ARGININE N-METHYLTRASSERASE 5 (PRMT5) PROTEIN INHIBITORS COOPERATIVE FOR METHYLTHIOADENOSINE (MTA)

Abstract

The present invention relates to compounds that inhibit the activity of the protein arginine N-methyltransferase 5 (PRMT5). In particular, the present invention relates to compounds, pharmaceutical compositions, and methods of use, such as methods for treating cancer, using the compounds and pharmaceutical compositions of the present invention.

Description

COMPOUNDS INHIBITORS OF THE PROTEIN ARGININE N-METHYL TRANSFERASE 5 (PRMT5) COOPERATIVE FOR METHYLTHIOADENOSINE (MTA) Field of Invention The present invention relates to compounds that are MTA cooperative inhibitors of protein arginine N-methyl transferase 5 (PRMT5). In particular, the present invention relates to compounds, pharmaceutical compositions comprising the compounds and methods for their use. Background of the Invention Protein arginine N-methyl transferase (PRMT5) is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) toward an omega-nitrogen of the guanidino function of L-arginine residues. of the protein (omega-monomethylation) and the transfer of a second methyl group to the other omeganitrogen, to produce symmetrical dimethylarginine (sDMA). PRMT5 forms a complex with MEP50 (methylosome protein 50), which is required for substrate recognition and targeting, and also, for histone 2A and histone 4 methyltransferase activity catalyzed by PRMT5 (e.g., see Ho et al. al., (2013) PLOS ONE 8 (8) : 10.1371 / annotation / e6b5348e-9052-44ab-8f0690d0ldc88fc2). Ref. 331469 Homozygous deletions of pl6 / CDKN2a are prevalent in cancer, and these mutations commonly involve co-deletion of adjacent genes, including the gene encoding methylthioadenosine phosphorylase (ΜΤΆΡ). It is estimated that approximately 15% of all human cancers have a homozygous deletion of the MTAP gene (e.g., see Firestone & Schramm (2017) J. Am. Chem Soc. 139(39):1375413760. doi: 10.1021 / jacs.7b05803. Epub 2017 Sep 20). Cells lacking MTAP activity have elevated levels of the MTAP substrate methylthioadenosine (MTA), which is a potent inhibitor of PRMT5. Inhibition of PRMT5 activity results in reduced methylation activity and increased sensitivity of cell proliferation to loss of PRMT5 activity or depletion. Therefore, loss of MTAP activity reduces PRMT5 methylation activity, making cells selectively dependent on PRMT5 activity. Brief Description of the Invention Therefore, we realized that MTA cooperative inhibition of PRMT5 activity in MTAP-deleted cancers will provide therapeutic benefit for a wide range of cancer types. The compounds of the present invention provide this therapeutic benefit as cooperative MTA inhibitors of PRMT5 that negatively modulate the activity of MTA-bound PRMT5 in a cell, particularly an MTAP-deficient cell, or for the treatment of various forms of MTAP-associated cancer. . There is a need to develop new inhibitors of PRMT5 cooperatives with MTA that are capable of inhibiting PRMT5 activity in the presence of high concentrations of MTA, in particular, in MTAP-deficient cells. In one aspect of the invention, compounds are provided that are represented by Formula (I): Formula (I) and its pharmaceutically acceptable salts: where: R1is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-Cl - C5 alkyl, -Y-cycloalkyl, -Y-heterocyclyl, -Y-aryl, -YarCl-C3alkyl or -Y-heteroaryl, wherein the cycloalkyl moieties, the heterocyclyl moieties, the aryl moieties, and the heteroaryl moieties are each optionally replaced with one or more R2; each Y is independently a bond or -NR4-; each R2is independently hydroxy, halogen, cyano, cyanomethyl, -(NR4)2? hydroxyalkyl, alkoxy, -SO2CI C3alkyl, -X-arCl-C3alkyl, heteroalkyl, C2- C4 alkynyl, -X-haloalkyl, -X-Cl - C5 alkyl, -Z-Cl - C5 alkyl, heterocyclyl, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, Z-aryl, or -X-heteroaryl, wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more R5; each each L is independently a bond or 01-03 alkylene; R3a and R3b are each independently hydrogen or deuterium, or R3a and R3b together are oxo; each R4 is independently hydrogen or 01-03 alkyl; each R5 is independently cyano, oxo, halogen, 01 - 03 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Zcycloalkyl, -X-arCl-C3alkyl, X-arCl-C3alkyl substituted with cyano -X-L-cycloalkyl, -X-L -heteroaryl optionally substituted with one or more Cl-C3alkyl or oxo, or -X-aryl; and R6is hydrogen, halogen, 01-03 alkyl, haloalkyl or alkoxy. In one aspect of the invention, compounds are provided that are represented by Formula (I-A): Formula (I-A) or one of its pharmaceutically acceptable salts, wherein R1, R2, R3a, R3b, R4, R5, R6, Y, X, Z and L are as each defined for Formula I. In one aspect of the invention, compounds are provided that are represented by Formula (I-B): Formula (I-B) or one of its pharmaceutically acceptable salts, wherein R1, R2, R3a, R3b, R4, Rb, R6, Y, X, Z and L are as each defined for Formula I. In one aspect of the invention, compounds are provided that are represented by Formula (I-C): Formula (I-C) or one of its pharmaceutically acceptable salts, wherein R1, R2, R3a, R3b, R4, R5, R6, Y, X, Z and L are as each defined for Formula I. In another aspect of the invention, compounds are provided that are represented by Formula (I-D): Formula (I-D) or one of its pharmaceutically acceptable salts: where: each Y is independently a bond or -NR4-; each R2 is independently hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SCgCl C3alkyl, -X-arCl-C3alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-Cl -C5 alkyl, -Z-Cl -C5 alkyl, heterocyclyl, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, Z-aryl, or -X-heteroaryl, where heterocyclyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more R5, or each each Z is independently a bond, -SO-, -SO2, -CH(OH)- or -C(O)-; each L is independently a bond or C1-C3 alkylene; each R4 is independently hydrogen or C1-C3 alkyl; each R5 is independently cyano, oxo, halogen, C1-03 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Zcycloalkyl, -X-arCl-C3alkyl, X-arCl-C3alkyl substituted with cyano, -X-L-cycloalkyl, - X-L-heteroaryl optionally substituted with one or more Cl-C3alkyl or oxo, or -X-aryl; and R6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy. In another aspect of the invention, intermediates are provided that are useful for the preparation of compounds of Formula (I), Formula (I-A), Formula (I-B) and Formula (I-C). In another aspect of the invention, there are provided pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In yet another aspect of the invention, methods are provided for inhibiting PRMT5 activity in a cell, comprising contacting the cell with a compound of Formula (I), Formula (I-A), Formula (I-B) and Formula (I-C) . In one embodiment, the contact is in vitro. In one embodiment, the contact is in vivo. Also provided herein is a method for inhibiting cell proliferation, in vitro or in vivo, wherein the method comprises contacting a cell with an effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B ), Formula (I-C) or a pharmaceutically acceptable salt of the compound, or a pharmaceutical composition of the compound as defined herein. In one embodiment, the cell is an MTAP-deficient cell. Additionally, methods of treating cancer in a patient are provided, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of the present invention, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. Also provided herein is a method of treating cancer in a patient in need thereof, wherein the method comprises (a) determining that the cancer is associated with a double deletion of MTAP (e.g., a cancer associated with MTAP); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (I-C) or a pharmaceutically acceptable salt of the compound, or a pharmaceutical composition of the compound. Detailed description of the invention The present invention relates to PRMT5 inhibitors cooperative with MTA. In particular, the present invention relates to compounds that inhibit the activity of PRMT5 in the presence of bound MTA, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of use thereof. DEFINITIONS Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention pertains. All patents, patent applications and publications referenced herein are incorporated by reference to the extent consistent with this disclosure. Terms and intervals have their generally stated definition, unless otherwise expressly defined. For reasons of simplicity, chemical moieties are defined and referred to throughout the description primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). However, the terms may also be used to express corresponding multivalent moieties in appropriate structural circumstances that are clear to those skilled in the art. For example, while an alkyl moiety generally refers to a monovalent radical (e.g., CH3-CH2-), in certain circumstances, a bivalent linking moiety may be alkyl, in which case, those skilled in the art will understand that the alkyl is a divalent radical (e.g. -CH2-CH2-), which is equivalent to the term alkylene. (Similarly, in circumstances where a divalent moiety is required and indicated as aryl, those skilled in the art will understand the term aryl to refer to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, according to the oxidation state). of the S). As used herein, PRMT5 refers to a mammalian protein arginine N-methyl transferase 5 (PRMT5) enzyme. As used herein, a PRMT5 inhibitor or MTA cooperative PRMT5 inhibitor refers to compounds of the present invention that are represented by Formula (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of PRMT5 in the presence of bound MTA in vitro or in vivo, or in cells expressing high levels of MTA. As used herein, MTAP refers to a mammalian methylthioadenosine phosphorylase (MTAP) enzyme. An MTAP-associated disease or disorder, as used herein, refers to diseases or disorders associated with MTAP, or mediated by MTAP, or that have a loss of MTAP activity, resulting in sensitization of the disorder. to the selective inhibition of PRMT5 activity. A non-limiting example of an MTAP-associated disease or disorder is an MTAP-associated cancer. The term amino refers to -NH2. The term acetyl refers to -C(O)CH3. As used herein, the term acyl refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl moieties are as defined herein. The term alkyl as used herein refers to saturated straight or branched chain aliphatic groups having 1 to 12 carbon atoms. Thus, alkyl encompasses Ci, C2, C3, C4, C5, Ce, C7, C3, Cg, Cío, Cu and Ci2 groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tere-butyl, pentyl, and hexyl. The term alkenyl as used herein means an unsaturated straight-chain or branched aliphatic group with one or more carbon-carbon double bonds, having 2 to 12 carbon atoms. Thus, alkenyl encompasses C2, C3, C4, C5, Ce, C7, Cg, Cg, Cío, Cu and C12 groups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl. The term alkynyl as used herein means an unsaturated straight-chain or branched aliphatic group with one or more carbon-carbon triple bonds, having 2 to 12 carbon atoms. Thus, alkynyl encompasses C2, C3, C4, C5, Cg, C7, Cg, Cg, Cío, Cu and C12 groups. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl and hexynyl. An alkylene, alkenylene or alkynylene group is an alkyl, alkenyl, or alkynyl group, as defined above, that is positioned between two additional chemical groups, and serves to connect them. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, without limitation, ethenylene, propenylene and butenylene. Examples of alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene. The term alkoxy refers to -OC1 - C6 alkyl. The term cycloalkyl as used herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. Thus, cycloalkyl includes C3, C4, C5, C6, C7, C8, C9, Ci0, Cu and C12 cyclic hydrocarbon groups. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term heteroalkyl refers to an alkyl group, as defined above, wherein one or more carbon atoms in the chain are independently replaced with O, S, or NRX, where Rx is hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl and methoxypropyl. An aryl group is a Ce-Ci4 aromatic moiety comprising one to three aromatic rings. Thus, aryl includes cyclic hydrocarbon groups Ce, Cío, C13, and Cu. An exemplary aryl group is a C6-Ci0 aryl group. Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl and fluorenyl. An aryl group further includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings are non-aromatic, provided that at least one ring is aromatic, such as indenyl. An aralkyl or aryloalkyl group comprises an aryl group covalently linked to an alkyl group where the moiety is linked to another group through the alkyl moiety. An exemplary aralkyl group is -(C1-C6)alkyl(C6 CIO)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. For example, an arCl-C3alkyl is an aryl group covalently bonded to a C1-C3 alkyl. A heterocyclyl or heterocyclic group is a mono- or bicyclic (fused or spiro) ring structure having 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for For example, 4 to 8 atoms, where one or more ring atoms are independently -C(O)-, N, NR4, O, or S, and the rest of the ring atoms are quaternary carbons or carbonyl. Examples of heterocyclic groups include, without limitation, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, THFyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, ditianyl, tritianyl, azatianyl, oxatianyl, dioxolanyl, oxazolidinyl, or xazolidinonyl , decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethylmorpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds that have adjacent O and / or S ring atoms. As used herein, L-heterocyclyl refers to a heterocyclyl group covalently linked to another group through an alkylene linker. As used herein, the term heteroaryl refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms; having 6, 10, or 14 shared π electrons in a cyclic array; and having, in addition to the carbon atoms, one to three heteroatoms that are each independently N, 0 or S. Heteroaryl also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the rings Fused rings are non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom. Examples of heteroaryl groups include acridinyl, azocynyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol2(3H)-one, 2H-benzo[b] [1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, in dolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridaz inyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, 1,2,5triazolyl, 1,3,4-triazolyl, and xanthenyl. An L-heteroaralkyl or L-heteroarylalkyl group comprises a heteroaryl group covalently linked to another group via an alkylene linker. Examples of heteroalkyl groups include a Ci-Cg alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, is oinodylmethyl, cinolinylmethyl, and benzothiophenylethyl. Compounds having adjacent O and / or S ring atoms are specifically excluded from the scope of this term. An arylene, heteroarylene, or heterocyclylene group is a bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined above, that is positioned between two additional chemical groups, and serves to connect them. As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as optionally substituted, without expressly stating the substituents, the group is intended to optionally have from one to four, preferably one to three, more preferably one or two non-hydrogen substituents. The term halogen or halo as used herein refers to chlorine, bromine, fluorine or iodine. The term haloalkyl refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Examples of haloalkyls are trifluoromethyl, difluoromethyl, flurochloromethyl, chloromethyl, and fluoromethyl. The term hydroxyalkyl refers to -alkyleneOH. As used herein, an effective amount of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of the PRMT5 enzyme. As used herein, a therapeutically effective amount of a compound is an amount that is sufficient to improve or otherwise reduce a symptom or stop or reverse the progression of a condition, or to negatively modulate or inhibit the activity of PRMT5. The amount may be administered as a single dosage, or may be administered according to a regimen, for which it is effective. As used herein, treatment means any way in which the symptoms or pathology of a condition, disorder or disease in a patient are improved or otherwise beneficially altered. As used herein, improvement of the symptoms of a particular disorder by the administration of a compound or a particular pharmaceutical composition refers to any decrease, whether permanent or temporary, lasting or transient, that can be attributed to or associated with the administration of the composition. COMPOUNDS In one aspect of the invention, compounds are provided that are represented by Formula (I): Formula (I) or one of its pharmaceutically acceptable salts: where: R1 is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-Cl-C5 alkyl, -Y-cycloalkyl, -Y-heterocyclyl, -Y-aryl, -YarCl-C3alkyl or -Y-heteroaryl, wherein the cycloalkyl moieties , the heterocyclyl moieties, the aryl moieties, and the heteroaryl moieties are each optionally substituted with one or more R2; each Y is a bond or -NR4-; each R2 is independently hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SO2CI C3alkyl, -X-arCl-C3alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-Cl - C5 alkyl, -Z-Cl - C5 alkyl, heterocyclyl, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, Z-aryl, or -X-heteroaryl, wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more R5; each X is independently a bond, O, S, -NR4o -NR4C(O)-; each Z is independently a bond, -SO-, -SO2, -CH(OH)- or -C(O)-; each L is independently a bond or C1-C3 alkylene; R3a and p>3b are either independently hydrogen or deuterium, or R3a and R3b together are oxo; each R4 is independently hydrogen or C1-C3 alkyl; each R5 is independently cyano, oxo, halogen, C1 - C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Zcycloalkyl, -X-arCl-C3alkyl, X-arCl-C3alkyl substituted with cyano, -X-L-cycloalkyl, - X-L-heteroaryl optionally substituted with one or more Cl-C3alkyl or oxo, or -X-aryl; and R6 is hydrogen, halogen, haloalkyl, C1-C3 alkyl or alkoxy. In one embodiment for compounds of Formula (I), R1 is hydrogen. In another embodiment for compounds of Formula (I), R1 is halogen. In certain embodiments, the halogen is bromine. In one embodiment for compounds of Formula (I), R1 is L-CN. In one embodiment, L is C1-C3 alkylene. In certain embodiments, the C1-C3 alkylene is methylene. In one embodiment for compounds of Formula (I), R1es Y-Cl - C5 alkyl. In one embodiment, Y is a bond, and the C1 C5 alkyl is methyl. In one embodiment, Y is -NR4- and the C1 C5 alkyl is methyl, ethyl or propyl. In one embodiment for compounds of Formula (I), R1 is hydroxyalkyl. In one embodiment for compounds of Formula (I), R1 is Y-heterocyclyl. In certain embodiments, Y is a bond and the heterocyclyl is azetidinyl, THFyl or morpholinyl. In one embodiment for compounds of Formula (I), R1 is Y-aryl wherein the aryl is optionally substituted with one or more R2. In certain embodiments, Y is a bond, and the aryl is phenyl optionally substituted with one or two R2. In one embodiment, the one or two R2 groups are each independently C1-C3 alkyl, cyano or halogen. In one embodiment for compounds of Formula (I), R1 is Y-cycloalkyl. In one embodiment, Y is a bond, and the cycloalkyl is cyclopentyl. In one embodiment for compounds of Formula (I), R1 is Y-heteroaryl optionally substituted with one or more R2. In certain embodiments, the heteroaryl is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, oxidazolyl, pyridyl, pyridiazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrazolopyridinyl, 1Hpyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridyl, tetrahydropyrazolopyrazinyl, 2H-4X4-imidazopyrimidinyl, 2H4X4 -imidazopyridazinyl, oxazolopyridyl