EA041815B1 - HETEROBICYCLIC MAT2A INHIBITORS AND METHODS OF USE FOR THE TREATMENT OF CANCER - Google Patents

Description

Prerequisites for the creation of the invention

Methionine adenosyltransferase (MAT), which is also known as S-adenosylmethionine synthetase, is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP, catalysis being considered the rate-limiting step of the methionine cycle. SAM is a donor of the propylamino group in the biosynthesis of polyamines, 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.

The two genes, designated MAT1A and MAT2A, code for two different catalytic isoforms of MAT, respectively. The third gene, MAT2B, encodes the regulatory subunit of MAT2A. MAT1A is specifically expressed in the liver of adults, while MAT2A is widely distributed. Since MAT isoforms differ in catalysis kinetics and regulatory properties, cells expressing MAT1A are characterized by a significantly higher content of SAM than cells expressing MAT2A. Reduced MAT2A promoter methylation 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 provides better growth of hepatoma cells. Since MAT2A plays a key role in promoting hepatoma cell growth, it is a target for anticancer therapy. Recent studies have shown that suppression of expression using small interfering RNA significantly suppresses growth and induces apoptosis of hepatoma cells (see, for example, T. Li et al., J. Cancer 7(10) (2016) 13171327).

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

MAT2A is deregulated in other cancers that lack MTAP deletion, including hepatocellular carcinoma and leukemia (J. Cai et al., Cancer Res. 58 (1998) 1444-1450; T.S. Jani et al., Cell. Res. 19 (2009 ) 358-369)). Suppression of MAT2A expression by RNA interference results in antiproliferative effects in various cancer models (H. Chen et al., Gastroenterology 133 (2007) 207-218; Q. Liu et al. Hepatol. Res. 37 (2007) 376-388) .

Many malignant human and mouse cells have lost MTAP activity. MTAP deficiency is not only found in tissue culture cells, but is also present in primary leukemias, gliomas, melanomas, pancreatic cancers, non-small cell lung cancers (NSCLC), bladder cancers, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcomas, ovarian cancers, endometrial cancers, breast cancers, soft tissue sarcomas, non-Hodgkin's lymphoma, and mesotheliomas. The gene encoding human MTAP is expressed in the 9p21 region of human chromosome 9p. This region also contains the tumor suppressor genes p16INK4A (also known as CDKN2A) and p15INK4B. These genes encode p16 and p15, which are inhibitors of the cyclin D-dependent kinases cdk4 and cdk6, respectively.

The p16INK4A transcript can alternatively be spliced in an alternate reading frame (ARF) to produce a transcript encoding p14ARF. p14ARF binds to MDM2 and prevents degradation of p53 (Pomerantz et al. (1998) Cell 92:713-723). The 9p21 region is of interest because it is frequently homozygous deleted in a variety of cancers, including leukemias, NSCLC, pancreatic cancers, gliomas, melanomas, and mesotheliomas. Deletions often inactivate more than one gene. For example, in Cairns et al. ((1995) Nat. Gen. 11:210-212) it was reported that after studying more than 500 primary tumors, almost all deletions identified in such tumors included a 170 kb region containing MTAP, p14ARF and p16INK4A. In Carson et al. (WO 99/67634) it was 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, it has been reported that a deletion of the MTAP gene, but not p16INK4A, indicates an early stage of cancer, while a deletion of the genes encoding p16 and MTAP indicates a later stage of cancer. In some patients with osteosarcoma, the MTAP gene was present at diagnosis but was deleted at a later time point (Garcia-Castellano et al., Clin. Cancer Res. 8(3) 2002 782-787).

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Brief summary of the invention

The invention relates to compounds that inhibit MAT2A. The compounds and their pharmaceutical compositions are useful in methods of treating a variety of cancers, including tumors that are refractory to conventional therapies such as surgery, radiation therapy, chemotherapy, and hormonal therapy.

Thus, in some embodiments, the present invention relates to compounds according to formula (IA) or pharmaceutically acceptable salts thereof:

R- R ,:K .L L .R'

O' γ N L (ΙΑ),

In formula (IA), L is O, S, NR, or a bond; and R is H or C ₁ -C ₆ alkyl.

R ¹ is selected from the group consisting of C ₁ -C ₆ alkyl and C ₃ -C ₆ carbocyclyl, where any alkyl in R ¹ is straight or branched and R ¹ is optionally substituted with 1-6 halogens.

Alternatively, if L is NR, then R and R ¹ in combination with L are 3-6 membered heterocycloalkyl, where 1-4 ring atoms are independently selected from N, O, and S.

R ² and R ³ are independently selected from the group consisting of C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, where 1-4 heteroaryl atoms are independently selected from N, O and S, and 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N, O and S. R ² and R ³ are independently and optionally substituted with one or more substituents selected from the group consisting of RA, ORA and halogen.

R ⁴ and R ⁵ are independently selected from the group consisting of H and C ₁ -C ₆ -alkylα.

RA is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C ₃ -C ₁₄ carbocyclyl, 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N, O and S, and 5-10 membered heteroaryl, where 1-4 heteroaryl atoms are independently selected from N, O and S.

Each alkyl or alkoxy moiety in R ^A is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo and S(0) _0-2 -(C ₁ -C ₆ alkyl).

According to additional embodiments, the present invention relates to compounds according to formula (IB) or their pharmaceutically acceptable salts:

where L is O, S, NR, or a bond;

R represents H or C ₁ -C ₆ -alkyl;

R ¹ is selected from the group consisting of C ₁ -C ₆ -alkyl and C ₃ -C ₆ -carbocyclyl, where any alkyl in R ¹ is straight or branched, and

R ¹ is optionally substituted with 1-6 halogens;

or if L is NR, then R and R ¹ in combination with L are 3-6 membered heterocycloalkyl, where 1-4 ring atoms are independently selected from N, O and S;

R ² and R ³ are independently selected from the group consisting of C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, where 1-4 heteroaryl atoms are independently selected from N, O and S, and 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N, O and S, where R ² and R ³ are independently and optionally substituted with one or more substituents selected from the group consisting of RA, ORA, NR ^A R ^B and halogen;

R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of H and C ₁ -C ₆ -αkylα;

RA and R ^B are independently selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C ₃ -C ₁₄ carbocyclyl, and 5-10 membered heteroaryl, where 1-4 heteroaryl atoms independently selected from N, O and S.

Each alkyl or alkoxy moiety in RA is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen and -S(O) _0-2 -(C1-C ₆ alkyl).

According to additional embodiments, the present invention relates to compounds according to formula II or their pharmaceutically acceptable salts:

In formula (II), L is O, S, NR, or a bond; and R is H or C ₁ -C ₆ alkyl. R ¹ is selected from the group consisting of C ₁ -C ₆ alkyl and C ₃ -C ₆ carbocyclyl, wherein any alkyl in R ¹ is straight or branched and R ¹ is optionally substituted with 1-6 halogens.

Alternatively, in some embodiments, if L is NR, then R and R ¹ in combination with L are 3-6 membered heterocycloalkyl, where 1-4 ring atoms are independently selected from N, O, and S, optionally substituted one or more R ^A .

R ² and R ³ are independently selected from the group consisting of C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, where 1-4 heteroaryl atoms are independently selected from N, O and S, and 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N, O and S, where R ² and R ³ are independently and optionally substituted with one or more substituents selected from the group consisting of R ^A , OR ^A , halogen.

Both R ⁴ and R ⁶ are H.

R ^a is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy.

Each alkyl and alkoxy moiety in R ^A is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen.

Compounds of formula (IA), (IB) or formula (II), or their pharmaceutically acceptable salts, may be formulated into a pharmaceutical composition also containing a pharmaceutically acceptable carrier.

Compounds of formula (IA), (IB) or formula (II), or pharmaceutically acceptable salts thereof, may be used to inhibit SAM synthesis in a cell, comprising contacting the cell with an effective amount of a compound of formula (IA), (IB) or formula (II) or a pharmaceutically acceptable salt thereof.

Compounds of formula (IA), (IB) or formula (II), or pharmaceutically acceptable salts thereof, can be used to inhibit SAM synthesis in a subject, comprising administering to the subject an effective amount of a compound of formula (IA), (IB) or formula (II) , or a pharmaceutically acceptable salt thereof.

Another embodiment is a method of treating cancer in a subject suffering from a tumor, comprising administering to the subject an effective amount of a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is an MTAP (methylthioadenosine phosphorylase) deletion cancer.

In an embodiment, also provided is a method of treating a cancer in a subject suffering from a tumor, wherein the cancer is characterized by decreased or absent MTAP gene expression, or reduced or absent MTAP protein function, compared to cancers in which the MTAP gene or protein is present and/ or fully functional, or compared to wild-type MTAP cancers, comprising administering to a subject a therapeutically effective amount of a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt thereof.

According to another embodiment, optionally in combination with any other embodiment described herein, the present invention relates to a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt thereof, useful for inhibiting SAM synthesis in a cell. . Alternatively, in some embodiments, optionally in combination with any other embodiment described herein, the compound is useful for inhibiting SAM synthesis in a subject. Another embodiment, optionally in combination with any other embodiment described herein, relates to the use of a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament to inhibit synthesis in a subject. SAM.

Yet another embodiment, optionally in combination with any other embodiment described herein, relates to a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject suffering from a tumor. . One embodiment, optionally in combination with any other embodiment described herein, is the use of a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in subject suffering from a tumor. In some embodiments, the cancer is a cancer with a deletion of MTAP, or is characterized by reduced or no expression of the MTAP gene, or reduced function of the MTAP protein, compared to cancers with expression or function of a fully functional MTAP gene, or cancers with full function of the MTAP gene. functional protein MTAP.

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Detailed description of the invention

The compounds described herein are MAT2A inhibitors. Therefore, the present invention relates to such compounds having a structure according to formula (IA), (IB) or formula (II), as well as to pharmaceutical compositions containing them. The compounds and compositions disclosed herein are useful in the treatment of cancer. Some cancers include various MTAP deletion cancers, ie. malignant tumors characterized by the absence or deletion of the MTAP gene.

Definitions.

Alkyl refers to straight, branched, or cyclic hydrocarbon groups, such as cycloalkyl, containing from 1 to about 20 carbon atoms. For example, alkyl may contain 1 to 10 carbon atoms or 1 to 6 carbon atoms. Exemplary alkyl includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like, and also includes branched straight chain alkyl isomers. groups, for example, without limitation -CH (CH ₃ ) ₂ , -CH (CH 3 ₎ (CH ₂ CH ₃ ), -CH (CH ₂ CH ₃ ) ₂ , -C (CH 3 ) 3 , -C (CH 2 CH 3 ) 3 , -CH2CH(CHz)2, -CHSCHSSCHMSCHSNz), -CHSCHSSCHSNz, -CH2C(CH3)3, -CH2C(CH2CH3)3, -CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CH2)2, - CH2CH2CH(CH3)(CH2CH3), -CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3, -CH(CH3)CH2CH(CH3)2,

-CH(CH ₃ )CH(CH ₃ )CH(CH ₃ ) ₂ , etc. Thus, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. The alkyl group may be unsubstituted or may be optionally substituted with one or more substituents described herein below.

The term "substituted alkyl" refers to an alkyl substituted at one or more positions, such as 1, 2, 3, 4, 5 or even 6 positions, whose substituents are attached to any available atom to form a stable compound by the substitution described herein. Optionally substituted alkyl refers to alkyl or substituted alkyl.

Each of the terms halogen, halide, or halo refers to F, Cl, Br, or I.

The term alkenyl refers to straight, branched or cyclic hydrocarbon groups, such as cycloalkenyl, containing from 2 to about 20 carbon atoms and containing 1-3, 1-2, or at least one carbon-carbon double bond. The term cycloalkenyl more specifically refers to alkenyl, such as C ₃ -C ₆ -cycloalkenyl. The alkenyl group may be unsubstituted or may be optionally substituted with one or more substituents described herein below.

Substituted alkenyl refers to alkenyl substituted at 1 or more, such as 1, 2, 3, 4, 5 or even 6 positions, whose substituents are attached to any available atom to form a stable compound by substitution described herein. Optionally substituted alkenyl refers to alkenyl or substituted alkenyl.

Alkyne or alkynyl refers to a straight or branched unsaturated hydrocarbon containing the specified number of carbon atoms and at least one triple bond. Examples of the (C ₂ -C ₈ )alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1pentyne, 2-pentyne, 1-hexine, 2-hexine, 3-hexine, 1-heptine, 2 -heptin, 3-heptin, 1-octyne, 2-octyne, 3-octyne and 4-octyne. The alkynyl group may be unsubstituted or may be optionally substituted with one or more substituents described herein below.

Substituted alkynyl refers to alkynyl substituted at 1 or more, such as 1, 2, 3, 4, 5 or even 6 positions, whose substituents are attached to any available atom to form a stable compound by substitution described herein. Optionally substituted alkenyl refers to alkynyl or substituted alkynyl.

The term alkoxy refers to an O-alkyl group containing the specified number of carbon atoms. For example, the (C1-C ₆ )alkoxy group includes -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-sec-butyl, -O-tert-butyl , -O-pentyl, -O-isopentyl, -O-neopentyl, O-hexyl, -O-isohexyl and -Oneohexyl.

The term carbocyclyl refers to a monocyclic, bicyclic, tricyclic or polycyclic 3 to 14 membered ring system which is either saturated as cycloalkyl or unsaturated as cycloalkenyl. The carbocyclyl may be attached at any atom. For example, carbocyclyl also provides fused rings, in which carbocyclyl, for example, is fused to an aryl or heteroaryl ring as defined herein. Illustrative examples of carbocyclyl include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, phenyl, naphthyl, anthracyl, benzofuranyl, and benzothiophenyl. The carbocyclyl group may be unsubstituted or may be optionally substituted with one or more substituents as described herein below.

Substituted carbocyclyl refers to a carbocyclyl substituted at 1 or more, for example 1, 2, 3, 4, 5 or even 6 positions, whose substituents are attached to any available atom to give a stable compound by substitution described herein. document. Optionally substituted carbocyclyl refers to carbocyclyl or substituted carbocyclyl.

Aryl, used alone or as part of another term, means a carbocyclic aromatic group, fused or unfused, containing the number of carbon atoms indicated, or up to 14 carbon atoms when the number is not indicated, as in the case of C ₆ -C ₁ 4-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. Table 7-2 [1985]). Specific aryl is phenyl. Aryl also includes aromatic ring systems that are optionally fused to a carbocyclyl ring as defined herein. The aryl group may be unsubstituted or may be optionally substituted with one or more substituents described herein below.

A substituted aryl is an aryl that is independently substituted with one or more substituents attached to any available atom to form a stable compound, where the substituents are described herein. Optionally substituted aryl refers to aryl or substituted aryl.

The term heteroatom refers to N, O, and S. The disclosed compounds that contain N or S atoms may optionally be oxidized to the corresponding N-oxides, sulfoxides, or sulfone compounds.

Heteroaryl, alone in combination with any other moiety described herein, refers to a monocyclic aromatic ring structure containing 5-10, e.g. 5 or 6 ring atoms, or a bicyclic aromatic group containing 8-10 atoms containing one or more , for example 1-4, 1-3 or 1-2 heteroatoms independently selected from the group consisting of O, S and N. Heteroaryl is also contemplated to include oxidized S or N forms such as sulfinyl, sulfonyl and N -oxide of the tertiary ring nitrogen atom. A carbon atom or heteroatom is the site of attachment of a heteroaryl ring structure, resulting in the formation of a stable compound. Examples of heteroaryl groups include, without limitation, pyridinyl, pyridazinyl, pyrazinyl, quinoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl and indolyl. The heteroaryl group may be unsubstituted or may be optionally substituted with one or more substituents as described herein below.

A substituted heteroaryl is a heteroaryl which is independently substituted, unless otherwise indicated, with one or more, e.g., 1, 2, 3, 4, or 5, also 1, 2, or 3, substituents, also 1 substituent, attached to any available atom with obtaining a stable compound, where the substituents are described in this document. Optionally substituted aryl refers to heteroaryl or substituted heteroaryl.

Heterocycloalkyl means a saturated or unsaturated non-aromatic monocyclic, bicyclic, tricyclic or polycyclic ring system that contains from 3 to 14, for example 3-6, atoms, where from 1 to 3 carbon atoms in the ring are replaced by O, S or N heteroatoms. Heterocycloalkyl optionally fused to an aryl or heteroaryl of 5 to 6 ring atoms and includes oxidized S or N forms such as sulfinyl, sulfonyl and N-oxide of the tertiary ring nitrogen atom. The point of attachment of the heterocycloalkyl ring is on a carbon atom or heteroatom, resulting in the formation of a stable ring. Examples of heterocycloalkyl groups include, without limitation, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl.

The heterocycloalkyl group may be unsubstituted or may be optionally substituted with one or more substituents as described herein below.

Optionally substituted heterocycloalkyl means a heterocycloalkyl which is substituted with 1-3 substituents, eg 1, 2 or 3 substituents, attached to any available atom to form a stable compound, where the substituents are described herein.

The terms nitrile or cyano may be used interchangeably and refer to the -CN group that is bonded to the carbon atom of a heteroaryl ring, an aryl ring, and a heterocycloalkyl ring.

The term oxo refers to the =O atom attached to a saturated or unsaturated moiety. The ═O atom may be attached to a carbon, sulfur or nitrogen atom that is part of a cyclic or acyclic moiety.

Hydroxyl or hydroxy refers to the -OH group.

The -CO ₂ H substituent can be replaced with bioisosteric substitutions such as

- 5 041815, etc., where R is characterized by the same definition as defined herein R ^A (see, for example, THE PRACTICE OF MEDICINAL CHEMISTRY (Academic Press: New York, 1996), p. 203).

The compounds described herein may exist in various isomeric forms, including configurational, geometric, and conformational isomers, including, for example, cis or trans conformations. The compounds may also exist in one or more tautomeric forms, including both individual tautomers and mixtures of tautomers. The term isomer is intended to encompass all isomeric forms of a compound of the present disclosure, including tautomeric forms of a compound. Compounds according to the present disclosure may also exist in acyclic or cyclized forms. In some cases, one or more of the cyclized forms may be the result of water loss. The specific composition of the acyclic or cyclized forms may depend on how the compound was isolated, stored, or administered. For example, a compound may exist predominantly in an acyclic form under acidic conditions, but cyclize under neutral conditions. All forms are included in the present invention.

Some of the compounds described herein may contain asymmetric centers and therefore exist in various enantiomeric and diastereomeric forms. The compound according to the present disclosure may be in the form of an optical isomer or diastereoisomer. Accordingly, the present invention encompasses the compounds described herein, in the form of their optical isomers, diastereoisomers, and mixtures thereof, including a racemic mixture, and their uses. Optical isomers of the compounds of the present disclosure can be obtained according to known techniques such as asymmetric synthesis, chiral chromatography, pseudo-moving bed technology, or by chemical separation of stereoisomers using optically active resolving agents.

Unless otherwise indicated, the term stereoisomer means a stereoisomer of a compound that is substantially free of other stereoisomers of the compound. Thus, a stereoisomerically pure compound containing one chiral center will be substantially free of the compound's opposite enantiomer. A stereoisomerically pure compound containing two chiral centers will be substantially free of other diastereoisomers of the compound. A typical stereoisomerically pure compound contains more than about 80 wt.% of one stereoisomer of the compound and less than about 20 wt.% of other stereoisomers of the compound, for example, more than about 90 wt.% of one stereoisomer of the compound and less than about 10 wt.% of other stereoisomers of the compound, or more than about 95 wt.% of one stereoisomer of the compound and less than about 5 wt.% of other stereoisomers of the compound, or more than about 97 wt.% of one stereoisomer of the compound and less than about 3 wt.% of other stereoisomers of the compound, or more than about 99 wt.% of one stereoisomer of the compound and less about 1 wt.% other stereoisomers of the compound. The stereoisomer described above can be considered as a composition containing two stereoisomers which are present in percentages of the respective mass fractions described above.

If there is a discrepancy between a depicted structure and the name given to that structure, then the depicted structure shall prevail. In addition, if the stereochemistry of a structure or part of a structure is not indicated, for example, by bold or dotted lines, then the structure or part of a structure should be interpreted as encompassing all of its stereoisomers. However, in some cases where there is more than one chiral center, the structures and names may be presented as separate stereoisomers to help describe the relative stereochemistry. From the methods used to prepare the compounds, those skilled in the art of organic synthesis will recognize when the compounds are obtained as single stereoisomers.

Unless expressly and specifically stated to the contrary, the term compound as used herein is inclusive in that it encompasses a compound or a pharmaceutically acceptable salt, stereoisomer and/or tautomer thereof. For example, a compound of formula I or formula II

- 6 041815 includes a pharmaceutically acceptable salt of the compound. By analogy, a compound of formula I or formula II includes a pharmaceutically acceptable salt of the tautomer of the compound.

As used herein, a pharmaceutically acceptable salt is a pharmaceutically acceptable addition salt of an organic or inorganic acid or base to a compound of the present disclosure. Exemplary pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate , benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavularate, dihydrochloride, edetate, edisylate, estolate, esylate, funarate, gluceptate, gluconate, glutamate, glycolylarsan hexalate , hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsilate, nitrate salts, N-methylglucamine, hydroxyl ammonium -2-naphthoate, oleate, oxalate, palmita t, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, para-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate , suramate, tannat, tartrate, theoclate, tosylate, triethiodide and valerate salts. A pharmaceutically acceptable salt may contain more than one charged atom in its structure. In this regard, a pharmaceutically acceptable salt may contain multiple counterions. Therefore, a pharmaceutically acceptable salt may contain one or more charged atoms and/or and one or more counterions.

The terms treat, treat, and treat refer to alleviating or eliminating a disease or symptoms associated with a disease. In certain embodiments, such terms refer to minimizing the spread or worsening of a disease by administering one or more prophylactic or therapeutic agents to a patient or subject with such a disease.

The terms prevent, prophylaxis, and prophylaxis refer to preventing the onset, recurrence, or spread of a disease in a patient or subject as a result of the administration of a prophylactic or therapeutic agent.

The term effective amount refers to an amount of a compound of the present disclosure or other active ingredient sufficient to provide a therapeutic or prophylactic effect in the treatment or prevention of a disease, or to delay or minimize symptoms associated with the disease. In addition, with respect to a compound of the present disclosure, a therapeutically effective amount means an amount of a therapeutic agent, alone or in combination with other treatments, that provides a therapeutic effect in the treatment or prevention of a disease. As used with respect to a compound of the present disclosure, the term may encompass an amount that improves overall treatment, ameliorates or prevents symptoms or causes of a disease, or enhances or synergizes with another therapeutic agent.

The patient or subject includes an animal such as a human, cow, horse, sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig. In some embodiments, the animal is a mammal, such as a non-primate animal or primate (eg, a monkey or a human). In the present disclosure, the terms patient and subject are used interchangeably. In one embodiment, the patient or subject is a human, and in other embodiments, the patient or subject is an infant, child, adolescent, or adult.

An inhibitor means a compound that prevents or reduces the amount of SAM synthesized. In some embodiment, the inhibitor binds to MAT2A.

Connections

As generally described above, the present invention relates to compounds according to formula (IA)

where L is O, S, NR, or a bond;

R represents H or C ₁ -C ₆ -alkyl;

R ¹ is selected from the group consisting of C ₁ -C ₆ -alkyl and C ₃ -C ₆ -carbocyclyl, where any alkyl in R ¹ is straight or branched, and

R ¹ is optionally substituted with 1-6 halogens;

- 7 041815 or if L is NR, then R and R ¹ in combination with L are 3-6 membered heterocycloalkyl, where 1-4 ring atoms are independently selected from N, O and S;

R ² and R ³ are independently selected from the group consisting of C ₆ -C ₁₀ -aryl, 5-10 membered heteroaryl, where

1-4 heteroaryl atoms are independently selected from N, O and S, and 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N, O and S, where R ² and R ³ are independently and optionally substituted with one or more substituents selected from the group consisting of R ^A , OR ^A and halogen;

R ⁴ and R ⁵ are independently selected from the group consisting of H and C ₁ -C ₆ alkyl;

R ^a is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C ₃ -C ₁₄ carbocyclyl, 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N , O and S, and 5-10 membered heteroaryl, where 1-4 heteroaryl atoms are independently selected from N, O and S;

where each alkyl or alkoxy moiety in R ^A is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen and -S(0) _0-2 -(C ₁ -C ₆ alkyl).

Alternatively, the present invention relates to compounds according to formula (IB)

where L is O, S, NR, or a bond;

R represents H or C ₁ -C ₆ -alkyl;

R ¹ is selected from the group consisting of C ₁ -C ₆ -alkyl and C ₃ -C ₆ -carbocyclyl, where any alkyl in R ¹ is straight or branched, and

R ¹ is optionally substituted with 1-6 halogens;

or if L is NR, then R and R ¹ in combination with L are 3-6 membered heterocycloalkyl, where 1-4 ring atoms are independently selected from N, O and S;

R ² and R ³ are independently selected from the group consisting of C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, where 1-4 heteroaryl atoms are independently selected from N, O and S, and 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N, O and S, where R ² and R ³ are independently and optionally substituted with one or more substituents selected from the group consisting of R ^A , OR ^A , NRARB and halogen;

R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of H and C ₁ -C ₆ alkyl;

R ^a and RB are independently selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C ₃ -C ₁₄ carbocyclyl, and 5-10 membered heteroaryl, where 1-4 heteroaryl atoms independently selected from N, O and S;

where each alkyl or alkoxy moiety in R ^A is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen and -S(0) _0-2 -(C ₁ -C ₆ alkyl).

The present invention also relates to compounds according to formula (II) and their pharmaceutically acceptable salts:

^R4

R\,A N. ,.And ^I .. . 11 ,to Ο'''γ ^Ν to No. (ΙΙ)

In formula II, L is O, S, NR, or a bond; and R is H or C ₁ -C ₆ alkyl.

R ¹ is selected from the group consisting of C ₁ -C ₆ alkyl and C ₃ -C ₆ carbocyclyl, where any alkyl in R ¹ is straight or branched and R ¹ is optionally substituted with 1-6 halogens.

Alternatively, in some embodiments, if L is NR, then R and R ¹ in combination with L are 3-6 membered heterocycloalkyl, where 1-4 ring atoms are independently selected from N, O, and S, optionally substituted one or more R ^A .

R ² and R ³ are independently selected from the group consisting of C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, where 1-4 heteroaryl atoms are independently selected from N, O and S, and 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N, O and S, where R ² and R ³ are independently and optionally substituted with one or more substituents selected from the group consisting of R ^A , OR ^A , halogen.

Both R ⁴ and R ⁶ are H.

R ^a and RB are independently selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy.

Each alkyl and alkoxy moiety in R ^A is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen.

In compounds of formula (IA), (IB) or formula (II), optionally in combination with another embodiment, each of R ⁴ , R ⁵ and R ⁶ (if present) may be H. Alternatively, , according to various embodiments, one of R ⁴ , R ⁵ and R ⁶ is H.

For example, R ⁴ is H. In another embodiment, R ⁵ is H. In still another embodiment, R ⁶ is H. In further embodiments, any two of R ⁴ , R ⁵ , and R ⁶ are is H. For example, R ⁴ and R ⁵ are H; R ⁴ and R ⁶ are H; or R ⁵ and R ⁶ are H.

According to other embodiments, in some compounds, R ² is C6C10-aryl or 5-10 membered heteroaryl. For example, R ² is C6- _C10 aryl such as phenyl.

According to another embodiment, in other compounds, R ² is a 5-10 membered heteroaryl that contains N as the only heteroatom in the ring. Thus, for example, R ² is pyridyl.

According to various embodiments, R ³ is 3-14 membered heterocycloalkyl or 5-10 membered heteroaryl. Examples include compounds in which R ³ is a C ₃ -C ₁₀ -heteroaryl containing only 2 ring atoms as heteroatoms independently selected from N, O, and S. Thus, exemplary heteroaryl groups include benzothiazolyl, benzoisothiazolyl .

Other embodiments, optionally in combination with any other embodiment described herein, refer to a compound in which L is O or NR. In these embodiments, R ¹ may be C1-C6 alkyl or C3-C6 carbocyclyl. For example, R ¹ is C1-C ₃ alkyl which is optionally substituted with 1-3 F.

In various embodiments, optionally in combination with any other embodiment, R ³ is C ₆ -C ₁₀ aryl.

Additional embodiments relate to a compound of formula (IA), (IB) or formula (II), in which L represents O or NR. Optionally in combination with said embodiment, embodiments are provided wherein R ¹ is C1-C6 alkyl or C3C6 carbocyclyl. In other embodiments, R ¹ is C 1 -C ₃ alkyl which is optionally substituted with 1 - 3 F.

According to various embodiments, other compounds are compounds in which L is O or NR and R is H; R ¹ is C1-C3 alkyl which is optionally substituted with 1-3 F; R ² is 3-14 membered heterocycloalkyl or 5-10 membered heteroaryl, where 1 ring atom is N, or C6-C ₁₀ aryl; R ³ is a 510-membered heteroaryl in which 1-3 ring atoms are independently selected from N, O and S; and each of R ⁴ , R ⁵ and R ⁶ (if any) is H.

In various embodiments, optionally in combination with any other embodiment, L is NR. For example, in some embodiments, L is NH.

According to various variants of implementation, the present invention relates to specific illustrative examples of spirofused compounds shown below in table. 1.

Table 1

101 G1. _Λ 'ί Ί ... ^with YU Ν - ¹ Ji Ν' Η 102 .0. ' t ... I Ό ... σ- χ Ν' Ν' 'τ7 \ / h V UN N..- 103 F ' ΐ A ...,. II 1 ... O'' · X'N''N' ί '? ^Η ν' ₅ -ν c-J ί. b-m '%; 104 _Ν Λ a, k dry; tg tg

- 9 041815

105 - ^; j '>' _ ' ι ' .1 ' - f > HV \ / I— l-' ^- Ά 106 Ρ-ι No. 9 l 1 i ,. 0- Xb X' N' ; H V Μ··' % A-· N C Ό- 107 0-. No. 9 A 1 1 .,, O - N N --- km χΝ < 9 s-- 108 '°7 N. '.1 j 1. i o'- ><'NX'U7 \ } ^HV N—' \ Cl n N'' H 109 "Ή. . Ν' xi -· -χ ^-- -· _Ν ^H J. ,.. Λ .... O'- XN W x / O ^HV N — to - to 'NH 110 x, , ... ..:> - _N ' N Λ XA o ' XN 'N '01 : r 7 ^ri ' N ' ( N' H 111 ,0, T 1 .. . I rt, Χ ^ν Ή' N ' X / k Ν'' H 112 '°'P ...,. --- N” r^ 'N A D AJ O'- XN ' N ' i ) ^H ( V n I ¹ , N' H FROM AA..1. ,. , 0 ><Ή' ΎΓ С ) Η II ^J V A (I Μ” li 114 .0.. ,ΐ. 11 ...,.. _Ν ' _Ν ,4. J... I , 0---.X JX Ό- Xj _n -nh )m'I,' ./-—/

- 10 041815

The present invention relates to additional specific illustrative examples of compounds of formula (IA) or (IB), shown below in table. 2.

- 11 041815

table 2

- 12 041815

- 13 041815

- 14 041815

- 15 041815

- 16 041815

- 17 041815

- 18 041815

- 19 041815

According to additional options for implementation, the present invention relates to the following specific illustrative compounds are presented in table. 3.

- 20 041815

Table 3

- 21 041815

- 22 041815

- 23 041815

- 24 041815

- 25 041815

- 26 041815

According to additional options for implementation, the present invention relates to the following specific illustrative compounds of formula I, presented below in table. 1-A.

Table 1-A

- 27 041815

105-A ^d- ! .1 J 106-A - . \.λ'' L.1 I 107-A Lk, A. λ-I < . 1 L -i- -- ^{x c} I ¹ j.>F; 108-A q “ J , 1' X-.G- 109-A -«.Yl....... ' Г Ί . 0.--Ύ _N - · _ο ύ О T Br 110-A ^v ,i. D. 1..,..-,, T '' ^u ' % 111-A °1 _l . 112-A 1---.,,..Ar ^x V CCFj 113-A -Ά1.,.., ί ^ή 114-A Ay 115-A -CQ.,^. .1 l 1 ,. ., j h , I 116-A ^Xl V. , 0 117-A ~γΙ'/...... Π Y OCC: 118-A II' ' /v-Y'.' L/Y* Z-4 \7 ίί. ΐ

- 28 041815

- 29 041815

According to various variants of implementation, the present invention relates to specific illustrative examples of compounds of formula II, presented below in table. 2-A.

- 30 041815

Table 2-A

139-A ci. . . XX .1 „ X 9 140-A .-x. x c 141-A CHHH.,,4 V 142-A about i 143-A ύχ _Λ o- [C 7-/ m O, ,F 144-A C ⁿ ' Π F 145-A XX _Y Χ-ΧνΑχ'-., X V 146-A / ζ' Ζ Ζ ί 147-A 148-A χχ _Υ1 X 149-A N.U. O' J 'N' O' -Q O„_,.F F 150-A A.A. Α _Λ cr 'j- 4 τ - CL J ί

Pharmaceutical compositions

Also contemplated is a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds according to formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, in admixture with a pharmaceutically acceptable carrier. In accordance with the generally accepted practice for the preparation of pharmaceutical preparations, the composition additionally contains one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, dyes, buffers, flavoring agents.

Such a pharmaceutical composition may contain a compound selected from the compounds shown in table. 1-3, 1-A and 2-A, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

The pharmaceutical composition is prepared, dosed and administered in a manner consistent with conventional medical practice. Determinative factors in this context include the particular disorder being treated, the particular subject being treated, the clinical condition of the subject, the cause of the disorder, the site of delivery of the agent, the route of administration, the schedule of administration, and other factors known to the attending physician.

The therapeutically effective amount of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) administered is determined by these factors and is the minimum amount necessary to exhibit a cytotoxic effect on the tumor or to inhibit MAT2A activity, or both. Such an amount may be less than the amount that is toxic to normal cells, or to the subject as a whole. Typically, in some embodiments, a therapeutically effective amount of a compound (a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure to be administered is in the range of about 0.01 to about 200 mg/kg, or about

- 31 041815 from about 0.1 to about 20 mg/kg of the patient's body weight per day, with the usual range being from about 0.3 to about 15 mg/kg per day. Oral unit dosage forms, such as tablets and capsules, may contain from about 0.1 mg to about 1000 mg of a compound (pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. According to another embodiment, such dosage forms contain from about 50 mg to about 500 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) according to the present disclosure. In yet another embodiment, such dosage forms contain from about 25 mg to about 200 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. According to yet another embodiment, such dosage forms contain from about 10 mg to about 100 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) according to the present disclosure. In a further embodiment, such dosage forms contain from about 5 mg to about 50 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In still other embodiments, such dosage forms contain from about 0.1 mg to about 10 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. According to any of the above embodiments, the dosage form may be administered once a day or twice a day.

The compositions may be administered orally, topically, parenterally, by inhalation or spray, or rectally in unit dosage form. The term parenteral includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques.

Suitable oral compositions include, without limitation, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs.

Also contemplated are pharmaceutical compositions suitable for a single unit dosage form that contains a compound of the present disclosure, or a pharmaceutically acceptable stereoisomer, salt, or tautomer thereof, and a pharmaceutically acceptable carrier.

Compositions suitable for oral administration may be prepared in accordance with any method known in the art for the manufacture of pharmaceutical compositions. For example, liquid formulations of the compounds of the present disclosure contain one or more agents selected from the group consisting of sweeteners, flavors, colors, and preservatives.

In the context of tablet formulations, a compound of the present disclosure in admixture with non-toxic pharmaceutical excipients is used to manufacture tablets. Examples of such fillers include, without limitation, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants, for example corn starch or alginic acid; binders such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated, or they may be coated by conventional coating techniques to retard disintegration and absorption in the gastrointestinal tract, thereby providing a delayed therapeutic effect for the desired period of time. For example, a time delay agent such as glycerol monostearate or glycerol distearate may be used.

Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with a solid inert diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium such as peanut butter, liquid paraffin or olive oil.

For aqueous suspensions, the compound of the present disclosure is mixed with excipients suitable to maintain a stable suspension. Examples of such excipients include, without limitation, sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic.

Oral suspensions may also contain dispersants or humectants such as a naturally occurring phosphatide, such as lecithin, or ethylene oxide condensates with long chain aliphatic alcohols, eg heptadecaethyleneoxycetanol, or ethylene oxide condensates with partial esters derived from fatty acids. and hexitan anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or npropyl parahydroxybenzoate, one or more colorants, one or more flavors, and one or more sweeteners, such as sucrose or saccharin.

- 32 041815

Oil suspensions can be prepared by suspending a compound of the present disclosure in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.

Sweetening agents, such as those mentioned above, and flavoring agents may be added to provide oral preparations with a pleasant taste. Such compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water can be prepared by preparing a mixture of a compound of the present disclosure and a dispersion aid or a humectant, a suspending aid and one or more preservatives. Suitable dispersion aids or wetting agents and suspension aids are illustrated by those already mentioned above. Additional excipients may also be present, such as sweetening, flavoring and coloring agents.

The pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or mixtures thereof. Suitable emulsifiers may be naturally occurring gums such as gum arabic or gum tragacanth, naturally occurring phosphatides such as soy, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a sedative, preservative, flavoring agents and colorants. The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension or an oily suspension. Such a suspension may be prepared according to techniques known in the art using one or more suitable dispersion aids, or humectants and suspension aids, as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, fatty oils have traditionally been used as a solvent or suspension medium. For this purpose, any light fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find their use in the preparation of injectable formulations.

Compounds of general formula (IA), (IB) or formula (II) can also be administered in the form of suppositories for rectal administration of the drug. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and will therefore soften in the rectum to release the drug. Such substances are cocoa butter and polyethylene glycols.

Compositions for parenteral administration are administered in a sterile environment. Depending on the base used and the concentration of the drug in the formulation, the parenteral formulation may be either a suspension or a solution containing the dissolved drug. Adjuvants such as local anesthetics, preservatives and buffering agents may also be added to parenteral compositions.

Application methods

The MAT2A enzyme catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and ATP in cells. Accordingly, according to another embodiment of the present disclosure, there is provided a method for inhibiting cellular synthesis of SAM from methionine and ATP, comprising administering to the cell an effective amount of a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt, stereoisomer or tautomer. In some embodiments, a compound of formula (IA), (IB), or formula (II) is used to identify other compounds that are inhibitors of MAT2A, such as in a competitive assay for MAT2A binding 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 according to the present disclosure.

The present invention also relates to a method of treating cancer in a subject suffering from a tumor, comprising administering to the subject an effective amount of a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt thereof. In one embodiment, optionally in combination with any other embodiment disclosed herein, the subject is a mammal, such as a human.

The present invention further relates to a method for treating cancer in

- 33 041815 of a subject suffering from a tumor, which includes administering to the subject an effective amount of a MAT2A inhibitor. In some embodiments, the MAT2A inhibitor is a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt thereof. In some embodiment, optionally in combination with any other embodiment disclosed herein, the subject is a mammal, such as a human.

In some embodiment, the cancer is an MTAP deletion cancer. Alternatively or in combination, other embodiments refer to a cancer selected from the group consisting of mesothelioma, neuroblastoma, intestinal carcinoma such as rectal carcinoma, colon carcinoma, familial adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinomas , carcinomas of the lip, carcinomas of the larynx, carcinomas of the hypopharynx, carcinomas of the tongue, carcinomas of the salivary gland, carcinomas of the stomach, adenocarcinomas, medullary carcinomas of the thyroid, papillary carcinomas of the thyroid, renal carcinomas, carcinomas of the parenchyma of the kidney, carcinomas of the ovary, carcinomas of the cervix, carcinomas of the body of the uterus, endometrial carcinomas, choriocarcinomas, pancreatic carcinomas, prostate carcinomas, bladder carcinomas, testicular carcinomas, breast carcinomas, urinary tract carcinomas, melanomas, brain tumors, head and neck cancer, lymphoma, acute lymphocytic leukemia (AL L), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), multiple myeloma (MM) , basalioma, teratoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma.

In other embodiments, the cancer is selected from lung cancer, non-small cell lung cancer, bronchial alveolar cell cancer of the lung, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer , ovarian cancer, rectal cancer, anal cancer, gastric cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, malignant tumor of the esophagus, malignant tumor of the small intestine, malignant tumor of the endocrine system, malignant thyroid tumor, malignant 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 malignancy , malignant tumor of the biliary tract, chronic or acute leukemia, lymphocytic lymphoma, neoplasia of the central nervous system (CNS), tumors of the spinal cord, brain stem glioma, glioblastoma multiforme, astrocytoma, schwannoma, ependymoma, medulloblastoma, meningiomas, squamous cell carcinomas, pituitary adenomas, including resistant and/or refractory forms of any of the above malignant tumors, or a combination of one or more of the above malignant tumors.

In some embodiments, the cancer is selected from the group consisting of acute B-lymphocytic leukemia (B-ALL), mesothelioma, lymphoma, pancreatic carcinoma, lung cancer, gastric cancer, esophageal cancer, bladder carcinoma, cancer brain, head and neck cancer, melanoma, and breast cancer.

In other embodiments, the lung cancer is non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma.

In other embodiments, the breast cancer is triple negative phenotype breast cancer (TNBC).

In other embodiments, the brain cancer is a brain cancer selected from the group consisting of glioma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumors, and craniopharyngioma.

In other embodiments, the cancer is a lymphoma selected from the group consisting of mantle cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), and adult T-cell leukemia/lymphoma (ATLL) . As used herein, adult T-cell leukemia/lymphoma refers to a rare and usually aggressive T-cell lymphoma that can be found in the blood (leukemia), lymph nodes (lymphoma), skin, or many sites in the body.

As described generally above, methylthioadenosine phosphorylase (MTAP) is an enzyme found in all normal tissues that catalyzes the conversion of methylthioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Adenine is used to generate adenosine monophosphate, and 5-methylthioribose-1-phosphate is converted to methionine and formate. Because of this route of use, 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 malignant human and mouse cells have lost MTAP activity. MTAP deficiency is not only found in tissue culture cells, but is also present in primary leukemias, gliomas, melanomas, pancreatic cancers, non-small cell lung cancers (NSCLC), bladder cancers, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcomas, ovarian cancers, endometrial cancers, breast cancers, soft tissue sarcomas, non-Hodgkin's lymphoma, and mesotheliomas. For example, the proliferation of malignant tumor cells that do not express MTAP, i.e. with a deletion of MTAP, is inhibited by downregulation of MAT2A expression by small hairpin RNAs (shRNA), which was confirmed using small molecule inhibitors of MAT2A (document K. Marjon et al., Cell Reports 15 (2016) 574-587, incorporated herein by reference ). A non-MTAP-expressing cancer is a cancer in which the MTAP gene has been deleted or lost or otherwise inactivated, or a cancer in which the MTAP protein has reduced or impaired function.

Accordingly, according to an embodiment of the present disclosure, a method of treating a cancer subject is provided, wherein the cancer is characterized by reduced or absent MTAP gene expression, or decreased MTAP protein function, compared to cancers in which the MTAP gene or protein is present and/or completely functional, or compared to malignant tumors with the wild-type MTAP gene. The method comprises administering to a subject a therapeutically effective amount of a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt thereof.

In another embodiment, a method of treating a subject with an MTAP deletion cancer is provided, comprising administering to the subject a therapeutically effective amount of a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt thereof. In some embodiment, the MTAP deletion cancer is selected from leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, cancer ovary, endometrial cancer, breast cancer, soft tissue sarcoma, lymphoma and mesothelioma.

In some embodiment, the MTAP deletion cancer is pancreatic cancer. In another embodiment, the MTAP deletion cancer is selected from bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, liver cancer, esophageal cancer, gastric cancer, colon cancer, head and neck cancer, kidney cancer, colon cancer, diffuse large B cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL), glioblastoma multiforme (GBM), and non-small cell cancer lung (NSCLC).

Genomic analysis of non-MTAP-expressing cell lines showed that cell lines that contain a KRAS mutation or a p53 mutation were susceptible to MAT2A inhibition. Accordingly, an embodiment of the present disclosure relates to a method of treating a cancer in a subject, wherein the cancer is characterized by decreased or absent MTAP expression, or the absence of an MTAP gene, or decreased MTAP protein function, said method comprising administering to the subject a therapeutically effective amount of a compound of formula ( IA), (IB) or formula (II), wherein said cancer is further characterized by the presence of a mutant KRAS or a mutant p53. In an embodiment, a method is provided for treating a subject with a non-MTAP-expressing mutant KRAS or mutant p53 cancer comprising administering to the subject an effective amount of a compound of formula (IA), (IB) or formula (II), or a pharmaceutically acceptable salt thereof. For example, the cancer is a non-MTAP-expressing mutant KRAS cancer, a non-MTAP-expressing p53-mutant cancer, or a non-MTAP-expressing cancer.

- 35 041815 malignant tumor with mutant KRAS and mutant p53.

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, with X being any amino acid substitution at that position. In a specific embodiment, the replacement is G12V, G12R, G12C, or G13D. According to another embodiment, the replacement 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 suppresses its tumor suppressor function. In an embodiment, said p53 mutation is Y126_splice, K132Q, M133K, R174fs, R175H, R196*, C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C, R280K, or A1592W. In an 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.

In another embodiment, the compounds disclosed herein are useful for the degradation of disease-associated proteins. An example of such an approach are PROTACs (PROteolysis TArgeting Chimeras - chimeras for targeted action on proteolysis). PROTACs are bifunctional molecules that contain both a ligand moiety selected from one of the compounds disclosed herein and capable of binding to a target protein, and a peptide moiety (called a degrone) that is recognized and polyubiquitinated by E3 ligase. Thus, PROTAC non-covalently binds to the target protein and recruits E3 ligase via the degron protein, resulting in polyubiquitination and degradation of the bound target. A number of publications describe the preclinical use of PROTACs in a variety of therapeutic areas, including oncology (see, for example, Lu et al. Chemistry & Biology 22 (2015) 755-763).

Examples

The present invention will become clearer in view of the following examples. The examples provided herein are illustrative and should not be construed as limiting the scope of the present disclosure.

