RU2809987C2 - Heterocyclic mat2a inhibitors and methods of their use for cancer treatment - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: group of inventions includes a compound of formula I, its pharmaceutically acceptable salt, a pharmaceutical composition containing it, a method of treatment and a method of its use. In formula (I), L represents either O, S, NR or a bond; R represents either H or C₁-C₆-alkyl; R¹ is selected from the group consisting of C₁-C₆-alkyl, C₃-C₆-cycloalkyl, -(C₁-C₆-alkyl)(C₃-C₆-cycloalkyl), where any alkyl in R¹ is straight or branched and R¹ is optionally substituted with 1-6 halogens or 1-6 deuterium; or when L is NR, then R and R¹ in combination with L are a 3-6 membered heterocycloalkyl in which 1-4 ring members are independently selected from N, O and S; R² is selected from the group consisting of C₂-C₆-alkynyl, C₆-C₁₀-aryl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkenyl, 5-10 membered heteroaryl, in which 1-4 heteroaryl members independently selected from N, O and S, where R² is optionally substituted with one substituent selected from R^A and halogen; R³ is selected from the group consisting of C₆-C₁₀-aryl, C₃-C₆-cycloalkenyl, 5-10 membered heteroaryl, in which 1-4 heteroaryl members are independently selected from N, O and S, and 3-A 6-membered heterocycloalkyl fused with a C₆-aryl, in which 1-4 heterocycloalkyl members are independently selected from N, O and S, wherein R³ is optionally substituted with one or two substituents which are selected from the group consisting of R^A, halogen, NR^AR^B, -C(O)NR^AR^B and -CN; R⁴ is selected from the group consisting of H, C₁-C₆-alkyl, optionally substituted with 1-3 halogens or 6-membered heterocycloalkoxy containing 1 heteroatom O, -(C₁-C₆-alkyl)NR^AR^B and -NR^AR^B; R⁵ is selected from H and halogen; R^A is independently selected from the group consisting of H, -hydroxy, oxo, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₃-C₆-cycloalkyl and 5-10 membered heteroaryl, in which 1-4 heteroaryl members independently selected from N, O and S; wherein each alkyl and alkoxy moiety R^A is optionally substituted with 1-3 substituents selected from the group consisting of deuterium and halogen; R^B are independently selected from the group consisting of H and C₁-C₆-alkyl.

EFFECT: compound of formula (I), which has the properties of an inhibitor of methionine adenosyltransferase isoform 2A (MAT2A).

43 cl, 2 tbl, 332 ex

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62/785519, filed December 27, 2018, the contents of which are incorporated by reference into the present invention in their entirety.

BACKGROUND OF THE ART

[0002] Methionine adenosyltransferase (MAT), which is also known as S-adenosylmethionine synthase, is a cellular enzyme that catalyzes the production of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP; catalysis is considered the rate-limiting step of the methionine cycle. SAM is a propylamino donor in polyamine biosynthesis, a major methyl donor for DNA methylation, and is involved in gene transcription and cell proliferation, as well as in the synthesis of secondary metabolites.

[0003] Two genes, designated MAT1A and MAT2A, encode two different catalytic isoforms of MAT, respectively. The third gene, MAT2B, encodes the regulatory subunit MAT2A. MAT1A is specifically expressed in adult liver, whereas MAT2A is widely distributed. Because MAT isoforms differ in catalytic kinetics and regulatory properties, cells expressing MAT1A have significantly higher levels of SAM than cells expressing MAT2A. MAT2A promoter hypomethylation and histone acetylation were found to cause upregulation of MAT2A expression. See, for example, M. Vázquez-Chantada et al. , Gastroenterology 138 (2010) 1943-53; M. Frau et al. , J. Hepatol. 59 (2013) 830-41; M. Frau et al. , Hepatology 56 (2012) 165-75; and R. M. Pascale et al. , Transl. Gastroenterol. Hepatol. 3 (2018) 36.

[0004] In hepatocellular carcinoma (HCC), down-regulation of MAT1A and up-regulation of MAT2A occurs, which is known as the MAT1A:MAT2A switch. The switch, accompanied by up-regulation of MAT2B, results in lower SAM content, which provides a growth advantage for hepatoma cells. Because MAT2A plays a critical role in facilitating hepatoma cell growth, it represents a target for anticancer therapy. Recent studies have shown that silencing by small interfering RNA significantly inhibits growth and induces apoptosis in hepatoma cells. See, for example, T. Li et al. , J. Cancer 7(10) (2016) 1317-1327.

[0005] Certain MTAP-deficient cancer cell lines 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 5-methylthioribose-1-phosphate. Adenine is utilized to form adenosine monophosphate, and 5-methylthioribose-1-phosphate is converted to methionine and formate. Because of this recycling pathway, MTA can serve as an alternative source of purine when de novo purine production is blocked, for example, by antimetabolites such as L-alanosine.

[0006] MAT2A is dysregulated 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. Silencing of MAT2A expression by RNA interference results in antiproliferative effects in several cancer models. H. Chen et al ., Gastroenterology 133 (2007) 207-218; Q. Liu et al. Hepatol. Res. 37 (2007) 376-388.

[0007] Many human and mouse malignant cells lack MTAP activity. MTAP deficiency is not only found in tissue culture cells, but deficiency is also present in primary leukemias, gliomas, melanomas, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcoma, cancer ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma and mesothelioma. The gene encoding human MTAP maps to region 9p21 on human chromosome 9p. This region also contains the tumor suppressor genes p16INK4A (also known as CDKN2A) and pl5INK4B. These genes encode p16 and p15, which are inhibitors of the cyclin D-dependent kinases cdk4 and cdk6, respectively.

[0008] The p16INK4A transcript may alternatively be an alternative reading frame (ARF) spliced into a transcript encoding pl4ARF. pl4ARF binds to MDM2 and prevents p53 degradation (Pomerantz et al. (1998) Cell 92: 713-723). The 9p21 chromosomal region is of interest because it is often homozygously deleted in a variety of cancers, including leukemias, NSLCs, pancreatic cancers, gliomas, melanomas, and mesotheliomas. Deletions often inactivate more than one gene. For example, Cairns et al. ((1995) Nat. Gen. 11:210-212) report that after studying more than 500 primary tumors, almost all of the deletions identified in these tumors affected the 170 kb region containing MTAP, pl4ARF and P16INK4A. Carson et al. (WO 99/67634) report that there is a correlation between the stage of tumor development and loss of homozygosity of the gene encoding MTAP and the gene encoding p16. For example, deletion of the MTAP gene, but not p16INK4A, has been reported to indicate cancer at an early stage of tumor development, while deletion of the genes encoding p16 and MTAP indicates cancer at a later stage of tumor development. In some patients with osteosarcoma, the MTAP gene was present at diagnosis but was later deleted (Garcia-Castellano et al ., Clin. Cancer Res . 8(3) 2002 782-787).

SUMMARY OF THE PRESENT INVENTION

[0009] The present invention relates to compounds that inhibit MAT2A. The compounds and their pharmaceutical compositions are useful in methods of treating various types of cancer, including types of cancer that are refractory to standard treatments such as surgery, radiation therapy, chemotherapy and hormonal therapy

[0010] Thus, in accordance with some embodiments, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, tautomer and/or isotopologue thereof:

[0011] In Formula I, L represents O, S, NR, or a bond. R represents H or C ₁ -C ₆ -alkyl.

[0012] R ¹ is selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₃ -C ₆ -carbocyclyl, -(C ₁ -C ₆ -alkyl)(C ₃ -C ₆ -carbocyclyl) and -(C ₁ -C ₆ -alkyl)(C ₃ -C ₆ -cycloalkenyl), where any alkyl in R ¹ is straight or branched. In one embodiment, R ¹ is optionally substituted with 1-6 halogens or 1-6 deuterium.

[0013] Alternatively, in one embodiment, when L is NR, then R and R ¹ in combination with L are a 3-6 membered heterocycloalkyl (wherein the 1-4 ring members are independently selected from N, O and S), optionally substituted with one or more R ^A .

[0014] R ² and R ³ are independently selected from the group consisting of C ₂ -C ₆ -alkynyl, C ₆ -C ₁₀ -aryl, C ₃ -C ₆ -carbocyclyl, 5-10 membered heteroaryl (where 1-4 heteroaryl members independently selected from N, O and S) and 3-14 membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members 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 R ^A , OR ^A , halogen, -N=NR ^A , -NR ^A R ^B , -(C ₁ -C ₆ -alkyl )NR ^A R ^B , -C(O)OR ^A , -C(O)NR ^A R ^B , -OC(O)R ^A , -Si(C ₁ -C ₆ -alkyl) ₃ and -CN.

[0015] R ⁴ is selected from the group consisting of H, C ₁ -C ₆ -alkyl (optionally substituted with one or more halogens, hydroxy or 3-14 membered heterocycloalkoxy (wherein the 1-4 heterocycloalkoxy members are independently selected from N, O and S)), -O(C ₁ -C ₆ -alkyl) (optionally substituted with one or more halogens), -OH, halogen, -CN, -(C ₁ -C ₆ -alkyl)NR ^A R ^B and -NR ^A R ^B .

[0016] R ⁵ is selected from the group consisting of H, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, halogen, -CN and -NR ^C R ^D .

[0017] R ^A and R ^B are independently selected from the group consisting of H, -CN, -hydroxy, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -NH ₂ , -S(O) _0-2 -(C ₁ -C ₆ -alkyl), -S(O) _0-2 -(C ₆ -C ₁₀ -aryl), - C(O)(C ₁ -C ₆ -alkyl), -C(O)(C ₃ -C ₁₄ -carbocyclyl), -C ₃ -C ₁₄ -carbocyclyl, -(C ₁ -C ₆ -alkyl)(C ₃ -C ₁₄ -carbocyclyl), C ₆ -C ₁₀ -aryl, 3-14-membered heterocycloalkyl and -(C ₁ -C ₆ -alkyl)-(3-14-membered heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O and S) and 5-10 membered heteroaryl (where the 1-4 heteroaryl members are independently selected from N, O and S).

[0018] Each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl and heteroaryl moiety of R ^A and R ^B is optionally substituted with one or more substituents selected from the group consisting of deuterium, hydroxy, halogen, -NR' ₂ (where each R' is independently selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₆ -C ₁₀ -aryl, 3- to 14-membered heterocycloalkyl, and -(C ₁ -C ₆ -alkyl)-(3-14 membered heterocycloalkyl) (where 1-4 ring members are independently selected from N, O and S), and 5-10 membered heteroaryl (where 1-4 heteroaryl members independently selected from N, O and S)), -NHC(O)(OC ₁ -C ₆ -alkyl), -NO ₂ , -CN, oxo, -C(O)OH, -C(O)O(C ₁ -C ₆ -alkyl), -C ₁ -C ₆ -alkyl (C ₁ -C ₆ -alkoxy), -C(O)NH ₂ , C ₁ -C ₆ -alkyl, -C(O)C ₁ - C ₆ -alkyl, -OC ₁ -C ₆ -alkyl, -Si(C ₁ -C ₆ -alkyl) ₃ , -S(O) _0-2 -(C ₁ -C ₆ -alkyl), C ₆ -C ₁₀ -aryl, -(C ₁ -C ₆ -alkyl)(C ₆ -C ₁₀ -aryl), 3-14-membered heterocycloalkyl and -(C ₁ -C ₆ -alkyl)-(3--14-membered heterocycle ) (where 1-4 heterocyclyl members are independently selected from N, O and S) and -O(C ₆ -C ₁₄ -aryl). Each alkyl, alkenyl, aryl and heterocycloalkyl substituent on R ^A and R ^B is optionally substituted with one or more substituents selected from the group consisting of deuterium, hydroxy, -OC ₁ -C ₆ -alkyl, halogen, -NH ₂ , -(C ₁ -C ₆ -alkyl)NH ₂ , -C(O)OH, CN and oxo.

[0019] Each R ^C and R ^D are independently selected from H and C ₁ -C ₆ -alkyl.

[0020] The present invention relates to, in another embodiment, a pharmaceutical composition containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, tautomer and/or isotopologue thereof, as described herein, and a pharmaceutically acceptable carrier.

[0021] In another embodiment, the present invention provides a method of treating cancer in a subject suffering from it, comprising administering to the subject an effective amount of a MAT2A inhibitor as described herein.

[0022] Yet another embodiment of the present invention is a method of inhibiting the synthesis of S-adenosylmethionine (SAM) in a cell, comprising introducing into the cell an effective amount of a compound or a pharmaceutically acceptable salt, tautomer and/or isotopologue thereof as described herein.

[0023] The present invention, in another embodiment, provides a method of inhibiting the synthesis of S-adenosylmethionine (SAM) in a subject, comprising administering to the subject an effective amount of at least one compound or a salt, tautomer and/or isotopologue thereof, as described in the present invention.

[0024] In one embodiment, the present invention provides a method of treating cancer in a subject suffering from it, where the cancer is characterized by decreased or absent expression of the methylthioadenosine phosphorylase (MTAP) gene, absence of the MTAP gene, or decreased function of the MTAP protein, compared to cancers wherein the MTAP gene or protein is present and/or fully functional, the method comprising administering to a subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt, tautomer and/or isotopologue thereof, as described herein.

[0025] The present invention also provides, in another embodiment, a compound or a pharmaceutically acceptable salt, tautomer and/or isotopologue thereof as described herein for inhibiting S-adenosylmethionine (SAM) synthesis.

[0026] In yet another embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, tautomer and/or isotopologue thereof, as described herein, for use in the treatment of cancer in a subject suffering from it.

[0027] The present invention also relates to the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of cancer.

DETAILED DESCRIPTION

[0028] The compounds described in the present invention are MAT2A inhibitors. Thus, the present invention relates not only to these compounds according to Formula I, but also to their pharmaceutical compositions, tautomers and isotopologues. The compounds and compositions are useful in the treatment of cancer. Some cancers include various MTAP-deleted cancers, that is, those cancers that are characterized by the absence or deletion of the MTAP gene/protein or reduced function of the MTAP protein.

Definitions

[0029] "Alkyl" refers to straight or branched chain hydrocarbyl groups of 1 to about 20 carbon atoms. For example, alkyl may contain from 1 to 10 carbon atoms or 1 to 6 carbon atoms. Examples of alkyl include 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 chain isomers of straight chain alkyl 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 , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ )(CH ₂ CH ₃ ), -CH ₂ CH(CH ₂ CH ₃ ) ₂ , -CH ₂ C(CH ₃ ) ₃ , -CH ₂ C(CH ₂ CH ₃ ) ₃ , -CH(CH ₃ )CH(CH ₃ )(CH ₂ CH ₃ ), -CH ₂ CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH( CH ₃ )(CH ₂ CH ₃ ), -CH ₂ CH ₂ CH(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ C(CH ₃ ) ₃ , -CH ₂ CH ₂ C(CH ₂ CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )CH(CH ₃ )CH(CH ₃ ) ₂ and the like. Thus, alkyl groups include primary alkyl groups, secondary alkyl groups and tertiary alkyl groups. The alkyl group may be unsubstituted or optionally substituted with one or more substituents, as described in the present invention below.

[0030] The phrase “substituted alkyl” refers to an alkyl substituted at one or more positions, for example, 1, 2, 3, 4, 5 or even 6 positions, where the substituents are attached at any accessible atom, giving a stable compound, with substitution, as described in the present invention. “Optionally substituted alkyl” refers to alkyl or substituted alkyl.

[0031] Each of the terms “halogen” refers to -F, -Cl, -Br or -I.

[0032] The term “alkenyl” refers to straight or branched chain hydrocarbyl groups containing from 2 to about 20 carbon atoms, containing 1-3, 1-2, or at least one carbon-carbon double bond. The alkenyl group may be unsubstituted or optionally substituted with one or more substituents, as described in the present invention below.

[0033] “Substituted alkenyl” refers to alkenyl substituted at 1 or more, for example 1, 2, 3, 4, 5 or even 6 positions, where the substituents are attached at any available atom, giving a stable compound, with substitution as described in the present invention. “Optionally substituted alkenyl” refers to alkenyl or substituted alkenyl.

[0034] “Alkyne or “alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing a specified number of carbon atoms and at least one triple bond. Examples of the alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne, 2-heptyne, 3 -heptine, 1-octyne, 2-octyne, 3-octyne and 4-octyne. The alkynyl group may be unsubstituted or optionally substituted with one or more substituents, as described in the present invention below.

[0035] “Substituted alkynyl” refers to an alkynyl substituted at 1 or more, for example 1, 2, 3, 4, 5 or even 6 positions, where the substituents are attached at any available atom, yielding a stable compound, with substitution as described in the present invention. “Optionally substituted alkynyl” refers to alkynyl or substituted alkynyl.

[0036] The term “alkoxy” refers to an -O-alkyl group containing the specified number of carbon atoms. For example, the (C ₁ -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 -O-neohexyl.

[0037] The term “carbocyclyl” refers to a monocyclic, bicyclic, tricyclic or polycyclic, 3-14 membered ring system that is either saturated, such as “cycloalkyl,” or unsaturated, such as “cycloalkenyl.” The term "cycloalkenyl" refers specifically to cyclic alkenyl, such as C ₃ -C ₆ -cycloalkenyl. Carbocyclyl can be attached via any atom. Carbocyclyl, for example, also includes fused rings, where, for example, carbocyclyl is fused to an aryl or heteroaryl ring, as defined herein. Representative examples of carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, phenyl, naphthyl, anthracyl, benzofuranyl, and benzothiophenyl. The carbocyclyl group may be unsubstituted or optionally substituted with one or more substituents, as described below in the present invention.

[0038] “Substituted carbocyclyl” refers to a carbocyclyl substituted at 1 or more, for example 1, 2, 3, 4, 5 or even 6 positions, where the substituents are attached at any available atom, yielding a stable compound, with substitution as described in the present invention. “Optionally substituted carbocyclyl” refers to carbocyclyl or substituted carbocyclyl.

[0039] “Aryl,” when used alone or as part of another term, means a carbocyclic aromatic group, fused or not, containing the specified number of carbon atoms or, if the number is not specified, up to 14 carbon atoms, such as C ₆ -C ₁₄ -aryl . Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl and the like (see, for example , Lang's Handbook of Chemistry (Dean, JA, ed) 13 ^th ed. table 7-2 [1985]). A particular 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 optionally substituted with one or more substituents, as described in the present invention below.

[0040] "Substituted aryl" is aryl that is independently substituted with one or more substituents attached at any accessible atom, yielding a stable compound wherein the substituents are as described herein. "Optionally substituted aryl" refers to aryl or substituted arilu.

[0041] The term “heteroatom” refers to N, O and S. Compounds that contain N or S atoms may optionally be oxidized to the corresponding N-oxide, sulfoxide or sulfone compounds.

[0042] “Heteroaryl”, alone or in combination with any other moiety described in the present invention, refers to a monocyclic aromatic ring structure containing 5-10, such as 5 or 6 ring atoms, or a bicyclic aromatic group containing 8-10 atoms containing one or more, such as 1-4, 1-3 or 1-2, heteroatoms independently selected from the group consisting of O, S and N. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl , sulfonyl and tertiary ring nitrogen N-oxide. The carbon or heteroatom represents the site of attachment of the heteroaryl ring structure so that a stable compound is formed. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, 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 optionally substituted with one or more substituents, as described in the present invention below.

[0043] “Substituted heteroaryl” is a heteroaryl that is independently substituted, unless otherwise specified, with one or more, for example 1, 2, 3, 4 or 5, also 1, 2 or 3 substituents, also 1 substituent attached at any accessible atom, yielding a stable compound wherein the substituents are as described herein: “Optionally substituted heteroaryl” refers to heteroaryl or substituted heteroaryl.

[0044] “Heterocycloalkyl” means a saturated or unsaturated non-aromatic monocyclic, bicyclic, tricyclic or polycyclic ring system that contains 3-14, such as 3-6, atoms, of which 1-4 carbon atoms in the ring are replaced by heteroatoms O, S or N. Heterocycloalkyl is optionally fused with an aryl or heteroaryl of 5-6 ring members, and includes oxidized S or N, such as sulfinyl, sulfonyl and tertiary ring nitrogen N-oxide. The site of attachment of the heterocycloalkyl ring is located at a carbon or heteroatom so that a stable ring is maintained. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl and dihydroindolyl. The heterocycloalkyl group may be unsubstituted or optionally substituted with one or more substituents, as described below in the present invention.

[0045] “Optionally substituted heterocycloalkyl” means a heterocycloalkyl that is substituted with 1-3 substituents, for example 1, 2 or 3 substituents attached at any available atom, yielding a stable compound where the substituents are as described herein.

[0046] “Heterocycloalkoxy” refers to an -O-heterocycloalkyl group containing a specified number of atoms in a monocyclic, bicyclic, tricyclic or polycyclic ring system and where 1-4 carbon atoms in the ring are replaced by O, S or N heteroatoms.

[0047] “Optionally substituted heterocycloalkoxy” refers to a heterocycloalkoxy group that is substituted with 1-3 substituents, for example 1, 2 or 3 substituents attached at any available atom, yielding a stable compound where the substituents are as described in the present invention.

[0048] The term “nitrile” or “cyano” can be used interchangeably and refers to a -CN group that is attached to the carbon atom of a heteroaryl ring, an aryl ring, and a heterocycloalkyl ring.

[0049] The term “oxo” refers to the =O atom attached to a saturated or unsaturated moiety. The =O atom can be attached to a carbon, sulfur or nitrogen atom that is part of a cyclic or acyclic moiety.

[0050] “Hydroxyl” or “hydroxy” refers to the -OH group.

[0051] The -CO ₂ H substituent can be replaced by nabioisosteric substituents such as:

And the like, wherein R has the same definition as R ^A as defined in the present invention. See, for example , The Practice of Medicinal Chemistry (Academic Press: New York, 1996), on page 203.

[0052] The compounds described in the present invention may exist in various isomeric forms, including configurational, geometric and conformational isomers, including, for example, cis or trans conformations. Compounds may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term “isomer” is intended to include all isomeric forms of the compound of the present invention, including tautomeric forms of the compound. The compounds of the present invention may also exist in open-chain or cyclized forms. In some cases, one or more cyclized forms may result from loss of water. The specific composition of the open-chain and cyclized forms may depend on how the compound is isolated, stored, or administered. For example, a compound may exist predominantly in an open form under acidic conditions, but cyclizes under neutral conditions. All forms are included in the present invention.

[0053] Certain compounds described in the present invention may contain asymmetric centers and, therefore, exist in different enantiomeric and diastereomeric forms. The compound of the present invention may be in the form of an optical isomer or a diastereomer. Accordingly, the present invention includes the compounds and their use as described herein, in the form of their optical isomers, diastereoisomers, and mixtures thereof, including a racemic mixture. Optical isomers of the compounds of the present invention can be prepared by known methods, such as asymmetric synthesis, chiral chromatography, simulated moving bed technology, or chemical resolution of stereoisomers using optically active resolving agents.

[0054] Unless otherwise specified, the term “stereoisomer” refers to one stereoisomer of a compound that contains substantially no other stereoisomers of that compound. Thus, a stereomerically pure compound containing one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound containing two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound, such as more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or more than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound. A stereoisomer, as described above, can be considered as a composition containing two stereoisomers, which are present in their respective weight percentages described in the present invention.

[0055] As used in the present invention, the term “isotopologue” is an isotopically enriched compound. As used in the present invention, and unless otherwise indicated, the term “isotopically enriched” refers to an atom having an isotopic composition different from the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of that atom. In isotopologue, "isotopic enrichment" refers to the percentage of inclusion of a certain amount of a specific isotope of a specified atom in a molecule instead of the natural isotopic composition of that atom. For example, a deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at a given position. Since the natural abundance of deuterium is about 0.0156%, the enrichment of deuterium at any position in a compound produced using unenriched starting materials is about 0.0156%.

[0056] Thus, as used in the present invention, and unless otherwise indicated, the term “isotopic enrichment factor” refers to the ratio between the isotopic composition and the natural isotopic composition of a specified isotope.

[0057] With respect to the compounds of the present invention, when a particular atomic position is designated as containing deuterium or “D” or “H ² ”, it is clear that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is approximately 0.015%. A position designated as containing deuterium typically has a maximum isotopic enrichment ratio, in particular embodiments, at least 1000 (15% deuterium inclusion), at least 2000 (30% deuterium inclusion), at least 3000 (45% deuterium inclusion). deuterium inclusion), at least 3500 (52.5% deuterium inclusion), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 ( 75% deuterium inclusion), at least 5500 (82.5% deuterium inclusion), at least 6000 (90% deuterium inclusion), at least 6333.3 (95% deuterium inclusion), at least 6466.7 (97% deuterium inclusion), at least 6600 (99% deuterium inclusion), or at least 6633.3 (99.5% deuterium inclusion) for each deuterium atom indicated. The isotopic enrichment and isotopic enrichment factor of the compounds of the present invention can be determined using standard analytical methods known to one skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0058] If there is a discrepancy between a depicted structure and the name given to that structure, then the depicted structure is determinative. In addition, unless the stereochemistry of a structure or part of a structure is indicated, for example, by bold or dashed lines, the structure or part of a structure should be interpreted to include all of its stereoisomers. However, in some cases where more than one chiral center is present, the structures and names may be presented as separate enantiomers to help describe the relative stereochemistry. Those skilled in the art of preparing organic compounds will know whether compounds are obtained as individual enantiomers in the processes used to prepare them.

[0059] As used herein and unless otherwise indicated, the term “compound” is inclusive in the sense that it includes the compound or a pharmaceutically acceptable salt, stereoisomer, isotopologue and/or tautomer thereof. Thus, for example, a compound of formula I or II includes a pharmaceutically acceptable salt of an isotopologue of the compound.

[0060] As used herein, a “pharmaceutically acceptable salt” is a pharmaceutically acceptable, organic or inorganic acid or base salt of the compound of the present invention. Representative 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, benzonate, bicarbonate , bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavularia, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucepate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine , hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naf toate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, embonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate , sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate salts. A pharmaceutically acceptable salt may contain more than one charged atom in its structure. In this case, the pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt may contain one or more charged atoms and/or one or more counterions.

[0061] The terms “treat” and “treating” refer to alleviating or eliminating a disease or symptoms associated with a disease. In some embodiments, these terms refer to minimizing the spread or exacerbation of a disease resulting from the administration of one or more prophylactic or therapeutic agents to a patient with the disease.

[0062] “The terms “prevent” and “prevention” refer to preventing the occurrence, recurrence or spread of a disease in a patient as a result of the administration of a prophylactic or therapeutic agent.

[0063] The term “effective amount” refers to an amount of a compound of the present invention or other active ingredient sufficient to provide a therapeutic or prophylactic effect in treating or preventing a disease or to delay or minimize symptoms associated with a disease. Moreover, a therapeutically effective amount with respect to a compound of the present invention means that amount of a therapeutic agent alone or in combination with other therapeutic agents that provides a therapeutic effect in the treatment or prevention of a disease. The term as used in connection with a compound of the present invention may include an amount that improves overall therapy, reduces or prevents symptoms or causes of disease, or enhances therapeutic efficacy or acts synergistically with another therapeutic agent.

[0064] "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 accordance with some embodiments, the animal is a mammal, such as a non-primate mammal and a primate (eg, monkey and human). In one embodiment, the patient is a human, such as an infant, child, adolescent, or adult.

[0065] “Inhibitor” means a compound that prevents or reduces the production of SAM. In one embodiment, the inhibitor binds to MAT2A. In one embodiment, the inhibitor inhibits MAT2A function.

CONNECTIONS

[0066] As described generally above, the present invention relates to compounds and pharmaceutically acceptable salts, tautomers and/or isotopologues thereof, wherein the compounds correspond to Formula I:

[0067] In Formula I, L represents O, S, NR or a bond. R represents H or C ₁ -C ₆ -alkyl.

[0068] R ¹ is selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₃ -C ₆ -carbocyclyl, -(C ₁ -C ₆ -alkyl)(C ₃ -C ₆ -carbocyclyl) and -(C ₁ -C ₆ -alkyl)(C ₃ -C ₆ -cycloalkenyl), where any alkyl in R ¹ is straight or branched. In one embodiment, R ¹ is optionally substituted with 1-6 halogens or 1-6 deuterium.

[0069] Alternatively, in one embodiment, when L is NR, then R and R ¹ in combination with L are a 3-6 membered heterocycloalkyl (wherein the 1-4 ring members are independently selected from N, O and S), optionally substituted with one or more R ^A .

[0070] R ² and R ³ are independently selected from the group consisting of C ₂ -C ₆ -alkynyl, C ₆ -C ₁₀ -aryl, C ₃ -C ₆ -carbocyclyl, 5-10 membered heteroaryl (where 1-4 heteroaryl members independently selected from N, O and S), and 3-14 membered heterocycloalkyl (wherein the 1-4 heterocycloalkyl members 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 R ^A , OR ^A , halogen, -N=NR ^A , -NR ^A R ^B , -(C ₁ -C ₆ -alkyl )NR ^A R ^B , -C(O)OR ^A , -C(O)NR ^A R ^B , -OC(O)R ^A , -Si(C ₁ -C ₆ -alkyl) ₃ and -CN.

[0071] R ⁴ is selected from the group consisting of H, C ₁ -C ₆ -alkyl (optionally substituted with one or more halogens, hydroxy or 3-14 membered heterocycloalkoxy (wherein the 1-4 heterocycloalkoxy members are independently selected from N, O and S)), -O(C ₁ -C ₆ -alkyl) (optionally substituted with one or more halogens), -OH, halogen, -CN, -(C ₁ -C ₆ -alkyl)NR ^A R ^B and -NR ^A R ^B .

[0072] R ⁵ is selected from the group consisting of H, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, halogen, -CN and -NR ^C R ^D .