or 5,6-dihydro-8Himidazooxazinyl, each optionally substituted with one or more R2. In one embodiment, Y is a link. In one embodiment, R1 is -Y-heteroaryl, Y is a bond, and the heteroaryl is azetidinyl, and R2 is -(NR4)2. In one embodiment, R1 is heteroaryl, Y is a bond, and the heteroaryl is tetrahydropyrazolepyrazinyl, optionally substituted with one or more R2. In one embodiment, tetrahydropyrazolopyrazinyl is 4,5,6,7tetrahydropyrazolo[l,5-a]pyrazin-3-yl optionally substituted with one or more R2. In one embodiment, the tetrahydropyrazolepyrazinyl is substituted with an R2. In one embodiment, R2 is -X-C1-C5 alkyl, arCl-C3alkyl, -Z-C1-C5 alkyl, -Z-cycloalkyl or -X-aryl. In one embodiment, R2 is -Zcycloalkyl, where Z is a bond, and the cycloalkyl is cyclopropyl. In one embodiment, R2 is -Z-cycloalkyl, where Z is -C(O)- and the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl. In an embodiment where R1 is Y-heteroaryl, Y is a bond and the heteroaryl is pyrazolopyridinyl optionally substituted with one or more R2. In one embodiment, the pyrazolylpyridinyl is substituted with an R2, where the R2 is alkoxy or -X-aryl. In one embodiment, the alkoxy is methoxy or isopropyloxy. In certain embodiments, the -X-aryl, the X is O and the aryl is phenyl. In one embodiment, Y is a bond, and the R1heteroaryl is pyridyl, optionally substituted with one or two R2. In certain embodiments, the pyridyl is substituted with an R2, where R2 is hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SO2CI - C3alkyl, arCl-C3alkyl, heteroalkyl, C2-C4 alkynyl, - X -Haloalquilo, -x -Cl -C5 Rent, -z -Cl -C5 Rent, heterociclil, -x -l -cycloalquilo, -z -cicloalquilo, -x -arilo, -z -arilo, or -x -heteroarile, where heterocyclyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more R5. In one embodiment, R1 is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl, and R2 is -X-Cl-C5 alkyl, X is a bond, and the C1-C5 alkyl is methyl, ethyl propyl, isopropyl, butyl , isobutyl, pentyl or isopentyl. In one embodiment, R1 is -Y-heteroaryl, Y is a bond, and the heteroaryl is pyridyl, and R2 is -X-haloalkyl, X is a bond, and the haloalkyl is difluoromethyl or trifluoromethyl. In another embodiment, R2 is -X-haloalkyl, where X is O, and where the haloalkyl is difluoromethyl or trifluoromethyl. In one embodiment, R1 is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl, and R2 is -X-L-cycloalkyl, where X is a bond, L is a bond and the cycloalkyl is cyclopropyl or cyclohexyl. In another embodiment, R2 is -X-L-cycloalkyl, where X is a bond, L is methylene, and the cycloalkyl is cyclopropyl. In one embodiment, R2 is -X-L-cycloalkyl, where X is O, L is methylene, and the cycloalkyl is cyclopropyl. In one embodiment, R1 is -Y-heteroaryl, Y is a bond, and the heteroaryl is pyridyl, and R2 is C2-C4 alkynyl, where the alkynyl is ethynyl or prop-2-ynyl. In another embodiment, R1 is -Y-heteroaryl, Y is a bond, and the heteroaryl is pyridyl, and R2 is -SO2CI - C3 alkyl, wherein the C1 -C3 alkyl is methyl. In one embodiment, R1 is -Y-heteroaryl, Y is a bond, and the heteroaryl is pyridyl, and R2 is heterocyclyl, where the heterocyclyl is morpholinyl or tertrahydropyranyl. In other embodiments, R1 is -Y-heteroaryl, Y is a bond, and the heteroaryl is pyridyl, and R2 is -X-heteroaryl, wherein the heteroaryl is optionally substituted with one or more R5. In one embodiment, In one embodiment, X is a bond, the heteroaryl is pyridyl or pyrimidinyl, each optionally substituted with an R5. In one embodiment, R1 is -Y-heteroaryl, Y is a bond, and heteroaryl is pyridyl, and R2 is arCl-C3alkyl, where arCl-C3alkyl is benzyl. In an embodiment where R1 is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl, and R2 is -X-heteroaryl, where the X is 0, and the heteroaryl is quinolinyl optionally substituted with one or more R5. In another embodiment, the X is -NR4-, and the heteroaryl is quinolinyl optionally substituted with one or more R5. In one embodiment, R1 is -Y-heteroaryl, Y is a bond, and heteroaryl is pyridyl, and R2 is -X-aryl, where X is O, and aryl is phenyl optionally substituted with one, two or three R5. In one embodiment, each of the one, two or three R5 groups is independently selected from the group consisting of cyano, halogen, C1-C3 alkyl and alkoxy. In one embodiment, In one embodiment, X is 0, and the aryl is phenyl optionally substituted with two R5 groups, where each R5 group is independently cyano. In one embodiment, X is -NR4-, and the aryl is phenyl optionally substituted with two R5 groups, where each R5 group is independently alkoxy. In certain embodiments, each alkoxy is methoxy. In one embodiment, R1 is -Y-heteroaryl, Y is a bond, and the heteroaryl is pyridyl, and R2 is halogen, where the halogen is chlorine or fluorine. In one embodiment, R1 is -Yheteroaryl, Y is a bond, and the heteroaryl is pyridyl, and R2 is -X-L-cycloalkyl, heterocyclyl or -X-aryl, wherein the aryl is optionally substituted with one or more R5. In one embodiment, R2 is -X-L-cycloalkyl, wherein X and L are each a bond, and the cycloalkyl is cyclohexyl. In one embodiment, R2 is heterocyclyl, wherein the heterocyclyl is tetrahydropyranyl. In one embodiment, R2 is -X-aryl, where the aryl is phenyl substituted with two R5, where each R5 is cyano. In certain embodiments, R1 is -Y-heteroaryl, Y is a bond, and heteroaryl is pyridyl substituted with two R2. In one embodiment, each R2 is independently -X-Cl -C5 alkyl, or one R2 is halogen or cycloalkyl, and the second R2 is -X-C1 -C5 alkyl, where X is a bond. In one embodiment for compounds of Formula (I), R1 is Y-heteroaryl, Y is a bond, and the heteroaryl is pyrimidinyl, optionally substituted with one or two R2. In one embodiment, the pyrimidinyl is substituted with an R2, where R2 is —X—C1-C5 alkyl or -X-haloalkyl. In one embodiment, each X is a link. In one embodiment for compounds of Formula (I), R1 is Y-heteroaryl, Y is a bond and the heteroaryl is quinolinyl, optionally substituted with one or two R2. In certain embodiments, the R2 group is cyan. In certain embodiments, one R2 group is cyano, and the second R2 is halogen or -X-Cl C5 alkyl. In one embodiment for compounds of Formula (I), R1 is Y-heteroaryl, Y is a bond, and the heteroaryl is isothiazolyl, optionally substituted with one or two R2. In one embodiment, R2 is -X-aryl optionally substituted with an R5, where the aryl is naphthyl substituted with an R5, where R5 is cyano. In one embodiment for compounds of Formula (I), R1 is Y-heteroaryl, Y is a bond, and the heteroaryl is pyrazolyl, optionally substituted with one, two or three R2 groups. In certain embodiments, the pyrazolyl is substituted with an R2, where R2 is cyano, -X-C1-C5 alkyl, hydroxyalkyl, arCl-C3alkyl or -X-aryl, where the aryl is optionally substituted with one or more R5. In one embodiment, R2 is -X-Cl-C5 alkyl, where X is a bond, and the C1-C5 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl. In other embodiments, the pyrazolyl is substituted with two R2 groups, wherein the two R2 groups are independently (1) -X-Cl - C5 alkyl, (2) -X-Cl - C5 alkyl and halogen, (3) - X-Cl - C5 alkyl and alkoxy, (4) -X-Cl - C5 alkyl and -N(R4)2, -(5) - C5 alkyl and arCl-C3alkyl, (7) -X-Cl - C5 alkyl and -X-L-cyclolalkyl, -(8) -X-Cl - C5 alkyl and -heterocyclyl, (9) -X-Cl - C5 alkyl and -X-aryl optionally substituted with one or more R5, (10) -X-Cl-C5 alkyl and -X-heteroaryl optionally substituted with one or more R5, (11) -X-Cl-C5 alkyl and cyanomethyl, (12 ) -X-Cl - C5 alkyl and cyano, (13) cyano and halogen, where the halogen is chlorine or fluorine, (14) cyano and -X-L-cycloalkyl, (15) independently halogen, (16) cyano and alkoxy, where each with cyano, and (21) halogen and -X-aryl. In an embodiment where R1 is pyrazolyl, the pyrazolyl is substituted with two R2, where one R2 is -X-Cl-C5 alkyl and the second R2 is -X-aryl optionally substituted with one or more R5. In one embodiment, each (2) an R5 is cyano and an R5 is -X-Cl-C5 alkyl, where X is a bond; (3) an R5 is cyano and an R5 is -X-L-cycloalkyl, where X is a bond and L is a bond, methylene or ethylene; (4) a cyano R5 and a halogen R5; (5) an R5 is cyano and an R5 is alkoxy; (6) each R5 is independently cyano, or (7) each R5 is independently halogen. In an embodiment where R1 is pyrazolyl, the pyrazolyl is substituted with two R2, where one R2 is -X-Cl-C5 alkyl and the second R2 is -X-aryl optionally substituted with one or more R5. In one embodiment, the X is a bond, and the aryl is naphthyl substituted with an R5, where R5 is cyano or halogen. In one embodiment, the naphthyl is substituted with two R5 groups, where one R5 is cyano and the second R5 is halogen, alkoxy or cyano. In one embodiment, the naphthyl is substituted with three R5 groups, where one R5 is cyano and the second R5 is Xhaloalkyl, and the third R5 is -X-L-cycloalkyl. In an embodiment where R1 is pyrazolyl, the pyrazolyl is substituted with two R2, where one R2 is -X-Cl-C5 alkyl and the second R2 is -X-aryl optionally substituted with one or more R5. In one embodiment, the (2) one R5 is cyano and two R5 are -X-Cl -C5 alkyl, where each X is a bond; (3) an R5 is cyano, an R5 is halogen, and an R5 is -X-Cl-C5 alkyl, wherein X is a bond; (4) one R5 is cyano and two R5 are alkoxy, (5) one R5 is cyano and two R5 are halogen (6) one R5 is cyano, one R5 is halogen and one R5 is alkoxy, (7) or one R5 is cyano, one R5 is halogen, and one R5 is -XL-cycloalkyl. In an embodiment where R1 is pyrazolyl, the pyrazolyl is substituted with two R2, where one R2 is -X-Cl-C5 alkyl and the second R2 is -X-heteroaryl optionally substituted with one or more R5. In one embodiment, each In one embodiment, the pyrazolyl is substituted with three R2, where each R2 is independently -X-Cl-C5 alkyl, and each X is a bond. In an embodiment where R1 is pyrazolyl, the pyrazolyl is substituted with three R2, where (1) one R2 is cyano and two R2 are halogen; (2) a cyano R2, a halogen R2 and an alkoxy R2. In other