List of abbreviations and terms:

anhydrous aq. min ml mmol mol MS NMR TLC HPLC rt Range: anhydrous water minute(s) milliliter millimole(s) mol(s) mass spectrometry nuclear magnetic resonance thin layer chromatography high performance liquid chromatography room temperature Hz δ J s d t sq m br. k.vd d.quint dd dt Solvents and reagents: hertz chemical shift binding constant singlet doublet triplet quartet multiplet broadened quartet of doublets doublet of quintets doublet of doublets doublet of triplets CHS13 DCM DMF Et ₂ O chloroform dichloromethane dimethylformamide diethyl ether

- 36 041815

EtOH ethanol EtOAc ethyl acetate EA ethyl acetate Meon methyl alcohol MeCN acetonitrile RE petroleum ether THF tetrahydrofuran ASON acetic acid HCl hydrochloric acid H2SO4 sulfuric acid NH4Cl ammonium chloride KOH potassium hydroxide NaOH sodium hydroxide K2CO3 potassium carbonate _{Na2CO3 _} sodium carbonate TFA trifluoroacetic acid Na2SO4 sodium sulfate NaBH4 sodium borohydride _NaHCO3 bicarbonate of soda LiHMDS lithium hexamethyldisylamide NaHMDS sodium hexamethyldisylamide LAH lithium aluminum hydride NaBH4 sodium borohydride LDA lithium diisopropylamide Et ₃ N triethylamine DMAP 4-(dimethylamino)pyridine DIPEA N,N-diisopropylethylamine NH4OH ammonium hydroxide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HOBt 1-hydroxybenzotriazole HATU O-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium Xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl BINAP 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl

General experimental part

In the following examples, reagents and solvents were purchased from commercial suppliers (such as Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Company) and used without further purification unless otherwise noted. Flash chromatography was performed on an Ez Purifier III using a 200-300 mesh silica gel column. 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 spectrometer (Brucker, Switzerland). Chemical shifts were given in parts per million (ppm, δ) with a downfield shift relative to tetramethylsilane. Mass spectra were obtained with electrospray ionization (ESI) on a Waters LCT TOF mass spectrometer (Waters, USA). HPLC chromatograms were recorded on an Agilent 1200 HPLC system (Agilent, USA, column: Ultimate 4.6x50 mm, 5 μm, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile). Microwave reactions were performed on an Initiator 2.5 microwave synthesizer (Biotage, Sweden).

- 37 041815

General Method I:

ABOUT'

Ύ % N

I I l to s

Alkyl- NH ₂

Aryl - NIH

CSF, DIPEA. DMSO

Stage E o

To

Vos

NaBH(OAc) ₃ , DCM

Stage G n^ ^R ' n

Alternative way:

R. ^J N τ · N k 1 . TFA. DCM □ S ' MS 'v / o ⁰ l·.'

Hoc θ Stage H

NaBH(OAc) ₃ , AsOH Mr. J ct

Stage C

Aryl^O

NaBI Ι(ΟΛ<:) ₅ , COM

Stage I

Alkyl- _NHZ

Alkyl-OH

Alkyl- SH tel . Dll4 A, DMSO or NaH, DMF

Stage J

ζ X = NH, O, S Rj n = 1 or 2

Preparation of Example 101 by General Procedure I:

Stage G

Step A: 1-tert-butyl-3-ethyl-3-(5-(dimethoxymethyl)-2-(methylthio)pyrimidin-4-yl)pyrrolidine1,3-dicarboxylate o-

To a solution of 1-tert-butyl-3-ethylpyrrolidine-1,3-dicarboxylate (4.8 g, 19.8 mmol, 1.5 eq.) in THF (30 ml) at -78°C for 1 h after addition funnel was added LiHMDS (1 M in THF, 26.4 ml, 26.4 mmol, 2.0 eq.). The mixture was stirred at -78°C for 4 h. Then, a solution of 4-chloro-5

- 38 041815 (dimethoxymethyl)-2-(methylthio)pyrimidine (3.1 g, 13.2 mmol, 1.0 eq.) in THF (10 ml). The reaction mixture was allowed to warm to room temperature and stirred for an additional 3 hours. Then, the reaction mixture was quenched by the addition of NH4Cl (sat. aq.) (50 ml) and was extracted with EtOAc (50 ml x 3). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated, and the resulting residue was purified by flash chromatography on silica gel (PE/EYAc=20/1-4/1) to obtain 1 tert-butyl-3-ethyl-3- (5-(Dimethoxymethyl)-2-(methylthio)pyrimidin-4-yl)pyrrolidin-1,3-dicarboxylate (3.2 g, 55% yield) as a yellow oil. LC-MS: m/z 442 [M+H]+.

Stage B: 1-tert-butyl-3-ethyl-3- (5-formyl-2- (methylthio) pyrimidin-4-yl) pyrrolidine-1,3 dicarboxylate m * N 5

Ito ^N

ABOUT

To a solution of 1-tert-butyl-3-ethyl-3-(5-(dimethoxymethyl)-2-(methylthio)pyrimidin-4-yl)pyrrolidine1,3-dicarboxylate (3.1 g, 7.0 mmol, 1, 0 eq.) in acetone (30 ml) was added a dilute solution of HCl (1N, aq.) (56.0 ml, 56.0 mmol, 8.0 eq.). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched by adding ice water (50 ml) and extracted with EtOAc (30 ml x 3). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated, and the crude residue was used directly without further purification (2.8 g, crude) as a colorless oil. LC-MS: m/z 396 [M+H] ⁺ .

Step C: tert-butyl-6-(4-methoxyphenyl)-2-(methylthio)-7-oxo-6,7-dihydro-5H-spiro[pyrido[4,3d]pyrimidine-8,3'-pyrrolidine] -1'-carboxylate o to A

J—' Voe/

To a solution of 1-tert-butyl-3-ethyl-3-(5-(dimethoxymethyl)-2-(methylthio)pyrimidin-4-yl)pyrrolidin1,3-dicarboxylate (2.8 g, 7.0 mmol, 1, 0 eq.) and 4-methoxyaniline (1.9 g, 15.4 mmol, 2.2 eq.) in DCE (18.0 ml) were added AcOH (1.4 ml, 24.5 mmol, 3.5 eq. .). The resulting solution was stirred at room temperature for 1 h. At this point in time, NaBH(AcO) ₃ (3.7 g, 17.5 mmol, 2.5 eq.) was added in portions over 0.5 h, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with ice water and extracted with EtOAc (30 ml x 3). All organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (PE/EtOAc=10/1-1/1) to give tert-butyl-6- (4-methoxyphenyl)-2-(methylthio)-7-oxo-6,7-dihydro-5Hspiro[pyrido[4,3-d]pyrimidine-8,3'-pyrrolidine]-1'-carboxylate (2.5 g, 79% yield) as a light brown solid. LC-MS: m/z 457 [M+H] ⁺ .

Stage D: tert-butyl-6-(4-methoxyphenyl)-2-(methylsulfonyl)-7-oxo-6,7-dihydro-5Hspiro[pyrido[4,3-d]pyrimidine-8,3'-pyrrolidine] -1'-carboxylate

To a solution of tert-butyl-6-(4-methoxyphenyl)-2-(methylthio)-7-oxo-6,7-dihydro-5H-spiro[pyrido[4,3d]pyrimidine-8,3'-pyrrolidine]- 1'-carboxylateα (500 mg, 1.1 mmol, 1.0 eq.) in DCM (10.0 ml) was added m-CPBA (565 mg, 3.3 mmol, 3.0 eq.) in small portions over 0.5 h. The resulting mixture was stirred at room temperature for an additional 2 h, after which it was quenched by the addition of ice water (20.0 ml) and extracted with DCM (20 ml x 3). The organic layers were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (PE/EJAc=2/1-1/1) with obtaining tert-butyl-6-(4-methoxyphenyl)-2-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-spiro[pyrido[4,3d]pyrimidine-8,3'-pyrrolidine]-1 '-carboxylate α (500 mg, 94% yield) as a white solid. LC-MS: m/z 489 [M+H] ⁺ .

Step E: tert-butyl-2-((cyclopropylmethyl)amino)-6-(4-methoxyphenyl)-7-oxo-6,7-dihydro-5Hspiro[pyrido[4,3-d]pyrimidine-8,3' -pyrrolidine]-1'-carboxylate

- 39 041815

To a solution of tert-butyl-6-(4-methoxyphenyl)-2-(methylsulfonyl)-7-oxo-6,7-dihydro-5Hspiro[pyrido[4,3-d]pyrimidine-8,3'-pyrrolidine]- 1'-carboxylate (1.2 g, 2.5 mmol, 1.0 eq.) in DMSO (15.0 ml) CsF (380 mg, 2.5 mmol, 1.0 eq.) was added at room temperature, DIPEA (967 mg, 7.5 mmol, 3.0 eq.) and cyclopropylmethanamine (532 mg, 7.5 mmol, 3.0 eq.). The resulting mixture was stirred at 80° C. overnight and then water (10 ml) was added. The reaction mixture was extracted with DCM (20 ml x 3), the organic layers were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography to give tert-butyl-2-((cyclopropylmethyl)amino)-6-(4methoxyphenyl)-7-oxo-6,7-dihydro-5H-spiro[pyrido[4,3- d]pyrimidine-8,3'-pyrrolidine]-1'-carboxylate (850 mg, 71% yield) as a white solid. LC-MS: m/z 480 [M+H]+.

Step F: 2-((cyclopropylmethyl)amino)-6-(4-methoxyphenyl)-5H-spiro[pyrido[4,3-d]pyrimidine8,3'-pyrrolidin]-7(6H)-one

MeSK a. d γ N

C Η va

To a solution of tert-butyl-2-((cyclopropylmethyl)amino)-6-(4-methoxyphenyl)-7-oxo-6,7-dihydro-5Hspiro[pyrido[4,3-d]pyrimidine-8,3'- pyrrolidine]-1'-carboxylate (850 mg, 1.8 mmol, 1.0 eq.) in DCM (10 ml) TFA (3 ml) was added at room temperature. The resulting mixture was stirred for 1 h, and then the reaction mixture was quenched by the addition of NaHCO ₃ (sat. aq. 20 ml). The resulting mixture was extracted with DCM (20 ml x 3), the organic layers were combined, washed with brine (30.0 ml), dried over Na ₂ SO ₄ and concentrated. Crude 2-((cyclopropylmethyl)-amino)-6-(4-methoxyphenyl)5H-spiro[pyrido[4,3-d]pyrimidin-8,3'-pyrrolidin]-7(6H)-one (500 mg, crude) was used without further purification as a white solid. LC-MS: m/z 380 [M+H] ⁺ .

Step G: 1'-((1H-pyrazol-3-yl)methyl)-2-((cyclopropylmethyl)amino)-6-(4-methoxyphenyl)-5Hspiro[pyrido[4,3-d]pyrimidine-8, 3'-pyrrolidine]-7(6H)-one (example 101)

To a solution of 6-(4-methoxyphenyl)-2-(methylsulfonyl)-5H-spiro[pyrido[4,3-d]pyrimidin-8,3'pyrrolidin]-7(6H)-one (56.0 mg, 0 15 mmol, 1.0 eq.) in DCE (3 ml) at room temperature were added 1H-pyrazole-3-carbaldehyde (28.0 mg, 0.29 mmol, 2.0 eq.) and AcOH (60.0 µl, catalytic amount). The resulting mixture was stirred for 1 h after which NaBH ₃ CN (10.0 mg, 0.158 mmol, 1.1 eq.) was added. The reaction mixture was stirred for an additional 0.5 h, after which it was quenched by the addition of ice water (2.0 ml) and extracted with DCM (5 ml x 3). The organic layers were combined, washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC to give 1'-((1H-pyrazol-3-yl)methyl)-2-((cyclopropylmethyl)amino)-6-(4-methoxyphenyl)-5Hspiro[pyrido[4, 3-d]pyrimidin-8,3'-pyrrolidine]-7(6H)-one (Example 101).

¹ H-NMR (400 MHz, CDCl3) δ: 8.47 (broad s, 1H), 8.13 (s, 1H), 7.54 (s, 1H), 7.18 (d, J=8 .6 Hz, 2H), 6.99 (d, J=8.6 Hz, 2H), 6.34 (s, 1H), 4.79 (d, J=15.4 Hz, 1H), 4, 52 (d, J=15.4 Hz, 1H), 4.38 (d, J=13.2 Hz, 1H), 4.31 (d, J=13.2 Hz, 1H), 4.11 ( d, J=10.8 Hz, 1H), 3.83 (s, 3H), 3.67 (d, J=10.8 Hz, 1H), 3.65-3.47 (m, 1H), 3.35-3.28 (m, H), 3.26-3.16 (m, 1H), 2.61-2.51 (m, 1H), 2.48-2.37 (m, 1H ), 1.15-1.04 (m, 1H), 0.60-0.50 (m, 2H), 0.32-0.23 (m, 2H) [NH alone was not observed due to CDCl3 overlay ]. LC-MS: m/z 460 [M+H] ⁺ .

Example 102: 1'-((1H-pyrazol-4-yl)methyl)-2-((cyclopropylmethyl)amino)-6-(4-methoxyphenyl)-5Hspiro[pyrido[4,3-d]pyrimidine-8, 3'-pyrrolidine]-7(6Н)-one

- 40 041815

The title compound was synthesized from intermediate 8a and lH-pyrazole4-carbaldehyde by general procedure I: (NaBH ₃ CN, HOAc, DCE).

¹ H-NMR (400 MHz, CDCl ₃ )(HCO2H salt) δ: 8.61 (s, 1H), 8.12 (s, 1H), 7.75 (s, 2H), 7.19 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 4.81 (d, J=15.2 Hz, 1H), 4.51 (d, J= 15.2 Hz, 1H), 4.44-4.30 (m, 2H), 4.22 (d, J=13.2 Hz, 1H), 3.83 (s, 3H), 3.68 ( d, J=11.6 Hz, 1H), 3.38-3.18 (m, 5H), 2.60-2.37 (m, 2H), 1.17-1.04 (m, 1H) , 0.570.48 (m, 2H), 0.29-0.22 (m, 2H). LC-MS: m/z 460 [M+H]+.

Example 103 2-((cyclopropylmethyl)amino)-6-(4-methoxyphenyl)-1'-(thiazol-4-ylmethyl)-5Hspiro[pyrido[4,3-d]pyrimidine-8,3'-pyrrolidine] -7( 6H) -he and - -. _ _

- P' 'I.

N—'

The title compound was synthesized from intermediate 8a and thiazole-4carbaldehyde by general procedure I: (NaBH ₃ CN, HOAc, DCE).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.76 (d, J=2.0 Hz, 1H), 8.07 (s, 1H), 7.33 (d, J=2.0 Hz , 1H), 7.18 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.53 (broad s, 1H), 4.65 (d, J=15.2 Hz, 1H), 4.57 (d, J=15.2 Hz, 1H), 4.06 (d, J=14.0 Hz, 1H), 4.01 (d , J=14.0 Hz, 1H), 3.81 (s, 3H), 3.51 (d, J=9.6 Hz, 1H), 3.43 (d, J=9.6 Hz, 1H ), 3.29 (m, 2H), 3.13-3.05 (m, 1H), 3.02-2.92 (m, 1H), 2.55-2.49 (m, 1H), 2.46-2.39 (m, 1H), 1.17-1.07 (m, 1H), 0.59-0.49 (m, 2H), 0.30-0.23 (m, 2H ). LC-MS: m/z 477 [M+H] ⁺ .

Example 104: 1'-cyclohexyl-2-((cyclopropylmethyl)amino)-6-(4-methoxyphenyl)-5Hspiro[pyrido[4,3-d]pyrimidine-8,3'-pyrrolidine]-7(6H)- He

The title compound was synthesized from intermediate 8a and cyclohexanone by general procedure I: (NaBH ₃ CN, HOAc, DCE).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.09 (s, 1H), 7.18 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.8 Hz , 2H), 5.54 (broad s, 1H), 4.70 (d, J=15.2 Hz, 1H), 4.55 (d, J=15.2 Hz, 1H), 3.82 (s, 3H), 3.47 (d, J=10.4 Hz, 1H), 3.36-3.29 (m, 3H), 2.98-2.92 (m, 1H), 2, 58-2.38 (m, 4H), 1.77 (m, 2H), 1.63-1.56 (m, 1H), 1.47-1.34 (m, 2H), 1.30- 1.04 (m, 6H), 0.60-0.50 (m, 2H), 0.30-0.24 (m, 2H). LC-MS: m/z 462 [M+H] ⁺ .

Example 105: methyl-3-(2-((cyclopropylmethyl)amino)-6-(4-methoxyphenyl)-7-oxo-6,7-dihydro-5Hspiro[pyrido[4,3-d]pyrimidine-8,3 '-pyrrolidine]-1'-yl) cyclobutanecarboxylate

The title compound was synthesized from intermediate 8a and methyl 3oxocyclobutanecarboxylate by general procedure I: (NaBH ₃ CN, HOAc, DCE).

1H-NMR (400 MHz, CDCl ₃ ) δ: 8.08 (s, 1H), 7.18 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 5.45 (broad s, 1H), 4.65 (d, J=15.2 Hz, 1H), 4.59 (d, J=15.2 Hz, 1H), 3.82 ( s, 3H), 3.67 (s, 3H), 3.41 (d, J=9.6 Hz, 1H), 3.343.28 (m, 2H), 3.26-3.15 (m, 2H ), 3.00-2.92 (m, 1H), 2.85-2.72 (m, 2H), 2.57-2.48 (m, 1H), 2.47-2.39 (m , 1H),

- 41 041815

2.37-2.26 (m, 4H), 1.16-1.04 (m, 1H), 0.58-0.50 (m, 2H), 0.32-0.24 (m, 2H ). LC-MS: m/z 492 [M+H]+.

Preparation of 2-((cyclopropylmethyl)amino)-6-(isoxazol-4-yl)-5H-spiro[pyrido[4,3-d]pyrimidine8,3'-pyrrolidin]-7(6H)-one (8b)

2-((Cyclopropylmethyl)amino)-6-(isoxazol-4-yl)-5Н-spiro[pyrido[4,3-d]pyrimidin-8,3'pyrrolidin]-7(6Н)-one 8b was synthesized from isoxazole -4-amine by general procedure I (CF step). LC-MS: m/z 341 [M+H]+.

Example 106 Preparation of 2-((cyclopropylmethyl)amino)-1'-(isoxazol-3-ylmethyl)-6-(isoxazol-4-yl)5H-spiro[pyrido[4,3-d]pyrimidin-8,3 '-pyrrolidine]-7(6H)-one

N' L

The title compound was synthesized from intermediate 8b and isoxazole-3carbaldehyde by general procedure I: (NaBH ₃ CN, HOAc, DCE).

1H-NMR (400 MHz, CDCl3) δ: 9.29 (s, 1H), 9.00 (s, 1H), 8.82 (s, 1H), 8.20 (s, 1H), 7.37 (t, J=5.6 Hz, 1H), 6.52 (s, 1H), 4.79 (s, 2H), 3.77 (s, 2H), 3.17-3.05 (m, 4H), 2.87-2.74 (m, 2H), 2.53-2.35 (m, 2H), 1.13-1.01 (m, 1H), 0.43-0.33 ( m, 2H), 0.25-0.16 (m, 2H). LC-MS: m/z 422 [M+H]+.

Example 107 2-((cyclopropylmethyl)amino)-6-(isoxazol-4-yl)-1'-(thiazol-4-ylmethyl)-5Hspiro[pyrido[4,3-d]pyrimidin-8,3'- pyrrolidine]-7(6H)-one

The title compound was synthesized from intermediate 8b and thiazole-4carbaldehyde by general procedure I: (NaBH ₃ CN, HOAc, DCE).

1H-NMR (400 MHz, MeOD-d4) δ: 9.14 (s, 1H), 8.95 (d, J=2.0 Hz, 1H), 8.88 (s, 1H), 8.19 (s, 1H), 7.53 (d, J=2.0 Hz, 1H), 4.80 (d, J=1.6 Hz, 2H), 4.59 (broad s, 1H), 4 .03 (s, 2H), 3.45 (d, J=10.0 Hz, 1H), 3.41 (d, J=10.0 Hz, 1H), 3.27 (d, J=4, 0 Hz, 1H), 3.26 (d, J=4.0 Hz, 1H), 3.03 (t, J=6.4 Hz, 2H), 2.60-2.43 (m, 2H) , 1.18-1.05 (m, 1H), 0.54-0.45 (m, 2H), 0.29-0.22 (m, 2H). LC-MS: m/z 438 [M+H]+.

Example 108: 1'-((4-chloro-1H-pyrazol-3-yl)methyl)-2-((cyclopropylmethyl)amino)-6-(isoxazol-4-yl)5H-spiro[pyrido [4.3 -d]pyrimidine-8,3'-pyrrolidine]-7(6H)-one

The title compound was synthesized from intermediate 8b and 4-chloro-Spyrazole-3-carbaldehyde by general procedure I: (NaBH ₃ CN, HOAc, DCE).

1H-NMR (400 MHz, MeOD-d4) δ: 9.19 (s, 1H), 8.92 (s, 1H), 8.27 (s, 1H), 7.76 (broad s, 1H) , 4.86 (s, 2H), 4.44-4.16 (m, 2H), 4.05-3.75 (m, 2H), 3.52-3.30 (m, 2H), 3 .28 (dd, J=6.8 Hz, 2.4 Hz, 2H), 2.67-2.57 (m, 1H), 2.51-2.41 (m, 1H), 1.19- 1.07 (m, 1H), 0.56-0.50 (m, 2H), 0.30-0.25 (m, 2H). LC-MS: m/z 455 [M+H]+.

Preparation of 6-(1H-benzo[d]imidazol-6-yl)-2-((cyclopropylmethyl)amino)-5H-spiro[pyrido[4,3d]pyrimidine-8,3'-pyrrolidine]-7(6H) -she (8s)

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6-(1H-benzo[d]imidazol-6-yl)-2-((cyclopropylmethyl)amino)-5H-spiro[pyrido[4,3-d]pyrimidine8,3'-pyrrolidine]-7(6H)- it (8c) was synthesized from 1H-benzo[d]imidazol-6-amine by general procedure I (steps C-F). LC-MS: m/z 390 [M+H]+.

Example 109 Preparation of 1'-((1H-pyrazol-3-yl)methyl)-6-(1H-benzo[d]imidazol-6-yl)-2((cyclopropylmethyl)amino)-5H-spiro[pyrido[ 4,3-d]pyrimidin-8,3'-pyrrolidine]-7(6Н)-one

The title compound was synthesized from intermediate 8c and 1H-pyrazole3-carbaldehyde by general procedure I: (NaBH ₃ CN, HOAc, DCE).

1H-NMR (400 MHz, DMSO-d6) δ: 12.55 (broad s, 2H), 8.26 (s, 1H), 8.21 (s, 1H), 7.69-7.42 ( m, 3H), 7.31 (t, J=5.6 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.17 (s, 1H), 4.77 ( d, J=15.6 Hz, 1H), 4.69 (d, J=15.2 Hz, 1H), 3.853.67 (m, 2H), 3.29-3.09 (m, 4H), 2.69-2.71 (m, 2H), 2.61-2.53 (m, 2H), 1.17-1.03 (m, 1H), 0.46-0.36 (m, 2H ), 0.27-0.17 (m, 2H). LC-MS: m/z 470 [M+H]+.

Preparation of 6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-5H-spiro[pyrido[4,3-d]pyrimidine8,3'-pyrrolidin]-7(6H)-one (8d)

6-(4-Methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-5H-spiro[pyrido[4,3-d]pyrimidin-8,3'pyrrolidin]-7(6H)-one (8d) was synthesized from 2,2,2-trifluoroethanamine by general procedure I (steps E, F). LC-MS: m/z 408 [M+H] ⁺ .

Example 110 Preparation of 1'-((1H-pyrazol-3-yl)methyl)-6-(4-methoxyphenyl)-2-((2,2,2trifluoroethyl)amino)-5H-spiro[pyrido[4,3 -d]pyrimidin-8,3'-pyrrolidine]-7(6H)-one

MeO..

: 1

[N

D ^: N'N'^CFj Г у Н

N—v 'ή

K ^: N

The title compound was synthesized from intermediate 8d and N-pyrazole3-carbaldehyde by general procedure I: (NaBH ₃ CN, HOAc, DCE).

1H-NMR (400 MHz, CDCl ₃ ) δ: 8.17 (s, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 6.19 (s, 1H), 4.73 (d, J=15.6 Hz, 1H), 4.58 (d, J=15.6Hz, 1H), 4.31-4.13(m, 2H), 3.99(d, J=14.0Hz, 1H), 3.89(d, J=14.0 Hz, 1H), 3.82 (s, 3H), 3.53-3.34 (m, 2H), 3.16-3.05 (m, 1H), 3.04-2.94 (m, 1H), 2.68-2.55 (m, 1H), 2.48-2.35 (m, 1H) 2 NH protons are not visible. LC-MS: m/z 488 [M+H] ⁺ .

Getting example 111:

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Step H: 6-(4-methoxyphenyl)-2-(methylsulfonyl)-5H-spiro[pyrido[4,3-b]pyrimidin-8,3'pyrrolidine]-7(6H)-one

To a solution of tert-butyl-6-(4-methoxyphenyl)-2-(methylsulfonyl)-7-oxo-6,7-dihydro-5Hspiro[pyrido[4,3-b]pyrimidine-8,3'-pyrrolidine]- 1'-carboxylate (500 mg, 1.0 mmol, 1.0 eq.) in DCM (5 ml) was added trifluoroacetic acid (1.5 ml) at room temperature. The resulting mixture was stirred for 1 h, and then the reaction mixture was quenched by the addition of cold NaHCO ₃ (50 ml, sat.

aq.) and extracted with DCM (50 ml x 2). The organic layers were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (PE/EA=3/1-1/1) to give 6-(4-methoxyphenyl)-2-(methylsulfonyl)5H-spiro[pyrido[4,3-b]pyrimidine-8, 3'-pyrrolidine]-7(6H)-one (340 mg, 85% yield) as a white solid. LC-MS: m/z 389 [M+H]+.

Step I: 1'-((1H-pyrazol-3-yl)methyl)-6-(4-methoxyphenyl)-2-(methylsulfonyl)-5H spiro[pyrido[4,3-b]pyrimidine-8,3' -pyrrolidine]-7(6H)-one

To a solution of 6-(4-methoxyphenyl)-2-(methylsulfonyl)-5H-spiro[pyrido[4,3-b]pyrimidin-8,3'pyrrolidin]-7(6H)-one (100 mg, 0.26 mmol, 1.0 eq.) in DCM (5 ml) at room temperature were added 1H-pyrazole-3-karbaldehyde (50 mg, 0.52 mmol, 2.0 eq.) and AcOH (60.0 μl, catalytic amount ). The resulting mixture was stirred for 1 h and then NaBH ₃ CN (16.0 mg, 0.25 mmol, 1.0 eq.) was added. After 0.5 h, the reaction mixture was quenched with ice water (10 ml) and extracted

DCM (10 ml x 3). All organic layers were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give 1'-((1H-pyrazol-3-yl)methyl)-6-(4-methoxyphenyl)-2(methylsulfonyl)-5H-spiro[pyrido[4,3-b ]pyrimidin-8,3'-pyrrolidin]-7(6H)-one (60.0 mg, 49% yield) as a white solid. LC-MS: m/z 469 [M+H] ⁺ .

Step J: 1'-((1H-pyrazol-3-yl)methyl)-2-(ethylamino)-6-(4-methoxyphenyl)-5H-spiro[pyrido[4,3b]pyrimidine-8,3'- pyrrolidine]-7(6H)-one (example 111)

To a solution of 1'-((1H-pyrazol-3-yl)methyl)-6-(4-methoxyphenyl)-2-(methylsulfonyl)-5H- 3'-pyrrolidin]-7(6H)-one (60.0 mg, 0.13 mmol, 1.0 eq.) in DMSO (1 mL) CsF (20.0 mg, 0.13 mmol) was added at room temperature , 1.0 eq.), DIPEA (50.0 mg, 0.39 mmol, 3.0 eq.) and ethanamine hydrochloride (30.0 mg, 0.37 mmol, 3.0 eq.). The resulting mixture was stirred at 80° C. overnight. Then, the reaction mixture was quenched by the addition of ice water (10 ml) and was extracted with DCM (10 ml x 3). All organic layers were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give 1'-((1H-pyrazol-3-yl)methyl)-N-ethyl-6-(4methoxyphenyl)-6,7-dihydro-5H-spiro[pyrido[4, 3-d]pyrimidine-8,3'-pyrrolidine]-2-amine (Example 111).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (HCOOH salt) δ: 8.26 (broad s, 1H), 8.19 (s, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.23 (d, J=8.8 Hz, 2H), 7.18 (t, J=6.0 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 6.14 (d, J=1.6 Hz, 1H), 4.68 (d, J=15.4 Hz, 1H), 4.58 (d, J=15.4 Hz, 1H) , 3.77 (s, 3H), 3.67 (s, 2H), 3.36-3.16 (m, 2H), 3.13-3.10 (m, 2H), 2.862.65 (m , 3H), 2.52-2.41 (m, 2H), 1.13 (t, J=7.2 Hz, 3H). LC-MS: m/z 434 [M+H]+.

Example

112:

1'-((1H-pyrazol-3-yl)methyl)-2-(cyclobutylamino)-6-(4-methoxyphenyl)-5H spiro[pyrido[4,3-d]pyrimidine-8,3'-pyrrolidine] -7 (6H) -on

The title compound was synthesized from intermediate 10a and cyclobutanamine using General Method I: (CsF, DIPEA, DMSO).

1H-NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.17 (d, J=8.8 Hz, 2H ), 6.94 (d, J=8.8 Hz, 2H), 6.22 (s, 1H), 4.70 (d, J=15.2 Hz, 1H), 4.53 (d, J =15.2 Hz, 1H), 4.49 (d, J=8.0 Hz, 1H), 4.45 (d, J=8.0 Hz, 1H), 4.09-4.04 (m , 1H), 3.96 (d, J=9.6 Hz, 1H), 3.82 (s, 3H), 3.57-3.48 (m, 1H), 3.43 (d, J= 9.6Hz, 1H), 3.233.12(m, 1H), 3.07-2.96(m, 1H), 2.62-2.52(m, 1H), 2.48-2.36 (m, 3H), 2.06-1.93 (m, 2H), 1.86-1.70 (m, 2H). LC-MS: m/z 460 [M+H] ⁺ .

Example

113:

1'-((1H-pyrazol-3-yl)methyl)-2-(isobutylamino)-6-(4-methoxyphenyl)-5H spiro[pyrido[4,3-d]pyrimidine-8,3'-pyrrolidine] -7 (6H) -on

The title compound was synthesized from intermediate 10a and 2-methylpropan-1-amine using General Method I: (CsF, DIPEA, DMSO).

1H-NMR (400 MHz, DMSO-d6) δ: 12.79-12.41 (br s, 1H), 8.18 (s, 1H), 7.69-7.35 (m, 1H), 7.29 (broad s, 1H), 7.24 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.12 (s, 1H ), 4.68 (d, J=15.2 Hz, 1H), 4.58 (d, J=15.2 Hz, 1H), 3.77 (s, 3H), 3.65 (s, 2H ), 3.21-3.03 (m, 4H), 2.85-2.65 (m, 2H), 2.49-2.40 (m, 2H), 1.99-1.81 (m , 1H), 0.88 (dd, J=6.8 Hz, 1.2 Hz, 6H). LC-MS: m/z 462 [M+H] ⁺ .

Example 114: 1'-((1H-pyrazol-3-yl)methyl)-2-(cyclopropylmethoxy)-6-(4-methoxyphenyl)-5Hspiro[pyrido[4,3-d]pyrimidine-8,3'- pyrrolidine]-7(6H)-one

The title compound was synthesized from intermediate 10a and cyclopropylmethanol by general procedure I: (Step J: alternative conditions: NaH, DMF).

To a solution of cyclopropylmethanol (50 mg, 0.7 mmol, 4.0 eq.) in anhydrous DMF (2 ml) at 0°C was added NaH (60% in mineral oil, 57 mg, 1.4 mmol, 8.0 eq. .). The resulting mixture was stirred

- 45 041815 at 0°C for 1 h. Then, a solution of 10a (82 mg, 0.18 mmol, 1.0 eq.) was added. The resulting mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was quenched with ice-cold NH4Cl (sat. aq., 10 ml) and extracted with DCM (10 ml x 3). The combined extracts were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by reverse phase preparative HPLC to give r-((III-pyrazol-3-yl)methyl)-2(cyclopropylmethoxy)-6-(4-methoxyphenyl)-5H-spiro[pyrido[4,3-d] pyrimidine-8,3'-pyrrolidine]-7(6H) she.

1H-NMR (400 MHz, DMSO-d6) δ: 12.82-12.41 (m, 1H), 8.50 (s, 1H), 7.68-7.31 (m, 1H), 7, 26 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.13 (s, 1H), 4.84 (d, J=15.6 Hz, 1H), 4.74 (d, J=15.6 Hz, 1H), 4.24-4.11 (m, 2H), 3.77 (s, 3H), 3.65 (s, 2H ), 3.20-3.05 (m, 2H), 2.90-2.81 (m, 1H), 2.76-2.66 (m, 1H), 2.98-2.53 (m , 2H), 1.37-124 (m, 1H), 0.61-0.52 (m, 2H), 0.39-0.33 (m, 2H). LC-MS: m/z 461 [M+H]+.

Example 115: 1'-((1H-pyrazol-3-yl)methyl)-2-((cyclopropylmethyl)thio)-6-(4-methoxyphenyl)-5Hspiro[pyrido[4,3-d]pyrimidine-8, 3'-pyrrolidine]-7(6H)-one

The title compound was synthesized from intermediate 10a and cyclopropylmethanethiol by general procedure I: (Step J: alternative method, NaH, DMF as prepared in Example 114).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 12.56 (br s, 1H), 8.55 (s, 1H), 7.53 (br s, 1H), 7.26 (d , J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.12 (d, J=1.2 Hz, 1H), 4.86 (d, J =16.4Hz, 1H), 4.76(d, J=16.4Hz, 1H), 3.78(s, 3H), 3.65(s, 2H), 3.20-3.12 (m, 3H), 3.03 (dd, J=13.6 Hz, 7.2 Hz, 1H), 2.94-2.84 (m, 1H), 2.79-2.68 (m, 1H), 2.59-2.43 (m, 2H), 1.27-1.17 (m, 1H), 0.58-0.46 (m, 2H), 0.35-0.26 ( m, 2H). LC-MS: m/z 477 [M+H]+.

Getting example 116:

O

bob 0.1 equiv acetone, rt 7

Stage B

NaBHAN H'JAC dUt

Stage D

IN HG

Stage F o

o ',1 <

Sh . P1I1 A □miao ao ^p s

Stage E

THF

Stage G he

Step A: methyl 8-(5-(dimethoxymethyl)-2-(methylthio)pyrimidin-4-yl)-1,4-dioxaspiro[4.5]decane 8-carboxylate

To a solution of methyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (3.9 g, 19.8 mmol, 1.5 eq.) in THF (30 ml) at -78°C for 1 h after addition funnel was added LiHMDS (1 M in THF, 26.4 ml, 26.4

- 46 041815 mmol, 2.0 eq.). The mixture was stirred at -78°C for 4 h. Then, a solution of 4-chloro-5(dimethoxymethyl)-2-(methylthio)pyrimidine (3.1 g, 13.2 mmol, 1.0 eq.) in THF was added (10 ml). The reaction mixture was allowed to warm to room temperature and stirred for an additional 3 h. Then, the reaction mixture was quenched by adding NH ₄ Cl (sat. aq., 50 ml) and was extracted with EtOAc (50 ml x 3). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated, and the resulting residue was purified by flash chromatography on silica gel (PE/EtOAc=20/1-4/1) to obtain methyl8-(5-(dimethoxymethyl)-2 -(methylthio)pyrimidin-4-yl)-1,4-dioxaspiro[4.5]decan-8-carboxylate (2.9 g, 55% yield) as a yellow oil. LC-MS: m/z 399 [M+H]+.

Step B: methyl 8-(5-formyl-2-(methylthio)pyrimidin-4-yl)-1,4-dioxaspiro[4.5]decan-8carboxylate

To a solution of methyl 8-(5-(dimethoxymethyl)-2-(methylthio)pyrimidin-4-yl)-1,4-dioxaspiro[4.5]decan8-carboxylate (1.6 g, 4.1 mmol, 1.0 eq.) in acetone (80 ml) was added p-TSA (68 mg, 0.4 mmol, 0.1 eq.). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched by adding ice water (50 ml) and extracted with EtOAc (30 ml x 3). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated, and the crude residue was used directly without further purification (1.5 g, crude) as a colorless oil. LC-MS: m/z 353 [M+H] ⁺ .

Step C: 6-(4-methoxyphenyl)-8-(1',4'-dioxaspiro [4.5]decane)-2-(methylthio)-5,6-dihydropyrido[4,3d]pyrimidine-7(8H)- He

To a solution of methyl 8-(5-formyl-2-(methylthio)pyrimidin-4-yl)-1,4-dioxaspiro[4.5]decan-8carboxylate (1.5 g, 4.3 mmol, 1.0 eq. ) and 4-methoxyaniline (1.2 g, 9.5 mmol, 2.2 eq.) in DCE (18 ml) AcOH (0.9 ml, 15.1 mmol, 3.5 eq.) was added. The resulting solution was stirred at room temperature for 1 h, after which NaBH ₃ CN (0.7 g, 10.8 mmol, 2.5 eq.) was added in several portions over 0.5 h, and the resulting mixture was stirred at room temperature during the night. The reaction mixture was quenched with ice water (10 ml) and extracted with EtOAc (30 ml x 3). All organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (PE/EtOAc=10/1-1/1) to give 6-(4-methoxyphenyl )-8-(1',4'-dioxaspiro[4.5]decane)-2-(methylthio)-5,6-dihydropyrido[4,3d]pyrimidin-7(8Н)-one (1.4 g, yield 79 %) as a light brown solid. LC-MS: m/z 428 [M+H] ⁺ .

Step D: 6-(4-methoxyphenyl)-8-(1',4'-dioxaspiro[4.5]decane)-2-(methylsulfonyl)-5,6dihydropyrido[4,3-b]pyrimidine-7(8H)- He

To a solution of 6-(4-methoxyphenyl)-8-(1',4'-dioxaspiro[4.5]decane)-2-(methylthio)-5,6dihydropyrido[4,3-d]pyrimudin-7(8H)-one (470 mg, 1.1 mmol, 1.0 eq.) in DCM (10 ml) mCPBA (565 mg, 3.3 mmol, 3.0 eq.) was added in several portions over 0.5 h. The resulting mixture was stirred at room temperature for an additional 2 hours, after which it was quenched by adding ice water (20 ml) and extracted with DCM (20 ml x 3). The organic layers were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (PE/EtOAc=2/1-1/1) with obtaining 6-(4-methoxyphenyl)-8-(1',4'-dioxaspiro[4.5]decane)-2-(methylsulfonyl)-5,6-dihydropyrido[4,3d]pyrimidin-7(8H)-one ( 475 mg, 94% yield as a white solid. LC-MS: m/z 460 [M+H] ⁺ .

Step E: 8-(1',4'-dioxaspiro[4.5]decane)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-5.6

- 47 041815 dihydropyrido[4,3-d]pyrimidin-7(8H)-one

To a solution of 6-(4-methoxyphenyl)-8-(1',4'-dioxaspiro[4.5]decane)-2-(methylsulfonyl)-5,6dihydropyrido[4,3-b]pyrimidin-7(8H)-one (1.1 g, 2.5 mmol, 1.0 eq.) in DMSO (15 ml) at room temperature was added CsF (380 mg, 2.5 mmol, 1.0 eq.), DIPEA (967 mg, 7 .5 mmol, 3.0 eq.) and 2,2,2 trifluoroethanamine (740 mg, 7.5 mmol, 3.0 eq.). The resulting mixture was stirred at 80° C. overnight and then water (10 ml) was added. The reaction mixture was extracted with DCM (20 ml x 3), the organic layers were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography to give 8-(1',4'-dioxaspiro[4.5]decane)-6-(4-methoxyphenyl)-2-((2,2,2trifluoroethyl)amino)-5,6- dihydropyrido[4,3-d]pyrimidin-7(8H)-one (850 mg, 71% yield) as a white solid. LC-MS: m/z 479 [M+H]+.

Step F: 6'-(4-methoxyphenyl)-2'-((2,2,2-trifluoroethyl)amino)-5'H-spiro[cyclohexane-1,8'pyrido[4,3-d]pyrimidine] -4,7'(6Ή)-dione

To a solution of 8-(1',4'-dioxaspiro[4.5]decane)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-5,6dihydropyrido[4,3-d ]pyrimidin-7(8H)-one (50.0 mg, 0.1 mmol, 1.0 eq.) in acetone (2.0 ml) was added 1N. HCl (aq.) (0.5 ml, 0.5 mmol, 5.0 eq.). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was then concentrated and purified by reverse phase preparative HPLC to give the title product (14 mg, 31% yield) as a white solid. LC-MS: m/z 435 [M+H] ⁺ .

Step G: 4-hydroxy-6'-(4-methoxyphenyl)-2'-((2,2,2-trifluoroethyl)amino)-5'H-spiro[cyclohexane1,8'-pyrido[4,3-d ]pyrimidine]-7'(6Ή)-one (Example 116)

I].

6n

To a solution of 6'-(4-methoxyphenyl)-2'-((2,2,2-trifluoroethyl)amino)-5'H-spiro[cyclohexane-1,8'pyrido[4,3-d]nirimidine]- 4,7'(6Ή)-dione (10 mg, 0.023 mmol, 1.0 eq.) in THF (4 ml) at -20°C was added NaBH ₄ (3.8 mg, 0.10 mmol, 4.0 equiv.). The mixture was stirred at -20°C for 1 hour Then, the reaction mixture was quenched by adding NH ₄ Cl (sat. aq., 5 ml) and was extracted with EtOAc (5 ml x 3). The organic layers were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase preparative HPLC to give 4hydroxy-6'-(4-methoxyphenyl)-2'-((2,2,2-trifluoroethyl)amino)-5'H-spiro[cyclohexane-1,8'- pyrido[4,3b]pyrimidine]-7'(6'H)-one (Example 116).

1H-NMR (400 MHz, CDCl ₃ ) δ: 8.14 (s, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 5.50-5.34 (m, 1H), 4.66 (s, 2H), 4.28-4.13 (m, 2H), 3.82 (s, 3H), 3.83 -3.72 (m, 1H), 2.31-1.77 (m, 8H). LC-MS: m/z 437 [M+H] ⁺ .

Getting example 117:

- 48 041815

Step A: 1-(5-amino-1,3,4-thiadiazol-2-yl)-6'-(4-methoxyphenyl)-2'-(methylsulfonyl)-5'Hspiro[pineridine-4,8'- pyrido[4,3-d]n-yrimidine]-7'(6Ή)-one

MeO. ,....

Mix > and _g

6'-(4-methoxyphenyl)-2'-(methylsulfonyl)-5'H-spiro[piperidine-4,8'-pyrido[4,3

d]pyrimidin]-7'(6'H)-one (prepared according to General Procedure I, steps A-D and H, (n=2) from 1-tert-butyl-4-ethylpiperidin-1,4-dicarboxylate. LC MS: m/z 403 [M+H]+) (150.0 mg, 0.37 mmol, 1.0 eq.), 5-bromo-1,3,4-thiadiazol-2-amine (80.0 mg, 0.45 mmol, 1.2 eq.), TEA (75.0 mg, 0.74 mmol, 2.0 eq.) and 3.0 ml DMF were stirred at rt. for 1 h. Then, the reaction mixture was concentrated under reduced pressure, and then purified by flash chromatography on silica gel to obtain 1-(5amino-1,3,4-thiadiazol-2-yl)-6'-(4- methoxyphenyl)-2'-(methylsulfonyl)-5'H-spiro[piperidin-4,8'nirido[4,3-d]nirimidin]-7'(6Ή)-one (100.0 mg, 54% yield) . LC-MS: m/z 502 [M+H] ⁺ .

Step B: 1-(5-amino-1,3,4-thiadiazol-2-yl)-6'-(4-methoxyphenyl)-2'-((2,2,2-trifluoroethyl)amino)-5' Hspiro[piperidin-4,8'-pyrido[4,3-d]n-pyrimidin]-7'(6Ή)-one (Example 117)

Mixture

1-(5-Amino-1,3,4-thiadiazol-2-yl)-6'-(4-methoxyphenyl)-2'-(methylsulfonyl)-5'Hspiro[pineridine-4,8'-pyrido[4 ,3-d]n-pyrimidin]-7'(6Ή)-one (100.0 mg, 0.2 mmol, 1.0 eq.), CsF (30.0 mg, 0.2 mmol, 1.0 eq. ), DIPEA (78.0 mg, 0.6 mmol, 3.0 eq.) and 2,2,2-trifluoroethanamine (60.0 mg, 0.6 mmol, 3.0 eq.) in 2.0 ml DMSO was stirred at 80°C for 3 hours Then, water (10.0 ml) was added and the resulting mixture was extracted with DCM (20 ml x 3). All organic layers were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give 1-(5-amino1,3,4-thiadiazol-2-yl)-6'-(4-methoxyphenyl)-2'-((2,2,2-trifluoroethyl) amino)-5'H-spiro[piperidin-4,8'pyrido[4,3-d]pyrimidin]-7'(6Ή)-one (Example 117).

1H-NMR (400 MHz, CDCl ₃ ) δ: 8.18 (s, 1H), 7.17 (d, J=9.2 Hz, 2H), 6.95 (d, J=9.2 Hz, 2H), 5.45 (t, J=6.4 Hz, 1H), 4.71-4.68 (broad s, 2H), 4.69 (s, 2H), 4.23-4.10 (m, 2H), 3.82 (s, 3H), 3.81-3.71 (m, 4H), 2.35-2.29 (m, 2H), 2.25-2.17 (m , 2H). LC-MS: m/z 5.

