, 0.42 mmol) in DMF (10 ml) NaH (60% dispersion in mineral oil, 12.6 mg, 0.524 mmol) was added in portions at 0°C. The resulting mixture was stirred at 0°C for 25 min. Then 4-(2-chloroethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1.5

a] pyrimidin-7(4H)-one (50 mg, 0.105 mmol). The mixture was heated to 80°C and stirred for 10 h.

After cooling to rt. water was added to give the title compound.

1H-NMR (DMSO-66): δ 8.99 (s, 1H), 8.92 (dd, J=4.30, 1.61 Hz, 1H), 8.41 (d, J=8.33 Hz, 1H), 8.21 (d,

J=1.88Hz, 1H), 8.17(s, 1H), 8.09(d, J=8.87Hz, 1H), 8.00(dd, J=8.87, 2.15 Hz, 1H), 7.59 (dd, J=8.19, 4.16 Hz,

1H), 7.48 (s, 5H), 7.39-7.43 (m, 2H), 7.30-7.35 (m, 3H), 4.84 (t, J=6.04 Hz , 2H), 4.45 (t, J=5.78 Hz, 2H). LC-MS: m/z 511.1 (M+H) ⁺ .

Compound 353.

Stage A1. (E)-methyl-3-(dimethylαmino)-2-(quinolin-6-yl)acrylate.

A mixture of methyl 2-(quinolin-6-yl)acetate (3.0 g, 14.9 mmol) and N,N-dimethylformamide dimethyl acetal (4.0 ml) in DMF was stirred at 85° C. for 12 h. cooling to rt the mixture was poured into water, extracted with ethyl acetate, dried with Na ₂ SO ₄ , filtered and concentrated to give the crude product (3.8 g) which was used directly in the next step without further purification.

LC-MS: m/z 257.3 (M+H) ⁺ .

Stage B1. 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

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 2 h. the solvent was removed under vacuum, saturated NaHCO ₃ (6 ml) was added and

- 242 042905 filtered the precipitate. The filter cake was washed with water (2 ml) and methanol (MeOH) (2 ml) to give 2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidine-7(4H)- it is in the form of a yellow solid (300 mg, 85% yield).

¹ H-NMR (DMSO-06): δ 12.69 (br. s., 1H), 8.91 (dd, J=4.0, 1.6 Hz, 1H), 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) ⁺ .

Stage C1. 4-(2-(tert-Butyldimethylsilyloxy)ethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

2,3-Diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one mixture (200 mg, 0.483 mmol), (2-bromoethoxy)(tert-butyl) dimethylsilane (173 mg, 0.724 mmol) and Cs ₂ CO ₃ (471 mg, 1.448 mmol) in DMF (10 ml) was stirred at 80°C overnight. After cooling to rt. the mixture was poured into water (20 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with water (2x30 ml) and brine (30 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (McOH:DCM=5:100) to give the title compound (130 mg, 47% yield).

LC-MS: m/z 573.2 (M+H) ⁺ .

Stage D1. 4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one.

4-(2-(tert-Butyldimethylsilyloxy)ethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one mixture (130 mg, 0.227 mmol) and TBAF (tetrabutylammonium fluoride) (59 mg, 0.227 mmol) in DCM (5 mL) was stirred at rt. for 3 hours. 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 give 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) ⁺ .

Step A. 2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-4(7H)-yl)ethyl methanesulfonate.

4-(2-hydroxyethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one mixture (250 mg, 0.545 mmol), MsCl ( 187 mg, 1.636 mmol) and Et ₃ N (165 mg, 1.636 mmol) in DCM (10 ml) were stirred at rt. over 3 h. The mixture was concentrated in vacuo and the residue purified by flash chromatography to give 2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5a]pyrimidine-4 (7H)-yl)ethyl methanesulfonate (200 mg) as a white solid.

LC-MS: m/z 537.1 (M+H) ⁺ .

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Step B Compound 353 4-(2-α-minoethyl)-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-a]n-rimidine 7(4H)-oh.

Solution of 2-(7-oxo-2,3-diphenyl-6-(quinolin-6-yl)pyrazolo[1,5-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 sealed tube for 2 days to give the title compound.

Ή-NMR (400 MHz, DMSOCH): δ 8.92 (dd, J=4.03, 1.34 Hz, 1H), 8.34-8.49 (m, 3H), 8.18 (dd, J=9.00, 1.75Hz, 1H), 8.10(d, J=8.87Hz, 1H), 7.58(dd, J=8.19, 4.16Hz, 1H), 7.50 (s, 5H), 7.40 (d, J=2.15 Hz, 2H), 7.28-7.35 (m, 3H), 4.01 (br. s., 2H), 2.56 (br. s., 2H).

LC-MS: m/z 458.0 (M+H) ⁺ .

Connection 354.

Stage A Stage B

2 3

Step A. 5-chloro-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrαzolo[1,5-a]pyrimidine 7(1H)-oh.

To a mixture of 5-chloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(1H)-one (synthesized according to the scheme for compound 286, 2.29 g, 5.36 mmol), Cs ₂ CO ₃ (3.49 g, 10.7 mmol) in DMF (30 ml) was added 1-(chloromethyl)-4-methoxybenzene (0.728 ml). The resulting mixture was stirred at 60°C for 16 hours. The mixture was added to H2O (30 ml) and extracted with dichloromethane (10 mlx3). The organic layer was dried with anhydrous sodium sulfate and concentrated to dryness in vacuo. The resulting solid was washed with methanol (MeOH) (5 ml) to give 5-chloro-1-(4methoxybenzyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine-7(1H) -one (1.6 g) as a white solid.

LC-MS: m/z 548.3 (M+H) ⁺ .

Step B Compound 354 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridazin-3-yloxy)pyrazolo[1,5a]pyrimidin-7(4H)-one.