embodiments, one R2 is alkoxy, and two R2 are independently halogen. In one embodiment for compounds of Formula (I), R1 is Y-heteroaryl, Y is a bond, and the heteroaryl is imidazolyl, lH-pyrrolopyridyl, tetrahydropyrazolopyrazinyl, 2H-4Á4imidazopyrimidinyl, 2ñ-4X4-imidazopyridazinyl, or oxazolopyridyl, each substituted with a group R2, where R2 is - X-C1 - C5 alkyl, where X is a bond. In one embodiment, the heteroaryl is IH-pyrrolopyridyl substituted with an R2, where R2 is cyano or -X-aryl. In certain embodiments, the X of -X-aryl is a bond, and the aryl is phenyl. In one embodiment, the heteroaryl is imidazolyl substituted with an R2, where R2 is hydroxyalkyl or -X-aryl. In one embodiment for compounds of Formula (I), R1 is Y-heteroaryl, Y is a bond, and heteroaryl is imidazopyridyl substituted with an R2 group, where R2 is cyano, alkoxy, halogen or -X-Cl-C5 alkyl. In other embodiments, the heteroaryl is imidazopyridyl substituted with two R2 groups, where one R2 is halogen and the second R2 group is -X-C1 -C5 alkyl or halogen. In one embodiment for compounds of Formula (I), R1es Y-aryl, Y is -NR4-, and aryl is phenyl optionally substituted with one or more R5. In one embodiment, R1 is -Y-arCl-C3alkyl. In one embodiment, Y is -NR4-, and arCl-C3alkyl is benzyl. In one embodiment, R3a and R3b are each hydrogen. In another embodiment, R3a and R3b are each deuterium. In certain embodiments, one of R3a and R3bes hydrogen, and the other is deuterium. In one embodiment, R3a and R3b taken together are oxo. In one embodiment, each R4 is hydrogen. In one embodiment, each R4 is independently C1-C3 alkyl. In one embodiment, one R4 is hydrogen and the other R4 is C1-C3 alkyl. In one embodiment, the cycloalkyl, aryl or heteroaryl rings are optionally substituted with one or more R5, where R5 is cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -XarCl -C3alkyl, -X-L-cycloalkyl or -X-aryl. In one embodiment, R6 is hydrogen. In one embodiment, R6 is halogen. In certain embodiments, the halogen is chlorine or fluorine. In one embodiment, Rses C1-C3 alkyl. In certain embodiments, the C1-C3 alkyl is methyl or ethyl. In one embodiment, R6 is alkoxy. In certain embodiments, the alkoxy is methoxy. In one embodiment, R6 is haloalkyl. In certain embodiments, the haloalkyl is trifluoromethyl. In one aspect of the invention, compounds are provided that are represented by Formula (I-A): or one of its pharmaceutically acceptable salts, wherein R1, R2, R3a, R3b, R4, R5, R6, Y, X, Z, and L are as each defined for Formula I. In one aspect of the invention, compounds are provided that are represented by Formula (I-B): Formula (I-B) or one of its pharmaceutically acceptable salts, wherein R1, R2, R3a, R3b, R4, R5, R6, Y, X, Z, and L are as each defined for Formula I. In one aspect of the invention, compounds are provided that are represented by Formula (I-C): Formula (I-C) or one of its pharmaceutically acceptable salts, wherein R1, R2, R3a, R3b, R4, R5, R6, Y, X, Z and L are as each defined for Formula I. In another aspect of the invention, compounds are provided that are represented by Formula (I-D): or one of its pharmaceutically acceptable salts: where: each Y is independently a bond or -NR4-; each R2 is independently hydroxy, halogen, cyano, cyanomethyl, -(NR4>2, hydroxyalkyl, alkoxy, -SO2CI C3alkyl, -X-arCl-C3alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-Cl -C5 alkyl, -Z-Cl -C5 alkyl, heterocyclyl, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, Z-aryl, or -X-heteroaryl, where heterocyclyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more R5, or each each Z is independently a bond, -SO-, -SO2, -CH(OH) — or -C(O)-; each L is independently a bond or C1-C3 alkylene; each R4 is independently hydrogen or C1-C3 alkyl; each R5 is independently cyano, oxo, halogen, C1 - C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Zcycloalkyl, -X-arCl-C3alkyl, X-arCl-C3alkyl substituted with cyano, -X-L-cycloalkyl, - X-L-heteroaryl optionally substituted with one or more Cl-C3alkyl or oxo, or -X-aryl; and R6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy. In one embodiment, the compound of Formula (I), Formula (I-A), Formula (I-B), and / or Formula (I-C) is: QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι F EITHER QRzzcn / zznz / q / υιλι QAzzcn / zznz / q / υιλι C.N. EITHER CL EITHER QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι QRzzcn / zznz / q / υιλι AH / ΝΗ ncXXX n nc X r Xr X o^yA o οΑΛ o y a ¿ a f and above pharmaceutically acceptable salts. In one embodiment, the compound of <nh2 n—, f2 —nai f nc\j lal l nc 2\ 'fvnh y aah a 7 γ tít o^x-'-'x o αν jj ¿ ci cr r n h2nr x 1 --n á ¾. 'jat n -aca naa>x o / y j O , ¿ A2 N H2N —n 3, 1 y A. 1 Nd / 1 F / J mu yA^pAA / NH AvcAynh / \ι ΓΙ X T Ji O O'^\¿yA o F HA Λ _ i NCxJ FAL y A I2 1 / of the compounds Formula (I) is: N=, H2A y. i Γ Τι Α^^ν NCvA pU^nh .A / ' Aaa oFX, ci 0 d N= HY ^-n A. 1 r Ti d^^N NCyA fULnh ry a χχ 0 l N=, HA A. 1 r Am^F njX fXXh ΐ / ΧΧ ci 0 f r or a pharmaceutically acceptable salt of the above compounds. The compounds of Formula (I), Formula (I-A), Formula (I-B) and Formula (I-C) can be formulated as pharmaceutical compositions. PHARMACEUTICAL COMPOSITIONS In another aspect, the invention provides pharmaceutical compositions comprising a PRMT5 inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient or diluent. The compounds of the invention can be formulated by any method well known in the art, and can be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal or intrarectal. In certain embodiments, the compounds of the invention are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be orally. The characteristics of the carrier will depend on the route of administration. As used herein, the term pharmaceutically acceptable means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredients. Therefore, the compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, for example, Remington's Pharmaceutical Sciences, 18th edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pennsylvania, 1990. As used herein, the term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the compounds identified above and exhibit minimal or no undesirable toxicological effects. Examples of such salts include, without limitation, acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like), and salts formed with organic acids such as acid acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid and polygalacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, specifically including the quaternary ammonium salt of the formula -NR+Z-, wherein R is hydrogen, alkyl or benzyl, and Z is a counterion. , including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate and diphenylacetate). The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to a patient without causing serious toxic effects in the treated patient. A dose of the active compound for all the conditions mentioned above is in the range of about 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more generally 0.5 to about 25 mg per kilogram of recipient's body weight per day. A typical topical dosage will range from 0.01 to 3% w / w in a suitable carrier. The effective dosage range of pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art. Pharmaceutical compositions comprising compounds of the present invention can be used in the methods described herein. METHODS OF USE In yet another aspect, the invention provides methods for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity in vitro is desired with an effective amount of a compound of Formula ( I), Formula (Ι-Ά), Formula (I-B) or Formula (I-C), pharmaceutically acceptable salts of the compounds, or pharmaceutical compositions containing the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the cell is an MTAP-deficient cell. The compositions and methods provided herein are considered particularly useful for inhibiting PRMT5 activity in a cell in vivo. In one embodiment, a cell in which inhibition of PRMT5 activity is desired is contacted in vivo with a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B) or Formula ( I-C), or a pharmaceutically acceptable salt thereof, to negatively modulate the activity of PRMT5. In other embodiments, a therapeutically effective amount of pharmaceutically acceptable salts or pharmaceutical compositions containing the compound of Formula (I), Formula (I-A), Formula (I-B) or Formula (I-C) may be used. In one embodiment, the cell is an MTAP-deficient cell. In one embodiment, negative modulation of PRMT5 activity occurs in the presence of bound MTA. By negatively modulating PRMT5 activity, particularly in cases of cells lacking MTAP activity, the methods are designed to inhibit PRMT5 activity to block cell proliferation. The cells can be contacted in a single dose or in multiple doses according to a particular treatment regimen to affect the desired negative modulation of PRMT5. The degree of PRMT5 inhibition can be monitored in vitro against the enzyme in the presence and absence of MTA, and in the cell, using well-known methods, including those described in Example B below, to evaluate the efficacy of the treatment and the dosages. In another aspect, methods of treating cancer are provided comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (I-C), pharmaceutically salts acceptable compounds, or pharmaceutical compositions comprising the compound or its pharmaceutically acceptable salts. In one embodiment, the cancer is an MTAP-associated cancer. The compositions and methods provided herein can be used for the treatment of a wide variety of cancer types, including tumors such as prostate, breast, brain, skin, cervical, testicular carcinomas, etc. More particularly, the types of cancer that can be treated by the compositions and methods of the invention include, without limitation, types of tumors such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, pulmonary, oral, ovarian, prostate and thyroid, and sarcomas. More