Getting example 118

Ηϋι

Meon

PPTS

HC(OMe}j 65 °C, 4 h

Stage A

UHMDS, THF

-78 °C - 0 °C

Stage B

OME

Mei Mr. ’ 'J / 'Ά A''

bn

120" N W min

Stage C ome £

MeO V ‘Ν

HCl

Ιι °C, 30 min eri' Stage D

Brf

MeO'

ΝΜΪΟΑύΊ! ¹ 1 al'jH L<b 22¾ 16 h

Stage E

o c 8(/

Step A: 2,4-dichloro-5-(dimethoxymethyl)pyrimidine

OMv

MeO X N

A α*Ά ^Γ ci

To a flask with MeOH (24.0 ml) was added 2,4-dichloropyrimidine-5-carbaldehyde (1.5159 g, 1.0 eq.), PPTS (215.0 mg, 0.1 eq.) and trimethylorthoformate (6 .0 ml). The reaction mixture was stirred at 65°C for 14 h, cooled to rt. and concentrated. The resulting residue was purified by column chromatography to give the title compound as an oil (1.4361 g, 75% yield). 1HNMR (400 MHz, chloroform-d) 5 8.73 (s, 1H), 5.54 (s, 1H), 3.38 (s, 7H). LC-MS: m/z 223, 225 [M+H] ⁺ .

- 49 041815

Step B: ethyl 1-benzyl-3-(2-chloro-5-(dimethoxymethyl)pyrimidin-4-yl)pyrrolidin-3-carboxylate and Me

MeO' / \JCO _z Et

Ethyl 1-benzylpyrrolidine-3-carboxylate (314.0 mg, 1.5 eq.) and THF (10.0 ml) were added to the flask. The mixture was cooled to -78°C and then LiHMDS (1.0 M in THF, 1.35 ml, 1.5 eq.) was added and stirred at -78°C for 30 min. To this mixture at -78°C was added 2,4-dichloro-5(dimethoxymethyl)pyrimidine (200.0 mg, 1.0 eq.). The reaction mixture was stirred at -78°C for 30 min, heated to 0°C and stirred for 1 h, after which it was quenched by adding silica gel. The resulting mixture was concentrated and purified by column chromatography to give the title compound (269.7 mg, 72% yield). LC-MS: m/z 420 [M+H]+.

Step C: ethyl-1-benzyl-3-(2-((cyclopropylmethyl)amino)-5-(dimethoxymethyl)pyrimidin-4yl)pyrrolidine-3-carboxylate

OME

Μ£!(}'·^''···|·Τ·'·' ⁴ ··Ν „ I.. .A .·.

''-y· \JcO _r Et ^h

Ethyl 1-benzyl-3-(2-chloro-5(dimethoxymethyl)pyrimidin-4-yl)pyrrolidin-3-carboxylate (269.7 mg, 1.0 eq) and cyclopropylmethanamine (2 .5 ml). The reaction mixture was stirred at 120° C. for 20 min using a Biotage microwave reactor and cooled to rt. The mixture was concentrated and purified by column chromatography to give the title compound (201.8 mg, 69% yield). LC-MS: m/z 455 [M+H] ⁺ .

Stage D: ethyl-1-benzyl-3-(2-((cyclopropylmethyl)-amino)-5-formylpyrimidin-4-yl)pyrrolidin3-carboxylate

In a flask with acetone was added 1N. HCl (0.4 ml) and ethyl 1-benzyl-3-(2-((cyclopropylmethyl)amino)-5(dimethoxymethyl)pyrimidin-4-yl)pyrrolidin-3-carboxylate (201.8 mg, 1.0 equiv.). The reaction mixture was stirred at 22°C for 30 min and quenched by adding aq. _NaHC03 . The mixture was concentrated and purified by column chromatography to give the title compound (165.7 mg, 91% yield). LC-MS: m/z 409 [M+H] ⁺ .

Step E: 1'-benzyl-2-((cyclopropylmethyl)amino)-6-(4-methoxybenzyl)-5,6-dihydro-7Hspiro[pyrido[4,3-d]pyrimidine-8,3'-pyrrolidine] -7-one (example 118)

Ethyl 1-benzyl-3-(2-((cyclopropylmethyl)amino)-5-formylpyrimidin-4yl)pyrrolidine-3-carboxylate (36.6 mg, 1.0 eq.), (4-methoxyphenyl) was added to the flask. methanamine (26 μl, 2.2 eq.), sodium triacetoxyborohydride (28.5 mg, 1.5 eq.), dichloroethane (DCE, 2.0 ml) and acetic acid (15 μl, 3.0 eq.). The reaction mixture was stirred at 22°C for 16 h, after which it was quenched by adding aq. NaHCO3. The mixture was concentrated and purified by column chromatography to give the title compound (Example 118). ¹ H-NMR (400 MHz, chloroform-d) δ 7.93 (s, 1H), 7.46-7.39 (m, 2H), 7.35-7.29 (m, 2H), 7, 27 (d, J=7.1 Hz, 1H), 7.19-7.12 (m, 2H), 6.87-6.79 (m, 2H), 4.75-4.59 (m, 2H), 4.194.05 (m, 2H), 3.98 (s, 2H), 3.78 (s, 3H), 3.47 (d, J=10.2 Hz, 1H), 3.34 ( d, J=10.2 Hz, 1H), 3.27 (t, J=6.3 Hz, 2H), 3.20 (s, 1H), 3.05 (dt, J=9.3, 7 .1 Hz, 1H), 2.57-2.38 (m, 2H), 1.13-1.03 (m, 1H), 0.58-0.47 (m, 2H), 0.26 ( dt, J=6.0, 4.5 Hz, 2H). m/z 484 [M+H] ⁺ .

Preparation of Example 119, 120, 121 and 122 by General Procedure II:

- 50 041815

ethyl 3-(2-chloro-5-(dimethoxymethyl)pyrimidin-4-yl)-1-(2-fluorobenzyl)pyrrolidine-3 Step A: carboxylate

Ethyl 1-(2-fluorobenzyl)pyrrolidine-3-carboxylate (2.02 g, 1.5 eq., prepared as in Example 118) and THF (15.0 ml) were added to the flask. The mixture was cooled to -78°C, and then added LiHMDS (1.0 M in THF, 8.1 ml, 1.5 eq.). The reaction mixture was stirred at -78°C for 40 min and 2,4-dichloro-5-(dimethoxymethyl)pyrimidine (1.1965 g, 1.0 eq.) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 1 h, heated to 0°C and stirred for 45 min, after which it was quenched by adding silica gel. The resulting mixture was concentrated and purified by column chromatography to give the title compound (1.30 g, 55% yield). LC-MS: m/z 438 [M+H]+.

Step B: ethyl 3-(2-((cyclopropylmethyl)amino)-5-(dimethoxymethyl)pyrimidin-4-yl)-1-(2fluorobenzyl)pyrrolidine-3-carboxylate

OME

Ethyl 3-(2-chloro-5(dimethoxymethyl)pyrimidin-4-yl)-1-(2-fluorobenzyl)pyrrolidine-3-carboxylate (398.8 mg, 1.0 eq) was added to the microwave tube. and cyclopropylmethanamine (2.5 ml). The reaction mixture was stirred at 120° C. for 20 min using a Biotage microwave reactor and cooled to rt. The mixture was concentrated and purified by column chromatography to give the title compound (312.3 mg, 73% yield). LC-MS: m/z 473 [M+H] ⁺ .

Step C: ethyl 3-(2-((cyclopropylmethyl)amino)-5-formylpyrimidin-4-yl)-1-(2fluorobenzyl)pyrrolidine-3-carboxylate

- 51 041815 ⁰

I Γ'^Ύ'^'Ν

,. Ji A / ν 'Ν' Ν'

J V-Ao^t ¹¹ V w ⁷

Ethyl 3-(2-((cyclopropylmethyl)amino)-5(dimethoxymethyl)pyrimidin-4-yl)-1-(2-fluorobenzyl)pyrrolidine-3-carboxylate (312.3 mg, 1 0 equiv.) and 1n. HCl (0.7 ml). The reaction mixture was stirred at 22°C for 15 min and quenched by adding aq. _NaHC03 . The mixture was concentrated and purified by column chromatography to give the title compound (230.0 mg, 82% yield). LC-MS: m/z 427 [M+H]+.

2-((Cyclopropylmethyl)amino)-1'-(2-fluorobenzyl)-6-((2-methoxypyridin-4-yl)methyl)-5,6-dihydro7H-spiro[pyrido[4,3-d]pyrimidine -8,3'-pyrrolidine]-7-one (Example 119)

General Procedure II (Step D): Ethyl 3-(2-((cyclopropylmethyl)amino)-5formylpyrimidin-4-yl)-1-(2-fluorobenzyl)pyrrolidine-3-carboxylate (30.0 mg, 1.0 eq.), (6methoxypyridin-3-yl)methanamine (21.4 mg, 2.2 eq.), sodium triacetoxyborohydride (22.4 mg, 1.5 eq.), dichloroethane (DCE, 2.0 ml) and acetic acid (14 µl, 3.0 eq.). The reaction mixture was stirred at 22°C for 16 h, after which it was quenched by adding aq. _NaHC03 . The mixture was concentrated and purified by column chromatography to give the title compound (Example 119). 1H NMR (400 MHz, chloroform-d) δ 8.06 (d, J=2.4 Hz, 1H), 7.96 (s, 1H), 7.52 (dd, J=8.5, 2.5 Hz, 2H), 7.23 (s, 1H), 7.11 (t, J=7.4 Hz, 1H), 7.01 (t, J=9.1 Hz, 1H), 6.70 ( d, J=8.5 Hz, 1H), 4.73-4.58 (m, 2H), 4.15 (s, 2H), 3.92 (d, J=0.8 Hz, 3H), 3.89 (s, 2H), 3.34-3.14 (m, 4H), 3.02 (s, 2H), 2.47 (ddt, J=25.8, 12.6, 6.4 Hz, 2H), 1.13-1.03 (m, 1H), 0.62-0.44 (m, 2H), 0.25 (d, J=5.0 Hz, 2H). LC-MS: m/z 503 [M+H]+.

6-(( 1 H-pyrazol-5 -yl)methyl)-2-((cyclopropylmethyl)amino)-1'-(2-fluorobenzyl)-5,6-dihydro-7Hspiro[pyrido[4,3-d] pyrimidine-8,3'-pyrrolidine]-7-one (example 120)

General Procedure II (Step D): Ethyl 3-(2-((cyclopropylmethyl)amino)-5formylpyrimidin-4-yl)-1-(2-fluorobenzyl)pyrrolidine-3-carboxylate (30.0 mg, 1.0 eq.), (6methoxypyridin-3-yl)methanamine (15.0 mg, 2.2 eq.), sodium triacetoxyborohydride (22.4 mg, 1.5 eq.), dichloroethane (DCE, 2.0 ml) and acetic acid (14 µl, 3.0 eq.). The reaction mixture was stirred at 22°C for 16 h, after which it was quenched by adding aq. _NaHC03 . The mixture was concentrated and purified by column chromatography to give the title compound (Example 120). 1HNMR (400 MHz, chloroform-d) δ 7.99 (s, 1H), 7.50 (t, J=5.0 Hz, 2H), 7.21 (ddd, J=7.4, 5.5 , 1.9 Hz, 1H), 7.11 (td, J=7.5, 1.3 Hz, 1H), 7.01 (ddd, J=9.7, 8.1, 1.3 Hz, 1H), 6.25 (d, J=2.1 Hz, 1H), 4.72 (s, 2H), 4.29 (s, 2H), 3.90 (s, 2H), 3.38- 3.13 (m, 4H), 3.02 (d, J=7.0 Hz, 2H), 2.51 (dt, J=12.7, 6.5 Hz, 1H), 2.40 (dt , J=12.6, 6.6 Hz, 1H), 1.13-1.01 (m, 1H), 0.59-0.47 (m, 2H), 0.25 (dt, J=6 ,1, 4.5 Hz, 2H). LC-MS: m/z 462 [M+H]+.

Example 121 2-((cyclopropylmethyl)amino)-1'-(2-fluorobenzyl)-6-(isoxazol-4-yl)-5,6-dihydro-7Hspiro[pyrido[4,3-d]pyrimidin-8 ,3'-pyrrolidine]-7-one

- 52 041815

General Procedure II (Step D): To a solution of ethyl 3-((2-cyclopropylmethylamino)-5formylpyrimidin-4-yl)-1-(2-fluorobenzyl)pyrrolidine-3-carboxylate (60 mg, 0.14 mmol, 1 eq.) in 1,2dichloroethane (0.7 ml) was added isoxazol-4-amine hydrochloride (25.4 mg, 0.21 mmol, 1.5 eq.). The mixture was stirred at 75°C for 1 h. The reaction mixture was cooled to 60°C after which sodium triacetoxyborohydride (60 mg, 0.28 mmol, 2 eq.) was added and stirred for an additional 3 h. The crude reaction mixture was purified column chromatography (CombiFlash, dichloromethane/methanol=100/0-80/20) to give the title compound (Example 121). ¹ H-NMR (400 MHz, chloroform-d) δ 9.01 (s, 1H), 8.66 (s, 1H), 8.15 (s, 1H), 7.50-7.44 (m, 1H), 7.21 (t, J=6.6 Hz, 1H), 7.10 (t, J=7.4 Hz, 1H), 7.01 (t, J=9.1 Hz, 1H) , 5.35 (s, 1H), 4.66 (s, 2H), 3.86 (s, 2H), 3.28 (td, J=7.2, 6.4, 3.0 Hz, 3H ), 3.20 (d, J=9.4 Hz, 1H), 2.99 (t, J=6.6 Hz, 2H), 2.56 (d, J=10.0 Hz, 2H), 1.09 (s, 1H), 0.60-0.51 (m, 2H), 0.27 (d, J=5.0 Hz, 2H). LC-MS: m/z 449 [M+H] ^- .

Example 122 2-((cyclopropylmethyl)amino)-1'-(2-fluorobenzyl)-6-(1H-pyrazol-4-yl)-5,6-dihydro-7Hspiro[pyrido[4,3-d]pyrimidine -8,3'-pyrrolidine]-7-one

General Procedure II (Step D): To a mixture of ethyl 3-((2-cyclopropylmethylamino)-5-formylpyrimidin4-yl)-1-(2-fluorobenzyl)-pyrrolidine-3-carboxylate (60 mg, 0.14 mmol, 1 eq.) and acetic acid (0.025 ml, 0.42 mmol, 3 eq.) in 1,2-dichloroethane (0.7 ml) was added isoxazol-4-amine hydrochloride (25.4 mg, 0.21 mmol, 1.5 eq.). The mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (60 mg, 0.28 mmol, 2 eq.) was added and the mixture was stirred for 48 hours at room temperature. The crude reaction mixture was purified by column chromatography (CombiFlash, dichloromethane/methanol=100/0-80/20). The appropriate fractions were combined and concentrated, the residue was washed with saturated solution of NaHCO ₃ and was extracted with dichloromethane (2x5 ml). The organic extracts were combined, dried over Na ₂ SO ₄ and concentrated to give the title compound (Example 122). 1H-NMR (400 MHz, chloroform-d) δ 8.12 (s, 1H), 7.96 (s, 2H), 7.46 (t, J=7.4 Hz, 1H), 7.18 ( d, J=7.0 Hz, 1H), 7.10-7.04 (m, 1H), 6.98 (dd, J=9.9, 8.2 Hz, 1H), 5.34 (s , 1H), 4.66 (s, 2H), 3.84 (d, J=2.5 Hz, 2H), 3.32-3.18 (m, 4H), 2.97 (d, J= 5.5 Hz, 2H), 2.54 (d, J=19.0 Hz, 3H), 1.07 (ddt, J=10.4, 7.4, 3.7 Hz, 1H), 0, 55-0.49 (m, 2H), 0.25 (q, J=5.1 Hz, 2H). LC-MS: m/z 448 [M+H]+.

- 53 041815

General Method III:

m-CPBA

DCM k.t., 4 h

Stage C

Stage E

I ₃ - B (OH) ₂

Stage F

Alternative p-TsOH pathway

Aliya- Eun ₂

Aryl - NH?

Cs/ligand, Cs-^GOj ml CsF, dioxane or acetonitrile. YuOoS acetone-H ₂ O

Stage G

SPLA

Step J p-TsOH, toluene oC. 14 h

Stage A liHMOS IHI

-I Ό-kt, 14 h

Stage B

YuOoS. b h

Stage to toluene, HOAc, TOOS

Stage H

Aryl —B(OH)

SHOAS 2 live.

pyridine. 4 eq

U SM to t.

Stage I

Alternative way:

_NH40Ac

HOAc-toluene (IL. 14 h

Alkyl-YN ₂

CsF. DIPEA. DMSO wOoC, 4 hours

Stage D

Method B: Chan Lam Combination

CGOAcg lyridin,

DCM. O2 (t etm , 40оС

HOAc-toluene ;1

- 54 041815

Ό

Meo't

Zee

Preparation of Example 123 according to General Procedure III:

MAO..

'Np-TsOH

Ό'

SG'%1 toluene, 30 °C, 14 h's ^t CPBA

OSI, k.t., 4 h stage A o ^u

Λ MeO'^y' 'N S, O'

DMSO, 100°Rf

LiHMDS, THF ct 14 h

Stage B

0°

M'O'

Stage C

Stage O

4a

MSHOAc

HN

N

HOA- toluene

100°С, 14 h

ABOUT

CFCut Ligand, Cs ₂ CO ₃ dioxane 1000'C

O"^;

N' ^S CF ₃

H ³

Stage E

C|

Ligand: [

7a

Stage F

Step A: 4-chloro-5-(dimethoxymethyl)-2-(methylthio)pyrimidine

4-Chloro-2-(methylthio)pyrimidine-5-carbaldehyde (15.0 g, 79.8 mmol, 1.0 eq.) and p-TsOH-H ₂ O (90.0 mg, 0.473 mmol, 0.006 eq. .) was dissolved in toluene (75.0 ml). Triethylorthoformate (42.3 g, 399.0 mmol, 5.0 eq.) was added to the solution at 0°C. The resulting solution was stirred at 30°C for an additional 14 hours Then, the mixture was immediately concentrated. The residue was redissolved in DCM (50.0 ml) and purified by silica gel flash chromatography eluting (PE/EA=10/1) to give the title product (18 g, 96% yield) as a colorless oil. LC-MS (ESI): m/z 235 [M+H]+.

Step B: methyl 2-(4-chlorophenyl)-2-(5-(dimethoxymethyl)-2-(methylthio)pyrimidin-4-yl)acetate ^h o

Methyl 2-(4-chlorophenyl)acetate (31.6 g, 170.9 mmol, 2.0 eq) was dissolved in anhydrous THF (200 ml), cooled to -65° C. under N2. LiHMDS (1N, in THF, 256 ml, 256.0 mmol, 3.0 eq.) was added dropwise to the -65° C. solution. After the addition, the resulting mixture was stirred at -65°C for 2 h, and then a solution of 4-chloro-5(dimethoxymethyl)-2-(methylthio)pyrimidine (20 g, 85.4 mmol, 1.0 eq.) in anhydrous THF (80 ml). After the addition, the reaction mixture was slowly warmed to room temperature and stirred at room temperature for 14 h. At this point in time, the mixture was quenched by adding NH ₄ Cl (sat. aq., 500 ml) and extracted with EA (500 ml x 3). The organic layers were combined, washed with brine (500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting (PE/EA=10:1-5:1) to give the desired product (30 g, 93% yield) as a yellow solid. LC-MS: m/z 383 [M+H] ⁺ .

Step C: methyl 2-(4-chlorophenyl)-2-(5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin-4yl)acetate

- 55 041815

To a solution of methyl 2-(4-chlorophenyl)-2-(5-(dimethoxymethyl)-2-(methylthio)pyrimidin-4-yl)acetate (30 g, 78.3 mmol, 1.0 eq.) in DCM (500 mL) 3-chloroperoxybenzoic acid (40.4 g, 235.1 mmol, 3.0 eq.) was added portionwise over 1 hour. The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM (1 L), washed with NaHCO ₃ (sat. aq., 1 L x 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting (PE/EA=10:1-2:1) to give the title product (27 g, 83% yield) as a white solid. LC-MS: m/z 415 [M+H]+.

Step D: methyl 2-(4-chlorophenyl)-2-(5-(dimethoxymethyl)-2-((2,2,2-trifluoroethyl)amino)pyrimidin4-yl)acetate

Mixture of methyl 2-(4-chlorophenyl)-2-(5-(dimethoxymethyl)-2-((2,2,2-trifluoroethyl)amino)pyrimidin-4yl)acetate (15 g, 36.1 mmol, 1, 0 eq.), CsF (5.5 g, 36.1 mmol, 1.0 eq.), DIPEA (23.3 g, 180.5 mmol, 5.0 eq.) and 2,2,2-trifluoroethanamine (35.8 g, 361.5 mmol, 10 eq.) in DMSO (150 ml) was stirred at 100° C. overnight in a sealed tube. Then, the reaction mixture was concentrated to remove excess 2,2,2-trifluoroethanamine. The resulting residue was poured into ice water (500 ml) and extracted with EA (500 ml x 3). The organic layers were combined, washed with brine (500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting (PE/EA=5:1-3:1) to give the title product (10 g, 64% yield) as a yellow solid. LC-MS: m/z 434 [M+H] ⁺ .

Step E: 8-(4-chlorophenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

A mixture of methyl 2-(4-chlorophenyl)-2-(5-(dimethoxymethyl)-2-((2,2,2-trifluoroethyl)amino)pyrimidin-4yl)acetate (30 g, 69.1 mmol, 1, 0 eq.), NH ₄ OAc (180 g, 779 mmol, 11.3 eq.), AcOH (75 ml) and toluene (150 ml) were stirred at 100°C for an additional 14 h. Then, the mixture was concentrated under conditions reduced pressure, and pour the residue into ice water (500 ml). This mixture was filtered and the collected precipitate was washed with NaHCO ₃ (sat. aq., 500 ml) and then with water (1 l). The resulting solid was dried under vacuum to give the title product (21 g, 85% yield) as a yellow solid. LC-MS: m/z 355 [M+H] ⁺ .

Stage F: (method A: Ullmann combination). 8-(4-chlorophenyl)-6-(2-methyl-2Н-indazol-5-yl)-2((2,2,2-trifluoroethyl)amino)pyrido[4,3-0]pyrimidine-7(6Н )-he (example 123)

A mixture of 8-(4-chlorophenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (100 mg, 0.28 mmol, 1, 0 eq.), 5-bromo-2-methyl-2H-indazole (119 mg, 0.56 mmol, 2.0 eq.), CuI (5.4 mg, 0.028 mmol, 0.1 eq.), N ¹ ,N ² -dimethylcyclohexane-1,2-diamine (8.1 mg, 0.056 mmol, 0.2 eq.), Cs ₂ CO ₃ (276 mg, 0.847 mmol, 3.0 eq.) and dioxane (2 ml ) was stirred at 100°C under N2 for 16 hours. The crude mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash chromatography to give 8-(4-chlorophenyl)-6-(2 -methyl-2H-indazol-5-yl)-2((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 123).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.91 (s, 1H), 8.59 (t, J=6.4 Hz, 1H), 8, 51 (s, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.72-7.64 (m, 3H), 7.38-7.28 (m, 3H), 4 .22 (s, 3H), 4.12-4.03 (m, 2H). LC-MS: m/z 485 [M+H]+.

Example 124 8-(4-chlorophenyl)-6-(1,2-dimethyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3 -d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 6a and 6-bromo-1,2dimethyl-1H-benzo[d]imidazole by General Procedure III, Method A (CuI, N1,N ² dimethylcyclohexane-1,2-diamine, Cs ₂ CO ₃ , 1,4-dioxane, 100°C).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.89 (s, 1H), 8.59 (t, J=6.4 Hz, 1H), 7, 74 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.8 Hz, 1H), 7.35 ( d, J=8.4 Hz, 2H), 7.26 (dd, J=8.4, 2.0 Hz, 1H), 4.15-4.01 (m, 2H), 3.75 (s , 3H), 2.57 (s, 3H). LC-MS: m/z 499 [M+H] ⁺ .

Example 125: 6-(benzo[c]isothiazol-5-yl)-8-(4-chlorophenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidine-7 (6H )-He to

V j J-A . ..

N j K η ^ν <'γ,'^ί'Άί ¹ Η ' α

The title compound was synthesized from intermediate 6a and 5bromobenzo[c]isothiazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, Cs ₂ CO ₃ , 1,4-dioxane, 100° C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 8.99 (s, 1H), 8.98 (s, 1H), 8.65 (t, J=6, 4 Hz, 1H), 8.15 (d, J=1.2 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H), 7.69 (d, J=8.4 Hz , 2H), 7.63 (dd, J=9.2, 2.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 4.16-4.03 (m, 2H). LC-MS: m/z 488 [M+H] ⁺ .

Example 126 8-(4-chlorophenyl)-6-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4 ,3-d]pyrimidin-7(6H)-one

N. ,.-Ch.

-N P'

- -<:· 'M' · ' Ν . - - .

CD V' AN CF, ⁿ

C/a

The title compound was synthesized from intermediate 6a and 5-bromo-2methyl-2H-pyrazolo[3,4-b]pyridine by General Procedure III, method A (CuI, N1,N ² dimethylcyclohexane-1,2-diamine, Cs ₂ CO ₃ , 1,4-dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.97 (s, 1H), 8.67 (d, J=2.4 Hz, 1H), 8.65 (t, J=6.4 Hz, 1H), 8.60 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 7.68 (d, J=8.4 Hz , 2H), 7.36 (d, J=8.8 Hz, 2H), 4.26 (s, 3H), 4.15-4.03 (m, 2H). LC-MS: m/z 486 [M+H] ⁺ .

Example 127 8-(4-chlorophenyl)-6-(1-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2trifluoroethylamino)pyrido[4,3-d]pyrimidine- 7(6Н)-one

The title compound was synthesized from intermediate 6a and 6-bromo-1-57 041815 cyclopropyl-III-benzo^]imidazole by General Procedure III, method A (CuI, N1,N ² dimethylcyclohexane-1,2-diamine, Cs ₂ CO ₃ , 1,4-dioxane, 100°C).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.91 (s, 1H), 8.60 (t, J=6.8 Hz, 1H), 8.38 (s, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.4 Hz , 2H), 7.36 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.8 Hz, 2H), 4.16-4.02 (m, 2H), 3 .57-3.48 (m, 1H), 1.13-1.04 (m, 4H). LC-MS: m/z 511 [M+H]+.

Example 128 8-(4-chlorophenyl)-6-(1-isopropyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2trifluoroethylamino)pyrido[4,3-d]pyrimidine- 7 (6H)-he

N · . J1

A

- ^J A A. ,-.

V' γ- Ν 'Ν ΌΗ

I. n

V

G1

The title compound was synthesized from intermediate 6a and 6-bromo-1isopropyl-1H-benzo[d]imidazole by General Procedure III, method A (CuI, N ¹ ,N ² dimethylcyclohexane-1,2-diamine, Cs2CO3, 1, 4-dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.94 (s, 1H), 8.62 (t, J=6.4 Hz, 1H), 8.51 ( s, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.34 (dd, J=8.4, 1.6 Hz, 1H), 4.84-4.74 (m, 1H ), 4.16-4.03 (m, 2H), 1.55 (d, J=6.8 Hz, 6H). LC-MS: m/z 513 [M+H] ⁺ .

Example 129 6-(benzo[d]thiazol-6-yl)-8-(4-chlorophenyl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3d]pyrimidin-7(6H)-one

That

The title compound was synthesized from intermediate 6a and 6bromobenzo[d]thiazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CS2CO3, 1,4-dioxane, 100°C). LC-MS: m/z 488 [M+H] ⁺ .

Example 130 8-(4-chlorophenyl)-6-(pyrazolo[1,5-a]pyridin-5-yl)-2-(2,2,2trifluoroethylamino)pyrido[4,3-d]pyrimidine-7( 6H)-on

A .1 'N' 'V '^N

A A o- γ kg -pj ci g 1

X

The title compound was synthesized from intermediate 6a and 5bromopyrazolo[1,5-a]pyridine by General Procedure III, Method A (CuI, N1,N ² dimethylcyclohexane-1,2-diamine, CS ₂ CO ₃ , 1,4- dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.98 (s, 1H), 8.96 (s, 1H), 8.83 (d, J=7.6 Hz, 1H), 8, 67 (t, J=6.4 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.99 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.09 (dd, J=7.2 Hz, 2.0 Hz, 1H), 6.79 (d, J= 1.2 Hz, 1H), 4.19-4.01 (m, 2H). LC-MS: m/z 471 [M+H] ⁺ .

Example 131 8-(4-chlorophenyl)-6-(cinnolin-6-yl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3d]pyrimidin-7(6H)-one

The title compound was synthesized from bromocinnoline intermediate 6a and 6 by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2-diamine, CS2CO3, 1,4-dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.51 (d, J=6.0 Hz, 1H), 9.05 (s, 1H), 9.02 (s, 1H), 8, 73 (d, J=6.4 Hz,

- 58 041815

1H), 8.63 (d, J=8.8 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.36 (d, J=5.6 Hz, 1H) , 8.16 (dd, J=9.2 Hz, 2.4 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz , 2H), 4.18-4.03 (m, 2H). LC-MS: m/z 483 [M+H]+.

Example

132:

trifluoroethylamino)pyrido[4,3-d]nupuMuguH-7(6Н)-one

8-(4-chlorophenyl)-6-(2,3-dimethyl-2H-indazol-5-yl)-2-(2,2,2-

The title compound was synthesized from intermediate 6a and 5-bromo-2,3dimethyl-2H-indazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, Cs ₂ CO ₃ , 1, 4-dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.92 (s, 1H), 8.59 (t, J=6.4 Hz, 1H), 7.89 ( d, J=1.2 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.8 Hz, 2H), 7.29 (dd, J=9.2 Hz, 2.0 Hz, 1H), 4.15-4.02 (m, 2H), 4.11 (s, 3H), 2.64 (s, 3H). LC-MS: m/z 499 [M+H] ⁺ .

Example 133 8-(4-chlorophenyl)-6-(2,3-dihydrobenzofuran-5-yl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3-d]pyrimidine-7(6H) -He

The title compound was synthesized from intermediate 6a and 5-bromo-2,3dihydrobenzofuran using General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, Cs ₂ CO ₃ , 1,4-dioxane, 100°C).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.96 (s, 1H), 8.82 (s, 1H), 8.58 (t, J=6.4 Hz, 1H), 7 .66 (d, J=8.4 Hz, 2H), 7.04 (s, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.24 (d, J=8, 4 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.63 (d, J=8.8 Hz, 2H), 2.82 (d, J=8.8 Hz , 2H), 4.15-4.03 (m, 2H), 3.26 (t, J=8.8 Hz, 2H). LC-MS: m/z 473 [M+H] ⁺ .

Example 134 8-(4-chlorophenyl)-6-(imidazo[1,2-a]pyridin-6-yl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3-d]pyrimidine- 7 (6H)-on

The title compound was synthesized from intermediate 6a and 6bromimidazo[1,2-a]pyridine by General Procedure III, Method A (CuI, N1,N ² dimethylcyclohexane-1,2-diamine, Cs ₂ CO ₃ , 1,4- dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.97 (s, 1H), 8.69 (t, J=6.4 Hz, 1H), 8.08 (s, 1H), 8.17 (d, J=9.2 Hz, 1H), 8.12 (s, 1H), 7.77-7.63 (m, 3H), 7.43 (dd, J=9.2 Hz, 1.6 Hz, 1H), 7.37 (d, J=8.8 Hz, 2H), 4.174.03 (m, 2H). LC-MS: m/z 471 [M+H] ⁺ .

Example 135: 8-(4-chlorophenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3-d] pyrimidine-7(6H)-one

The title compound was synthesized from intermediate 6a and 6-bromo-1methyl-1H-benzo[d]imidazole by General Procedure III, method A (CuI, N1,N ² dimethylcyclohexane-1,2-diamine, Cs ₂ CO ₃ , 1,4-dioxane, 100°C).

- 59 041815 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.99 (s, 1H), 8.91 (s, 1H), 8.61 (t, J=6.4 Hz, 1H ), 8.34 (s, 1H), 7.85 (d,

J=2.0 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.36 (d, J= 8.8 Hz, 2H), 7.35 (dd, J=8.0 Hz, 2.0 Hz,

1H), 4.15-4.02 (m, 2H), 3.87 (s, 3H). LC-MS: m/z 485 [M+H]+.

Example 136 6-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-8-(4-chlorophenyl)-2-((2,2,2-trifluoroethyl)amino) pyrido[4,3-d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 6a and 6-bromo[1,2,4]triazolo[4,3-a]pyridine by General Procedure III, Method A (CuI, N1,N ² dimethylcyclohexane-1,2-diamine , Cs2CO3, 1,4-dioxane, 100°C).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.41 (s, 1H), 9.00 (s, 1H), 8.98 (s, 1H), 8.95 (s, 1H) , 8.72 (t, J=6.4 Hz, 1H), 7.92 (d, J=9.6 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7 .58 (dd, J=9.6 Hz, 1.6 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 4.17-4.03 (m, 2H). LC-MS: m/z 472 [M+H] ⁺ .

Example

137:

trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

8-(4-chlorophenyl)-6-(2-(2-(dimethylamino)ethyl)-2H-indazol-5-yl)-2-((2,2,2-

The title compound was synthesized from intermediate 6a and 2-(5-bromo2H-indazol-2-yl)-N,N-dimethylethanamine via General Procedure III, Method A (CuI, N ¹ ,N ² dimethylcyclohexane-1,2- diamine, Cs2CO3, 1,4-dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.92 (s, 1H), 8.59 (t, J=6.4 Hz, 1H), 8.55 (s, 1H), 7.90 (d, J=1.2 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.68 (d, J=8.8 Hz , 2H), 7.35 (d, J=8.8 Hz, 2H), 7.33 (dd, J=9.2 Hz, 2.0H, 1H), 4.56 (t, J=6, 4 Hz, 2H), 4.14-4.03 (m, 2H), 2.81 (t, J=6.4 Hz, 1H), 2.18 (s, 6H). LC-MS: m/z 542 [M+H] ⁺ .

Example 138 8-(4-chlorophenyl)-6-(2-methylbenzo[d]oxazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidine -7 (6H) -he

The title compound was synthesized from intermediate 6a and 5-bromo-2methylbenzo[d]oxazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, Cs ₂ CO ₃ , 1,4- dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.90 (s, 1H), 8.61 (t, J=6.4 Hz, 1H), 7.91( s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 4.16-4.01 (m, 2H), 2.67 (s, 3H). LC-MS: m/z 486 [M+H] ⁺ .

Example

139:

8-(4-chlorophenyl)-6-(quinolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one

The title compound was synthesized from Bromoquinoline Intermediate 6a and 6-60 041815 by General Procedure III, Method A (CuI, N,N-dimethylcyclohexane-1,2-diamine,

CS2CO3, 1,4-dioxane, 100°C).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (d, J=4.0 Hz, 1.6 Hz, 1H), 9.02 (s, 1H), 9.00 (s, 1H), 8.67 (t, J=6.4 Hz, 1H), 8.48 (d, J=8.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H) , 8.17 (d, J=9.2 Hz, 1H), 7.94 (dd, J=9.2 Hz, 2.4 Hz, 1H), 7.70 (d, J=8.4 Hz , 2H), 7.66 (dd, J=8.4 Hz, 4.0 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 4.17-4.03 (m , 2H). LC-MS: m/z 482 [M+H]+.

Example 140 8-(4-chlorophenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3 -d]pyrimidin-7(6Н)-one □ „ N

G to . ~

N'

ON '''N Η

I J

The title compound was synthesized from intermediate 6a and 5-bromo-1methylpyridin-2(1H)-one by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane 1,2-diamine, Cs ₂ CO ₃ , 1 ,4-dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.86 (s, 1H), 8.65 (t, J=6.4 Hz, 1H), 8.14 (d, J=2.8 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.63 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.35 (d, J=8.8 Hz, 2H), 6.48 (d, J=9.6 Hz, 1H), 4.14-4.00 (m, 2H), 3.48 (s , 3H). LC-MS: m/z 462 [M+H] ⁺ .

Example 141 8-(4-chlorophenyl)-6-(1-ethyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d ]pyrimidine-7(6Н)-one

The title compound was synthesized from intermediate 6a and 6-bromo-1ethyl-1H-benzo[d]imidazole by General Procedure III, method A (CuI, N ¹ ,N ² -dimethylcyclohexane 1,2-diamine, Cs ₂ CO ₃ , 1,4-dioxane, 100°C).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.92 (s, 1H), 8.60 (t, J=6.4, 1H), 8.41 (s, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.4 Hz , 2H), 7.36 (d, J=8.4 Hz, 2H), 7.34 (dd, J=8.4 Hz, 2.0 Hz, 1H), 4.31 (q, J=7 .2 Hz, 2H), 4.15-4.02 (m, 2H), 1.43 (t, J=7.2 Hz, 3H). LC-MS: m/z 499 [M+H] ⁺ .

Example 142 8-(4-chlorophenyl)-6-(2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidine-7(6H)- He

The title compound was synthesized from intermediate 6a and 5-bromo-2-((2(trimethylsilyl)ethoxy)methyl)-2H-indazole by General Procedure III, Method A (CuI, N1,N ² dimethylcyclohexane-1,2- diamine, Cs ₂ CO ₃ , 1,4-dioxane, 100° C.) and then deprotection with TFA by general procedure I (step F).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 13.37 (s, 1H), 8.97 (s, 1H), 8.92 (s, 1H), 8.60 (t, J=6 .4 Hz, 1H), 8.21 (s, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.72-7.65 (m, 3H), 7.48 (dd , J=8.8 Hz, 2.0 Hz, 1H), 7.35 (d, J=8.8 Hz, 2H), 4.164.02 (m, 2H). LC-MS: m/z 471 [M+H] ⁺ .

Preparation of 8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (6b)

8-(4-Methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6Н)-one (6b) was synthesized from -(4-methoxyphenyl)acetate by general procedure III (steps B-E). LC-MS: m/z

351 [M+H]+.

Example 143 6-(imidazo[1,2-a]pyridin-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d]pyrimidine -7(6H)-one

OME

The title compound was synthesized from intermediate 6b and 6bromimidazo[1,2-a]pyridine by General Procedure III, Method A (CuI, N1,N ² dimethylcyclohexane-1,2-diamine, CsF, 1,4-dioxane, 100 °C).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.75 (s, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.78 (d, J=10.0 Hz, 1H), 7.76 (s, 1H), 7.71-7.65 (m, 3H), 7.25 (dd, J=10.0, 2.0 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 5.81 (t, J=6.4 Hz, 1H), 4.21-4.07 (m, 2H), 3.86 (s, 3H) . LC-MS: m/z 467 [M+H] ⁺ .

Example 144 8-(4-methoxyphenyl)-6-(quinoxalin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimudin-7(6H)-one

The title compound was synthesized from intermediate 6b and 6bromoquinoxaline by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2-diamine, CsF, 1,4-dioxane, 100° C.).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.70 ( s, 1H), 8.19 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.11 (d, J=2.4 Hz, 1H), 7.91 ( dd, J=8.8 Hz, 2.4 Hz, 1H), 7.66 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5 .71 (t, J=6.4 Hz, 1H), 4.14-4.03 (m, 2H), 3.79 (s, 3H). LC-MS: m/z 479 [M+H] ⁺ .

Example 145: 8-(4-methoxyphenyl)-6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-((2,2, 2trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6Н)-one

The title compound was synthesized from intermediate 6b and 6-bromo-4methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine by General Procedure III, Method A (CuI, N1,N ² dimethylcyclohexane- 1,2-diamine, CsF, 1,4-dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.13 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.61 (dd , J=8.0 Hz, 2.4 Hz, 1H), 5.72 (t, J=6.4 Hz, 1H), 4.32 (t, J=4.4 Hz, 2H), 4, 18-4.06 (m, 2H), 3.84 (s, 3H), 3.31 (t, J=4.4 Hz, 2H), 2.88 (s, 3H). LC-MS: m/z 498 [M+H] ⁺ .

Example 146 8-(4-methoxyphenyl)-6-(quinazolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one

N ' 1 i .

O - H N CF.

, But

OME

The title compound was synthesized from intermediate 6b and 6bromoquinazoline by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2-diamine,

- 62 041815

CsF, 1,4-dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 9.43 (s, 1H), 9.00 (s, 1H), 8.97 (s, 1H), 8 .61 (t, J=6.4 Hz, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.23 (dd, J=8.8 Hz, 2.4 Hz, 1H ), 8.18 (d, J=8.8 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.18-4.04 (m, 2H), 3.78 (s, 3H).

LC-MS: m/z 479 [M+H]+.

Example 147 6-(2,3-dihydrobenzofuran-5-yl)-8-(4-methoxyphenyl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d]pyrimidine-7(6H )-He

bf'.fe

The title compound was synthesized from intermediate 6b and 5-bromo-2,3dihydrobenzofuran by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100°C ).

1H-NMR (400 MHz, CDCl ₃ ) δ 8.70 (s, 1H), 8.13 (s, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.31 (s , 1H), 7.11 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 6.87 (d, J=8 .4 Hz, 1H), 5.69 (t, J=5.6 Hz, 1H), 4.66 (t, J=8.8 Hz, 2H), 4.21-4.07 (m, 2H ), 3.85 (s, 3H), 3.27 (t, J=8.8 Hz, 2H). LC-MS: m/z 469 [M+H]+.

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-((2,2,2-trifluoroethyl)amino)purido[4,3-d]pyrimidin7(6H)-one (6c)

NG T \

O > U\rF1

OCHF- 6 s

8-(4-(Difluoromethoxy)phenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (6с) was synthesized from methyl-2- (4-(difluoromethoxy)phenyl)acetate by General Procedure III (step BE). LC-MS: m/z 387 [M+H]+.

Example 148 8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d] pyrimidine-7(6H)-one

-.-.-g··' Ύ

D . ...

N'। N t

OCHF,

The title compound was synthesized from intermediate 6c and 5-bromo-2methyl-2H-indazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100 °C).

¹ H-NMR (400 MHz, DMSO-d6) δ: 8.97 (s, 1H), 8.90 (s, 1H), 8.57 (t, J=6.4 Hz, 1H), 8, 51 (s, 1H), 7.90 (d, J=1.2 Hz, 1H), 7.72-7.69 (m, 3H), 7.34 (dd, J=9.2 Hz, 2 .0 Hz, 1H), 7.26 (t, Jhf=74.4 Hz, 1H), 7.11 (d, J=8.8 Hz, 2H), 4.22 (s, 3H), 4, 15-4.02 (m, 2H). LC-MS: m/z 517 [M+H] ⁺ .

Example 149 8-(4-(difluoromethoxy)phenyl)-6-(2-methylbenzo[d]oxazol-5-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d] pyrimidin-7(6H)-one g - J J N-- Ν N

L1.1

C t % \ F

H'

The title compound was synthesized from intermediate 6c and 5-bromo-2methylbenzo[d]oxazole by General Procedure III, method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100 °C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.97 (s, 1H), 8.89 (s, 1H), 8.59 (t, J=6.0 Hz, 1H), 7, 91 (d, J=2.0 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.52 ( dd, J=8.8 Hz, 2.0 Hz, 1H), 7.26 (t, J _HF =74.4 Hz, 1H),

- 63 041815

7.11 (d, J=8.8 Hz, 2H), 4.15-4.01 (m, 2H), 2.67 (s, 3H). LC-MS: m/z 518 [M+H]+.

Example 150: 8-(4-(difluoromethoxy)phenyl)-6-(2-methylbenzo[d]thiazol-6-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d] pyrimidin-7(6Н)-one

□SNS

The title compound was synthesized from intermediate 6c and 6-bromo-2methylbenzo[d]thiazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100 °C).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.94 (s, 1H), 8.63 (t, J=6.4 Hz, 1H), 8, 29 (d, J=2.0 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.65 ( dd, J=8.8 Hz, 2.4 Hz, 1H), 7.27 (t, Jhf=74.4 Hz, 1H), 7.12 (d, J=8.8 Hz, 2H), 4 .15-4.03 (m, 2H), 2.87 (s, 3H). LC-MS: m/z 534 [M+H] ⁺ .

Example 151 8-(4-(difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4, 3-d]pyrimidin-7(6Н)-one

The title compound was synthesized from intermediate 6c and 6-bromo-1methyl-1H-benzo[d]imidazole by General Procedure III, method A (CuI, N1,N ² dimethylcyclohexane-1,2-diamine, CsF, 1.4 -dioxane, 100°C).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.98 (s, 1H), 8.70 (s, 1H), 8.59 (t, J=6.4 Hz, 1H), 8 .35 (broad s, 1H), 7.86 (d, J=1.2 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.70 (d, J= 8.8 Hz, 2H), 7.34 (d, J=8.4 Hz, 2.0 Hz, 1H), 7.28 (t, J _hf =74.4 Hz, 1H), 7.11 ( e, J=8.8 Hz, 2H), 4.15-4.02 (m, 2H), 3.87 (s, 3H). LC-MS: m/z 517 [M+H] ⁺ .

Example 152 8-(4-(difluoromethoxy)phenyl)-6-(2-ethyl-2H-indazol-5-yl)-2-((2,2,2trifluoroethyl)amino)pyrido [4,3-d] pyrimidin-7(6Н)-one

SANS

The title compound was synthesized from intermediate 6c and 5-bromo-2ethyl-2H-indazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100 °C).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.97 (s, 1H), 8.89 (s, 1H), 8.57 (t, J=6.4 Hz, 1H), 8 .56 (s, 1H), 7.90 (d, J=1.2 Hz, 1H), 7.75-7.67 (m, 3H), 7.33 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.26 (t, Jhf=74.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 4.51 (kv, J=7, 2 Hz, 2H), 4.17-4.02 (m, 2H), 1.54 (t, J=7.2 Hz, 3H). LC-MS: m/z 531 [M+H] ⁺ .

Example 153 8-(4-(difluoromethoxy)phenyl)-6-(2-isopropyl-2H-indazol-5-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d] pyrimidin-7(6Н)-one

UN

The title compound was synthesized from intermediate 6c and 5-bromo-2isopropyl-2H-indazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100 °C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.97 (s, 1H), 8.88 (s, 1H), 8.58 (s, 1H), 8.57 (t, J=6 .4 Hz, 1H), 7.88 (d,

- 64 041815

J=1.6Hz, 1H), 7.75-7.67(m, 3H), 7.32(dd, J=8.8Hz, 2.0Hz, 1H), 7.26(t, J _HF =74.4 Hz, 1H), 7.11 (d, J=8.8 Hz,

2H), 4.89 (hept, J=6.8 Hz, 1H), 4.15-4.02 (m, 2H), 1.58 (d, J=6.8 Hz, 6H). LC-MS: m/z 545 [M+H]+.