5-Chloro-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin7(1H)-one mixture (200 mg, 0.365 mmol), KF (1 .7 g, 29 mmol) and 18-crown-6 (481 mg, 1.825 mmol) in NMP (N-methylpyrrolidone)(N-methylpyrrolidone) (3 ml) were stirred at 180°C for 4 h under microwave radiation in in a sealed tube to give 6-(4-methoxyphenyl)-2,3-diphenyl-5-(pyridazin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7(4H)-oh.

¹ H-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) ⁺ .

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Compound 355.

A mixture of 5-chloro-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (synthesized according to the scheme for compound 286, 200 mg, 0.45 mmol) and sodium phenolate (105 mg, 0.9 mmol) in N-methyl2-pyrrolidone (NMP) (3 mL) was stirred at 170° C. for 2 h under microwave irradiation in a sealed tube to give 6-(4- methoxyphenyl)-5-phenoxy-2,3diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one.

¹ H-NMR (DMSO-d ₆ ): δ 7.48 (br. s., 2H), 7.42 (br. s., 4H), 7.26-7.37 (m, 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 ., 3H).

LC-MS: m/z 485.9 (M+H)+.

Compound 356.

Suspension of 5-chloro-7-methoxy-6-(4-methoxyphenyl)-2,3-diphenylpyrazolo[1,5-a]pyrimidine (synthesized according to the scheme for 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, 0.05 mmol, 0.2 eq.) and Cs ₂ CO ₃ (150 mg, 0.46 mmol, 2 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. The residue was purified by flash chromatography to give the title compound 2 (70 mg, 64.2% yield) as a yellow solid.

LC-MS: m/z 520.7 (M+H) ⁺ .

LC-MS: m/z 499.1 (M+n) ⁺ .

Step B Compound 356 6-(4-methoxyphenyl)-2,3-diphenyl-5-(phenylamino)pyrazolo[1,5a]pyrimidin-7(4H)-one.

A solution of 7 7-methoxy-6-(4-methoxyphenyl)-N,2,3-triphenylpyrazolo[1,5-a]pyrimidine-5-amine (70 mg, 0.14 mmol) in 4 M HCl in 1.4 -dioxane (3 ml) was stirred at room temperature. within 2 hours the Solvent and volatiles were removed under vacuum. The mixture was basified with NaHCO ₃ solution to pH 8 and concentrated in vacuo to give the title compound 6-(4-methoxyphenyl)-2,3diphenyl-5-(phenylamino)pyrazolo[1,5-a]pyrimidine-7( 4H)-he.

- 245 042905 ¹ H-NMR (DMSO): 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)+.

Compound 358.

Step A. 6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5 -a]pyrimidin-7(4H)-one.

ΛΑ \ A o O N

Suspension of 6-bromo-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidine-7(4H)- she (synthesized according to the scheme for compound 305, 150 mg, 0.29 mmol) and 6-methoxypyridin-3-ylboronic acid (133 mg, 0.87 mmol), PdCl ₂ (dppf (21 mg, 0.03 mmol) and Na ₂ CO ₃ (61 mg, 0.58 mmol) in 1,4-dioxane/water (10/1 mL) was stirred and heated to 85° C. for 16 h under N _2. The reaction mixture was then cooled to RT The dark filtrate was concentrated in vacuo The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1) to give the title product (40 mg, 25% yield) as a white solid.

LC-MS: m/z 546.3 (M+H) ⁺ .

Step B. 6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)pyrazolo[1,5a]pyrimidin-7(4H)-one.

n

V'AAa \ oh

O N

A mixture of 6-(6-methoxypyridin-3-yl)-5-methyl-2-phenyl-3-(piperidin-1-yl)-4-((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a ]pyrimidin-7(4H)-one (40 mg, 0.07 mmol) and HCl in MeOH (0.5 mol, 10 ml, 5 mmol) were stirred at room temperature. for 1 h, whereby the target product was obtained.

1H-NMR (DMSO-dg): δ 11.47 (br. s., 1H), 8.12 (dd, J=1.6 Hz, 2.8 Hz, 3H), 7.67 (dd, J =2.4Hz, 2.4Hz, 1H), 7.50-7.40(m, 3H), 6.90(d, J=8.0Hz, 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) ⁺ .

Example 2 Biochemical analysis.

In a reaction catalysed by the MAT2A enzyme, L-Met and ATP are converted to SAM, inorganic phosphate and inorganic diphosphate. The enzymatic activity of MAT2A was determined by direct chemical detection of inorganic phosphate by adding sulfuric acid and ammonium molybdate to the reaction mixture with the enzyme, in which highly chromogenic malachite green phosphomolybdate was stoichiometrically formed with absorption maxima at 620–650 nm. Thus, the concentration of malachite green phosphomolybdate generated in the detection reaction is directly related to the amount of product produced by the MAT2A enzyme. For this method of detection and quantification of phosphates, there are several commercial kits, such as PiColorLock Gold (Innova Biosciences).

A typical reaction was performed in a final volume of 50 µl containing buffer (Tris (tris(hydroxymethyl)aminomethane), pH 8.0, 50 mM KCl, 15 mM MgCl ₂ , 300 µM EDTA, bovine serum albumin at a concentration of 0.005% w/v .) and 1 µg/mL MAT2A. Compounds at the desired concentration were added in 1 μl of DMSO; a typical dose-response curve contained ten 3-fold dilution points between compound concentrations. A mixture of MAT2A enzyme and inhibitor was preincubated for 60 min at 25°C; the enzymatic reaction was started by adding L-Met and ATP to a final concentration of 80 and 100 μM, respectively. The reaction was allowed to proceed for 60 min at rt, then the reaction was stopped by adding 13 μl of PiColor Lock reagent. After an additional 5 min incubation at rt. 5 μl PiColor Stabilizer was added and further incubated

- 246 042905 reaction mixtures at 25°C for 25 min. The product obtained was quantified by spectrophotometric analysis at 623 nm and compared with a standard phosphate curve.