specifically, these compounds can be used to treat: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, liomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, liomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi sarcoma, liomioma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, liomioma); genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronphroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma , chondromyxofibroma, osteoid osteoma and giant cell tumors; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pretumoral cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa thecal cell tumors, cell tumors Sertoli-Leydig, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma , basal cell carcinoma, squamous cell carcinoma, Kaposi sarcoma, atypical moles, dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and adrenal glands: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In one embodiment, the cancer is an MTAP-associated cancer selected from hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, and head and neck cancer. The concentration and route of administration for the patient will vary according to the cancer being treated. The compounds, their pharmaceutically acceptable salts and the pharmaceutical compositions comprising the compounds and salts may also be co-administered with other antineoplastic compounds, for example, chemotherapy, or used in combination with other treatments, such as radiation or surgery, or as adjunctive therapy. before surgery or after operation. GENERAL REACTION SCHEME, INTERMEDIARIES AND EXAMPLES GENERAL REACTION SCHEMES The compounds of the present invention can be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or can be prepared using other conventional reagents and methods well known to those skilled in the art. For example, intermediates for preparing compounds and compounds of Formula (I), Formula (I-A), Formula (I-B) or Formula (I-C) of the present invention can be prepared according to General Reaction Schemes I-XVI: GENERAL REACTION SCHEME I OBn OBn OBn 6b CN where R1—Aryl / Heteroaryl. Hal - Cl. Br or I Compounds of Formula (I) where R1 is aryl or heteroaryl can be prepared according to General Reaction Scheme I. Compounds 7a and 7b are both examples of Formula (I) where R1 is aryl or heteroaryl and R3a and R3b are H. A cyclic haloaryl anhydride 1 is treated with bis(nucleophile) such as hydrazine hydrate in acetic acid at elevated temperature to form a phthalhydrazide 2 which is treated with a halogenating agent, for example POCI3 to achieve trihalophthalazine. 3. Treatment of trihalophthalazine 3 with an alcohol, for example, benzyl alcohol and NaH in THF at 0°C, provides dihaloalkoxyphthalazine 4a and 4b as a mixture of regioisomers. The mixture of 4a and 4b is subjected to palladium-catalyzed cross-coupling conditions, such as Stille coupling or Suzuki coupling with aryl / heteroaryl metal reagents, for example, with the corresponding aryl / heteroaryltributyltin or aryl / heteroaryl acids. / boronic esters in order to provide substituted haloalkoxyphthalazine 5a and 5b as a mixture of regioisomers. The mixture of substituted haloalkoxyphthalazine 5a and 5b is subjected to metal-mediated cyanation conditions with, for example, Pd2(dba)2, dppf, Zn and ZnCN2in DMF at elevated temperature, and the resulting mixture of cyanoalkoxyphthalazine 6a and 6b is subjected to hydrogenation conditions, for example with Pd / C, HC1 and H2 in methanol in order to obtain the phthalazinone methylamine mixture 7a and 7b. The regioisomeric mixture of 7a and 7b is separated by chromatography, such as supercritical fluid chromatography (SFC) in order to provide the desired compounds 7a and 7b of Formula (I). GENERAL REACTION SCHEME II where R1= Aryl / Hctcroaryl. Hal = Cl. Bro I Compounds of Formula (I) wherein R1 is aryl or heteroaryl can be prepared according to general reaction Scheme II. Compounds 7a and 7b are both examples of Formula (I) where R1 is aryl or heteroaryl and R3a and R3b are H. The mixture of regioisomers 4a and 4b is separated by chromatography, such as supercritical fluid chromatography (SFC). in English) in order to obtain isomerically pure dihaloalkoxyphthalazines 4a and 4b. 4a or 4b is then subjected to metal-mediated cross-coupling conditions, e.g., Suzuki conditions, with aryl / heteroaryl boronic acids / esters to provide the substituted haloalkoxyphthalazine 5a or 5b. The substituted haloalkoxyphthalazine 5a or 5b is subjected to metal-mediated cyanation conditions, with, for example, Pd2(dba)3, dppf, Zn and ZnCN2en DMF at elevated temperature in order to deliver cyanoalkoxyphthalazine 6a or 6b. Cyanoalkoxyphthalazine 6a or 6b is subjected to hydrogenation conditions, for example with Pd / C, HC1 and H2 in methanol in order to obtain phthalazinone 7a or 7b in order to provide the desired compounds of Formula (I). GENERAL REACTION SCHEME III-A Compounds of Formula (I) wherein R1 is aryl, heteroaryl, heterocyclyl or alkyl can be prepared according to General Reaction Scheme III-A. Compound 7a is an example of Formula (I) where R1 is aryl, heteroaryl, heterocyclyl or alkyl, and R3a and R3b are H. 1(5-halo-2-methylophenyl)ethenone 8a is treated with an oxidant, for example, KMnO4 in water at 50°C to provide 2-(carboxycarbonyl)-4-halobenzoic acid 9a. Condensation of 9a, for example, with hydrazine hydrate in ethanol at elevated temperature, produces 7-halo-4-oxo-3,4-dihydrophthalazine-1carboxylic acid 10a which is then esterified with acid and alcohol, for example, sulfuric acid and methanol. Methyl 7-halo-4-oxo3,4-dihydrophthalazine-l-carboxylate is reduced by hydride reduction, for example with sodium borohydride and CaCY in methanol, in order to achieve 6-halo-4(hydroxymethyl)phthalazine -1(2H)-one 12a, which is then treated with halogenating agent, for example, thionyl chloride, for 12 hours to provide 6-halo-4(halomethyl)phthalazin-1(2H)-one 13a. Nucleophilic SN2 displacement of 13a with a nitrogen nucleophile, e.g., potassium phthalimide in DMF at elevated temperature supplies 14a, which undergoes metal-mediated cross-coupling conditions, e.g., Suzuki conditions, with boronic acids / asters of aryl / heteroaryl / heterocyclyl / alkyl to provide phthalazinone coupling product 15a. The phthalimide protecting group of 15a is removed under solvolysis conditions, for example, with hydrazine hydrate in ethanol in order to provide the desired compound 7a of Formula (I). GENERAL REACTION SCHEME III-B where R1 = Aryl, heteroaryl, alkyl, and Hal = Cl, Br or I Compounds of Formula (I) wherein R1 is aryl, heteroaryl, heterocyclyl or alkyl can be prepared according to general reaction Scheme III-B. Compound 7b is an example of Formula (I) where R1 is aryl, heteroaryl, heterocyclyl or alkyl and R3a and R3b are H. The l-(5-halo-2methylophenyl)ethenone 8b is treated with an oxidant, for example KMnO4 in water at 50 °C in order to supply 2(carboxycarbonyl)-4-halobenzoic acid 9b. Condensation of 9b, for example with hydrazine hydrate in ethanol at elevated temperature produces 7-halo-4-oxo-3,4-dihydrophthalazine-1carboxylic acid 10b which is then esterified with acid and alcohol, for example sulfuric acid and methanol . Methyl 7-halo-4-oxo 3,4-dihydrophthalazine-l-carboxylate 11b is reduced by hydride reduction, for example with sodium borohydride and CaCl2 in methanol, to achieve 6-halo-4(hydroxymethyl)phthalazin-1(2H)-one 12b, which is then treated with halogenating agent, for example, thionyl chloride, for 12 hours to provide 6-halo-4(halomethyl)phthalazin-1(2H)-one 13b. Nucleophilic SN2 displacement of 13b with a nitrogen nucleophile, e.g., potassium phthalimide in DMF at elevated temperature supplies 14b, which undergoes metal-mediated cross-coupling conditions, e.g., Suzuki conditions with aryl boronic acids / esters. / heteroaryl / heterocyclyl / alkyl in order to provide the phthalazinone coupling product 15b. The phthalimide protecting group of 15b is removed under solvolysis conditions, for example with hydrazine hydrate in ethanol in order to provide the desired compound 7b of Formula (I). GENERAL REACTION SCHEME IV-A where R2= O-aryl, O-heteroaryl, and Hal = Cl, Br or I The Compounds of Formula (I) where R1 is pyridyl and R2es -O-aryl or -O-heteroaryl can be prepared according to General Reaction Scheme IV-A. Compound 29 is an example of Formula (I) where R1 is pyridyl, R2 is -0-aryl or -O-heteroaryl, and R3a and R3b are H. 5-Bromopyridin-3-ol 25 is heated with an aryl / heteroaryl halide appropriately substituted 26, for example, in a mixture of DMF and NaH, in order to supply 3-halo-5-R2-oxypyridine 27. 3-halo-5-R2pyridine 27 is coupled with boronic acid, Intermediate AN under conditions of palladium-catalyzed cross-coupling, e.g. Suzuki coupling, to generate the R2-pyridyl coupling product 28. The R2-pyridyl coupling product 28 is subjected to solvolysis conditions, e.g. with hydrazine hydrate in ethanol , in order to supply the free amine 29 of Formula (I). GENERAL REACTION SCHEME IV-B or or 27 28-Boc 29 where R2= O-aryl, O-heteroaryl, and Hal = Cl, Br or I Compounds of Formula (I) wherein R1 is pyridyl and R2 is -0-aryl or -O-heteroaryl can be prepared according to General Reaction Scheme IV-B. Compound 29 is an example of Formula (I) where R1 is pyridyl, R2 is -0-aryl or -O-heteroaryl, and R3a and R3b are H. 5-Bromopyridin-3-ol 25 is heated with aryl / heteroaryl halide 26 , for example, in a mixture of DMF and NaH, in order to supply 3-bromo-5-R2pyridine 27. 3-bromo-5-R2-pyridine 27 is coupled with boronic acid Intermediate J under conditions of catalyzed cross-coupling with palladium, for example, Suzuki conditions, in order to generate the coupling product 28-Boc. The coupling product 28-Boc is subjected to acidic conditions, for example with TFA, in order to provide the desired compound 29 of Formula (I). GENERAL REACTION SCHEME IV-C R2= -C1-C5 alkyl, heterocyclyl, -L-cycloalkyl, CH2-aryl and CH?