Example 154 6-(2-cyclopropyl-2H-indazol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d] pyrimidine-7(6Н)-one >ΧΊ " .

” 'N'

X D X .

O' Ύ Ν N' OF.

I ⁿ

X Τ' OGHF _?

The title compound was synthesized from intermediate 6c and 5-bromo-2-cyclopropyl-2H-indazole by General Procedure III, method A (CuI, N ¹ ,N ² -dimethylcyclohexane 1,2-diamine, CsF, 1,4-dioxane, 100 °C).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.89 (s, 1H), 8.65 (s, 1H), 8.57 (t, J=6, 4 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.73-7.66 (m, 3H), 7.33 (dd, J=9.2 Hz, 2, 0 Hz, 1H), 7.26 (t, Jhf=74.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 4.27-4.17 (m, 1H) , 4.15-4.01 (m, 2H), 1.37-1.28 (m, 2H), 1.19-1.10 (m, 2H). LC-MS: m/z 543 [M+H]+.

Example 155 8-(4-(difluoromethoxy)phenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[ 4,3-d]pyrimidin-7(6Н)-one

The title compound was synthesized from intermediate 6c and 5-bromo-1methylpyridin-2(1H)-one by General Procedure III, method A (CuI, N ¹ ,N ² -dimethylcyclohexane 1,2-diamine, CsF, 1,4- dioxane, 100°C).

¹ H-NMR (400 MHz, DMSO-d6) 5 8.95 (s, 1H), 8.86 (s, 1H), 8.66 (t, J=6.4 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.63 (dd, J=10.0 Hz, 2.8 Hz, 1H), 7.28 (t, J _HF =74.4 Hz, 1H), 7.11 (d, J=8.8 Hz, 2H), 6.48 (d, J=9.2 Hz, 1H), 4 .14-4.02 (m, 2H), 3.48 (s, 3H). LC-MS: m/z 494 [M+H]+.

Example 156 6-(benzo[d]thiazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d] pyrimidine-7(6H)-one

The title compound was synthesized from intermediate 6c and 6bromobenzo[d]thiazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100° C.).

1H-NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.98 (s, 1H), 8.96 (s, 1H), 8.64 (t, J=6.0 Hz, 1H), 8.44 (d, J=1.2 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.78-7.66 (m, 3H), 7.27 (t, Jhf=74.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 4.18-4.02 (m, 2H). LC-MS: m/z 520 [M+H]+.

Example 157 8-(4-(difluoromethoxy)phenyl)-6-(imidazo[1,2-a]pyridin-6-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3- d]pyrimidin-7(6Н)-one

Ί

A-N. l

-m' •'γ'

-7, Ν Ν' Π

Λ ⁿ

I! 2 Y.,

The title compound was synthesized from intermediate 6c and 6bromimidazo[1,2-a]pyridine by General Procedure III, Method A (CuI, N1,N ² dimethylcyclohexane-1,2-diamine, CsF, 1,4-dioxane, 100 °C).

- 65 041815

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.16 (s, 1H), 9.00 (s, 1H), 8.95 (s, 1H), 8.70 (t, J=6, 4 Hz, 1H), 8.27 (s,

1H), 7.91 (s, 1H), 7.90 (d, J=9.6 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.27 (t, J _H F=74.4 Hz,

1H), 7.13 (d, J=8.8 Hz, 2H), 4.17-4.03 (m, 2H). LC-MS: m/z 503 [M+H]+.

Example

158:

trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

8-(4-(difluoromethoxy)phenyl)-6-(2,3-dimethyl-2H-indazol-5-yl)-2-((2,2,2-

The title compound was synthesized from intermediate 6c and 5-bromo-2,3dimethyl-2H-indazole by General Procedure III, method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane , 100°C).

1H-NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.90 (s, 1H), 8.56 (t, J=6.4 Hz, 1H), 7.89 ( d, J=1.6 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.60 (d, J=9.2 Hz, 1H), 7.29 (dd, J=9.2Hz, 2.0Hz, 1H), 7.27(t, Jhf=74.4Hz, 1H), 7.11(d, J=8.8Hz, 2H), 4.10 (s, 3H), 4.15-4.02 (m, 2H), 2.64 (s, 3H). LC-MS: m/z 531 [M+H]+.

Example 159 8-(4-(difluoromethoxy)phenyl)-6-(quinolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7( 6H)-on

The title compound was synthesized from intermediate 6c and 6bromoquinoline using General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2-diamine, CsF, 1,4-dioxane, 100° C.).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 9.01 (s, 1H), 9.00 (s, 1H), 8.85 (t, J=6 .4 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.25 (d, J=2.4 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.95 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.67 (dd, J= 8.4 Hz, 4.4 Hz, 1H), 7.27 (t, Jhf=74.4 Hz, 1H), 7.13 (d, J=8.8 Hz, 2H), 4.17-4 .03 (m, 2H). LCMS: m/z 514 [M+H]+.

Preparation of 2-((2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pyrido[4,3-d]pyrimidin7(6H)-one (6d)

8-(4-(Difluoromethoxy)phenyl)-2-((2,2,2-trifluoroethyl)-amino)pyrido[4,3-d]pyrimidin-7(6H)-one (6d) was synthesized from methyl-2 -(4-(trifluoromethoxy)phenyl)acetate by General Procedure III (Steps B-E). LC-MS: m/z 405 [M+H] ⁺ .

Example 160 Preparation of 6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)-8-(4(trifluoromethoxy)phenyl)pyrido[4,3- d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 6d and 5-bromo-2methyl-2H-indazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100 °C).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.98 (s, 1H), 8.93 (s, 1H), 8.60 (t, J=6.0 Hz, 1H), 8 .51 (s, 1H), 7.91 (d, J=1.2 Hz, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.71 (d, J=9, 1 Hz, 1H), 7.34 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 4.22 (s, 3H ), 4.14-4.00 (m, 2H). LC-MS: m/z 535 [M+H] ⁺ .

Preparation of 7(6Н)-one (6e)

2-((2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethyl)phenyl)pyrido[4,3^]pyrimidine- 66 041815

2-((2,2,2-Trifluoroethyl)amino)-8-(4-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidin-7(6H)-one (6e) was synthesized from methyl-2- (4-(trifluoromethyl)phenyl)acetate by General Procedure III (step BE). LC-MS: m/z 389 [M+H]+.

Example 161 Preparation of 6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)-8-(4(trifluoromethyl)phenyl)pyrido[4,3- d]pyrimidin-7(6H)-one

Ν ^Ν D , -j- -y '-m

D ,1

О''ύ'Ν'Ν''Cl , I ^н η

V

The title compound was synthesized from intermediate 6e and 5-bromo-2methyl-2H-indazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100 °C).

¹ H-NMR (400 MHz, DMSO-d6) δ: 9.00 (s, 1H), 8.97 (s, 1H), 8.65 (t, J=6.4 Hz, 1H), 8, 52 (s, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.35 (dd, J=9.2 Hz, 2.0 Hz, 1H), 4.23 (s, 3H) , 4.13-4.00 (m, 2H). LC-MS: m/z 519 [M+H] ⁺ .

Preparation of 8-(4-cyclonronylphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]n-yrimidin-7(6H)one (6f) ί I j .

-Ν Ή' THU, AND A HI

8-(4-Cyclopropylphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6Н)-one (6f) was synthesized from methyl-2-(4- cyclopropylphenyl)acetate by general procedure III (steps B-E). LCMS: m/z 361 [M+H]+.

Example 162 Preparation of 8-(4-cyclopropylphenyl)-6-(2-methylquinolin-6-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d]pyrimidine-7(6H) -she

The title compound was synthesized from intermediate 6f and 6-bromo-2methylquinoline by General Procedure III, method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2-diamine, CsF, 1,4-dioxane, 100°C ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.94 (s, 1H), 8.56 (t, J=6.4 Hz, 1H), 8, 34 (d, J=8.4 Hz, 1H), 8.15 (d, J=2.4 Hz, 1H), 8.04 (d, J=9.2 Hz, 1H), 7.86 ( dd, J=8.8 Hz, 2.4 Hz, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.4 Hz, 1H), 7 .01 (d, J=8.0 Hz, 2H), 4.16-4.03 (m, 2H), 2.71 (s, 3H), 1.98-1.86 (m, 1H), 0.99-0.91 (m, 2H), 0.71-0.63 (m, 2H). LC-MS: m/z 520 [M+H] ⁺ .

Example 163 8-(4-cyclopropylphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-(trifluoromethyl)quinolin6-yl)pyrido[4,3-d]pyrimidin-7( 6H)-he

- 67 041815

The title compound was synthesized from intermediate 6f and 6-bromo-2(trifluoromethyl)quinoline using General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane 1,2-diamine, CsF, 1,4-dioxane, 100 °C).

1H-NMR (400 MHz, DMSO-d6) δ: 8.99 (s, 1H), 8.98 (s, 1H), 8.83 (d, J=8.4 Hz, 1H), 8.60 (t, J=6.4 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.33 (d, J=9.2 Hz, 1H), 8.14-8 .07 (m, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 4.17-4.04 (m, 2H), 1.97-1.88 (m, 1H), 0.99-0.92 (m, 2H), 0.70-0.63 (m, 2H). LC-MS: m/z 556 [M+H]+.

Example

164:

8-(4-cyclopropylphenyl)-6-(2,3-dihydrobenzofuran-5-yl)-2-((2,2,2 trifluoroethyl)amino)pyrido[4,3-d]pyrimidine-7(6Н)- He

The title compound was synthesized from intermediate 6f and 5-bromo-2,3dihydrobenzofuran by General Procedure III, method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100°C ).

1H-NMR (400 MHz, DMSO-d6) δ: 8.99 (s, 1H), 8.82 (s, 1H), 8.54 (t, J=6.4 Hz, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.45 (s, 1H), 7.28 (dd, J=8.5 Hz, 2.4 Hz, 1H), 7.06 (d, J =8.0 Hz, 2H), 6.96 (d, J=8.4 Hz, 1H), 4.69 (t, J=8.8 Hz, 2H), 4.21-4.06 (m , 2H), 3.31 (t, J=8.8 Hz, 2H), 2.03-1.93 (m, 1H), 1.05-0.97 (m, 2H), 0.77- 0.66 (m, 2H). LC-MS: m/z 479 [M+H] ^- .

Example

165:

8-(4-cyclopropylphenyl)-6-(imidazo[1,2-a]pyridin-6-yl)-2-((2,2,2 trifluoroethyl)amino)pyrido[4,3-d]pyrimidine-7 (6H)-he

The title compound was synthesized from intermediate 6f and 6bromimidazo[1,2-a]pyridine by General Procedure III, Method A (CuI, N1,N ² dimethylcyclohexane-1,2-diamine, CsF, 1,4-dioxane, 100 °C).

¹ H-NMR (400 MHz, DMSO-d6) δ: 8.96 (d, J=1.2 Hz, 1H), 8.95 (s, 1H), 8.92 (s, 1H), 8. 59 (t, J=6.4 Hz, 1H), 8.06 (s, 1H), 7.71 (s, 1H) 7.69 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.41 (dd, J=9.6 Hz, 2.0 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 4.17-4.03 (m, 2H), 1.98-1.88 (m, 1H), 0.99-0.91 (m, 2H), 0.71-0.62 (m, 2H ). LC-MS: m/z 477 [M+H] ⁺ .

Example 166 6-(benzo[4]thiazol-6-yl)-8-(4-cyclopropylphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidine-7 (6H)-he

The title compound was synthesized from intermediate 6f and 6bromobenzo[d]thiazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100° C.).

1H-NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.95 (s, 1H), 8.90 (s, 1H), 8.56 (t, J=6.4 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.71 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.0 Hz,

- 68 041815

2H), 4.18-4.01 (m, 2H), 1.98-1.86 (m, 1H), 0.99-0.89 (m, 2H), 0.71-0.63 ( m, 2H). LC-MS: m/z 494 [M+H]+.

Example 167 8-(4-cyclopropylphenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 6f and 1-bromo-4methoxybenzene using General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2-diamine, CsF, 1,4-dioxane, 100°C ).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.94 (s, 1H), 8.77 (s, 1H), 8.49 (t, J=6.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 7.00 (d , J=8.4 Hz, 2H), 4.14-4.00 (m, 2H), 3.83 (s, 3H), 1.97-1.87 (m, 1H), 0.99- 0.91 (m, 2H), 0.70-0.63 (m, 2H). LC-MS: m/z 467 [M+H]+.

Example 168: 8-(4-cyclopropylphenyl)-6-(quinolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one । ⁴ l - ...] (C N

H

The title compound was synthesized from intermediate 6f and 6bromoquinoline by General Procedure III, method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2-diamine, CsF, 1,4-dioxane, 100° C.).

1H-NMR (400 MHz, DMSO-d6) δ 9.03 (dd, J=4.4 Hz, 1.6 Hz, 1H), 8.98 (s, 1H), 8.96 (s, 1H) , 8.58 (t, J=6.4 Hz, 1H), 8.48 (dd, J=8.4, 1.7 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.93 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.66 (dd, J=8, 4 Hz, 4.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 4.17-4.04 (m, 2H), 1.981.89 (m, 1H), 1.00-0.91 (m, 2H), 0.72-0.63 (m, 2H). LC-MS: m/z 488 [M+H]+.

Preparation of 8-(4-chlorophenyl)-2-(ethylamino)pyrido[4,3-d]pyrimidin-7(6H)-one (6g)

UN' 'Ν

D D. D σ'· ή ν -· ' Η

G ι

8-(4-Chlorophenyl)-2-(ethylamino)pyrido[4,3-d]pyrimidin-7(6H)-one (6g) was synthesized from ethanamine by general procedure III (steps D, E). LC-MS: m/z 301 [M+H]+.

Example 169 Preparation of 8-(4-chlorophenyl)-2-(ethylamino)-6-(2-methyl-2H-indazol-5-yl)pyrido[4,3d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 6g and 5-bromo-2methyl-2H-indazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, Cs ₂ CO ₃ , 1,4- dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.86 (s, 1H), 8.77 (s, 1H), 8.49 (s, 1H), 8.07 (t, J=5 .6 Hz, 1H), 7.87 (d, J=1.2 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.69 (d, J=9.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 2H), 7.31 (dd, J=9.2 Hz, 2.0 Hz, 1H), 4.22 (s, 3H) , 3.30-3.20 (m, 2H), 1.11 (t, J=7.2 Hz, 1H) LC-MS: m/z 431 [M+H]+.

Preparation of 2-(ethylamino)-8-(4-(trifluoromethoxy)phenyl)pyrido[4,3-d]pyrimidin-7(6Н)-one (6h)

- 69 041815

HN N

D D,.

Ο 'Ν'Ν' □α _{2 6h}

2-(Etylamino)-8-(4-(trifluoromethoxy)phenyl)pyrido[4,3-d]pyrimidin-7(6Н)-one (6h) was synthesized from methyl 2-(4-(trifluoromethoxy)phenyl)acetate by general procedure III (stages B-E). LC-MS: m/z 351 [M+H]+.

Example 170 Preparation of 2-(ethylamino)-6-(2-methyl-2H-indazol-5-yl)-8-(4(trifluoromethoxy)phenyl)pyrido[4,3-d]pyrimidin-7(6H)- He

ska _

The title compound was synthesized from intermediate 6h and 5-bromo-2methyl-2H-indazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100 °C).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 8.09 (t, J=5, 6 Hz, 1H), 7.88 (d, J=1.2 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.69 (d, J=9.2 Hz , 1H), 7.32 (dd, J=9.2 Hz, 1.2 Hz, 1H), 7.29 (d, J=8.8 Hz, 2H), 4.22 (s, 3H), 3.30-3.20 (m, 2H), 1.10 (t, J=6.8 Hz, 3H). LC-MS: m/z 481 [M+H] ⁺ .

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(ethylamino)pyrido[4,3-b]pyrimidin-7(6H)-one (6i)

ΙΙΝ^ν ^ Ν

4. D D _Λ

O-% 'N' NT n o

QCHF _? KI

8-(4-(Difluoromethoxy)phenyl)-2-(ethylamino)pyrido[4,3-b]pyrimidin-7(6H)-one (6i) was synthesized from methyl 2-(4-(difluoromethoxy)phenyl)acetate by general procedure III (stages B-E). LC-MS: m/z 333 [M+H]+.

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(ethylamino)-6-(2-methyl-2H-indazol-5-yl)pyrido[4,3b]pyrimidin-7(6H)-one (Example 171 )

oc? G.

The title compound was synthesized from intermediate 6i and 5-bromo-2methyl-2H-indazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100 °C).

1H-NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.76 (s, 1H), 8.49 (s, 1H), 8.04 (t, J=5.6 Hz, 1H), 7.87 (d, J=1.2 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.69 (d, J=9.2 Hz, 1H), 7.31 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.26 (t, H _and 74.4 Hz, 1H), 7.11 (d, J=8, 4 Hz, 2H), 4.22 (s, 3H), 3.31-3.15 (m, 2H), 1.11 (t, J=7.2 Hz, 3H). LC-MS: m/z 463 [M+H]+.

Preparation of 2-(cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)pyrido[4,3-b]pyrimidin-7(6H)-one (6j)

UN ' g' Ν .

J „·.

U . Ν Ν

I ¹¹

OS HF; 6j

2-(Cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)pyrido[4,3-d]pyrimidin-7(6H)-one (6j) was synthesized from cyclopropanamine by general procedure III (steps D, E). LC-MS: m/z 345 [M+H]+.

Example 172 Preparation of 2-(cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2Nindazol-5-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

- 70 041815

OCHF

The title compound was synthesized from intermediate 6j and 5-bromo-2methyl-2H-indazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100 °C).

1H-NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.83 (s, 1H), 8.55 (s, 1H), 8.25 (d, J=4.0 Hz, 1H), 7.97-7.87 (m, 3H), 7.76 (d, J=9.2 Hz, 1H), 7.38 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.30 (t, Jhf=74.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 4.18 (s, 3H), 2.87- 2.76 (m, 1H), 0.77-0.70 (m, 2H), 0.66-0.58 (m, 2H). LC-MS: m/z 475 [M+H]+.

Preparation of 8-(4-chlorophenyl)-2-(cyclopropulamino)pyrido[4,3-d]pyrimidin-7(6Н)-one (6k)

€.1 1 ZA j - N' V

Q

CL tic

8-(4-Chlorophenyl)-2-(cyclopropylamino)nirido[4,3-d]pyrimidin-7(6H)-one (6k) was synthesized from cyclopropanamine by general procedure III (steps D, E). LC-MS: m/z 313 [M+H] ⁺ .

Example 173 Preparation of 8-(4-chlorophenyl)-2-(cyclopropylamino)-6-(2-methyl-2H-indazol-5yl)pyrido[4,3-d]pyrimidin-7(6H)-one

The title compound was synthesized from methyl-2H-indazole by General Procedure III, diamine, CsF, 1,4-dioxane, 100° C.).

from intermediate 6k and 5-bromo-2method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,21H-NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.79 (s , 1H), 8.50 (s, 1H), 8.22 (d, J=4.0 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.85 (d , J=8.4 Hz, 2H), 7.70 (d, J=9.2 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.33 (dd, J =9.2 Hz, 2.0 Hz, 1H), 4.23 (s, 3H), 2.82-2.73 (m, 1H), 0.73-0.64 (m, 2H), 0 .59-0.53 (m, 2H) LC-MS: m/z 443 [M+H]+.

Preparation of 2-(cyclobutylamino)-8-(4-(difluoromethoxy)phenyl)pyrido[4,3-d]pyrimidin-7(6H)-one (6l)

2-(Cyclobutylamino)-8-(4-(difluoromethoxy)phenyl)pyrido[4,3-d]pyrimidin-7(6H)-one (6l) was synthesized from cyclobutanamine by general procedure III (steps D, E). LC-MS: m/z 359 [M+H] ⁺ .

Example 174 Preparation of 2-(cyclobutylamino)-8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol5-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 61 and 5-bromo-2methyl-2H-indazole by General Procedure III, method A (CuI, P ¹ ,X2-dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100° C).

- 71 041815

Ή-NMR (400 MHz, DMSO-d6) δ: 8.86 (s, 1H), 8.76 (s, 1H), 8.49 (s, 1H), 8.33 (d, J=6, 8 Hz, 1H), 7.82 (d,

J=1.2 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.68 (d, J=9.2 Hz, 1H), 7.31 (dd, J= 9.2Hz, 2.0Hz, 1H), 7.27(t, Jhf=74.4

Hz, 1H), 7.13 (d, J=8.8 Hz, 2H), 4.22 (s, 3H), 4.23-4.11 (m, 1H), 2.23-2.11 (m, 2H), 2.09-1.93 (m, 2H). LC-MS:

m/z 489 [M+H]+.

Preparation of 2-((2,2-difluoroethyl)amino)-8-(4-(difluoromethoxy)phenyl)pyrido[4,3-d]pyrimidin-7(6H)one (6m)

2-((2,2-Difluoroethyl)amino)-8-(4-(difluoromethoxy)-phenyl)pyrido[4,3-b]pyrimidin-7(6Н)-one (6m) was synthesized from 2,2-difluoroethanamine by general procedure III (stages D, E). LC-MS: m/z 369 [M+H] ⁺ .

Example 175 Preparation of 2-((2,2-difluoroethyl)amino)-8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2Nindazol-5-yl)pyrido[4,3-b]pyrimidine -7(6H)-she

The title compound was synthesized from intermediate 6m and 5-bromo-2methyl-2H-indazole by General Procedure III, Method A (CuI, N ¹ ,N ² -dimethylcyclohexane-1,2diamine, CsF, 1,4-dioxane, 100 °C).

Ή-NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.87 (s, 1H), 8.51 (s, 1H), 7.89 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.2 Hz, 3H), 7.32 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.25 (t, H _and 74.4 Hz, 1H), 7.12 (d, J=8.8 Hz, 2H), 6.12 (tt, J _hf =56.4 Hz, 4.0 Hz, 1H), 4.22 ( s, 3H), 3.60 (dt, J _HF = 14.8 Hz, 4.0 Hz, 2H). LC-MS: m/z 499 [M+H] ⁺ .

The following compounds were synthesized by General Method III, Method A:

101-A . .. -.y -> ... I 8-(4-chlorophenyl)-6-(2-(2-hydroxy-2methylpropyl)-2Н-indazol-5-yl)-2-(2,2,2trifluoroethylamino)pyrido[4,3d]pyrimidin-7(6Н )-He (synthesized from 8-(4-chlorophenyl)-2((2,2,2-trifluoroethyl)amino)pyrido[4,34]pyrimidin-7(6H)-one and 1-(5-bromo-2Nindazol-2- yl)-2-methylpropan-2-ol (reference: Organic Letters, 16 (I), 31143117; 2014)) LC-MS (ESI): m/z 543 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) (tautomer ratio 7:1) δ 9.05 (s, 0.15H), 8.99 (s, 0.15H), 8.97 (s, 0. 85H), 8.93 (s, 0.85H), 8.59 (t, 1=6.5 Hz, 1H), 8.46 (d, J=l.0 Hz, 1H), 7.92 ( dd, J=2.0, 0.8 Hz, 1H), 7.76-7.72 (m, 1H), 7.70-7.66 (m, 1.75H), 7.55 (d, 1=8.3Hz, 0.25H), 7.40(d, J=8.2Hz, 0.25H), 7.36(dd, J=8.2, 1.6Hz, 1.75H ), 7.34-7.31 (m, 1H), 4.89 (s, 1H), 4.39 (s, 2H), 4.23 (s, 0.25H), 4.08 (pent, 1=9.3 Hz, 1.75H), 1.13 (s, 6H). 102-A -4 l. „ 4,L Г . f 8-(4-chlorophenyl)-2-(2,2- difluoroethylamino)-6-(2-methyl-2H- indazol-5-yl)pyrido[4,3-4]pyrimidine- 7(6Н)-one LC-MS (ESI): m/z 467 [M+H] ⁺ . 'P-NMR (400 MHz,) δ 8.94 (s, 1H), 8.88 (s, 1H), 8.50 (s, 1H), 8.38 (t, J=6.0 Hz, 1Н), 7.89 (d, J=l.9 Hz, 1Н), 7.70 (dd, J=8.8, 6.8 Hz, ZN), 7.41-7.27 (m, ZN ), 6.12 (tg, Jhf=56.3, J=4.1 Hz, 1H), 4.22 (s, 3H), 3.70-3.54 (m, 2H). (10:1 tautomer ratio. Only major peaks shown)

Stage F: (method B: combination according to Chan-Lam). 8-(4-Methoxyphenyl)-6-(pyridin-4-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-b]pyrimidin-7(6H)-one (Example 176)

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Example 176: Blend

8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidine Method B:

combination according to Chan Lam

HN

Η ’ he g l ° ' t and

ome

6b

CuiOAch, pyridine DCM. Oh, (1 atm). 40"C

Stage F

Ohfe

7(6H)-one (70.0 mg, 0.2 mmol, 1.0 eq.), pyridin-4-ylboronic acid (50.0 mg, 0.4 mmol, 2.0 eq.), copper acetate (P) (73.0 mg, 0.4 mmol, 2.0 eq.) and pyridine (63.0 mg, 0.8 mmol, 4.0 eq.) in DCM (3.0 ml) were stirred at 40 °C during the night in an O ₂ atmosphere. Thereafter, the reaction mixture was diluted with DCM (10.0 ml), washed with H ₂ O (10 ml x 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 8-(4methoxyphenyl)-6-(pyridin-4-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidine-7(6H )-she.

¹ H-NMR (400 MHz, CDCl3) δ: 8.82 (d, J=6.0 Hz, 2H), 8.75 (s, 1H), 8.08 (s, 1H), 7.68 ( d, J=9.2 Hz, 2H), 7.48 (d, J=6.4 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 5.81 (t, J=6.8 Hz, 1H), 4.19-4.08 (m, 2H), 3.82 (s, 3H). LC-MS: m/z 428 [M+H]+.

Example 177 Preparation of 6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2trifluoroethyl)amino)pyrido[4 ,3-d]pyrimidin-7(6Н)-one

The title compound was synthesized from intermediate 6b and (2,3dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid by General Procedure III, Method B (Cu(OAc) ₂ , pyridine, DCM, O ₂ (1 atm), 40°C).

1H-NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.74 (s, 1H), 8.49 (t, J=6.4 Hz, 1H), 7.58 ( t, J=8.8 Hz, 2H), 7.10 (d, J=2.0 Hz, 1H), 7.01 (s, 1H), 7.00 (d, J=2.4 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 4.32 (s, 4H), 4.15-4.01 (m, 2H), 3.78 (s, 3H). LC-MS: m/z 485 [M+H]+.

Example 178 8-(4-(difluoromethoxy)phenyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((2,2,2trifluoroethyl)amino)pyrido [4,3-d]pyrimidin-7(6Н)-one

from

The title compound was synthesized from intermediate 6c and (2,3dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid by General Procedure III, Method B (Cu(OAc) ₂ , pyridine, DCM, O ₂ ( 1 atm), 40°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.94 (s, 1H), 8.79 (s, 1H), 8.56 (t, J=6.4 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.26 (t, Jhf=74.4 Hz, 1H), 7.11 (d, J=2.8 Hz, 1H), 7.09 (d , J=8.8 Hz, 2H), 7.12-7.01 (m, 2H), 4.31 (s, 4H), 4.124.03 (m, 2H). LC-MS: m/z 521 [M+H]+.

Example 179 2-(cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)-6-(quinolin-6-yl)pyrido[4,3d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 6j and quinolin-6ylboronic acid using General Procedure III, Method B (Cu(OAc) ₂ , pyridine, DCM, O ₂ (1 atm), 40° C.).

1H-NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J=4.0 Hz, 1.6 Hz, 1H), 8.88 (s, 1H), 8.87 (s, 1H) , 8.48 (d, J=8.0

- 73 041815

Hz, 1H), 8.27 (d, J=4.4 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.93 (dd, J=8.8 Hz, 2.0 Hz, 1H),

7.88 (d, J=8.8 Hz, 2H), 7.66 (dd, J=8.8 Hz, 4.4 Hz, 1H), 7.26 (t, Jhf=74.4 Hz, 1H), 7.13 (d, J=8.8 Hz, 2H), 2.832.74 (m, 1H), 0.74-0.65 (m, 2H), 0.62-0.53 (m , 2H). LC-MS: m/z 472 [M+H]+.

Preparation of 8-(4-bromophenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3^]pyrimidin-7(6H)-one (6n)

8-(4-Bromophenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3^]pyrimidin-7(6Н)-one (6n) was synthesized from methyl-2-(4-bromophenyl )acetate by general procedure III (steps B-E). LC-MS: m/z 399, 401 [M+H]+.

Example

180:

receiving

8-(4-bromophenyl)-6-(quinolin-6-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 6n and quinolin-6ylboronic acid using General Procedure III, Method B (Cu(OAc) ₂ , pyridine, DCM, O ₂ (1 atm), 40° C.).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (d, J=4.0 Hz, 1H), 9.02 (s, 1H), 9.00 (s, 1H), 8.68 (t, J=6.0 Hz, 1H), 8.48 (d, J=8.4 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.17 (d , J=9.2 Hz, 1H), 7.94 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.69-7.61 (m, 3H), 7.51 (d , J=8.8 Hz, 2H), 4.17-4.03 (m, 2H). LC-MS: m/z 526, 528 [M+H] ⁺ .

The following compound was synthesized by general procedure III (alternative route; steps G-J): _______________________________________________________________________________

103-A - - _Ν ί Η )-He LC-MS (ESI): m/z 529 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.82 (d, J=2.5 Hz, 1H), 8.45 (s, 1H), 7.86 (s, 1H), 7.69 (d, J=9.1 Hz, 1H), 7.58 (d, 1=8.1 Hz, 2H), 7.48 (d, 1=8.3 Hz , 2H), 7.31 (dd, J=9.1, 2.0 Hz, 1H), 4.19 (s, 3H), 4.05 (q, J=9.6 Hz, 2H). (tautomer ratio 6:1. Only major peaks shown)

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Getting example 181:

. b

- P ' _________ he Si (OAc) ₂ 2 equiv. pyridine, 4 equiv.

OSM.k.t.

Stage I

SH ₄ OAc toluene, HOAc, 100°С

Stage H

LiMLUJS ΓΗΓ

-65 'C - kt., 14 h

Stage B

Step G: methyl 2-(5-formyl-2-(methylthio)pyrimidin-4-yl)-2-(4-methoxyphenyl)acetate

To a solution of methyl 2-(5-(dimethoxymethyl)-2-(methylthio)pyrimidin-4-yl)-2-(4-methoxyphenyl)acetate (570 mg, 1.5 mmol 1.0 eq.) in acetone/ H ₂ O (5.0/5.0 ml) was added p-TsOH (77 mg, 0.45 mmol, 0.3 eq.). Then, the mixture was stirred at 70°C for 2 hours. The resulting mixture was extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title product (450 mg, 90% yield) as a yellow oil. LC-MS (ESI): m/z 333 [M+H]+.

Step H: 8-(4-methoxyphenyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-7(6H)-one

To a mixture of 2-(5-formyl-2-(methylthio)pyrimidin-4-yl)-2-(4-methoxyphenyl)acetate (450 mg, 1.35 mmol, 1.0 eq.) in toluene/HOAc (5 0/5.0 ml) was added NH ₄ OAc (2.7 g, 350.6 mmol, 26.0 eq.). The resulting mixture was stirred at 100° C. for 5 hours. At this point in time, the mixture was concentrated in vacuo and diluted with DCM and H2O. The aqueous layer was extracted with DCM (10.0 ml x 2), the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel flash chromatography eluting (DCM/MeOH=150:1-50:1) to give the title product (180 mg, 44% yield) as a brown solid. LC-MS (ESI): m/z 300 [M+H] ⁺ .

Step I: 8-(4-methoxyphenyl)-2-(methylthio)-6-(quinolin-6-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

To a solution of 8-(4-methoxyphenyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-7(6H)-one (210.0 mg, 0.7 mmol, 1.0 eq.) in DCM (5.0 ml) was added quinolin-6-ylboronic acid (240 mg, 1.4 mmol, 2.0 eq.), Cu(OAc) ₂ (250 mg, 1.4 mmol, 2.0 eq.) and pyridine (221 mg, 2.8 mmol, 4.0 eq.). The mixture was stirred at 40° C. under O ₂ (1 atm) overnight. The solvent was removed in vacuo and the residue was diluted with DCM and H ₂ O. The aqueous layer was extracted with DCM (10.0 ml x 2), the combined organic layers were dried over Na ₂ SO ₄ and concentrated to obtain a brown oil. The residue was purified by the method

- 75 041815 flash chromatography on silica gel eluting (DCM/MeOH=200:1-50:1) to give the title product (250 mg, 83% yield) as a brown solid. LC-MS (ESI): m/z 427 [M+H]+.

Step J: 8-(4-methoxyphenyl)-6-(quinolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one ( example 181)

OME

To a solution of 8-(4-methoxyphenyl)-2-(methylthio)-6-(quinolin-6-yl)pyrido[4,3-d]pyrimidin-7(6H)-one (63 mg, 0.15 mmol, 1.0 eq.) in HOAc (1.0 ml) was added 2,2,2-trifluoroethanamine (300 mg, 3.0 mmol, 20.0 eq.). Then, the mixture was sealed and stirred at 100°C overnight. The resulting mixture was concentrated to a brown oil and purified by silica gel flash chromatography to give 8-(4-methoxyphenyl)-6-(quinolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido [4,3d]pyrimidin-7(6H)-oneα (Example 181) ¹ H-NMR (400 MHz, CDCl3) δ 9.02 (dd, J=4.3, 1.7 Hz, 1H), 8, 76 (s, 1H), 8.28-8.16 (m, 3H), 7.95 (d, J=2.4 Hz, 1H), 7.82 (dd, J=8.9, 2, 4 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.51 (dd, J=8.3, 4.3 Hz, 1H), 6.96 (d, J= 8.5 Hz, 2H), 5.74 (t, J=6.4 Hz, 1H), 4.16 (q, J=8.3 Hz, 2H), 3.85 (s, 3H). LC-MS: m/z 478 [M+H] ⁺ .

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(methylthio)-6-(quinolin-6-yl)pyrido[4,3-d]pyrimidin7(6H)-one (10c)

8-(4-(Difluoromethoxy)phenyl)-2-(methylthio)-6-(quinolin-6-yl)pyrido[4,3-d]pyrimidin-7(6Н)-one (10с) was synthesized from methyl-2 -(4-(difluoromethoxy)phenyl)acetate by General Procedure III (Step B, GJ). LC-MS: m/z 463 [M+H] ⁺ .

Example 182 Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(isopropylamino)-6-(quinolin-6yl)pyrido[4,3-d]pyrimidin-7(6H)-one

0^-^^

II O'

OCHF _?

The title compound was synthesized from intermediate 10c and propane-2amine according to the procedure of Example 181, Step J (HOAc, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (dd, J=4.4 Hz, 2.0 Hz, 1H), 8.88 (s, 1H), 8.86 (s, 1H ), 8.48 (d, J=7.6 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.93 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.66 (dd, J=8.4 Hz, 4.4 Hz, 1H) 7.27 (t, J _HF =74.4 Hz, 1H), 7.13 (d, J=8, 8 Hz, 2H), 4.003.90 (m, 1H), 1.16 (d, J=6.4 Hz, 6H). LC-MS: m/z 474 [M+H] ⁺ .

Example 183 2-(cyclobutylamino)-8-(4-(difluoromethoxy)phenyl)-6-(quinolin-6-yl)pyrido[4,3d]pyrimidin-7(6H)-one

oghf ₂

The title compound was synthesized from intermediate 10c and cyclobutanamine according to the procedure of Example 181, step J (HOAc, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.02 (dd, J=4.0 Hz, 1.6 Hz, 1H), 8.88 (s, 1H), 8.86 (s, 1H), 8.47 (d, J=8.4 Hz, 1H), 8.42 (d, J=6.4 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H) , 8.15 (d, J=8.4 Hz, 1H), 7.92 (dd, J=9.2 Hz, 2.4 Hz,

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1H), 7.74 (d, >8.8 Hz, 2H), 7.65 (dd, >8.4 Hz, 4.0 Hz, 1H), 7.27 (t, _JHF =74.4 Hz, 1H), 7.15 (d, >8.8 Hz, 2H),

4.25-4.12 (m, 1H), 2.23-2.12 (m, 2H), 2.09-1.92 (m, 2H), 1.71-1.54 (m, 2H ). LC-MS: m/z 486 [M+H] ⁺ .

Example 184 8-(4-(difluoromethoxy)phenyl)-2-(methylamino)-6-(quinolin-6-yl)pyrido[4,3d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 10c and methylamine hydrochloride according to the procedure of Example 181, step J (HOAc, 100°C).

^-NMR (400 MHz, DMSO-d ₆ ) 5: 9.02 (dd, >4.0 Hz, 1.6 Hz, 1H), 8.88 (s, 1H), 8.87 (s, 1H ), 8.47 (d, >8.0 Hz, 1H), 8.23 (d, >2.0 Hz, 1H), 8.15 (d, >9.2 Hz, 1H), 8.07 -8.02 (m, 1H), 7.93 (dd, >9.2 Hz, 2.0 Hz, 1H), 7.79 (d, >8.8 Hz, 2H), 7.66 (dd , >8.4 Hz, 4.0 Hz, 1H), 7.27 (t, J _HF = 74.6 Hz, 1H), 7.14 (d, >8.8 Hz, 2H), 2.82 (d, >5.6 Hz, ZN). LC-MS: m/z 446 [M+H] ⁺ .

Example 185: 2-(azetidin-1-yl)-8-(4-(difluoromethoxy)phenyl)-6-(quinolin-6-yl)pyrido[4,3-

d] pyrimidin-7(6H)-one

fire

The title compound was synthesized from Intermediate 10c and Azetidine following the procedure of Example 181, Step J (HOAc, 100°C).

^-NMR (400 MHz, DMSO-d ₆ ) δ: 9.02 (dd, >4.4 Hz, 1.6 Hz, 1H), 8.945 (s, 1H), 8.944 (s, 1H), 8, 47 (d, >7.6 Hz, 1H), 8.23 (d, >2.0 Hz, 1H), 8.14 (d, >8.8 Hz, 1H), 7.93 (dd, > 8.4 Hz, 2.0 Hz, 1H), 7.76 (d, >8.8 Hz, 2H), 7.65 (dd, >8.4 Hz, 4.4 Hz, 1H), 7, 26 (t, J _HF =74.4 Hz, 1H), 7.11 (d, >8.8 Hz, 2H), 4.24 (t, >6.4 Hz, 2H), 4.06 (t , >5.2 Hz, 2H), 2.36-2.25 (m, 2H). LC-MS: m/z 472 [M+H] ⁺ .

Preparation of 8-(4-bromoφenyl)-6-(4-methoκciφenyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-7(6H)-one (10p)

Vg

8-(4-Bromophenyl)-6-(4-methoxyphenyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-7(6Н)-one (10p) was synthesized from methyl-2-(4-bromophenyl )acetate by general procedure III (step B, GJ). LC-MS: m/z 454, 456 [M+H] ⁺ .

Example 186 Preparation of 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-((3,3,3trifluoropropyl)amino)pyrido[4,3-b]pyrimidin-7(6H)-one

B'

The title compound was synthesized from intermediate 10n and 3,3,3trifluoropropane-1-amine hydrochloride according to the procedure of Example 181, Step J (HOAc, 100°C).

*H-NMR (400 MHz, CDC1 ₃ ) δ 8.66 (s, 1H), 8.11 (s, 1H), 7.61 (d, >8.4 Hz, 2H), 7.49 (d , >8.4 Hz, 2H), 7.36 (d, >8.8 Hz, 2H), 7.01 (d, >8.8 Hz, 2H), 5.74 (t, >6.0 Hz, 1H), 3.86 (s, 3H), 3.65 (q, >6.4 Hz, 2H), 2.50-2.36 (m, 2H). LC-MS: m/z 519.521 [M+H] ⁺ .

Example 187 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-(methyl(2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one

-77041815

The title compound was synthesized from intermediate 10n and 2,2,2trifluoro-N-methylethanamine according to the procedure of Example 181, step J (HOAc, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ main isomer: 9.01 (s, 1H), 8.89 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 4, 66 (q, J=9.2 Hz, 2H), 3.83 (s, 3H), 3.15 (s, 3H). minor isomer: 9.07 (s, 1H), 8.92 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 4H), 7.09 (d, J=8.8 Hz, 2H), 4.46 (q, J=9.2 Hz, 2H), 3.83 (s, 3H), 3.33 (s, 3H). The ratio of the two isomers is 2:1. LCMS: m/z 519, 521 [M+H]+.

Example 188 8-(4-bromophenyl)-2-(ethylamino)-6-(4-methoxyphenyl)pyrido[4,3-d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 10n and ethylamine hydrochloride according to the procedure of Example 181, step J (HOAc, 100°C).

1H-NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.68 (s, 1H), 8.06 (t, J=6.0 Hz, 1H), 7.64 ( d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8Hz, 2H), 3.83(s, 3H), 3.29-3.17(m, 2H), 1.10(t, J=7.2Hz, 3H). LC-MS: m/z 451, 453 [M+H]+.

Example 189 8-(4-bromophenyl)-2-((2,2-difluoroethyl)amino)-6-(4-methoxyphenyl)pyrido[4,3d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 10n and 2,2difluoroethanamine according to the procedure of Example 181, step J (HOAc, 100°C).

1H-NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.79 (s, 1H), 8.37 (t, J=6.0 Hz, 1H), 7.61 ( d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8Hz, 2H), 6.11(tt, Jhf=56.2Hz, 4.4Hz, 1H), 3.83(s, 3H), 3.60(tt, J=14, 4Hz, 4.4Hz, 2H). LC-MS: m/z 487, 489 [M+H]+.

Example 190 8-(4-bromophenyl)-2-((cyclopropylmethyl)amino)-6-(4-methoxyphenyl)pyrido[4,3d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 10n and cyclopropylmethanamine according to the procedure of Example 181, step J (HOAc, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (s, 1H), 8.67 (s, 1H), 8.16 (t, J=6.0 Hz, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.8 Hz, 2H), 7.07 (d , J=8.4 Hz, 2H), 3.82 (s, 3H), 3.11 (t, J=6.4 Hz, 2H), 1.100.95 (m, 1H), 0.44-0 .32 (m, 2H), 0.18-0.07 (m, 2H). LC-MS: m/z 477, 479 [M+H]+.

Example 191 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-(propylamino)pyrido[4,3-d]pyrimidin-7(6H)one

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The title compound was synthesized from intermediate 10n and 1 aminopropane hydrochloride according to the procedure of Example 181, step J (HOAc, 100° C.).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (s, 1H), 8.68 (s, 1H), 8.11 (t, J=6.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.08 (d , J=8.4 Hz, 2H), 3.82 (s, 3H), 3.22-3.12 (m, 2H), 1.59-1.44 (m, 2H), 0.84 ( t, J=7.2 Hz, 3H). LC-MS: m/z 465, 467 [M+H]+.

Getting example 192

Step K: 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one (Example 192 ) L..........

Ν। \ . -II _L η , K ^L SS ' I Vg

A mixture of methyl 2-(4-bromophenyl)-2-(5-(dimethoxymethyl)-2-((2,2,2-trifluoroethyl)amino)pyrimidin-4yl)acetate (800 mg, 1.67 mmol, 1, 0 eq.; prepared according to the procedure of Example 123, step BD), 4-methoxyaniline (410 mg, 3.34 mmol, 2.0 eq.), AcOH (4.0 ml), toluene (8.0 ml) and 0.8 ml of water was stirred at 100°C for 5 hours. The mixture was concentrated under reduced pressure, the residue was purified by flash chromatography on silica gel to obtain 8-(4-bromophenyl)-6-(4methoxyphenyl)-2-( (2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 192)

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 8.83 (s, 1H), 8.59 (t, J=6.0 Hz, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.09 (d , J=8.8 Hz, 2H), 4.16-4.00 (m, 2H), 3.84 (s, 3H). LC-MS (ESI): m/z 505, 507 [M+H] ⁺ .

Example 193: 8-(4-chlorophenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one re. ......

The title compound was synthesized from intermediate 5a and

4-methoxyaniline according to the procedure of Example 192, step K (HOAc-toluene, 100°C).

1H-NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.16 (s, 1H), 7.69 (d, J=8.0 Hz, 2H), 7.41-7, 32 (m, 4H), 7.02 (d, J=8.8 Hz, 2H), 5.76 (t, J=6.4 Hz, 1H), 4.18-4.05 (m, 2H ), 3.87 (s, 3H). LC-MS: m/z 461 [M+H] ⁺ .

Example 194 8-(4-methoxyphenyl)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3 -d]pyrimidin-7(6H)-one

OME

The title compound was synthesized from intermediate 5b and 5-amino-1methylpyridin-2(1H)-one according to the procedure of Example 192, step K (HOAc-toluene, 100°C).

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1H-NMR (400 MHz, CDCl ₃ ) δ 8.73 (s, 1H), 8.07 (s, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.61 (d , J=2.0 Hz, 1H),

7.45 (dd, J=9.6 Hz, 2.4 Hz, 1H), 6.95 (dd, J=8.4 Hz, 2H), 6.68 (d, J=10.0 Hz, 1H), 5.75 (t, J=5.6 Hz, 1H), 4.184.06 (m, 2H), 3.86 (s, 3H), 3.60 (s, 3H). LC-MS: m/z 458 [M+H] ⁺ .

Example 195 8-(4-(difluoromethoxy)phenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimudin-7(6H) -He

The title compound was synthesized from intermediate 5c and 4methoxyaniline according to the procedure of Example 192, step K (HOAc-toluene, 100°C).

1H-NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.36 (d , J=8.8 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.54 (t, J _H F=74.6 Hz, 1H), 5.95 (t, J=5.6 Hz, 1H), 4.17-4.02 (m, 2H), 3.86 (s, 3H). LC-MS: m/z 493 [M+H] ⁺ .