The 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-labeled MAT2A, the cells were disrupted by 4 passes through an M-Yl 10 microfluidizer (Microfluidics) set at a pressure of approximately 3.5 MPa (500 psi) and then centrifuged at 22,000 rcf (relative centrifugal field - relative centrifugal field). acceleration) for 20 min at 4°C. The supernatant was collected and loaded at 15 cm/hr onto a Histrap FF 5x1 ml (GE) column, which was equilibrated with 50 mM Tris, 500 mM NaCl, pH 7.4. Host cell contaminants were removed by washing the column with equilibration buffer followed by equilibration buffer containing 20 mM imidazole and 60 mM imidazole to baseline. The MAT2A protein was eluted by adding buffer containing 250 mM imidazole, dialyzed in 50 mM NaCl, 50 mM Tris, pH 7.4, flash frozen in liquid nitrogen and stored at -80° C. until use.

Compounds, which are presented in table. 1 and 2 were tested using the above assay and the compounds were found to inhibit MAT2A with an IC ₅₀ according to the following: (A) less than 100 nM, (B) 100 nM to 1 μM, and (C) 1 up to 10 μm, as shown in table. 3 below.

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Example 3 Cellular Targeting Interaction Assay (SAM).

Measurement of MAT2A activity in cells was carried out by direct quantitative determination of the content of SAM: the product of its enzymatic activity. Cancer cells were treated with suitable MAT2A inhibitors for a suitable incubation period and then the cells were lysed using a reagent that quenched any additional enzymatic activity. Soluble metabolites, including SAM, were collected and the content of SAM was determined directly from the lysate using quantitative LC/MS.

A typical assay was performed using the HCT116 human colon carcinoma cell line, which was genetically engineered to have the MTAP gene removed (commercially available from Horizon Discovery). This cell line was used because the loss of the MTAP gene was determined to predetermine susceptibility to MAT2A inhibitors. Cells were seeded in 96-well plates at the appropriate cell density. Then 24 h later, the cells were treated with a potential inhibitor of MAT2A. Prior to addition to cells, the compound was first serially diluted in DMSO, typically by a 3-fold serial dilution to give 10 dosing points. The compound was then transferred to the working plate in the cell culture medium by adding 5 μl of the compound in DMSO to 495 μl of the cell culture medium. This working material was then added to the cells with an additional 5-fold dilution by adding 25 µl of working material to 100 µl of cells in culture medium. After adding the compound, the cells were incubated at 37°C/5% CO ₂ for 4 hours.

To quantify SAM levels after treatment with compound, cells were gently washed once in ammonium carbonate buffer (75 mM at pH 7.4), placed on dry ice, and lysed with metabolite extraction buffer (80% chilled methanol and 20% acetic acid containing 50 ng/ml deuterated d3SAM). After centrifugation at 4°C and 3200 rpm for 30 min, the supernatant was collected and stored at -80°C until analysis by liquid chromatography-mass spectrometry (LC/MS). LC/MS analysis was performed using Xevo TQS (Milford, MA) operating in positive electrospray mode, with chromatographic separation using a Waters Acquity BEH Amide column. Multiple Response Monitoring (MRM) data were obtained for SAM and the d3SAM standard using the MRM transitions 399.2/250.1 and 402.2/250.1 amu. respectively. In a typical LC/MS assay, the initial flow rate was 0.5 ml/min 25% H ₂ O:ACN (95/5, v/v) - 1% FA (formic acid) -10 mM NH ₄ OAc (mobile phase A), 75% H ₂ O:ACN (5/95, v/v) - 1% FA - 10 mM NH ₄ OAc (mobile phase B), at 0.2 min 25% MA (mobile phase A ), at 0.5 min 65% MA, at 1.1 min 25% MA with a total analysis time of 2.5 min.

Example 4 Cell Proliferation Inhibition Assay.

The effect of a test compound on cancer cell growth was evaluated by treating cancer cells with the compound for 4 days and then measuring proliferation using an ATP-based cell proliferation readout (Cell Titer Glo, Promega Corporation).

In a typical assay, an isogenic pair of HCT116 human colon carcinoma cell lines that differ only in MTAP deletion status (HCT116 MTAP+/+ and HCT116 MTAP-/-) were plated in 96-well plates at appropriate cell densities. Then 24 h later, the cells were treated with a potential inhibitor of MAT2A. Prior to addition to cells, the compound was first serially diluted in DMSO, usually as a 3-fold serial dilution, to give 10 dosing points. The compound was then transferred to the working plate in the cell culture medium by adding 5 μl of the compound in DMSO to 495 μl of the cell culture medium. This working material was then added to the cells with an additional 5-fold dilution by adding 25 µl of working material to 100 µl of cells in culture medium. After compound addition, cells were incubated at 37°C/5% CO2 for 4 days.

To determine the inhibition of cell proliferation, cells were allowed to equilibrate to rt. for 30 min and then treated with 125 µl of Cell Titer Glo reagent. The plate was then shaken for 15 minutes to ensure complete mixing and complete cell lysis. Next, the luminescent signal of the Cell Titer Glo reagent was measured using a plate luminometer and normalized to a standard ATP curve. The indicated measured luminescence value was converted to a proliferation index by subtracting from each data point the ATP luminescence measured for the control plate obtained at the time of treatment with the compound (ie day 0). Compound activity was then presented as % change in proliferation relative to the DMSO intraplate control.