-heteroaryl, where L is a bond or C1-C3 alkylene© The Compounds of Formula (I) wherein R1 is 5-R2-6,7dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl and R2 is -C1 - C5 alkyl, heterocyclyl, -L-cycloalkyl, -CH2 -aryl and -CH2heteroaryl where L is a bond or C1 - C3 alkylene can be prepared according to General Reaction Scheme IV-C. Compound 34 is an example of Formula (I) wherein R1 is 5R2-6, 7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl, R2 is -C1-C5 alkyl, heterocyclyl, -L-cycloalkyl, -CH2-aryl and -CH2-heteroaryl where L is a bond or C1 - C3 alkylene and R3a and R3b are H. 3-Bromo-4,5, 6, 7 tetrahydropyrazolo[1,5-a]pyrazine 30 is reacted with aldehyde or ketone 31 under reductive amination conditions, for example, with sodium borohydride in methanol, to form R2-substituted product 32. Amination product 32 is coupled with boronic ester Intermediate AN under cross-coupling catalyzed with palladium, for example, Suzuki conditions, in order to supply the coupling product 33. The coupling product 33 is then exposed to solvolysis conditions, for example with hydrazine hydrate, to supply the free amine 34 of Formula ( YO) . GENERAL REACTION SCHEME IV-D Compounds of Formula (I) wherein R1 is aryl or heteroaryl can be prepared according to General Reaction Scheme IV-D. Compound 94 is an example of Formula (I) where R1 is an appropriately substituted aryl or heteroaryl, and R3a and R3b are H. The boronic ester N-Boc Intermediate J is coupled with a substituted aryl / heteroaryl halide 92 under cross-coupling conditions catalyzed with palladium, for example, Suzuki coupling conditions, in order to generate N-Boc-R1-substituted coupling product 90. The N-Boc-R1-substituted coupling product 90 is subjected to acidic conditions to eliminate the group Boc, for example TFA, in order to achieve R1-substituted amine 94 of Formula (I). GENERAL REACTION SCHEME IV-E F R2= -C1-C5 alkyl, heterocyclyl, -L-cycloalkyl, CH2-aryl and CHo-heteroaryl, where L is a bond or C1-C3 alkylene© The Compounds of Formula (I) wherein R1 is 5-R2-6,7dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl and R2 is -C1 - C5 alkyl, heterocyclyl, -L-cycloalkyl, -CH2 -aryl and -CH2heteroaryl where L is a bond or C1 - C3 alkylene can be prepared according to General Reaction Scheme IV-E. Compound 34 is an example of Formula (I) where R1 is 5R2-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl, R2 is -C1 - C5 alkyl, heterocyclyl, -L- cycloalkyl, -CH2-aryl and -CH2-heteroaryl where L is a bond or C1 - C3 alkylene and R3a and R3b are H. 3-Bromo-5-R2-6,7-dihydro-4H-pyrazolo [ 1,5a]pyrazine 32 is borylated, for example, with Miyaura conditions, to provide the boron ato ester 32a—Bpin. The borylation product 32a-Bpin is coupled with Intermediate F under palladium-catalyzed cross-coupling conditions, e.g., Suzuki conditions, to provide the coupling product 33a. The coupling product 33a is deprotected under acidic conditions, for example TFA, to provide the amine 34a of Formula (I). GENERAL REACTION SCHEME IV-F where R2 = aryl or heteroaryl, and Hal = Cl, Br or I Compounds of Formula (I) wherein R1 is 5-R2-6,7dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl and R2 is aryl or heteroaryl can be prepared according to General Reaction Scheme IV -F. Compound 34 is an example of Formula (I) where R1 is 5-R2-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine3-yl, R2 is aryl or heteroaryl and R3a and R3b are H. The 3- Bromo4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 30 is reacted with aryl / heteroaryl halide 26, under copper catalyst-mediated Ullman coupling conditions, for example, with Cu(1)1 , CS2CO3, L-proline in DMF, at elevated temperature, to form the amination product 32. The R2-substituted amination product 32 is coupled with AN Intermediate under palladium-catalyzed cross-coupling conditions, e.g. Suzuki, in order to supply the coupling product 33. The coupling product 33 is subjected to solvolysis conditions, for example, hydrazine hydrate, to supply the amine 34 of Formula (I). GENERAL REACTION SCHEME IV-G 383940where R;= -C(O)-aryl or -C(O)-heteroaryl Compounds of Formula (I) wherein R1 is 5-R2-6,7dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl and R2 is -C(O)-aryl or —C(O)-heteroaryl They can be prepared according to General Reaction Scheme IV-G. Compound 40 is an example of Formula (I) where R1 is 5-R2-6,7-dihydro-4H-pyrazolo[1,5a]pyrazine-3-yl, R2 is -C(O)-aryl or -C( O)-heteroaryl and R3a and R3bson H. 3-Bromo-4,5,6,7-tetrahydropyrazolo[1,5a]pyrazine 30 is coupled to carboxylic acid 37 with a coupling reagent, for example, 1[bis(dimethylamino methylene]-lH-l,2,3-triazolo[4,5b]pyridinium 3-oxide hexafluorophosphate (HATU) with a base such as triethylamine in DMF to form amide 38. Amide 38 couples with boronic ester Intermediate AN, under palladium-catalyzed cross-coupling conditions, e.g., Suzuki coupling, to produce coupling product 39. R2-coupling product 39 is subjected to solvolysis conditions, e.g. with hydrazine monohydrate, in order to remove the phthalimide moiety and provide the amine compound of Formula (I). GENERAL REACTION SCHEME IV-H where R = alkyl, aryl or heteroaryl, and Hal = Cl, Br or I Compounds of Formula (I) wherein R1 is l-methyl-5R2-lH-pyrazol-4-yl and R2 is alkyl, aryl or heteroaryl can be prepared according to General Reaction Scheme IV-H. Compound 45 is an example of Formula (I) where R1 is l-methyl-5-R2-lH-pyrazol-4-yl, R2 is alkyl, aryl or heteroaryl and R3a and R3b are H. 4-bromo-l-methyl-lA -pyrazole 41 is coupled with alkyl / aryl / heteroaryl substituted halide 42, for example, with palladium acetate, DavePhos, tetrabutylammonium acetate, pivalic acid in NMP at elevated temperature to provide R2-substituted bromopyrazole 43. R2-substituted bromopyrazole 43 is coupled with Intermediate AN under palladium-mediated cross-coupling conditions, e.g., Suzuki conditions, to provide R2-substituted coupling product 44. The coupling product 44 is subjected to solvolysis conditions, e.g. hydrazine in order to supply amine 45 of Formula (I). GENERAL REACTION SCHEME IV-I R2= -S-aryl or -S-heteroaryl Compounds of Formula (I) wherein R1 is pyridyl, R2 is -S-aryl or -S-heteroaryl can be prepared according to General Reaction Scheme IV-I. Compound 57 is an example of Formula (I) where R1 is pyridyl, R2 is -S-aryl or -S-heteroaryl and R3a and R3b are H. 3-Bromo-5-fluoropyridine 53a is subjected to SNAr substitution conditions, e.g. , sodium aryl / heteroaryl thiolate 54, NaH in DMF at elevated temperature, to provide 3-bromo-5(aryl / heteroarylthio)pyridine 55. 3-bromo-5(aryl / heteroarylthio)pyridine 55 is coupled with ester boronic AN intermediate under palladium cross-coupling conditions, e.g. Suzuki conditions, in order to supply R2-pyridyl-cross-coupling product 56. The R2-pyridyl-cross-coupling product 56 is subjected to solvolysis conditions, with for example, hydrazine hydrate, in order to produce amine 57 of Formula (I). GENERAL REACTION SCHEME IV-J where R2= -S-aryl or -S-heteroaryl where R2= -S(O)-aryl or -S(O)-heteroaryl Compounds of Formula (I) wherein R1 is pyridyl, R2 is -S(O)-aryl or -S(O)-heteroaryl can be prepared according to General Reaction Scheme IVJ. Compound 94 is an example of Formula (I) where R1 is pyridyl, R2 is -S(0)-aryl or -S(O)-heteroaryl and R3a and R3b are H. 3-Bromo-5-(R2-thio)pyridine 55 is subjected to oxidation conditions, for example, mCPBA in dichloromethane at room temperature, in order to achieve 3bromo-5-(R2-sulfinyl)pyridine 92. 3-bromo-5-(R2sulfinyl)pyridine 92 is coupled with ester boronic intermediate AN under palladium-catalyzed cross-coupling conditions, for example Suzuki conditions, to provide R2-substituted sulfinylpyridyl product 93. The R2-substituted sulfinylpyridyl product 93 is subjected to solvolysis conditions, for example with hydrazine hydrate, to obtain the R2-substituted sulfinylpyridyl amine 94 of Formula (I). GENERAL REACTION SCHEME IV-K 107 108 109 110 or TFA Compounds of Formula (I) wherein R1 is l-methyl-5-R2lH-pyrazol-4-yl and R2 is alkyl, aryl or heteroaryl can be prepared according to General Reaction Scheme IV-K. Compound 111 is an example of Formula (I) where R1 is l-methyl-5-R2-lH-pyrazol-4-yl, R2 is alkyl, aryl or heteroaryl and R3a and R3b are H. H-R2107 is halogenated, for example with a halogenating agent such as Nbromosuccinimide or N-chlorosuccinimide under palladium-catalyzed conditions such as palladium acetate, in the presence of an acid such as p-toluenesulfonic acid, in a solvent such as dichloroethane, at elevated temperature, for example, 70 °C, in order to obtain halide 108. 4-Bromo-lmethyl-lH-pyrazole 41 is coupled with alkyl / aryl / heteroaryl-substituted halide 108, for example with palladium acetate, DavePhos, tetrabutylammonium acetate, pivalic acid in NMP at elevated temperature in order to provide R2-substituted bromopyrazole 109. R2-substituted bromopyrazole 109 is coupled with Intermediate J under palladium-mediated cross-coupling conditions, for example Suzuki conditions, in order to provide N-Boc-coupling product. R2-substituted 110. The coupling product 110 is subjected to acidic conditions to remove the Boc group, for example, TEA, to achieve R2-substituted amine 111 of Formula (I). GENERAL REACTION SCHEME V R!