Example 196 6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pyrido[4,3-d]pyrimidine-7 (6H) -He

The title compound was synthesized from intermediate 5d and 4 methoxyaniline according to the procedure of Example 192, step K (HOAc-toluene, 100° C.).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.73 (s, 1H), 8.18 (s, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.37 ( d, J=8.8 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 5.76 (t, J=6.4 Hz, 1H), 4.17-4.05 (m, 2H), 3.87 (s, 3H). LC-MS: m/z 511 [M+H]+.

Example 197 6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethyl)phenyl)pyrido[4,3-d]pyrimidine-7 (6H) -He

The title compound was synthesized from intermediate 5e and 4methoxyaniline according to the procedure of Example 192, step K (HOAc-toluene, 100°C).

1H-NMR (400 MHz, CDCl ₃ ) δ 8.93 (s, 1H), 8.20 (s, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.63 (d , J=8.4 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 5.76 (t, J =6.0 Hz, 1H), 4.16-4.04 (m, 2H), 3.87 (s, 3H). LC-MS: m/z 495 [M+H]+.

Preparation of methyl 2-(6-cyclopropylpyridin-3-yl)-2-(5-(dimethoxymethyl)-2-((2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)acetate (5o)

Methyl 2-(6-cyclopropylpyridin-3-yl)-2-(5-(dimethoxymethyl)-2-((2,2,2trifluoroethyl)amino)pyrimidin-4-yl)acetate (5о) was synthesized from methyl-2 -(6-cyclopropylpyridin-3yl)acetate by General Procedure III (Steps B-D). LC-MS: m/z 441 [M+H]+.

Example 198 8-(6-cyclopropylpyridin-3-yl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H )-He

- 80 041815

The title compound was synthesized from intermediate 5o and 4methoxyaniline according to the procedure of Example 192, step K (HOAc-toluene, 100°C).

1H-NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.82 (s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.58 ( t, J=6.4 Hz, 1H), 7.84 (dd, J=8.0 Hz, 2.4 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7 .23 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 4.14-4.00 (m, 2H), 3.83 (s, 3H), 2.14-2.05 (m, 1H), 0.97-0.90 (m, 4H). LC-MS: m/z 468 [M+H]+.

Preparation of methyl 2-(4-cyclobutylphenyl)-2-(5-(dimethoxymethyl)-2-((2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)acetate (5p)

Methyl 2-(4-cyclobutylphenyl)-2-(5-(dimethoxymethyl)-2-((2,2,2-trifluoroethyl)amino)pyrimidin-4yl)acetate (5р) was synthesized from methyl-2-(4- cyclobutylphenyl)acetate by general procedure III (BD step). LC-MS: m/z 454 [M+H] ⁺ .

8-(4-Cyclobutylphenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin7(6H)-one (Example 199)

The title compound was synthesized from intermediate 5p and 4methoxyaniline according to the procedure of Example 192, step K (HOAc-toluene, 100°C).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.77 (s, 1H), 8.49 (t, J=6.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.09 (d , J=8.8 Hz, 2H), 4.15-4.00 (m, 2H), 3.59-3.48 (m, 1H), 2.37-2.24 (m, 2H), 2.19-2.04 (m, 2H), 2.03-1.90 (m, 1H), 1.88-1.76 (m, 1H). LC-MS: m/z 481 [M+H] ⁺ .

Getting example 200

Step A: 6,8-bis(4-methoxyphenyl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-7(6H)-one

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To a solution of 6,8-bis(4-methoxyphenyl)-2-(methylthio)pyrido[4,3-0]pyrimidin-7(6H)-one (180 mg, 0.4 mmol, 1.0 eq.) in DCM (15 ml) was added mCPBA (76 mg, 0.4 mmol, 1.0 eq.) at -5°C. Then, the mixture was stirred at -5°C for 3 hours. The solvent was removed under vacuum, and the resulting mixture was purified by preparative TLC (PE/EA=1/4) to obtain 6,8-bis(4-methoxyphenyl)-2 (methylsulfinyl)pyrido[4,3-d]pyrimidin-7(6H)-one (65 mg, 35% yield) as a yellow solid. LC-MS: m/z 422 [M+H]+.

Step B: 6,8-bis(4-methoxyphenyl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 200)

To a solution of 6,8-bis(4-methoxyphenyl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-7(6H)-one (65 mg, 0.15 mmol, 1.0 eq.), DIPEA (10.0 mg, 0.75 mmol, 5 eq.) in THF (3.0 ml) was added 2,2,2 trifluoroethanamine (75 mg, 0.75 mmol, 5 eq.). Then, the mixture was stirred at 25°C overnight, the resulting mixture was concentrated in vacuo, after which it was diluted with DCM (10 ml) and H ₂ O (10 ml). The aqueous layer was extracted with DCM (10.0 ml x 2) and the combined organic layers were concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography to give 6,8-bis(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin7(6H)-one (example 200).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.69 (s, 1H), 8.12 (s, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.36 ( d, J=9.2 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.84 (t, J=6.4 Hz, 1H), 4.19-4.06 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H). LC-MS: m/z 457 [M+H] ⁺ .

Getting example 201

chf ₂

Step A: 6-(quinolin-6-yl)-8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((2, 2,2trifluoroethyl)amino)pyrido[4,3-0]pyrimidin-7(6Н)-one

- 82 041815

A mixture of 8-(4-bromophenyl)-6-(quinolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin7(6H)-one (Example 180 , 160 mg, 0.3 mmol, 1.0 eq.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2dioxaborolane ) (116 mg, 0.46 mmol, 1.5 eq.), Pd(dppf)Cl ₂ (22 mg, 0.03 mmol, 0.1 eq.) and KOAc (90 mg, 0.91 mmol, 3 0 eq.) in 1,4-dioxane (5.0 ml) was stirred at 80° C. overnight under N2 atmosphere. The mixture was filtered through a thin pad of Celite® and the filtrate was concentrated under reduced pressure. The residue was then further purified by silica gel flash chromatography to give the title product (110 mg, 63% yield) as a yellow solid. LC-MS (ESI): m/z 574 [M+H]+.

Step B: 8-(4-hydroxyphenyl)-6-(quinolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-

d] pyrimidin-7(6H)-one

HE

A mixture of 6-(quinolin-6-yl)-8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((2,2, 2 trifluoroethyl)amino)-pyrido[4,3-d]pyrimidin-7(6H)-one (100 mg, 0.17 mmol, 1.0 eq.) and H ₂ O ₂ (30% aq., 350 mg , 3.49 mmol, 20.0 eq.) in MeOH (4.0 ml) was stirred at 0°C for 1 h. The mixture was diluted with EtOAc (10.0 ml) and washed with NaS ₂ O ₃ (sat. aq. ., 10.0 ml). The organic layer was concentrated under reduced pressure to give 8-(4-hydroxyphenyl)-6-(quinolin-6-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d]pyrimidine-7 (6H)-one (75.0 mg, 95% yield) as a yellow solid, which was carried on without further purification. LC-MS: m/z 464 [M+H] ⁺ .

Step C: 8-(4-(2,2-difluoroethoxy)phenyl)-6-(quinolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d] pyrimidin-7(6H)-one (Example 201)

To a mixture of 8-(4-hydroxyphenyl)-6-(quinolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one (50 0 mg, 0.11 mmol, 1.0 eq.) in THF (3.0 ml) at 0°C was added 2,2 difluoroethyl trifluoromethanesulfonate (25.0 mg, 0.12 mmol, 1.1 eq.) and Cs ₂ CO ₃ (70.0 mg, 0.22 mmol, 2.0 eq.), after which the resulting mixture was allowed to warm to room temperature and stirred for an additional 3 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by the method reverse phase preparative HPLC to give 8-(4-(2,2difluoroethoxy)phenyl)-6-(quinolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3- d]pyrimidin-7(6H)-one (Example 201).

¹ H-NMR (400 MHz, DMSO-d6) δ 9.03 (dd, J=8.4 Hz, 1.6 Hz, 1H), 8.99 (s, 1H), 8.97 (s, 1H ), 8.59 (t, J=6.4 Hz, 1H), 8.48 (d, J=7.6 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 7.94 (dd, J=9.2 Hz, 2.4 Hz, 1H), 7.69-7.61 (m, 3H), 6.97 (d, J=8.8 Hz, 2H), 6.41 (tt, Jhf=56.2 Hz, 3.6 Hz, 1H), 4.34 (t.sq., J=14.8 Hz, 3.6 Hz, 2H), 4.18-4.04 (m, 2H). LC-MS (ESI): m/z 528 [M+H] ⁺ .

Get example 202

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Step A: 6-(4-methoxyphenyl)-8-(4-(1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-3-yl)phenyl)-2((2.2, 2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6Н)-one

A mixture of 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3^]pyrimidin7(6H)-one (Example 192, 70, 0 mg, 0.1 mmol, 1.0 eq.), (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3yl)boronic acid (77.0 mg, 0.3 mmol, 3 0 equiv.), Pd(dppf)Cl ₂ (8.0 mg, 0.01 mmol, 0.1 equiv.) and K3PO4 (88.0 mg, 0.4 mmol, 4.0 equiv.) in dioxane /H ₂ O (4/1, 5.0 ml) was stirred at 100°C overnight under nitrogen atmosphere. The mixture was cooled to rt, diluted with water (10.0 ml), extracted with EtOAc (20.0 ml x 2), washed with brine (10.0 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA=5/1) to give the desired product (70.0 mg, 88% yield) as a yellow solid. LC-MS: m/z 577 [M+H]+.

Step B: 8-(4-(1H-pyrazol-3-yl)phenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrudo[4,3-d] pyrimidin-7(6H)-one (Example 202)

ZyZ

z- ^χ' -ι m

k. -.· X ' Г Λ rl CF ₃ н ^s

A mixture of 6-(4-methoxyphenyl)-8-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)phenyl)-2-((2,2,2trifluoroethyl) amino)-pyrido[4,3-d]pyrimidin-7(6H)-one (50.0 mg, 0.1 mmol, 1.0 eq.) and HCl (1 M aq., 0.3 ml, 3 0 eq.) in MeOH (1.0 ml) was stirred at rt. within 30 min. Then, the solution was concentrated, and the resulting residue was purified by reverse-phase preparative HPLC to obtain 8(4-(1H-pyrazol-3-yl)phenyl)-6-(4-methoxyphenyl)-2-((2,2,2 -trifluoroethyl)amino)-pyrido[4,3-d]pyrimidin7(6H)-one (Example 202).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.97 (s, 1H), 8.81 (s, 1H), 8.55 (t, J=6.4 Hz, 1H), 7, 81-7.66 (m, 4H), 7.48 (d, J=9.2 Hz, 2H), 7.40-7.16 (m, 2H), 7.09 (d, J=8, 8 Hz, 2H), 6.72 (s, 1H), 4.15-4.03 (m, 2H), 3.83 (s, 3H). LC-MS: m/z 493 [M+H] ⁺ .

Example 203: 8-(4-(1H-pyrazol-3-yl)phenyl)-6-(quinolin-6-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3- d] pyrimidin-7(6H)-one

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The title compound was synthesized from Example 180 and 1-(tetrahydro-2H-pyran-2-yl)5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-III- pyrazole according to the procedure of Example 202 (steps A-B).

¹ H-NMR (400 MHz, DMSO-d6) δ 9.03 (dd, J=4.4 Hz, 1.6 Hz, 1H), 9.01 (s, 1H), 9.00 (s, 1H ), 8.63 (t, J=6.4 Hz, 1H), 8.49 (d, J=7.2 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.16 (s, 1H), 7.96 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.77 ( d, J=8.8 Hz, 2H), 7.73 (d, J=8.8 Hz, 2H), 7.71 (broad s, 1H), 7.66 (dd, J=8.4 Hz, 4.4 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 4.20-4.04 (m, 2H). LC-MS: m/z 514 [M+H]+.

Example 204 Preparation of 8-(4-(azetidin-1-yl)phenyl)-6-(4-methoxyphenyl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d]pyrimidine-7 (6H) - she

A mixture of 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin7(6H)-one (Example 192, 100 mg, 0.2 mmol, 1.0 eq.), azetidine (114.0 mg, 2.0 mmol, 10.0 eq.), Pd ₂ (dba) ₃ (18.0 mg, 0.02 mmol, 0.1 eq.), Ru-Phos (18.0 mg, 0.04 mmol, 0.2 eq.) and K3PO4 (127 mg, 0.6 mmol, 3.0 eq.) in toluene (2.0 ml) was stirred at 100° C. in a sealed tube overnight under nitrogen. The mixture was concentrated and the residue was purified by reverse phase preparative HPLC to give 8-(4-(azetidin-1-yl)phenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino )-pyrido[4,3d]pyrimidin-7(6H)-one (Example 204).

¹ H-NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.70 (s, 1H), 8.43 (t, J=6.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 6.35 (d , J=8.4 Hz, 2H), 4.18-4.04 (m, 2H), 3.84 (s, 3H), 3.82 (t, J=7.2 Hz, 4H), 2 .36-2.26 (m, 2H). LC-MS: m/z 482 [M+H] ⁺ .

Getting example 205

Step A: dimethyl-2-(4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)amino)-6,7dihydropyrido[4,3-d]pyrimidine- 8-yl)phenyl)malonate

- 85 041815

To a solution of 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3d]nupuMuguH-7(6H)-OHa (200.0 mg, 0.396 mmol, 1.0 eq.) in toluene (5.0 ml) was added K ₃ PO ₄ (168.0 mg, 0.792 mmol, 2.0 eq.), X-Phos (40.0 mg, 0.084 mmol, 0 .2 eq.) and Pd ₂ (dba) ₃ (38.0 mg, 0.045 mmol, 0.1 eq.). Then, the resulting mixture was stirred at 100°C for 2 hours under N2 atmosphere. The reaction mixture was diluted with EtOAc (10.0 ml), washed with H ₂ O (10 ml x 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (PE/EA=3/11/1) to give the title product (130 mg, 59% yield) as a yellow solid. LC-MS: m/z 557 [M+H]+.

Stage B: methyl-2-(4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)amino)-6,7-dihydropyrido[4,3-d] pyrimidin-8-yl)phenyl)acetate

A

Ο^ΎΤί Ν Cfs J ” V.

To a solution of 2-(4-(6-(4-methoxyphenyl)-7-oxo-2-(2,2,2-trifluoroethylamino)-6,7-dihydropyrido[4,3d]pyrimidin-8-yl)phenyl) malonate (130.0 mg, 0.234 mmol, 1.0 eq.) in DMSO (2.0 mL) was added aq. NaCl (0.55 M, 2.0 ml, 5.0 eq.). The resulting mixture was stirred at 150°C for 6 h. Then, the reaction mixture was diluted with ethyl acetate (10.0 ml), washed with H2O (10.0 ml x 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (PE/EA=1/1) to give 2-(4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2trifluoroethyl)amino)-6,7- dihydropyrido[4,3-d]pyrimidin-8-yl)phenyl)acetate (85.0 mg, 73% yield) as a yellow solid. LC-MS: m/z 499 [M+H] ⁺ .

Step C: 8-(4-(2-hydroxyethyl)phenyl)-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3d]pyrimidin-7(6H)-one ( example 205) /£ x' ' 7 ΪΙ

VVA A.1 4 . l- ν 9 he

To a solution of methyl 2-(4-(6-(4-methoxyphenyl)-7-oxo-2-(2,2,2-trifluoroethylamino)-6,7dihydropyrido[4,3-d]pyrimidin-8-yl) phenyl)acetate (85.0 mg, 0.170 mmol, 1.0 eq.) in THF (3.0 ml) LiAlH4 (32.0 mg, 0.842 mmol, 5.0 eq.) was added at 0°C. The resulting mixture was stirred at 0°C for 30 min. The reaction mixture was then quenched with sodium sulfate decahydrate (100 mg), filtered and concentrated. Then, a mixture of the residue and DDQ (57.0 mg, 0.251 mmol, 1.5 eq.) in THF (3.0 mL) was stirred at rt. for 1 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give 8-(4-(2-hydroxyethyl)phenyl)-6-(4methoxyphenyl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3-d]pyrimidine-7(6H )-she (example 205).

1H-NMR (400 MHz, DMSO-de) δ 8.94 (s, 1H), 8.77 (s, 1H), 8.50 (t, J=6.4 Hz, 1H), 7.55 ( d, J=8.0 Hz, 2H), 7.46 (d, J=9.2 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 7.09 (d, J=9.2 Hz, 2H), 4.64 (t, J=5.2 Hz, 1H), 4.18-4.04 (m, 2H), 4.15-4.02 (m, 2 H), 3.83 (s, 3H), 3.67-3.58 (m, 2H), 2.74 (t, J=7.2 Hz, 2H). LC-MS: m/z 471 [M+H] ⁺ .

Getting example 206

- 86 041815

Step A: 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-pyrido [4,3D ]pyrimidin-7 (6Н)-one

To a solution of 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3d]pyrimidin-7(6H)-one (Example 192, 350.0 mg, 0.7 mmol, 1.0 eq.) in anhydrous DMF (5.0 ml) at 0°C was added NaH (60% in oil, 57.0 mg, 1.4 mmol, 2.0 eq.) . The mixture was stirred at 0° C. for 1 h and then SEMCl (141.0 mg, 0.86 mmol, 1.2 eq.) was added. The resulting mixture was stirred at rt. for 1 h. Then, the reaction mixture was quenched by adding ice-cold aq. NH ₄ Cl (10.0 ml) and extracted with DCM (10.0 ml x 2). The combined extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography to give 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)((2(trimethylsilyl)ethoxy)methyl)amino)pyrido[4, 3-d]pyrimidin-7(6H)-one (350.0 mg, 77% yield) as a yellow solid. LC-MS: m/z 635 [M+H]+.

Step B: methyl 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7- dihydropyrido[4,3-d]pyrimidin-8-yl)benzoate

- 87 041815 d d ,.

0= = 0 '\''4' L.Fj ,<K ^{S1 Μ} ^qXq

To a solution of 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)((2(trimethylsilyl)ethoxy)methyl)amino)-pyrido[4,3-d ]pyrimidin-7(6H)-one (350.0 mg, 0.55 mmol, 1.0 eq.) in toluene/MeOH (1/1, v/v, 10.0 ml) was added at room temperature TEA (167.0 mg, 1.65 mmol, 3.0 eq.) and Pd(dppf)Cl ₂ (37.0 mg, 0.05 mmol, 0.1 eq.). The resulting mixture was stirred at 100° C. under CO (1 atm) overnight. The resulting mixture was diluted with water (20.0 ml) and extracted with EtOAc (20.0 ml x 3). The organic layers were combined, washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (PE/EA=3/1-1/2) to give methyl 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl) ((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8-yl)benzoate (280.0 mg, 83% yield) as a yellow solid. LC-MS: m/z 615 [M+H]+.

Step C: 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[ 4,3-d]pyrimidin-8-yl)benzoic acid

AND.

1.1

F SEM

NO-Zhs

To a solution of methyl 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido [4,3-d]pyrimidin-8-yl)benzoate (280.0 mg, 0.46 mmol, 1.0 eq.) in THF (5.0 mL) LiOH (1N, aq., 4.6 ml, 4.6 mmol, 10.0 eq.). The resulting mixture was stirred overnight. Then, the reaction mixture was poured into water (20.0 ml) and adjusted to pH 6.0 by adding dilute HCl solution (1N). The mixture was extracted with EtOAc (20.0 ml x 3), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (PE/EA=2:1-0:1) to give 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)(( 2(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8-yl)benzoic acid (250.0 mg, 91% yield) as a yellow solid. LC-MS: m/z 601 [M+H] ⁺ .

Step D: 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[ 4,3-d]pyrimidin-8-yl)benzamide

O't I.

ГГ Ж ,χ ,1 J. ...

С- γ· >Г N OF.: Jx SEM shm'Zha

To a solution of 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4 ,3-d]pyrimidin-8-yl)benzoic acid (250.0 mg, 0.42 mmol, 1.0 eq.) in DMF (5 ml) was added NH ₄ Cl (133.0 mg, 2.08 mmol , 5.0 eq.), DIPEA (268.0 mg, 2.08 mmol, 5.0 eq.) and HATU (316.0 mg, 0.83 mmol, 2.0 eq.). The resulting mixture was stirred at room temperature for 2 hours Then, the reaction mixture was diluted with water (20 ml) and was extracted with DCM (20 ml x 3). The combined extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (PE/EA=1/1) to give 4-(6-(4methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy )methyl)amino)-6,7dihydropyrido[4,3-d]pyrimidin-8-yl)benzamide (200 mg, 80% yield) as a yellow solid. LC-MS: m/z 600 [M+H] ⁺ .

Step E: (Z)-N-((dimethylamino)methylene)-4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2(trimethylsilyl)ethoxy )methyl)amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8-yl)benzamide

- 88 041815

A mixture of 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4, 3-d]pyrimidin-8-yl)benzamide (100.0 mg, 0.17 mmol, 1.0 eq.) and DMF-DMA (2.0 ml) were stirred at 80° C. overnight. Then, the reaction mixture was concentrated to give the crude product as a yellow oil. LC-MS: m/z 655 [M+H]+.

Step F: 8-(4-(III-1,2,4-triazol-3-yl)phenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)((2( trimethylsilyl)ethoxy)-methyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one

O A G I!

\ '14

I J L .

with 'j m n and.

To a solution of (Z)-N-((dimethylamino)methylene)-4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl )amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8yl)benzamide (120 mg, 0.17 mmol, 1.0 eq.) in AcOH (2 ml) at room temperature was added hydrazine monohydrate (27 .0 mg, 0.84 mmol, 5.0 eq.). The resulting mixture was stirred at 100°C for 2 hours Then, the reaction mixture was diluted with NaHCO ₃ (sat. aq., 20 ml) and was extracted with EtOAc (20 ml x 3). The combined extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (PE/EA=1/1) to give 8-(4-(1H-1,2,4triazol-3-yl)phenyl)-6-(4-methoxyphenyl)-2-(( 2,2,2-trifluoroethyl)((2(trimethylsilyl)ethoxy)methyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (80 mg, 76% yield) as a yellow solid. LC-MS: m/z 624 [M+H] ⁺ .

Step G: 8-(4-(1H-1,2,4-triazol-3-yl)phenyl)-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3 -d]pyrimidin-7(6H)-one

To a solution of 8-(4-(1H-1,2,4-triazol-3-yl)phenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)((2(trimethylsilyl )ethoxy)-methyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (80 mg, 0.13 mmol, 1.0 eq.) in DCM (3.0 ml) at room temperature trifluoroacetic acid (1.0 ml) was added. The resulting mixture was stirred for 5 h before being concentrated and purified by reverse phase preparative HPLC to give 8-(4-(1H-1,2,4-triazol-3-yl)phenyl)-6-(4-methoxyphenyl )-2-(2,2,2trifluoroethylamino)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 206).

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.84 (s, 1H), 8.58 (t, J=6.4 Hz, 1H), 8.43 (broad s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.48 (d, J=8, 8 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 4.16-4.02 (m, 2H), 3.81 (s, 3H). LC-MS: m/z 494 [M+H] ⁺ .

Getting example 207

- 89 041815

6-(isoxazol-4-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-5,6 Step A:

dihydropyrido[4,3-d]pyrimidin-7(4aH)-one

To a solution of methyl 2-(5-formyl-2-((2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)-2-(4methoxyphenyl)acetate (prepared according to General Procedure III, step G) (76 mg, 0.2 mmol, 1.0 eq.), isoxazol-4-amine (42 mg, 0.5 mmol, 2.5 eq.) in DCE/MeOH (3/0.5 ml), HOAc (42 mg, 0.7 mmol, 3.5 eq.). The mixture was stirred at 45°C overnight, and then the mixture was cooled to 0°C, NaBH ₃ CN (12 mg, 0.2 mmol, 1.0 eq.) was added to the reaction mixture in one portion, after which the resulting mixture was left to warm to room temperature and stirred an additional 12 h, after which it was quenched by the addition of DCM (10 ml) and H2O (10 ml). The aqueous layer was extracted with DCM (10 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by preparative TLC (PE/EA=1/2) to give 6-(isoxazol-4-yl)-8-(4-methoxyphenyl)-2-((2,2,2trifluoroethyl)amino)-5.6 -dihydropyrido[4,3-d]pyrimidin-7(4aH)-one (51 mg, 44% yield) as a white solid. LC-MS: m/z 420 [M+H]+.

Step B: 6-(isoxazol-4-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-

d] pyrimidin-7(6H)-one

6-(isoxazol-4-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-5,6-dihydropyrido[4,3d]pyrimidine-7(4aH) mixture -one (51.0 mg, 0.12 mmol, 1.0 eq.) and DDQ (40.0 mg, 0.18 mmol, 1.5 eq.) in THF (3.0 ml) were stirred at rt. T. for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase preparative HPLC to give 6-(isoxazol-4-yl)-8(4-methoxyphenyl)-2-((2,2,2- trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 207).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.62 (s, 1H), 9.20 (s, 1H), 9.00 (s, 1H), 8.97 (s, 1H), 8.66 (t, J=6.4 Hz, 1H) 7.57 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.15 -4.03 (m, 2H), 3.79 (s, 3H). LC-MS: m/z 418 [M+H] ⁺ .

Example 208 8-(4-methoxyphenyl)-6-(1H-pyrazol-4-yl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidine-7(6H)- He

The title compound was synthesized from intermediate 1 and 1H-pyrazole-4amine as in the case of preparation according to the procedure of Example 207 (steps A-B).

¹ H-NMR (600 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.93 (s, 1H), 8.51 (broad s, 1H), 8.13 (s, 2H) , 7.56 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 4.13-4.03 (q, J=9.6 Hz, 2H), 3.78 (s, 3H). LC-MS: m/z 417 [M+H] ⁺ .

- 90 041815

General Method V:

NIS, SPLA

ROH

YuyuMo. I UN toluene stage C stage D intermediate

SOCT DMF

AlCh, Nai

MhLN bU Yu

Stage G

NaH, R.XH x-o, s

Stage I

Stage K intermediate

R;;B(QH) _; ; OR

R ₃ B(OHh

X = ΛίΗ. ABOUT

Stage P

TsOH, Nai intermediate I

Pd(PPh ₃ )4, Cs ₂ CO ₃ dioxane, 100 °C

DCM 40°C

Stage F

MtCN SO °C

Stage Q

CufOAeh, pyridine

DCM. 40°C

Stage L

I d FTh . . l.s//' dioxane, 100 °C

Stage Μ

CsF. cui. MeCN. 100°C

Stage R

W(dppt)Ck Us,CO, dioxane, HjO, 100 °C

Stage E

CujOAcJ,. pyridine

DCM. 40°C

Stage H

R_bit > H x or K. - !

Preparation of 8-bromo-2-chloro-7-methoxy-1,6-naphthyridine (key intermediate I). General procedure V (access to key intermediate I):

- 91 041815

intermediate compound I

Stage A: 3-bromo-5-iodine-2-methoxypyridine-4-amine

NIS (4, 9 g, 21.7 mmol, 1.1 eq.), and the reaction mixture was stirred at room temperature for 16 h. Then, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 ml) and washed with water (50 ml x 2). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (eluent: PE/EtOAc=4/1) to give 3-bromo-5iodo-2-methoxypyridine-4-amine (6.0 g, 92% yield) as a white solid . LC-MS: m/z 329 [M+H]+.

Stage B: (E)-ethyl-3-(4-amino-5-bromo-6-methoxypyridin-3-yl)acrylate

A mixture of 3-bromo-5-iodo-2-methoxypyridine-4-amine (6 g, 18.3 mmol, 1.0 eq.), tri-ortho-tolylphosphine (553 mg, 1.8 mmol, 0.1 eq. .), NaHCO ₃ (2.7 g, 32.1 mmol, 1.8 eq.), ethyl acrylate (2 g, 20.1 mmol, 1.1 eq.) and Pd(OAc) ₂ (205 mg, 0 .9 mmol, 0.05 eq.) in DMF (30 mL) was stirred at 70° C. under N2 for 16 h. Then, the reaction mixture was diluted with 10% aq. LiCl (50 ml) and extracted with EtOAc (50 ml x 3). All organic layers were combined, washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (eluent: PE/EtOAc=3/1) to give (E)-ethyl-3-(4-amino-5-bromo-6-methoxypyridin-3-yl)acrylate (4, 5 g, 82% yield as a white solid. LC-MS: m/z 301 [M+H] ⁺ .

Step C: 8-bromo-7-methoxy-1,6-naphthyridin-2(1H)-one

To a solution of (E)-ethyl-3-(4-amino-5-bromo-6-methoxypyridin-3-yl)acrylate (1.5 g, 5.0 mmol, 1.0 eq.) in EtOH (10 ml ) was added 15% aq. NaSMe (2.6 g, 5.5 mmol, 1.1 eq.). The resulting mixture was stirred at room temperature overnight. The precipitate was collected by filtration, the filter cake was washed with EtOAc (10 ml) and then dried to give 8-bromo-7-methoxy-1,6-naphthyridin-2(1H)-one (1.0 g, 79% yield) as a yellow solid. LC-MS: m/z 255 [M+H] ⁺ .

Step D: 8-bromo-2-chloro-7-methoxy-1,6-naphthyridine (key intermediate I)

N ' ii ..1 J

A mixture of 8-bromo-7-methoxy-1,6-naphthyridin-2(1H)-one (2.3 g, 9.0 mmol, 1.0 equiv.) and POCl3 (12.0 ml) was stirred at 80° C for 2 hours Then, the reaction mixture was poured into chilled NaHCO ₃ (sat. aq., 150 ml) and was extracted with EtOAc (50 ml x 4). All organic layers were combined, washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (eluent: PE/EtOAc=3/1) to give 8-bromo-2-chloro7-methoxy-1,6-naphthyridine (1.9 g, 77% yield) as not quite white solid. LC-MS: m/z 273 [M+H] ⁺ .

Preparation of 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethylthio)-1,6naphthyridin-7(6H)-one (Example 209 )

- 92 041815

Step E: 8-(4-chlorophenyl)-7-methoxy-1,6-naphthyridin-2(1H)-one

A mixture of 8-bromo-7-methoxy-1,6-naphthyridin-2(1H)-one (10 g, 39.4 mmol, 1.0 eq.), Pd(dppf)Cl ₂ (1.4 g, 1 .9 mmol, 0.05 eq.), Cs ₂ CO ₃ (25.6 g, 78.5 mmol, 2.0 eq.) and 4-chlorophenylboronic acid (9.2 g, 59.0 mmol, 1, 5 eq.) in dioxane/water (200 ml, 9/1, v/v) was stirred at 100°C under N2 for

hours Then, the reaction mixture was diluted with water (100 ml) and was extracted with EtOAc (50 ml x 5). All organic layers were combined, washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: PE/EtOAc=2/1) to give 8-(4-chlorophenyl)-7-methoxy-1,6-naphthyridin-2(1H)-one (10.0 g, 89% yield). ) as a white solid. LC-MS: m/z 287 [M+H]+.

Stage F: 2-chloro-8-(4-chlorophenyl)-7-methoxy-1,6-naphthyridine

DMF ( 6.1 g, 83.6 mmol, 3.0 eq.) and SOCl ₂ (8.2 g, 83.6 mmol, 3.0 eq.). Then, the reaction mixture was stirred at 80° C. for 16 hours. The resulting mixture was cooled to room temperature, concentrated, quenched by adding ice-cold NaHCO ₃ (sat. aq., 50 ml) and was extracted with EtOAc (50 ml x 2). All organic layers were combined, washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, the residue was purified by silica gel flash chromatography (eluent: PE/EtOAc=5/1) to obtain 2chloro-8-(4-chlorophenyl)-7-methoxy-1,6-naphthyridine (7.0 g, 83% yield) as a white solid. LC-MS: m/z 305 [M+H] ⁺ .

Step G: 2-chloro-8-(4-chlorophenyl)-1,6-naphthyridin-7(6H)-one

AlCl ₃ (1.8 g, 13.5 mmol, 2.0 eq.) and NaI (2.2 g, 13.3 mmol, 2.0 eq.). The resulting mixture was stirred at 80°C for 8 hours.

Then, the reaction mixture was quenched by adding ice water (20 ml) and was extracted with EtOAc (20 ml x 3). All organic layers were combined, washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (eluent: DCM/acetone=2/1) to give 2-chloro8-(4-chlorophenyl)-1,6-naphthyridin-7(6H)-one (1.5 g, 79% yield as a white solid. LC-MS:

- 93 041815 m/z 291 [M+H]+.

Step H: 2-chloro-8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one

To a solution of 2-chloro-8-(4-chlorophenyl)-1,6-naphthyridin-7(6H)-one (1.5 g, 5.2 mmol, 1.0 eq.) in DCM (20.0 ml ) was added Cu(OAc)2 (1.2 g, 5.6 mmol, 1.1 eq.), pyridine (1.2 g, 15.2 mmol, 3.0 eq.) and 2-methyl2H-indazole- 5-ylboronic acid (1.4 g, 8.0 mmol, 1.5 eq.). The reaction mixture was stirred at 40° C. under O2 for 16 h and then concentrated under reduced pressure and purified by silica gel flash chromatography (eluent: PE/EIOAc=1/1) to give 2-chloro-8-( 4chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one (1.4 g, 65% yield) as an orange solid. LC-MS: m/z 421 [M+H]+.

Step I: 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)thio)-1,6naphthyridine-7(6H) -on (example 209)

NaH (60% suspension in mineral oil, 43, 0 mg, 1.1 mmol, 3.0 eq.). The mixture was stirred at 0° C. for 0.5 h. (6H)-one (150.0 mg, 0.36 mmol, 1.0 eq.) in THF (1 ml). The reaction mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was quenched by adding NH ₄ Cl (sat. aq., 10 ml) and was extracted with EtOAc (10 ml x 3). All organic layers were combined, washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure.

The residue was purified by reverse phase preparative HPLC to give 8-(4chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)thio)-1,6 -naphthyridine-7(6H)-one (Example 209).

1H-NMR (400 MHz, DMSO-d6) δ: 8.92 (s, 1H), 8.51 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.37 (dd , J=9.2 Hz, 2.0 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 4.23 (s, 3H), 4.21-4.08 (m , 2H). LC-MS: m/z 501 (M+H)+.

Example 210 8-(4-chlorophenyl)-2-cyclopropoxy-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin7(6H)-one

The title compound was synthesized from intermediate 8 and cyclopropanol by general procedure V (step I) (NaH, anhydrous TNG, 0° C. - rt).

1H-NMR (400 MHz, DMSO-d6) δ: 8.78 (s, 1H), 8.50 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.40 (d , J=8.8 Hz, 2H), 7.34 (dd, J=9.2 Hz, 2.0 Hz, 1H), 6.53 (d, J=9.2 Hz, 1H), 4, 23 (s, 3H), 4.21-4.14 (m, 2H), 0.74-0.72 (m, 4H). LC-MS: m/z 443 [M+H]+.

Preparation of 6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)-1,6-naphthyridine-7 (6H)-one (example 211)

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Method A.

Step J: 8-bromo-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2-amine (10a) N·^^ . l .1

Ό b' -N^CF ₃

NG ⁿ

10a

A mixture of 8-bromo-2-chloro-7-methoxy-1,6-naphthyridine (1.0 g, 3.8 mmol, 1.0 eq.), CsF (860.0 mg, 5.7 mmol, 1, 5 eq.) and 2,2,2-trifluoroethanamine (1.9 g, 18.8 mmol, 5.0 eq.) in DMSO (10.0 ml) was stirred at 100°C for 2 h. Then, the mixture poured into ice water (100 ml) and extracted with EtOAc (50 ml x 4). All organic layers were combined, washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: PE/EIUAc=2/1) to give 8-bromo-7-methoxy-N-(2,2,2trifluoroethyl)-1,6-naphthyridine-2-amine (900 mg, 71% yield) as a white solid. LC-MS: m/z 336 [M+H]+.

Step K: 8-bromo-2-(2,2,2-trifluoroethylamino)-1,6-naphthyridin-7(6H)-one (11a) >

about ^; - g ' Y '' Ti^ce H B, ^M

111

A mixture of 8-bromo-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2-amine (300.0 mg, 0.8 mmol, 1.0 eq.) and AlCl ₃ (301.5 mg, 2.2 mmol, 3.0 eq.) in DCE (10 mL) was stirred at 80°C for 2 h. The solvent was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography ( eluent: DCM/MeOH=10/1) to give 8-bromo-2-(2,2,2-trifluoroethylamino)-1,6naphthyridin-7(6H)-one (220.0 mg, 92% yield) as yellow solid. LC-MS: m/z 322 [M+H] ⁺ .

Step L: 8-bromo-6-(2-methyl-2H-ivdazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)-1,6-naphthyridin7(6H)-one (12a )

12a

8-Bromo-6-(2-methyl-2Н-indazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)-1,6-naphthyridin-7(6Н)-one (12а) was synthesized from intermediate 11a and (2-methyl-2H-indazol-5-yl)boronic acid by general procedure V (step H). LC-MS: m/z 452 [M+H] ⁺ .

Step M: 6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)-8-(4(trifluoromethoxy)phenyl)-1,6-naphthyridine- 7(6H)-one (example 211)

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The title compound was synthesized from intermediate 12a and (4(trifluoromethoxy)phenyl)boronic acid using General Method V (Step M).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.52 (s, 1H), 8.48 (s, 1H), 8.34 (t, J=6.4 Hz, 1H), 7 .85 (dd, J=2.0 Hz, 0.4 Hz, 1H), 7.76 (d, J=9.2 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H ), 7.66 (d, J=9.2 Hz, 1H), 7.31 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 6.49 (d, J=8.8 Hz, 1H), 4.22 (s, 3H), 4.18-4.07 (m, 2H). LC-MS: m/z 534 [M+H]+.

Example 212: 8-(6-cyclopropylpyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2trifluoroethyl)amino)-1,6-naphthyridine- 7(6H)-he N .--4-.

.d 1 .

G 'HELL N Г-1 '' С F ₃ ] II

The title compound was synthesized from intermediate 12a and (6-cyclopropylpyridin-3-yl)boronic acid using General Method V (Step M).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.61 (d, J=1.2 Hz, 1H), 8.50 (s, 1H), 8.48 (s, 1H), 8 .34 (t, J=6.4 Hz, 1H), 7.87-7.80 (m, 2H), 7.75 (d, J=9.2 Hz, 1H), 7.67 (d, J=8.8Hz, 1H), 7.32(dd, J=9.2Hz, 2.0Hz, 1H), 7.22(d, J=8.4Hz, 1H), 6.50 (d, J=8.8 Hz, 1H), 4.22 (s, 3H), 4.21-4.10 (m, 2H), 2.14-2.05 (m, 1H), 0, 98-0.88 (m, 4H). LC-MS: m/z 491 [M+H]-.

Example 213: 6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)-8-(4(trifluoromethyl)phenyl)-1,6-naphthyridine- 7(6Н)-one 4.-..,.-4-.. — .

' 4 ΪГ ^Λ ' U II ' СГн '

CF:

The title compound was synthesized from intermediate 12a and (4(trifluoromethyl)phenyl)boronic acid using General Method V (Step M).

¹ H-NMR (400 MHz, DMSO-d6) δ: 8.56 (s, 1H), 8.48 (s, 1H), 8.40 (t, J=6.4 Hz, 1H), 7, 89-7.80 (m, 3H), 7.78 (d, J=9.2 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.33 (dd, J=9.2 Hz, 2.0 Hz, 1H), 6.52 (d, J=9.2 Hz, 1H), 4.22 ( s, 3H), 4.21-4.06 (m, 2H). LC-MS: m/z 518 [M+H] ⁺ .

Example 214 8-(4-(2,2-difluoroethyl)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2trifluoroethyl)amino)-1,6 -naphthyridine-7(6H)-one

The title compound was synthesized from intermediate 12a and (4-(2,2difluoroethyl)phenyl)boronic acid using General Method V (Step M).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.47 (s, 2H), 8.31 (broad s, 1H), 7.84 (d, J=1.6 Hz, 1H) , 7.74 (d, J=9.2 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.0 Hz, 2H), 7 .30 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 2H), 6.49 (d, J=8.8 Hz, 1H ), 6.24 (tt, J _HF = 56.6 Hz, 4.8 Hz, 1H), 4.22 (s, 3H), 4.23-4.10 (m, 2H), 3.18 ( dt, J _hf =18.2 Hz, 4.8 Hz, 2H). LC-MS: m/z 514 [M+H] ⁺ .

Preparation of 2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridin7(6H)-one (Example 215)

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Method B.

Step N: 8-bromo-2-chloro-1,6-naphthyridin-7(6H)-one

Λ O'^f K' -CI

Ιίι

AlCl ₃ (15 .9 g, 120.0 mmol, 3.0 eq.). Then, the resulting mixture was stirred at 80°C for 2 h and extinguished by adding water (19.4 ml, 1.1 mol, 27.0 eq.) at 10°C. The quenched mixture was stirred at room temperature for 0.5 h and then filtered. The filter cake was washed with DCM/EtOH (200 mL, 10/1, v/v) and the filtrate was concentrated to give 8-bromo-2-chloro1,6-naphthyridin-7(6H)-one (9.8 g , crude) as a yellow solid, which was used directly in the next step. LC-MS: m/z 261 [M+H]+.

Step O: 8-bromo-2-ethoxy-1,6-naphthyridine-7(6H)-one ill.

P ’ Π Ί Y Y

NaOEt (27.2 g, 400.0 mmol, 10.0 eq.). The resulting solution was stirred at 100°C for 5 hours. Then, the mixture was poured into ice-cold NH4Cl (sat. aq., 200 ml) and adjusted to pH=6 by adding 1N. HCl (aq.). The mixture was extracted with EtOAc (100 ml x 4), the organic layers were combined, washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: DCM/EtOH=50/1-10/1) to give 8-bromo-2-ethoxy-1,6-naphthyridin-7(6H)-one (5.3 g , 49% yield) as a brown solid. LC-MS: m/z 271, 273 [M+H] ⁺ .

Preparation of 8-bromo-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one

8-Bromo-2-ethoxy-6-(2-methyl-2Н-indazol-5-yl)-1,6-naphthyridin-7(6Н)-one was synthesized from intermediate 11b and 2-methyl-2Н-indazol- 5-ylboronic acid according to the procedure of Example 209 (step H). LC-MS: m/z 399, 401 [M+H] ⁺ .

Example 215 Preparation of 2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-8-(4-(trifluoromethyl)phenyl)-1,6naphthyridin-7(6H)-one

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The title compound was synthesized from intermediate 12b and 4(trifluoromethyl)phenylboronic acid by general procedure V (step M) (Pd(PPh ₃ ) ₄ , Cs ₂ CO3, dioxane, 100°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.81 (s, 1H), 8.50 (s, 1H), 7.99 (d, J=9.2 Hz, 1H), 7, 91 (d, J=1.6 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.74-7.67 (m, 3H), 7.35 (dd, J =9.2 Hz, 2.0 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 4.23 ( s, 3H), 1.26 (t, J=7.2 Hz, 3H). LC-MS: m/z 465 [M+H]+.

Example 216 8-(6-(difluoromethyl)pyridin-3-yl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-1,6naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 12b and 2(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine by general procedure V (step M).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.95 (d, J=1.2 Hz, 1H), 8.85 (s, 1H), 8.51 (s, 1H), 8, 27 (dd, J=8.4Hz, 2.0Hz, 1H), 8.02 (d, J=9.2Hz, 6H), 7.92 (d, J=1.2Hz, 1H) , 7.72 (d, J=3.6 Hz, 1H), 7.70 (d, J=2.8 Hz, 1H), 7.36 (dd, J=9.2 Hz, 2.0 Hz , 1H), 6.98 (t, Jhf=55.2 Hz, 1H), 6.59 (d, J=9.2 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H ), 4.23 (s, 3H), 1.27 (t, J=7.2 Hz, 3H). LC-MS: m/z 448 [M+H] ⁺ .

Example 217 2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-8-(4-(trifluoromethoxy)phenyl)-1,6-naphthyridin7(6H)-one

The title compound was synthesized from intermediate 12b and (4(trifluoromethoxy)phenyl)boronic acid using General Method V (Step M).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.77 (s, 1H), 8.50 (s, 1H), 7.98 (d, J=9.0 Hz, 1H), 7 .89 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.70 (d, J=9.0 Hz, 1H), 7.37 -7.30(m, 3H), 6.55(d, J=9.0Hz, 1H), 4.25(kv, J=7.2Hz, 2H), 4.22(s, 3H) , 1.25 (t, J=7.2 Hz, 3H). LC-MS: m/z 481 [M+H] ⁺ .

Example 218 8-(6-(difluoromethoxy)pyridin-3-yl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-1,6naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 12b and 2(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine by general procedure V (step M).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.77 (s, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.49 (s, 1H), 8, 18 (dd, J=4.4Hz, 2.0Hz, 1H), 7.99 (d, J=8.8Hz, 1H), 7.89 (d, J=2.0Hz, 1H) , 7.74 (t, Jhf=73.2 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.35 (dd, J=9.2 Hz, 2.0 Hz , 1H), 7.10 (d, J=8.4 Hz, 1H), 6.57 (d, J=9.2 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H ), 4.22 (s, 3H), 1.27 (t, J=7.2 Hz, 3H). LC-MS: m/z 464 [M+H] ⁺ .

Example 219 2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-8-(6-methylpyridin-3-yl)-1,6-naphthyridin7(6H)-one

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The title compound was synthesized from intermediate 12b and (6methylpyridin-3-yl)boronic acid using General Method V (Step M).

¹ H-NMR (400 MHz, DMSO-d6) δ: 8.75 (s, 1H), 8.70 (broad s, 1H), 8.50 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.93 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.71 ( d, J=9.2 Hz, 1H), 7.35 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 6 .55 (d, J=8.8 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 4.23 (s, 3H), 1.28 (t, J=7, 2 Hz, 3H). LC-MS: m/z 412 [M+H]+.

Example 220 2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)-1,6naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 12b and (6(trifluoromethyl)pyridin-3-yl)boronic acid using General Method V (Step M).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.05 (d, J=7.8 Hz, 1H), 8.88 (s, 1H), 8.51 (s, 1H), 8 .37 (dd, J=8.0 Hz, 2.0 Hz, 1H), 8.04 (d, J=9.2 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H ), 7.92 (d, J=8.4 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.37 (dd, J=9.6 Hz, 2.0 Hz, 1H), 6.61 (d, J=9.2 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.23 (s, 3H), 1.28 ( t, J=7.2 Hz, 3H). LC-MS: m/z 466 [M+H] ⁺ .