Claims (85)

CLAIM 1. A compound according to formula IA or a pharmaceutically acceptable salt thereof O where RA 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-, 3-14-membered heterocycle, where from 1 to 4 elements of the heterocyclic ring are N, O or S, heterocyclo-C ₁ -C ₆ -alkyl-, where from 1 to The 4 elements of the heterocyclic ring are heteroatoms selected from N, O and S, (3-14 membered heterocyclo)oxy-, C ₆ -C ₁₄ -aryl, (C ₆ -C ₁₄ -aryl)-C ₁ -C ₆ -alkyl-, C ₆ -C ₁₄ -aryloxy-, -(CH2)o-6NR ¹ (CH2)o-6C(0)R ² , NR ¹ R ² , C(O)NR ¹ R ² , NR ¹ C (NR ² )NR ¹ R ² , NR ¹ C(NR ² )(=NR ¹ ), SR ¹ , -CN and -OH; R ^B is selected from the group consisting of H, C ₂ -C ₆ -alkenyl and C ₁ -C ₆ -alkyl; R ^C , R ^d and R ^e are independently selected from the group consisting of C ₃ -C ₁₄ -carbocycle, C ₆ -C ₁₄ -aryl and 3-14-membered heterocycle, where from 1 to 4 elements of the heterocyclic ring are heteroatoms, selected from N, O and S; 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, C ₂ -C ₆ -alkynyl, NH2, -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) and -C ₃ -C ₁₄ -carbocycle , C ₆ -C ₁₄ -aryl and 3-14-membered heterocycle or heterocyclo(C ₁ -C ₆ -alkyl)-, where from 1 to 4 elements of the heterocyclic ring are heteroatoms selected from N, O and S, each the heterocycle independently contains from 5 to 14 ring atoms, contains carbon atoms and at least one N, S or O, and the specified compound according to formula IA is not 4-(3-adamantyl-7-oxo-2cyclopropyl-5-( 4-(trifluoromethyl)phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)benzonitrile, wherein RA is unsubstituted or one or more of C ₁ -C ₆ alkyl, C ₂ -C ₆ -alkenyl, C ₁ -C ₆ -alkoxy, C ₆ -C ₁₄ -aryl and heterocycle in RA are substituted with one or more of R ¹ , OR ¹ , halogen, -N=NR ¹ , NR ¹ R ² , -(C1- C6-alkyl)NR ¹ R ² , -C(O)OR ¹ , -C(O)NR ¹ R ² , -OC(O)R ¹ , -CN, -OP(O)(OR ¹ )1. ₂ or oxo, wherein R ^B is unsubstituted or substituted with one or more R ¹ , wherein said one or more of R ^C , R ^D and R ^E are independently unsubstituted or substituted with one or more of R ¹ , -OR ¹ , halogen, - NR ¹ R ² , -(C ₁ -C ₆ -alkyl)-NR ¹ R ² , -C(O)OR ¹ , -C(O)NR ¹ R ² , -NO2, -CN or oxo, with one or more of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -C ₁₄ aryl, carbocycle or heterocycle in R ¹ and R ² are independently unsubstituted or substituted with one or more of hydroxy, halo, -NH2, -NHC(O)(OC ₁ -C ₆ -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)C ₁ -C ₆ -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 -aryl), 3-14-membered heterocycle or heterocyclo(C ₁ -C ₆ -alkyl)-, where from 1 to 4 ring elements of the heterocycle are N, O or S, or -O(C ₆ -C ₁₄ -aryl), wherein one or more of C ₁ -C ₆ -alkyl, C ₆ -C ₁₄ -aryl and heterocyclo-substituents in one or both of R ¹ and R ² are independently unsubstituted or substituted by one or more of hydroxy, -OC ₁ -C ₆ -alkyl, halogen, -NH2, -(C ₁ -C ₆ -alkyl)NH ₂ , -C(O)OH, CN or oxo. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein RA is unsubstituted. 3. The compound according to claim 1 or its pharmaceutically acceptable salt, where one or more of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₁ -C ₆ -alkoxy, C ₆ -C ₁₄ -aryl and heterocycles in RA are substituted with one or more of R ¹ , OR ¹ , halogen, -N=NR ¹ , NR ¹ R ² , -(C1-C6-alkyl)NR ¹ R ² , -C(O)OR ¹ , -C (O)NR ¹ R ² , -OC(O)R ¹ , -CN, -OP(O)(OR ¹ ) ₁ . ₂ or oxo. 4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^B is unsubstituted. 5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ^B is substituted with one or more R ¹ . 6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein one or more of R ^C , R ^D and R ^E are unsubstituted. 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein one or more of R ^C , R ^D and R ^E is substituted with one or more of R ¹ , -OR ¹ , halogen, -NR ¹ R ² , -(C1- C6-alkyl)-NR ¹ R ² , -C(O)OR ¹ , -C(O)NR ¹ R ² , -NO2, -CN or oxo. 8. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one or more of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -C ₁₄ -aryl, carbocycle or heterocycle in R ¹ and R ² is substituted with one or more of hydroxy, halo, -NH2, -NHC(O)(OC ₁ -C ₆ -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) C ₁ C ₆ -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 -aryl), 3-14-membered - 254 042905 heterocycle or heterocyclo(C1-C ₆ -alkyl)-, where from 1 to 4 ring elements of the heterocycle are N, O or S, or -O(C ₆ -C ₁₄ -aryl). 9. The compound according to claim 1 or its pharmaceutically acceptable salt, where one or more of C 1 -C ₆ alkyl, C ₆ -C ₁₄ aryl and heterocyclo substituents on one or both of R ¹ and R ² are unsubstituted. 