= cycloalkyl or heterocyclyl Compounds of Formula (I) where R1 is cycloalkyl or heterocyclyl can be prepared according to General Reaction Scheme V. Compound 7a is an example of Formula (I) where R1 is cycloalkyl or heterocyclyl and R3a and R3b are H. 2-((7-bromo-4-oxo-3,4-dihydrophthalazin-1yl)methyl)isoindoline-1,3-dione Intermediate F couples with a 4-6 membered ring olefin boronic acid 17 under conditions of palladium catalyzed coupling, e.g., Suzuki coupling conditions, in order to provide the appropriate olefin coupling product 18. The olefin coupling product 18 is then subjected to hydrogenation conditions, e.g., Pd / C and H2, in order to provide the appropriate hydrogenation product 19. The hydrogenation product is then subjected to hydrazine solvolysis conditions, for example, with hydrazine hydrate in order to provide the primary amine compound 7a of Formula (I). GENERAL REACTION SCHEME VI-A AN INTERMEDIARY cross coupling Cu(cat) or Pd(cat) EITHER Compounds of Formula (I) wherein R1 is N-linked heteroaryl or N-linked heterocyclyl can be prepared according to General Reaction Scheme VI-A. Compound 22 is an example of Formula (I) where R1 is N-linked heteroaryl or N-linked heterocyclyl and R3a and R3b are H. The boronic ester intermediate AN is subjected to metal-catalyzed cross-coupling conditions, e.g. Ullman, Buchwald-Hartwig or Chan-Lam, with a nitrogen-containing heterocyclyl or a nitrogen-containing heteroaryl 20 in order to provide the appropriate N-coupled product 21. This N-coupled product 21 is subjected to solvolysis conditions, e.g. with hydrazine hydrate, to remove the phthalimide to provide the desired primary amine 22 of Formula (I). GENERAL REACTION SCHEME VI-B INTERMEDIATE F cross coupling Cu(cat) or Pd(cat) n2h4*h2o R.1=N-linked heteroalkyl. N-linked aryl / heteroalkyl, or N-linked aralkyl Compounds of Formula (I) wherein R1 is N-linked heteroaryl or N-linked heterocyclyl can be prepared according to General Reaction Scheme VI-B. Compound 23 is an example of Formula (I) where R1 is N-linked heteroaryl or N-linked heterocyclyl and R3a and R3b are H. 2-((7bromo-4-oxo-3, 4-dihydrophthalazin-l-yl)methyl )isoindoline-1,3dione Intermediate F is subjected to metal-catalyzed cross-coupling conditions, for example, Ullman, Buchwald-Hartwig or Chan-Lam conditions, with a nitrogen-containing heterocyclyl or nitrogen-containing heteroaryl in order to provide the appropriate N-coupled product 21a. This N-coupled product 21a is then subjected to solvolysis conditions, for example, with hydrazine hydrate in order to supply the desired primary amine 91a of Formula (I). GENERAL REACTION SCHEME VI-C cross coupling Cu(cat) or Pd(cat) R.1—N-linked heteroalkyl, N-linked aryl / heteroalkyl, or N-linked aralkyl Compounds of Formula (I) wherein R1 is N-linked heteroalkyl, N-linked aryloheteroalkyl or N-linked aralkyl can be prepared according to General Reaction Scheme VI-C. Compound 24 is an example of Formula I where R1 is N-linked heteroalkyl, N-linked aryloheteroalkyl or N-linked aralkyl and R3a and R3b are H. 2-((6-bromo-4-oxo-3,4dihydrophthalazin-l- yl)methyl)isoindoline-1,3-dione intermediate F, is subjected to metal-catalyzed cross-coupling conditions, for example, Ullman, Buchwald-Hartwig or Chan-Lam conditions with a heteroalkyl / arylheteroalkyl / aralkyl amine in order of providing the appropriate N-coupled product 21b. This N-coupled product 21b is then subjected to solvolysis conditions, for example, with hydrazine hydrate in order to provide the desired R1-substituted product 91b of Formula (I) GENERAL REACTION SCHEME VII where R2=O-aryl or O-heteroaryl. and Hal = Cl, Br or 1 The Compounds of Formula (I) where R1 is pyridyl and R2es 0-aryl or O-heteroaryl can be prepared according to General Reaction Scheme VII. Compound 29 is an example of Formula (I) where R1 is pyridyl, R2 is 0-aryl or O-heteroaryl and R3a and R3b are H. 3-Bromo-5-hydroxypyridine 25 couples with boronic ester Intermediate AN under cross-coupling conditions palladium catalyzed, for example, the coupling of Suzuki conditions Pd(dppf)C12, NaHCOa, dioxane / water at 80°C, in order to generate coupling product 28-OH. The coupling product 28-OH is subjected to SNAr reaction conditions, for example, K2CO3 in DMF at 110°C with R2-substituted aryl / heteroaryl halide 26, to provide R2-substituted aryl / heteroaryl pyridyl ether 28. The R2-substituted aryl / heteroaryl pyridyl ether 28 is subjected to solvolysis conditions, for example, hydrazine hydrate, in order to provide the free amine 29 of Formula (I). GENERAL REACTION SCHEME VIII-A Compounds of Formula (I) wherein R1 is pyridyl and R2 is aryl or heteroaryl can be prepared according to general reaction Scheme VIII-A. Compound 85 is an example of Formula (I) where R1 is pyridyl, R2 is aryl or heteroaryl and R3a and R3b are H. Intermediate CB is borylated under Miyaura conditions, for example, with bis(pinacolato)diboron, Pd(dppf)C12 , KOAc in dioxane at elevated temperature to provide boronic acid 86. Boronic acid 86 is coupled with R2halide 26 under palladium-catalyzed cross-coupling conditions, e.g. Suzuki conditions, to produce R2-pyridyl coupling product 84. R2- pyridyl coupling product 84 is subjected to solvolysis conditions, for example with hydrazine hydrate, in order to provide primary amine 85 of Formula (I) GENERAL REACTION SCHEME VIII-B where R2= aryl or heteroaryl Compounds of Formula (I) wherein R1 is pyridyl and R2 is aryl or heteroaryl can be prepared according to General Reaction Scheme VIII-B. Compound 85 is an example of Formula (I) where R1 is pyridyl, R2 is aryl or heteroaryl and R3a and R3b are H. Intermediate AN is coupled with 3-bromo-5-iodopyridine 53b under palladium-catalyzed cross-coupling conditions, e.g. Suzuki conditions, in order to obtain 3-bromo-pyridyl coupling product Intermediate CB. Intermediate CB is then coupled with aryl / heteroaryl-substituted boronic ester under palladium-catalyzed cross-coupling conditions, e.g., Suzuki coupling conditions, to provide pyridyl R2-substituted coupling product 84. Coupling product 84 is subjected to solvolysis, for example with hydrazine hydrate, to provide primary amine 85 of Formula (I). GENERAL REACTION SCHEME IX-A where R.1= aryl / heteroaryl, R3a= alkyl, and Hal = Cl, Br or 1 Compounds of Formula (I), where R1 is aryl or heteroaryl, R3a is alkyl and R3bes H, can be prepared according to General Reaction Scheme IX-A. Compound 100 is an example of Formula (I) where R1 is aryl or heteroaryl, R3a is alkyl and R3bes H. Methyl 7-halo-4-oxo-3,4dihydrophthalazine-l-carboxylate is reduced using hydride reduction conditions, for example, sodium borohydride, CaCI2 in methanol at 0°C, to achieve primary alcohol 6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12a. 6halo-4-(hydroxymethyl)phthalazin-1 (2H)-one 12a is reacted with an oxidant, for example, MnCQ in dichloroethane to provide 7-halo-4-oxo-3,4-dihydrophthalazine-1carbaldehyde 95 7-Halo-4-oxo-3,4-dihydrophthalazine-1carbaldehyde 95 is converted to the sulfinamide compound 96 for example by adding t-butanesulfinamide, titanium tetraiso-propoxide in THF and heating to 60°C for 12 hours. t-Butyl sulfonamide 96 is then reacted with alkylmagnesium halide in THF at -78°C to generate methyl sulfonamide 97. Methyl sulfonamide 97 is coupled with an appropriate Rx-substituted boronic ester under palladium-catalyzed cross-coupling conditions. , for example Suzuki conditions, to provide R1-substituted coupling product 99. The R1-substituted coupling product 99 is desulfinylated under acidic conditions, for example HCl / dioxane in order to provide R1-substituted primary amine 100 of Formula (I). GENERAL REACTION SCHEME IX-B where R1= aryl / heteroaryl, R3yl= alkyl, and Hal = Cl, Br or 1 Compounds of Formula (I), where R1 is aryl or heteroaryl, R3a is alkyl and R3bes H, can be prepared according to General Reaction Scheme IX-B. Compounds 9-5a and 9-5b are examples of Formula (I) where R1 is aryl or heteroaryl, R3a is alkyl and R3bes H. The t-butyl sulfinamide intermediate 97 is borylated under Miyaura conditions, for example, with bis(pinacolato )diboron, Pd(dppf)CI2, KOAc in dioxane at elevated temperature to provide 9-2 boronic ester which is then coupled reacted with an appropriate R1-substituted halide under palladium-catalyzed cross-coupling conditions, e.g. of Suzuki, to supply coupling product R1-replaced 9-3. The R1-substituted 9-3 coupling product is desulfinylated under acidic conditions, for example HCl / dioxane in order to provide R1-substituted 9-4 primary amine of Formula (I). The racemic mixture of 9-4 is then separated into the corresponding pure enantiomers by prep HPLC. chiral and / or chiral SFC, in order to 9-5b, examples of compounds of GENERAL REACTION SCHEME Formula (I). where R1= aryl / heteroaryl, R6= H, halogen, C1-C3 alkyl or alkoxy Compounds of Formula (I) where R1 is aryl, heteroaryl, heterocyclyl or alkyl can be prepared according to General Reaction Scheme alkyl, R3a and R3b are H and R6 is hydrogen, halogen, C1-C3 alkyl or alkoxy. 1-(5-Bromo-2methyl-3-substituted phenyl)ethanone 10-1 is treated with an oxidant, for example, KMnO4 in water at 50°C to provide 4-bromo-2-(carboxycarbonyl)-acid. 6-substituted-benzoic acid 10—2. Condensation of 10-2, for example, with hydrazine hydrate in ethanol at elevated temperature, produces 7-bromo-4-oxo3,4-dihydrophthalazine-5-substituted-l-carboxylic acid 10-3 which is then esterified with acid and alcohol, for example, sulfuric acid and methanol in order to obtain 10—4 ester. Methyl 7-bromo-4-oxo3,4-dihydrophthalazine-5-substituted-l-carboxylate 10-4 is reduced by hydride reduction, for example with sodium borohydride and CaC12 in methanol, in order to achieve 6-bromo -4(hydroxymethyl)-8-substituted-phthalazin-1(2H)-one 10—5, which is then treated with halogenating agent, for example thionyl chloride for 12 hours to provide 6-halo-4(chloromethyl )-8-substituted-phthalazin-1(2H)-one 10—6. Nucleophilic displacement SN2 of 10-6 with a nitrogen nucleophile for example potassium phthalimide in DMF at elevated temperature provides 10-7, which is borylated, for example with Miyaura conditions, in order to obtain boron ate ester 10-8. Palladium-mediated cross-coupling conditions, for example, Suzuki conditions, with boronic ester 10-8 and aryl / heteroaryl / heterocyclyl / alkyl halides provide phthalazinone coupling product 10-9. The phthalimide protecting group of 10-9 is removed under solvolysis conditions, for example with hydrazine hydrate in ethanol in order to provide the desired compound 10-10 of Formula (I). GENERAL REACTION SCHEME XI 11-5 11-6 11-7 where R!