[0073] R ^A and R ^B are independently selected from the group consisting of H, -CN, -hydroxy, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, -NH ₂ , -S(O) _0-2 -(C ₁ -C ₆ -alkyl), -S(O) _0-2 -(C ₆ -C ₁₀ -aryl), - C(O)(C ₁ -C ₆ -alkyl), -C(O)(C ₃ -C ₁₄ -carbocyclyl), -C ₃ -C ₁₄ -carbocyclyl, -(C ₁ -C ₆ -alkyl)(C ₃ -C ₁₄ -carbocyclyl), C ₆ -C ₁₀ -aryl, 3-14-membered heterocycloalkyl and -(C ₁ -C ₆ -alkyl)-(3-14-membered heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O and S) and 5-10 membered heteroaryl (where the 1-4 heteroaryl members are independently selected from N, O and S).

[0074] Each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl and heteroaryl moiety of R ^A and R ^B is optionally substituted with one or more substituents selected from the group consisting of deuterium, hydroxy, halogen, -NR' ₂ (where each R' is independently selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₆ -C ₁₀ -aryl, 3-14 membered heterocycloalkyl and - (C ₁ -C ₆ -alkyl)-(3-14 membered heterocycloalkyl) (where 1-4 ring members are independently selected from N, O and S) and 5-10 membered heteroaryl (where 1-4 heteroaryl members are independently selected from N, O and S), -NHC(O)(OC ₁ -C ₆ -alkyl), -NO ₂ , -CN, oxo, -C(O)OH, -C(O)O(C ₁ -C ₆ -alkyl), -C ₁ -C ₆ -alkyl (C ₁ -C ₆ -alkoxy), -C(O)NH ₂ , C ₁ -C ₆ -alkyl, -C(O)C ₁ -C ₆ - alkyl, -OC ₁ -C ₆ -alkyl, -Si(C ₁ -C ₆ -alkyl) ₃ , -S(O) _0-2 -(C ₁ -C ₆ -alkyl), C ₆ -C ₁₀ -aryl , -(C ₁ -C ₆ -alkyl)(C ₆ -C ₁₀ -aryl), 3-14-membered heterocycloalkyl and -(C ₁ -C ₆ -alkyl)-(3-14-membered heterocycle) (where 1 -4 heterocyclyl members are independently selected from N, O and S) and -O(C ₆ -C ₁₄ -aryl). Each alkyl, alkenyl, aryl and heterocycloalkyl substituent on R ^A and R ^B is optionally substituted with one or more substituents selected from the group consisting of hydroxy, -OC ₁ -C ₆ -alkyl, halogen, -NH ₂ , -(C ₁ - C ₆ -alkyl)NH ₂ , -C(O)OH, CN and oxo.

[0075] Each R ^C and R ^D are independently selected from H and C ₁ -C ₆ -alkyl.

[0076] In some embodiments, R ⁴ is selected from the group consisting of H, C ₁ -C ₆ -alkyl (optionally substituted with one or more halogens, hydroxy, or 3-14 membered heterocycloalkoxy (wherein 1-4 heterocycloalkoxy members are independently selected from N, O and S)), -O(C ₁ -C ₆ -alkyl), -(C ₁ -C ₆ -alkyl)NR ^A R ^B and -NR ^A R ^B (where R ^A and R ^B are independently selected from H and C ₁ -C ₆ -alkyl); and R ⁵ is selected from the group consisting of H, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and -NR ^C R ^D .

[0077] In other embodiments, at least one of R ⁴ and R ⁵ is H. For example, R ⁴ is H, or R ⁵ is H. Alternatively, each of R ⁴ and R ⁵ is H .

[0078] Optionally in combination with any other embodiment described in the present invention, various embodiments provide a compound of formula I, wherein R ² is an optionally substituted C ₆ -C ₁₀ -aryl or an optionally substituted 5-10 membered heteroaryl. In one embodiment, R ² is optionally substituted C ₆ -C ₁₀ -aryl, such as optionally substituted phenyl. In another embodiment, R ² is an optionally substituted 5-10 membered heteroaryl, and wherein 1 ring member is N. For example, R ² is an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 6-membered heteroaryl , an example of which is optionally substituted pyridyl.

[0079] In some embodiments, optionally in combination with any other embodiment described in the present invention, R ³ is an optionally substituted 3-14 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl. Non-limiting examples of R ³ are selected from the group consisting of benzothiazolyl, benzoisothiazolyl, benzoxazolyl, pyridinyl, pyridinonyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, cinnolinyl, isoxazole silt, pyrazolyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxynyl and tetrahydrobenzodioxynyl, each of which may optionally be substituted.

[0080] In other embodiments, R ³ is optionally substituted C ₆ -C ₁₀ -aryl. An example is optionally substituted phenyl.

[0081] The present invention provides certain compounds of Formula I wherein R ² is an optionally substituted phenyl and R ³ is an optionally substituted 3-14 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl.

[0082] In various embodiments, the present invention provides a compound of Formula I wherein L is O or NR. Additionally, in further embodiments, R ¹ is an optionally substituted C ₁ -C ₆ alkyl or an optionally substituted C ₃ -C ₆ carbocyclyl. Example R ¹ is C ₁ -C ₃ alkyl, which is optionally substituted with 1-3 F.

[0083] A subset of compounds of Formula I, according to one embodiment, are those compounds wherein L is O or NR and R is H; R ¹ represents C ₁ -C ₃ -alkyl, which is optionally substituted with 1-3 F; R ² represents optionally substituted 3-14 membered heterocycloalkyl or optionally substituted 5-10 membered heteroaryl (where 1 heterocycloalkyl or heteroaryl member is N) or optionally substituted C ₆ -C ₁₀ -aryl; R ³ represents an optionally substituted 3-14 membered heterocycloalkyl or an optionally substituted 5-10 membered heteroaryl, wherein the 1-3 heterocycloalkyl or heteroaryl members are independently selected from N, O and S; and R ⁴ and R ⁵ are each H. In some embodiments, L is NR.

[0084] In various embodiments, the present invention provides specific examples of compounds of Formula I and their pharmaceutically acceptable salts, tautomers and/or isotopologues set forth in Table 1 below:

[0085] Table 1

101 159 102 160 103 161 104 162 105 163 106 164 107 165 108 166 109 167 110 168 111 169 112 170 113 171 114 172 115 173 116 174 117 175 118 176 119 177 120 178 121 179 122 180 123 181 124 182 125 183 126 184 127 185 128 186 129 187 130 188 131 189 132 190 133 191 134 192 135 193 136 194 137 195 138 196 139 197 140 198 141 199 142 200 143 201 144 202 145 203 146 204 147 205 148 206 149 207 150 208 151 209 152 210 153 211 154 212 155 213 156 214 157 215 158 216 217

[0086] In other various embodiments, the present invention provides additional specific examples of compounds of Formula I and their pharmaceutically acceptable salts, tautomers and/or isotopologues set forth in Table 2 below.

[0087] Table 2

301 317 302 318 303 319 304 320 305 321 306 322 307 323 308 324 309 325 310 326 311 327 312 328 313 329 314 330 315 331 316 332

Pharmaceutical composition

[0088] The present invention also provides pharmaceutical compositions containing a therapeutically effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, and/or isotopologue, in admixture with a pharmaceutically acceptable carrier. In some embodiments, the composition further contains, in accordance with accepted pharmaceutical practice for preparing pharmaceutical preparations, one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavoring agents.

[0089] In one embodiment, the pharmaceutical composition contains a compound selected from the compounds shown in Table 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer and/or isotopologue thereof, and a pharmaceutically acceptable carrier.

[0090] The pharmaceutical composition of the present invention is formulated, dosed and administered in accordance with good medical practice. Factors to be considered in this context include the particular disease 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 practitioner.

[0091] The “therapeutically effective amount” of a compound (or a pharmaceutically acceptable salt, stereoisomer, tautomer and/or isotopologue thereof) that is administered is governed by such considerations, and is the minimum amount required to produce a cytotoxic effect on cancer, or to inhibit activity MAT2A, or both. The amount may be less than an amount toxic to normal cells or the subject as a whole. Typically, the initial therapeutically effective amount of a compound (or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof) of the present invention that is administered ranges from about 0.01 to about 200 mg/kg, or from about 0.1 to about 20 mg/kg the patient's body weight per day, with a typical initial range being from about 0.3 to about 15 mg/kg/day. Oral dosage forms, such as tablets and capsules, may contain from about 1 mg to about 1000 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present invention. In another embodiment, the dosage form contains from about 50 mg to about 500 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present invention. In yet another embodiment, the 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 invention. In yet another embodiment, the dosage forms contain from about 10 mg to about 100 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present invention. In a further embodiment, these 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 invention.

[0092] The compositions can be administered orally, topically, parenterally, inhalation or nebulization, or rectally in dosage forms. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion methods.

[0093] Suitable oral compositions of the present invention include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

[0094] Included within the scope of the present invention are pharmaceutical compositions suitable for unit dosages that contain a compound of the present invention or a pharmaceutically acceptable stereoisomer, salt or tautomer thereof and a pharmaceutically acceptable carrier.

[0095] Compositions suitable for oral administration can be prepared according to any method known in the art of preparing pharmaceutical compositions. For example, liquid formulations of compounds contain one or more agents selected from the group consisting of sweeteners, flavorings, colors and preservatives to obtain pharmaceutically acceptable preparations of a MAT2A inhibitor.

[0096] For the tablet composition, the compound of the present invention in admixture with non-toxic pharmaceutically acceptable excipients is used in the preparation of tablets.

[0097] Examples of these excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants, such as corn starch or alginic acid; binders such as starch, gelatin or gum; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known coating methods to retard disintegration and absorption in the gastrointestinal tract and thus provide prolonged therapeutic effect over the required period of time. For example, a time-release material such as glyceryl monostearate or glyceryl distearate may be used.

[0098] Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid 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 oil, liquid paraffin or olive oil.

[0099] For aqueous suspensions, the compound of the present invention is mixed with suitable excipients suitable to maintain a stable suspension. Examples of these excipients include, but are not limited to, sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia.

[00100] Oral suspensions may also contain dispersing or wetting agents such as a natural phosphatide, such as lecithin, or fatty acid condensates of alkylene oxide, such as polyoxyethylene stearate, or condensates of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensates ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[00101] Oily suspensions can be formulated by suspending a compound of the present invention in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions may contain a thickening agent such as beeswax, paraffin wax or cetyl alcohol.

[00102] Sweeteners, such as those mentioned above, and flavorings can be added to produce palatable oral preparations. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[00103] Dispersible powders and granules, suitable for preparing an aqueous suspension by the addition of water, provide the compound of the present invention in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents have already been mentioned above. Additional excipients may also be present, such as sweeteners, flavors and colors.

[00104] The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, natural phosphatides, for example soybean, lecithin and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and products condensing said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavorings.

[00105] Syrups and elixirs can be formulated with sweeteners, for example, glycerin, propylene glycol, sorbitol or sucrose. These compositions may also contain an emollient, a preservative, a flavoring agent and a coloring agent. Pharmaceutical compositions may be in the form of a sterile injection, an aqueous suspension or an oily suspension. This suspension can be formulated in accordance with the prior art using those suitable dispersing or wetting agents and suspending agents 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, a solution in 1,3-butanediol. Acceptable carriers and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as a solvent or suspending medium. Any tasteless, fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable drugs.

[00106] The compounds of general formula I can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[00107] Compositions for parenteral administration are administered in a sterile environment. Depending on the carrier used and the concentration of drug in the formulation, the parenteral formulation can be either a suspension or a solution containing the drug dissolved. Adjuvants such as local anesthetics, preservatives and buffering agents may also be added to parenteral compositions.

METHODS OF USE

[00108] The MAT2A enzyme catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and ATP in cells. Accordingly, in another embodiment, the present invention provides a method of inhibiting SAM synthesis in a cell, comprising administering to the cell an effective amount of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer and/or isotopologue thereof. In one embodiment, the cell is in a subject. In some embodiments, a compound of Formula I is used to identify other compounds that are inhibitors of MAT2A, for example, in a competition assay for binding to MAT2A or inhibition of SAM synthesis. Binding to MAT2A or inhibition of SAM synthesis by a test compound having a detectable label can be measured with and without the presence of an unlabeled compound of the present invention.

[00109] The present invention also provides a method of treating cancer in a subject suffering from it, comprising administering to the subject an effective amount of a MAT2A inhibitor as described herein. In some embodiments, the MAT2A inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, optionally in combination with any other embodiment, the subject is a mammal, such as a human.

[00110] In one embodiment, the cancer is a cancer with the MTAP removed. In some embodiments, the cancer is a cancer selected from the group consisting of mesothelioma, neuroblastoma, intestinal cancer such as rectal cancer, colon cancer, familial adenomatous polyposis cancer and hereditary nonpolyposis colorectal cancer, esophageal carcinoma, lip carcinoma, carcinoma larynx, 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 body carcinoma, endometrial carcinoma, carcinoma chorionic cinomas , pancreatic carcinoma, prostate carcinoma, bladder carcinoma, testicular carcinoma, breast carcinoma, urinary tract carcinoma, melanoma, brain cancer, head and neck cancer, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), multiple myeloma (MM), basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma , seminomas, rhabdomyosarcomas, osteosarcomas, chondrosarcomas, myosarcomas, liposarcomas, fibrosarcomas, Ewing's sarcomas and plasmacytomas.

[00111] In other embodiments, the cancer is selected from lung cancer, non-small cell lung cancer, bronchioloalviolar cell cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer colon, anal cancer, stomach cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, mesothelioma, hepatocellular cancer , biliary tract cancer, chronic or acute leukemia, lymphocytic lymphoma, central nervous system (CNS) neoplasms, spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwannoma, ependymomas medulloblastoma, meningioma, squamous cell carcinomas, pituitary adenomas, including resistant and/or refractory versions of any of the above cancers, as well as a combination of one or more of the above cancers.

[00112] In some embodiments, the cancer is selected from the group consisting of B-cell acute 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.

[00113] In other embodiments, the lung cancer is non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and squamous cell lung cancer.

[00114] In other embodiments, the breast cancer is triple negative breast cancer (TNBC).

[00115] 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.

[00116] In yet 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, the term adult T-cell leukemia/lymphoma refers to a rare and often aggressive T-cell lymphoma that can be found in the blood (leukemia), lymph nodes (lymphoma), skin, or many areas of the body.

[00117] 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 utilized to give adenosine monophosphate, and 5-methylthioribose-1-phosphate is converted to methionine and formate. Because of this disposal pathway, MTA can serve as an alternative source of purines when de novo purine acquisition is blocked, for example, by antimetabolites such as L-alanosine. Many human and mouse malignant cells lack MTAP activity. MTAP deficiency is found not only in tissue culture cells, but also in primary leukemias, gliomas, melanomas, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcomas, non-Hodgkin's lymphoma and mesothelioma. For example, proliferation of cancer cells that are MTAP null, i.e. with MTAP deleted, is inhibited by suppression of MAT2A expression using shRNA, which was confirmed using a small molecule inhibitor of MAT2A. K. Marjon et al ., Cell Reports 15 (2016) 574-587, incorporated herein by reference. An MTAP null cancer or an MTAP deleted cancer is a cancer in which the MTAP gene has been deleted, lost, or otherwise inactivated, or a cancer in which the MTAP protein has reduced or impaired function or reduced presence.

[00118] Accordingly, in one embodiment of the present invention, a method is provided for treating cancer in a subject where the cancer is characterized by decreased or absent expression of MTAP or the absence of the MTAP gene or decreased function of the MTAP protein compared to cancers where the gene and/or MTAP cancers and, or compared to cancers, with the wild-type MTAP gene. The method involves administering to a subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, tautomer and/or isotopologue thereof.

[00119] In another embodiment, a method of treating MTAP-removed cancer in a subject is provided, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the MTAP-deleted 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, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, lymphoma and mesothelioma.

[00120] In one embodiment, the cancer with the MTAP removed is pancreatic cancer. In another embodiment, the MTAP-deleted cancer is selected from bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, liver cancer, esophageal cancer, stomach 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 lung cancer (NSCLC).

[00121] Genomic analysis of MTAP null cell lines revealed that cell lines containing a KRAS mutation or a p53 mutation were sensitive to MAT2A inhibition. Accordingly, an embodiment of the present invention provides a method of treating cancer in a subject, wherein the cancer is characterized by decreased or absent expression of MTAP or the absence of the MTAP gene or decreased function of the MTAP protein, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I, wherein said cancer is further characterized by the presence mutant KRAS or mutant p53. In one embodiment, a method of treating MTAP null cancer having mutant KRAS or mutant p53 in a subject is provided, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt, tautomer and/or isotopologue thereof. For example, the cancer is MTAP null and KRAS mutant, MTAP null and p53 mutant, or each of MTAP null, KRAS mutant and p53 mutant.

[00122] The term “mutant KRAS” or “KRAS mutation” refers to a KRAS protein comprising an activating mutation that alters its normal function and the gene encoding the protein. For example, a KRAS mutant protein may contain a single amino acid substitution at position 12 or 13. In a particular embodiment, the KRAS mutant includes a G12X or G13X substitution, where X is any amino acid substitution at that position. In a particular embodiment, the replacement is G12V, G12R, G12C, or G13D. In another embodiment, the replacement is G13D. By “mutant p53” or “p53 mutation” is meant a p53 protein (or a gene encoding the protein) comprising a mutation that inhibits or eliminates its tumor suppressor function. In one embodiment, said p53 mutation is Y126_splice, K132Q, M133K, R174fs, R175H, R196*, C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C, R282W, A159V or R280K. In one embodiment, the aforementioned cancer is non-small cell lung cancer (NSCLC), pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer, or ovarian cancer.

[00123] In another embodiment, the compounds described in the present invention are useful as ligands for the degradation of proteins associated with disease. An example of such an approach is PROTAC (PROteolysis TArgeting Chimeras). PROTACs are bifunctional molecules that contain both a ligand moiety selected from one of the compounds described in the present invention, which is capable of binding the target protein, and a ligase-targeting moiety, such as a peptide moiety (called a degron), which is recognized and polyubiquitinated E3 ligase. Thus, PROTAC non-covalently binds to the target protein and recruits E3 ligase through the degron, leading to polyubiquitinylation and degradation of the bound target. A number of publications describe the preclinical use of PROTACs in various therapeutic areas, including oncology. See, for example , Lu et al . Chemistry & Biology 22 (2015) 755-763.

[00124] ASPECTS

[00125] Aspect 1. Compound of Formula I:

Where

L represents O, S, NR or bond;

R represents H or C ₁ -C ₆ -alkyl;

R ¹ is selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₃ -C ₆ -carbocyclyl, -(C ₁ -C ₆ -alkyl)(C ₃ -C ₆ -carbocyclyl ) and -(C ₁ -C ₆ -alkyl)(C ₃ -C ₆ -cycloalkenyl), where

any alkyl in R ¹ is straight or branched, and

R ¹ is optionally substituted with 1-6 halogens;

or when L is NR, then R and R ¹ in combination with L are 3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O and S), optionally substituted by one or more R ^A ;

R ² and R ³ are independently selected from the group consisting of C ₆ -C ₁₀ -aryl, C ₃ -C ₆ -carbocyclyl, 5-10 membered heteroaryl (where 1-4 heteroaryl members are independently selected from N, O and S) and 3-14 membered heterocycloalkyl (wherein the 1-4 heterocycloalkyl members are independently selected from N, O and S),

where R ² and R ³ are independently and optionally substituted with one or more substituents that are selected from the group consisting of R ^A , OR ^A , halogen, -N=N- R ^A , NR ^A R ^B , -(C ₁ -C ₆ -alkyl)NR ^A R ^B , -C(O)OR ^A , -C(O)NR ^A R ^B , -OC(O)R ^A and -CN;

R ⁴ is selected from the group consisting of H, C ₁ -C ₆ -alkyl (optionally substituted with one or more halogens), -O(C ₁ -C ₆ -alkyl) (optionally substituted with one or more halogens), -OH, halogen , -CN, -(C ₁ -C ₆ -alkyl)NR ^A R ^B and -NR ^A R ^B ;

R ⁵ is selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, halogen, -CN and -NR ^C R ^D ;

R ^A and R ^B are independently selected from the group consisting of H, -CN, -hydroxy, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C _6- alkynyl, -NH ₂ , -S(O) _0-2 -(C ₁ -C ₆ -alkyl), -S(O) _0-2 -(C ₆ -C ₁₀ -aryl), -C(O )(C ₁ -C ₆ -alkyl), -C(O)(C ₃ -C ₁₄ -carbocyclyl), -C ₃ -C ₁₄ -carbocyclyl, -(C ₁ -C ₆ -alkyl)(C ₃ -C ₁₄ -carbocyclyl), C ₆ -C ₁₀ -aryl, 3-14 membered heterocycloalkyl and -(C ₁ -C ₆ -alkyl)-(3-14 membered heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N , O and S) and 5-10 membered heteroaryl (where 1-4 heteroaryl members are independently selected from N, O and S);

Wherein each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl and heteroaryl moiety R ^A and R ^B is optionally substituted with one or more substituents but selected from the group consisting of hydroxy, halogen, -NR' ₂ (wherein each R' independently selected from the group consisting of C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₆ -C ₁₀ -aryl, 3-14 membered heterocycloalkyl and -(C ₁ -C ₆ -alkyl)-(3-14 membered heterocycloalkyl) (where 1-4 ring members are independently selected from N, O and S) and 5-10 membered heteroaryl (where 1-4 heteroaryl members are independently selected from N, O and S), -NHC(O)(OC ₁ -C ₆ -alkyl), -NO ₂ , -CN, oxo, -C(O)OH, -C(O)O(C ₁ -C ₆ -alkyl ), -C ₁ -C ₆ -alkyl(C ₁ -C ₆ -alkoxy), -C(O)NH ₂ , C ₁ -C ₆ -alkyl -C(O)C ₁ -C ₆ -alkyl -OC ₁ -C ₆ -alkyl, -Si(C ₁ -C ₆ -alkyl) ₃ , -S(O) _0-2 -(C ₁ -C ₆ -alkyl), C ₆ -C ₁₀ -aryl, -(C ₁ -C ₆ -alkyl)(C ₆ -C ₁₀ -aryl), 3-14-membered heterocycloalkyl and -(C ₁ -C ₆ -alkyl)-(3-14-membered heterocycle) (where 1-4 heterocyclic members are independently selected from N, O and S) and -O(C ₆ -C ₁₄ -aryl), wherein each alkyl, alkenyl, aryl and heterocycloalkyl in R ^A and R ^B is optionally substituted with one or more substituents selected from the group consisting of hydroxy , -OC ₁ -C ₆ -alkyl, halogen, -NH ₂ , -(C ₁ -C ₆ -alkyl)NH ₂ , -C(O)OH, CN and oxo,

Each R ^C and R ^D are independently selected from H and C ₁ -C ₆ -alkyl;

or a pharmaceutically acceptable salt thereof.

[00126] Aspect 2. The connection according to aspect 1, where

R ⁴ is selected from the group consisting of H, C ₁ -C ₆ -alkyl, optionally substituted with one or more halogens, -O(C ₁ -C ₆ -alkyl), -(C ₁ -C ₆ -alkyl)NR ^A R ^B and -NR ^A R ^B (where R ^A and R ^B are independently selected from H and C ₁ -C ₆ -alkyl); And

R ⁵ is selected from the group consisting of H, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and -NR ^C R ^D .

[00127] Aspect 3. The compound according to aspect 1 or 2, wherein at least one of R ⁴ and R ⁵ is H.

[00128] Aspect 4. A compound according to any one of aspects 1-3, wherein R ⁴ is H.

[00129] Aspect 5. A compound according to any of aspects 1-4, wherein R ⁵ is H.

[00130] Aspect 6. A compound according to any one of aspects 1-5, wherein R ⁴ and R ⁵ are each H.

[00131] Aspect 7. A compound according to any of aspects 1-6, wherein R ² is C ₆ -C ₁₀ -aryl or 5-10 membered heteroaryl.

[00132] Aspect 8. The compound of aspect 7, wherein R ² is C ₆ -C ₁₀ -aryl.

[00133] Aspect 9. The compound of Aspect 8 wherein R ² is phenyl.

[00134] Aspect 10. The compound of Aspect 7 wherein R ² is a 5-10 membered heteroaryl and wherein 1 ring member is N.

[00135] Aspect 11. The compound of aspect 10, wherein R ² is a 5- or 6-membered heteroaryl.

[00136] Aspect 12. The compound of aspect 10 or 11, wherein R ² is a 6-membered heteroaryl.

[00137] Aspect 13. A compound according to any of aspects 10-12, wherein R ² is pyridyl.

[00138] Aspect 14. A compound according to any one of aspects 1-12, wherein R ³ is a 3-14 membered heterocycloalkyl or a 5-10 membered heteroaryl.

[00139] Aspect 15. The compound of aspect 14, wherein R ³ is selected from the group consisting of benzothiazolyl, benzoisothiazolyl, benzoxazolyl, pyridinyl, pyridinonyl, pyridazinyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, tria zolopyridinyl, cinnolinyl, isoxazolyl, pyrazolyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxynyl and tetrahydrobenzodioxynyl.

[00140] Aspect 16. A compound according to any of aspects 1-12, wherein R ³ is C ₆ -C ₁₀ -aryl.

[00141] Aspect 17. The compound of aspect 16, wherein R ³ is phenyl.

[00142] Aspect 18. A compound according to any of aspects 1-6, wherein R ² is phenyl and R ³ is 3-14 membered heterocycloalkyl or 5-10 membered heteroaryl.

[00143] Aspect 19. A compound according to any one of aspects 1-18, wherein L is O or NR.

[00144] Aspect 20. The compound of aspect 19, wherein R ¹ is C ₁ -C ₆ -alkyl or C ₃ -C ₆ -carbocyclyl.

[00145] Aspect 21. The compound of aspect 19 or 20, wherein R ¹ is C ₁ -C ₃ alkyl which is optionally substituted with 1-3 F.

[00146] Aspect 22. The connection according to aspect 1, where

L represents O or NR, and R represents H;

R ¹ represents C ₁ -C ₃ -alkyl, which is optionally substituted with 1-3 F;

R ² represents 3-14 membered heterocycloalkyl or 5-10 membered heteroaryl (where 1 heterocycloalkyl or heteroaryl member is N) or C ₆ -C ₁₀ -aryl;

R ³ represents 3-14 membered heterocycloalkyl or 5-10 membered heteroaryl, where 1-3 heterocycloalkyl or heteroaryl members are independently selected from N, O and S; And

R ⁴ and R ⁵ are each H.

[00147] Aspect 23. The connection according to aspect 22, where L represents NR.

[00148] Aspect 24. The connection according to aspect 1, where the connection is selected from the following table:

101 159 102 160 103 161 104 162 105 163 106 164 107 165 108 166 109 167 110 168 111 169 112 170 113 171 114 172 115 173 116 174 117 175 118 176 119 177 120 178 121 179 122 180 123 181 124 182 125 183 126 184 127 185 128 186 129 187 130 188 131 189 132 190 133 191 134 192 135 193 136 194 137 195 138 196 139 197 140 198 141 199 142 200 143 201 144 202 145 203 146 204 147 205 148 206 149 207 150 208 151 209 152 210 153 211 154 212 155 213 156 214 157 215 158 216 217

[00149] Aspect 25. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of aspects 1-24 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[00150] Aspect 26. A method of treating cancer in a subject suffering from it, comprising administering to the subject an effective amount of a MAT2A inhibitor c according to any one of aspects 1-24.

[00151] Aspect 27. The method of aspect 26, wherein the cancer is a cancer with the MTAP removed.

[00152] Aspect 28. A method of inhibiting S-adenosylmethionine (SAM) synthesis in a cell, comprising administering to the cell an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1-24.

[00153] Aspect 29. The method according to aspect 28, where the cell is in the subject.

[00154] Aspect 30. A method of inhibiting S-adenosylmethionine (SAM) synthesis in a subject, comprising administering to the subject an effective amount of at least one compound or a salt thereof according to any of aspects 1-24.

[00155] Aspect 31. A method of treating cancer in a subject suffering from it, comprising administering to the subject an effective amount of a compound according to any of aspects 1-24.

[00156] Aspect 32. The method of aspect 31, wherein the cancer is a cancer with the MTAP removed.

[00157] Aspect 33. The method according to any one of aspects 26, 27, 31, and 32, wherein the cancer is selected from the group consisting of mesothelioma, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, and hereditary nonpolyposis colorectal carcinoma. esophagus, 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, carcinoma uterine body , endometrial carcinoma, chorionic carcinoma, pancreatic carcinoma, prostate carcinoma, bladder carcinoma, testicular carcinoma, breast carcinoma, urinary tract carcinoma, melanoma, brain tumors, lymphoma, head and neck cancer, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, vascular melanoma shells, seminomas, rhabdomyosarcomas, osteosarcomas, chondrosarcomas, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytomas.

[00158] Aspect 34. The method according to aspect 31 or 32, wherein the cancer is selected from the group consisting of B-cell acute 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.

[00159] Aspect 35. The method of aspect 34, wherein the cancer is lung cancer selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and squamous cell lung cancer.

[00160] Aspect 36. The method of aspect 34, wherein the cancer is a brain cancer selected from the group consisting of glioma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumors, and craniopharyngioma.

[00161] Aspect 37. The method of aspect 34, wherein the cancer is triple negative breast cancer (TNBC).

[00162] Aspect 38. The method of aspect 34, wherein 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, and adult T-cell leukemia/lymphoma .

[00163] Aspect 39. A method of treating cancer in a subject suffering from it, where the cancer is characterized by decreased or absent expression of the methylthioadenosine phosphorylase (MTAP) gene, absence of the MTAP gene, or decreased functioning of the MTAP protein compared to cancers where the gene is present and/or fully functional or an MTAP protein, the method comprising administering to a subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1-24.