10. The compound according to claim 9 or its pharmaceutically acceptable salt, where one or more of C ₁ -C6-αkyl, C ₆ -C ₁₄ -aryl and heterocyclo-substituents in R ¹ and R ² are replaced by one or more of hydroxy, - OC ₁ -C ₆ -alkyl, halogen, -NH ₂ , -(C ₁ -C ₆ -αkyl)NH ₂ , -C(O)OH, CN or oxo. 11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, where RD and R ^E are independently selected from C ₃ -C ₁₄ -carbocycle, C ₆ -C ₁₄ -aryl and 3-14-membered heterocycle, where from 1 to 4 elements of the heterocyclic ring are heteroatoms selected from N, O and S. 12. A compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein RD and R ^E are independently selected from C ₃ -C ₁₄ carbocycle and C ₆ -C ₁₄ aryl. 13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein RD and R ^E are independently selected from C ₅ -C ₇ carbocycle and C ₆ -C ₁₀ aryl. 14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein RD and R ^E are independently selected from cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and phenyl. 15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein one of RD and R ^E is cyclohexyl or cyclohexenyl and the other is phenyl. 16. A compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R ^A is selected from the group consisting of C1- _C6 alkyl, _C2 - _C6 alkenyl, C1- _C6 alkoxy, _C3 -C ₁₄ -carbocycle, (C ₃ -C ₁₄ -carbocyclo)C1-C ₆ -alkyl-, 3-14-membered heterocycle, where from 1 to 4 elements of the heterocyclic ring are N, O or S, heterocyclo (C1- C ₆ -alkyl)-, where from 1 to 4 elements of the heterocyclic ring are N, O or S, C ₆ -C ₁₄ -aryl, (C ₆ -C ₁₄ -aryl) -C 1 -C ₆ -alkyl-, C ₆ -C ₁₄ -aryloxy, -(CH2)o-6NR1(CH2)o-6C(O)R ² , NR1R ² , NR1C(NR ² )NR1R ² , -CN and -OH. 17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R ^A is selected from the group consisting of C1-C ₆ alkyl, -(CH ₂ ) ₀ . ₆ NR1(CH ₂ ) ₀ . ₆ C(O)R ² , NR1R ² and NR1C(NR ² )NR1R ² . 18. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R ^A is C1-C ₆ alkyl or NR1R ² . 19. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R ^A is NR1R ² . 20. A compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein R ¹ is H. 21. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is a compound according to formula IB O where RC is ^C ₃ -C ₁₄ -carbocycle or 3-14-membered heterocycle, where from 1 to 4 elements of the heterocyclic ring are heteroatoms selected from N, O and S; RD and R ^e independently represent C ₃ -C ₁₄ -carbocycle or 3-14-membered heterocycle, where from 1 to 4 elements of the heterocyclic ring are heteroatoms selected from N, O and S; R1 is selected from the group consisting of H, C1- _C6 alkyl, _C3 - _C14 carbocycle and 3-14 membered heterocycle, where 1 to 4 heterocyclic ring elements are heteroatoms selected from N, O and S ; where each heteroaryl in R ¹ contains from 1 to 4 elements of the heteroaryl ring, which are heteroatoms selected from N, O and S, and ^RC is unsubstituted or substituted by one or more of hydroxy, halogen, -NH ₂ , C ₆ - C ₁₄ -aryl, (C ₆ -C ₁₄ -aryl) -C1 -C ₆ -alkyl-, carboxy, -CN, oxo, C1 -C ₆ -alkyl, C1 -C ₆ -alkoxy or -NH (C ₁ - C ₆ -alkyl), where one or more of the substituents C1-C ₆ -alkyl, C1-C ₆ -alkoxy or NH(C ₁ -C ₆ -alkyl) are independently unsubstituted or substituted with one or more of hydroxy, halogen, - NH ₂ , carboxy, -CN or oxo, wherein one or both of ^RD and R ^E are independently unsubstituted or independently substituted with one or more of hydroxy, halogen, -NH ₂ , C ₆ -C ₁₄ -aryl, (C ₆ - C ₁₄ -aryl) -C1-C ₆ -alkyl-, carboxy, -CN, oxo, C1-C ₆ -alkyl, C1-C ₆ -alkoxy or -NH(C ₁ -C ₆ -alkyl), where one or more of the substituents C1-C ₆ -alkyl, C1-C ₆ -alkoxy and NH(C ₁ -C ₆ -alkyl) are independently unsubstituted or substituted with one or more of hydroxy, halogen, -NH2, carboxy, -CN or oxo, where R ₁ is unsubstituted or substituted by one or more of hydroxy, halogen, -NH ₂ , -NO ₂ , -CN, oxo, carboxy, -C(O)OC1-C ₆ -alkyl, (C1-C ₆ -alkyl) OS1-C ₆ -alkyl-, -C (O)NH ₂ , C1-C ₆ -alkyl, -C (O) H, C1-C ₆ -alkoxy, (C ₁ -C ₆ -αkyl) N (H) -C ₆ -C ₁₄ -aryl-, (C ₆ -C ₁₄ -aryl) -C1-C ₆ -alkyl-, 5-7-membered heteroaryl, (5-7-membered heteroaryl) -C1-C ₆ -alkyl -, C ₆ -C ₁₄ -aryloxy, (C ₆ -C ₁₄ -aryl) (C1-C ₆ -alkoxy) -, - 255 042905 (5-7-membered heteroaryl)oxy- or (5-7-membered heteroaryl)(C1-C6-alkoxy), where one or more substituents are C1-C6-alkyl, C1-C6-alkoxy, (Cl -C _b -alkyl) N (H) -, -C (O) OS1-C6-alkyl, (C ₁ -C ₆ -alkyl) OC ₁ -C ₆ alkyl-, -C (O) NH2, C _b - C ₁₄ -aryl, (C _b -C ₁₄ -aryl) C ₁ -C _b -alkyl-, 5-7-membered heteroaryl, (5-7-membered heteroaryl) -C ₁ -C _b -alkyl-, C _b -C ₁₄ -aryloxy, (C _b -C ₁₄ -aryl) (C ₁ -C _b -alkoxy) -, (5-7-membered heteroaryl) oxy- and (5-7-membered heteroaryl) (C ₁ -C _b -alkoxy)- are independently unsubstituted or substituted by one or more of hydroxy, halo, -NH2, (C ₁ -C _b -alkyl)N(H)-, -COOH, -CN or oxo. 22. A compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein ^RC is unsubstituted. 23. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein ^RC is substituted with one or more of hydroxy, halogen, -NH2, C _b -C ₁₄ -aryl, (C _b -C ₁₄ -aryl) -C ₁ -C _b -alkyl-, carboxy, -CN, oxo, C ₁ -C _b -alkyl, C ₁ -C _b -alkoxy or - NH(C ₁ -C _b -alkyl). 24. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein one or more of the substituents C ₁ -C _b -alkyl, C ₁ -C _b -alkoxy or NH(C ₁ -C _b -alkyl) are independently substituted with one or more from hydroxy, halogen, -NH2, carboxy, -CN or oxo. 25. A compound according to any one of claims 21-24, or a pharmaceutically acceptable salt thereof, wherein one or both of R ^d and R ^e are unsubstituted. 