Example 221 8-(6-cyclopropylpyridin-3-yl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-1,6naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 12b and (6-cyclopropylpyridin-3-yl)boronic acid using General Method V (Step M).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.93 (s, 1H), 8.89 (s, 1H), 8.51 (s, 1H), 8.04 (d, J=9 .2 Hz, 1H), 7.91 (d, J=1.2 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.35 (dd, J=9.2 Hz, 2.0 Hz, 1H), 6.63 (d, J=9.2 Hz, 1H), 4.31 (kv, J= 6.8 Hz, 2H), 4.23 (s, 3H), 2.36-2.25 (m, 1H), 1.31 (t, J=6.8 Hz, 3H), 1.27- 1.20 (m, 2H), 1.171.09 (m, 2H). LC-MS: m/z 437 [M+H] ⁺ .

Example 222: 8-(4-(1H-1,2,4-triazol-3-yl)phenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-1,6naphthyridine- 7 (6H)-he

The title compound was synthesized from intermediate 12b and 3-(4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-1,2,4triazole by general procedure V (step M) followed by deprotection with TFA by general procedure I (step F).

1H-NMR (400 MHz, DMSO-d6) δ: 14.05 (br s, 1H), 8.75 (s, 1H), 8.50 (s, 1H), 8.39 (br s, 1H),

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8.01 (d, J=8.4 Hz, 2H), 7.98 (d, J=9.2 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7. 77 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.8 Hz,

1H), 7.35 (dd, J=8.8 Hz, 2.0 Hz, 1H), 6.55 (d, J=9.2 Hz, 1H), 4.27 (q, J=7, 2 Hz, 2H), 4.23 (s, 3H), 1.27 (t, J=7.2

Hz, 3H). LC-MS: m/z 464 [M+H]+.

Example 223 8-(4-(1H-nirazol-3-yl)phenyl)-2-ethoxy-6-(2-methyl-2H-undazol-5-yl)-1,6-naphthyridine 7(6H)-one

The title compound was synthesized from intermediate 12b and 3-(4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-pyrazole by General Method V (Step M) followed by TFA deprotection by General Method I (Step F).

1H-NMR (400 MHz, DMSO-d6) δ: 12.87 (br s, 1H), 8.70 (s, 1H), 8.49 (s, 1H), 7.97 (d, J= 9.2 Hz, 1H), 7.89 (d, J=1.2 Hz, 1H), 7.85-7.69 (m, 6H), 7.35 (dd, J=9.2 Hz, 2.0 Hz, 1H), 6.73 (s, 1H), 6.54 (d, J=8.8 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 4 .22 (s, 3H), 1.27 (t, J=7.2 Hz, 3H). LC-MS: m/z 463 [M+H] ⁺ .

224:

An example of naphthyridine-7(6H)-one

8-(4-(1H-imidazol-4-yl)phenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-1,6-

The title compound was synthesized from intermediate 12b and 4-(4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1H-imidazole by General Method V (Step M) followed by TFA deprotection by General Method I (Step F).

1H-NMR (400 MHz, DMSO-d6) δ: 12.14 (br s, 1H), 8.70 (s, 1H), 8.50 (s, 1H), 7.96 (d, J= 8.8 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.78-7.58 (m, 7H), 7.35 (dd, J=9.2 Hz, 2.0 Hz, 1H), 6.53 (d, J=9.2 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 4.23 (s, 3H), 1 .27 (t, J=7.2 Hz, 3H). LC-MS: m/z 463 [M+H] ⁺ .

Preparation of 8-bromo-2-ethoxy-6-(2-(2-(methylsulfonyl)-ethyl)-2H-indazol-5-yl)-1,6-naphthyridin7(6H)-one (12c)

8-Bromo-2-ethoxy-6-(2-(2-(methylsulfonyl)ethyl)-2Н-indazol-5-yl)-1,6-naphthyridin-7(6Н)-one 12с was synthesized from intermediate 11b and 2-(2-(methylsulfonyl)ethyl)-2H-indazol-5ylboronic acid by General Procedure V (Step L). LC-MS: m/z 491.493 [M+H] ⁺ .

Example 225 Preparation of 8-(4-chlorophenyl)-2-ethoxy-6-(2-(2-(methylsulfonyl)ethyl)-2H-indazol-5-yl)1,6-naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 12c and 4-chlorophenylboronic acid using General Method V (Step M).

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Ή-NMR (400 MHz, DMSO-d ₆ ) δ: 8.76 (s, 1H), 8.62 (s, 1H), 8.00-7.93 (m, 2H), 7.87 (d , J=8.8 Hz, 1H),

7.66 (d, J=8.8 Hz, 2H), 7.42-7.36 (m, 3H), 6.54 (d, J=9.2 Hz, 1H), 4.91 (t , J=6.8Hz, 2H), 4.26(kv, J=6.8Hz,

2H), 3.80 (t, J=6.8 Hz, 2H), 2.94 (s, 3H), 1.27 (t, J=6.8 Hz, 3H). LC-MS: m/z 523 [M+H]+.

Preparation of 8-bromo-2-ethoxy-6-(1-methyl-1 H-benzo[d]imidazol-6-yl)-1,6-naphthyridin-7(6H)-one (12d)

8-bromo-2-ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,6-naphthyridin-7(6Н)-one 12d was synthesized from intermediate 11b and (1- methyl-1H-benzo[d]imidazol-6-yl)boronic acid by general procedure V (step L). LC-MS: m/z 399 [M+H]+.

Example 226 Preparation of 2-ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)-1,6-naphthyridine-7 (6H) - she

The title compound was synthesized from intermediate 12d and (6(trifluoromethyl)pyridin-3-yl)boronic acid using General Method V (Step M).

1H-NMR (400 MHz, DMSO-d6) δ: 9.05 (d, J=1.6 Hz, 1H), 8.88 (s, 1H), 8.37 (dd, J=8.4 Hz , 2.0 Hz, 1H),

8.35 (s, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.80 (d, J=8 .4 Hz, 1H), 7.38 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 4.28 (kv, J=7.2 Hz, 2H), 3.88 (s, 3H), 1.28 (t, J=7.2 Hz, 3H). LC-MS: m/z 466 [M+H]+.

Example 227 2-ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-(trifluoromethyl)phenyl)-1,6naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 12d and (4(trifluoromethyl)phenyl)boronic acid using General Method V (Step M).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.80 (s, 1H), 8.34 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7, 90-7.84 (m, 3H), 7.79 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.36 (dd, J =8.8Hz, 2.4Hz, 1H), 6.57(d, J=8.8Hz, 1H), 4.25(kv, J=7.2Hz, 2H), 3.88( s, 3H), 1.26 (t, J=7.2 Hz, 3H). LC-MS: m/z 465 [M+H] ⁺ .

Example 228 8-(6-cyclopropylpyridin-3-yl)-2-ethoxy-6-(1-methyl-1 H-benzo[d]imidazol-6-yl)-1,6naphthyridin-7(6H)-one

N /% ' .1 _Λ J. ~

Х 'Ν' Ό'

L ,Ν

Λ

The title compound was synthesized from intermediate 12d and (6-cyclopropylpyridin-3-yl)boronic acid using General Method V (Step M).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.74 (s, 1H), 8.64 (d, J=1.6 Hz 1H), 8.34 (s, 1H), 7.97 (d, J=9.2 Hz, 1H), 7.89 (dd, J=8.0 Hz, 2.4 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.35 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.56 (d, J=9.2 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.88 (s, 3H), 2.16-2, 06 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 0.99-0.88 (m, 4H). LC-MS: m/z 438 [M+H] ⁺ .

Example 229: 8-(6-(difluoromethoxy)pyridin-3-yl)-2-ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)1,6-naphthyridin-7(6H )-He

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OCHF^

The title compound was synthesized from intermediate 12d and 2(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine by general procedure V (step M).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.77 (s, 1H), 8.51 (d, J=1.6 Hz, 1H), 8.34 (s, 1H), 8. 19 (dd, J=8.8Hz, 2.0Hz, 1H), 8.00 (d, J=9.2Hz, 1H), 7.86 (d, J=2.0Hz, 1H) , 7.79 (d, J=8.4 Hz, 1H), 7.75 (t, Jhf=73.2 Hz, 1H), 7.36 (dd, J=9.2 Hz, 2.0 Hz , 1H), 7.10 (d, J=9.2 Hz, 1H), 6.58 (d, J=9.2 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H ), 3.88 (s, 3H), 1.28 (t, J=7.2 Hz, 3H). LC-MS: m/z 464 [M+H] ⁺ .

Preparation of 8-bromo-2-ethoxy-6-(quinolin-6-yl)-1,6-naphthyridin-7(6H)-one (12e)

8-Bromo-2-ethoxy-6-(quinolin-6-yl)-1,6-naphthyridin-7(6H)-one (12e) was synthesized from intermediate 11b and quinolin-6-ylboronic acid using general procedure V ( stage L). LCMS: m/z 396 (M+H)+.

Example 230 Preparation of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(quinolin-6-yl)-1,6-naphthyridin7(6H)-one

The title compound was synthesized from intermediate 12e and 2-(4(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane by general procedure V (step M).

¹ H-NMR (400 MHz, DMSO-d6) δ: 9.02 (dd, J=4.4 Hz, 2.0 Hz, 1H), 8.83 (s, 1H), 8.48 (dd, J=8.8 Hz, 1.2 Hz, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 7.97 (d, J=9.2 Hz, 1H), 7.94 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.65 (dd, J=8.4 Hz, 4.0 Hz, 1H), 7.28 (t, Jhf=74.4 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.57 (d, J=8.8 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H) . LC-MS: m/z 460 [M+H] ⁺ .

Example 231 8-(6-cyclopropylpyridin-3-yl)-2-ethoxy-6-(quinolin-6-yl)-1,6-naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 12e and (6-cyclopropylpyridin-3-yl)boronic acid using General Method V (Step M).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.02 (dd, J=4.0 Hz, 2.0 Hz, 1H), 8.84 (s, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.47 (dd, J=8.8 Hz, 2.0 Hz, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.16 (d, J=9.2 Hz, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.94 (dd, J=9.2 Hz, 2.4 Hz, 1H), 7.90 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.65 (dd, J=8.4 Hz, 4.4 Hz, 1H), 7.28 (d, J= 8.0 Hz, 1H), 6.58 (d, J=9.2 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 2.16-2.06 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 0.98-0.91 (m, 4H). LC-MS: m/z 435 [M+H] ⁺ .

Example 232: 8-(6-(difluoromethoxy)pyridin-3-yl)-2-ethoxy-6-(quinolin-6-yl)-1,6-naphthyridin-7(6H)one

- 102 041815

OCHF The title compound was synthesized from intermediate 12e and 2(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine by general procedure V (step M).

1H-NMR (400 MHz, DMSO-d6) δ: 9.02 (dd, J=4.2 Hz, 2.0 Hz, 1H), 8.89 (s, 1H), 8.53 (d, J =2.0 Hz, 1H), 8.48 (dd, J=8.4 Hz, 1.2 Hz, 1H), 8.25 (d, J=2.4 Hz, 1H), 8.21 ( dd, J=8.4 Hz, 2.4 Hz, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H), 7 .96 (dd, J=9.0 Hz, 2.0 Hz, 1H), 7.76 (t, Jhf=73.2 Hz, 1H), 7.66 (dd, J=8.4 Hz, 4 .2 Hz, 1H), 7.11 (dd, J=8.4 Hz, 0.4 Hz, 1H), 6.61 (d, J=9.0 Hz, 1H), 4.28 (kv, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H). LC-MS: m/z 461 (m+H) ⁺ .

Preparation of 8-bromo-2-(cyclopropylmethoxy)-1,6-naphthyridin-7(6Н)-one (11с)

8-Bromo-2-(cyclopropylmethoxy)-1,6-naphthyridin-7(6H)-one 11c was synthesized from intermediate 14 and cyclopropylmethanol by general procedure V (step O). LC-MS: m/z 295 [M+H]+.

Preparation of 8-bromo-2-(cyclopropylmethoxy)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)one (12f)

8-Bromo-2-(cyclopropylmethoxy)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one (12f) was synthesized from intermediate 11c and 2-methyl -2H-indazol-5-ylboronic acid by general procedure V (step L). LC-MS: m/z 425, 427 [M+H)+.

Example 233 Preparation of 8-(4-chlorophenyl)-2-(cyclopropylmethoxy)-6-(2-methyl-2H-indazol-5-yl)-1,6naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 12f and 4chlorophenylboronic acid using General Method V (Step M).

¹ H-NMR (400 MHz, DMSO-d6) δ: 8.75 (s, 1H), 8.49 (s, 1H), 7.97 (d, J=9.2 Hz, 1H), 7, 89 (dd, J=2.0Hz, 0.4Hz, 1H), 7.70 (d, J=9.2Hz, 1H), 7.65 (d, J=8.8Hz, 2H) , 7.39 (d, J=8.8 Hz, 2H), 7.33 (dd, J=9.2 Hz, 2.0 Hz, 1H), 6.57 (d, J=9.2 Hz , 1H), 4.22 (s, 3H), 4.08 (d, J=7.6 Hz, 2H), 1.23-1.11 (m, 1H), 0.53-0.46 ( m, 2H), 0.260.20 (m, 2H). LC-MS: m/z 457 [M+H]+.

Example 234 Preparation of 8-(4-chlorophenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2trifluoroethylamino)-1,6-naphthyridine-7( 6H) -she

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Step P: 8-(4-chlorophenyl)-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2-amine (15a)

A mixture of 8-bromo-7-methoxy-R-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2-amine (300.0 mg, 0.9 mmol, 1.0 eq.), Pd( PPh ₃ ) ₄ (52.0 mg, 0.05 mmol, 0.05 eq.), Cs ₂ CO ₃ (580.0 mg, 1.8 mmol, 2.0 eq.) and 4chlorophenylboronic acid (208.0 mg, 1.3 mmol, 1.5 eq.) in dioxane/water (5.0 ml, 9/1, v/v) was stirred at 100°C under N2 for 16 h. Then, the reaction mixture diluted with water (20 ml) and extracted with EtOAc (20 ml x 3). All organic layers were combined, washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: PE/EA=2/1) to give 8-(4-chlorophenyl)-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6-naphthyridine -2-amine (300 mg, 92% yield) as a white solid. LC-MS: m/z 368 [M+H]+.

Step Q: 8-(4-chlorophenyl)-2-(2,2,2-trifluoroethylamino)-1,6-naphthyridin-7(6H)-one (16a) i

0 ^l ' T W ' TG CF ₃ f ⁿ

With ϊ

WITH! 16a

A mixture of 8-(4-chlorophenyl)-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2-amine (300 mg, 0.8 mmol, 1.0 eq.), TsOH (422 mg, 2.5 mmol, 3.0 eq.), NaI (407.0 mg, 2.5 mmol, 3.0 eq.) in MeCN (10 ml) was stirred at 80°C for 2 h The reaction mixture was then quenched with ice water (10 ml) and extracted with EtOAc (10 ml x 3). The organic layers were combined, washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (DCM/MeOH=20/1) to give 8-(4-chlorophenyl)-2-(2,2,2-trifluoroethylamino)-1,6-naphthyridine-7(6H)- it (280 mg, 97% yield) as a white solid. LC-MS: m/z 354 [M+H] ⁺ .

Example 234 Step R: 8-(4-chlorophenyl)-6-(1-methyl-III-benzo[0]imidazol-6-yl)-2-(2,2,2trifluoroethylamino)-1,6-naphthyridin- 7(6Н)-one

8-(4-chlorophenyl)-2-(2,2,2-trifluoroethylamino)-1,6-naphthyridin-7(6H)-one mixture (50.0 mg, 0.14 mmol, 1.0 eq.) , CuI (26.6 mg, 0.14 mmol, 1.0 eq.), CsF (63.8 mg, 0.4 mmol, 3.0 eq.), N ¹ ,N ² -dimethylcyclohexane 1,2-diamine (29.8 mg, 0.2 mmol, 1.5 eq) and 6-bromo-1-methyl-1H-benzo[d]imidazole (44.3 mg, 0.2 mmol, 1.5 eq) in MeCN (3 ml) was stirred at 100° C. under N2 atmosphere for 3 h. Then, the reaction mixture was diluted with water (10 ml) and extracted with EtOAc (10 ml x 3). The organic layers were combined, washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to

- 104 041815 low pressure. The residue was purified by reverse phase preparative HPLC to give 8-(4-chlorophenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethylamino)- 1,6naphthyridine-7(6H)-one (Example 234).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.40-8.28 (m, 2H), 7.82 (s, 1H), 7.75 ( d, J=9.2 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.37-7.28 (m, 3H), 6.51 (d, J=8 .8 Hz, 1H), 4.22-4.10 (m, 2H), 3.87 (s, 3H). LC-MS: m/z 484 [M+H]+.

Example 235: 8-(4-chlorophenyl)-6-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2-(2,2,2-trifluoroethylamino)- 1,6-naphthyridine-7(6H)-one

The title compound was synthesized from intermediate 16a and 6-bromo-1methyl-1H-benzo[d][1,2,3]triazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.53 (s, 1H), 8.41 (t, J=6.0 Hz, 1H), 8.17 (d, J=3.6 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H), 7.75 (d, J=9.2 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.54 (dd, J=9.2 Hz, 1.6 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 6.52 (d, J=9, 2 Hz, 1H), 4.35 (s, 3H), 4.23-4.10 (m, 2H). LC-MS: m/z 485 [M+H] ⁺ .

Example 236 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethylamino)-1,6naphthyridin-7(6H)-one

................ΐΜ · ·ί* ; Η

The title compound was synthesized from intermediate 16a and 5-bromo-2methyl-2H-indazole by general procedure V (step R).

¹ H-NMR (400 MHz, DMSO-d6) δ: 8.51 (s, 1H), 8.47 (s, 1H), 8.36 (t, J=6.4 Hz, 1H), 7, 84 (d, J=1.2 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.64 ( d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.31 (dd, J=9.2 Hz, 2.0 Hz, 1H), 6 .50 (d, J=9.2 Hz, 1H), 4.22 (s, 3H), 4.09-4.06 (m, 2H). LC-MS: m/z 484 [M+H] ⁺ .

Example 237: 8-(4-chlorophenyl)-6-(2,3-dimethyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethylamino)-1,6naphthyridine-7(6H)- He

The title compound was synthesized from intermediate 16a and 5-bromo-2,3dimethyl-2H-indazole by general procedure V (step R).

¹ H-NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.34 (broad s, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7. 33(d, J=8.4Hz, 2H), 7.27(d, J=8.8Hz, 1H), 6.50(d, J=8.8Hz, 1H), 4.18- 4.03 (m, 2H), 4.10 (s, 3H), 2.64 (s, 3H). LC-MS: m/z 498 [M+H] ⁺ .

Example 238 8-(4-chlorophenyl)-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylamino)-1,6-naphthyridin7(6H)-one

The title compound was synthesized from intermediate 16a and 1-bromo-4-methoxybenzene by general procedure V (step R).

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1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.41 (s, 1H), 8.34 (t, J=6.0 Hz, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.62 (d,

J=8.4 Hz, 2H), 7.43 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.07 (d, J= 8.8 Hz, 2H), 6.49 (d, J=9.2 Hz, 1H),

4.20-4.07 (m, 2H), 3.83 (s, 3H). LC-MS: m/z 460 [M+H]+.

Preparation of 8-(4-(difluoromethoxy)phenyl)-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2-amine (15b)

8-(4-(Difluoromethoxy)phenyl)-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6-naphthyridine-2-amine (15b) was synthesized from intermediate 10а and 2-(4- (difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane by General Procedure V (Step P). LC-MS: m/z 400 [M+H] ⁺ .

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethylamino)-1,6-naphthyridin-7(6Н)-one (16b)

8-(4-(Difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethylamino)-1,6-naphthyridin-7(6H)-one (16b) was synthesized from intermediate 15b by general procedure V (step Q ). LC-MS: m/z 386 [M+H] ⁺ .

Example 239: 8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2trifluoroethylamino)-1,6-naphthyridine-7(6H) -He

T.·. Ή

The title compound was synthesized from intermediate 16b and 5-bromo-2methyl-2H-indazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.49 (s, 1H), 8.48 (s, 1H), 8.31 (t, J=6.0 Hz, 1H), 7, 84 (d, J=1.6 Hz, 1H), 7.75 (d, J=9.2 Hz, 1H), 7.71-7.64 (m, 3H), 7.31 (dd, J =9.2 Hz, 1.6 Hz, 1H), 7.25 (t, 1^=74.4 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 6.49 (d, J=9.2 Hz, 1H), 4.22 (s, 3H), 4.21-4.09 (m, 2H). LC-MS: m/z 516 [M+H] ⁺ .

Example 240: 8-(4-(difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2trifluoroethylamino)-1,6-naphthyridin- 7(6Н)-one

The title compound was synthesized from intermediate 16b and 6-bromo-1methyl-1H-benzo[d]imidazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-de) δ: 8.49 (s, 1H), 8.33 (broad s, 1H), 8.32 (s, 1H), 7.81 (d, J= 1.6 Hz, 1H), 7.78-7.72 (m, 2H), 7.66 (d, J=8.8 Hz, 2H), 7.31 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.25 (t, K. 74.4 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 6.51 (d, J=9, 2 Hz, 1H), 4.22-4.10 (m, 2H), 3.87 (s, 3H). LC-MS: m/z 516 [M+H] ⁺ .

Example 241 8-(4-(difluoromethoxy)phenyl)-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylamino)-1,6naphthyridin-7(6H)-one

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The title compound was synthesized from intermediate 16b and 1-bromo-4-methoxybenzene by general procedure V (step R).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.40 (s, 1H), 8.30 (t, J=5.6 Hz, 1H), 7.73 (d, J=9, 2 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.43 (d, J=9.2 Hz, 2H), 7.24 (t, Jhf=74.4 Hz , 1H), 7.08 (d, J=8.8 Hz, 2H), 7.07 (d, J=9.2 Hz, 2H), 6.48 (d, J=9.2 Hz, 1H ), 4.20-4.07 (m, 2H), 3.82 (s, 3H). LC-MS: m/z 492 [M+H]+.

Preparation of 8-bromo-N-cyclopropyl-7-methoxy-1,6-naphthyridine-2-amine 10b

8-bromo-N-cyclopropyl-7-methoxy-1,6-naphthyridine-2-amine 10b was synthesized from key intermediate I and cyclopropanamine by general procedure V (step J). LC-MS: m/z 294 [M+H] ⁺ .

Preparation of N-cyclopropyl-8-(4-(difluoromethoxy)phenyl)-7-methoxy-1,6-naphthyridine-2-amine (15c)

N-cyclopropyl-8-(4-(difluoromethoxy)phenyl)-7-methoxy-1,6-naphthyridine-2-amine (15c) was synthesized from intermediate 10b and 2-(4-(difluoromethoxy)phenyl)-4, 4,5,5-Tetramethyl-1,3,2dioxaborolane by General Procedure V (Step P). LC-MS: m/z 358 [M+H] ⁺ .

Preparation of 2-(cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)-1,6-naphthyridin-7(6H)-one (16c)

2-(Cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)-1,6-naphthyridin-7(6H)-one (16c) was synthesized from intermediate 15c by general procedure V (step Q). LC-MS: m/z 344 [M+H] ⁺ .

Example 242 Preparation of 2-(cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2Nindazol-5-yl)-1,6-naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 16c and 5-bromo-2methyl-2H-indazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.46 (s, 1H), 8.37 (br s, 1H), 7.90 (br s, 1H), 7.84-7 .81 (m, 2H), 7.87 (d, J=9.2 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.29 (dd, J=9, 2, 2.0 Hz, 1H), 7.23 (t, Jhf=74.6 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 6.31 (t, J= 8.8 Hz, 1H), 4.22 (s, 3H), 2.80-2.70 (m, 1H), 0.80-0.61 (m, 2H), 0.55-0.42 (m, 2H). LC-MS: m/z 474 [M+H] ^- .

Preparation of 8-bromo-2-ethoxy-7-methoxy-1,6-naphthyridine (10c) j j с '-, -I с br

Item

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8-Bromo-2-ethoxy-7-methoxy-1,6-naphthyridine 10c was synthesized from key intermediate I and EtONa/EtOH by general procedure V (step J). LC-MS: m/z 283 [M+H]+.

Preparation of 8-(4-chlorophenyl)-2-ethoxy-7-methoxy-1,6-naphthyridine (15d)

8-(4-Chlorophenyl)-2-ethoxy-7-methoxy-1,6-naphthyridine (15d) was synthesized from compound 10c and 4-chlorophenylboronic acid by general procedure V (step P). LC-MS: m/z 315 [M+H]+.

Preparation of 8-(4-chlorophenyl)-2-ethoxy-1,6-naphthyridin-7(6Н)-one (16d)

Cl 16d

8-(4-chlorophenyl)-2-ethoxy-7-methoxy-1,6-naphthyridine mixture (550.0 mg, 1.8 mmol, 1.0 eq.), TsOH (958.0 mg, 5.3 mmol, 3.0 eq.), LiCl (115.0 mg, 5.3 mmol, 3.0 eq.) in DMF (12.0 ml) was stirred at 120°C for 5 h. . NH ₄ Cl (10 ml). The mixture was extracted with EA (10 ml x 3), the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (PE/EA=4/1-0/1) to give 8-(4-chlorophenyl)-2ethoxy-1,6-naphthyridin-7(6H)-one (180 mg, yield 34%) as a yellow solid. LC-MS: m/z 301 [M+H]+.

Example 243 Preparation of 8-(4-chlorophenyl)-2-ethoxy-6-(quinolin-6-yl)-1,6-naphthyridin-7(6H)-one

The title compound was synthesized from bromoquinoline intermediate 16d and 6 by general procedure V (step R).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.02 (dd, J=8.0, 1.6 Hz, 1H), 8.85 (s, 1H), 8.48 (d, J=7.2Hz 1H), 8.24(d, J=2.4Hz, 1H), 8.16(d, J=8.8Hz, 1H), 7.98(d, J=9 .2 Hz, 1H), 7.95 (dd, J=8.8, 2.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.65 (dd, J = 8.4, 4.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 6.57 (d, J=9.2 Hz, 1H), 4.27 (q , J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H). LC-MS: m/z 428 [M+H] ⁺ .

Example 244 8-(4-chlorophenyl)-2-ethoxy-6-(quinoxalin-6-yl)-1,6-naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 16d and 6bromoquinoxaline by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d6) δ: 9.06 (dd, J=4.4 Hz, 2.0 Hz, 2H), 8.88 (s, 1H), 8.38 (d, J =2.4 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.09 (dd, J=9.0 Hz, 2.0 Hz, 1H), 7.98 ( d, J=9.0 Hz, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 6.58 (d, J=9.0 Hz, 1H), 4.27 (kv, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H). LC-MS: m/z 429 [M+H] ^- .

Example 245 8-(4-chlorophenyl)-6-(cinnolin-6-yl)-2-ethoxy-1,6-naphthyridin-7(6H)-one

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The title compound was synthesized from bromocinnoline intermediate 16d and 6 by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.49 (d, J=6.0 Hz, 1H), 8.87 (s, 1H), 8.62 (d, J=9.2 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.33 (d, J=6.0 Hz, 1H), 8.18 (d, J=6.4 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.69 (d, J=8.6 Hz, 2H) , 7.42 (d, J=8.6 Hz, 2H), 6.59 (d, J=9.2 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 1 .28 (t, J=7.2 Hz, 3H). LC-MS: m/z 429 [M+H]+.

Example 246 8-(4-chlorophenyl)-2-ethoxy-6-(quinazolin-6-yl)-1,6-naphthyridin-7(6H)-one

The title compound was synthesized from bromoquinazoline intermediate 16d and 6 by general procedure V (step R).

¹ H-NMR (400 MHz, DMSO-d6) δ: 9.71 (s, 1H), 9.42 (s, 1H), 8.86 (s, 1H), 8.44 (d, J=2 .0 Hz, 1H), 8.24 (dd, J=8.8 Hz, 2.0 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.97 (d, J=9.2Hz, 1H), 7.68(d, J=8.4Hz, 2H), 7.41(d, J=8.4Hz, 2H), 6.59(d, J= 8.8 Hz, 1H), 4.27 (d, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H). LC-MS: m/z 429 [M+H]+.

Example 247 8-(4-chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 16d and 5-bromo-2methyl-2H-indazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d6) δ: 8.75 (s, 1H), 8.50 (s, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.70 (d, J=9.1 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.40 (d , J=8.6 Hz, 2H), 7.33 (dd, J=9.2 Hz, 2.4 Hz, 1H), 6.54 (d, J=9.2 Hz, 1H), 4, 25 (q, J=6.8 Hz, 2H), 4.22 (s, 3H), 1.27 (t, J=6.8 Hz, 3H). LC-MS: m/z 431 [M+H] ⁺ .

Example 248 8-(4-chlorophenyl)-2-ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,6-naphthyridin7(6H)-one

The title compound was synthesized from intermediate 16d and 6-bromo-1methyl-1H-benzo[d]imidazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d6) δ: 8.74 (s, 1H), 8.34 (s, 1H), 7.97 (d, J=9.0 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.40 (d , J=8.4 Hz, 2H), 7.34 (dd, J=8.5 Hz, 2.0 Hz, 1H), 6.55 (d, J=9.0 Hz, 1H), 4, 25(q, J=7.2Hz, 2H), 3.87(s, 3H), 1.27(t, J=7.2Hz, 3H). LC-MS: m/z 431 [M+H] ⁺ .

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-7-methoxy-1,6-naphthyridine (15e)

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8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-7-methoxy-1,6-naphthyridine (15e) was synthesized from intermediate 10c and 2-(4-(difluoromethoxy)phenyl)-4,4,5, 5-Tetramethyl-1,3,2-dioxaborolane by General Procedure V (Step P). LC-MS: m/z 347 [M+H]+.

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-1,6-naphthyridin-7(6H)-one (16e) o'-- x

BASIC 1st

8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-1,6-naphthyridin-7(6H)-one (16e) was prepared from intermediate 16d by general procedure V (step Q). LC-MS: m/z 333 [M+H] ⁺ .

Example 249 Preparation of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(1-(2-(methylsulfonyl)ethyl)-6oxo-1,6-dihydropyridip-3-yl)-1,6- naphthyridip-7(6Н)-opα

With

snu

The title compound was synthesized from intermediate 16e and 5-bromo-1(2-(methylsulfonyl)-ethyl)pyridin-2(1H)-one by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.61 (s, 1H), 8.17 (d, J=2.8 Hz, 1H), 7.93 (d, J=9.2 Hz, 1H), 7.69 (dd, J=9.6 Hz, 2.8 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.28 (t, J _H F=74.4Hz, 1H), 6.55(d, J=9.2Hz, 1H), 6.52(d, J=9.6Hz, 1H), 4.34(t, J= 7.2 Hz, 2H), 4.24 (q, J=7.2 Hz, 2H), 3.61 (t, J=7.2 Hz, 2H), 3.08 (s, 3H), 1 .26 (t, J=7.2 Hz, 3H). LC-MS: m/z 532 [M+H] ⁺ .

Example 250 8-(4-(difluoromethoxy)pheyl)-2-ethoxy-6-(4-methoxyphenyl)-1,6-naphthyridin-7(6H)-one

OCHF ₌

The title compound was synthesized from intermediate 16e and 1-bromo-4-methoxybenzene by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.64 (s, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H), 7.27 (t, Jhf=74.4 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 6.52 (d, J=9.2 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H) , 3.83 (s, 3H), 1.26 (t, J=7.2 Hz, 3H). LC-MS: m/z 439 [M+H] ⁺ .

Example 251: 8-(4-(difluoromethoxy)fepyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin7(6H)-one

The title compound was synthesized from intermediate 16e and 1-bromo-4-methoxybenzene by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.73 (s, 1H), 8.50 (s, 1H), 7.96 (d, J=9.2 Hz, 1H), 7, 89 (d, J=1.6 Hz, 1H), 7.73-7.65 (m, 3H), 7.34 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7, 28 (t, Jhf=74.4 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 6.54 (d, J=8.8 Hz, 1H), 4.25 ( q, J=7.2 Hz, 2H), 4.22 (s, 3H), 1.27 (t, J=7.2 Hz, 3H). LC-MS: m/z 463 [M+H] ⁺ .

Example 252: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-( 1 -methyl-1 H-benzo[d] [ 1,2,3]triazol-6-yl)-1,6- 110 041815 naphthyridine-7 (6H)-one

OCHi >

The title compound was synthesized from intermediate 16e and 6-bromo-1methyl-1H-benzo[d][1,2,3]triazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.76 (s, 1H), 8.22-8.17 (m, 2H), 7.96 (d, J=9.2 Hz, 1H ), 7.69 (d, J=8.8 Hz, 2H), 7.58 (dd, J=8.8 Hz, 2.0 Hz, 1H), 8.28 (t, J _H F=74 .4 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.57 (d, J=9.2 Hz, 1H), 4.35 (s, 3H), 4, 26 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). LC-MS: m/z 464 [M+H]+.

Example 253 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,6naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 16e and 6-bromo-1methyl-1H-benzo[d]imidazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.79 (s, 1H), 8.45 (broad s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.94 (broad s, 1H), 7.88 (broad s, 1H), 7.65 (d, J=8.6 Hz, 2H), 7.41 (d, J=6.0 Hz , 1H), 7.34 (t, J _H F=74.4 Hz, 1H), 7.22 (d, J=8.6 Hz, 2H), 6.60 (d, J=8.8 Hz , 1H), 4.32(q, J=7.2Hz, 2H), 3.94(s, 3H), 1.33(t, J=7.2Hz, 3H). LC-MS: m/z 463 [M+H] ⁺ .

Preparation of 8-bromo-7-methoxy-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridine (10d) . Gs..

'O' at 'M' ST TF.

&

10d

8-Bromo-7-methoxy-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridine (10d) was synthesized from key intermediate I and 2,2,2-trifluoroethanol via General Method V (Step J) . LC-MS: m/z 337 [M+H] ⁺ .

Preparation of 8-(4-chlorophenyl)-7-methoxy-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridine (15f)

Dal

CI 1Ы

8-(4-Chlorophenyl)-7-methoxy-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridine (15f) was synthesized from compound 10d and 4-chlorophenylboronic acid by general procedure V (step P). LC-MS: m/z 369 [M+H] ⁺ .

Preparation of 8-(4-chlorophenyl)-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-7(6H)-one (16f) ϋ' ^L C cl _J o

^C| 1"

8-(4-Chlorophenyl)-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-7(6H)-one (16f) was synthesized from compound 15f by general procedure V (step Q). LC-MS: m/z 355 [M+H] ⁺ .

Example 254 Preparation of 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethoxy)-1,6naphthyridin-7(6H)-one

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The title compound was synthesized from intermediate 16f and 5-bromo-2methyl-2H-indazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.86 (s, 1H), 8.50 (s, 1H), 8.10 (d, J=9.2 Hz, 1H), 7, 91 (d, J=2.0 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.41 ( d, J=8.8 Hz, 2H), 7.35 (dd, J=9.2 Hz, 2.0 Hz, 1H), 6.71 (d, J=9.2 Hz, 1H), 4 .93 (q, J=9.2 Hz, 2H), 4.23(s, 3H). LC-MS: m/z 485 [M+H]+.

Example 255 8-(4-chlorophenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethoxy)-1,6naphthyridine-7(6H )-He

The title compound was synthesized from intermediate 16f and 6-bromo-1methyl-1H-benzo[d]imidazole by general procedure V (step R).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.85 (s, 1H), 8.34 (s, 1H), 8.10 (d, J=9.2 Hz, 1H), 7 .87 (d, J=2.0 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 7.35(dd, J=8.8 Hz, 2.0 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 4.93 (kv, J=9.2 Hz, 2H), 3.87 (s, 3H). LC-MS: m/z 485 [M+H] ⁺ .

Preparation of 8-(4-(difluoromethoxy)phenyl)-7-methoxy-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridine (15g)

8-(4-(Difluoromethoxy)phenyl)-7-methoxy-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridine (15g) was synthesized from compound 10d and 2-(4-(difluoromethoxy)phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane by general procedure V (step P). LC-MS: m/z 401 [M+H] ⁺ .

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-7(6Н)-one (16g)

8-(4-(Difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-7(6H)-one (16g) was synthesized from compound 15g by general procedure V (step Q) . LC-MS: m/z 387 [M+H] ⁺ .

Example 256 Preparation of 8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2trifluoroethoxy)-1,6-naphthyridine-7(6H )-she

The title compound was synthesized from intermediate 16g and 5-bromo-2methyl-2H-indazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.85 (s, 1H), 8.51 (s, 1H), 8.10 (d, J=9.2 Hz, 1H), 7, 91 (d, J=2.0 Hz, 1H), 7.73-7.67(m, 3H), 7.35 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7, 28 (t, Jhf=74.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 2H), 6.70 (d, J=9.2 Hz, 1H), 4.92 ( kv, J=8.8 Hz, 2H), 4.23 (s, 3H). LC-MS: m/z 517 [M+H] ⁺ .

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Example 257: 8-(4-(difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2trifluoroethoxy)-1,6-naphthyridine- 7(6Н)-one

The title compound was synthesized from intermediate 16g and 6-bromo-1methyl-1H-benzo[d]imidazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.84 (s, 1H), 8.34 (s, 1H), 8.10 (d, J=9.2 Hz, 1H), 7, 87 (d, J=2.0 Hz, 1H), 7.79(d, J=8.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.36 ( dd, J=8.8 Hz, 2.0 Hz, 1H), 7.28 (t, Jhf=74.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 2H), 6 .71 (d, J=9.2 Hz, 1H), 4.93 (q, J=8.8 Hz, 2H), 3.88 (s, 3H). LC-MS: m/z 517 [M+H] ⁺ .

Example 258 8-(4-(difluoromethoxy)phenyl)-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethoxy)-1,6naphthyridin-7(6H)-one

The title compound was synthesized from intermediate 16g and 1-bromo-4-methoxybenzene by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.81 (s, 1H), 8.13 (d, J=9.2 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.34 (t, Jhf=74.4 Hz, 1H), 7.22 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 6.74 (d, J=8.8 Hz, 1H), 4.97 (q, J=8.8 Hz, 2H) , 3.89 (s, 3H). LC-MS: m/z 493 [M+H]+.

Preparation of 8-bromo-2-(ethylthio)-7-methoxy-1,6-naphthyridine (10e)

8-Bromo-2-(ethylthio)-7-methoxy-1,6-naphthyridine (10e) was synthesized from key intermediate I and sodium ethanethiolate by general procedure V (step J). LC-MS: m/z 299, 301 [M+H] ⁺ .

Preparation of 8-(4-chlorophenyl)-2-(ethylthio)-7-methoxy-1,6-naphthyridine (15h)

8-(4-Chlorophenyl)-2-(ethylthio)-7-methoxy-1,6-naphthyridine (15h) was synthesized from compound 10e and 4chlorophenylboronic acid by general procedure V (step P). LC-MS: m/z 331 [M+H] ⁺ .

Preparation of 8-(4-chlorophenyl)-2-(ethylthio)-1,6-naphthyridin-7(6H)-one (16h)

8-(4-Chlorophenyl)-2-(ethylthio)-1,6-naphthyridin-7(6H)-one (16h) was synthesized from compound 15h by general procedure V (step Q). LC-MS: m/z 317 [M+H] ⁺ .

Example 259 Preparation of 8-(4-chlorophenyl)-2-(ethylthio)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin7(6H)-one

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The title compound was synthesized from intermediate 16h and 5-bromo-2methyl-2H-indazole by general procedure V (step R).

¹ H-NMR (400 MHz, DMSO-d6) δ: 8.82 (s, 1H), 8.50 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7, 84 (d, J=8.8 Hz,

1H), 7.71 (d, J=9.2 Hz, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H) , 7.35 (dd, J=9.2 Hz, 2.0 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 4.23 (s, 3H), 2.99 (kv, J=7.2 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H). LC-MS: m/z 447 [M+H]+.

Preparation of 8-bromo-7-methoxy-2-propyl-1,6-naphthyridine (10f) neither

To a mixture of 8-bromo-2-chloro-7-methoxy-1,6-naphthyridine (300.0 mg, 1.1 mmol, 1.0 eq.) and Fe(acac) ₃ (387.0 mg, 1, 1 mmol, 1.0 eq.) in THF/NMP (5.0 ml/0.5 ml) at rt. 11.0 ml of propylmagnesium bromide (1M solution in diethyl ether, 11.0 mmol, 10.0 eq.) was added slowly. The mixture was stirred at rt. for 1 h and carefully quenched by adding water. The mixture was diluted with EtOAc, washed with water and then brine (30 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (PE/EtOAc=5/1) to give 8-bromo-7-methoxy-2-propyl-1,6-naphthyridine (180 mg, 59% yield) as a yellow solid. LCMS: m/z 281, 283 [M+H] ⁺ .

Preparation of 8-(4-(difluoromethoxy)phenyl)-7-methoxy-2-propyl-1,6-naphthyridine (15i)

C ' P ' ran - you

8-(4-(Difluoromethoxy)phenyl)-7-methoxy-2-propyl-1,6-naphthyridine 15i was synthesized from compound 10f and 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl -1,3,2-dioxaborolane by general procedure V (step P). LC-MS: m/z 345 [M+H] ⁺ .

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-propyl-1,6-naphthyridin-7(6Н)-one (16i)

8-(4-(Difluoromethoxy)phenyl)-2-propyl-1,6-naphthyridin-7(6H)-one (16i) was synthesized from compound 15i by general procedure V (step Q). LC-MS: m/z 331 (M+H) ⁺ .

Example 260 Preparation of 8-(4-(difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2propyl-1,6-naphthyridin-7(6H)-one

N i : -1

С-···-· N

The title compound was synthesized from intermediate 16i and 6-bromo-1methyl-1H-benzo[d]imidazole by general procedure V (step R).

1H-NMR (400 MHz, DMSO-d6) δ: 8.87 (s, 1H), 8.34 (s, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.6 Hz, 2H), 7.36 (dd , J=8.8 Hz, 2.0 Hz, 1H), 7.29 (t, Jhf=74.4 Hz, 1H), 7.16 (d, J=8.6 Hz, 2H), 6, 93 (d, J=8.8 Hz, 1H), 3.88(s, 3H), 2.70-2.66 (m, 2H), 1.73-1.62 (m, 2H), 0 .92 (t, J=7.2 Hz, 3H). LC-MS: m/z 461 [M+H] ⁺ .

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The following compounds were synthesized by general procedure V (steps J, P, Q, and R):

104-A > -CO. ... Г '°' I ^{ъ σ} with t s 6H)-one (synthesized from 8-(4-chlorophenyl)-2-ethoxy-1,6-naphthyride in-7(6H)-one & 5-bromo-2-isopropyl-2H-indazole (reference: Organic Letters , 16 (I), 3114-3117; 2014)) LC-MS (ESI): m/z 459 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.57 (d, >0.9 Hz, 1H), 7.96 (d, >9.1 Hz, 1H ), 7.87 (dd, >2.1, 0.8 Hz, 1H), 7.72 (dt, >9.1, 0.9 Hz, 1H), 7.70-7.64 (m, 2H), 7.43-7.38 (m, 2H), 7.33 (dd, >9.1, 2.1 Hz, 1H), 6.54 (d, >9.0 Hz, 1H), 4.89 (hept, J-6.6 Hz, 1H), 4.26 (q, >7.0 Hz, 2H), 1.58 (d, J=6.6 Hz, 6H), 1.27 (t, >7.1 Hz, ZN). 105-A G| '7 ^X O- τ'Ν'Ό' C: 8-(4-chlorophenyl)-6-(2,3-dimethyl-2Nindazol-5-yl)-2-ethoxy-1,6-naphthyr idin- 7( 6H)-he LC-MS (ESI): m/z 445 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.98 (d, >9.0 Hz, 1H), 7.88 (d, >1.9 Hz, 1H ), 7.70-7.64 (m, 2H), 7.60 (d, >9.1 Hz, 1H), 7.44-7.37 (m, 2H), 7.29 (dd, > 9.1, 2.0 Hz, 1H), 6.54 (d, >9.0 Hz, 1H), 4.25 (q, J=7.0 Hz, 2H), 4.10 (s, ZN ), 2.64 (s, ZN), 1.27 (t, >7.1 Hz, ZN). 106-A η Ύ 31 8-(4-chlorophenyl)-2-ethoxy-6-(2-methyl-2Hbenzo[<1][1,2,3]triazol-5-yl)-1,6- naphthyridine-7(6H)-one (synthesized from 8-(4-chlorophenyl)-2ethoxy-1,6-naphthyride in-7(6H)-one & 5- bromo-2-methyl-2H-benzo[(1] [1,2,3 ]triazole (reference: WO 2007/84451) LC-MS (ESI): m/z 432 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.20 (dd, >2.0, 0.7 Hz, 1H), 8.05 (d, >9, 0 Hz, 1H), 7.97 (d, J=9.2 Hz, 1H), 7.67 (d, >8.5 Hz, 2H), 7.58 (dd, >9.0, 2, 0 Hz, 1H), 7.41 (d, J=8.6 Hz, 2H), 6.56 (d, >9.0 Hz, 1H), 4.56 (s, ZN), 4.26 ( kv, >7.1 Hz, 2H), 1.27 (t, >7.0 Hz, ZN). 107-A A 0; 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6(1-(2-(methylsulfonyl)ethyl)-6-oxo-1,6dihydropyride in-3-yl)-1,6-naphthyridine7(6H) -He LC-MS (ESI): m/z 532 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.17 (d, >2.9 Hz, 1H), 7.94 (d, >9.1 Hz, 1H ), 7.69 (dd, >9.7, 2.9 Hz, 1H), 7.63 (d, >8.6 Hz, 1H), 7.41 (d, >8.6 Hz, 2H) , 6.56 (d, >9.0 Hz, 1H), 6.52 (d, >9.7 Hz, 1H), 4.34 (t, >7.1 Hz, 2H), 4.24 ( q, >7.1 Hz, 2H), 3.61 (t, >7.1 Hz, 2H), 3.08 (s, ZN), 1.26 (t, >7.1 Hz, ZN).