[00164] Aspect 40. A compound according to any of aspects 1-24, or a pharmaceutically acceptable salt thereof, for inhibiting S-adenosylmethionine (SAM) synthesis.

[00165] Aspect 41. A compound according to any one of aspects 1-24, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject suffering from it.

[00166] Aspect 42. The connection of aspect 41, wherein the cancer is a cancer with the MTAP removed.

[00167] Aspect 43. The compound of aspect 41 or 42, wherein the cancer is selected from the group consisting of mesothelioma, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma and hereditary nonpolyposis colorectal cancer, esophageal carcinoma, lip carcinoma, carcinoma larynx, 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 body carcinoma, endometrial carcinoma, carcinoma chorionic cinomas , pancreatic carcinoma, prostate carcinoma, bladder carcinoma, testicular carcinoma, breast carcinoma, urinary tract carcinoma, melanoma, brain tumors, lymphoma, head and neck cancer, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyo sarcomas, osteosarcomas, chondrosarcomas, myosarcomas, liposarcomas, fibrosarcomas, Ewing's sarcomas and plasmacytomas.

[00168] Aspect 44. The compound of aspect 41 or 42, wherein the cancer is selected from the group consisting of B-cell acute 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.

[00169] Aspect 45. The compound of aspect 44, wherein the cancer is lung cancer selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and squamous cell lung cancer.

[00170] Aspect 46. The compound of aspect 44, wherein the cancer is triple negative breast cancer (TNBC).

[00171] Aspect 47. The compound of aspect 44, wherein the cancer is a brain cancer selected from the group consisting of glioma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumors, and craniopharyngioma.

[00172] Aspect 48. The compound according to any one of aspects 41-43, wherein 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.

EXAMPLES

[00173] The present invention will be more fully understood with reference to the following examples. The examples should not, however, be interpreted as limiting the scope of the present invention.

[00174] List of units and terms:

anhydrous anhydrous aq. water min Minute(s) ml milliliter mmol Millimole (millimoles) mole Mole (moths) MS Mass spectrometry NMR Nuclear magnetic resonance TLC Thin layer chromatography HPLC High performance liquid chromatography RT(r.t.) Room temperature

[00175] NMR spectra

Hz hertz δ Chemical shift J Binding constant With singlet d doublet T triplet kv quartet m multiplet ear widened kvd Quartet of doublets dquin doublet of quintets dd Doublet of doublets dt Doublet of triplets

[00176] Solvents and reagents:

CHCl ₃ chloroform DCM dichloromethane DMF dimethylformamide Et ₂ O Diethyl ether EtOH Ethanol EtOAc ethyl acetate E.A. ethyl acetate MeOH Methyl alcohol MeCN acetonitrile P.E. Petroleum ether THF tetrahydrofuran AcOH Acetic acid HCl Hydrochloric acid _{H2SO4 _} Sulfuric acid _NH4Cl Ammonium chloride KOH Potassium hydroxide NaOH sodium hydroxide _{K2CO3 _} potassium carbonate Na ₂ CO ₃ sodium carbonate T.F.A. trifluoroacetic acid _{Na2SO4 _} sodium sulfate NaBH ₄ sodium borohydride _NaHCO3 bicarbonate of soda LiHMDS lithium hexamethyldisylamide NaHMDS sodium hexamethyldisilylamide LAH lithium aluminum hydride NaBH ₄ 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' - tetra-methyluronium Xphos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl BINAP 2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl

[00177] General experimental part

[00178] In the following examples, reagents and solvents were obtained from commercial sources (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. Plates for analytical and preparative thin layer chromatography (TLC) - HSGF 254 (thickness 0.15-0.2 mm, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were obtained on a Brucker AMX-400 NMR instrument (Brucker, Switzerland). Chemical shifts are reported in parts per million (ppm, δ) relative to tetramethylsilane. Mass spectra were obtained using electrospray ionization (ESI) on a Waters LCT TOF mass spectrometer (Waters, USA). HPLC chromatograms were obtained by liquid chromatography on an Agilent 1200 (Agilent, USA, column: Ultimate 4.6 mm x 50 mm, 5 µm, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile). Microwave reactions were carried out using an Initiator 2.5 microwave synthesizer (Biotage, Sweden).

[00179] General Method I:

[00180] Structure connections1.9, 1.11 And1.12 was prepared according to the scheme shown as General Method I. Starting from pyrazinone1.1, used electrophilic bromination to obtain heterocyclic bromide1.2. Required R₃ group was introduced using Chan-Lam condensation, obtaining the compound1.3. At this stage, the required R₄And R₅ groups were introduced using either the Suzuki cross-coupling reaction with the reagent1.4 (method A), or Stille cross-coupling with reagent1.5(method B). The resulting intermediate1.6 cyclized to the required bicyclic backbone1.7under basic conditions. Required R₂ group was administered using the Suzuki cross-coupling reaction, obtaining the compound1.8. Then connection1.8 alkylated by introducing the required R₁ group and obtaining the final connections of the structure1.9. Alternatively, connection1.8 chlorinated to give aryl chloride1.10, and the required R₁ introduced by nucleophilic aromatic substitution, yielding the final compounds of the structure1.11(method C). Alternatively, connection1.8 activated using BOP and the required N-linked R₁ introduced by nucleophilic aromatic substitution, yielding the final compounds of the structure1.12(method D).

[00181] Obtaining Example 101 by General Method I (Method A):

[00182] Step A: 5-amino-6-bromo-4-chloropyrazin-3(2H)-one

[00183] To a suspension of 5-amino-4-chloropyrazin-3(2H)-one (1.2 g, 8.2 mmol, 1.0 eq.) and NaOAc (0.74 g, 9.1 mmol, 1 ,1 eq.) in MeCN (40 ml) was added Br ₂ (1.45 g, 9.1 mmol, 1.1 eq.) at 80°C for 5 min with a syringe. The resulting mixture was stirred at 80°C for an additional 1 hour. After cooling to room temperature, the volatiles were removed under reduced pressure, diluted with ice-cold H ₂ O (20 ml), the resulting white precipitate was filtered, and the filter residue was collected and dried under reduced pressure to obtain 5-amino-6-bromo-4-chloropyrazin-3(2H)-one (1.48 g, 80% yield) as a white solid. LC-MS (ESI): m/z 224, 226 [M+H] ⁺ .

[00184] Step B: 5-amino-6-bromo-4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrazin-3(2H)-one

[00185] To a suspension of 5-amino-6-bromo-4-chloropyrazin-3(2H)-one (590 mg, 2.63 mmol, 1.0 eq.) in DMF (15 ml) was added (2-methyl- 2H-Indazol-5-yl)boronic acid (555 mg, 3.15 mmol, 1.2 eq.), Cu(OAc) ₂ (478 mg, 2.63 mmol, 1.0 eq.) and pyridine (422 µl, 5.26 mmol, 2.0 eq.). The resulting mixture was stirred at 50 ^° C. (air atmosphere) for 8 hours and the reaction was monitored by TLC. Once complete, the reaction mixture was diluted with H ₂ O (30 ml), the resulting suspension was stirred for an additional 30 min, the precipitate was collected and washed with ice-cold H ₂ O (30 ml x 3) and dried under reduced pressure, yielding 5-amino-6- bromo-4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrazin-3(2H)-one (770 mg, 82% yield) as a gray-white solid. LC-MS (ESI): m/z 354, 356 [M+H] ⁺ .

[00186] Step C: Ethyl (E)-3-(4-amino-5-chloro-1-(2-methyl-2H-indazol-5-yl)-6-oxo-1,6-dihydropyrazine-3- yl)acrylate

[00187] To a solution of 5-amino-6-bromo-4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrazin-3(2H)-one (500 mg, 1.41 mmol, 1 .0 eq.) in DMF (10 ml) was added ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (350 mg, 1.55 mmol, 1.1 eq.), Pd(dppf)Cl ₂ (103 mg, 0.14 mmol, 0.1 eq.) and K ₂ CO ₃ (389 mg, 2.82 mmol, 2.0 eq.) . The reaction mixture was stirred at 80°C for 16 hours under N ₂ atmosphere. The reaction mixture was poured into ice water (30 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the crude residue was purified by flash column chromatography on silica gel to give ethyl (E)-3-(4-amino-5-chloro-1-(2-methyl-2H -indazol-5-yl)-6-oxo-1,6-dihydropyrazin-3-yl)acrylate (316 mg, 60% yield) as a yellow solid. LC-MS (ESI): m/z 374 [M+H] ⁺ .

[00188] Step D: 4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione

[00189] To a solution of ethyl (E)-3-(4-amino-5-chloro-1-(2-methyl-2H-indazol-5-yl)-6-oxo-1,6-dihydropyrazin-3-yl )acrylate (400 mg, 1.07 mmol, 1.0 eq.) in EtOH (10 ml) was added K ₂ CO ₃ (295 mg, 2.14 mmol, 2.0 eq.) at room temperature. The reaction mixture was stirred at 80 ^o C for 3 hours. Ice water (30 ml) was then added and the mixture was extracted with EtOAc (30 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the crude residue was purified by flash column chromatography on silica gel to give 4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3.2 -c]pyridazine-3,6(2H,5H)-dione (319 mg, 85% yield) as a yellow solid. LC-MS (ESI): m/z 328 [M+H] ⁺ .

[00190] Step E: 4-(4-chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione

[00191] 4-Chloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione solution (1 g, 3.05 mmol, 1.0 eq.), (4-chlorophenyl)boronic acid (954 mg, 6.1 mmol, 2.0 eq.), Pd(OAc) ₂ (68 mg, 0.3 mmol, 0.1 eq. .), S-Phos (251 mg, 0.61 mmol, 0.2 eq.) and K ₂ CO ₃ (1.26 g, 9.15 mmol, 3.0 eq.) in dioxane/H ₂ O ( 110 ml, 10/1, v/v) were stirred at 110 ^o C in an atmosphere of N ₂ for 2 hours. Ice water (30 ml) was added and the mixture was extracted with EtOAc (30 ml x 3), the combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure, the crude residue was purified by flash column chromatography on silica gel to give 4-(4- chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione (700 mg, 57% yield) as a yellow solid remainder. LC-MS: m/z 404 [M+H] ⁺ .

[00192] Step F: 4-(4-chlorophenyl)-6-(cyclopropylmethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)- He

[00193] 4-(4-Chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione solution (200 mg , 0.495 mmol, 1.0 eq.), (bromomethyl)cyclopropane (0.2 ml, 2.0 mmol, 4.0 eq.), Cs ₂ CO ₃ (484 mg, 1.5 mmol, 3.0 eq. .) in DMF (3 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by pre-HPLC to give 4-(4-chlorophenyl)-6-(cyclopropylmethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3, 2-c]pyrazin-3(2H)-one (example 101) .

[00194] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.55 (s, 1H), 8.07 (d, J=2.0 Hz, 1H), 8.04 (d, J= 9.6 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.76 (d, J=9.2 Hz, 1H), 7.56 (d, J=8, 4 Hz, 2H), 7.51 (dd, J=9.2 Hz, 1.6 Hz, 1H), 7.04 (d, J=9.2 Hz, 1H), 4.28 (s, 3H ), 4.21 (d, J=7.2 Hz, 2H), 1.36-1.19 (m, 1H), 0.64-0.57 (m, 2H), 0.37-0, 33 (m, 2H).

[00195] LC-MS (ESI) : m/z 458 [M+H] ⁺

[00196] Obtaining Example 102 by General Method I (Method B):

[00197] Step C: 4-chloro-6-hydroxy-2-(2-methyl-2H-indazol-5-yl)-8-(trifluoromethyl)pyrido[3,2-c]pyrazin-3(2H)- He

[00198] Solution of 5-amino-6-bromo-4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrazin-3(2H)-one (1 g, 2.8 mmol, 1. 0 eq.), ethyl (Z)-4,4,4-trifluoro-3-(tributylstannyl)but-2-enoate (ref: Synlett, 2012 , 23 , 755-759) (2.6 g, 5.6 mmol, 2.0 eq.), Pd(PPh ₃ ) ₄ (655 mg, 0.567 mmol, 0.2 eq.) and CuI (216 mg, 1.13 mmol, 0.4 eq.) in DMF (10 ml ) in an atmosphere of N ₂ was stirred at 100 ^o C for 16 hours. The reaction mixture was quenched with CsF(sat.aq) (30 ml) and stirred for an additional 30 min, the resulting suspension was filtered, the precipitate was collected and triturated with EtOAc (20 ml) to give 4-chloro-6-hydroxy-2- (2-methyl-2H-indazol-5-yl)-8-(trifluoromethyl)pyrido[3,2-c]pyrazin-3(2H)-one (800 mg, 71% yield) as a yellow solid. LC-MS (ESI): m/z 396 [M+H] ⁺ .

[00199] 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-8-(trifluoromethyl)pyrido[3,2 -c]pyrazin-3(2H)-one (Example 102) was prepared from 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2,2- difluoroethyl trifluoromethanesulfonate general method I (Stage E, F).

[00200] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.56 (s, 1H), 8.07 (s, 1H), 7.87 (d, J=8.8 Hz, 2H) , 7.76 (d, J=9.2 Hz, 1H), 7.61 (s, 1H), 7.50 (dd, J=9.2 Hz, 1.6 Hz, 1H), 7.38 (t, J _HF =73.6 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 6.43 (tt, J _HF =54.0 Hz, J=2.8 Hz , 1H), 4.63 (td, J _HF= 14.8 Hz, J=2.8 Hz, 2H), 4.25 (s, 3H).

[00201] LC-MS (ESI) : m/z 568 [M+H] ⁺ .

[00202] Obtaining example 103 in general method I (method C):

[00203] Step G: 6-chloro-4-(4-chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one

[00204] 4-(4-Chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione solution (100 mg , 0.284 mmol, 1.0 eq.) in POCl ₃ (5 ml) was stirred at 80°C for 2 hours. Excess POCl ₃ was removed under reduced pressure and the residue was carefully poured into ice-cold NaHCO ₃ (sat. aq.) (10 ml), the resulting mixture was extracted with DCM (10 ml x 3), the combined organic layers were washed with brine (10 ml) and dried over Na ₂ SO ₄ , concentrated under reduced pressure, the crude residue was purified by flash column chromatography on silica gel to give 6-chloro-4-(4-chlorophenyl)-2-(2-methyl-2H-indazole-5 -yl)pyrido[3,2-c]pyrazin-3(2H)-one (60 mg, 57% yield) as a red solid. LC-MS (ESI): m/z 422 [M+H] ⁺ .

[00205] Step H: 4-(4-chlorophenyl)-6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)- He

[00206] 6-Chloro-4-(4-chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one solution (60 mg , 0.142 mmol, 1.0 eq.), ethylamine hydrochloride (58 mg, 0.71 mmol, 5.0 eq.), CsF (108 mg, 0.71 mmol, 5.0 eq.) and DIPEA (92 mg , 0.71 mmol, 5.0 eq.) in THF (3 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by pre-HPLC to give 4-(4-chlorophenyl)-6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2- c]pyrazin-3(2H)-one (example 103) .

[00207] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.46 (s, 1H), 8.34 (t, J=5.2 Hz, 1H), 7.94 (d, J= 1.2 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.67 (d, J=9.2 Hz, 1H), 7.61 (d, J=9, 2 Hz, 1H), 7.45-7.40 (m, 3H), 6.79 (d, J=9.2 Hz, 1H), 4.22 (s, 3H), 3.37-3, 30 (m, 2H), 1.15 (t, J=7.2 Hz, 3H).

[00208] LC-MS (ESI) : m/z 431 [M+H] ⁺ .

[00209] Obtaining example 301 in general method I (method D):

[00210] Step I: 2-(2-methyl-2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)-6-((2,2,2-trifluoroethyl)amino)pyrido[ 3,2-c]pyrazin-3(2H)-one (Example 301)

[00211] To a solution of 6-hydroxy-2-(2-methyl-2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)pyrido[3,2-c]pyrazin-3(2H) -one (100 mg, 0.26 mmol, 1.0 eq.), BOP (173 mg, 0.39 mmol, 1.5 eq.) in DMF (5 ml) was added DIEA (0.13 ml, 0. 78 mmol, 3.0 eq.). The resulting mixture was stirred at room temperature for 30 min, then 2,2,2-trifluoroethane-1-amine (0.06 mL, 0.78 mmol, 3.0 eq) was added and stirred for an additional 2 hours at room temperature. Once complete, the reaction was quenched by adding ice water (10 ml) and extracted with EtOAc (10 ml x 3), dried over Na ₂ SO ₄ and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 2-(2-methyl -2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3,2-c]pyrazin-3(2H) -on (example 301).

[00212] ¹ H NMR (400 MHz, DMSO- d6 ) δ: 8.86 (s, 1H), 8.80 (s, 1H) _, 8.47 (s, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.96 (s, 1H), 7.77 (d, J=9.5 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H) , 7.42 (d, J=9.7 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 6.92 (d, J=9.6 Hz, 1H), 4 .30-4.22 (m, 2H), 4.21 (s, 3H), 2.51 (s, 3H).

[00213] LC-MS (ESI) : m/z 466 [M+H] ⁺ .

[00214] The method given above for General Method I (Method A) was used to prepare the following compounds using suitable starting compounds:

Connection No. Structure Characteristics Example 104
6-ethoxy-2-(2-methyl-2H-indazol-5-yl)-4-(4-(trifluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 482.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.02 (d, J=1.6 Hz, 1H), 7.99 (d, J=9.6 Hz , 1H), 7.92 (d, J=8.8 Hz, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H ), 7.44 (d, J=8.0 Hz, 2H), 6.96 (d, J=9.6 Hz, 1H), 4.34 (kv, J=6.8 Hz, 2H), 4.23 (s, 3H), 1.31 (t, J=7.2 Hz, 3H). Example 105
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(4-methoxyphenyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 476.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 7.99 (d, J=9.6 Hz, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.57 (d , J=8.8 Hz, 2H), 7.30 (t, J _HF =73.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 7.01 (d, J=9.2 Hz, 1H), 6.36 (t, J _HF =54.4 Hz, 1H), 4.55 (td, J _HF =15.2 Hz, J=2.8 Hz, 2H), 3.82 (s, 3H). Example 106
6-(2,2-difluoroethoxy)-4-(4-methoxyphenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 464.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.03 (d, J=9.2 Hz, 1H), 8.01 (s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.50-7.41 (m, 1H), 7.05 (d, J= 9.6 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.41 (t, J _HF =54.4 Hz, 1H), 4.60 (td, J _HF = 14.8 Hz, J=2.8 Hz, 2H), 4.23 (s, 3H), 3.83 (s, 3H). Example 107
4-(6-cyclopropylpyridin-3-yl)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H )-He LC-MS (ESI): m/z 475.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.81 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 8.07 (d, J=1.2 Hz, 1H), 8.04 (s, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.48 (dd, J=8.8 Hz , 1.6 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.09 (d, J=9.2 Hz, 1H), 6.42 (tt, J _HF = 54.5 Hz, J=3.2 Hz, 1H), 4.62 (td, J _HF =15.2, J=3.2 Hz, 2H), 4.24 (s, 3H), 2.23 -2.13 (m, 1H), 1.04-0.98 (m, 4H). Example 108
6-(2,2-difluoroethoxy)-4-(4-(methoxy-d ₃ )phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3 (2H)-he LC-MS (ESI): m/z 467.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.49 (s, 1H), 8.03 (d, J=9.6 Hz, 1H), 8.01 (d, J=1.6 Hz , 1H), 7.80 (d, J=8.8 Hz, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.45 (dd, J=9.2 Hz, 2 .0 Hz, 1H), 7.04 (d, J=9.6 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.41 (tt, J _HF =54, 4 Hz, J=3.2 Hz, 1H), 4.60 (td, J _HF =15.2 Hz, 3.2 Hz, 2H), 4.22 (s, 3H). Example 109
6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4-(4-(trifluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H) -He LC-MS (ESI): m/z 518.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.51 (s, 1H), 8.08 (d, J=9.2 Hz, 1H), 8.04 (d, J=1.6 Hz , 1H), 7.92 (d, J=8.8 Hz, 2H), 7.72 (d, J=9.2 Hz, 1H), 7.48 (dd, J=9.2 Hz, 2 ,0 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.08 (d, J=9.2 Hz, 1H), 6.39 (tt, J _HF =54, 4 Hz, J=3.6 Hz, 1H), 4.58 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H), 4.23 (s, 3H). Example 110
6-ethoxy-4-(4-(methoxy-d ₃ )phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 431.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.49 (s, 1H), 7.99 (s, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.8 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.00 (d , J=8.0 Hz, 2H), 6.93 (d, J=9.2 Hz, 1H), 4.35 (d, J=6.8 Hz, 2H), 4.22 (s, 3H ), 1.33 (t, J=6.8 Hz, 3H). Example 111
4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-6-propoxypyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 478.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.97 (d, J=9.2 Hz , 1H), 7.85 (d, J=8.8 Hz, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.46 (dd, J=9.2 Hz, 2 .0 Hz, 1H), 7.34 (t, J _HF =74.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.96 (d, J=9, 2 Hz, 1H), 4.25 (t, J=6.8 Hz, 2H), 4.23 (s, 3H), 1.72 (kv, J=7.2 Hz, 2H), 0.92 (t, J=7.6 Hz, 3H). Example 112
6-ethoxy-2-(4-methoxyphenyl)-4-(6-methylpyridin-3-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 389.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.82 (d, J=2.0 Hz, 1H), 8.06 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.97 (d, J=9.2 Hz, 1H), 7.59 (dd, J=7.2 Hz, 2.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.08 (dd, J=6.8 Hz, 2.0 Hz, 2H), 6.95 (d, J=9.6 Hz, 1H), 4.32 (kv, J=6, 8 Hz, 2H), 3.83 (s, 3H), 2.51 (s, 3H), 1.31 (t, J=7.2 Hz, 3H). Example 113
4-(4-chlorophenyl)-6-cyclopropoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 444.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.51 (s, 1H), 8.02 (d, J=1.6 Hz, 1H), 7.99 (d, J=9.6 Hz , 1H), 7.93 (dd, J=6.8 Hz, 1.6 Hz, 2H), 7.71 (d, J=9.3 Hz, 1H), 7.53 (dd, J=6 ,8 Hz, 2.0 Hz, 2H), 7.47 (dd, J=8.8 Hz, 1.6Hz, 1H), 6.93 (d, J=9.2 Hz, 1H), 4, 28-4.24 (m, 1H), 4.29 (s, 3H), 0.91-0.83 (m, 4H). Example 114
4-(4-cyclopropylphenyl)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 474.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.03 (d, J=9.6 Hz, 1H), 8.01 (d, J=2.0 Hz , 1H), 7.72-7.68 (m, 3H), 7.45 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.14 (d, J=8.8 Hz , 2H), 7.04 (d, J=9.6 Hz, 1H), 6.40 (td, J _HF =54.4 Hz, J=3.6 Hz, 1H), 4.58 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H), 4.22 (s, 3H), 2.01-1.95 (m, 1H), 1.04-0.97 (m, 2H), 0.77-0.70 (m, 2H). Example 115
6-ethoxy-4-(4-methoxyphenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 428.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.49 (s, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.94 (d, J=9.6 Hz , 1H), 7.80 (d, J=8.8 Hz, 2H), 7.70 (d, J=9.2 Hz, 1H), 7.45 (dd, J=9.2 Hz, 2 .0 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H), 6.93 (d, J=9.2 Hz, 1H), 4.35 (kv, J=7.2 Hz, 2H), 4.22 (s, 3H), 3.82 (s, 3H), 1.33 (t, J=7.2 Hz, 3H). Example 116
4-(4-chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)-6-(2,2,2-trifluoroethoxy)pyrido[3,2-c]pyrazin-3(2H)- He LC-MS (ESI): m/z 486.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.11 (d, J=9.4 Hz, 1H), 8.03 (s, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.47 (d , J=9.7 Hz, 1H), 7.12 (d, J=9.4 Hz, 1H), 4.99 (kv, J _HF =8.9 Hz, 2H), 4.22 (s, 3H). Example 117
4-(4-chlorophenyl)-6-ethoxy-2-(4-methoxyphenyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 408.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 7.95 (d, J=9.3 Hz, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.59 (d , J=8.6 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.08 (d, J=8.6 Hz, 2H), 6.93 (d, J =9.4 Hz, 1H), 4.32 (kv, J=6.8 Hz, 2H), 3.84 (s, 3H), 1.31 (t, J=6.9 Hz, 3H). Example 118
4-(4-chlorophenyl)-2-(4-methoxyphenyl)-6-(2,2,2-trifluoroethoxy)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 462.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.09 (d, J=9.4 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.61 (d , J=8.9 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.14-7.07 (m, 3H), 4.98 (kv, J _HF =8 .9 Hz, 2H), 3.84 (s, 3H). Example 119
4-(4-chlorophenyl)-6-ethoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 432.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.98 (d, J=9.4 Hz , 1H), 7.81 (d, J=9.7 Hz, 2H), 7.71 (d, J=9.1 Hz, 1H), 7.51 (d, J=8.5 Hz, 2H ), 7.46 (dd, J=9.1 Hz, 1.8 Hz, 1H), 6.95 (d, J=9.4 Hz, 1H), 4.34 (kv, 2H), 4, 23 (s, 3H), 1.32 (t, J=7.0 Hz, 3H). Example 120
4-(6-(difluoromethoxy)pyridin-3-yl)-6-ethoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 465.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.70 (d, J=2.1 Hz, 1H), 8.52 (s, 1H), 8.36 (dd, J=8.5 Hz , 2.2 Hz, 1H), 8.02 (d, J=9.7 Hz, 2H), 7.82 (t, J _HF =72.0 Hz, 1H), 7.74 (d, J= 9.1 Hz, 1H), 7.49 (dd, J=9.0 Hz, 1.9 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.00 (d , J=9.4 Hz, 1H), 4.38 (kv, J=7.0 Hz, 2H), 4.24 (s, 3H), 1.35 (t, J=7.0 Hz, 3H ). Example 121
6-ethoxy-2-(2-methyl-2H-indazol-5-yl)-4-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 483.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.78 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.49-8.42 (m, 1H) , 8.04 (d, J=9.3 Hz, 2H), 7.74 (d, J=9.0 Hz, 1H), 7.49 (d, J=9.1 Hz, 1H), 7 .43 (d, J=8.5 Hz, 1H), 7.01 (d, J=9.5 Hz, 1H), 4.37 (kv, J=7.0 Hz, 2H), 4.24 (s, 3H), 1.34 (t, J=7.0 Hz, 3H). Example 122
4-(6-(difluoromethoxy)pyridin-3-yl)-6-ethoxy-2-(4-methoxyphenyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 441.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.66 (d, J=1.9 Hz, 1H), 8.32 (dd, J=8.6 Hz, 2.4 Hz, 1H), 7.98 (d, J=9.4 Hz, 1H), 7.80 (t, J _HF =72 Hz, 1H), 7.67-7.57 (m, 2H), 7.24-7, 15 (m, 1H), 7.15-7.05 (m, 2H), 6.97 (d, J=9.4 Hz, 1H), 4.35 (kv, J=7.1 Hz, 2H ), 3.84 (s, 3H), 1.32 (t, J=7.1 Hz, 3H). Example 123
4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-6-(2,2,2-trifluoroethoxy)pyrido[3,2-c]pyrazin-3( 2H)-on LC-MS (ESI): m/z 518.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.10 (d, J=9.4 Hz, 1H), 8.03 (d, J=1.4 Hz , 1H), 7.88 (d, J=8.0 Hz, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.47 (dd, J=9.1 Hz, 2 .0 Hz, 1H), 7.35 (t, J _HF =72.0 Hz, 1H), 7.25 (d, J _HF =8.8 Hz, 2H), 7.11 (d, J=9 .4 Hz, 1H), 5.00 (kv, J=9.0 Hz, 2H), 4.22 (s, 3H). Example 124
4-(4-chlorophenyl)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 468.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.07 (d, J=9.2 Hz, 1H), 8.02 (d, J=1.6 Hz , 1H), 7.83 (d, J=8.4 Hz, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H ), 7.47 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.07 (d, J=9.6 Hz, 1H), 6.38 (tt, J _HF =54, 4 Hz, J=3.2 Hz, 1H), 4.59 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H), 4.23 (s, 3H). Example 125
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H) -He LC-MS (ESI): m/z 500.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.06 (d, J=9.6 Hz, 1H), 8.02 (d, J=1.2 Hz , 1H), 7.87 (d, J=8.8 Hz, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.46 (dd, J=9.2 Hz, 2 .0 Hz, 1H), 7.34 (t, J _HF =74.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.06 (d, J=9, 6 Hz, 1H), 6.40 (td, J _HF =54.4 Hz, J=3.2 Hz, 1H), 4.59 (td, J _HF =15.2 Hz, J=3.2 Hz , 2H), 4.22 (s, 3H). Example 126
6-(2,2-difluoroethoxy)-4-(6-(difluoromethoxy)pyridin-3-yl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin- 3(2H)-one LC-MS (ESI): m/z 501.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.68 (d, J=2.4 Hz, 1H), 8.51 (s, 1H), 8.34 (dd, J=8.4 Hz , 2.4 Hz, 1H), 8.09 (d, J=9.2 Hz, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.80 (t, J _HF = 74.0 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.47 (dd, J=9.2 Hz, 1.6 Hz, 1H), 7.20 (d , 1H), 7.09 (d, J=8.8 Hz, 1H), 6.41 (td, J _HF =54.4 Hz, J=3.2 Hz, 1H), 4.61 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H), 4.22 (s, 3H). Example 127
6-ethoxy-2-(2-methyl-2H-indazol-5-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 467.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.15 (s, 1H), 8.52 (s, 1H), 8.49 (d, J=6.8 Hz, 1H), 8.06 -8.02 (m, 3H), 7.73 (d, J=8.8 Hz, 1H), 7.49 (dd, J=8.8 Hz, 1.6 Hz, 1H), 7.01 (d, J=9.6 Hz, 1H), 4.35 (kv, J=7.2 Hz, 2H), 4.23 (s, 3H), 1.32 (t, J=7.2 Hz , 3H). Example 128
6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[3,2-c]pyrazin- 3(2H)-one LC-MS (ESI): m/z 519.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.77 (s, 1H), 8.51 (s, 1H), 8.43 (dd, J=8.8 Hz, 2.0 Hz, 1H ), 8.10 (d, J=9.6 Hz, 1H), 8.04 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.47 (dd, J =8.8 Hz, 1.6 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.10 (d, J=9.6 Hz, 1H), 6.40 ( tt, J _HF =54.4 Hz, J=3.2 Hz, 1H), 4.60 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H), 4.22 (s, 3H). Example 129
4-(4-(difluoromethoxy)phenyl)-6-(2-fluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 482.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.03-8.01 (m, 2H), 7.86 (dd, J=6.8 Hz, 2, 0 Hz, 2H), 7.70 (d, J=8.8 Hz, 1H), 7.45 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.34 (t, J _HF =74.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.02 (d, J=9.6 Hz, 1H), 4.82-4.80 ( m, 1H), 4.70-4.69 (m, 1H), 4.58-4.56 (m, 1H), 4.51-4.49 (m, 1H), 4.22 (s, 3H). Example 130
6-(2,2-difluoroethoxy)-4-(6-methoxypyridin-3-yl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H )-He LC-MS (ESI): m/z 465.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.64 (d, J=1.2 Hz, 1H), 8.51 (s, 1H), 8.16 (dd, J=8.4 Hz , 2.0 Hz, 1H), 8.06 (d, J=9.6 Hz, 1H), 8.03 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.47 (dd, J=9.2 Hz, 1.2 Hz, 1H), 7.08 (d, J=9.6 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.42 (t, J _HF =54.4 Hz, 1H), 4.62 (td, J _HF =14.8 Hz, J= 2.8 Hz, 2H), 4.23 (s, 3H), 3.93 (s, 3H). Example 131
6-(cyclobutylmethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 504.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.97 (d, J=13.6 Hz , 1H), 7.86 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.46 (dd, J=9.2 Hz, 2 .0 Hz, 1H), 7.35 (t, J _HF =74.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.96 (d, J=9, 2 Hz, 1H), 4.30 (d, J=6.8 Hz, 2H), 4.23 (s, 3H), 2.8-2.63 (m, 1H), 2.11-1, 97 (m, 2H), 1.92-1.70 (m, 4H). Example 132
4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-6-(3,3,3-trifluoropropoxy)pyrido[3,2-c]pyrazin-3( 2H)-he-he LC-MS (ESI): m/z 532.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.51 (s, 1H), 8.03 (d, J=9.6 Hz, 1H), 8.02 (d, J=1.6 Hz , 1H), 7.86 (d, J=8.8 Hz, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.46 (dd, J=9.2 Hz, 2 .0 Hz, 1H), 7.34 (t, J _HF =72.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.97 (d, J=9, 6 Hz, 1H), 4.53 (t, J=6.0 Hz, 2H), 4.23 (s, 3H), 2.87-2.75 (m, 2H). Example 133
6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4-phenylpyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 434.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 8.02 (d, J=2.0 Hz , 1H), 7.76 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.48-7.39 (m, 4H), 7 .06 (d, J=9.6 Hz, 1H), 6.39 (td, J _HF =54.4 Hz, J=3.2 Hz, 1H), 4.56 (td, J _HF =15, 2 Hz, J=3.6 Hz, 2H), 4.22 (s, 3H). Example 134
6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4-(pyridin-4-yl)pyrido[3,2-c]pyrazin-3(2H)- He LC-MS (ESI): m/z 435.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.67 (d, J=5.6 Hz, 2H), 8.51 (s, 1H), 8.10 (d, J=9.6 Hz , 1H), 8.04 (d, J=1.2 Hz, 1H), 7.75 (d, J=6.0 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H ), 7.72 (d, J=9.2 Hz, 1H), 7.47 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.09 (d, J=9.2 Hz, 1H), 6.40 (td, J _HF =54.0 Hz, J=3.2 Hz, 1H), 4.59 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H), 4.22 (s, 3H). Example 135
4-(4-(difluoromethoxy)phenyl)-6-ethoxy-2-(4-methoxyphenyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 440.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.01 (d, J=9.6 Hz, 1H), 7.90 (d, J=8.8 Hz, 2H), 7.65 (d , J=8.8 Hz, 2H), 7.41 (t, J _HF =74.0 Hz, 1H), 7.30 (d, J=8.8 Hz, 2H), 7.15 (d, J=9.2 Hz, 2H), 7.00 (d, J=9.2 Hz, 1H), 4.39 (kv, J=7.2 Hz, 2H), 3.90 (s, 3H) , 1.37 (t, J=7.2 Hz, 3H). Example 136
6-ethoxy-2-(4-methoxyphenyl)-4-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 459.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.74 (d, J=2.4 Hz, 1H), 8.40 (dd, J=8.8 Hz, 2.0 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.60 (d, J=9.2 Hz, 2H), 7.40 (d, J=8.4 Hz, 1H), 7, 09 (d, J=8.8 Hz, 2H), 6.98 (d, J=9.2 Hz, 1H), 4.34 (kv, J=7.2 Hz, 2H), 3.84 ( s, 3H), 1.31 (t, J=7.2 Hz, 3H). Example 137
6-(cyclopropylmethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 490.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.49 (s, 1H), 8.00 (dd, J=2.0 Hz, 0.8 Hz, 1H), 7.97 (d, J =9.2 Hz, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 1H), 7.45 (dd, J=9 .2 Hz, 2.0 Hz, 1H), 7.34 (t, J _HF =74.0 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 6.98 (d , J=9.2 Hz, 1H), 4.22 (s, 3H), 4.15 (d, J=7.2 Hz, 2H), 1.28-1.08 (m, 1H), 0 .62-0.42 (m, 2H), 0.32-0.13 (m, 2H). Example 138
4-(4-(difluoromethoxy)phenyl)-6-isopropoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 478.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.49 (s, 1H), 8.00 (dd, J=2.0 Hz, 0.8 Hz, 1H), 7.96 (d, J =9.2 Hz, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 1H), 7.45 (dd, J=9 .2 Hz, 2.0 Hz, 1H), 7.34 (t, J _HF =74.0 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 6.90 (d , J=9.2 Hz, 1H), 5.23-5.08 (m, 1H), 4.22 (s, 3H), 1.30 (d, J=6.0 Hz, 6H). Example 139
6-(2,2-difluoroethoxy)-4-(6-(methoxy-d ₃ )pyridin-3-yl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c ]pyrazin-3(2H)-one LC-MS (ESI): m/z 468.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.64 (d, J=1.2 Hz, 1H), 8.51 (s, 1H), 8.16 (dd, J=8.4 Hz , 2.0 Hz, 1H), 8.07 (d, J=9.6 Hz, 1H), 8.03 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.47 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.08 (d, J=9.6 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.43 (td, J _HF =54.4 Hz, J=3.2 Hz, 1H), 4.62 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H) , 4.23 (s, 3H). Example 140
4-(3-chlorophenyl)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 468.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 (s, 1H), 8.07 (d, J=9.2 Hz, 1H), 8.03 (s, 1H), 7.84 ( s, 1H), 7.75-7.74 (m, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.48-7.46 (m, 3H), 7.07 (d, J=9.2 Hz, 1H), 6.40 (t, J _HF =54.4 Hz, 1H), 4.58 (t, J _HF =14.0 Hz, 2H), 4.22 (c, 3H). Example 141
4-(4-(difluoromethoxy)phenyl)-6-isobutoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 492.5 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.49 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.97 (d, J=9.2 Hz , 1H), 7.85 (d, J=9.6 Hz, 2H), 7.70 (d, J=9.2 Hz, 1H), 7.45 (dd, J=9.2 Hz, 2 .0 Hz, 1H), 7.33 (t, J _HF =74.0 Hz, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.96 (d, J=9, 2 Hz, 1H), 4.22 (s, 3H), 4.09 (d, J=6.8 Hz, 2H), 2.10-1.98 (m, 1H), 0.92 (d, J=6.7 Hz, 6H). Example 142
(prepared using ( E )-methyl 4-(tetrahydro-2H-pyran-2-yloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but- 2-enoate (ref: Tetrahedron 2012, 68 , 3444-3449)
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-8-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 614.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.51 (s, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.85 (d, J=8.8 Hz , 2H), 7.71 (d, J=9.2 Hz, 1H), 7.48 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.34 (t, J _HF = 74.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.95 (s, 1H), 6.40 (tt, J _HF =54.4 Hz, J=3 ,2 Hz, 1H), 4.98 (d, J=16.4 Hz, 1H), 4.83 (d, J=16.4 Hz, 2H), 4.59 (td, J _HF =15, 2 Hz, J=3.2 Hz, 2H), 4.23 (s, 3H), 3.79-3.74 (m, 1H), 3.49-3.40 (m, 1H), 1, 83-1.45 (m, 6H). Example 143 2-(benzo[d]thiazol-6-yl)-4-(4-chlorophenyl)-6-(2,2-difluoroethoxy)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 471 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 9.55 (s, 1H), 8.55 (d, J=2.1 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 8.08 (d, J=9.4 Hz, 1H), 7.92-7.79 (m, 3H), 7.60-7.47 (m, 2H), 7.11 (d , J=9.4 Hz, 1H), 6.42 (td, J=54.3, 3.3 Hz, 1H), 4.61 (td, J=15.2, 3.3 Hz, 2H) . Example 144 2-(benzo[d]thiazol-6-yl)-6-(2,2-difluoroethoxy)-4-(4-methoxyphenyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 467 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 9.54 (s, 1H), 8.53 (s, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.03 ( d, J=9.4 Hz, 1H), 7.94-7.70 (m, 3H), 7.12-6.96 (m, 3H), 6.42 (t, J=54.3 Hz , 1H), 4.61 (td, J=15.2, 3.3 Hz, 2H), 3.83 (s, 3H). Example 145
2-(benzo[d]thiazol-6-yl)-4-(4-(difluoromethoxy)phenyl)-6-ethoxypyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 467 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 8.53 (d, J=2.1 Hz, 1H), 8.24 (d, J=8.7 Hz, 1H), 7.97 (d, J=9.4 Hz, 1H), 7.91-7.80 (m, 3H), 7.35 (t, J=74.0 Hz, 1H), 7. 25 (d, J=8.8 Hz, 2H), 6.97 (d, J=9.4 Hz, 1H), 4.34 (kv, J=7.1 Hz, 2H), 1.32 ( t, J=7.1 Hz, 3H). Example 146
2-(benzo[d]thiazol-6-yl)-4-(4-(difluoromethoxy)phenyl)-6-isopropoxypyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 481 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.24 (d, J=8.7 Hz, 1H), 7.96 (d, J=9.4 Hz, 1H), 7.83 (m, 3H), 7.35 (t, J=74.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.92 (d, J=9.4 Hz, 1H), 5.16 (hept, J=6.6 Hz, 1H), 1.31 (d, J= 6.2 Hz, 6H). Example 147 2-(benzo[d]thiazol-6-yl)-4-(6-cyclopropylpyridin-3-yl)-6-(2,2-difluoroethoxy)pyrido[3,2-c]pyrazin-3(2H)- He LC-MS (ESI): m/z 478 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 8.86 (d, J=2.1 Hz, 1H), 8.59 (d, J=2.1 Hz, 1H), 8.31 (d, J=8.7 Hz, 1H), 8.18-8.02 (m, 2H), 7.90 (dd, J=8.7, 2.1 Hz, 1H ), 7.45 (d, J=8.1 Hz, 1H), 7.15 (d, J=9.4 Hz, 1H), 6.46 (tt, J=54.3, 3.4 Hz , 1H), 4.66 (td, J=15.1, 3.4 Hz, 2H), 2.23 (td, J=7.7, 5.0 Hz, 1H), 1.10-0, 98 (m, 4H). Example 148 2-(benzo[d]thiazol-6-yl)-6-(2,2-difluoroethoxy)-4-(6-(difluoromethoxy)pyridin-3-yl)pyrido[3,2-c]pyrazine-3( 2H)-on LC-MS (ESI): m/z 504 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 9.54 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.35 (dd, J=8.6, 2.4 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.09 (d, J=9.4 Hz, 1H), 7.86 (dd, J=8.7, 2.2 Hz, 1H), 7.80 (t, J=72.8 Hz, 1H), 7.21 (d, J=8 .6 Hz, 1H), 7.11 (d, J=9.4 Hz, 1H), 6.41 (td, J=54.2, 3.3 Hz, 1H), 4.62 (td, J =15.1, 3.4 Hz, 3H). Example 149 6-(2,2-difluoroethoxy)-4-(4-hydroxycyclohex-1-en-1-yl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazine -3(2H)-on LC-MS: m/z 454.2 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.47 (s, 1H), 7.99-7.94 (m, 2H), 7.68 (d, J=9.2 Hz, 1H) , 7.39 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.00 (d, J=9.6 Hz, 1H), 6.46 (tt, J _HF =54.4 Hz, 3.6 Hz, 1H), 5.86-5.80 (m, 1H), 4.74 (d, J=4.0 Hz, 1H), 4.71 (td, J=14.8 Hz, 3.6 Hz, 2H), 4.19 (s, 3H), 3.92-3.79 (m, 1H), 2.51-2.41 (m, 3H), 2.15-2 .02 (m, 1H), 1.95-1.85 (m, 1H), 1.65-1.53 (m, 1H). Example 150
6-(2,2-difluoroethoxy)-4-(1H-indol-5-yl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H )-He LC-MS: m/z 473.1 (M+H)+.
1H NMR (400 MHz, DMSO- _d6 ) δ: 11.18 (br s, 1H), 8.49 (s, 1H), 8.06-8.01 (m, 3H), 7.71 (d , J=9.2 Hz, 1H), 7.56 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.47 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.36 (t, J=2.8 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H) , 6.49-6.46 (m, 1H), 6.40 (td, J _HF =54.8 Hz, 3.6 Hz, 1H), 4.56 (td, J=14.8 Hz, 3 .6 Hz, 2H), 4.22 (s, 3H). Example 151 2-(benzo[d]thiazol-6-yl)-6-(2,2-difluoroethoxy)-4-(4-methoxy-d ₃ -phenyl)pyrido[3,2-c]pyrazin-3(2H) -He LC-MS: m/z 470.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.52 (s, 1H), 8.52 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.03 (d, J=9.2 Hz, 1H), 7.87-7.76 (m, 3H), 7.06 (d, J=9.6 Hz, 1H), 7.01 (d, J= 8.8 Hz, 2H), 6.41 (td, J _HF =54.4 Hz, 3.2 Hz, 1H), 4.60 (td, J=14.8 Hz, 3.2 Hz, 2H) . Example 152 6-(2,2-difluoroethoxy)-4-(4-methoxycyclohex-1-en-1-yl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazine -3(2H)-on LC-MS: m/z 468.2 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.47 (s, 1H), 7.99-7.93 (m, 2H), 7.68 (d, J=9.2 Hz, 1H) , 7.39 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.01 (d, J=9.6 Hz, 1H), 6.46 (tt, J _HF =56.4 Hz, 3.6 Hz, 1H), 5.88-5.82 (m, 1H), 4.71 (td, J _HF =15.2 Hz, 3.6 Hz, 2H), 4.21 (s , 3H), 3.60-3.51 (m, 1H), 3.31 (s, 3H), 2.61-2.41 (m, 3H) 2.21-2.09 (m, 1H) , 2.04-1.94 (m, 1H), 1.72-1.58 (m, 1H). Example 153 6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4-(1H-pyrazol-5-yl)pyrido[3,2-c]pyrazin-3(2H )-one (derived from 4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione and tert-butyl 5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate, then removing Boc TFA-DCM) LC-MS: m/z 424.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 13.31 (br s, 1H), 8.52 (s, 1H), 8.13 (d, J=9.2 Hz, 1H), 8, 02 (d, J=1.2 Hz, 1H), 7.76-7.69 (m, 2H), 7.56-7.50 (m, 1H), 7.47 (dd, J=9, 2 Hz, 1.6 Hz, 1H), 6.78 (d, J=9.2 Hz, 1H), 6.55 (tt, J _HF =54.0 Hz, 3.2 Hz, 1H), 4 .92 (td, J=14.8 Hz, 3.2 Hz, 2H), 4.23 (s, 3H). Example 302
6-(cyclopropylmethoxy)-2-(2-methyl-2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 439 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.82 (d, J=1.8 Hz, 1H), 8.49 (s, 1H), 8.07 (dd, J=8.0 Hz , 2.2 Hz, 1H), 8.01 (dd, J=2.0 Hz, 0.7 Hz, 1H), 7.99 (d, J=9.4 Hz, 1H), 7.70 ( d, J=9.1 Hz, 1H), 7.45 (dd, J=9.1 Hz, 2.0 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 6 .99 (d, J=9.4 Hz, 1H), 4.22 (s, 3H), 4.16 (d, J=7.3 Hz, 2H), 2.53 (s, 3H), 1 .27-1.17 (m, 1H), 0.58-0.50 (m, 2H), 0.33-0.25 (m, 2H). Example 303
6-(cyclopropylmethoxy)-4-(6-cyclopropylpyridin-3-yl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 465 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.77 (d, J=1.8 Hz, 1H), 8.49 (s, 1H), 8.03 (dd, J=8.1 Hz , 2.2 Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 7.98 (d, J=9.4 Hz, 1H), 7.70 (d, J=9 .2 Hz, 1H), 7.45 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 6.99 (d, J=9.4 Hz, 1H), 4.22 (s, 3H), 4.16 (d, J=7.3 Hz, 2H), 2.21-2.11 (m, 1H), 1, 25-1.21 (m, 1H), 1.05-0.93 (m, 4H), 0.59-0.47 (m, 2H), 0.33-0.22 (m, 2H). Example 304
2-(benzo[d]thiazol-6-yl)-4-(4-cyclopropylphenyl)-6-(2,2-difluoroethoxy)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 477 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.53 (s, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.23 (d, J=8.7 Hz , 1H), 8.03 (d, J=9.4 Hz, 1H), 7.83 (dd, J=8.7 Hz, 2.1 Hz, 1H), 7.70 (d, J=8 .3 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.07 (d, J=9.4 Hz, 1H), 6.40 (tt, J _HF =54, 4 Hz, J=3.3 Hz, 1H), 4.59 (td, J _HF =15.1 Hz, J=3.3 Hz, 2H), 2.07-1.90 (m, 1H), 1.08-0.95 (m, 2H), 0.84-0.64 (m, 2H).

[00215] The method given above for General Method I (Method C) was used to prepare the following compounds using suitable starting compounds:

Connection No. Structure Characteristics Example 154
4-(4-chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3,2-c]pyrazin-3( 2H)-on LC-MS (ESI): m/z 485.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.83 (t, J=6.0 Hz, 1H), 8.47 (s, 1H), 7.96 (d, J=1.2 Hz , 1H), 7.78-7.76 (m, 3H), 7.68 (d, J=9.2 Hz, 1H), 7.45-7.41 (m, 3H), 6.92 ( d, J=9.2 Hz, 1H), 4.27-4.17 (m, 2H), 4.21 (s, 3H). Example 155
4-(4-chlorophenyl)-6-(cyclopropylamino)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 443.0 [M+H]+.
1H NMR (400 MHz, DMSO- _d6 ) δ: 8.46 (s, 1H), 8.45 (s, 1H), 7.97-7.95 (m, 3H), 7.67 (d, J=9.2 Hz, 1H), 7.61 (d, J=9.2 Hz, 1H), 7.45-7.41 (m, 3H), 6.73 (d, J=8.4 Hz, 1H), 4.22 (s, 3H), 2.88-2.86 (m, 1H), 0.76-0.74 (m, 2H), 0.59-0.54 (m, 2H). Example 156
4-(4-chlorophenyl)-6-((2,2-difluoroethyl)amino)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H) -He LC-MS (ESI): m/z 467.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.67 (t, J=6.0 Hz, 1H), 8.47 (s, 1H), 7.96 (d, J=2.0 Hz , 1H), 7.79 (d, J=8.8 Hz, 2H), 7.73 (d, J=9.2 Hz, 1H), 7.68 (d, J=9.2 Hz, 1H ), 7.45-7.41 (m, 3H), 6.90 (d, J=9.2 Hz, 1H), 6.17 (tt, J _HF =56.0 Hz, J=3.6 Hz, 1H), 4.22 (s, 3H), 3.79-3.69 (m, 2H). Example 157
6-(2-fluoroethoxy)-4-(4-(methoxy-d ₃ )phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H )-He LC-MS (ESI): m/z 449.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.49 (s, 1H), 8.00-7.98 (m, 2H), 7.79 (d, J=8.8 Hz, 2H) , 7.71 (d, J=9.2 Hz, 1H), 7.45 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.01-6.99 (m, 3H) , 4.83 (t, J=4.0 Hz, 1H), 4.71 (t, J=4.0 Hz, 1H), 4.59 (t, J=4.0 Hz, 1H), 4 .51 (t, J=4.0 Hz, 1H), 4.23 (s, 3H). Example 158
4-(4-(difluoromethoxy)phenyl)-6-(ethylthio)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 480.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.86-7.83 (m, 3H) , 7.71 (d, J=9.2 Hz, 1H), 7.47 (dd, J=8.8 Hz, 1.6 Hz, 1H), 7.34 (t, J _HF =74.0 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.21 (d, J=9.2 Hz, 1H), 4.23 (s, 3H), 3.08 ( kv, J=7.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H). Example 159
4-(4-(difluoromethoxy)phenyl)-6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 463.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.46 (s, 1H), 8.32 (t, J=5.2 Hz, 1H), 7.94 (d, J=1.2 Hz , 1H), 7.86 (d, J=8.8 Hz, 2H), 7.67 (d, J=9.2 Hz, 1H), 7.61 (d, J=9.6 Hz, 1H ), 7.41 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.31 (t, J _HF =74.0 Hz, 1H), 7.18 (d, J=8, 8 Hz, 2H), 6.79 (d, J=9.6 Hz, 1H), 4.22 (s, 3H), 3.45-3.21 (m, 2H), 1.15 (t, J=7.2 Hz, 3H). Example 160
4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3,2-c]pyrazine -3(2H)-on LC-MS (ESI): m/z 517.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.80 (t, J=6.4 Hz, 1H), 8.47 (s, 1H), 7.96 (d, J=2.0 Hz , 1H), 7.81 (d, J=8.8 Hz, 2H), 7.77 (d, J=9.6 Hz, 1H), 7.68 (d, J=9.2 Hz, 1H ), 7.42 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.32 (t, J _HF =74.0 Hz, 1H), 7.18 (d, J=8, 8 Hz, 2H), 6.91 (d, J=9.6 Hz, 1H), 4.27-4.18 (m, 2H), 4.21 (s, 3H). Example 161
4-(4-(difluoromethoxy)phenyl)-6-(ethoxy-d ₅ )-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)- He LC-MS (ESI): m/z 469.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.43 (s, 1H), 7.94 (d, J=1.6 Hz, 1H), 7.91 (d, J=9.2 Hz , 1H), 7.80 (d, J=8.8 Hz, 2H), 7.64 (d, J=9.2 Hz, 1H), 7.39 (dd, J=8.8 Hz, 2 ,0 Hz, 1H), 7.28 (t, J _HF =74.0 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 6.88 (d, J=9, 6 Hz, 1H), 4.16 (s, 3H). Example 162
6-(cyclopropylamino)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 475.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.47 (s, 1H), 8.42 (d, J=4.4 Hz, 1H), 8.00 (d, J=9.2 Hz , 2H), 7.95 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.61 (d, J=9.6 Hz, 1H ), 7.42 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.30 (t, J _HF =74.0 Hz, 1H), 7.18 (d, J=8, 8 Hz, 2H), 6.73 (d, J=9.6 Hz, 1H), 4.22 (s, 3H), 2.89-2.86 (m, 1H) 0.77-0.73 (m, 2H), 0.58-0.54 (m, 2H). Example 163
4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-6-(pyrrolidin-1-yl)pyrido[3,2-c]pyrazin-3(2H) -He 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.73 (d, J=9.7 Hz, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.43 (dd, J=9.1, 2.0 Hz, 1H), 7.31 (t, J=74.3 Hz, 1H), 7.20-7.15 (m, 2H), 7.06 (d, J=9.7 Hz, 1H), 4.21 (s, 3H), 3.64 (t, J=6.8 Hz, 2H), 3.55 (t, J=6.8 Hz, 2H), 1.99 (p, J=6 .2 Hz, 2H), 1.89 (p, J=6.4 Hz, 2H). Example 164
6-(azetidin-1-yl)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H) -He 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (s, 1H), 7.94 (dd, J=2.0, 0.8 Hz, 1H), 7.92-7.84 (m , 2H), 7.70 (d, J=9.5 Hz, 1H), 7.70-7.63 (m, 1H), 7.42 (dd, J=9.2, 2.0 Hz, 1H), 7.30 (t, J=74.2 Hz, 1H), 7.16 (d, J=8.9 Hz, 2H), 6.80 (d, J=9.5 Hz, 1H) , 4.36-4.26 (m, 2H), 4.21 (s, 3H), 4.14-4.04 (m, 2H), 2.34 (h, J=7.3 Hz, 2H ). Example 165 4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-6-((2,2,2-trifluoroethyl)thio)pyrido[3,2-c]pyrazine -3(2H)-on LC-MS: m/z 534.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.51 (s, 1H), 8.04 (d, J=1.2 Hz, 1H), 7.99 (d, J=9.2 Hz , 2H), 7.80 (d, J=8.8 Hz, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.48 (dd, J=9.2 Hz, 2 .0 Hz, 1H), 7.38 (d, J=9.2 Hz, 1H), 7.33 (t, J _HF =74.0 Hz, 1H), 7.24 (d, J=8, 8 Hz, 2H), 4.22 (s, 3H), 4.19 (kv, J=10.4 Hz, 2H). Example 305
6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 412 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.84 (d, J=2.0 Hz, 1H), 8.46 (s, 1H), 8.36 (t, J=5.3 Hz , 1H), 8.07 (dd, J=8.0 Hz, 2.2 Hz, 1H), 7.93 (d, J=1.4 Hz, 1H), 7.66 (d, J=9 ,2 Hz, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.41 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 6.80 (d, J=9.5 Hz, 1H), 4.21 (s, 3H), 3.21 (br, 2H), 2.5 (s, 3H), 1.13 (t, J=7.2 Hz, 3H). Example 306
6-(cyclopropylamino)-2-(2-methyl-2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 424 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.95 (s, 1H), 8.52 (d, J=4.1 Hz, 1H), 8.46 (s, 1H), 8.19 (dd, J=8.1 Hz, 2.1 Hz, 1H), 7.94 (s, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.61 (d, J =9.4 Hz, 1H), 7.41 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 6.75 ( d, J=9.5 Hz, 1H), 4.21 (s, 3H), 2.89-2.82 (m, 1H), 2.51 (s, 3H), 0.76-0.72 (m, 2H), 0.59-0.54 (m, 2H). Example 307
6-(ethylamino)-4-(6-methoxypyridin-3-yl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 428 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.61 (d, J=2.3 Hz, 1H), 8.45 (s, 1H), 8.36 (d, J=5.8 Hz , 1H), 8.13 (dd, J=8.6 Hz, 2.3 Hz, 1H), 7.93 (d, J=1.3 Hz, 1H), 7.66 (d, J=9 ,1 Hz, 1H), 7.60 (d, J=9.5 Hz, 1H), 7.40 (dd, J=9.1 Hz, 2.0 Hz, 1H), 6.85 (d, J=8.9 Hz, 1H), 6.82 (d, J=8.9 Hz, 1H), 4.21 (s, 3H), 3.89 (s, 3H), 3.45 (s, 2H), 1.14 (t, J=7.2 Hz, 3H). Example 308
6-(cyclopropylamino)-4-(6-methoxypyridin-3-yl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 440 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.72 (s, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.27 (d, J=8, 4 Hz, 1H), 7.94 (s, 1H), 7.67 (d, J=9.1 Hz, 1H), 7.60 (d, J=9.4 Hz, 1H), 7.41 (dd, J=9.2 Hz, 1.9 Hz, 1H), 6.83 (s, 1H), 6.78 (s, 1H), 4.21 (s, 3H), 3.88 (s , 3H), 2.89-2.82 (m, 1H), 0.76-0.72 (m, 2H), 0.59-0.54 (m, 2H). Example 309
4-(6-cyclopropylpyridin-3-yl)-6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 438 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.77 (d, J=2.0 Hz, 1H), 8.45 (s, 1H), 8.33 (d, J=5.5 Hz , 1H), 8.03 (dd, J=8.1 Hz, 2.2 Hz, 1H), 7.93 (d, J=1.4 Hz, 1H), 7.66 (d, J=9 ,1 Hz, 1H), 7.60 (d, J=9.5 Hz, 1H), 7.40 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 6.78 (d, J=9.6 Hz, 1H), 4.20 (s, 3H), 3.24 (br, 2H), 2.14-2, 11 (m, 1H), 1.14 (t, J=7.2 Hz, 3H), 0.97-0.94 (m, 4H). Example 310
4-(6-(difluoromethyl)pyridin-3-yl)-6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H) -He LC-MS: m/z 448 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.06 (s, 1H), 8.52-8.43 (m, 2H), 8.38 (dd, J=8.1 Hz, 1, 9 Hz, 1H), 7.96 (d, J=1.4 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.67 (d, J=9.2 Hz , 1H), 7.65 (d, J=9.6 Hz, 1H), 7.42 (dd, J=9.1 Hz, 2.0 Hz, 1H), 6.99 (t, J _HF = 55.1 Hz, 1H), 6.82 (d, J=9.6 Hz, 1H), 4.21 (s, 3H), 3.34 (br, 2H), 1.14 (t, J= 7.2 Hz, 3H). Example 311
2-(benzo[d]thiazol-6-yl)-4-(4-cyclopropylphenyl)-6-(ethylamino)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 440 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.49 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.29 (t, J=5.7 Hz , 1H), 8.19 (d, J=8.6 Hz, 1H), 7.77 (dd, J=8.8 Hz, 2.1 Hz, 1H), 7.69 (d, J=8 .3 Hz, 2H), 7.59 (d, J=9.5 Hz, 1H), 7.07 (d, J=8.3 Hz, 2H), 6.79 (d, J=9.6 Hz, 1H), 3.41 (br, 2H), 1.98-1.92 (m, 1H), 1.14 (t, J=7.2 Hz, 3H), 1.02-0.91 (m, 2H), 0.76-0.62 (m, 2H). Example 312
4-(4-cyclopropylphenyl)-6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 437 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.45 (s, 1H), 8.22 (t, J=5.6 Hz, 1H), 7.91 (s, 1H), 7.67 (t, J=9.3 Hz, 3H), 7.58 (d, J=9.5 Hz, 1H), 7.39 (dd, J=9.1 Hz, 2.0 Hz, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.76 (d, J=9.5 Hz, 1H), 4.21 (s, 3H), 3.30 (ush, 2H), 2.02-1.87 (m, 1H), 1.14 (t, J=7.2 Hz, 3H), 1.02-0.90 (m, 2H), 0.77-0.64 ( m, 2H). Example 313
4-(6-(difluoromethoxy)pyridin-3-yl)-6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H) -He LC-MS: m/z 464 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.63 (d, J=2.3 Hz, 1H), 8.43 (s, 1H), 8.30 (dd, J=8.6 Hz , 2.3 Hz, 1H), 7.92 (s, 1H), 1.12 (t, J _HF =73.2 Hz, 1H), 7.66 (d, J=9.1 Hz, 1H) , 7.61 (d, J=9.5 Hz, 1H), 7.40 (dd, J=9.1 Hz, 2.0 Hz, 1H), 7.11 (d, J=8.6 Hz , 1H), 6.79 (d, J=9.5 Hz, 1H), 4.18 (s, 3H), 3.34 (kv, J=7.2 Hz, 2H), 1.12 (t , J=7.2 Hz, 3H). Example 314
4-(6-cyclopropylpyridin-3-yl)-6-((2,2-difluorocyclopropyl)methoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin- 3(2H)-one LC-MS: m/z 501 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.77 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.07-7.98 (m, 3H) , 7.70 (d, J=9.1 Hz, 1H), 7.45 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.38 (d, J=7.8 Hz , 1H), 7.02 (d, J=9.4 Hz, 1H), 4.57-4.46 (m, 1H), 4.35-4.14 (m, 4H), 2.26- 2.11 (m, 2H), 1.71-1.98 (m, 1H), 1.50-1.45 (m, 1H), 1.02-0.83 (m, 4H).