26. A compound according to any one of claims 21-24, or a pharmaceutically acceptable salt thereof, wherein one or both of R ^d and R ^e are independently substituted with one or more of hydroxy, halo, -NH2, C ₆ -C ₁₄ -aryl, (C ₆ -C ₁₄ -aryl) -C ₁ -C ₆ -alkyl-, carboxy, -CN, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy or -NH (C ₁ -C ₆ -alkyl ). 27. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein one or more of the substituents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and NH(C ₁ -C ₆ -alkyl) are independently substituted with one or more from hydroxy, halogen, -NH2, carboxy, -CN or oxo. 28. A compound according to any one of claims 21-27, or a pharmaceutically acceptable salt thereof, wherein R ¹ is unsubstituted. 29. A compound according to any one of claims 21-27, or a pharmaceutically acceptable salt thereof, wherein R ¹ is substituted with one or more of hydroxy, halogen, -NH2, -NO2, -CN, oxo, carboxy, -C(O)OC ₁ - C ₆ -alkyl, (C ₁ -C ₆ -alkyl)OC ₁ -C ₆ -alkyl-, -C (O)NH ₂ , C ₁ -C ₆ -alkyl, -C (O) H, "alkoxy, ( C ₁ -C ₆ -alkyl)N (H) -C ₆ -C ₁₄ aryl-, (C ₆ -C ₁₄ -aryl) -C ₁ -C ₆ -alkyl-, 5-7-membered heteroaryl, (5- 7-membered heteroaryl)-C ₁ -C ₆ -alkyl-, “-aryloxy, (“-aryl) (“alkoxy)-, (5-7-membered heteroaryloxy- or (5-7-membered heteroaryl) (C ₁ -C ₆ -alkoxy)-. 30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, where one or more of the substituents "alkyl," alkoxy, (C ₁ -C ₆ -alkyl) N (H) -, - C (O) OC ₁ -C ₆ -alkyl, ("alkyl) O" alkyl-, -C (O) NH ₂ , "-aryl, (C ₆ -C ₁₄ -aryl) C ₁ -C ₆ -alkyl-, 5-7-membered heteroaryl, ( 5-7-membered heteroaryl) -C ₁ C ₆ -alkyl-, "-aryloxy, (C ₆ -C ₁₄ -aryl) (C ₁ -C ₆ -alkoxy)-, (5-7-membered heteroaryl) oxy- and (5-7 membered heteroaryl)(C ₁ -C ₆ -alkoxy)- optionally substituted with one or more of hydroxy, halo, -NH2, (C ₁ -C ₆ -alkyl)N(H)-, -COOH, -CN or oxo. 31. A compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein ^RD is an α-carbocycle. 32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein ^RD is substituted with one or more of hydroxy, halo, -NH2, -C(O)OH, -CN, oxo, "alkyl," alkoxy, or (C ₁ - C ₆ -alkyl)N(H)-. 33. A compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein said "alkyl," alkoxy, or (C ₁ -C ₆ -alkyl) N(H)- are substituted with one or more of hydroxy, halo, -NH2, -C( O)OH, -CN or oxo. 34. A compound according to claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein ^RD is phenyl. 35. A compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein ^RD is cyclohex-1-en-1-yl. 36. A compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein R ^E is an α-carbocycle. 37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein R ^E is substituted with one or more of hydroxy, halo, -NH2, -C(O)OH, -CN, oxo, "alkyl," alkoxy, or (C ₁ - C ₆ -alkyl)N(H)-. 38. The compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein one or more of the substituents "alkyl," alkoxy and (C ₁ -C ₆ -alkyl) N (H) - are substituted with one or more of hydroxy, halogen, -NH ₂ , -C(O)OH, -CN or oxo. 39. The compound according to claim 21 or a pharmaceutically acceptable salt thereof, wherein R ^E is selected from the group consisting of cyclohex-1-en-1-yl, ( ² H ₉ ) cyclohex-1-en-1-yl, cyclohexan-1 ,3-dien-1-yl, 4,4-difluorocyclohex1-en-1-yl, cyclopent-1-en-1-yl, cyclopentyl, pyridin-3-yl, pyridin-2-yl, 4-methoxypyridin-3yl , pyridin-2-yl, 1H-pyrazol-4-yl, 1H-pyrrol-3-yl, 4,4-difluoropiperidin-1-yl, 5,6-dihydro-2Hpyran-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-silt. 40. A compound according to claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R ^E is phenyl. 41. The compound according to claim 40, or a pharmaceutically acceptable salt thereof, wherein ^RD is cyclo- - 256 042905 logex-1-en-1-yl. 42. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein ^RC is substituted with one or more of hydroxy, halogen, -NH2, -C(O)OH, -CN, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy or (C ₁ -C ₆ -alkyl)N(H)-. 43. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, where one or more substituents from C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and (C ₁ -C ₆ -alkyl) N(H) - optional substituted with one or more of hydroxy, halo -NH ₂ , -C(O)OH, -CN or oxo. 44. The compound according to claims 1-20, 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-4methoxyphenyl, 2-chloro-4-hydroxyphenyl, 2-fluoro-4-methoxyphenyl, 3-amino-4-hydroxyphenyl, 3-amino4-fluorophenyl, 3-(N,N-dimethylaminoethoxy)-4 -hydroxyphenyl, 3-chloro-2-hydroxyphenyl, 3-hydroxyethoxy-4-hydroxyphenyl ϊ ιΓΤ h ₂ n. JL JI N Oh AND . 45. The compound of claim 21, 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-2methylquinolin-6-yl, 2-aminoquinazolin-6-yl, 4-aminoquinazolin-6 -yl, cinnolin-6-yl, quinoxalin-6yl, 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[1,2a]pyridin-6-yl, 46. A compound according to claim 44, or a pharmaceutically acceptable salt thereof, wherein ^RC is 4-methoxyphenyl. 47. A compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a 3-14 membered heterocycle. 48. A compound according to claim 47, or a pharmaceutically acceptable salt thereof, wherein R ¹ is substituted with one or more of hydroxy, halogen, -NH2, -NO ₂ , -C(O)OH, -C(O)OC ₁ -C ₆ - alkyl, (C ₁ -C ₆ -alkyl)N(H)C(O)-, -CN, oxo, C ₁ -C ₆ -alkyl, -C(O)H, C ₁ -C ₆ -alkoxy or ( C ₁ -C ₆ -αkyl)N(H)-. 