- 115 041815

The following compounds were synthesized by general procedure V (method B):

O -S- LC-MS (ESI): m/z 555 [M+H] ⁺ . th Cj /] ^-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.63 (d, CO.9 Hz, 1H), 7.96 (d, C9.1 Hz, 1H), 7.93 (dd, C2.1, 0.8 Hz, 1H), 7.74 108-A (dt, C9.2, 0.9 Hz, 1H), 7.69 (d, C8.8 Hz, 8-(4-(difluoromethoxy)phenyl)-2- 2H), 7.38 (dd, C9.1, 2.1 Hz, 1H), 7.27 (t, ethoxy-6-(2-(2- J _hf =74.4 Hz, 1H), 7.16 (d, 1=8.8 Hz, 2H), (methylsulfonyl) ethyl) -2H- 6.54 (d, C9.0 Hz, 1H), 4.94 (t, C6.8 Hz, indazol-5 -yl)-1, 6-naphthyridine- 2H), 4.26 (kv, C7.1 Hz, 2H), 3.91 (t, J=6.8 7(6Н)-one Hz, 2H), 2.95 (s, ZN), 1.27 (t, C7.1 Hz, ZN). -X1 .. ... - - „ γ LC-MS (ESI): m/z 475 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.75 (s, c''' 'τΓ 'Ό' ' 1H), 8.50 (s, 1H), 7.97 (d, 1=9.1 Hz, 1H), 109-A ι ι, Ύ Br 7.92-7.87 (m, 1H), 7.70 (d, 1=9.1 Hz, 1H), 7.61 (d, C8.6 Hz, 2H), 7.53 (d, C8.6 Hz, 8-(4-bromophenyl)-2-ethoxy-6-(2- 2H), 7.34 (dd, C9.1, 2.0 Hz, 1H), 6.54 (d, methyl-2H-indazol-5 -yl) -1,6- C8.9 Hz, 1H), 4.30-4.21 (m, 5H), 1.27 (t, naphthyridine-7(6H)-one C7.1 Hz, ZN). LC-MS (ESI): m/z 518 [M+H] ⁺ G' ' 'H-NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.57-8.47 (m, 2H), 8.20 (dd, C8.6, 2.4 γ ¹ Hz, 1H), 8.13 (d, C9.0 Hz, 1H), 7.93 (d, PO-A = , C2.0 Hz, 1H), 7.76 (t, J _H f=73.1 Hz, 1H), 8-(6-(difluoromethoxy)pyridine-3 - 7.72 (d, C9.1 Hz, 1H), 7.37 (dd, C9.1, 2.0 yl)-6-(2-methyl-2H-indazol-5-yl)-2- Hz, 1H), 7.11 (d, C8.6 Hz, 1H), 6.74 (d, (2,2,2-trifluoroethoxy)-1,6- C9.0 Hz, 1H), 4.94 (kv, J=9.0 Hz, 2H), 4.23 naphthyridine-7(6H)-one (s, ZN). with........ LC-MS (ESI): m/z 427 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.37-8.29 (m, 2H), 8.19 (s, 1H), 7.93 (d, C9.1 Hz, 1H), 7.83 (d, C 1.9 Hz, 1H), 7.78 111-A 2-ethoxy-6-(1-methyl-1Hbenzo[c1]imidazol-6-yl)-8-(6(methylamino)pyridin-3-yl)-1,6naphthyridin-7(6H)-one (d, C8.5 Hz, 1H), 7.71 (dd, C8.7, 2.4 Hz, 1H), 7.32 (dd, 1=8.5, 2.0 Hz, 1H), 6 .52 (d, C8.9 Hz, 1H), 6.44 (d, C8.7 Hz, 1H), 6.39 (t, C4.9 Hz, 1H), 4.30 (q, C7.1 Hz, 2H), 3.87 (s, ZN), 2.79 (d, J=4.5 Hz, ZN), 1.30 (t, C7.0 Hz, ZN). AS , . ί f LC-MS (ESI): m/z 536 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.64 (d, C2.3 Hz, 1H), 8.36 (s, 1H), 112-A t L 6-(1-methyl-1H-benzo[4]imide azol-6yl)-2-(2,2,2-trifluoroethoxy)-8-(6(trifluoromethoxy)pyridin-3-yl)1, 6- naftir idine-7(6Н)-one 8.29 (dd, C8.5, 2.4 Hz, 1H), 8.14 (d, J=9.0 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.39 (dd, 1=8.5, 2.1 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H ), 6.76 (d, J=9.0 Hz, 1H), 4.95 (q, J=9.0 Hz, 2H), 3.88 (s, 3H).

- 116 041815

113-A -th i -,. •L' - ABOUT I 8-(6-cyclopropylpyridin-3-yl)-6(2-methyl-2Н-indazol-5-yl)-2-(2,2,2trifluoroethoxy)-1,6-naphthyridin7(6Н)-one LC-MS (ESI): m/z 492 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.65 (dd, >2.2, 0.8 Hz, 1H), 8.51 (s, 1H), 8.10 (d, >9.0 Hz, 1H), 7.93-7.87 (m, 2H), 7.72 (dt, 1=9.2, 0.9 Hz, 1H), 7. 35 (dd, >9.1, 2.0 Hz, 1H), 7.30 (dd, >8.1, 0.8 Hz, 1H), 6.71 (d, >9.0 Hz, 1H) , 4.93 (q, >9.1 Hz, 2H), 4.23 (s, ZN), 2.12 (tg, >7.6, 5.2 Hz, 1H), 0.95 (ddd, >7.3, 5.5, 2.3 Hz, 4H). 114-A Oh t l~.. C o 2-ethoxy-6-(4-methoxyphenyl)-8-(6methylpyridin-3-yl)-1,6- naphthyridine-7(6H)-one LC-MS (ESI): m/z 388 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.68 (dd, >2.2, 0.8 Hz, 1H), 8.66 (s, 1H), 7.95 (d, >9, 1 Hz, 1H), 7.90 (dd, >8.0, 2.3 Hz, 1H), 7.47 (d, >8.9 Hz, 2H), 7.24 (d, >8.1 Hz, 1H), 7.09 (d, >9.0 Hz, 2H), 6.54 (d, >9.0 Hz, 1H), 4.25 (kv, >7.0 Hz, 2H), 3.83 (s, ZN), 2.48 (s, ZN), 1.26 (t, >7.0 Hz, ZN). 115-A -iGA. . ......'» .... ' ϊ ^{1 Ώ} = P t -'-CD, 2-(2,2-difluoroethoxy)-8-(4-(methoxy03)phenyl)-6-(2- methyl-2H-indazol-5yl)-1,6-naphthyridin-7(6H)-one LC-MS (ESI): m/z 466 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.50 (s, 1H), 8.03 (d, >9.0 Hz, 1H), 7.89 ( s, 1H), 7.71 (d, >9.2 Hz, 1H), 7.58 (d, >8.8 Hz, 2H), 7.34 (dd, >9.1, 2.1 Hz , 1H), 6.92 (d, >8.8 Hz, 2H), 6.63 (d, >9.0 Hz, 1H), 6.35 (t, >4.7 Hz, 1H), 4 .50 (td, J _hf =15.0, >3.6 Hz, 2H), 4.23 (s, ZN). 116-A ...... J Ί.’ L ’ . 1 uh 8-(4-(methoxy^3)phenyl)-6-(2-methyl- 2Н-indazol-5-yl)-2-(2,2,2trifluoroethoxy)-1,6-naphthyr idin7(6Н)-one LC-MS (ESI): m/z 484 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.50 (s, 1H), 8.07 (d, >9.0 Hz, 1H), 7.90 ( s, 1H), 7.71 (d, >9.1 Hz, 1H), 7.59 (d, >8.5 Hz, 2H), 7.34 (dd, >9.1, 2.1 Hz , 1H), 6.92 (d, >8.4 Hz, 2H), 6.67 (d, >8.9 Hz, 1H), 4.94 (q, >9.1 Hz, 2H), 4 .22 (s, 3N).

- 117 041815

117-A D '' Ϊ 1 'I” I i T osg 2-ethoxy-8-(4-(methoxy-b3)phenyl)-6(2-methyl-2H-indazol-5-yl)-1,6- naphthyridine-7(6H)-one LC-MS (ESI): m/z 430 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.49 (s, 1H), 7.94 (d, >9.1 Hz, 1H), 7.87 ( s, 1H), 7.70 (d, >9.1 Hz, 1H), 7.58 (d, >8.4 Hz, 2H), 7.33 (d, >9.3 Hz, 1H), 6.91 (d, >8.2 Hz, 2H), 6.51 (d, >9.0 Hz, 1H), 4.35-4.08 (m, 5H), 1.26 (q, > 7.4 Hz, ZN). 118-A -G/ ,,·“·ν _ — ·— T Η —· L* ” 5 %.- * 8-(6-(difluoromethyl)pyridin-3-yl)6-(2-methyl-2H-indazol-5-yl)-2(2,2,2-trifluoroethoxy)-1,6- naphthyridine-7(6H)-one LC-MS (ESI): m/z 502 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.96 (broad s, 2H), 8.52 (s, 1H), 8.29 (dd, >8.1, 2.1 Hz, 1H ), 8.15 (d, >9.0 Hz, 1H), 7.94 (dd, >2.1, 0.8 Hz, 1H), 7.75-7.73 (m, 1H), 7 .71 (dd, >2.2, 1.3 Hz, 1H), 7.38 (dd, >9.1, 2.1 Hz, 1H), 6.99 (t, Jhf=55.1 Hz, 1H), 6.76 (d, >9.0 Hz, 1H), 4.94 (q, >9.0 Hz, 2H), 4.23 (s, 3H). 119-A -Ή Ί . ' ϊ ' I ^r 1 ,1 I. 1 (6H)-he LC-MS (ESI): m/z 467 [M+H] ⁺ . SNMR (400 MHz, DMSO-d6) δ 9.41 (s, 2H), 8.96 (s, 1H), 8.52 (s, 1H), 8.07 (d, >9.1 Hz, 1H ), 7.94 (dd, >2.0, 0.8 Hz, 1H), 7.777.69 (m, 1H), 7.38 (dd, >9.1, 2.1 Hz, 1H), 6 .66 (d, >9.0 Hz, 1H), 4.33 (q, >7.1 Hz, 2H), 4.23 (s, ZN), 1.30 (t, >7.1 Hz, ZN). 120-A D i . _ ^g ' Π 1 . ¹ I ¹ I (6H)-he LC-MS (ESI): m/z 492 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.65 (d, >2.1 Hz, 1H), 8.34 (s, 1H), 8.10 ( d, >9.0 Hz, 1H), 7.94-7.88 (m, 1H), 7.87 (d, >2.0 Hz, 1H), 7.79 (d, >8.6 Hz , 1H), 7.36 (dd, >8.6, 2.0 Hz, 1H), 7.30 (d, >8.0 Hz, 1H), 6.72 (d, >9.0 Hz, 1Н), 4.94 (kv, >9.0 Hz, 2Н), 3.87 (s, ZN), 2.12 (d.kv., >12.8, 7.9, 6.7 Hz, 1Н ), 0.96 (dt, >10.0, 3.3 Hz, 4H).

- 118 041815

121-A ^GF 3 2-ethoxy-6-(4-methoxyphenyl)-8-(6(trifluoromethoxy)pyridin-3-yl)1,6-naphthyr idin-7(6H)-one LC-MS (ESI): m/z 458 [M+H] ⁺ Ή-NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.60 (dd, >2.4, 0 .7 Hz, 1H), 8.26 (dd, >8.5, 2.4 Hz, 1H), 7.99 (d, >9.1 Hz, 1H), 7.49 (d, J=8 .9 Hz, 2H), 7.30 (dd, >8.5, 0.7 Hz, 1H), 7.10 (d, >9.0 Hz, 2H), 6.57 (d, >9, 0 Hz, 1H), 4.26 (q, >7.0 Hz, 2H), 3.84 (s, ZN), 1.26 (t, >7.1 Hz, ZN). 122-A i. .□ . ,. \'.kJ o ί 8-(4-chlorophenyl)-2-ethoxy-4-methyl6-(2-methyl-2H-indazol-5-yl)-1,6naphthyridin-7(6H)-one (synthesized from 3-bromo-5-iodo-2-methoxypyridine-4-amine and ethyl (E)-but-2-enoate via general methodology V (sequence R1-R3-R2, method B, steps B-D and L-O)) LC-MS (ESI): m/z 445 [M+H] ⁺ . Ή-NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.49 (s, 1H), 7.89 (d, >1.9 Hz, 1H), 7.69 (d , >9.1 Hz, 1H), 7.65-7.59 (m, 2H), 7.43-7.37 (m, 2H), 7.34 (dd, >9.1, 2.0 Hz, 1H), 6.42 (d, >1.3 Hz, 1H), 4.28-4.16 (m, 5H), 2.43 (s, ZN), 1.25 (t, >7 .0 Hz, ZN). 123-A ‘‘G'”’ C) g 2-(2,2-difluoroethoxy)-8-(6(difluoromethoxy)pyridine in-3-yl)-6(2-methyl-2Н-indazol-5-yl)- 1,6naphthyridine-7( 6H)-on LC-MS (ESI): m/z 500 [M+H] ⁺ . Ή-NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.55-8.49 (m, 2H), 8.19 (dd, >8.5, 2.4 Hz, 1H), 8.08 (d, >9.1 Hz, 1H), 7.92 (dd, >2.1, 0.8 Hz, 1H), 7.76 (t, J _HF = 73.1 Hz , 1H), 7.72 (dt, >9.2, 0.9 Hz, 1H), 7.36 (dd, >9.1, 2.0 Hz, 1H), 7.10 (dd, >8 .6, 0.7 Hz, 1H), 6.69 (d, >9.0 Hz, 1H), 6.36 (tg, J _HF =54.6, >3.4 Hz, 1H), 4, 53 (td, J _HF =15.1, >3.4 Hz, 2H), 4.23 (s, 3H).

- 119 041815

124-A ' ' j II 7. 6-(2-methyl-2H-indazol-5-yl)-2- (2,2,2-trifluoroethoxy)-8-(6(trifluoromethyl)pyridin-3-yl)-1,6naphthyridin-7(6Н)-one LC-MS (ESI): m/z 520 [M+H] ⁺ 'H-NMR (400 MHz, DMSO-d6) δ 9.06 (d, >2.0 Hz, 1H), 9.00 (s , 1H), 8.53 (s, 1H), 8.39 (dd, >8.2, 2.0 Hz, 1H), 8.17 (d, >9.1 Hz, 1H), 7.96 (dd, >2.1, 0.8 Hz, 1H), 7.92 (dd, >8.3, 0.8 Hz, 1H), 7.73 (dd, >9.2, 0.9 Hz , 1H), 7.39 (dd, >9.1, 2.0 Hz, 1H), 6.78 (d, >9.0 Hz, 1H), 4.95 (q, >9.0 Hz, 2H), 4.24 (s, 3H). 125-A —g/ J 1 L t । f. “ ’-IF V 2-(2,2-difluoroethoxy)-6-(2-methyl- 2Н-indazol-5-yl)-8-(6- (trifluoromethoxy)pyridin-3-yl)1,6-naphthyr idin-7(6Н)-one LC-MS (ESI): m/z 518 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.63 (dd, >2.4, 0.6 Hz, 1H), 8.52 (s, 1H), 8.29 (dd, >8.5, 2.4 Hz, 1H), 8.10 (d, >9.1 Hz, 1H), 7.93 (dd, >2.0, 0.8 Hz, 1H), 7.72 (dt, >9.1, 0.9 Hz, 1H), 7.37 (dd, >9.1, 2.1 Hz, 1H), 7.31 (dd, >8, 4, 0.7 Hz, 1H), 6.70 (d, >9.0 Hz, 1H), 6.35 (tg, J _HF =54.6, >3.5 Hz, 1H), 4.52 (td, J _H f=15.0, >3.6 Hz, 2H), 4.23 (s, ZN). 126-A -'3 , A 7 Tchg. 2-(2,2-difluoroethoxy)-8-(4- (difluoromethoxy)phenyl)-6-(2-methyl- 2H-indazol-5-yl)-1,6-naphthyr idine- 7(6Н)-one LC-MS (ESI): m/z 499 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.51 (s, 1H), 8.06 (d, >9.1 Hz, 1H), 7.91 ( dd, >2.1, 0.8 Hz, 1H), 7.78-7.63 (m, ZN), 7.35 (dd, >9.1, 2.0 Hz, 1H), 7.28 (t, Jhf=74.3 Hz, 1H), 7.17 (d, >8.7 Hz, 2H), 6.66 (d, >9.0 Hz, 1H), 6.35 (tg, J _Hf =54.7, >3.5 Hz, 1H), 4.51 (td, >15.0, 3.5 Hz, 2H), 4.23 (s, 3H).

- 120 041815

127-A RF . , ' * H ¹ -. r, 0 PSNG; 8-(6-(difluoromethoxy)pyridin-3yl)-6-(1-methyl-1H-benzo[<1]imidazol-6-yl)-2-(2,2,2trifluoroethoxy)-1,6-naphthyridine7 (6H)-he LC-MS (ESI): m/z 518 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.53 (d, >2.4 Hz, 1H), 8.35 (s, 1H), 8.20 ( dd, >8.5, 2.4 Hz, 1H), 8.13 (d, J=9.0 Hz, 1H), 7.89 (t, >2.0 Hz, 1H), 7.76 ( t, J _HF =73.1 Hz, 1H), 7.80 (d, >8.5 Hz, 1H), 7.38 (dd, >8.5, 2.1 Hz, 1H), 7.11 (d, >8.5 Hz, 1H), 6.75 (d, >9.0 Hz, 1H), 4.94 (q, >9.0 Hz, 2H), 3.88 (s, ZN) . 128-A S-T-.-- 1.1 L - N ? ^r F. and t )-1,6naphthyridine-7(6H)-one LC-MS (ESI): m/z 520 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.99 (s, 1H), 8.39 (d, J=8.7 Hz, 1H), 8.36 (s, 1H), 8.17 (d, >9.0 Hz, 1H), 7.967.89 (m, 2H), 7.81 (d, >8.5 Hz, 1H), 7.40 (dd , >8.7, 2.0 Hz, 1H), 6.79 (d, >9.0 Hz, 1H), 4.95 (kv, >9.0 Hz, 2H), 3.88 (s, ZN). 129-A O. I II F °CHNG _g LC-MS (ESI): m/z 440 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.50 (dd, >2.3, 0.7 Hz, 1H), 8.16 (dd, >8, 5, 2.4 Hz, 1H), 7.98 (d, >9.1 Hz, 1H), 7.76 (t, J _hf =73.1 Hz, 1H), 7.48 (d, >8 .9 Hz, 2H), 7.13-7.07 (m, ZN), 6.56 (d, >9.0 Hz, 1H), 4.26 (q, >7.1 Hz, 2H), 3.83 (s, ZN), 1.27 (t, >7.1 Hz, ZN).

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130-A 0 6-(2-methyl-2H-indazol-5-yl)-8-(6methylpyridin-3-yl)-2-(2,2,2trifluoroethoxy)-1,6-naphthyridin7(6H)-one LC-MS (ESI): m/z 466 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.71 (d, J=2.2 Hz, 1H), 8.52 (s, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.98-7.90 (m, 2H), 7.72 (d, J=9.1 Hz, 1H), 7.37 (dd, J= 9.l, 2.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 6.72 (d, J=9.0 Hz, 1H), 4.94 (q, J=9.0 Hz, 2H), 4.23 (s, CL), 2.51 (s, CL-closed). 131-A F XX . v' N C' ZF., 0 η 6-(2-methyl-2H-indazol-5-yl)-2(2,2,2-trifluoroethoxy)-8-(6(trifluoromethoxy)pyridin-3-yl)1,6-naphthyr idin-7( 6H)-he LC-MS (ESI): m/z 536 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.64 (d, J=2.4 Hz, 1H), 8.52 (s, 1H), 8.29 (dd, J=8.5, 2.4 Hz, 1H), 8.14 (d, J=9.0 Hz, 1H), 7.94 (dd, J=2.l, 0.8 Hz, 1H), 7.767.69 (m, 1H), 7.37 (dd, J=9.l, 2.0 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 6, 75 (d, J=9.0 Hz, 1H), 4.94 (q, J=9.1 Hz, 2H), 4.23 (s, 3H). 132-A 1' ι ι. 0' γ N 0' ' 9 2-ethoxy-6-(1-methyl-1Hbenzo[4]imidazol-6-yl)-8-(6methylpyridin-3-yl)-1,6naphthyridin-7(6H)-one LC-MS (ESI): m/z 412 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.70 (d, >2.2 Hz, 1H), 8.34 (s, 1H), 7.98 ( d, J=9.1 Hz, 1H), 7.93 (dd, J=8.0, 2.3 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7, 79 (d, J=8.5 Hz, 1H), 7.35 (dd, 1=8.5, 2.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.56 (d, J=9.0 Hz, 1H), 4.27 (q, J=7.0 Hz, 2H), 3.88 (s, ZN), 1.28 (t, 1=7 ,0Hz, ZN).

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133-A >>> D > a III.. O' TG O' OCFj 2-ethoxy-6-(2-methyl-2H-indazol-5yl)-8-(6-(trifluoromethoxy)pyridine- 3-yl)-1,6-naphthyride in-7(6H)-one LC-MS (ESI): m/z 482 [M+H] ⁺ 'H-NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.62 (d, >2.3 Hz , 1H), 8.51 (s, 1H), 8.28 (dd, >8.5, 2.4 Hz, 1H), 8.01 (d, J=9.0 Hz, 1H), 7, 91 (d, >2.0 Hz, 1H), 7.72 (d, >9.1 Hz, 1H), 7.36 (dd, >9.1, 2.0 Hz, 1H), 7.31 (d, >8.5 Hz, 1H), 6.59 (d, J=9.0 Hz, 1H), 4.28 (q, 1=7.1 Hz, 2H), 4.23 (s, ZN), 1.27 (t, >7.1 Hz, ZN). 134-A -Th, . . ' 'Ϊ I... 1.4 t 8-(4-chlorophenyl)-2-ethoxy-3-methyl6-(2-methyl-2H-indazol-5-yl)-1,6naphthyridin-7(6H)-one (synthesized from 3-bromo-5-iodo-2-methoxypyridine-4-amine and ethyl methacrylate through general methodology V (sequence R1-R3-R2, method B, steps B-D and L-O)) LC-MS (ESI): m/z 445 [M+H] ⁺ . 'H-NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.49 (s, 1H), 7.86 (dd, >2.0, 0.8 Hz, 1H), 7.72 (d, >1.4 Hz, 1H), 7.71-7.65 (m, ZN), 7.39 (d, >8.5 Hz, 2H), 7.32 (dd, > 9.1, 2.1 Hz, 1H), 4.28 (q, >7.0 Hz, 2H), 4.22 (s, VN), 2.12 (d, >1.2 Hz, VN) , 1.29 (t, >7.0 Hz, ZN).

General Method VI:

MSHOAc toluene. HOAc, 100 °C

Stage C

L _l p-TsOH

Alkyl-OH qO 1'1 ._______

NaH. THF _Οα η1γ'' ^Λ '^Ν< -Ο^ ¹ acetone-Nye

Stage A ^R ' 2 Stage B

Arml \u003d B (OH) ₂

Cu(OAc) ₂ 2 equiv. pyridine, 4 eq. DCM, O ₂ , 40 h

Stage D

Getting example 261:

Step A: methyl 2-(4-bromophenyl)-2-(5-(dimethoxymethyl)-2-(2,2,2-trifluoroethoxy)pyrimidin-4yl)acetate

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NaH (60% in mineral oil, 60 mg, 1.5 mmol, 3 equiv.). The mixture was stirred at 0°C for 30 min. Then, methyl 2-(4-bromophenyl)-2-(5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin-4yl)acetate (1a) (prepared by General Procedure III using methyl-2-(4bromophenyl) acetate (steps A-C)) (230 mg, 0.5 mmol, 1.0 eq.), and then the mixture was stirred at room temperature (25°C) for an additional 3 hours. Then, the reaction mixture was poured into chilled NH ₄ Cl (sat. waves), and the aqueous layer was extracted with EtOAc (10 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated to give a brown oil which was purified by silica gel chromatography (PE/EA=20/1-10/1) to give methyl 2-(4-bromophenyl)-2-(5(dimethoxymethyl )-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)acetate (150 mg, 62% yield) as a white solid. LC-MS: m/z 479, 481 [M+H] ⁺ .

Step B: methyl 2-(4-bromophenyl)-2-(5-formyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)acetate

To a solution of methyl 2-(4-bromophenyl)-2-(5-(dimethoxymethyl)-2-(2,2,2-trifluoroethoxy)pyrimidin-4yl)acetate (120 mg, 0.25 mmol, 1.0 eq. .) in acetone (1.5 ml) and H ₂ O (1.5 ml) was added p-TSA (10 mg, 0.075 mmol, 0.3 eq.). The resulting mixture was stirred at 70°C for 1 h. Then, the reaction mixture was extracted with EtOAc (5 ml x 3), dried over anhydrous Na2SO4 and concentrated to give 2-(4-bromophenyl)-2-(5-formyl-2-(2 ,2,2-trifluoroethoxy)pyrimidin-4-yl)acetate (86 mg, crude) as a white solid. LC-MS: m/z 433, 435 [M+H] ⁺ .

Step C: 8-(4-bromophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one

To a solution of 2-(4-bromophenyl)-2-(5-formyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)acetate (86 mg, 0.20 mmol, 1.0 eq.) in AcOH (1 ml) and toluene (1 ml) was added NH ₄ OAc (512 mg, 6.4 mmol, 320 eq.). The resulting mixture was stirred at 100°C for 1.5 h, and then extinguished the reaction mixture by adding NaHCO ₃ (aq.). The reaction mixture was extracted with EtOAc (5 ml x 3), dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting crude product was purified by silica gel chromatography to give 8-(4-bromophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one (60 mg, yield 75%) as a brown solid. LC-MS: m/z 400, 402 [M+H]+.

Step D: 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin7(6H)-one

To a solution of 8-(4-bromophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one (60 mg, 0.15 mmol, 1.0 eq. .) in DCM (3 ml) was added (4-methoxyphenyl)boronic acid (32 mg, 0.3 mmol, 2.0 eq.), Cu(OAc) ₂ (54 mg, 0.3 mmol, 2.0 eq. .) and pyridine (48 mg, 0.6 mmol, 4.0 eq.). Then, the mixture was stirred at 40° C. under O2 (1 atm) overnight. The crude mixture was concentrated under reduced pressure to give a brown oil and then the resulting residue was purified by reverse phase preparative HPLC to give 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-(2,2,2- 124 041815 trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 261).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.22 (s, 1H), 9.19 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7, 57 (d, J=8.4 Hz,

2H), 7.52 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 4.95 (q, J=8.8 Hz, 2H) , 3.84 (s, 3H). LC-MS: m/z 506,

508 [M+H]+.

Preparation of 8-(4-chlorophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6Н)-one (4b) hN ι Ζ - 'n t1 ’ r I.

C4b

8-(4-Chlorophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one (4b) was synthesized from methyl-2-(4-chlorophenyl)- 2-(5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin-4-yl)acetate by General Procedure VI (Steps A-C) LC-MS: m/z 356 [M+H] ⁺ .

Example 262 Preparation of 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H )-she ~nL J o

Cl

The title compound was synthesized from intermediate 4b and 2-methyl-2Nindazol-5-ylboronic acid by general procedure VI (step D) (Cu(OAc)2, pyridine, O ₂ atmosphere, DCM, 40° C.).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.28 (s, 1H), 9.23 (s, 1H), 8.54 (s, 1H), 7.96 (d, J=2 .0 Hz, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.38 (dd, J=9.2 Hz, 2.0 Hz, 1H), 4.95 (kv, J=9.2 Hz, 2H), 4.23 (s, 3H) . LC-MS: m/z 486 [M+H] ⁺ .

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one (4с)

-Ί - Ί

L ¹ ·* Ch..,· I |·'- ••L'T: IX·

W t J.'j "..V G-G J ^L - V

8-(4-(Difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6Н)-one (4с) was synthesized from methyl-2-(4- (difluoromethoxy)phenyl)-2-(5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin4-yl)acetate by General Procedure VI (Steps A-C). LC-MS: m/z 388 [M+H] ⁺ .

Example 263 Preparation of 8-(4-(difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2(2,2,2-trifluoroethoxy)pyrido[4,3 -d]pyrimidin-7(6Н)-one ' d .1 ζ ~

O’ TG Ό TRz

About psn ^₽ ·

The title compound was synthesized from intermediate 4c and 1-methyl-1Hbenzo[d]imidazol-6-ylboronic acid using General Method VI (Step D) (Cu(OAc)2, pyridine, O2 atmosphere, DCM, 40°C) .

¹ H-NMR (400 MHz, DMSO-d6) δ: 9.26 (s, 1H), 9.24 (s, 1H), 8.37 (s, 1H), 7.91 (d, J=2 .0 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.40 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.29 (t, Jhf=74.2 Hz, 1H), 7.19 (d, J=8.8 Hz, 2H), 4.96 (kv, J= 7.2 Hz, 2H), 3.88 (s, 3H). LC-MS: m/z 518 [M+H] ⁺ .

Example 264 8-(4-(difluoromethoxy)phenyl)-6-(quinolin-6-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3d]pyrimidin-7(6H)-one

- 125 041815

The title compound was synthesized from intermediate 4c and quinolin-6ylboronic acid by general procedure VI (step D) (Cu(OAc)2, pyridine, O2 atmosphere,

DCM, 40°C).

¹ H-NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.29 (s, 1H), 9.09 (dd, J=4.2, 1.7 Hz, 1H ), 8.55 (d, J=8.3 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.24 (d, J=9.0 Hz, 1H), 8.02 (dd, J=9.0 Hz, 2.4 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.72 (dd, J=8.3 Hz, 4.2 Hz, 1H), 7.34 (t, J _no =74.2 Hz, 1H), 7.23 (d, J=8.8 Hz, 2H), 5.01 (q, J=8 .9 Hz, 2H). LCMS: m/z 515 [M+H]+.

Example 265 8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(2,2,2trifluoroethoxy)pyrido[4,3-d]pyrimidine-7 (6Н)-he */ n-r.-if-Gu | !

.A A e

O' 'About CFj

CCHF

The title compound was synthesized from intermediate 4c and 2-methyl-2Nindazol-5-ylboronic acid by general procedure VI (step D) (Cu(OAc)2, pyridine, O ₂ atmosphere, DCM, 40° C.).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.26 (s, 1H), 9.23 (s, 1H), 8.54 (s, 1H), 7.96 (d, J=2 .0 Hz, 1H), 7.757.70 (m, 3H), 7.38 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.29 (t, Jhf=74.4 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 4.96 (q, J=9.0 Hz, 2H), 4.23 (s, 3H). LC-MS: m/z 518 [M+H] ⁺ .

Example 266 6-(1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-(2,2,2trifluoroethoxy)pyrido[4,3-d]pyrimidine-7 (6H)-he ' And 1 .

cX ''A'AF''' 'sdt-r·

OCH The title compound was synthesized from intermediate 4c and 1-((2(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-ylboronic acid via General Method VI (Step D) (Cu(OAc) ₂ , pyridine, O ₂ atmosphere, DCM, 40° C.), followed by deprotection with TFA by general procedure I (step F).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.26 (s, 1H), 9.23 (s, 1H), 8.45 (broad s, 1H), 8.38 (s, 1H), 7.85 (br s, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.37 (br s, 1H), 7.29 (t, Jhf=74 .0 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 4.96 (q, J=9.2 Hz, 2H). LC-MS: m/z 504 [M+H] ⁺ .

Preparation of 8-(4-cyclopropylphenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6Н)-one (4d)

8-(4-Cyclopropylphenyl)-2-(2,2,2-trifluoroethoxy)-pyrido[4,3-d]pyrimidin-7(6Н)-one (4d) was synthesized from methyl-2-(4-cyclopropylphenyl) -2-(5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin-4yl)acetate by General Procedure VI (Steps A-C). LC-MS: m/z 362 [M+H] ⁺ .

Example 267 Preparation of 8-(4-cyclopropylphenyl)-6-(quinolin-6-yl)-2-(2,2,2 trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one

- 126 041815

The title compound was synthesized from intermediate 4d and quinolin-6ylboronic acid by general procedure VI (step D) (Cu(OAc)2, pyridine, O2 atmosphere, DCM, 40°C).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.31 (s, 1H), 9.23 (s, 1H), 9.04 (dd, J=4.4 Hz, 1.6 Hz , 1H), 8.49 (d, J=7.2 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H ), 7.97 (d, J=9.0 Hz, 2.4 Hz, 1H), 7.66 (dd, J=8.4 Hz, 4.4 Hz, 1H), 7.56 (d, J=8.4Hz, 2H), 7.09(d, J=8.4Hz, 2H), 4.97(q, J=9.2Hz, 2H), 1.99-1.90( m, 1H), 1.010.93 (m, 2H), 0.73-0.67 (m, 2H). LC-MS: m/z 489 [M+H]+.

Preparation of 2-(2,2,2-trifluoroethoxy)-8-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3yl)phenyl)pyrido [4 ,3-d] pyrimidin-7(6Н)-one (4е) || [''

1Г* j” Ά' 'L and >

^#1 D/ 4e

2-(2,2,2-Trifluoroethoxy)-8-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3yl)phenyl)pyrido[4, 3-d]pyrimidin-7(6Н)-one (4е) was synthesized from methyl-2-(5-(dimethoxymethyl)-2(methylsulfonyl)pyrimidin-4-yl)-2-(4-(1-((2 -(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3yl)phenyl)acetate by general procedure VI (steps A-C). LC-MS: m/z 519 [M+H] ⁺

Example 268: Preparation of 8-(4-(1H-1,2,4-triazol-3-yl)phenyl)-6-(quinolin-6-yl)-2-(2,2,2trifluoroethoxy)pyrido [4, 3-d] pyrimidin-7(6Н)-one

N . at '

I: . Ί

ΠN

The title compound was synthesized from intermediate 4e and quinolin-6ylboronic acid by general procedure VI (step D) (Cu(OAc) ₂ , pyridine, O ₂ atmosphere, DCM, 40° C.), followed by TFA deprotection by general procedure I (stage F).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 14.20 (broad s, 1H), 9.38 (s, 1H), 9.27 (s, 1H), 9.05 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.51 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 8.31 (d, J=2, 0 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.05 (d, J=8.4 Hz, 2H), 8.00 (dd, J=9.2 Hz , 2.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.68 (dd, J=8.4 Hz, 4.0 Hz, 1H), 4.99 ( kv, J=8.8 Hz, 2H). LC-MS: m/z 516 [M+H] ⁺ .

Preparation of 8-(4-chlorophenyl)-2-ethoxypyrido[4,3-d]pyrimidin-7(6Н)-one (4f)

J J ,

O'' V' Ό' d

Cl

8-(4-Chlorophenyl)-2-ethoxypyrido[4,3-d]pyrimidin-7(6Н)-one (4f) was synthesized from methyl-2-(4chlorophenyl)-2-(5-(dimethoxymethyl)-2- (methylsulfonyl)pyrimidin-4-yl)acetate and EtOH by general procedure VI (steps A-C). LC-MS: m/z 302 [M+H] ⁺ .

Preparation of 8-(4-chlorophenyl)-2-ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrido[4,3d]pyrimidin-7(6H)-one (Example 269)

- 127 041815

The title compound was synthesized from intermediate 4f and 1-methyl-Nibenzo[d]imidazol-6-ylboronic acid by general procedure VI (step D) (Cu(OAc) ₂ , pyridine, O ₂ atmosphere, DCM, 40°C ).

'H-NMR (400 MHz, DMSO-d6) δ: 9.17 (s, 2H), 8.36 (s, 1H), 7.89 (d, J=2.0 Hz, 1H), 7, 81 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.38 ( dd, J=8.4Hz, 2.4Hz, 1H), 4.30(q, J=7.2Hz, 2H), 3.88(s, 3H), 1.31(t, J= 7.2 Hz, 3H). LC-MS: m/z 432 [M+H]+.

Example 270 8-(4-chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pyrido[4,3-d]pyrimidin7(6H)-one

The title compound was synthesized from intermediate 4f and 2-methyl-2Nindazol-5-ylboronic acid by general procedure VI (step D) (Cu(OAc)2, pyridine, O ₂ atmosphere, DCM, 40° C.).

'H-NMR (400 MHz, DMSO-d6) δ: 9.17 (s, 1H), 9.15 (s, 1H), 8.53 (s, 1H), 7.94 (d, J=2 .0 Hz, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.36 (dd, J=9.2 Hz, 2.0 Hz, 1H), 4.29 (kv, J=7.2 Hz, 2H), 4.23 (s, 3H) , 1.30 (t, J=7.2 Hz, 3H). LC-MS: m/z 432 [M+H]+.

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[4,3-d]pyrimidin-7(6Н)-one (4g)

8-(4-(Difluoromethoxy)phenyl)-2-ethoxypyrido[4,3-d]pyrimidin-7(6Н)-one (4g) was synthesized from methyl-2-(4-(difluoromethoxy)phenyl)-2-( 5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin-4-yl)acetate and EtOH by general procedure VI (steps A-C). LC-MS: m/z 334 [M+H] ⁺ .

Example 271 Preparation of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(quinolin-6-yl)pyrido[4,3d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate 4g and quinolin-6ylboronic acid by general procedure VI (step D) (Cu(OAc)2, pyridine atmosphere, O2, DCM, 40°C).

'H-NMR (400 MHz, DMSO-d6) δ: 9.30 (s, 1H), 9.22 (s, 1H), 9.08 (dd, J=4.3 Hz, 1.6 Hz, 1H), 8.54 (d, J=8.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.23 (d, J=9.0 Hz, 1H) , 8.01 (dd, J=9.0 Hz, 2.4 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.71 (dd, J=8.8 Hz , 4.3 Hz, 1H), 7.34 (t, J _H F=74.4 Hz, 1H), 7.23 (d, J=8.8 Hz, 2H), 4.35 (q, J =7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H). LC-MS: m/z 461 [M+H]+.

Example 272 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pyrido[4,3d]pyrimidin-7(6H)-one

- 128 041815

The title compound was synthesized from intermediate 4g and 2-methyl-2Nindazol-5-ylboronic acid by general procedure VI (step D) (Cu(OAc)2, pyridine, O ₂ atmosphere, DCM, 40° C.).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.16 (s, 1H), 9.15 (s, 1H), 8.53 (s, 1H), 7.95 (d, J=2 .0 Hz, 1H), 7.757.70 (m, 3H), 7.36 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.29 (t, J _no =74.4 Hz , 1H), 7.17 (d, J=8.4 Hz, 2H), 4.30 (q, J=7.2 Hz, 2H), 4.23 (s, 3H), 1.31 (t , J=7.2 Hz, 3H). LC-MS: m/z 464 [M+H]+.

Preparation of 2-cyclopropoxy-8-(4-(difluoromethoxy)phenyl)pyrido[4,3-d]pyrimidin-7(6H)-one (4h)

2-Cyclopropoxy-8-(4-(difluoromethoxy)phenyl)pyrido[4,3-d]pyrimidin-7(6H)-one (4h) was synthesized from methyl-2-(4-(difluoromethoxy)phenyl)-2- (5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin-4yl)acetate and cyclopropanol by general procedure VI (steps A-C). LC-MS: m/z 346 [M+H] ^- .

Example 273 Preparation of 2-cyclopropoxy-8-(4-(difluoromethoxy)phenyl)-6-(quinolin-6yl)pyrido[4,3-d]pyrimidin-7(6H)-one

The title compound was synthesized from intermediate (4h) and quinolin-6ylboronic acid by general procedure VI (step D) (Cu(OAc)2, pyridine, O ₂ atmosphere, DCM, 40° C.).

1H-NMR (400 MHz, DMSO-d6) δ: 9.28 (s, 1H), 9.17 (s, 1H), 9.04 (dd, J=4.4 Hz, 1.6 Hz, 1H ), 8.49 (d, J=8.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.97 (dd, J=9.0 Hz, 2.4 Hz, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.67 (dd, J=8.4 Hz, 4.4 Hz, 1H), 7.28 (t, J _H F=74.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 2H), 4.28-4.19 ( m, 1H), 0.800.73 (m, 4H). LC-MS: m/z 473 [M+H] ⁺ .

Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethylthio)pyrido[4,3-d]pyrimidin-7(6H)one (4i)

I 1 Λ _Λ

Ο yw S''CF _a

G]

OCHFs

8-(4-(Difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethylthio)pyrido[4,3-d]pyrimidin-7(6Н)-one (4i) was synthesized from methyl-2-(4- (difluoromethoxy)phenyl)-2-(5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin4-yl)acetate and 2,2,2-trifluoroethanethiol by General Procedure VI (Steps A-C). LC-MS: m/z 404 [M+H] ^- .

Example 274 Preparation of 8-(4-(difluoromethoxy)phenyl)-6-(quinolin-6-yl)-2-(2,2,2trifluoroethylthio)pyrido[4,3-d]pyrimidin-7(6H)-one

L-k ] I] . .

^x< '''< ., 'fk-'-J h

CCHF

- 129 041815

The title compound was synthesized from intermediate 4i and quinolin-6ylboronic acid by general procedure VI (step D) (Cu(OAc)2, pyridine, O2 atmosphere,

DCM, 40°C).

1H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.36 (s, 1H), 9.12 (s, 1H), 9.08 (dd, J=4.3 Hz, 1.6 Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.22 (d, J=9.0 Hz, 1H) , 8.01 (dd, J=9.0 Hz, 2.4 Hz, 1H), 7.71 (dd, J=8.4 Hz, 4.3 Hz, 1H), 7.68 (d, J =8.8Hz, 2H), 7.29(t, Jhf=74.0Hz, 1H), 7.19(d, J=8.8Hz, 2H), 4.11(kv, J=10 .4 Hz, 2H). LC-MS: m/z 531 [M+H]+.

Example 135-A: 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-((methylsulfonyl)methyl)-1,6naphthyridin-7(6H)-one

Step A. methyl-2-(8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-7-oxo-6,7-dihydro-1,6naphthyridin-2-yl) -2-(methylsulfonyl)acetate.

To a solution of 2-chloro-8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one (200 mg, 0.47 mmol , 1.0 eq., synthesized in example 209) in DMSO (3.0 ml) at room temperature was added Cs ₂ CO ₃ (308 mg, 0.95 mmol, 2.0 eq.) and methyl-2-(methylsulfonyl )acetate (144 mg, 0.95 mmol, 2.0 eq.) The reaction mixture was stirred at 100°C for 14 h. The resulting mixture was poured into ice water, the reaction mixture was extracted with EtOAc (20 ml x 3), combined organic the layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give methyl 2-(8-(4chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-7-oxo-6,7-dihydro-1,6 -naphthyridin-2-yl)-2(methylsulfonyl)acetate (70 mg, 23% yield) as a yellow solid. LC-MS (ESI): m/z 537 [M+H] ⁺ .

Step B. 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-((methylsulfonyl)methyl)-1,6naphthyridin-7(6H)-one (135-A ).

To a solution of methyl-2-(8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-7-oxo-6,7-dihydro-1,6naphthyridin-2-yl)- 2-(methylsulfonyl)acetate (30 mg, 0.05 mmol, 1.0 equiv.) in THF (3 ml) at room temperature was added 6N aq. HCl (1 ml). The reaction mixture was stirred at 100°C for 14 hours. The reaction mixture was extracted with EtOAc (20 ml x 3), the combined organic layers were washed with brine (20 ml), dried over Na2SO4 and concentrated under reduced pressure, the residue was purified by reverse phase preparative HPLC to give 8-(4-chlorophenyl)-6-(2methyl-2H-indazol-5-yl)-2-((methylsulfonyl)methyl)-1,6-naphthyridin-7(6H)-one.

1H-NMR (400 MHz, DMSO-d ₆ ) (tautomer ratio 5:2) δ (ppm): 9.04 (s, 1H), 8.56 (d, J=8.1 Hz, 0 .4H), 8.52 (s, 1H), 8.42 (s, 0.4H), 8.15 (d, J=8.6 Hz, 1H), 7.94 (d, J=2, 0 Hz, 1H), 7.75 (d, J=8.1 Hz, 0.4H), 7.72 (d, J=9.1 Hz, 1H), 7.66 (d, J=8, 9 Hz, 0.4H), 7.60 (d, J=8.6 Hz, 2H), 7.50 (d, J=8.7 Hz, 0.8H), 7.40 (m, 3H) , 7.08 (d, J=8.7 Hz, 1H), 4.77 (s, 0.8H), 4.66 (s, 2H), 4.23 (s, 3H), 4.20 ( s, 1.2H), 3.01 (s, 3H), 2.84 (s, 1.2H). LC-MS (ESI): m/z 479 [M+H] ⁺ .

Example 136-A: Preparation of 8-(4-chlorophenyl)-2-(methoxymethyl)-6-(2-methyl-2H-indazol-5-yl)-1,6naphthyridin-7(6H)-one

Step A: 8-(4-chlorophenyl)-2-(methoxymethyl)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)one.

2-Chloro-8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one solution (100 mg, 0.24 mmol, 1.0 eq., synthesized in example 209), tributyl(methoxymethyl)stannane (159 mg, 0.48 mmol, 2.0 eq.) and Pd(PPh ₃ ) ₄ (24 mg, 0.024 mmol, 0.1 eq. .) in dioxane (5 ml) was stirred at 50°C for 14 h under N ₂ atmosphere. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give 8-(4-chlorophenyl)-2-(methoxymethyl)-6-(2-methyl-2H-indazol-5-yl)-1,6naphthyridin-7(6H)-one (136-A). LC-MS (ESi): m/z 431 [M+H] ⁺ .

Example 137-A: preparation of 2-ethoxy-8-(6-(fluoromethyl)pyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)- 130 041815

1,6-naphthyridine-7(6H)-one

Step A: 2-ethoxy-8-(6-(fluoromethyl)pyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyride in7(6H)-one.