[00216] The method given above for General Method I (Method D) was used to prepare the following compounds using suitable starting compounds:

Connection No. Structure Characteristics Example 315
6-((cyclopropylmethyl)amino)-4-(6-cyclopropylpyridin-3-yl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H) -He LC-MS: m/z 464 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.75 (d, J=2.2 Hz, 1H), 8.48 (t, J=5.7 Hz, 1H), 8.45 (s , 1H), 8.00 (dd, J=8.1 Hz, 2.1 Hz, 1H), 7.93 (d, J=1.3 Hz, 1H), 7.66 (d, J=9 ,0 Hz, 1H), 7.61 (d, J=9.5 Hz, 1H), 7.40 (dd, J=9.2 Hz, 1.9 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.85 (d, J=9.5 Hz, 1H), 4.20 (s, 3H), 3.20 (t, J=6.2 Hz, 2H) , 2.15-2.09 (m, 1H), 1.12-0.86 (m, 5H), 0.50-0.36 (m, 2H), 0.22-0.09 (m, 2H). Example 316
6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,2-c]pyrazin-3(2H) -He LC-MS: m/z 466 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.15 (s, 1H), 8.53 (t, J=5.2 Hz, 1H), 8.48 (d, J=7.2 Hz , 2H), 8.01-7.88 (m, 2H), 7.66 (t, J=8.4 Hz, 2H), 7.43 (dd, J=9.2 Hz, 1.9 Hz , 1H), 6.83 (d, J=9.6 Hz, 1H), 4.21 (s, 3H), 3.31 (br, 2H), 1.14 (t, J=7.2 Hz , 3H). Example 317
4-(6-(difluoromethyl)pyridin-3-yl)-2-(2-methyl-2H-indazol-5-yl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3,2 -c]pyrazin-3(2H)-one LC-MS: m/z 502 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.06 (s, 1H), 9.01 (s, 1H), 8.48 (s, 1H), 8.33 (d, J=9, 7 Hz, 1H), 7.98 (d, J=1.7 Hz, 1H), 7.81 (d, J=9.3 Hz, 1H), 7.73 (d, J=7.9 Hz , 1H), 7.69 (d, J=9.2 Hz, 1H), 7.44 (dd, J=9.1 Hz, 1.9 Hz, 1H), 7.00 (d, J=3 .6 Hz, 1H), 6.92 (t, J _HF =55.2 Hz, 1H), 4.21 (s, 5H). Example 318
6-((2,2-difluoroethyl)amino)-2-(2-methyl-2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)pyrido[3,2-c]pyrazin- 3(2H)-one LC-MS: m/z 448 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.79 (d, J=1.8 Hz, 1H), 8.73 (t, J=5.2 Hz, 1H), 8.46 (s , 1H), 8.04 (dd, J=8.0 Hz, 2.2 Hz, 1H), 7.95 (d, J=1.4 Hz, 1H), 7.71 (d, J=9 ,2 Hz, 1H), 7.68 (dd, J=9.2 Hz, 1H), 7.41 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 6.92 (d, J=9.6 Hz, 1H), 6.15 (tt, J _HF =56.0 Hz, J=3.8 Hz, 1H), 4.21 (s, 3H), 3.75 (t, J _HF =15.8 Hz, 2H), 2.51 (s, 3H). Example 319
6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)-4-(6-(methyl-d ₃ )pyridin-3-yl)pyrido[3,2-c]pyrazin-3 (2H)-he LC-MS: m/z 484 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.02 (s, 1H), 8.81 (t, J=5.2 Hz, 1H), 8.48 (s, 1H), 8.36 (d, J=9.7 Hz, 1H), 7.98 (d, J=1.3 Hz, 1H), 7.76 (d, J=9.5 Hz, 1H), 7.73 (d , J=8.2 Hz, 1H), 7.69 (d, J=9.1 Hz, 1H), 7.43 (dd, J=9.1 Hz, 1.9 Hz, 1H), 7, 00 (t, J _HF =55.0 Hz, 1H), 6.94 (d, J=9.5 Hz, 1H), 6.16 (tt, J _HF =56.4 Hz, J=3.8 Hz, 1H), 4.21 (s, 3H), 3.75 (t, J _HF =15.8 Hz, 2H). Example 320
6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)-4-(6-(methyl-d ₃ )pyridin-3-yl)pyrido[3,2-c]pyrazin-3 (2H)-he
Prepared using the (6-(methyl-d ₃ )pyridin-3-yl)boronic acid intermediate as described. LC-MS: m/z 415 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.85 (d, J=1.5 Hz, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.07 (dd, J=8.1 Hz, 2.2 Hz, 1H), 7.94 (d, J=1.4 Hz, 1H), 7.66 (d, J=9.2 Hz, 1H), 7.61 (d, J=9.6 Hz, 1H), 7.41 (dd, J=9.1 Hz, 2.0 Hz, 1H), 7.27 (d, J=8, 1 Hz, 1H), 6.80 (d, J=9.5 Hz, 1H), 4.21 (s, 3H), 3.33 (kv, J=7.2 Hz, 2H, overlapped with H2O peak ), 1.14 (t, J=7.2 Hz, 3H).

[00217] Preparation of (6-(methyl-d ₃ )pyridin-3-yl)boronic acid intermediate:

[00218] Step A: 5-methoxy-2-(methyl-d ₃ )pyridine

[00219] To a solution of 2-bromo-5-methoxypyridine (7 g, 37.2 mmol, 1.0 eq.) and Fe(acac) ₃ (1.31 g, 3.71 mmol, 0.1 eq.) in anhydrous THF (70 ml), CD ₃ MgI (1 M in THF) (93 ml, 93 mmol, 2.5 eq.) was added dropwise at 0 ^o C under N ₂ atmosphere, the resulting mixture was stirred for 3 hours at 0 ^o C. Once complete, the reaction was quenched by adding NH ₄ Cl (sat. aq.) (200 ml), then extracted with EtOAc (70 ml x 3), the combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 5-methoxy-2-(methyl-d ₃ )pyridine (4 g, 85%) as a colorless oil. LC-MS (ESI): m/z 127 [M+H] ⁺ .

[00220] Step B: 6-(methyl-d ₃ )pyridin-3-ol

[00221] L- selectride (1 _M in THF) (37.8 mL, 37.8 mmol, 3.0 eq.) through a dropping funnel at 0°C dropwise, after addition, the reaction mixture was warmed to room temperature, then transferred to a preheated oil bath (110 ^° C ), stirred for an additional 3 hours. Once complete, the reaction was again cooled to 0 ^° C., quenched by the addition of MeOH (10 ml) carefully, the resulting mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to give 6-(methyl-d ₃ )pyridine-3 -ol (1.2 g, 84.3%) as a pale yellow solid. LC-MS (ESI): m/z 113 [M+H] ⁺ .

[00222] Step C: 6-(methyl-d ₃ )pyridin-3-yl trifluoromethanesulfonate

[00223] To a solution of 6-(methyl-d ₃ )pyridin-3-ol (500 mg, 4.46 mmol, 1.0 eq.) and pyridine (0.54 ml, 6.69 mmol, 1.5 eq. .) in dry DCM (10 ml), trifluoromethanesulfonic anhydride (1.13 ml, 6.69 mmol, 1.5 eq.) was added dropwise via syringe at 0°C. The resulting mixture was warmed to room temperature and stirred for an additional 2 hours. Once complete, the reaction was quenched by adding H ₂ O (20 ml), then extracted with EtOAc (20 ml x 3), the combined organic layers were washed with dilute HCl (0.5 N, aq) (20 ml), brine (20 ml) , dried over Na ₂ SO ₄ and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to obtain 6-(methyl-d ₃ )pyridin-3-yl trifluoromethanesulfonate (1.0 g, 91%) as a colorless oil . LC-MS (ESI): m/z 245 [M+H] ⁺ .

[00224] Step D: (6-(methyl-d ₃ )pyridin-3-yl)boronic acid

[00225] To a solution of 6-(methyl-d ₃ )pyridin-3-yl trifluoromethanesulfonate (1.0 g, 4.09 mmol, 1.0 eq.) in dry 1,4-dioxane (10 ml), add bis (pinacolato)diboron (2.08 g, 8.2 mmol, 2.0 eq.), KOAc (1.6 g, 16.4 mmol, 4.0 eq.) and Pd(dppf)Cl ₂ (300 mg , 0.41 mmol, 0.1 eq.). The resulting mixture was stirred at 100°C under N ₂ atmosphere for 16 hours. Once complete, the crude mixture was filtered through a short pad of ^Celite® , the filtrate was concentrated under reduced pressure, and the residue was purified by pre-RP-HPLC to give (6-(methyl- _d3 )pyridin-3-yl)boronic acid (460 mg, 80%) . LC-MS (ESI) : m/z 141 [M+H] ⁺ .

[00226] General Method II:

[00227] Structure connections2.8 And2.11 was prepared according to the scheme shown as General Method II. Based on pyrazinone2.1, the heterocycle was benzylated to give the compound2.2. Required R₄ and R₅ groups were introduced using the Suzuki cross-coupling reaction, obtaining compounds of the structure2.3. Then, connection2.3 cyclized under basic conditions to obtain a bicyclic compound2.4. Required R₂ group was administered using the Suzuki coupling reaction, obtaining the compound2.5. Then, connection2.5 chlorinated to give aryl chloride2.6. Required R₁ the group was introduced by nucleophilic aromatic substitution, which simultaneously debenzylated the heterocyclic ring, giving the compound2.7. Finally, the required R₃ the group was introduced using Ullmann condensation (method A) or Chan-Lam condensation (method B), obtaining compounds of the structure2.8. Alternatively, connection2.5 BOP can be activated and reacted with the required R₁-amine, giving a heterocycle2.9 (method C). The benzyl group was removed using tert-BuOK to give the heterocycle2.10, and the required R₃ the group was introduced using Ullmann condensation, obtaining compounds of the structure2.11.

[00228] General Method IIa (Method C):

[00229] General Method IIa (Method C) was later developed using PMB as an alternative protecting group to the Bn protecting group shown in General Method II (Method C). Deblocking of heterocycle 2.16 under acidic conditions led to convergent structures of compounds 2.11 .

[00230] Preparation of Example 166 by General Method II (Method A):

[00231] Step A: 5-amino-2-benzyl-6-bromo-4-chloropyrazin-3(2H)-one

[00232] To a solution of 5-amino-6-bromo-4-chloropyrazin-3(2H)-one (3 g, 13.4 mmol, 1.0 eq.), K ₂ CO ₃ (3.7 g, 26 .8 mmol, 2.0 eq.) in DMF (50 ml) was added BnBr (2.5 g, 14.7 mmol, 1.1 eq.), the reaction mixture was stirred at 80 ^o C overnight. The reaction mixture was diluted with 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 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel, yielding 5-amino-2-benzyl-6-bromo-4-chloropyrazin-3(2H)-one as a white solid (2.46 g, 59% yield). LC-MS (ESI) m/z 314, 316 [M+H] ⁺ .

[00233] Step B: Ethyl (E)-3-(4-amino-1-benzyl-5-chloro-6-oxo-1,6-dihydropyrazin-3-yl)acrylate

[00234] To a solution of 5-amino-2-benzyl-6-bromo-4-chloropyrazin-3(2H)-one (2.46 g, 7.8 mmol, 1.0 eq.), K ₂ CO ₃ ( 2.2 g, 15.6 mmol, 2.0 eq), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (1 .94 g, 8.6 mmol, 1.1 eq.) in DMF (40 ml) was added Pd(dppf)Cl ₂ (0.57 g, 0.8 mmol, 0.1 eq.) under N ₂ atmosphere, the reaction mixture was stirred at 100 ^o C for 3 hours. The reaction mixture was diluted with H ₂ O (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 and concentrated under reduced pressure, the residue was purified by silica gel column chromatography, yielding ethyl (E)-3-(4-amino-1-benzyl-5-chloro-6-oxo-1,6-dihydropyrazin-3-yl)acrylate as a brown solid (1.89 g, 71% yield ). LC-MS (ESI): m/z 334 [M+H] ⁺ .

[00235] Step C: 2-benzyl-4-chloropyrido[3,2-c]pyridazine-3,6(2H,5H)-dione

[00236] To a stirred solution of ethyl (E)-3-(4-amino-1-benzyl-5-chloro-6-oxo-1,6-dihydropyrazin-3-yl)acrylate (1.89 g, 5.66 mmol, 1.0 eq.) in EtOH (20 ml) was added K ₂ CO ₃ (2.34 g, 16.98 mmol, 3.0 eq.), the reaction mixture was stirred at 80°C overnight. The reaction mixture was diluted with water (30 ml) and extracted with EtOAc (30 ml x 3), the combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude 2-benzyl-4-chloropyrido[3,2-c]pyridazine -3,6(2H,5H)-dione as a brown solid (1.5 g), which was used in the next step without further purification. LC-MS (ESI): m/z 288 [M+H] ⁺ .

[00237] Step D: 2-benzyl-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione

[00238] To a stirred solution of 2-benzyl-4-chloropyrido[3,2-c]pyridazin-3,6(2H,5H)-dione (1.5 g, 5.2 mmol, 1.0 eq.), 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2 g, 7.2 mmol, 1.4 eq.), K ₂ CO ₃ (1 .54 g, 11.1 mmol, 2.1 eq.), X-Phos (0.52 g, 1.1 mmol, 0.2 eq.) in dioxane/H ₂ O (88 ml, 10/1 , v/v) Pd(OAc) ₂ (0.12 g, 0.55 mmol, 0.1 eq.) was added under N ₂ atmosphere. The reaction mixture was stirred at 110 ^° C overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give 2-benzyl-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione (1 .4 g, 68% yield) as a white solid. LC-MS (ESI): m/z 396 [M+H] ⁺ .

[00239] Step E: 2-benzyl-6-chloro-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one

[00240] 2-Benzyl-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione (400 mg, 1.01 mmol, 1.0 eq .) was dissolved in POCl ₃ (4 ml), the resulting mixture was stirred at 80 ^o C for 4 hours. Excess POCl ₃ was removed under reduced pressure and the residue was poured into ice-cold NaHCO ₃ (sat. aq.) (20 ml) and extracted with DCM (30 ml x 3), the combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. pressure, yielding crude 2-benzyl-6-chloro-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one as a yellow solid (400 mg, 95% yield ). LC-MS (ESI): m/z 414 [M+H] ⁺ .

[00241] Step F: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one

[00242] To a solution of 2-benzyl-6-chloro-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one (400 mg, 0.97 mmol, 1, 0 eq), 2,2-difluoroethan-1-ol (396 mg, 4.8 mmol, 5.0 eq) in anhydrous THF (8 ml) was added tert-BuOK (541 mg, 4.8 mmol, 5 ,0 eq.) in several portions at 0 ^o C, after addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EtOAc (30 ml x 3), the combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 6-(2. 2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one as a yellow solid (150 mg, 42% yield). LC-MS (ESI): m/z 370 [M+H] ⁺ .

[00243] Step G: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2,3-dimethyl-2H-indazol-5-yl)pyrido[3,2- c]pyrazin-3(2H)-one (method A )

[00244] To a stirred suspension of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one (70 mg, 0.19 mmol , 1.0 eq.) in MeCN (3 ml) was added 5-bromo-2,3-dimethyl-2H-indazole (64.0 mg, 0.28 mmol, 1.5 eq.), CuI (36.2 mg, 0.19 mmol, 1.0 eq.), N ¹ ,N ² -dimethylcyclohexane-1,2-diamine (26.9 mg, 0.19 mmol, 1.0 eq.) and CsF (57.6 mg, 0.38 mmol, 2.0 eq.). The reaction was stirred in a sealed tube at 85°C overnight under N ₂ and concentrated under reduced pressure. The residue was purified by pre-HPLC to give 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2,3-dimethyl-2H-indazol-5-yl)pyrido[3,2 -c]pyrazin-3(2H)-one (example 166) .

[00245] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.07 (d, J=9.4 Hz, 1H), 7.98 (d, J=1.4 Hz, 1H), 7 .87 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 1H), 7.42 (dd, J=9.1 Hz, 2.0 Hz, 1H ), 7.35 (t, J _HF =72.0 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.06 (d, J=9.4 Hz, 1H) , 6.41 (td, J _HF =54.4 Hz, J=3.3 Hz, 1H), 4.59 (td, J _HF =15.1 Hz, J=3.3 Hz, 2H), 4 .10 (s, 3H), 2.64 (s, 3H).

[00246] LC-MS (ESI) : m/z 514 [M+H] ⁺ .

[00247] Preparation of Example 167 by General Method II (Method B):

[00248] Step G: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrido[3, 2-c]pyrazin-3(2H)-one (method B)

[00249] To a suspension of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one (70 mg, 0.19 mmol, 1.0 eq.) in DMF (5 ml) was added 1-methyl-1H-benzo[d]imidazol-6-ylboronic acid (33.4 mg, 0.23 mmol, 1.2 eq.), Cu(OAc ) ₂ (34.5 mg, 0.19 mmol, 1.0 eq.) and pyridine (30.0 mg, 0.38 mmol, 2.0 eq.). After the mixture was stirred at 50°C overnight under air, the reaction mixture was quenched by adding H ₂ O (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure, the residue was purified by pre-HPLC to give 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(1-methyl -1H-benzo[d]imidazol-6-yl)pyrido[3,2-c]pyrazin-3(2H)-one (example 167) .

[00250] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.34 (s, 1H), 8.06 (d, J=9.4 Hz, 1H), 7.92 (d, J= 1.8 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.6 Hz, 1H), 7.47 (dd, J=8, 6 Hz, 2.0 Hz, 1H), 7.35 (t, J _HF =72.0 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.07 (d, J=9.4 Hz, 1H), 6.41 (td, J _HF =54.4 Hz, 3.3 Hz, 1H), 4.60 (td, J _HF =15.1 Hz, 3.3 Hz , 2H), 3.88 (s, 3H).

[00251] LC-MS (ESI) : m/z 500 [M+H] ⁺ .

[00252] Preparation of Example 321 by General Method II (Method C):

[00253] Step H: 2-benzyl-4-(6-(difluoromethyl)pyridin-3-yl)-6-((ethyl- _d5 )amino)pyrido[3,2-c]pyrazin-3(2H) -He

[00254] To a solution of 2-benzyl-4-(6-(difluoromethyl)pyridin-3-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione (250 mg, 0.66 mmol, 1.0 eq.) in DMF (2 ml) was added BOP (436 mg, 0.99 mmol, 1.5 eq.) and DIEA (584 μl, 3.29 mmol, 5.0 eq.), reaction the mixture was stirred at room temperature for 1 hour, then ethylamine-d ₅ hydrochloride (86 mg, 0.99 mmol, 1.5 eq.) was added, the resulting mixture was stirred at room temperature for an additional 0.5 hour. Once complete, the reaction was quenched by adding ice water (10 ml) and extracted with EtOAc (10 ml x 3), dried over Na ₂ SO ₄ and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 4-(6-( difluoromethyl)pyridin-3-yl)-6-((ethyl-d ₅ )amino)pyridopyrazin-3(2H)-one (234 mg, 86%) as a yellow solid. LC-MS (ESI) : m/z 413 [M+H] ⁺ .

[00255] Step I: 4-(6-(difluoromethyl)pyridin-3-yl)-6-((ethyl- _d5 )amino)pyrido[3,2-c]pyrazin-3(2H)-one

[00256] To a solution of 2-benzyl-4-(6-(difluoromethyl)pyridin-3-yl)-6-((ethyl- _d5 )amino)pyridopyrazin-3(2H)-one (185 mg, 0.45 mmol, 1.0 eq.) in THF/DMF (2 ml, 1/1) tert-BuOK (251 mg, 2.25 mmol, 5.0 eq.) was added, the reaction mixture was stirred at 70°C for 8 hours. Once complete, the pH was adjusted to ~7 by adding 1 N HCl (aq), then the mixture was extracted with DCM (10 ml x 3). The combined organic layers were washed with brine (20 ml) and dried over Na ₂ SO ₄ , concentrated under reduced pressure, the residue was purified by flash chromatography to give 4-(6-(difluoromethyl)pyridin-3-yl)-6-((ethyl- d ₅ )amino)pyridopyrazin-3(2H)-one (50 mg) as a yellow solid. LC-MS (ESI) : m/z 323 [M+H] ⁺ .

[00257] Step J: 4-(6-(difluoromethyl)pyridin-3-yl)-6-((ethyl-d ₅ )amino)-2-(2-(methyl-d ₃ )-2H-indazol-5 -yl)pyrido[3,2-c]pyrazin-3(2H)-one

[00258] To a solution of 4-(6-(difluoromethyl)pyridin-3-yl)-6-((ethyl- _d5 )amino)pyridopyrazin-3(2H)-one (50 mg, 0.16 mmol, 1, 0 eq.) and 5-bromo-2-(methyl-d ₃ )-2H-indazole (50 mg, 0.23 mmol, 1.5 eq.) in ACN (1 ml) was added CuI (30 mg, 0. 16 mmol, 1.0 eq.), CsF (47 mg, 0.31 mmol, 2.0 eq.), N1,N2-dimethylcyclohexane-1,2-diamine (22 mg, 0.16 mmol, 1.0 eq.), the resulting mixture was stirred at 85 ^o C for 14 hours. Once complete, the reaction mixture was diluted with H ₂ O (5 ml), extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml) and dried over Na ₂ SO ₄ , concentrated under reduced pressure, the residue was purified by pre-RP-HPLC to give 4-(6-(difluoromethyl)pyridin-3-yl)-6-(( ethyl-d ₅ )amino)-2-(2-(methyl-d ₃ )-2H-indazol-5-yl)pyridopyrazin-3(2H)-one (example 321) .

[00259] ¹ H NMR (400 MHz, DMSO- d6 ) δ (ppm): 9.06 (s, _1H ), 8.46 (d, J =2.6 Hz, 2H), 8.39 (d , J =8.0 Hz, 1H), 7.95 (s, 1H), 7.73 (d, J =8.2 Hz, 1H), 7.66 (dd, J =11.5, 9, 4 Hz, 2H), 7.42 (dd, J =9.2, 1.9 Hz, 1H), 6.99 (t, J =55.1 Hz, 1H), 6.82 (d, J = 9.6 Hz, 1H).

[00260] LC-MS (ESI): m/z 456 [M+H] ⁺ .

[00261] Preparation of Example 322 by General Method IIa (Method C):

[00262] Step A: 5-amino-6-bromo-4-chloro-2-(4-methoxybenzyl)pyrazin-3(2H)-one

[00263] To a solution of 5-amino-6-bromo-4-chloropyrazin-3(2H)-one (2.0 g, 8.91 mmol, 1.0 eq.) and K ₂ CO ₃ (2.5 g , 17.8 mmol, 2.0 eq.) in DMF (20 ml) was added PMBCl (1.3 ml, 9.8 mmol, 1.1 eq.), the reaction mixture was stirred at 80°C for 14 hours. Once complete, the reaction mixture was diluted with 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 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 5-amino-6-bromo-4-chloro-2-(4-methoxybenzyl)pyrazin-3(2H)-one (2.0 g, 45%) as a white solid. LC-MS (ESI): m/z 344 [M+H] ⁺ .

[00264] Step B: Ethyl (E)-3-(4-amino-5-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrazin-3-yl)acrylate

[00265] To a solution of 5-amino-6-bromo-4-chloro-2-(4-methoxybenzyl)pyrazin-3(2H)-one (2.0 g, 5.8 mmol, 1.0 eq.), K ₂ CO ₃ (2.0 g, 14.5 mmol, 2.5 eq.) and ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)acrylate (1.44 g, 6.4 mmol, 1.1 eq.) in DMF (20 ml) was added Pd(dppf)Cl ₂ (0.43 g, 0.6 mmol, 0.1 eq.) , the reaction mixture was stirred at 100 ^o C in an atmosphere of N ₂ for 5 hours. The reaction mixture was diluted with H ₂ O (30 ml) and extracted with EtOAc (50 ml x 3), the combined organic layers were washed with brine (40 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure, the residue was purified by silica gel column chromatography, yielding ethyl (E)-3-(4-amino-5-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrazin-3-yl)acrylate as a brown solid (1.4 g , 53%). LC-MS (ESI): m/z 364 [M+H] ⁺ .

[00266] Step C: 4-chloro-2-(4-methoxybenzyl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione

[00267] To a stirred solution of ethyl (E)-3-(4-amino-5-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrazin-3-yl)acrylate (1.4 g , 3.85 mmol, 1.0 eq.) in EtOH (20 ml) was added K ₂ CO ₃ (1.6 g, 11.54 mmol, 3.0 eq.), the reaction mixture was stirred at 80°C for 14 hours. The reaction mixture was diluted with water (30 ml) and extracted with EtOAc (30 ml x 3), the combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude 4-chloro-2-(4-methoxybenzyl)pyrido[3, 2-c]pyridazine-3,6(2H,5H)-dione (0.6 g, crude) as a brown solid, which was used in the next step without further purification. LC-MS (ESI): m/z 318 [M+H] ⁺ .

[00268] Step D: 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione

[00269] To a solution of 4-chloro-2-(4-methoxybenzyl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione (0.2 g, 0.63 mmol, 1.0 eq.), 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (152 mg, 0.88 mmol, 1.4 eq.), K ₂ CO ₃ (217 mg, 1.57 mmol, 2.5 eq.) and X-Phos (33 mg, 0.06 mmol, 0.1 eq.) in 1,4-dioxane/H ₂ O (8 ml , 10/1, v/v) Pd(OAc) ₂ (15 mg, 0.06 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 110 ^o C under N ₂ atmosphere overnight. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)pyrido[3,2-c]pyridazin- 3,6(2H,5H)-dione (120 mg, 46%) as a white solid. LC-MS (ESI): m/z 411 [M+H] ⁺ .

[00270] Step E: 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3,2-c ]pyrazin-3(2H)-one

[00271] To a solution of 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione (100 mg , 0.24 mmol, 1.0 eq.) in DMF (2 ml) was added BOP (180 mg, 0.36 mmol, 1.5 eq.) and DIEA (157 mg, 1.22 mmol, 5.0 eq. .), the reaction mixture was stirred at room temperature for 1 hour, then 2,2,2-trifluoroethane-1-amine (36 mg, 0.36 mmol, 1.5 eq.) was added, the resulting mixture was stirred at room temperature temperature for an additional 0.5 hour. Once complete, the reaction was quenched by adding ice water (10 ml) and extracted with EtOAc (10 ml x 3), dried over Na ₂ SO ₄ and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 4-(6-( difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3,2-c]pyrazin-3(2H)-one (80 mg , 67%) as a yellow solid. LC-MS (ESI) : m/z 492 [M+H] ⁺ .