49. The compound according to claim 48 or its pharmaceutically acceptable salt, where one or more of the substituents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and (C ₁ -C ₆ -alkyl)N(H)-, C(O)OC ₁ -C ₆ -alkyl and (C ₁ -C ₆ -alkyl)N(H)C(O)- substituted with one or more of hydroxy, halogen, -NH2, (C ₁ -C ₆ -alkyl )N(H), -C(O)H, -CN or oxo. - 257 042905 50. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein 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 and 1,2,4-triazin-3-yl, each optionally substituted with one or more of F, Cl, CN, OH, - NO2, -NH2, -NHMe, -C(O)NH ₂ or methoxy. 51. The compound of claim 50 wherein R ¹ is optionally substituted with one or more of F, Cl, CN, OH, -NO ₂ , -NH2 , -NHMe, -C(O)NH2 or methoxy. 52. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, where R ¹ is selected from the group consisting of - 258 042905 53. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, where R ¹ is selected from the group consisting of 54. Compound of formula (I) or a pharmaceutically acceptable salt thereof where ring A and ring B are independently C ₃ -C ₁₄ carbocycle or heterocycle, each of which is unsubstituted or substituted by one or more of hydroxy, halogen, amino, carboxy, CN, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy or alkylamino, where one or more of the substituents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and C ₁ -C ₆ -alkylamino are independently unsubstituted or substituted by hydroxy, halogen, amino, carboxy CN or oxo; ring C is a C ₃ -C ₁₄ carbocycle or heterocycle; And R1 is H or C ₁ -C ₆ alkyl, C ₃ -C ₁₄ carbocycle or heterocycle; where each heterocycle or heteroaryl independently contains 5-14 ring atoms and contains carbon atoms and at least one N, S or O; ring C is unsubstituted or substituted by one or more of hydroxy, halogen, amino, carboxy, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ alkylamino, wherein one or more of the substituents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and C ₁ -C ₆ -alkylamino are unsubstituted or substituted by hydroxy, halogen, amino, carboxy, CN or oxo; R1 is unsubstituted or substituted by one or more of hydroxy, halogen, amino, NO ₂ , CN, oxo, carboxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkoxyalkyl, aminocarbonyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ -acyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₄ -aryl, C ₆ -C ₁₄ -aryl-C ₁ -C ₆ -alkyl, heteroaryl, heteroaryl-C ₁ -C ₆ -alkyl, C ₆ -C ₁₄ -aryloxy, C ₆ -C ₁₄ -aryl-C ₁ -C ₆ -alkoxy, heteroaryloxy or heteroaryl-C ₁ O ₆ -alkoxy, where one or more of substituents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aminocarbonyl , C ₆ -C ₁₄ -aryl, C ₆ -C ₁₄ -aryl-C ₁ -C ₆ - 259 042905 alkyl, heteroaryl, heteroaryl-C1-C ₆ -alkyl, C ₆ -C ₁₄ -aryloxy, C ₆ -C ₁₄ -aryl-C1-C ₆ -alkoxy, heteroaryloxy and heteroaryl-C1-C ₆ -alkoxy are independently unsubstituted or substituted with hydroxy, halogen, amino, C ₁ -C ₆ -alkylamino, carboxy, CN or oxo. 55. The compound of claim 53, wherein each of Ring A and Ring B is optionally substituted with one or more of hydroxy, halo, amino, carboxy, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or alkylamino. 56. A compound according to claim 54 or 55, or a pharmaceutically acceptable salt thereof, wherein one or both of ring A and ring B are unsubstituted. 57. A compound according to claim 54 or 55, or a pharmaceutically acceptable salt thereof, wherein one or both of ring A and ring B are substituted with one or more of hydroxy, halo, amino, carboxy, CN, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy or C ₁ -C ₆ -alkylamino. 58. The compound according to claim 57 or a pharmaceutically acceptable salt thereof, wherein one or more of the substituents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and C ₁ -C ₆ -alkylamino are substituted by hydroxy, halogen, amino, carboxy , CN or oxo. 59. A compound according to any one of claims 54-57, or a pharmaceutically acceptable salt thereof, wherein ring C is unsubstituted. 60. The compound according to any one of claims 54-57, or a pharmaceutically acceptable salt thereof, wherein ring C is substituted with one or more of hydroxy, halo, amino, carboxy, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ -alkoxy or C ₁ -C ₆ -alkylamino. 61. The compound according to claim 60 or a pharmaceutically acceptable salt thereof, wherein one or more of the substituents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkOcci and C ₁ -C ₆ -alkylamino are substituted by hydroxy, halogen, amino, carboxy , CN or oxo. 62. A compound according to any one of claims 54-61, or a pharmaceutically acceptable salt thereof, wherein R1 is unsubstituted. 63. The compound according to any one of claims 54-61, or a pharmaceutically acceptable salt thereof, wherein R ¹ is substituted with one or more of hydroxy, halogen, amino, NO ₂ , CN, oxo, carboxy, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkoxyalkyl, aminocarbonyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -acyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₄ -aryl, C ₆ -C ₁₄ -aryl-C ₁ -C ₆ -alkyl, heteroaryl, heteroaryl-C ₁ -C ₆ -alkyl, C ₆ -C ₁₄ -aryloxy, C ₆ -C ₁₄ -aryl-C ₁ -C ₆ -alkoxy, heteroaryloxy or heteroaryl-C ₁ -C ₆ alkoxy. 