To a solution of 2-ethoxy-8-(6-(hydroxymethyl)pyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)-1,6naphthyridin-7(6H)-one (synthesized from 8-bromo-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-1,6naphthyridin-7(6H)-one (synthesized in Example 215) and (6-(hydroxymethyl)pyridine-3 -yl)boronic acid by general procedure V (step M)) (150 mg, 0.35 mmol, 1.0 eq.) in DCM (4 ml) at 0° C. under N ₂ was added DAST (161 mg, 0 .70 mmol, 2.0 eq.). The resulting mixture was stirred at 0°C for an additional 1 h, after which the reaction mixture was quenched by adding ice water (3 ml). The resulting mixture was extracted with EtOAc (10 ml x 3), the combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give 2-ethoxy-8-(6(fluoromethyl)pyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridine- 7(6H)-one (137-A).

1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.86 (d, J=2.1 Hz, 1H), 8.81 (s, 1H), 8.51 (s, 1H ), 8.15 (dd, J=8.0, 2.1 Hz, 1H), 8.01 (d, J=9.1 Hz, 1H), 7.92 (dd, J=2.1, 0.8 Hz, 1H), 7.72 (dt, J=9.1, 0.9 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.36 (dd, J=9.1, 2.1 Hz, 1H), 6.58 (d, J=9.0 Hz, 1H), 5.50 (d, Jhf=47.2 Hz, 2H), 4.27 ( q, J=7.2 Hz, 2H), 4.23 (s, 3H), 1.28 (t, J=7.1 Hz, 3H). LC-MS (ESI): m/z 431 [M+H]+.

Example 138-A Preparation of 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(3,3,3-trifluoropropyl)1,6-naphthyridine-7(6H )-she

Step A: (3,3,3-trifluoropropyl)magnesium bromide.

Magnesium turnings (136 mg, 5.65 mmol, 1.0 eq.) were suspended in anhydrous THF (4 ml) and then 3-bromo-1,1,1-trifluoropropane (1.0 g , 5.65 mmol, 1.0 eq.). The flask was gently heated using a heat gun until gas formation was observed on the surface of the magnesium chips. The resulting mixture was stirred at 70° C. for an additional 1 hour and then the flask was allowed to cool to room temperature, resulting in a pale gray solution. The crude Grignard was used in the next step without any further purification or separation.

Step B: 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(3,3,3-trifluoropropyl)-1,6-naphthyridin7(6H)-one.

To a solution of 2-chloro-8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one (100 mg, 0.24 mmol , 1.0 eq., synthesized in example 209) and Fe(acac) ₃ (85 mg, 0.24 mmol, 1.0 eq.) in a mixture of THF/NMP (4.4 ml, 10/1, vol. /v) at room temperature was added dropwise a crude solution of (3,3,3-trifluoropropyl)magnesium bromide (2 ml, 2.4 mmol, 10 eq). The resulting mixture was stirred at room temperature for 14 h, and then extinguished the reaction mixture by adding NH ₄ Cl (sat. aq.) (5 ml) at 0°C. The mixture was extracted with EtOAc (10 ml x 3), the combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to give 7(6H)-one (138-A).

1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.94 (s, 1H), 8.51 (s, 1H), 8.04 (d, J=8.7 Hz, 1H ), 7.93 (dd, J=2.1, 0.8 Hz, 1H), 7.72 (dt, J=9.0, 0.9 Hz, 1H), 7.67-7.60 ( m, 2H), 7.41 (d, J=8.6 Hz, 2H), 7.37 (dd, J=9.1, 2.0 Hz, 1H), 7.00 (d, J=8 .7 Hz, 1H), 4.23 (s, 3H), 3.03 (t, J=7.6 Hz, 2H), 2.77-2.60 (m, 2H). LC-MS (ESI): m/z 483 [M+H] ⁺ .

- 131 041815

General Method VII

Compounds of structure 10.11 were prepared according to the general procedure VII. Substituted pyridine 10.1 was treated with NBS to give bromopyridine 10.2, reacted with NaOMe to give methoxypyridine 10.3, and then reduced to give diaminopyridine 10.4. 10.4 was reacted with ethyl bromoacetate to give compound 10.5 and then treated with base to give bicyclic structure 10.6. After treatment with POCl ₃ to give compound 10.7 and demethylation to give compound 10.8, the desired R groups can be introduced. The desired R1 group is introduced via a nucleophilic aromatic substitution reaction to give compounds of structure 10.9. The desired R ₃ group is introduced via copper-mediated Chan-Lam coupling to give compounds of structure 10.10. The desired R ₂ group is introduced via palladium-mediated Suzuki coupling to give final compounds of structure 10.11.

Example 139-A Preparation of 139-A by General Procedure VII

Step A: 3-bromo-2-chloro-5-nitropyridine-4-amine.

NBS (6.16 g, 34.6 mmol , 1.2 eq.). After stirring at room temperature for 4 hours, most of the solvent was removed under reduced pressure, the residue was suspended in cold water (30 ml), the solid was filtered and dried under reduced pressure to give 3-bromo-2-chloro-5- nitropyridine-4-amine (6.2 g, 85% yield) as an off-white solid. LC-MS (ESI): m/z 252, 254 [M+H]+.

Stage B: 3-bromo-2-methoxy-5-nitropyridine-4-amine.

A solution of NaOMe (freshly prepared from Na (658 mg , 28.6 mmol, 1.2 eq.) in 5 ml anhydrous MeOH). The reaction mixture was heated at reflux for 12 hours. The methanol was removed under reduced pressure, the residue was suspended in cold water (50 ml), the resulting precipitate was filtered, washed with ice water and dried under vacuum to give 3-bromo-2-methoxy - 132 041815

5-nitropyridine-4-amine (5.8 g, 98% yield) as an off-white solid. LC-MS (ESI):

m/z 248, 250 [M+H]+.

Step C: 5-bromo-6-methoxypyridine-3,4-diamine.

To a solution of 3-bromo-2-methoxy-5-nitropyridine-4-amine (5.8 g, 23.3 mmol, 1.0 eq.) and NH4Cl (6.35 g, 116.5 mmol, 5.0 equiv.) in EtOH/H ₂ O (40 ml, 3/1, vol./vol.) was added powdered iron (5.22 g, 93.2 mmol, 4.0 equiv.), and the resulting mixture was heated to 80 °C for 4 h. The mixture was allowed to cool to room temperature, filtered through a thin layer of Celite® and extracted with EtOAc (30 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography to give 5-bromo-6-methoxypyridine 3,4-diamine (4.0 g, 79% yield) as brown solid, which was to be used as soon as possible in the next step. LC-MS (ESI): m/z 218, 220 [M+H] ⁺ .

Step D: ethyl-(4-amino-5-bromo-6-methoxypyridin-3-yl)glycinate.

To a mixture of 5-bromo-6-methoxypyridine-3,4-diamine (3.6 g, 16.4 mmol, 1.0 eq.) and TEA (2.5 ml, 18.0 mmol, 1.1 eq. ) in anhydrous toluene (30 ml) at 0°C was added dropwise ethyl-2-bromoacetate (3.0 g, 18.0 mmol, 1.1 eq.). After the addition, the reaction mixture was allowed to warm to room temperature and stirred for an additional 4 h. Then, the reaction mixture was quenched by the addition of NH ₄ Cl (sat. aq.) (20 ml), the resulting mixture was extracted with EtOAc (30 ml x 3), combined the organic layers were dried over Na ₂ SO ₄ and then concentrated under reduced pressure to give a crude mixture (5.2 g, crude oil) which was used in the next step without further purification.

Step E: 8-bromo-7-methoxypyrido[3,4-b]pyrazin-2(1H)-one.

A mixture of ethyl (4-amino-5-bromo-6-methoxypyridin-3-yl)glycinate (5.2 g) and DBU (2.74 g, 18.0 mmol, 1.1 eq.) in toluene (20 ml) was heated under reflux for 14 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel flash chromatography to give 8-bromo-7-methoxypyrido[3,4-b]pyrazin-2(1H)-one (2.1 g, 50% overall yield after two steps) as an off-white solid. LC-MS (ESI): m/z 256, 258 [M+H] ⁺ .

Step F: 8-bromo-2-chloro-7-methoxypyrido[3,4-b]pyrazine.

To a solution of 8-bromo-7-methoxy-1H,2H-pyrido[3,4-b]pyrazin-2-one (1.5 g, 5.85 mmol, 1.0 eq.) in toluene/DCE (40 ml, 1/1, v/v) was added POC13 (2.70 g, 17.6 mmol, 3.0 eq.), and the reaction mixture was stirred at 90°C for 15 h. Then, the reaction mixture was concentrated under reduced pressure, the residue was diluted with ice water (50 ml), basified to pH=7-8 with Na ₂ CO ₃ (sat. aq.) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel flash chromatography to give 8-bromo-2-chloro-7-methoxypyrido[3,4b]pyrazine (1 g, 3.64 mmol, 62%) as a pale yellow oil. LC-MS (ESI): m/z 274, 276 [M+H] ⁺ .

Step G: 8-bromo-2-chloropyrido[3,4-b]pyrazin-7-ol.

Anhydrous AlCl ₃ (0.73 g, 5.46 mmol, 1.5 eq.), and the reaction mixture was stirred at 70°C for 2 h. The reaction mixture was cooled to 0°C, quenched with ice water (50 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography to give 8-bromo-2-chloropyrido[3,4-b]pyrazine -7-ol (700 mg, 74% yield) as a pale yellow solid. LC-MS (ESI): m/z 260, 262 [M+H] ⁺ .

Step H: 8-bromo-2-(2,2-difluoroethoxy)pyrido[3,4-b]pyrazin-7-ol.

Cs2CO3 (978 mg, 3.0 mmol, 2.0 eq.), and the reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was cooled to 0°C, quenched with ice water (30 ml), adjusted to pH =6 by adding dilute HCl (1N, aq.) and was extracted with DCM (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography to give 8-bromo-2-(2,2-difluoroethoxy)pyrido[ 3,4-b]pyrazin-7-ol (30 mg, 7%) as a pale yellow solid. LC-MS (ESI): m/z 306, 308 [M+H] ⁺ .

Step I: 8-bromo-2-(2,2-difluoroethoxy)-6-(2-methyl-2H-indazol-5-yl)pyrido[3,4-b]pyrazin-7(6H)-one.

A mixture of 8-bromo-2-(2,2-difluoroethoxy)pyrido[3,4-b]pyrazin-7-ol (30 mg, 0.1 mmol), (2-methyl-2Nindazol-5-yl)boronic acid (35 mg, 0.2 mmol), Cu(OAc) ₂ (29 mg, 0.15 mmol, 1.5 eq.), pyridine (24 μl, 0.3 mmol, 0.3 eq.) and TEA ( 42 μl, 0.3 mmol, 0.3 eq.) in DCM (0.5 ml) was stirred under O ₂ atmosphere at 40°C for 15 h. The reaction mixture was diluted with H ₂ O (5 ml) and extracted with DCM ( 5 ml x 3). The combined organic layers were washed with brine (5 ml), dried over Na ₂ SO ₄ and the residue was purified by silica gel flash chromatography to give 8-bromo-2-(2,2-difluoroethoxy)-6-(2methyl-2H- indazol-5-yl)pyrido[3,4-b]pyrazin-7(6H)-one (20 mg, 46%) as a yellow solid. LC-MS (ESI): m/z 436, 438 [M+H] ⁺ .

- 133 041815

Step J: 2-(2,2-difluoroethoxy)-8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5yl)pyrido[3,4-b]pyrazine-7(6H )-He.

A mixture of 8-bromo-2-(2,2-difluoroethoxy)-6-(2-methyl-2H-indazol-5-yl)pyrido[3,4-b]pyrazin-7(6H)-one (20 mg, 0.046 mmol, 1.0 eq.), (4-(difluoromethoxy)phenyl)boronic acid (17 mg, 0.092 mmol, 2.0 eq.), Pd(dppf)Cl ₂ (6.8 mg, 0.009 mmol, 0 ,2 eq.) and Cs ₂ CO ₃ (50 mg, 0.138 mmol, 3.0 eq.) in dioxane/H ₂ O (0.5 ml, 9/1, v/v) was stirred at 100° C under N2 for 15 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC to give 2-(2,2-difluoroethoxy)-8-(4-(difluoromethoxy)phenyl)-6-( 2methyl-2H-indazol-5-yl)pyrido[3,4-b]pyrazin-7 (6H)-one (13 9-A).

1H-NMR (400 MHz, DMSO-d6) δ: 8.85 (s, 1H), 8.51 (s, 1H), 8.26 (s, 1H), 7.93 (d, J=1, 2Hz, 1H), 7.737.67(m, 3H), 7.35(dd, J=9.2Hz, 2.0Hz, 1H), 7.29(t, Jhf=V4.2Hz, 1H ), 7.18 (d, J=8.8 Hz, 2H), 6.41 (tt, Jhf=54.2 Hz, J=3.2 Hz, 1H), 4.57 (td, Jhf=14 .8 Hz, J=3.2 Hz, 2H), 4.23 (s, 3H). LC-MS (ESI): m/z 500 [M+H]+.

The procedure presented above for General Procedure VII was used to synthesize the following compounds using the appropriate starting materials: ____________________

Example Structure Characterization 140-A ./' ν H s 2-ethoxy-8-(4-methoxyphenyl)-6-(2- methyl-2Н-indazol- 5 - yl)pyrido[3,4-b]pyrazin-7(6H)-one LC-MS (ESI): m/z 428 [M+H]+. 'H-NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (s, 1H), 8.50 (s, 1H), 8.11 (s, 1H), 7.91 (d, >2, 0 Hz, 1H), 7.70 (d, >9.1 Hz, 1H), 7.607.54 (m, 2H), 7.34 (dd, >9.1, 2.1 Hz, 1H), 6 .94 (d, J=8.8 Hz, 2H), 4.32 (q, >7.1 Hz, 2H), 4.23 (s, ZN), 3.79 (s, ZN), 1, 33 (t, >7.0 Hz, ZN). IGA D ... g+, A Ί L - . and j h _ y ψ 2-(2,2-difluoroethoxy)-8-(4methoxyphenyl)-6-(2-methyl-2Nindazol-5-yl)pyrido[3,4- b]pyrazin-7(6H)-one LC-MS (ESI): m/z 464 [M+H]+. 'H-NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (s, 1H), 8.50 (s, 1H), 8.23 (s, 1H), 7.92 (d, >2, 1 Hz, 1H), 7.70 (d, >9.0 Hz, 1H), 7.58 (d, >8.8 Hz, 2H), 7.34 (dd, >9.1, 2.0 Hz, 1H), 6.94 (d, >8.9 Hz, 2H), 6.41 (tg, Jhf=54.3, >3.3 Hz, 1H), 4.57 (td, J _HF = 15.1, >3.3 Hz, 2H), 4.23 (s, ZN), 3.79 (s, ZN). 142-A L 1 _ Ύ '4" 's C-ι d 8-(4-chlorophenyl)-2-ethoxy-6- (quinolin-6-yl)pyrido[3,4- b]pyrazin-7(6H)-one LC-MS (ESI): m/z 429 [M+H]+. 'H-NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (dd, >4.2, 1.7 Hz, 1H), 8.94 (s, 1H), 8.49 (d, >8 .2 Hz, 1H), 8.27 (d, >2.4 Hz, 1H), 8.208.14 (m, 2H), 7.96 (dd, >9.0, 2.4 Hz, 1H), 7.72-7.62 (m, ZN), 7.49-7.40 (m, 2H), 4.33 (q, >7.0 Hz, 2H), 1.34 (t, >7, 1 Hz, ZN). 143-A w ^Ν -Π L ν - - N g ^Ν ₁ - 1 l p T n o f 1. 1 [1 2 > ha o F G 2-(2,2-difluoroethoxy)-6-(2-methyl- 2H -indazol-5-yl)-8-(6(trifluoromethoxy)pyridin-3 yl)pyrido[3,4-b]pyrazin-7(6H)-one LC-MS (ESI): m/z 519 [M+H]+. 'H-NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.64 (d, >2.3 Hz, 1H), 8.52 (s, 1H), 8.31 (s, 1H), 8.30 (dd, >8.6, 2.5 Hz, 1H), 7.96 (dd, >2.1, 0.8 Hz, 1H), 7.73 (dd, >9.1, 0.9 Hz, 1H), 7.38 (dd, >9.1, 2.1 Hz, 1H), 7.34 (d, >8.5 Hz, 1H), 6.42 (tg, Jhf=54.2, >3.3 Hz, 1H), 4.60 (td, _JHF =15.1, >3.3 Hz, 2H), 4.24 (s, 3H).

- 134 041815

144-A o A- A o ''' ^r A n F i ^T 2H-indazol-5-yl)pyrido[3,4-b]pyrazin-7(6H)-one LC-MS (ESI): m/z 501 [M+H]+. 'H-NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.56-8.49 (m, 2H), 8.29 (s, 1H), 8.19 (dd , J=8.6, 2.3 Hz, 1H), 7.94 (s, 1H), 7.72 (d, J=9.l Hz, 1H), 7.67 (t, J _H f= 73.1 Hz, 1H), 7.37 (dd, J=9.2, 2.0 Hz, 1H), 7.13 (d, 1-8.5 Hz, 1H), 6.42 (t, J _HF =54.2 Hz, 1H), 4.59 (td, J _hf =15.2, J=3.2 Hz, 2H), 4.23 (s, 3H). 145-A —Ν Ί ί X·· -X o-^· Άν A'···· ί , ^F / 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-methyl-2H-indazole -5 - yl)pyrido[3,4-b]pyrazin-7(6H)-one LC-MS (ESI): m/z 464 [M+H]+. 'H-NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (s, 1H), 8.50 (s, 1H), 8.14 (s, 1H), 7.92 (dd, J=2 .0, 0.8 Hz, 1H), 7.74-7.66 (m, ZN), 7.35 (dd, J=9.l, 2.1 Hz, 1H), 7.30 (t, J _HF =74.3 Hz, 1H), 7.18 (d, J=8.7 Hz, 2H), 4.32 (kv, J=7.0 Hz, 2H), 4.23 (s, ZN ), 1.33 (t, J=7.0 Hz, ZN). 146-A -% -Ι A,. v N w '^1 V' y and ά 8-(4-chlorophenyl)-2-(2,2- difluoroethoxy)-6-(2-methyl-2Nindazol-5-yl)pyrido[3,4- b]pyrazin-7(6H)-one LC-MS (ESI): m/z 468 [M+H]+. 'H-NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (s, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 7.94 (d, J=2 .0 Hz, 1H), 7.71 (d, J=9.1 Hz, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.36 (dd, J=9, l, 2.1 Hz, 1H), 6.42 (tg, J _HF =54.2, 1-3.2 Hz, 1H), 4, 58 (td, J _HF =15.2, J=3.2 Hz, 2H), 4.23 (s, 3N). 147-A N. _w T' ‘ 8-(4-chlorophenyl)-2-ethoxy-6-(2- methyl-2Н-indazol- 5 - yl)pyrido[3,4-b]pyrazin-7(6H)-one LC-MS (ESI): m/z 432 [M+H]+. ^X H-NMR (400 MHz, chloroform-d) δ 8.38 (s, 1H), 7.99 (d, J=ll.4 Hz, 2H), 7.81 (d, J=9.1 Hz , 1H), 7.75 (d, J=l.9 Hz, 1H), 7.66 (d, J=8.5 Hz, 2H), 7.37 (dd, J=8.7, 1, 9 Hz, ZN), 4.37 (q, J=7.l Hz, 2H), 4.27 (s, ZN), 1.39 (t, J=7.l Hz, ZN).

- 135 041815

148-A Ί h 1 I Ί X Ϊ ^f 7(6Н)-one LC-MS (ESI): m/z 483 [M+H]+. 'H-NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (d, >0.5 Hz, 1H), 8.63 (d, >2.3 Hz, 1H), 8.52 (s, 1H), 8.29 (dd, >8.5, 2.4 Hz, 1H), 8.19 (s, 1H), 7.94 (dd, >2.1, 0.8 Hz, 1H), 7.72 (dt, >9.1, 0.9 Hz, 1H), 7.40-7.30 (m, 2H), 4.35 (kv, >7.0 Hz, 2H), 4.23 (s, ZN), 1.33 (t, >7.1 Hz, ZN). 149-A MX_N. 'L J If ‘9 F 8-(6-(difluoromethoxy)pyridin-3yl)-2-ethoxy-6-(2-methyl-2Н- indazol-5-yl)pyrido[3,4- b]pyrazin-7(6H)-one LC-MS (ESI): m/z 465 [M+H]+. 'H-NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (d, J=0.6 Hz, 1H), 8.54-8.48 (m, 2H), 8.22-8.14 (m, 2H), 7.93 (dd, >2.0, 0.8 Hz, 1H), 7.77 (t, J _hf =73.0 Hz, 1H), 7.71 (dt, >9 .2, 0.9 Hz, 1H), 7.36 (dd, >9.1, 2.0 Hz, 1H), 7.12 (dd, >8.6, 0.7 Hz, 1H), 4 .33 (q, >7.1 Hz, 2H), 4.23 (s, ZN), 1.33 (t, >7.1 Hz, ZN). 150-A A A 0 V hi 0 ABOUT 0.F 8-(4-(difluoromethoxy)phenyl)-2- ethoxy-6-(4- methoxyphenyl)pyrido[3,4- b]pyrazin-7(6H)-one LC-MS (ESI): m/z 440 [M+H]+. 'H-NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.13 (s, 1H), 7.67 (d, >8.6 Hz, 2H), 7.53 -7.45 (m, 2H), 7.39 (t, _JHF =73.5 Hz, 1H), 7.18 (d, >8.5 Hz, 2H), 7.10 (d, >8 .9 Hz, 2H), 4.30 (q, >7.0 Hz, 2H), 3.84 (s, ZN), 1.32 (t, >7.1 Hz, ZN).

Example 275 Biochemical analysis.

The MAT2A protein was expressed with recombinant baculovirus in infected SF9 cells using the Bac-to-Bac system cloned into the pFASTBACl vector (Invitrogen, Carlsbad, CA). Recombinant MAT2A was isolated from a cell lysate obtained from 150 g of infected cells by HP Ni Sepharose column chromatography. The recombinant MAT2A homodimer was eluted with 250 and 500 mM imidazole, the MAT2A containing fractions were identified by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and pooled.

To determine the inhibitory activity of the compounds against the MAT2A homodimer, the protein was diluted to 4 μg/ml with assay buffer (50 mM Tris, pH 8.0, 50 mM KCl, 15 mM MgCl ₂ , 0.3 mM EDTA, 0.005% [wt./ vol.] bovine serum albumin [BSA]). The test compound was prepared in 100% dimethyl sulfoxide (DMSO) at a concentration 50 times the final target concentration. To 40 μl of the diluted enzyme solution was added 1 μl of the diluted compound solution, and the mixture was left to equilibrate for 60 min at 25°C. The enzymatic assay method was initiated by adding 10 µl of the substrate mixture (500 µM ATP, pH 7.0, 400 µM Lmethionine in 1x assay buffer) and the mixture was incubated for an additional 60 min at 25°C. The reaction was stopped and the free phosphate released by the enzyme in stoichiometric amounts was measured by the production of S-adenosylmethionine (SAM) using the PiColorLock Gold kit (Innova Biosciences, UK). The absolute amounts of the product were determined by comparison with a standard curve for potassium phosphate buffer, pH 8.0.

The specific compounds disclosed herein were tested according to the assay method described above and found to inhibit MAT2A according to the following IC ₅₀ scores shown in Table 1 below. 4: (A) less than 100 nM, (B) 100 nM to 1 µM, and (C) 1 to 10 µM.

- 136 041815

Example 276 Cellular Target Binding Assay (SAM)

The measurement of MAT2A activity in cells was carried out by direct quantitative determination of the content of SAM as a product of enzyme activity. Cancer cells were treated with potential MAT2A inhibitors for an appropriate incubation period and then the cells were lysed using a reagent that quenched any subsequent enzymatic activity. Soluble metabolites, including SAM, were collected and the content of SAM in the lysate was measured using quantitative LC-MS/MS analysis.

A generic analysis was performed using the human colon carcinoma HCT116 cell line, which was genetically engineered to have the MTAP gene removed (commercially available from Horizon Discovery). This cell line was used because it was determined that the loss of the MTAP gene determines sensitivity to MAT2A inhibitors. Cells were seeded in 96-well plates at the appropriate cell density. After 24 hours, the cells were treated with a potential MAT2A inhibitor. Prior to addition to cells, the compound was first serially diluted with 100% DMSO, typically in a 3-fold serial dilution variant, starting at 500-fold maximum dose and giving a 10-point dose curve, including a DMSO-only control. Then, the compound was 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. Then, the specified initial working mass was added to the cells by additional 5-fold dilutions, adding 25 μl of the original working mass to 100 μl of cells in culture medium. After adding the compound, the cells were incubated at 37°C/5% CO ₂ for 72 h.

To quantify SAM content 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% water ( v/v) with 1 M final concentration of acetic acid using 200 ng/ml deuterated d3SAM as an internal control). 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/tandem mass spectrometry (LC-MS/MS). LC-MS/MS analysis was performed using an API6500 Mass Spectrometer (Sciex, Framingham, MA, USA) operating in positive ion sputtering mode and equipped with a Waters UPLC Acquity BEN Amide column (Waters, Milford, MA, USA). For SAM and standard with d3SAM, multiple reaction monitoring (MRM) data were obtained using MRM transitions of 399.2^250.1 amu. and 402.2^250.1 a.m.u. respectively. In a typical LC-MS/MS analysis, the initial flow rate was 0.5 ml/min 25% mobile phase A (acetonitrile/water=5/95 (v/v) with 1% formic acid and 10 mM ammonium acetate) and 75% mobile phase B (acetonitrile/water=95/5 (v/v) with 1% formic acid and 10 mM ammonium acetate): 0.2-0.5 min - 75%^35% mobile phase B , 25%^65% mobile phase A; 0.5 min - 65% mobile phase A and 35% mobile phase B; 1.0-1.1 min -35%^75% mobile phase B, 65%^25% mobile phase A; 1.1 min - 25% mobile phase A and 75% mobile phase B, for a total run time of 1.5 min.

The specific compounds disclosed herein were tested according to the assay method described above and found to inhibit SAM according to the following IC ₅₀ scores shown in Table 1 below. 4: (A) less than 100 nM (>60% of maximum inhibition), (B) 100 nM to 1 μM (>60% of maximum inhibition), and (NT) for no testing.

Example 277 Cell Proliferation Inhibition Assay.

The effect of a test compound on cancer cell growth was assessed by treating cancer cells with the compound for 4 days and then measuring proliferation by reading cell proliferation data based on ATP assay (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. After 24 hours, the cells were treated with a potential MAT2A inhibitor. Prior to addition to cells, the compound was first serially diluted with 100% DMSO, typically in a 3-fold serial dilution variant, starting at 500-fold maximum dose and giving a 10-point dose curve, including a DMSO-only control. Then, the compound was 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. Then, the specified initial working mass was added to the cells by additional 5-fold dilutions, adding 25 μl of the original working mass to 100 μl of cells in culture medium. After adding the compound, the cells were incubated at 37°C/5% CO ₂ for 4 days.

To measure inhibition of cell proliferation, cells were allowed to equilibrate to room temperature for 30 min and then treated with 125 μl of Cell Titer Glo reagent. Then,

- 137 041815 the plate was covered with aluminum foil and mixed by shaking for 15 minutes to ensure good mixing and complete cell lysis. Then, the luminescence signal was measured using a Veritas 1.9.2 luminometer plate using an ATP standard curve to confirm sample-to-sample reproducibility of the assay. The resulting luminescence measurement was converted to a proliferation index by subtracting from each measured value the ATP luminescence signal measured in the control well (no cells) and dividing by the ATP luminescence signal measured in the 0.2% DMSO control well, corrected for the signal in control well. Then, the activity of the compound was presented as the percent change in proliferation relative to the DMSO control, plotted against the log ₁₀ value of the compound concentration, expressed in moles/liter (M).

The specific compounds disclosed herein were tested according to the assay method described above and found to inhibit cell proliferation according to the following IC ₅₀ scores shown in Table 1 below. 4: (A) less than 100 nM (>30% inhibition of maximum for MTAP-/-; inhibition >10% of maximum for MTAP+/+), (B) 100 nM to 10 μM inhibition >30% of maximum for MTAR-/-; inhibition >10% of maximum for MTAP+/+), (C) greater than 10 μM, and (NT) for no testing.

Table 4

Connection No. Enzyme inhibition (Example 275) Inhibition of SAM in cells after 72 hours (MTAP-/-; Example 276) Relative growth inhibition after 4 days (MTAP-/-; Example 277) Relative growth inhibition after 4 days (MTAP+/+; Example 277) 101 IN NT NT NT 102 WITH NT NT NT 103 IN NT NT NT

- 138 041815

104 WITH NT NT NT 105 With NT NT NT 106 With NT NT NT 107 With NT NT NT 108 With NT NT NT 109 V NT NT NT 110 V NT NT NT 111 With NT NT NT 112 V NT NT NT 113 V NT NT NT 114 V NT NT NT 115 V NT NT NT 116 With NT NT NT 117 With NT NT NT 118 With NT NT NT 119 With NT NT NT 120 With NT NT NT 121 V NT NT NT 122 V NT NT NT 123 A A A IN 124 A A A c 125 A NT NT NT 126 WITH NT NT NT 127 A A A C 128 A NT NT NT 129 A IN IN C 130 A NT NT NT 131 A NT NT NT 132 A A A C 133 A A A c 134 A NT NT NT 135 A A A IN 136 IN NT NT NT 137 A IN IN c

- 139 041815

138 IN NT NT NT 139 A A IN C 140 IN NT NT NT 141 A A A C 142 IN NT NT NT 143 A IN IN C 144 A IN IN c 145 A A A c 146 IN NT NT NT 147 A IN IN c 148 A A A V 149 A NT NT NT 150 A A IN IN 151 A A A V 152 A A A With 153 A A A With 154 A NT NT NT 155 A IN IN IN 156 A A A With 157 A A IN With 158 A A A With 159 A A A V 160 A A A With 161 A A A With 162 A NT NT NT 163 WITH NT NT NT 164 A NT NT NT 165 A NT NT NT 166 A A A WITH 167 A IN IN With 168 A A A With 169 A A A With 170 A NT NT NT 171 A A A WITH

- 140 041815

172 A A A c 173 A NT NT NT 174 A NT NT NT 175 A NT NT NT 176 IN NT NT NT 177 A A IN C 178 A A IN IN 179 A IN V c 180 A A A c 181 A A IN c 182 A A V c 183 A IN IN c 184 A NT NT NT 185 C NT NT NT 186 IN NT NT NT 187 c NT NT NT 188 A A IN c 189 A A IN V 190 A NT NT NT 191 A NT NT NT 192 A A IN C 193 A IN IN c 194 IN NT NT NT 195 A A A c 196 A NT NT NT 197 IN NT NT NT 198 A IN IN C 199 C NT NT NT 200 A IN IN IN 201 IN NT NT NT 202 A IN IN C 203 A IN c c 204 IN NT NT NT 205 A A IN c

- 141 041815

206 A IN IN IN 207 IN NT NT NT 208 A NT NT NT 209 A A A WITH 210 A A A WITH 211 A A A With 212 A A A With 213 A A A With 214 A NT NT NT 215 A A A IN 216 A A A V 217 A A IN With 218 A A A V 219 A A A V 220 A A A V 221 A A IN With 222 A A IN With 223 A IN IN With 224 A IN With With 225 IN A V V 226 A A A V 227 A A A V 228 A A A V 229 A A A V 230 A A A V 231 A A IN With 232 A A A With 233 A A A With 234 A A A With 235 A A A With 236 A A A With 237 A A A With 238 A NT NT NT 239 A A A V

- 142 041815

240 A A A C 241 A A A IN 242 A A A G 243 A A A C 244 A A A IN 245 A A IN C 246 A IN IN IN 247 A A A IN 248 A A A IN 249 A A IN IN 250 A A A IN 251 A A A IN 252 A A IN V 253 A A A V 254 A A A With 255 A A A With 256 A A IN V 257 A A A V 258 A A IN V 259 A A A With 260 A A A With 261 A NT NT NT 262 A A IN With 263 A NT NT NT 264 A A IN IN 265 A A A With 266 IN NT NT NT 267 A NT NT NT 268 A IN IN WITH 269 A A IN With 270 A A A With 271 A NT NT NT 272 A A IN WITH 273 A NT NT NT

- 143 041815

274 A NT NT NT 101-A A A A C 102-A A A A IN 103-A A A A c 104-A A A IN V 105-A A A A V 106-A A A IN With 107-A A A A V 108-A A A A V 109-A A A A V 110-A A A A V 111-A A A A V 112-A A A A V 113-A A A A V 114-A A A A V 115-A A A A V 116-A A A A With 117-A A A A V 118-A A A A V 119-A A A A V 120-A A A A V 121-A A A IN V 122-A A A A V 123-A A A A V 124-A A A IN V 125-A A A A V 126-A A A A V 127-A A IN A V 128-A A A A V 129-A A A IN V 130-A A A A V 131-A A A IN V 13 2-A A A A V 133-A A A A V

- 144 041815

134-A A A A With 135-A IN NT NT NT 13 6-A A NT NT NT 13 7-A A A A IN 138-A A IN IN V 13 9-A A A A V 140-A A A A With 141-A A A A V 142-A A IN IN With 143-A A A A V 144-A A A IN V 145-A A A A V 146-A A A A V 147-A A A A With 148-A A A IN V 149-A A A IN V 150-A A A IN V

Additional compounds are presented below in table. 5 are characterized by greater than 10 μM enzyme inhibition (Example 275) or less than 50% inhibition at the maximum concentration.

Table 5

_ν Ν—ί \ G. - ϊ 1 Г·,'Г ‘ί μ id / d;4 1% .. - ¹ d No. I > / VV n - / and > vJ J. .L !L > ...j- - _N . .. _4? , ί n V k............../ Ί' ^! ' X

- 145 041815

- 146 041815

- 147 041815

- 148 041815

- 149 041815

v X-". T1,. “ I Ji X . -γ a '4---7 G h .. OK :?g 'x T Ν' (Ί > ABOUT At Ή Ό ... .... X1. 'THAT . . e - ;< n ’k to \ e ___/ g'-'X ί · / .AU _M X. to x _H ^- -f. ,1. . L. D 1 X A c>-;x; 'fj -r ^ν-τ οί-· χ zg ' J a-ψ \ a' t f M nU N—' ί \ V/ A h , f _ _ ^JC1 suuuu Chna N-J Μ— Η i >l .Λ ^ί; ^ύΠι η . 1 g ΎΆ ''TIT and-··' χ ^χ Ν ! .Η ^yXi . τ e y , . ο π < - / \ 'THAT . ,. ' ‘ 1 ϊ .. < _4π l 1- τ .. --x ^rr ' ^κ ' \/ С-Ί· '-Ν' υ^ ( ₍ ) η V ΗΟ OH Η η lz ΑΊ. T'T ^-'Τ. ''νΧ'-Ν ^ ^: · - ·~Ύ^·Ν „х .к Α ,· ^._ . 1. ί □ χ> ^χ Ν Ν '-n ( ' ^h Ύ Λ S ^Ν V '. / / \ neither he Q κ

- 150 041815

Claims (24)

1. Compound or pharmaceutically acceptable salt thereof according to formula (IA) where L is O, S, NR, or a bond; R represents H or C ₁ -C ₆ -alkyl; R ¹ is selected from the group consisting of C ₁ -C ₆ -alkyl and C ₃ -C ₆ -carbocyclyl, where any alkyl in R ¹ is straight or branched, and R ¹ is optionally substituted with 1-6 halogens; or if L is NR, then R and R ¹ in combination with L are 3-6 membered heterocycloalkyl, where 1-4 ring atoms are independently selected from N, O and S; R ² and R ³ are independently selected from the group consisting of C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, where 1-4 heteroaryl atoms are independently selected from N, O and S, and 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N, O and S, where R ² and R ³ are independently and optionally substituted with one or more substituents selected from the group consisting of R ^A , OR ^A and halogen; R ⁴ and R ⁵ are independently selected from the group consisting of H and C ₁ -C ₆ alkyl; R ^a is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C ₃ -C ₁₄ carbocyclyl, 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N , O and S, and 5-10 membered heteroaryl, where 1-4 heteroaryl atoms are independently selected from N, O and S; where each alkyl or alkoxy moiety in R ^A is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen and -S(Q) _o . ₂ -(C ₁ -C ₆ alkyl). 2. Compound or pharmaceutically acceptable salt thereof according to formula (IB) where L is O, S, NR, or a bond; R is H or C1- _C6 alkyl; R ¹ is selected from the group consisting of C 1 -C ₆ -alkyl and C ₃ -C ₆ -carbocyclyl, where any alkyl in R ¹ is straight or branched, and R ¹ is optionally substituted with 1-6 halogens; or if L is NR, then R and R ¹ in combination with L are 3-6 membered heterocycloalkyl, where 1-4 ring atoms are independently selected from N, O and S; R ² and R ³ are independently selected from the group consisting of C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, where 1-4 heteroaryl atoms are independently selected from N, O and S, and 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N, O and S, where R ² and R ³ are independently and optionally substituted with one or more substituents selected from the group consisting of R ^A , QR ^a , NR ^a R ^b and halogen; R ⁴ , R ⁵ and R ⁶ are independently selected from the group consisting of H and C1-C ₆ alkyl; R ^a and R ^B are independently selected from the group consisting of H, C1- _C6 alkyl, C1- _C6 alkoxy, -C3-C14 carbocyclyl, and 5-10 membered heteroaryl, wherein 1-4 heteroaryl atoms are independently selected from N , O and S; where each alkyl or alkoxy moiety in R ^A is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen and -S(Q) ₀ . ₂ -(C1- _C6 alkyl). 3. Compound or pharmaceutically acceptable salt thereof according to formula (II) where L is O, S, NR, or a bond; R represents H or C ₁ -C ₆ -alkyl; R ¹ is selected from the group consisting of C ₁ -C ₆ -alkyl and C ₃ -C ₆ -carbocyclyl, where any alkyl in R ¹ is straight or branched, and R ¹ is optionally substituted with 1-6 halogens; or if L is NR, then R and R ¹ in combination with L are 3-6 membered heterocycloalkyl, where 1-4 ring atoms are independently selected from N, O, and S, optionally substituted with one or more R ^A ; R ² and R ³ are independently selected from the group consisting of C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl, where 1-4 heteroaryl atoms are independently selected from N, O and S, and 3-14 membered heterocycloalkyl, where 1-4 heterocycloalkyl atoms are independently selected from N, O and S, where R ² and R ³ are independently and optionally substituted with one or more substituents selected from the group consisting of R ^A , OR ^A , halogen; both R ⁴ and R ⁶ are H; R ^a is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy; where each alkyl and alkoxy moiety in R ^A is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen. 4. A compound or a pharmaceutically acceptable salt thereof according to claims 1, 2, wherein at least one of R ⁴ , R ⁵ and R ⁶ (if present) is H. 5. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-2 or 4, wherein each of R ⁴ , R ⁵ and R ⁶ (if present) is H. 6. A compound according to any one of claims 1-5, wherein R ² is C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl. 7. A compound or pharmaceutically acceptable salt thereof according to claim 6, wherein R ² is C ₆ -C ₁₀ aryl, preferably phenyl. 8. A compound or pharmaceutically acceptable salt thereof according to claim 6, wherein R ² is 5-10 membered heteroaryl and where 1 ring atom is N, preferably pyridyl. 9. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein R ³ is 3-14 membered heterocycloalkyl or 5-10 membered heteroaryl selected from the group consisting of benzothiazolyl, benzisothiazolyl, benzoxazolyl, pyridinyl, pyridinonyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, cinnolinyl, isoxazolyl, pyrazolyl, benzofuranyl, dihydrobenzofuranyl and tetrahydrobenzodioxinyl. 10. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ³ is C ₆ -C ₁₀ aryl. 11. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein L is O or NR. 12. A compound or pharmaceutically acceptable salt thereof according to claim 11, wherein R ¹ is C1C ₃ alkyl which is optionally substituted with 1-3 F. 13. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L is O or NR and R is H; R ¹ is C ₁ -C ₃ alkyl which is optionally substituted with 1-3 F; R ² is 3-14 membered heterocycloalkyl or 5-10 membered heteroaryl, where 1 heterocycloalkyl or heteroaryl atom is N, or C ₆ -C ₁₀ -aryl; R ³ is 3-14 membered heterocycloalkyl or 5-10 membered heteroaryl, where 1-3 heterocycloalkyl or heteroaryl atoms are independently selected from N, O and S; and each of R ⁴ , R ⁵ and R ⁶ (if any) is H. 14. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein L is NR. 15. A compound or pharmaceutically acceptable salt thereof according to claim 13 or 14, wherein R ³ is 5-10 membered heteroaryl, where 2 heteroaryl atoms are independently selected from N, O, and S. 16. A compound or a pharmaceutically acceptable salt thereof according to claim 13 or 14, wherein R ³ is C ₆ -C ₁₀ aryl. 17. The connection according to claim 1, where the connection is selected from the following table: - 152 041815 - 153 041815 - 154 041815 - 155 041815 - 156 041815 - 157 041815 - 158 041815 - 159 041815 - 160 041815 or a pharmaceutically acceptable salt thereof. 18. The connection according to claim 1 or 2, where the connection is selected from the following table: - 161 041815 - 162 041815 - 163 041815 - 164 041815 - 165 041815 - 166 041815 or a pharmaceutically acceptable salt thereof, or selected from the following table: - 167 041815 101-A X ⁴ N -4 ⁴ -k DL _a Ί r 102-A L ¹ , ¹ , l H 9 103-A f.. ’ If I fl I I ~ fl fl CF *H Rr 104-A LT i ,. —'M'-p ¢2 T 105-A ...........Μ , ί ΐ Ί ί'< 106-A - T . ,. ' I ri.. °' I ⁰ Ci X 107-A 1 ?:-= 108-A 0 _ΐ_ P _l ⁵ 9 . .' _: - 168 041815 109-A 3'1 . . ' W , c J _{? a} 1. t Y Br 110-A ” 7 5 , ,. 'UI .,h..... 111-A 112-A '1Γ'. P'P., , j , , ,. h ., Ϊ ₇ 113-A-33 . , 'ΪΎ1 „ 7 A 114-A ^L T1 ,,. i L 1 , 115-A ... . 3‘P: ., -os, 116-A C3.,0 117-A 3l3 .... ., X 7 1 ., D 'j TV C Φ OCD ₃ 118-A .- / 1} <jj h A 119-A , , -A'% M ,/1 120-A : ¹ y,, Ci I 121-A A'.' II 7 1 122-A-3 . . . Ά D 1 , 0- -j' Ή '0' ^v u X - 169 041815 123-A -dfz ".. 77G7. o l'h 1 ' ,1 125-A 7:7.. . . ' 1 77.... O' γ H O CHF,- C ¹ '7 Ύ ^Ν 127-A Ν - Π ¹ ' Ν Ό 'cf; u or ig. 129-A ........ J.x. J... O'- Ν O- - °'CHF- 131-A CO, .=. 'ri: ... .- --'-y _|; . ...i| CV 133-A -777 ... . ' ϊ : i . 0 ' γ-GG .T o= T 3CF ₃ 135-A Ci. ·' i . \ - 1e i 13 7-A Ν”/'] ' Ϊ f ϋ । N 0 Il ¹ X' 124-A h. %] =7> [ΓΊ 4..rj T 126-A 0'7 . .... CyO_. ' ₁ 1 Odr^ 128-A <75 u-..H _th -=,.,.¾ ί 7 Cf-, 130-A O 7 -. 0 '7 0- y Έ ϋ''CF.= Ο _Ί y... Μ 13 2-A =7 ο-7 O 13 4-A-'JJ; . - ,- ,, . _; .= _Γ .. j „ .. . 1 ί Ί 13 6-A N -to Ί ! Τι., .>! ,. 1, 138-A N . N 1 7' v . . ο - % 1 1 3 ΓII π or a pharmaceutically acceptable salt thereof. 19. The compound according to claim 3, where the compound is selected from the following table: - 170 041815 13 9-A •a x.. ·, Ϊ.Ι . ^J I. '7 140-A 0 g y " 141-A -XI L ABOUT I 142-A eleven 143-A A Ch- - 1 n a F 144-A Ν.,χ ν. Ο' ¹ j Ν 9 j ^F Π ' V 145-A 11 0 , N -T ί ί _τ = F 146-A χΛ Ν ·Ν···^· ^Ν η ςι α 147-А DA _Q -·^ 9 148-А Ji ί—' -π < , ² Ο / 149-А s ί , ^f o 7 ·' o L / i-·' N Ζ Ζ o' 150-А ' ^ϋ η ... _Ν 1 -Λ · ^! 0 0 - I or a pharmaceutically acceptable salt thereof. 20. A method of treating cancer in a subject suffering from a tumor, comprising administering to the subject an effective amount of a compound according to any one of claims 1-19. 21. The method of claim 20, wherein the cancer is a methylthioadenosine phosphorylase (MTAP) deletion cancer selected from the group consisting of mesothelioma, neuroblastoma, rectal carcinoma, colon carcinoma, familial adenomatous polyposis carcinoma, and hereditary non-polyposis colorectal cancer, esophageal carcinoma, lip carcinoma, 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, endometrial carcinoma, choriocarcinoma, pancreatic carcinoma, prostate carcinoma, bladder carcinoma, testicular carcinoma, breast carcinoma, urinary tract carcinoma, melanoma, brain tumor, lymphoma, head and neck cancer, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, melanoma choroid, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma. 22. The method of claim 20 or 21, wherein the cancer is selected from the group consisting of acute B-lymphocytic leukemia (B-ALL), mesothelioma, lymphoma, pancreatic carcinoma, lung cancer, gastric cancer, esophageal cancer, bladder cancer, brain cancer, head and neck cancer, melanoma, and breast cancer. 23. The method of claim 22, wherein the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma, the brain cancer is a malignant - 171 041815 a brain tumor selected from the group consisting of glioma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumors and craniopharyngioma, the breast cancer is a triple negative phenotype breast cancer (TNBC), the cancer is is a lymphoma selected from the group consisting of mantle cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma, and adult T-cell leukemia/lymphoma. 24. A method of treating a cancer in a subject suffering from a tumor, wherein the cancer is characterized by reduced or absent methylthioadenosine phosphorylase (MTAP) gene expression, absence of the MTAP gene, or reduced function of the MTAP protein, compared to cancers in which the MTAP gene or protein is present and/ or fully functional, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-19.