[00272] Step F: 4-(6-(difluoromethyl)pyridin-3-yl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3,2-c]pyrazin-3(2H)- He

[00273] To a solution of 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3,2-c] pyrazin-3(2H)-one (80 mg, 0.16 mmol, 1.0 eq.) in TFA (2 ml) was added TfOH (142 μl, 1.6 mmol, 10.0 eq.) and Et ₃ SiH (128 μl, 0.8 mmol, 5.0 eq.), the reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction was quenched with 10 ml NaHCO ₃ (sat. aq.), extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml) and dried over Na ₂ SO ₄ , concentrated under reduced pressure, the residue was purified by flash chromatography on silica gel to give 4-(6-(difluoromethyl)pyridin-3-yl)-6-(( 2,2,2-trifluoroethyl)amino)pyrido[3,2-c]pyrazin-3(2H)-one (40 mg, 66%) as a yellow solid. LC-MS (ESI) : m/z 372 [M+H] ⁺ .

[00274] Step G: 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-(methoxy-d ₃ )phenyl)-6-((2,2,2-trifluoroethyl)amino)pyrido [3,2-c]pyrazin-3(2H)-one (example 322 )

[00275] 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-(methoxy-d ₃ )phenyl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3, 2-c]pyrazin-3(2H)-one (Example 322) was prepared from 4-(6-(difluoromethyl)pyridin-3-yl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3 ,2-c]pyrazin-3(2H)-one and 1-bromo-4-(methoxy-d ₃ )benzene by general method II (method C, Step J ).

[00276] ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.98 (s, 1H), 8.93 (t, J =5.9 Hz, 1H), 8.30 (dd , J =8.0 Hz, 1.6 Hz, 1H), 7.79 (d, J =9.5 Hz, 1H), 7.73 (d, J =8.2 Hz, 1H), 7, 59-7.53 (m, 2H), 7.09-7.04 (m, 2H), 7.00 (t, J _HF =56.0 Hz, 1H), 6.93 (d, J =9 .5 Hz, 1H), 4.23-4.15 (m, 2H).

[00277] LC-MS (ESI) : m/z 481 [M+H] ⁺ .

[00278] The method given above for General Method II (Method A) was used to prepare the following compounds using suitable starting compounds:

Connection No. Structure Characteristics Example 168
4-(4-chlorophenyl)-6-ethoxy-2-(quinolin-6-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 429.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.00 (dd, J=4.4 Hz, 1.6 Hz, 1H), 8.51 (d, J=7.2 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 8.07 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 8.01 (d, J=9.2 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.64 (dd, J=8.4 Hz, 4.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.0 (d, J=9.2 Hz, 1H), 4.34 (kv, J=6, 8 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H). Example 169
2-(benzo[d]thiazol-6-yl)-6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 503.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.53 (s, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.24 (d, J=8.4 Hz , 1H), 8.06 (d, J=9.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.85 (dd, J=8.8 Hz, 2 .4 Hz, 1H), 7.35 (t, J _HF =74.0 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.09 (d, J=9, 6 Hz, 1H), 6.41 (td, J _HF =54.4 Hz, J=3.2 Hz, 1H), 4.60 (td, J _HF =15.2 Hz, J=3.2 Hz , 2H). Example 170
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(imidazo[1,2-a]pyridin-6-yl)pyrido[3,2-c]pyrazine-3( 2H)-on LC-MS (ESI): m/z 486.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.13 (s, 1H), 8.11 (s, 1H), 8.06 (d, J=9.6 Hz, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.73 (d, J=9.6 Hz, 1H), 7.70 (s, 1H), 7.58 (dd, J=9.6 Hz , 1.6 Hz, 1H), 7.35 (t, J _HF =74.0 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.10 (d, J= 9.2 Hz, 1H), 6.37 (td, J _HF =54.4 Hz, J=3.2 Hz, 1H), 4.60 (td, J _HF =15.2 Hz, J=3, 2 Hz, 2H). Example 171
(prepared using 5-bromo-3-methoxy-2-methyl-2H-indazole (link: Organic Letters, 2011 , 13 , 3138-3141)
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(3-methoxy-2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin- 3(2H)-one LC-MS (ESI): m/z 530.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.12 (d, J=1.6 Hz, 1H), 8.07 (d, J=9.6 Hz, 1H), 7.86 (d , J=8.8 Hz, 2H), 7.49 (d, J=9.2 Hz, 1H), 7.37 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7, 34 (t, J _HF =74.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.06 (d, J=9.2 Hz, 1H), 6.40 (td, J _HF =54.4 Hz, J=3.2 Hz, 1H), 4.59 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H), 4.29 (s , 3H), 3.91 (s, 3H). Example 172
(prepared using 6-bromo-2-methoxy-1-methyl-1H-benzo[d]imidazole (ref: Heterocycles, 2008 , 75 , 1907-1911)
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methoxy-1-methyl-1H-benzo[d]imidazol-6-yl)pyrido[3,2- c]pyrazin-3(2H)-one LC-MS (ESI): m/z 530.0 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.05 (d, J=9.2 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.68 (d , J=2.0 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7, 34 (t, J _HF =74.0 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.06 (d, J=9.2 Hz, 1H), 6.36 (td, J _HF =54.4 Hz, J=3.2 Hz, 1H), 4.60 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H), 4.15 (s , 3H), 3.57 (s, 3H). Example 173
4-(4-chlorophenyl)-6-(2,2-difluoroethoxy)-2-(2,3-dimethyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)- He LC-MS (ESI): m/z 482.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.07 (d, J=9.2 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.82 (d , J=8.4 Hz, 2H), 7.61 (d, J=9.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.41 (dd, J =9.2 Hz, 2.0 Hz, 1H), 7.07 (d, J=9.2 Hz, 1H), 6.41 (tt, J _HF =54.2 Hz, J=3.2 Hz , 1H), 4.59 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H), 4.10 (s, 3H), 2.64 (s, 3H). Example 174
(prepared using 5-bromo-3-methoxy-2-methyl-2H-indazole (link: Organic Letters, 2011 , 13 , 3138-3141)
4-(4-chlorophenyl)-6-(2,2-difluoroethoxy)-2-(3-methoxy-2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H )-He LC-MS (ESI): m/z 498.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.12 (d, J=2.0 Hz, 1H), 8.08 (d, J=9.2 Hz, 1H), 7.82 (d , J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.48 (s, 1H), 7.36 (dd, J=9.2 Hz, 2 .0 Hz, 1H), 7.07 (d, J=9.2 Hz, 1H), 6.40 (tt, J _HF =54.4 Hz, J=3.2 Hz, 1H), 4.58 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H), 4.29 (s, 3H), 3.91 (s, 3H). Example 175
(prepared using 5-bromo-3-(methoxy-d ₃ )-2-methyl-2H-indazole (link: Organic Letters, 2011 , 13 , 3138-3141)
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(3-(methoxy-d ₃ )-2-methyl-2H-indazol-5-yl)pyrido[3,2 -c]pyrazin-3(2H)-one LC-MS (ESI): m/z 533.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.12 (d, J=1.2 Hz, 1H), 8.07 (d, J=9.6 Hz, 1H), 7.87 (d , J=8.8 Hz, 2H), 7.50 (d, J=9.2 Hz, 1H), 7.37 (dd, J=9.2 Hz, 1.6 Hz, 1H), 7, 34 (t, J _HF =74.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.07 (d, J=9.2 Hz, 1H), 6.40 (td, J _HF =54.2 Hz, J=3.2 Hz, 1H), 4.59 (td, J _HF =15.2 Hz, J=3.2 Hz, 2H), 3.91 (s , 3H). Example 176 2-(cinnolin-6-yl)-6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 498 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (d, J=5.9 Hz, 1H), 8.63 (d, J=9.2 Hz, 1H), 8.51 (d, J=2.2 Hz, 1H), 8.38 (d, J=5.8 Hz, 1H), 8.30 (dd, J=9.1, 2.3 Hz, 1H), 8.08 ( d, J=9.4 Hz, 1H), 7.94-7.86 (m, 2H), 7.36 (t, J=73.9 Hz, 1H), 7.32-7.22 (m , 2H), 7.12 (d, J=9.4 Hz, 1H), 6.41 (td, J=54.3, 3.3 Hz, 1H), 4.61 (td, J=15, 1, 3.3 Hz, 2H). Example 177 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,2-c ]pyrazin-3(2H)-one LC-MS (ESI): m/z 504 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (d, J=9.4 Hz, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.34 (t, J=74.0 Hz, 1H), 7.24 (d, J=8.7 Hz, 2H), 7.20 (d, J=2.5 Hz, 1H), 7.12 (dd, J= 8.7, 2.5 Hz, 1H), 7.05 (d, J=9.4 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.39 (tm, J=54.1, 3.3 Hz, 1H), 4.57 (td, J=15.1, 3.4 Hz, 2H), 4.31 (s, 4H). Example 178 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2,3-dihydrobenzofuran-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 488 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (d, J=9.4 Hz, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.51 (d, J=2.2 Hz, 1H), 7.39-7.35 (m, 1H), 7.35 (t, J=74.2 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.05 (d, J=9.4 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.39 (tt, J=54.4, 3 .3 Hz, 1H), 4.67-4.51 (m, 4H), 3.26 (t, J=8.8 Hz, 2H). Example 179 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(quinazolin-6-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 498 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 9.76 (s, 1H), 9.41 (s, 1H), 8.58 (d, J=2.4 Hz, 1H), 8.38 ( dd, J=9.0, 2.4 Hz, 1H), 8.20 (d, J=9.0 Hz, 1H), 8.09 (d, J=9.4 Hz, 1H), 7, 90 (d, J=8.7 Hz, 2H), 7.35 (t, J=73.8 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.12 ( d, J=9.4 Hz, 1H), 6.41 (t, J=54.4 Hz, 1H), 4.61 (td, J=15.1, 3.3 Hz, 2H). Example 180 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl )pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 517 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 8.01 (d, J=9.4 Hz, 1H), 7.87-7.79 (m, 2H), 7.32 (t, J=74 ,0 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.03 (d, J=9.4 Hz, 1H), 6.92 (s, 1H), 6, 79 (ush s, 2H), 6.38 (td, J=54.4, 3.4 Hz, 1H), 4.57 (td, J=15.1, 3.4 Hz, 2H), 4, 29 (dd, J=5.3, 3.5 Hz, 2H), 3.29 (t, J=4.4 Hz, 2H), 2.83 (s, 3H). Example 181 4-(6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-3-oxopyrido[3,2-c]pyrazin-2(3H)-yl)benzonitrile LC-MS (ESI): m/z 471 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 8.10-8.01 (m, 3H), 7.95 (d, J=8.3 Hz, 2H), 7.85 (d, J=8 .8 Hz, 2H), 7.35 (t, J=74.0 Hz, 1H), 7.25 (d, J=8.5 Hz, 2H), 7.10 (d, J=9.4 Hz, 1H), 6.40 (td, J=54.3, 3.4 Hz, 1H), 4.59 (td, J=15.1, 3.4 Hz, 2H). Example 182
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)pyrido[3 ,2-c]pyrazin-3(2H)-one LC-MS: m/z 501.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.27 (d, J=1.2 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.87 (d , J=8.8 Hz, 2H), 7.70 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.34 (t, J _HF =74.0 Hz, 1H), 7 .25 (d, J=8.8 Hz, 2H), 7.08 (d, J=9.6 Hz, 1H), 6.40 (tt, J _HF =54.4 Hz, 3.2 Hz, 1H), 4.58 (td, J=14.8 Hz, 3.6 Hz, 2H), 4.56 (s, 3H). Example 183
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(quinolin-6-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 497.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.01 (s, 1H), 8.51 (d, J=8.4 Hz, 1H), 8.37 (s, 1H), 8.12 -8.02 (m, 1H), 7.89 (d, J=8.0 Hz, 2H), 7.68-7.59 (m, 1H), 7.35 (t, J _HF =74, 0 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.10 (d, J=9.6 Hz, 1H), 6.41 (tt, J _HF =54.4 Hz, 3.6 Hz, 1H), 4.60 (td, J=14.8 Hz, 3.6 Hz, 2H). Example 184 2-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2 -c]pyrazin-3(2H)-one LC-MS: m/z 487.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.41 (s, 1H), 9.18 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.94 (d, J=9.6 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.75 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.35 (t, J _HF =74.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.12 (d, J=9.2 Hz, 1H), 6 .40 (td, J _HF =54.4 Hz, 3.6 Hz, 1H), 4.60 (td, J=14.8 Hz, 3.6 Hz, 2H). Example 185 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(4-(methylamino)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 475.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.02 (d, J=9.2 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.40 (d , J=8.8 Hz, 2H), 7.33 (t, J _HF =74.0 Hz, 1H), 7.23 (d, J=8.8 Hz, 2H), 7.03 (d, J=9.2 Hz, 1H), 6.62 (d, J=8.8 Hz, 2H), 6.39 (tt, J _HF =54.4 Hz, 3.2 Hz, 1H), 6, 06 (kv, J=4.8 Hz, 1H), 4.56 (td, J _HF =14.8 Hz, 3.2 Hz, 2H), 2.73 (d, J=4.8 Hz, 3H ). Example 186
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(thiazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 466.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.05 (s, 1H), 8.66 (s, 1H), 8.12 (d, J=9.2 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.37 (t, J _HF =74.0 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.17 ( d, J=9.2 Hz, 1H), 6.40 (td, J _HF =54.4 Hz, 3.2 Hz, 1H), 4.58 (td, J _HF =15.2 Hz, 3, 2 Hz, 2H). Example 187
(prepared using 4-methoxycyclohex-1-en-1-yl trifluoromethanesulfonate (ref: Journal of the American Chemical Society, 2018 , 140 , 2446-2449) 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(4-methoxycyclohex-1-en-1-yl)pyrido[3,2-c]pyrazin-3(2H) -He LC-MS: m/z 480.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.03 (d, J=9.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.33 (t , J _HF =74.0 Hz, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.02 (d, J=9.6 Hz, 1H), 6.37 (tm, J _HF =54.4 Hz, 3.2 Hz, 1H), 5.94-5.89 (m, 1H), 4.55 (td, J _HF =14.8 Hz, 3.2 Hz, 2H) , 3.63-3.52 (m, 1H), 3.31 (s, 3H), 2.61-2.41 (m, 3H). 2.24-2.15 (m, 1H), 2.03-1.92 (m, 1H), 1.85-1.71 (m, 1H).

[00279] The method given above for General Method II (Method B) was used to prepare the following compounds using suitable starting compounds:

Connection No. Structure Characteristics Example 188
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(pyridin-4-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 447 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ 8.82-8.76 (m, 2H), 8.05 (d, J=9.5 Hz, 1H), 7.89-7.78 (m , 4H), 7.35 (t, J=74.0 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.10 (d, J=9.4 Hz, 1H ), 6.40 (td, J=54.3, 3.3 Hz, 1H), 4.59 (td, J=15.1, 3.3 Hz, 2H). Example 189
4-(6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-3-oxopyrido[3,2-c]pyrazin-2(3H)-yl)-N-methylbenzamide LC-MS: m/z 503.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.59 (kv, J=4.4 Hz, 1H), 8.05 (d, J=9.6 Hz, 1H), 7.99 (d , J=8.8 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.34 (t, J _HF =74.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.08 (d, J=9.6 Hz, 1H), 6.39 (tm, J _HF =54.4 Hz, 3.6 Hz, 1H), 4.58 (td, J=14.8 Hz, 3.2 Hz, 2H), 2.82 (d, J=4.8 Hz, 3H) . Example 190 2-(4-chlorophenyl)-6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 480.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.04 (d, J=9.6 Hz, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.73 (d , J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.34 (t, J _HF =74.0 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.07 (d, J=9.6 Hz, 1H), 6.39 (tt, J _HF =54.0 Hz, 3.2 Hz, 1H), 4, 58 (td, J=15.2 Hz, 3.2 Hz, 2H). Example 191 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(4-fluorophenyl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 464.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.04 (d, J=9.6 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.76-7 .71 (m, 2H), 7.40 (t, J=8.8 Hz, 2H), 7.35 (t, J _HF =74.0 Hz, 1H), 7.25 (d, J=8 .4 Hz, 2H), 7.07 (d, J=9.2 Hz, 1H), 6.40 (td, J _HF =54.0 Hz, 3.6 Hz, 1H), 4.58 (td , J=15.2 Hz, 3.6 Hz, 2H). Example 192 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(quinoxalin-6-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 498.1 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.06-9.04 (m, 2H), 8.48 (d, J=2.0 Hz, 1H), 8.27 (d, J= 9.2 Hz, 1H), 8.12 (dd, J=9.2 Hz, 2.0 Hz, 1H), 8.09 (d, J=9.6 Hz, 1H), 7.89 (d , J=8.8 Hz, 2H), 7.35 (t, J _HF =74.0 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.11 (d, J=9.2Hz, 1H), 6.41 (tt, J _HF =54.4 Hz, 3.2 Hz, 1H), 4.61 (td, J=14.8 Hz, 3.6 Hz, 2H ). Example 193
6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(1H-pyrazol-4-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 436.1 (M+H)+.
1H NMR (400 MHz, DMSO- _d6 ) δ: 13.23 (br s, 1H), 8.60-8.51 (m, 1H), 8.22-8.13 (m, 1H), 8 .07 (d, J=9.2 Hz, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.34 (t, J _HF =74.0 Hz, 1H), 7. 26 (d, J=8.4 Hz, 2H), 7.08 (d, J=9.2 Hz, 1H), 6.38 (tt, J _HF =54.4 Hz, 3.2 Hz, 1H ), 4.56 (td, J=14.8 Hz, 3.2 Hz, 2H).

[00280] The method given above for General Method II (Method C) was used to prepare the following compounds using suitable starting compounds:

Connection No. Structure Characteristics Example 323
6-((ethyl-d ₅ )amino)-2-(2-methyl-2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)pyrido[3,2-c]pyrazin-3 (2H)-he LC-MS: m/z 417 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.84 (d, J=1.9 Hz, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.06 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.94 (d, J=1.4 Hz, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.61 (d, J=9.5 Hz, 1H), 7.41 (dd, J=9.1 Hz, 2.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 6.79 (d, J=9.6 Hz, 1H), 4.21 (s, 3H), 2.51 (s, 3H). Example 324
4-(6-(difluoromethyl)pyridin-3-yl)-6-((ethyl-d ₅ )amino)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c] pyrazin-3(2H)-one LC-MS: m/z 453 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.06 (s, 1H), 8.47 (s, 2H), 8.38 (dd, J=8.1 Hz, 1.8 Hz, 1H ), 7.96 (d, J=1.4 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.66 (t, J=9.6 Hz, 2H), 7.42 (dd, J=9.2 Hz, 2.0 Hz, 1H), 6.99 (t, J _HF =55.1 Hz, 1H), 6.82 (d, J=9.6 Hz , 1H), 4.21 (s, 3H). Example 325
6-((ethyl-d ₅ )amino)-2-(2-(methyl-d ₃ )-2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)pyrido[3,2- c]pyrazin-3(2H)-one LC-MS: m/z 420 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.84 (d, J=1.5 Hz, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.07 (dd, J=8.1 Hz, 2.1 Hz, 1H), 7.94 (d, J=1.1 Hz, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.61 (d, J=9.5 Hz, 1H), 7.41 (dd, J=9.1 Hz, 2.0 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 6.79 (d, J=9.5 Hz, 1H), 2.51 (s, 3H). Example 326
4-(6-(difluoromethyl)pyridin-3-yl)-6-(ethylamino)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,2-c] pyrazin-3(2H)-one LC-MS: m/z 425 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.03 (s, 1H), 8.54 (t, J=5.3 Hz, 1H), 8.35 (d, J=9.7 Hz , 1H), 8.21 (d, J=2.8 Hz, 1H), 7.77-7.69 (m, 2H), 7.63 (d, J=9.5 Hz, 1H), 7 .06 (t, J _HF =55.2 Hz, 1H), 6.83 (d, J=9.6 Hz, 1H), 6.47 (d, J=9.7 Hz, 1H), 3, 49 (s, 3H), 3.31 (kv, J=7.2 Hz, 2H), 1.13 (t, J=7.2 Hz, 3H). Example 327
4-(6-(difluoromethyl)pyridin-3-yl)-2-(1,2-dimethyl-1H-benzo[d]imidazol-6-yl)-6-(ethylamino)pyrido[3,2-c] pyrazin-3(2H)-one LC-MS: m/z 462 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.06 (s, 1H), 8.50 (t, J=5.7 Hz, 1H), 8.38 (d, J=9.8 Hz , 1H), 7.76 (d, J=1.6 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.65 (d, J=9.6 Hz, 1H ), 7.60 (d, J=8.2 Hz, 1H), 7.33 (dd, J=8.5 Hz, 2.0 Hz, 1H), 6.99 (t, J _HF =55, 1 Hz, 1H), 6.83 (d, J=9.6 Hz, 1H), 3.75 (s, 3H), 3.32 (kv, J=7.2 Hz, 2H), 2.56 (s, 3H), 1.14 (t, J=7.2 Hz, 3H). Example 328
6-(2,2-difluoroethoxy)-4-(6-(difluoromethyl)pyridin-3-yl)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrido[3, 2-c]pyrazin-3(2H)-one LC-MS: m/z 462 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.03 (s, 1H), 8.38 (d, J=7.3 Hz, 1H), 8.30 (d, J=2.6 Hz , 1H), 8.09 (d, J=9.4 Hz, 1H), 7.82-7.77 (m, 2H), 7.12 (d, J=9.6 Hz, 1H), 7 .04 (t, J _HF =54.8 Hz, 1H), 6.52 (d, J = 9.7 Hz, 1H), 6.39 (t, J _HF =54.4 Hz, 1H), 4 .59 (td, J _HF =15.2 Hz, J=2.8 Hz, 2H), 3.51 (s, 3H). Example 329
4-(6-(difluoromethyl)pyridin-3-yl)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-((2,2,2-trifluoroethyl)amino )pyrido[3,2-c]pyrazin-3(2H)-one LC-MS: m/z 479 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.20 (t, J=6.4 Hz, 1H), 8.97 (s, 1H), 8.29 (d, J=8.8 Hz , 1H), 8.23 (d, J=2.9 Hz, 1H), 7.79 (d, J=9.4 Hz, 1H), 7.73 (d, J=9.0 Hz, 2H ), 7.01 (d, J=9.6 Hz, 1H), 7.01 (t, J _HF =55.0 Hz, 1H), 6.48 (d, J=9.8 Hz, 1H) , 4.25-4.18 (m, 2H), 3.50 (s, 3H). Example 330
6-(ethylamino)-2-(2-(methyl-d ₃ )-2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)pyrido[3,2-c]pyrazin-3( 2H)-on LC-MS: m/z 415 (M+H)+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.85 (d, J=1.8 Hz, 1H), 8.46 (s, 1H), 8.35 (t, J=5.2 Hz , 1H), 8.07 (dd, J=8.0 Hz, 2.2 Hz, 1H), 7.94 (d, J=1.4 Hz, 1H), 7.67 (d, J=9 ,1 Hz, 1H), 7.61 (d, J=9.5 Hz, 1H), 7.41 (dd, J=9.1 Hz, 1.9 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 6.79 (d, J=9.5 Hz, 1H), 3.36 (kv, J=7.2 Hz, 2H), 2.50 (s, 3H) , 1.14 (t, J=7.2 Hz, 3H).

[00281] General Method III:

[00282] Compounds of structure 3.6 were prepared according to the scheme shown as General Method III. Starting from the substituted pyrazinone 3.1 (prepared by General Method I (Step AB)), the required R ₄ group was introduced using a Suzuki cross-coupling reaction to give the vinyl derivative 3.2 . The double bond in 3.2 was then oxidized to give carbonyl 3.3 . The required R ₂ group was introduced using a Suzuki cross-coupling reaction to give compound 3.4 . The required R ₅ group was introduced using Horner-Wadsworth-Emmons olefination, which resulted in bicyclic heterocycle 3.5 after tandem intramolecular cyclization. Finally, the required R ₁ group was introduced by an alkylation reaction, yielding compounds of structure 3.6 .

[00283] Obtaining Example 194 by General Method III:

[00284] Step A: 5-amino-4-chloro-2-(2-methyl-2H-indazol-5-yl)-6-vinylpyrazin-3(2H)-one

[00285] Solution of 5-amino-6-bromo-4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrazin-3(2H)-one (2 g, 5.67 mmol, 1. 0 eq., General Method I , (Step AB) ), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.738 g, 11.34 mmol, 2.0 eq.) , Pd(dppf)Cl ₂ (0.826 g, 1.13 mmol, 0.2 eq.), K ₂ CO ₃ (2.336 g, 16.99 mmol, 3.0 eq.) in dioxane/EtOH (48 ml, 3/1, v/v) in an atmosphere of N ₂ was stirred at 80°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to give 5-amino-4-chloro-2-(2-methyl-2H-indazol-5-yl)-6-vinylpyrazin-3(2H )-one (1.02 g, 60% yield) as a yellow solid. LC-MS (ESI): m/z 302 [M+H] ⁺ .

[00286] Step B: 4-amino-5-chloro-1-(2-methyl-2H-indazol-5-yl)-6-oxo-1,6-dihydropyridazine-3-carbaldehyde

[00287] 5-Amino-4-chloro-2-(2-methyl-2H-indazol-5-yl)-6-vinylpyrazin-3(2H)-one solution (1.6 g, 5.3 mmol, 1 .0 eq.), NaIO ₄ (3.4 g, 15.9 mmol, 3.0 eq.) and K ₂ OsO ₄ -2H ₂ O (98 mg, 0.26 mmol, 0.05 eq.) in THF/H ₂ O (20 ml, 3:1) was stirred at room temperature for 3 hours, and the resulting mixture was filtered and extracted with DCM (50 ml x 3). The filtrate was washed with brine (30 ml) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to give 4-amino-5-chloro-1-(2-methyl-2H-indazol-5-yl)-6-oxo-1,6-dihydropyridazine-3-carbaldehyde as white solid residue (1 g, 62% yield). LC-MS (ESI): m/z 304 [M+H] ⁺ .

[00288] Step C: 4-amino-5-(4-(difluoromethoxy)phenyl)-1-(2-methyl-2H-indazol-5-yl)-6-oxo-1,6-dihydropyridazine-3-carbaldehyde

[00289] 4-Amino-5-chloro-1-(2-methyl-2H-indazol-5-yl)-6-oxo-1,6-dihydropyridazine-3-carbaldehyde solution (650 mg, 2.15 mmol, 1.0 eq.), 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (934 mg, 3.46 mmol, 1.6 eq.) , Pd(OAc) ₂ (52 mg, 0.215 mmol, 0.1 eq.), X-Phos (205 mg, 0.43 mmol, 0.2 eq.), K ₂ CO ₃ (594 mg, 4.3 mmol, 2.0 eq.) in dioxane/H ₂ O (11 ml, 10/1, v/v) was stirred at 110°C under N ₂ atmosphere for 3 hours. H ₂ O was added and the resulting mixture was extracted with EtOAc (30 ml x 3), the combined organic layers were dried over Na ₂ SO ₄ , concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 4-amino-5- (4-(difluoromethoxy)phenyl)-1-(2-methyl-2H-indazol-5-yl)-6-oxo-1,6-dihydropyridazine-3-carbaldehyde (650 mg, 69% yield) as a yellow solid remainder. LC-MS (ESI): m/z 412 [M+H] ⁺ .

[00290] Step D: 4-(4-(difluoromethoxy)phenyl)-7-fluoro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6( 2H,5H)-dione

[00291] To a suspension of 4-amino-5-(4-(difluoromethoxy)phenyl)-1-(2-methyl-2H-indazol-5-yl)-6-oxo-1,6-dihydropyridazine-3-carbaldehyde ( 150 mg, 0.36 mmol, 1.0 eq.) and ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (132 mg, 0.55 mmol, 1.5 eq.) in MeCN (5 ml) was added NaH (30 % suspension in mineral oil, 175 mg, 2.19 mmol, 6.0 eq.) in several portions at 0 ^o C in an atmosphere of N ₂ . After stirring at room temperature overnight, the resulting mixture was poured into ice-cold NH ₄ Cl (sat. aq.) (10 ml), then extracted with EtOAc (10 ml x 3), the combined organic layers were washed with brine (20 ml) and dried over Na ₂ SO ₄ , concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 4-(4-(difluoromethoxy)phenyl)-7-fluoro-2-(2-methyl-2H-indazole -5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione (120 mg, 73% yield) as a yellow solid. LC-MS (ESI): m/z 454 [M+H] ⁺ .

[00292] 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-7-fluoro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c ]pyrazin-3(2H)-one (Example 194 ) was prepared from 4-(4-(difluoromethoxy)phenyl)-7-fluoro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2 -c]pyridazine-3,6(2H,5H)-dione and 2,2-difluoroethyl trifluoromethanesulfonate in a manner similar to that described in General Method I ( Step F ).

[00293] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.56 (s, 1H), 8.10 (d, J=10.0 Hz, 1H), 8.07 (d, J= 1.2 Hz, 1H), 7.91 (d, J=9.2 Hz, 2H), 7.77 (d, J=9.2 Hz, 1H), 7.51 (dd, J=9, 2 Hz, 2.0 Hz, 1H), 7.41 (t, J _HF =74.0 Hz, 1H), 7.32 (d, J=9.2 Hz, 2H), 6.50 (tt, J _HF =54.0 Hz, 3.2 Hz, 1H), 4.71 (td, J _HF =15.2 Hz, J = 3.2 Hz, 2H), 4.28 (s, 3H).