64. The compound according to claim 63 or a pharmaceutically acceptable salt thereof, where one or more of the substituents is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -alkoxycarbonyl , C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, aminocarbonyl, C ₆ -C ₁₄ -aryl, C ₆ -C ₁₄ -aryl-C ₁ -C ₆ -alkyl, heteroaryl, heteroaryl-C ₁ - C ₆ -alkyl, C ₆ -C ₁₄ -aryloxy, C ₆ -C ₁₄ -aryl-C ₁ -C ₆ -alkoxy, heteroaryloxy and heteroaryl-C ₁ -C ₆ -alkoxy are substituted by hydroxy, halogen, amino, C ₁ - C ₆ -alkylamino, carboxy, CN or oxo. 65. The compound according to claim 1 or 54, which is selected from the following table, or a pharmaceutically acceptable salt thereof: - 260 042905 - 261 042905 - 262 042905 - 263 042905 - 264 042905 - 265 042905 - 266 042905 - 267 042905 - 268 042905 - 269 042905 66. The compound according to claim 1, which is selected from the following table, or its pharmaceutically acceptable salt: - 270 042905 - 271 042905 - 272 042905 - 273 042905 - 274 042905 - 275 042905 - 276 042905 - 277 042905 - 278 042905 - 279 042905 - 280 042905 - 281 042905 or a pharmaceutically acceptable salt thereof. 68. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 69. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. - 282 042905 70. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 71. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 72. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 73. A method for inhibiting the synthesis of S-adenosylmethionine (SAM) from methionine and adenosine triphosphoric acid (ATP) under the action of methionine adenosyltransferase-2A (MAT2A) in a cell, which includes introducing into said cell an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1- 72. 74. A method of treating cancer in a subject suffering from it, wherein said cancer is characterized by reduced or absent expression of the methylthioadenosine phosphorylase (MTAP) gene, the absence of the MTAP gene, or reduced function of the MTAP protein, comprising administering to said subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of pp.1-72. 75. The method of claim 74, wherein said cancer is selected from the group consisting of neuroblastoma, rectal carcinoma, colon carcinoma, familial adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, lip carcinoma, laryngeal carcinoma, hypopharynx carcinoma, carcinoma tongue, salivary gland carcinomas, gastric carcinomas, adenocarcinomas, medullary thyroid carcinomas, papillary thyroid carcinomas, renal carcinomas, renal parenchymal carcinomas, ovarian carcinomas, cervical carcinomas, corpus uterine carcinomas, endometrial carcinomas, choriocarcinomas, pancreatic carcinomas, prostate carcinomas glands, testicular carcinomas, breast carcinomas, bladder carcinomas, melanomas, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia/lymphoma, hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratomas, retinoblastomas, choroidal melanomas, seminomas, rhabdomyosarcomas, craniopharyngiomas, osteosarcomas, chondrosarcomas, myosarcomas, liposarcomas, fibrosarcomas, Ewing's sarcomas, and plasmacytomas. 76. The method of claim 75, wherein said cancer has a null MTAP level. 77. The method of claim 74 or 75, wherein said cancer contains a KRAS mutation. 78. The method of claim 77, wherein said KRAS mutation is an amino acid substitution at residue 12 or 13. 79. The method of claim 77 wherein said KRAS mutation is G12C, G12R, G12V, or G13D. 80. The method of claim 75 or 76, wherein said cancer contains a p53 mutation. 81. The method of claim 80, wherein said p53 mutation is Y126_splice, K132Q, M133K, R174fs, R175H, R196*, C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C, R1582W or R280K. 82. A pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 72 and a pharmaceutically acceptable carrier, for inhibiting synthesis - 283 042905 S-adenosylmethionine (SAM) from methionine and ATP by MAT2A in the cell. 83. A pharmaceutical composition for the treatment of a disease or condition mediated by MAT2A overexpression, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-72 and a pharmaceutically acceptable carrier. 84. Pharmaceutical composition for the treatment of cancer characterized by decreased or absent expression of methylthioadenosine phosphorylase (MTAP), absence of the MTAP gene, or reduced function of the MTAP protein, comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-72 and a pharmaceutically acceptable carrier. 85. The use of a compound according to any one of claims 1-72, or a pharmaceutically acceptable salt thereof, for inhibiting the synthesis of S-adenosylmethionine (SAM) from methionine and ATP by MAT2A in a cell. 86. The use of a compound according to any one of claims 1-72, or a pharmaceutically acceptable salt thereof, for the treatment of cancer in a subject suffering from it, wherein said cancer is characterized by reduced or absent expression of methylthioadenosine phosphorylase (MTAP), the absence of the MTAP gene, or reduced function of the MT AP protein.