[00294] LC-MS (ESI) : m/z 518 [M+H] ⁺ .

[00295] The method given above for General Method III was used to prepare the following compounds using suitable starting compounds:

Connection No. Structure Characteristics Example 195
4-(4-(difluoromethoxy)phenyl)-6-ethoxy-7-fluoro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one LC-MS (ESI): m/z 482.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.50 (s, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.94 (d, J=10.4 Hz , 1H), 7.88-7.83 (m, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.45 (dd, J=9.2 Hz, 2.0 Hz , 1H), 7.35 (t, J _HF =74.0 Hz, 1H), 7.28-7.23 (m, 2H), 4.42 (kv, J=7.2 Hz, 2H), 4.23 (s, 3H), 1.36 (t, J=7.2 Hz, 3H). Example 196
4-(4-(difluoromethoxy)phenyl)-6-(ethylamino)-7-fluoro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H) -He LC-MS (ESI): m/z 481.2 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.58 (t, J=5.6 Hz, 1H), 8.47 (s, 1H), 7.96-7.91 (m, 1H) , 7.90-7.79 (J=8.4 Hz, 2H), 7.68 (d, J=9.2 Hz, 1H), 7.58 (d, J=11.2 Hz, 1H) , 7.41 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.31 (t, J _HF =74.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 4.22 (s, 3H), 3.55-3.33 (m, 2H), 1.15 (t, J=7.2 Hz, 3H). Example 197
4-(4-(difluoromethoxy)phenyl)-7-fluoro-2-(2-methyl-2H-indazol-5-yl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3,2 -c]pyrazin-3(2H)-one LC-MS (ESI): m/z 535.1 [M+H]+.
1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.05 (s, 1H), 8.48 (s, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.77 (d, J=10.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.43 (dd , J=9.2 Hz, 2.0 Hz, 1H), 7.33 (t, J _HF =74.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 2H), 4 .22 (s, 3H), 4.22-4.14 (m, 2H).

[00296] Preparation of 4-(4-bromophenyl)-6-ethoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (Example 198 )

[00297] Step A: 4-(4-aminophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione

[00298] Tert-Butyl (4-(2-(2-methyl-2H-indazol-5-yl)-3,6-dioxo-2,3,5,6-tetrahydropyrido[3,2-c]pyrazine solution -4-yl)phenyl)carbamate (derived from 4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione & (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid in a general wayI (method A, Stage E)) (180 mg, 0.372 mmol) in TFA/DCM (1 ml/5 ml) was stirred at room temperature for 1 hour. 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 flash column chromatography on silica gel to give 4-(4-aminophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3 ,6(2H,5H)-dione (116 mg, 79% yield) as a yellow solid. LC-MS (ESI):m/z 385 [M+H]⁺.

[00299] Step B: 4-(4-bromophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione

[00300] To a solution of 4-(4-aminophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione (200 mg, 0.52 mmol, 1.0 eq.) and CuBr (299 mg, 2.08 mmol, 4.0 eq.) in ACN (10 ml) was added tert-butyl nitrite (215 mg, 2.08 mmol, 4 ,0 eq.) at 0°C dropwise for 10 min. The reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was quenched with Na ₂ SO ₃ (sat. aq.) (20 ml), extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 4-(4-bromophenyl)-2-(2-methyl-2H- indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione as a yellow solid (70 mg, 30% yield). LC-MS (ESI): m/z 448 [M+H] ⁺ .

[00301] Stage C:

[00302] 4-(4-Bromophenyl)-6-ethoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (Example 198) prepared from 4-(4-bromophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione and iodoethane general method I (method A, stage F).

[00303] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.49 (s, 1H), 8.00 (d, J =1.6 Hz, 1H), 7.97 (d , J =9.6 Hz, 1H), 7.75 (d, J =8.4 Hz, 2H), 7.70 (d, J =9.2 Hz, 1H), 7.64 (d, J =8.4 Hz, 2H), 7.45 (dd, J =8.8 Hz, 1.6 Hz, 1H), 6.95 (d, J =9.2 Hz, 1H), 4.33 ( kv, J =7.2 Hz, 2H), 4.22 (s, 3H), 1.32 (t, J =7.2 Hz, 3H).

[00304] LC-MS (ESI) : m/z 476, 478 [M+H] ⁺ .

[00305] Preparation of 4-(4-bromophenyl)-6-isopropoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (Example 199 )

[00306] 4-(4-Bromophenyl)-6-isopropoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (Example 199) prepared from 4-(4-bromophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione and 2-iodopropane general method I (method A, Stage F).

[00307] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.49 (s, 1H), 8.00 (dd, J =2.0 Hz, 0.8 Hz, 1H), 7.96 (d, J =9.4 Hz, 1H), 7.74-7.68 (m, 3H), 7.64 (d, J =8.6 Hz, 2H), 7.45 (dd , J =9.1 Hz, 2.0 Hz, 1H), 6.90 (d, J =9.4 Hz, 1H), 5.15 (hept, J =6.2 Hz, 1H), 4, 22 (s, 3H), 1.30 (d, J =6.2 Hz, 6H).

[00308] LC-MS (ESI) : m/z 490, 492 [M+H] ⁺ .

[00309] Preparation of 4-(4-bromophenyl)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H )-she (example 200)

[00310] 4-(4-bromophenyl)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H) -one (example 200) was prepared from 4-(4-bromophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)- dione and 2,2-difluoroethyl trifluoromethanesulfonate general way I (method A, Stage F).

[00311] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.51 (s, 1H), 8.07 (d, J =9.2 Hz, 1H), 8.03 (d , J =1.6 Hz, 1H), 7.76 (d, J =8.8 Hz, 2H), 7.72 (d, J =9.2 Hz, 1H), 7.66 (d, J =8.4 Hz, 2H), 7.47 (dd, J =9.2 Hz, 2.0 Hz, 1H), 7.08 (d, J =9.2 Hz, 1H), 6.41 ( tt, J _HF =54.4 Hz, 3.2 Hz, 1H), 4.59 (td, J _HF =15.2 Hz, J =3.2 Hz, 2H), 4.23 (s, 3H) .

[00312] LC-MS (ESI) : m/z 512, 514 [M+H] ⁺ .

[00313] Preparation of 2-(benzo[d]thiazol-6-yl)-4-(4-bromophenyl)-6-(2,2-difluoroethoxy)pyrido[3,2-c]pyrazin-3(2H)- she (example 201)

[00314] Methods similar to those described in the example were followed198,.2-(Benzo[d]thiazol-6-yl)-4-(4-bromophenyl)-6-(2,2-difluoroethoxy)pyrido[3,2-c]pyrazin-3(2H)-one (example 201) was prepared from tert-butyl (4-(2-(benzo[d]thiazol-6-yl)-3,6-dioxo-2,3,5,6-tetrahydropyrido[3,2-c]pyrazine -4-yl)phenyl)carbamate step A-B (example198) and 2,2-difluoroethyl trifluoromethanesulfonate general way I (method A, Stage F).

[00315] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.53 (s, 1H), 8.54 (d, J =2.1 Hz, 1H), 8.25 (d , J =8.7 Hz, 1H), 8.07 (d, J =9.4 Hz, 1H), 7.85 (dd, J =8.7 Hz, 2.1 Hz, 1H), 7, 76 (d, J =8.6 Hz, 2H), 7.66 (d, J =8.6 Hz, 2H), 7.09 (d, J =9.4 Hz, 1H), 6.41 ( tt, J _HF =54.4, 3.4 Hz, 1H), 4.60 (td, J =15.2, 3.4 Hz, 2H).

[00316] LC-MS (ESI) : m/z 515, 517 [M+H] ⁺ .

[00317] Preparation of 2-(benzo[d]thiazol-6-yl)-4-(4-bromophenyl)-6-isopropoxypyrido[3,2-c]pyrazin-3(2H)-one (Example 202)

[00318] 2-(Benzo[d]thiazol-6-yl)-4-(4-bromophenyl)-6-isopropoxypyrido[3,2-c]pyrazin-3(2H)-one (Example 202) was prepared from 2 -(benzo[d]thiazol-6-yl)-4-(4-bromophenyl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione and 2-iodopropane general way I (method A, Stage F).

[00319] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 8.52 (d, J =2.1 Hz, 1H), 8.24 (d, J =8 .7 Hz, 1H), 7.96 (d, J =9.4 Hz, 1H), 7.83 (dd, J =8.7, 2.1 Hz, 1H), 7.72 (d, J =8.6 Hz, 2H), 7.65 (d, J =8.6 Hz, 2H), 6.93 (d, J = 9.4 Hz, 1H), 5.16 (hept, J =6 .4 Hz, 1H), 1.31 (d, J =6.4 Hz, 6H).

[00320] LC-MS (ESI) : m/z 493, 495 [M+H] ⁺ .

[00321] Preparation of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(3-(dimethylamino)-2-methyl-2H-indazol-5-yl)pyrido[3, 2-c]pyrazin-3(2H)-one (Example 203) and 4-(4-(difluoromethoxy)phenyl)-6-(dimethylamino)-2-(3-(dimethylamino)-2-methyl-2H-indazole -5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (Example 204)

[00322] Step A: 2-(3-bromo-2-methyl-2H-indazol-5-yl)-6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3, 2-c]pyrazin-3(2H)-one

[00323] To a suspension of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazine -3(2H)-one (Example 125) (200 mg, 0.4 mmol, 1.0 eq) in ACN (4 ml) was added NBS (75 mg, 0.42 mmol, 1.05 eq). Then, the reaction was stirred at 80°C for 3 hours. The reaction was concentrated under reduced pressure and the residue was purified directly by flash column chromatography on silica gel to give 2-(3-bromo-2-methyl-2H-indazol-5-yl)-6-(2,2-difluoroethoxy)-4- (4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)-one (160 mg, 69% yield) as a yellow solid. LC-MS (ESI): m/z 578; 580 [M+H] ⁺ .

[00324] Step B: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(3-(dimethylamino)-2-methyl-2H-indazol-5-yl)pyrido[ 3,2-c]pyrazin-3(2H)-one and 4-(4-(difluoromethoxy)phenyl)-6-(dimethylamino)-2-(3-(dimethylamino)-2-methyl-2H-indazol-5 -yl)pyrido[3,2-c]pyrazin-3(2H)-one

[00325] To a suspension of 2-(3-bromo-2-methyl-2H-indazol-5-yl)-6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2 -c]pyrazin-3(2H)-one (160 mg, 0.28 mmol, 1.0 eq.) in toluene (3 ml) added Cs₂CO₃ (90 mg, 0.28 mmol, 1.0 eq.), Pd₂(dba)₃ (25 mg, 0.028 mmol, 0.10 eq), Ru-Phos (26 mg, 0.055 mmol, 0.2 eq) and dimethylamine (2 M in THF) (1.4 mL, 2.8 mmol, 10 ,0 eq.). The reaction was then sealed in a pressure-resistant tube and stirred at 100°C for 5 hours under N₂. The reaction was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography and prep RP-HPLC to give 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2- (3-(dimethylamino)-2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one(example 203)And 4-(4-(difluoromethoxy)phenyl)-6-(dimethylamino)-2-(3-(dimethylamino)-2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3( 2H)-on(example 204).

[00326] Example 203:

[00327] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.11 (s, 1H), 8.08 (d, J =9.4 Hz, 1H), 7.87 (d , J =8.4 Hz, 2H), 7.55 (d, J =9.2 Hz, 1H), 7.36 (d, J =10.6 Hz, 1H), 7.35 (t, J _HF =74.0 Hz, 1H), 7.26 (d, J =8.2 Hz, 2H), 7.06 (d, J =9.3 Hz, 1H), 6.41 (tt, J _HF =54.4 Hz, J =3.3 Hz, 1H), 4.59 (td, J _HF =15.1 Hz, J =3.3 Hz, 2H), 3.99 (s, 3H), 2 .97 (s, 6H).

[00328] LC-MS (ESI) : m/z 543 [M+H] ⁺ .

[00329] Example 204:

[00330] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.04 (dd, J = 2.0, 0.8 Hz, 1H), 7.93-7.84 (m, 2H), 7.76 (d, J =9.8 Hz, 1H), 7.52 (dd, J =9.1, 0.8 Hz, 1H), 7.33 (dd, J =9.2 , 2.0 Hz, 1H), 7.31 (t, J _HF = 74.2, 1H), 7.27 (d, J = 9.8 Hz, 1H), 7.22-7.16 (m , 2H), 3.99 (s, 3H), 3.23 (s, 3H), 3.17 (s, 3H), 2.96 (s, 6H).

[00331] LC-MS (ESI) : m/z 506 [M+H] ⁺ .

[00332] Preparation of 4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-6-propylpyrido[3,2-c]pyrazin-3(2H)-one ( example 205)

[00333] To a mixture of 6-chloro-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)- she (derived from 4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione and 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane general method I (method C, Stage E, G) (120 mg, 0.26 mmol, 1.0 eq.) and Fe(acac)₃ (93 mg, 0.26 mmol, 1.0 eq.) to THF (5 ml) and NMP (1 ml) was added n-propylmagnesium bromide (1 M in diethyl ether) (4.0 ml, 4.0 mmol, 15 .4 eq.) drop by drop at 0^oC in N atmosphere₂. The reaction mixture was stirred at room temperature overnight and quenched carefully with ice water (10 ml). The crude mixture was extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by pre-RP-HPLC to give 4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-6-propylpyrido[3,2-c]pyrazin-3( 2H)-on(Example 205).

[00334] ¹ H NMR (400 MHz, DMSO- d6 ) δ (ppm): 8.51 (s, _1H ), 8.04 (s, 1H), 7.99 (d, J =9.1 Hz , 1H), 7.83 (d, J =8.6 Hz, 2H), 7.72 (d, J =9.2 Hz, 1H), 7.49 (d, J =9.1 Hz, 1H ), 7.35 (t, J _HF =72.0 Hz, 1H), 7.29 (d, J =9.3 Hz, 1H), 7.26 (d, J =8.6 Hz, 2H) , 4.23 (s, 3H), 2.78 (t, J =7.4 Hz, 2H), 1.82-1.61 (m, 2H), 0.94 (t, J =7.4 Hz, 3H).

[00335] LC-MS (ESI) : m/z 462 [M+H] ⁺ .

[00336] Preparation of 4-cyclohexyl-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one ( example 206)

[00337] Step A: 4-chloro-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)- He

[00338] Mixture of 4,6-dichloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (300 mg, 0.87 mmol, 1.0 eq., prepared by general method I (method A, steps AD), 2,2-difluoroethyl trifluoromethanesulfonate (278 mg, 1.3 mmol, 1.49 eq.) and Cs ₂ CO ₃ (565 mg, 1. 7 mmol, 1.95 eq.) in DMF (8 ml) was stirred at room temperature for 3 hours and quenched with ice water (10 ml). The crude mixture was extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine ( 20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure.The crude residue was purified by flash column chromatography on silica gel to give 4-chloro-6-(2,2-difluoroethoxy)-2-(2-methyl-2H- indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (250 mg, 74% yield) as a yellow solid LC-MS (ESI): m/z 392 [M+ H] ⁺ .

[00339] Step B: 4-cyclohexyl-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)- He

[00340] A mixture of 4-chloro-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-2H,3H-pyrido[3,2-c]pyrazin-3- she (100 mg, 0.26 mmol, 1.0 eq.), Fe(acac) ₃ (90 mg, 0.26 mmol, 1.0 eq.) and NMP/THF mixture (0.5mL/5 ml) stirred at 0 ^o C in an atmosphere of N ₂ . Cyclohexylmagnesium bromide (1 M in diethyl ether) (2.6 ml, 2.6 mmol, 10.0 eq.) was added dropwise at 0 ^o C. The mixture was then warmed to room temperature and stirred overnight, the reaction was monitored by TLC, after completion, the reaction was quenched with ice water (10 ml), the crude mixture was extracted with EtOAc (10 ml x 3), the combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure, the crude residue was purified by prep -HPLC, yielding 4-cyclohexyl-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one ( example 206) .

[00341] ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm) 8.48 (s, 1H), 7.99-7.92 (m, 2H), 7.69 (d, J =9 ,1 Hz, 1H), 7.39 (dd, J =9.1, 2.0 Hz, 1H), 7.02 (d, J =9.4 Hz, 1H), 6.50 (t, J _HF =54.2 Hz, 1H), 4.79 (td, J _HF =15.1, 3.2 Hz, 2H), 4.22 (s, 3H), 2.36-2.32 (m, 1H), 1.88-1.69 (m, 4H), 1.63-1.55 (m, 2H), 1.43-1.19 (m, 4H).

[00342] LC-MS (ESI) : m/z 439 [M+H] ⁺ .

[00343] Preparation of 6-(2,2-difluoroethoxy)-4-(4-hydroxyphenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H )-she (example 207)

[00344] A mixture of 4-chloro-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one ( 100 mg, 0.25 mmol, 1.0 eq.), Pd(OAc) ₂ (12 mg, 0.05 mmol, 0.2 eq.), K ₂ CO ₃ (105 mg, 0.75 mmol, 3 .0 eq.) and (4-hydroxyphenyl)boronic acid (53 mg, 0.38 mmol) in a mixture of dioxane/water (5 ml, 10/1, v/v) was stirred at 100°C under N ₂ atmosphere. The reaction mixture was then poured into ice water (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by pre-RP-HPLC to give 6-(2,2-difluoroethoxy)-4-(4-hydroxyphenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c] pyrazin-3(2H)-one (example 207) .

[00345] ¹ H NMR (400 MHz, DMSO- d6 ) δ (ppm): 8.49 (s, _1H ), 8.04-7.97 (m, 2H), 7.77-7.62 ( m, 3H), 7.44 (dd, J =9.1, 1.9 Hz, 1H), 7.03 (d, J =9.4 Hz, 1H), 6.83 (d, J =8 ,4 Hz, 2H), 6.42 (td, J _HF =54.5, 3.5 Hz, 1H), 4.61 (td, J =15.0, 3.5 Hz, 2H), 4, 22 (s, 3H).

[00346] LC-MS (ESI) : m/z 450 [M+H] ⁺ .

[00347] Preparation of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(3-ethyl-2-methyl-2H-indazol-5-yl)pyrido[3,2- c]pyrazin-3(2H)-one (example 208)

[00348] Step A: 1-(5-bromo-2-methyl-2H-indazol-3-yl)ethanol

[00349] To a solution of 5-bromo-2-methyl-2H-indazole (500 mg, 2.37 mmol, 1 eq.) in THF (10 ml) was added n-BuLi (2.5 M in hexane) (4, 7 ml, 11.85 mmol, 5 eq.) dropwise at -65°C under N ₂ atmosphere. After 3 hours, acetaldehyde (5 M in THF) (0.6 mL, 3.0 mmol, 1.27 eq.) was added. The reaction was then slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into saturated aqueous NH ₄ Cl (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography to give 1-(5-bromo-2-methyl-2H-indazol-3-yl)ethanol (500 mg, 83% yield) as a yellow solid. LC-MS (ESI): m/z 255, 257 [M+H] ⁺ .

[00350] Step B: 5-bromo-3-ethyl-2-methyl-2H-indazole

[00351] A mixture of 1-(5-bromo-2-methyl-2H-indazol-3-yl)ethanol (200 mg, 0.78 mmol, 1 eq.), triethylsilane (453 mg, 3.9 mmol, 5 eq. .), TFA (889 mg, 7.8 mmol, 10 eq.) in DCM (5 ml) was stirred at 40°C for 16 hours. The mixture was then poured into saturated aqueous NaHCO ₃ (10 ml) at 0 ^o C, and extracted with DCM (10 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography to give 5-bromo-3-ethyl-2-methyl-2H-indazole (80 mg, 43% yield) as a yellow solid. LC-MS (ESI): m/z 239, 241 [M+H] ⁺ .

[00352] 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(3-ethyl-2-methyl-2H-indazol-5-yl)pyrido[3,2-c ]pyrazin-3(2H)-one (Example 208) was prepared from 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H)- she and 5-bromo-3-ethyl-2-methyl-2H-indazole general method II (method A, Stage G).

[00353] ¹ H NMR (400 MHz, DMSO- d6 ) δ: 8.13 (d, J =9.2 Hz, _1H ), 8.07 (dd, J =2.0 Hz, 0.8 Hz , 1H), 7.93 (d, J =8.8 Hz, 2H), 7.68 (dd, J =9.2 Hz, 0.8 Hz, 1H), 7.48 (dd, J =8 .8 Hz, 1.6 Hz, 1H), 7.41 (t, J _HF =74.0 Hz, 1H), 7.31 (d, J =8.8 Hz, 2H), 7.13 (d , J =9.2 Hz, 1H), 6.47 (td, J _HF =54.4 Hz, 3.2 Hz, 1H), 4.65 (td, J _HF =15.2 Hz, 3.2 Hz, 2H), 4.20 (s, 3H), 3.17 (kv, J =7.2 Hz, 2H), 1.33 (t, J =7.2 Hz, 3H).

[00354] LC-MS (ESI) : m/z 528 [M+H] ⁺ .

[00355] Preparation of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(hydroxymethyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3, 2-c]pyrazin-3(2H)-one (Example 209) and 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(difluoromethyl)-2-(2-methyl) -2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (Example 210)

[00356] Step A: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(hydroxymethyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[ 3,2-c]pyrazin-3(2H)-one

[00357] To a solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-8-(((tetrahydro-2H -pyran-2-yl)oxy)methyl)pyrido[3,2-c]pyrazin-3(2H)-one (example142,obtained from (E)-methyl 4-(tetrahydro-2H-pyran-2-yloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-2-enoate (link: Tetrahedron2012, 68, 3444-3449) general method I (method A, stage EF) (180 mg, 0.3 mmol, 1.0 eq.) in dioxane (3 ml) was added 1N HCl (aq) (1 ml, 1 mmol, 3.3 eq.) at room temperature, and the resulting mixture stirred at room temperature for 2 hours. The reaction was then quenched with ice water (20 ml) and 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 flash column chromatography on silica gel to give 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(hydroxymethyl)-2-(2-methyl- 2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (example209).

[00358] ¹ H NMR (400 MHz, DMSO- d6 ) δ (ppm): 8.50 (s, 1H), 8.04 (s, 1H), 7.84 ₍ d, J =8.4 Hz , 2H), 7.70 (d, J =9.6 Hz, 1H), 7.49 (d, J =8.8 Hz, 1H), 7.34 (t, J _HF =74.0 Hz, 1H), 7.24 (d, J =8.4 Hz, 2H), 6.94 (s, 1H), 6.39 (tt, J _HF =54.4 Hz, 3.2 Hz, 1H), 5.63 (s, 1H), 4.83 (s, 2H), 4.58 (td, J _HF =15.2 Hz, 3.2 Hz, 2H), 4.22 (s, 3H).

[00359] LC-MS (ESI) : m/z 530 [M+H] ⁺ .

[00360] Step B: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3 -dihydropyrido[3,2-c]pyridazine-8-carbaldehyde

[00361] To a solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(hydroxymethyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3 ,2-c]pyrazin-3(2H)-one (60 mg, 0.1 mmol, 1.0 eq.) in CHCl ₃ (5 ml) was added freshly activated MnO ₂ (96 mg, 1.0 mmol, 10. 0 eq.) in one serving. The resulting mixture was then stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. Once complete, the reaction mixture was filtered through a short pad of ^Celite® and the filtrate was concentrated under reduced pressure to give crude 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H- indazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyridazin-8-carbaldehyde (50 mg) as a yellow solid, which was used in the next step without further purification. LC-MS: m/z 528 [M+H] ⁺ .

[00362] Step C: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(difluoromethyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[ 3,2-c]pyrazin-3(2H)-one

[00363] To a solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3- Dihydropyrido[3,2-c]pyridazine-8-carbaldehyde (50 mg, crude) in DCM (3 ml) was added to DAST (46 mg) at -60 ^o C. After addition, it was warmed to room temperature and stirred for an additional 16 hours. After completion of the reaction, ice water (10 ml) was added and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure, the residue was purified by pre-RP-HPLC to give 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl )-8-(difluoromethyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (Example 210 ).

[00364] ¹ H NMR (400 MHz, DMSO- d6 ) δ (ppm): 8.53 (s, _1H ), 8.08 (d, J =2.0 Hz, 1H), 7.86 (d , J =8.8 Hz, 2H), 7.73 (d, J =9.2 Hz, 1H), 7.51 (dd, J =9.2 Hz, 2.0 Hz, 1H), 7, 45 (t, J _HF =53.6 Hz, 1H), 7.36 (t, J _HF =74.0 Hz, 1H), 7.30-7.25 (m, 3H), 6.41 (tt , J _HF =54.4 Hz, 3.2 Hz, 1H), 4.61 (td, J _HF =15.2 Hz, 3.2 Hz, 2H), 4.23 (s, 3H).

[00365] LC-MS (ESI) : m/z 550 [M+H] ⁺ .

[00366] Preparation of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-((dimethylamino)methyl)-2-(2-methyl-2H-indazol-5-yl)pyrido [3,2-c]pyrazin-3(2H)-one (Example 211)

[00367] Step A: (6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2, 3-dihydropyrido[3,2-c]pyrazin-8-yl)methylmethanesulfonate

[00368] To a solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(hydroxymethyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3 ,2-c]pyrazin-3(2H)-one (90 mg, 0.17 mmol, 1.0 eq., example 209 ) in DCM (3 ml) was added MsCl (29 mg, 0.25 mmol, 1. 47 eq.) and TEA (34 mg, 0.34 mmol, 2.0 eq.) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice water (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to give (6-(2,2-difluoroethoxy)-4-(4- (difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyrazin-8-yl)methylmethanesulfonate (90 mg, 87 % yield) as a yellow solid. LC-MS: m/z 608 [M+H] ⁺ .

[00369] Step B: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-((dimethylamino)methyl)-2-(2-methyl-2H-indazol-5-yl )pyrido[3,2-c]pyrazin-3(2H)-one

[00370] To a solution of (6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3 -dihydropyrido[3,2-c]pyrazin-8-yl)methylmethanesulfonate (50 mg, 0.08 mmol, 1.0 eq.) in DMSO (3 ml) was added NH(Me) ₂ HCl salt (33 mg, 0 .41 mmol, 5.1 eq.), NaI (23 mg, 0.16 mmol, 2.0 eq.) and NaHCO ₃ (14 mg, 0.16 mmol, 2.0 eq.) at room temperature, and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was then poured into ice water (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by pre-RP-HPLC to give 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-((dimethylamino)methyl)-2-(2-methyl-2H-indazol- 5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (example 211) .

[00371] ¹ H NMR (400 MHz, DMSO- d6 ) δ (ppm) 8.52 (s, 1H ₎ , 8.05 (d, J =2.0 Hz, 1H), 7.84 (d, J =8.8 Hz, 2H), 7.72 (d, J =9.2 Hz, 1H), 7.49 (dd, J =9.2, 2.0 Hz, 1H), 7.36 ( t, J _HF =74.0 Hz, 1H), 7.25 (d, J =8.8 Hz, 2H), 6.96 (s, 1H), 6.40 (tt, J _{HF =} 54.4 , 3.4 Hz, 1H), 4.23 (s, 3H), 3.77 (s, 2H), 2.29 (s, 6H).

[00372] LC-MS (ESI) : m/z 557 [M+H] ⁺ .

[00373] Preparation of 8-amino-6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2- c]pyrazin-3(2H)-one (Example 212)

[00374] Step A: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3 -dihydropyrido[3,2-c]pyridazine-8-carboxylic acid

[00375] To a mixture of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3- dihydropyrido[3,2-c]pyridazine-8-carbaldehyde (120 mg, 0.23 mmol, 1.0 eq., prepared as in Example 210 Step B) and HCO ₂ H (0.1 ml, 2.65 mmol , 11.5 eq.) in H ₂ O (0.5 ml) slowly added H ₂ O ₂ (30% by weight in H ₂ O, 0.1 ml, 1.14 mmol, 5 eq.) at 4 ^o C, and the mixture was stirred at room temperature for 6 hours. The mixture was then poured into H ₂ O (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure, the crude residue was purified by flash column chromatography on silica gel to give 6-(2,2-difluoroethoxy)-4-(4-( difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyridazine-8-carboxylic acid (80 mg, 52% yield ) as a yellow solid. LC-MS (ESI): m/z 544 [M+H] ⁺ .

[00376] Step B: 8-amino-6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3, 2-c]pyrazin-3(2H)-one

[00377] To a solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3- dihydropyrido[3,2-c]pyridazine-8-carboxylic acid (80 mg, 0.15 mmol, 1.5 eq.) in DMF (2 ml) was added TEA (22 mg, 0.22 mmol, 1.45 eq. .) and DPPA (61 mg, 0.22 mmol, 1.45 eq.), and the mixture was stirred at room temperature for 3 hours. Then, 0.3 ml of water was added to the solution, and the reaction mixture was stirred at 100°C overnight. The reaction was cooled to room temperature, and poured into H ₂ O (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure, the crude residue was purified by pre-RP-TLC to give 8-amino-6-(2,2-difluoroethoxy)-4-(4 -(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (Example 212) .

[00378] ^1H NMR (400 MHz, DMSO- d6 ) δ (ppm): 8.49 (s, _1H ), 8.05 (d, J =1.2 Hz, 1H), 7.83 (d , J =8.8 Hz, 2H), 7.69 (d, J = 9.2 Hz, 1H), 7.51 (dd, J =9.2 Hz, 1.6 Hz, 1H), 7, 32 (t, J _HF =74.0 Hz, 1H), 7.23-7.14 (m, 4H), 6.31 (tt, J _HF =54.0 Hz, 3.6 Hz, 1H), 5.83 (s, 1H), 4.47 (td, J =14.8 Hz, 3.6 Hz, 2H), 4.22 (s, 3H).

[00379] LC-MS (ESI): m/z 515 [M+H] ⁺ .

[00380] Preparation of 6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4-((trimethylsilyl)ethynyl)pyrido[3,2-c]pyrazin-3( 2H)-one (Example 213), 6-(2,2-difluoroethoxy)-4-ethynyl-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3( 2H)-one (Example 214) and 4-((1H-pyrazol-3-yl)ethynyl)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido [3,2-c]pyrazin-3(2H)-one (Example 215)

[00381] Step A: 6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4-((trimethylsilyl)ethynyl)pyrido[3,2-c]pyrazin- 3(2H)-one

[00382] A mixture of 4-chloro-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one ( 180 mg, 0.46 mmol, 1.0 eq., prepared as in Example 206 Step A), trimethyl((tributylstannyl)ethynyl)silane (268 mg, 0.69 mmol, 1.5 eq.) and Pd(PPh ₃ ) ₄ (58 mg, 0.05 mmol, 0.11 eq.) in dioxane (5 ml) was stirred at 80 ^o C under N ₂ for 15 hours. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel flash column chromatography to give 6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4-((trimethylsilyl) ethynyl)pyrido[3,2-c]pyrazin-3(2H)-one (example 213) .

[00383] ^1H NMR (400 MHz, DMSO- d6 ) δ (ppm): 8.50 (s, 1H ₎ , 8.08 (d, J =9.6 Hz, 1H), 7.98 (d , J =1.6 Hz, 1H), 7.70 (d, J =9.2 Hz, 1H), 7.41 (dd, J =9.2 Hz, 2.0 Hz, 1H), 7, 09 (d, J =9.2 Hz, 1H), 6.54 (td, J _HF =54.8 Hz, 3.6 Hz, 1H), 4.82 (td, J _HF =14.4 Hz, 3.6 Hz, 2H), 4.22 (s, 3H), 0.28 (s, 9H).

[00384] LC-MS (ESI) : m/z 454 [M+H] ⁺ .

[00385] Step B: 6-(2,2-difluoroethoxy)-4-ethynyl-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)- He

[00386] Mixture of 6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4-((trimethylsilyl)ethynyl)pyrido[3,2-c]pyrazin-3( 2H)-one (126 mg, 0.28 mmol, 1.0 eq.) and Cs ₂ CO ₃ (183 mg, 0.56 mmol, 2.0 eq.) in 2,2-difluoroethane-1-ol ( 4 ml) was stirred at room temperature for 4 hours. The resulting mixture was poured into H ₂ O (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to give 6-(2,2-difluoroethoxy)-4-ethynyl-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin- 3(2H)-one (example 214) .

[00387] ¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.51 (s, 1H), 8.08 (d, J =9.2 Hz, 1H), 7.99 (d , J =1.6 Hz, 1H), 7.72 (d, J =9.6 Hz, 1H), 7.41 (dd, J =9.2 Hz, 2.0 Hz, 1H), 7, 10 (d, J =9.2 Hz, 1H), 6.52 (tt, J _HF =54.4 Hz, 3.2 Hz, 1H), 5.02 (s, 1H), 4.83 (td , J _HF =14.8 Hz, 3.2 Hz, 2H), 4.23 (s, 3H).

[00388] LC-MS (ESI): m/z 382 [M+H] ⁺ .

[00389] Step C: 4-((1H-pyrazol-3-yl)ethynyl)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3, 2-c]pyrazin-3(2H)-one

[00390] A mixture of 6-(2,2-difluoroethoxy)-4-ethynyl-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one ( 50 mg, 0.13 mmol, 1.0 eq.), DIPEA (50 mg, 0.39 mmol, 3.0 eq.), Pd(PPh₃)₂Cl₂(10 mg, 0.013 mmol, 0.1 eq.) and 3-iodo-1H-pyrazole (101 mg, 0.52 mmol, 4.0 eq.) and CuI (25 mg, 0.13 mmol, 1.0 eq.) in DMF (5 ml) stirred at room temperature under N₂ within 4 hours. The reaction mixture was then poured into H₂O (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by pre-RP-HPLC to give 4-((1H-pyrazol-3-yl)ethynyl)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido [3,2-c]pyrazin-3(2H)-one(example 215).

[00391] ¹ H NMR (400 MHz, DMSO- d6 ) δ (ppm): 13.39 (br, s, 1H), 8.52 ₍ s, 1H), 8.09 (d, J =9, 2 Hz, 1H), 8.01 (s, 1H), 7.91-7.81 (m, 1H), 7.72 (d, J =9.2 Hz, 1H), 7.44 (dd, J =9.2 Hz, 2.0 Hz, 1H), 7.11 (d, J =9.2Hz, 1H), 6.62 (s, 1H), 6.55 (tm, J _HF =54, 4 Hz, 3.2 Hz, 1H), 4.88 (td, J _HF =14.8 Hz, 3.2 Hz, 2H), 4.23 (s, 3H).

[00392] LC-MS (ESI) : m/z 448 [M+H] ⁺ .

[00393] Preparation of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(4-oxocyclohexyl)pyrido[3,2-c]pyrazin-3(2H)-one (Example 216)

[00394] Solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)pyrido[ 3,2-c]pyrazin-3(2H)-one (derived from 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyrazin-3(2H )-one and 1,4-dioxaspiro[4,5]dec-7-en-8-yl trifluoromethanesulfonate general method II (method A, stage G)) (10 mg, 0.0197 mmol) and conc. HCl (0.1 ml) in THF (1.5 ml) was stirred at room temperature for 2 hours. The reaction was poured into saturated aqueous NaHCO₃(5 ml) and extracted with EA (5 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na₂SO₄ and concentrated under reduced pressure. Then a mixture of the residue and Rh(PPh₃)₃Cl (18 mg, 0.0197 mmol) in toluene (3 ml) was stirred at room temperature overnight under H₂. The mixture was then poured into H₂O (5 ml) and extracted with EtOAc (5 ml x 3). The combined organic layers were washed with brine (10 ml), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by pre-RP-HPLC to give 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(4-oxocyclohexyl)pyrido[3,2-c]pyrazin-3(2H )-He(example 216).

[00395] ¹ H NMR (400 MHz, DMSO- d6 ) δ (ppm): 8.02 (d, J = 9.6 Hz, 1H), 7.82 ₍ d, J = 8.8 Hz, 2H ), 7.34 (t, J _HF =74.0 Hz, 1H), 7.24 (d, J =8.8 Hz, 2H), 7.02 (d, J =9.6 Hz, 1H) , 6.37 (tt, J _HF =54.4 Hz, 2.8 Hz, 1H), 5.62 (hept, J =4.8 Hz, 1H), 4.54 (td, J _HF =14, 8 Hz, 2.8 Hz, 2H), 2.78-2.63 (m, 2H), 2.45-2.23 (m, 2H), 2.29-2.14 (m, 1H) ( HCO ₂ H salt).

[00396] LC-MS (ESI) : m/z 466 [M+H] ⁺ .

[00397] Preparation of 4-(4-(difluoromethoxy)phenyl)-6-ethoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (example 217)

[00398] Mixture of 6-chloro-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (derived from 4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione and 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane general method I (method C, stage E, G) (120 mg, 0.26 mmol, 1.0 eq.) and EtONa (177 mg, 2.6 mmol, 10.0 eq.) in EtOH (8 ml) were stirred at 40^oC for 3 hours. The reaction mixture was then poured into ice water (10 ml) and extracted with DCM (10 ml x 3). The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure. The crude residue was purified by pre-RP-HPLC, obtaining4-(4-(difluoromethoxy)phenyl)-6-ethoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyrazin-3(2H)-one (example 217).

[00399] ¹ H NMR (400 MHz, DMSO- d6 ) δ: 8.49 (s, 1H), 8.04 (d, J =1.2 Hz, 1H) _, 7.97 (d, J = 9.2 Hz, 1H), 7.86 (d, J =8.8 Hz, 2H), 7.70 (d, J =9.2 Hz, 1H), 7.45 (dd, J =9, 2 Hz, 2.0 Hz, 1H), 7.34 (t, J _HF =74.0, 1H), 7.24 (d, J =8.8 Hz, 2H), 6.95 (d, J =9.6 Hz, 1H), 4.34 (kv, J =7.2 Hz, 2H), 4.22 (s, 3H), 1.32 (t, J =7.2 Hz, 3H).

[00400] LC-MS (ESI): m/z 464 [M+H] ⁺ .

[00401] Preparation of 5-(6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyrazine -4-yl)-1H-indole-3-carbonitrile (Example 331)

[00402] To a solution of 7-(2,2-difluoroethoxy)-3-(2-methyl-2H-indazol-5-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-5-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (54 mg, 0.09 mmol, 1.0 eq.) (derived from 4-chloro-2 -(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione and 5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (ref: WO2018215316) general method I (method A, stage E and F)) in DCM (3 ml) was added TFA (1 ml), the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure, the residue was dissolved in MeOH (2 ml) and conc. N.H.₄OH (1 ml), the resulting mixture was stirred at room temperature overnight. Once complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by RP-HPLC to give 5-(6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-3-oxo -2,3-dihydropyrido[3,2-c]pyrazin-4-yl)-1H-indole-3-carbonitrile (example331).

[00403] ¹ H NMR (400 MHz, DMSO- d6 ) δ (ppm): δ 12.29 (s, 1H), 8.50 ₍ s, 1H), 8.29 (s, 1H), 8, 12 (d, J =0.9 Hz, 1H), 8.10-8.01 (m, 2H), 7.75 (dd, J =8.6 Hz, 1.5 Hz, 1H), 7, 71 (d, J =9.2 Hz, 1H), 7.60 (d, J =8.7 Hz, 1H), 7.49 (dd, J =9.1 Hz, 2.0 Hz, 1H) , 7.06 (d, J =9.4 Hz, 1H), 6.38 (td, J _HF =54.5 Hz, J =3.3 Hz, 1H), 4.54 (td, J _HF = 15.0 Hz, J =3.4 Hz, 2H), 4.22 (s, 3H).

[00404] LC-MS (ESI) : m/z 498 [M+H] ⁺ .

[00405] Preparation of 5-(6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyrazin-4-yl )-1H-indole-3-carbonitrile (example 332)

[00406] To a solution of 5-(6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyrazin-4- yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (100 mg, 0.17 mmol) (derived from 4-chloro-2-(2-methyl-2H-indazole -5-yl)pyrido[3,2-c]pyridazin-3,6(2H,5H)-dione and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (ref: WO2018215316) by general method I (method A, step E; method D, step I) ) in DCM (6 ml ) TFA (6 ml) was added and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then concentrated under reduced pressure, the residue was dissolved in MeOH (4 ml) and conc. NH ₄ OH (2 ml), the resulting mixture was stirred at room temperature for an additional 6 hours. Once complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by pre-RP-HPLC to give 5-(6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3 -dihydropyrido[3,2-c]pyrazin-4-yl)-1H-indole-3-carbonitrile (Example 332) .

[00407] ^1H NMR (400 MHz, DMSO- d6 ) (ppm): δ 12.17 (s, _1H ), 8.45 (s, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.76 (d, J =9.0 Hz, 1H), 7.66 (d, J =9, 1 Hz, 1H), 7.64 (d, J =9.1 Hz, 1H), 7.51 (d, J =8.9 Hz, 1H), 7.43 (d, J =8.9 Hz , 1H), 6.78 (d, J =9.3 Hz, 1H), 4.21 (s, 3H), 3.31 (kv, J =7.1 Hz, 2H), 1.14 (t , J =7.1 Hz, 3H).

[00408] LC-MS (ESI) : m/z 461 [M+H] ⁺ .

[00409] Biochemical analysis

[00410] Mat2A protein was expressed by recombinant baculovirus in SF9-infected cells using the Bac-Bac system cloned into the pFASTBAC1 vector (Invitrogen, Carlsbad, CA). Recombinant MAT2A was isolated from cell lysate of 150 g of infected cells using HP Ni Sepharose column chromatography. Recombinant MAT2A homodimer was eluted with 250 and 500 mM imidazole, and fractions containing MAT2A were identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and pooled.

[00411] To determine the inhibitory capacity of the compounds against the MAT2A homodimer, the protein was diluted to 4 μg/ml in assay buffer (50 mM Tris, pH 8.0, 50 mM KCl, 15 mM MgCl ₂ , 0.3 mM EDTA, 0.005% [00411] w/v] bovine serum albumin [BSA]). The test compound was prepared in 100% dimethyl sulfoxide (DMSO) at 50 times the required final concentration. 1 μl of diluted compound was added to 40 μl of diluted enzyme, and the mixture was allowed to equilibrate for 60 minutes at 25°C. The enzyme assay was initiated by adding 10 μL of substrate mixture (500 μM ATP, pH 7.0, 400 μM L-methionine in 1× assay buffer) and the mixture was incubated for an additional 60 min at 25 °C. The reaction was stopped and the released phosphate released by the enzyme in stoichiometric amounts upon production of S-adenosylmethionine (SAM) was measured using a PiColorLock Gold kit (Innova Biosciences, UK). Absolute amounts of product were determined by comparison with a standard curve for potassium phosphate buffer, pH 8.0.

[00412] Specific compounds described in the present invention were tested in the above assay and were determined to inhibit MAT2A with an IC ₅₀ according to the following scores: (A) less than 100 nM (>40% maximal inhibition), (B) between 100 nM and 1 µM (>40% maximal inhibition), and (C) between 1 µM and 10 µM (>40% maximal inhibition), as shown in Table 2 below.

[00413] Cell-based target interaction assay (SAM)

[00414] Measurement of MAT2A activity in cells was made by directly quantifying the content of its enzymatic activity product, SAM. Cancer cells were treated with candidate MAT2A inhibitors for a suitable incubation period, and the cells were then lysed using a reagent that reduced any further enzymatic activity. Soluble metabolites, including SAM, were collected, and SAM itself was directly measured in the lysate using quantitative LC-MS/MS.

[00415] A typical assay was performed using the human colon carcinoma cell line HCT116, which has been genetically engineered to delete the MTAP gene (commercially available from Horizon Discovery). This cell line was used because loss of the MTAP gene was determined to predict sensitivity to MAT2A inhibitors. Cells were seeded in 96-well dishes at the appropriate cell density. Cells were then treated 24 hours later with a candidate MAT2A inhibitor. Before addition to cells, the compound was first serially diluted in 100% DMSO, typically as a three-fold serial dilution, starting at 500-fold maximum dose with 10 dosing points, including a DMSO-only control. The compound was then transferred to a working plate in cell culture medium by adding 5 μl of compound in DMSO to 495 μl of cell culture medium. This working solution was then added to the cells through a further 5-fold dilution by adding 25 μl of working solution to 100 μl of cells in the culture medium. After addition of the compound, the cells were incubated at 37°C/5% CO ₂ for 72 hours.

[00416] To quantify SAM concentration after compound treatment, 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% cold methanol and 20% water ( v/v) with acetic acid at a final concentration of 1M with 200 ng/ml deuterated d ₃ -SAM as an internal control). After centrifugation at 4°C and 3200 rpm for 30 minutes, 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 spray mode and equipped with a Waters UPLC Acquity (Waters, Milford, MA, USA) BEH Amide column. Multiple reaction monitoring data were obtained for SAM and the d ₃ -SAM standard using a pair of mass transitions at m/z 399.2→250.1 and 402.2→250.1, respectively. In a typical LC-MS/MS analysis, the initial flow rate was 0.5 mL/min of 25% mobile phase A (acetonitrile and water at 5:95 (v/v) with 1% formic acid and 10 mM ammonium acetate) and 75% mobile phase B (acetonitrile and water at 95:5 (v/v) with 1% formic acid and 10 mM ammonium acetate), 0.2-0.5 minutes with 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 minutes with 35%-75% mobile phase B, 65%-25% mobile phase A, at 1 ,1 min 25% mobile phase A and 75% mobile phase B for a total run time of 1.5 min.

[00417] Specific compounds described in the present invention were tested in the above assay and were determined to inhibit SAM with an IC ₅₀ according to the following scores: (A) less than 100 nM (>60% maximal inhibition), (B) between 100 nM and 1 µM (>60% maximal inhibition), (C) greater than or equal to 1 µM (>60% maximal inhibition), and (NT) not tested, as shown in Table 2 below.

[00418] Cell proliferation inhibition test

[00419] The effect of a test compound on cancer cell growth was assessed by treating cancer cells with the compound for 4 days followed by measuring proliferation using ATP-based cell proliferation data (Cell Titer Glo, Promega Corporation).

[00420] 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 seeded in 96-well dishes at the appropriate cell density. After 24 hours, cells were treated with a candidate MAT2A inhibitor. Before addition to cells, the compound was first serially diluted in 100% DMSO, typically as a three-fold serial dilution, starting at 500-fold maximum dose with 10 dosing points, including a DMSO-only control. The compound was then transferred to a working stock plate in cell culture medium by adding 5 μl of compound in DMSO to 495 μl of cell culture medium. This working solution was then added to the cells through a further 5-fold dilution by adding 25 μl of working solution to 100 μl of cells in the culture medium. After addition of the compound, cells were incubated at 37°C/5% CO ₂ for 4 days.

[00421] To measure inhibition of cell proliferation, cells were allowed to equilibrate to room temperature for 30 minutes and then treated with 125 μl of Cell Titer Glo reagent. The plate was then covered with aluminum foil and shaken for 15 minutes to ensure complete mixing and complete cell lysis. The luminescence signal was then measured using a Veritas plate luminometer version 1.9.2 using an ATP standard curve to confirm run-to-run reproducibility of the assay. This luminescence index was converted to a proliferation index by subtracting from each data point the ATP luminescence signal measured in the blank well (no cells) and dividing by the ATP luminescence signal measured in the 0.2% DMSO control well, well corrected for the signal in the blank well. Compound activity was then presented as the percentage change in proliferation relative to the intraplate DMSO control versus log10 compound concentration in molar (M) units.

[00422] Specific compounds described in the present invention were tested in the above assay and were determined to inhibit cell proliferation with an IC ₅₀ according to the following scores: (A) less than 100 nM (>30% maximal inhibition for MTAP-/ -; 10% maximal inhibition for MTAP+/+), (B) between 100 nM and 1 µM (>30% maximal inhibition for MTAP-/-; >10% maximal inhibition for MTAP+/+), (C) greater than or equal to 1 µM, and ( NT ) was not tested as shown in Table 2 below.

[00423] Table 2

Example Enzyme inhibition Cellular 72 h inhibition of SAM (MTAP -/-) 4 Daytime relative growth inhibition (MTAP -/-) 4 Daily relative growth inhibition (MTAP +/+) 101 A A B C 102 A A B C 103 A A A C 104 A B B C 105 A B B C 106 A A A B 107 A A A C 108 A A A C 109 A A A C 110 A A A B 111 A A A C 112 A B B C 113 A A B C 114 A A A C 115 A A A B 116 A A A C 117 A A A C 118 B NT NT NT 119 A A A C 120 A A A C 121 A A A C 122 A B A C 123 A A A B 124 A A A B 125 A A A B 126 A A A C 127 A A A C 128 A A A C 129 A A A C 130 A A A B 131 A B C C 132 A B B C 133 A A B C 134 A B C C 135 A A B C 136 A B B C 137 A A A C 138 A A A C 139 A A A B 140 A B A C 141 A A B C 142 A B B C 143 A A A C 144 A A A C 145 A A A C 146 A A A C 147 A B B C 148 A B B C 149 A A B C 150 A A A C 151 A A A C 152 A A A B 153 B C C C 154 A A A C 155 A A A C 156 A A A C 157 A B B C 158 A A A C 159 A A A C 160 A A A C 161 A A A C 162 A A A C 163 A C C C 164 B NT NT NT 165 A A A B 166 A A A C 167 A A A C 168 A A B C 169 A A A A 170 A A B C 171 A A A C 172 A A A C 173 A A A B 174 A A A C 175 A A A B 176 A A B B 177 A A A B 178 A A A B 179 A A B C 180 A A A C 181 C NT NT NT 182 A A A B 183 A A A B 184 A A B C 185 B NT NT NT 186 B NT NT NT 187 A B C C 188 A B B C 189 A B B C 190 C NT NT NT 191 B B C C 192 A A B B 193 A B B C 194 A B A C 195 A A C C 196 A A A C 197 A A A C 198 A A A C 199 A A A C 200 A A A C 201 A A A C 202 A A A C 203 A A A B 204 A NT NT NT 205 A A A C 206 A B B C 207 A A B C 208 A A A B 209 A A A C 210 A A B C 211 A B B C 212 A A A B 213 B NT C C 214 B C C C 215 A C B C 216 B NT NT NT 217 A A A B 301 A A A C 302 A A A C 303 A A A C 304 A A B B 305 A A A C 306 A NT NT NT 307 A A A C 308 A NT NT NT 309 A A A C 310 A A A C 311 A NT NT NT 312 A NT NT NT 313 A A A B 314 A NT NT NT 315 A A A C 316 A A A C 317 A A A C 318 A A A C 319 A A A C 320 A NT NT NT 321 A A A C 322 A NT NT NT 323 A A A A 324 A NT NT NT 325 A NT NT NT 326 A NT NT NT 327 A A A C 328 B NT NT NT 329 B NT NT NT 330 A NT NT NT 331 A A A C 332 A NT NT NT

Claims (82)

1. Compound of formula I , where L represents O, S, NR or bond; R represents H or C ₁ -C ₆ -alkyl; R ¹ is selected from the group consisting of C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl and -(C ₁ -C ₆ -alkyl)(C ₃ -C ₆ -cycloalkyl), where any alkyl in R ¹ is straight or branched and R ¹ is optionally substituted with 1-6 halogens or 1-6 deuterium; or when L represents NR, then R and R ¹ in combination with L represent a 3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O and S; R ² is selected from the group consisting of C ₂ -C ₆ -alkynyl, C ₆ -C ₁₀ -aryl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkenyl, 5-10 membered heteroaryl, in which 1 -4 heteroaryl members independently selected from N, O and S, where R ² is optionally substituted with one substituent selected from R ^A and halogen; R ³ is selected from the group consisting of C ₆ -C ₁₀ -aryl, C ₃ -C ₆ -cycloalkenyl, 5-10 membered heteroaryl, in which 1-4 heteroaryl members are independently selected from N, O and S, and 3- 6-membered heterocycloalkyl fused with C ₆ -aryl, in which 1-4 heterocycloalkyl members are independently selected from N, O and S, wherein R ³ is optionally substituted with one or two substituents which are selected from the group consisting of R ^A , halogen, NR ^A R ^B , -C(O)NR ^A R ^B and -CN; R ⁴ is selected from the group consisting of H, C ₁ -C ₆ -alkyl, optionally substituted with 1-3 halogens or 6-membered heterocycloalkoxy containing 1 heteroatom O, -(C ₁ -C ₆ -alkyl)NR ^A R ^B and -NR ^A R ^B ; R ⁵ is selected from H and halogen; R ^A is independently selected from the group consisting of H, -hydroxy, oxo, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl and 5-10 membered heteroaryl, in which 1 -4 heteroaryl members independently selected from N, O and S; wherein each alkyl and alkoxy moiety R ^A is optionally substituted with 1-3 substituents selected from the group consisting of deuterium and halogen; and R ^B is independently selected from H and C ₁ -C ₆ -alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein at least one of ^R4 and ^R5 is H. 3. Connection according to any one of paragraphs. 1, 2, where R ⁴ represents H. 4. Connection according to any one of paragraphs. 1-3, where R ⁵ represents H. 5. Connection according to any one of paragraphs. 1-4, where each of R ⁴ and R ⁵ represents H. 6. Connection according to any one of paragraphs. 1-5, where R ² represents an optionally substituted C ₆ -C ₁₀ -aryl or an optionally substituted 5-10 membered heteroaryl. 7. The compound according to claim 6, where R ² represents an optionally substituted C ₆ -C ₁₀ -aryl. 8. A compound according to claim 7, wherein R ² represents optionally substituted phenyl. 9. A compound according to claim 6, wherein ^R2 is an optionally substituted 5-10 membered heteroaryl and wherein 1 ring member is N. 10. A compound according to claim 9, wherein R ² is an optionally substituted 5- or 6-membered heteroaryl. 11. A compound according to claim 9 or 10, wherein R ² represents an optionally substituted 6-membered heteroaryl. 12. Connection according to any one of paragraphs. 9-11, where R ² represents optionally substituted pyridyl. 13. Connection according to any one of paragraphs. 1-11, where R ³ represents an optionally substituted 3-6 membered heterocycloalkyl fused with a C ₆ -aryl, or an optionally substituted 5-10 membered heteroaryl. 14. The compound according to claim 13, where R ³ is selected from the group consisting of benzothiazolyl, benzoisothiazolyl, benzoxazolyl, pyridinyl, pyridinonyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, cinno linyl, isoxazolyl , pyrazolyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxynyl and tetrahydrobenzodioxynyl, each of which may be optionally substituted. 15. Connection according to any one of paragraphs. 1-11, where R ³ represents optionally substituted C ₆ -C ₁₀ -aryl. 16. A compound according to claim 15, wherein R ³ is optionally substituted phenyl. 17. Connection according to any one of paragraphs. 1-5, where R ² represents an optionally substituted phenyl and R ³ represents an optionally substituted 3-6 membered heterocycloalkyl fused to a C ₆ -aryl, or an optionally substituted 5-10 membered heteroaryl. 18. Connection according to any one of paragraphs. 1-17, where L represents O or NR. 19. The compound according to claim 18, where R ¹ represents an optionally substituted C ₁ -C ₆ -alkyl or an optionally substituted C ₃ -C ₆ -cycloalkyl. 20. A compound according to claim 18 or 19, where R ¹ represents C ₁ -C ₃ alkyl, which is optionally substituted with 1-3 F. 21. Connection according to claim 1, where L represents O or NR and R represents H; R ¹ represents C ₁ -C ₃ -alkyl, which is optionally substituted with 1-3 F; R ² represents an optionally substituted 5-10 membered heteroaryl, in which 1 heteroaryl member is N, or an optionally substituted C ₆ -C ₁₀ -aryl; R ³ is an optionally substituted 3-6 membered heterocycloalkyl fused with a C ₆ -aryl, or an optionally substituted 5-10 membered heteroaryl, wherein 1-3 heterocycloalkyl or heteroaryl members are independently selected from N, O and S; And ^R4 and ^R5 are each H. 22. The compound according to claim 21, where L represents NR. 23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where the compound is selected from the following table: 24. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following table 25. A pharmaceutical composition having inhibitory activity against MAT2A, containing a therapeutically effective amount of a compound according to any one of claims. 1-24 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 26. A method of treating cancer sensitive to MAT2A inhibition in a subject suffering from it, comprising administering to the subject an effective amount of a MAT2A inhibitor or a pharmaceutically acceptable salt thereof according to any one of claims. 1-24. 27. The method of claim 26, wherein the cancer is a cancer with the MTAP removed. 28. A method of treating cancer sensitive to MAT2A inhibition in a subject suffering from it, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims. 1-24. 29. The method of claim 28, wherein the cancer is a cancer with the MTAP removed. 30. Method according to any one of paragraphs. 26-28, wherein the cancer is selected from the group consisting of mesothelioma, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma and hereditary nonpolyposis colorectal cancer, esophageal carcinoma, lip carcinoma, laryngeal carcinoma, hypopharynx carcinoma, tongue carcinoma, carcinoma salivary gland, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, renal parenchymal carcinoma, ovarian carcinoma, cervical carcinoma, uterine body carcinoma, endometrial carcinoma, chorionic carcinoma, pancreatic carcinoma, prostate carcinoma, carcinoma ohms bladder, testicular carcinoma, breast carcinoma, urinary tract carcinoma, melanoma, brain tumors, lymphoma, head and neck cancer, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) posarcomas, fibrosarcomas, sarcomas Ewing and plasmacytomas. 31. The method of claim 28 or 29, wherein the cancer is selected from the group consisting of B-cell acute 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. 32. The method of claim 31, wherein the cancer is lung cancer selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma and squamous cell lung cancer. 33. The method of claim 31, wherein the cancer is a brain cancer selected from the group consisting of glioma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumors and craniopharyngioma. 34. The method of claim 31, wherein the cancer is triple negative breast cancer (TNBC). 35. The method of claim 31, wherein 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, and adult T-cell leukemia/lymphoma. 36. Use of a compound according to any one of paragraphs. 1-24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of cancer sensitive to MAT2A inhibition. 37. Use according to claim 36, wherein the cancer is a cancer with the MTAP removed. 38. Use according to claim 36 or 37, wherein the cancer is selected from the group consisting of mesothelioma, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma and hereditary nonpolyposis colorectal cancer, esophageal carcinoma, lip carcinoma, laryngeal carcinoma, carcinoma hypopharynx, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, renal parenchymal carcinoma, ovarian carcinoma, cervical carcinoma, uterine body carcinoma, endometrial carcinoma, chorionic carcinoma, carcinoma pancreatic cinomas gland, prostate carcinoma, bladder carcinoma, testicular carcinoma, breast carcinoma, urinary tract carcinoma, melanoma, brain tumors, lymphoma, head and neck cancer, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia ( AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, osteosarcoma, chondrosarcomas, myosarcomas , liposarcomas, fibrosarcomas, Ewing's sarcomas and plasmacytomas. 39. Use according to claim 36 or 37, wherein the cancer is selected from the group consisting of B-cell acute 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. 40. Use according to claim 39, wherein the cancer is lung cancer selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma and squamous cell lung cancer. 41. Use according to claim 39, wherein the cancer is triple negative breast cancer (TNBC). 42. Use according to claim 39, wherein the cancer is a brain cancer selected from the group consisting of glioma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumors and craniopharyngioma. 43. The use of claim 39, wherein 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 .