= aryl / heteroaryl, R3a, R3bson D, and R' = H, halogen, C1-C3 alkyl or alkoxy and Compounds of Formula (I) wherein R1 is aryl, heteroaryl, heterocyclyl or alkyl can be prepared according to general reaction Scheme XI. Compound 11-7 is an example of Formula (I) where R1 is aryl, heteroaryl, heterocyclyl or alkyl, R3a and R3bson D and R6 is hydrogen, halogen, C1-C3 alkyl or alkoxy. Methyl 7-bromo-4oxo-3, 4-dihydrophthalazine-5-substituted-l-carboxylate 10-4 is reduced by reduction with deuteride, for example with sodium borodeuteride and CaCl in methanol-d4, in order to achieve 6- bromo-4-((hydroxy-d)methyl-d2)-8-substituted-phthalazinl(2H)-one 11-2, which is then treated with halogenating agent, for example thionyl chloride for 12 hours in order to provide 6-bromo-4-(chloromethyl-d2)-8-substitutedphthalazin-1(2H)-one 11-3. Nucleophilic SN2 displacement of 11-3 with a nitrogen nucleophile, e.g. potassium phthalimide in DMF at elevated temperature provides 11-4, which is borylated, e.g. with Miyaura conditions, to obtain boron ate ester 11- 5. Palladium-mediated cross-coupling conditions, for example Suzuki conditions, with boronic ester 11-5 and aryl / heteroaryl / heterocyclyl / alkyl halides provide phthalazinone coupling product 11-6. The phthalimide protecting group of 11-6 is removed under solvolysis conditions, for example with hydrazine hydrate in ethanol in order to provide the desired compound 11-7 of Formula (I). GENERAL REACTION SCHEME XII 12-1 12-2 12-3 where R2= aryl / heteroaryl, and R6= H, halogen, C1-C3 alkyl or alkoxy Compounds of Formula (I) wherein R2 is aryl or heteroaryl can be prepared according to general reaction Scheme XII. Compound 12-3 is an example of Formula (I) where R2 is aryl or heteroaryl, R3a and R3b are H, R6 is hydrogen, halogen, C1-C3 alkyl or alkoxy and substituent is alkyl, aryl or heteroaryl. Bromo or chloro compound 12-1 is subjected to palladium-mediated cross-coupling conditions, for example, Suzuki conditions, with an alkyl / aryl / heteroaryl boronic acid / ester in order to obtain substituent coupled product 12-2. The BOC group is then removed with acidic conditions, for example TEA, in order to achieve 12-3 R2-substituted amine of Formula (I). GENERAL REACTION SCHEME XIII 13-1 13-2 13-3 Compounds of Formula (I) wherein R1 is alkylcyano can be prepared according to general reaction Scheme XIII. Compound 13-3 is an example of Formula (I) where R1 is -CH2CN. Bromo or chloro compound 13-1 is subjected to palladium-mediated cross-coupling conditions, for example Suzuki conditions, with an isoxazole acid / boronic ester in order to obtain substituent-coupled product 13-2. The isoxazole is then subjected to hydrazine hydrate in an alcoholic solvent such as ethanol at elevated temperature, followed by acid work, for example, with HC1 at pH 1 in order to obtain 13-3 nitrile product of Formula (I). GENERAL REACTION SCHEME XIV Protect Protect 14-1 14-2 14-3 where R2= aryl / heteroaryl, and R6= alkoxy Compounds of Formula (I) wherein R2 is aryl or heteroaryl and R6 is alkoxy can be prepared according to General Reaction Scheme XIV. Compound 14-3 is an example of Formula (I) where R2 is aryl or heteroaryl, and R6 is alkoxy. The fluorine compound 14-1 with the amine suitably protected with, for example, a BOC group or phthalimide group is subjected to aromatic SN2 conditions with -F as the leaving group and the corresponding oxy anion as the nucleophile. For example, with a sodium alkyl oxide in a polar solvent with heating in order to obtain substituted product substituent 14—2. The protecting group is then removed under appropriate conditions. For example, BOC is removed under acidic conditions such as HC1 or TFA in dioxane, or the phthalimide group is removed under nucleophilic basic conditions such as hydrazine hydrate in ethanol with heating, in order to achieve 14—3 R6-substituted amine. Formula (I). 100 GENERAL REACTION SCHEME XV Protect Protect 15-1 15-2 15-3 where R2= aryl / heteroaryl, and R6= C1-C3 alkyl Compounds of Formula (I) wherein R2 is aryl or heteroaryl and R6 is C1-C3 alkyl can be prepared according to General Reaction Scheme XV. Compound 15-3 is an example of Formula (I) where R2 is aryl or heteroaryl, and R6 is C1-C3 alkyl. The chloro compound 15-1 with the amine suitably protected with, for example, a BOC group or phthalimide group is coupled with the appropriate C1-C3 trialkyloborane under palladium-catalyzed cross-coupling conditions, for example, SuzukiMiyaura coupling conditions, a In order to supply the corresponding R6-replaced coupling product 15-2. The protecting group is then removed under appropriate conditions. For example, BOC is removed under acidic conditions such as HC1 in dioxane or TFA in dioxane, and the phthalimide group is removed under basic nucleophilic conditions such as hydrazine hydrate in ethanol with heating in order to achieve R6-substituted amine 15—3 of Formula (I). 101 GENERAL REACTION SCHEME XVI 16-4 Br0I 1NTERM. J cross coupling Pd(cat) Compounds of Formula (I) wherein R1 is l-methyl-5R2-lH-pyrazol-4-yl and R2 is alkyl, aryl or heteroaryl can be prepared according to general reaction Scheme XVI. Compound 16-6 is an example of Formula (I) where R1 is 1methyl-5-R2-1H-pyrazol-4-yl, R2 is alkyl, aryl or heteroaryl and R3a and R3b are H. H-R216-1 is halogenated, e.g. , with a halogenating agent such as N-bromosuccinimide or Nyodosuccinimide under palladium-catalyzed conditions such as palladium acetate in the presence of an acid such as p-toluenesulfonic acid in a solvent such as dichloroethane at elevated temperature, for example 70 ° C at in order to obtain 16-2 halide. The bromine or iodine compound 16-2 is subjected to palladium-mediated cross-coupling conditions, for example Suzuki conditions, with l-methyl-5-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)-IH-pyrazole in order to obtain coupled product 16—3. l-methyl-5-R2-lH-pyrazole 16—3 is halogenated, 102 for example, with a halogenating agent such as Nbromosuccinimide or N-iodosuccinimide in a polar solvent such as acetonitrile in order to obtain 4-halo-l-methyl-5-R2-lHpyrazole compound 16—4. 4-Bromo-l-methyl-5-R2-lH-pyrazole 16— 4 is coupled with Intermediate J under palladium-mediated cross-coupling conditions, e.g., Suzuki conditions, to provide N-Boc coupling product -R2 replaced 16-5. The coupling product 16-5 is subjected to acidic conditions to remove the Boc group, for example TEA, to achieve R2-substituted amine 16-6 of Formula (I). INTERMEDIARIES C, D and E INTERMEDIARY E Step 1: A mixture of 5-bromoisobenzofuran-l,3-dione (55.0 g, 242 mmol, 1.00 eq.) and acetic acid (165 mL) was stirred at 125°C for 1 hour. After that time, the mixture was cooled to 10 °C, and hydrazine hydrate (12.7 g, 254 mmol, 12.4 mL, 1.05 eq.) was added dropwise, to achieve the formation 103 of a thick white precipitate. An additional amount of acetic acid (55 mL) was added, and the mixture was stirred at 125 °C for another 30 min. After that time, the mixture was cooled, diluted with acetic acid (150 mL) and filtered. The filter cake was washed with acetic acid (50 mL χ 3), dried, and then dissolved in a 5% (w / w) sodium hydroxide solution (800 mL). The solution was acidified with acetic acid (200 mL) to obtain a thick white precipitate, which was filtered. The filter cake was washed with water (50 mL χ 3) followed by methanol, then dried under vacuum to obtain 6-bromo-2,3-dihydrophthalazine-l,4dione 2a (45.6 g, crude) in the form of a white solid. This solid was then used in the next step without further purification. RMNXH (400 MHz, DMSO-d&) δ = 8.17 (d, J = 2.0 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.95 - 7.89 (m, 1 HOUR) . Step 2: A solution of 6-bromo-2,3-dihydrophthalazine1,4-dione 2a (20.0 g, crude) in phosphorus oxychloride (330 g, 2.15 mol, 200 mL) was stirred at 120 °C for 12 hours. After that time, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (150 mL) and added dropwise to ice water. The mixture was then extracted with dichloromethane (300 mL χ 3), and the combined organic layers were washed with aqueous sodium bicarbonate solution (200 mL χ 5), brine (200 mL χ 2), dried over sodium sulfate, were filtered and concentrated under reduced pressure to obtain 6-bromo-1,4-dichloro-phthalazine 3a 104 (14.5 g, crude) as a yellow solid. This solid was then used in the next step without further purification. Η2NMR (400 MHz, CDC13) δ = 8.49 (d, J = 1.2 Hz, 1H), 8.23 ​​- 8.15 (m, 2H). Step 3: A solution of benzyl alcohol (4.59 g, 42.4 mmol, 4.41 mL) and sodium hydride (3.77 g, 94.3 mmol, 60% dispersion in mineral oil) in THE (30 mL) was stirred at 0 °C for 0.5 hours. The mixture was then added dropwise to a solution of 6-bromo-l,4-dichloro-phthalazine 3a (13.1 g, crude) in THE (80 mL) at 0 °C. The reaction mixture was warmed to 10°C and stirred at 10°C for 1 hour. After that time, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL χ 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10-25%) to obtain Intermediate C, a 1:1 mixture of 4-benzyloxy-7bromo-l-chloro-phthalazine 4c and 4-benzyloxy-6-bromo-l-chlorophthalazine 4d (9.79 g, 28.0 mmol, 66% yield) as a yellow solid. 2H NMR (400 MHz, CDCla) δ = 8.39 (d, J = 1.2 Hz, 1H), 8.35 (d, J = 1.6 Hz, 1H), 8.17 - 8.10 (m , 1H), 8, 08 - 8.05 (m, 1H), 8.04 (d, J = 2.0 Hz, 1H), 8.00 (dt, J = 1.6, 8.4 Hz, 1H), 7.59 - 7.53 (m, 4H), 7.47 - 7.36 (m, 6H), 5.70 (s, 4H). 105 Step 4: The regioisomers of Intermediate C, a 1:1 mixture of 4c and 4d (9.79 g, 28.0 mmol) were separated by SFC (column: DAICEL CHIRALPAK AD (250 χ 30 mm, 10 pm ) ; mobile phase: [0.1% NH3H2O ​​MeOH]; B%: 0%-60%; 40 min) in order to obtain Intermediate D, 4-benzyloxy-7-bromo-l-chloro-phthalazine (2.40 g, 6.86 mmol) as a white solid, and Intermediate E, 4-benzyloxy-6-bromo-l- chloro-phthalazine (2.54 g, 7.27) as a white solid. Intermediate D: 4-benzyloxy-7-bromo-l-chloro-phthalazine: 1H NMR (400 MHz, CDC13) δ = 8.36 (d, J =2.0 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.99 (dd, J =2.0, 8.8 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.46 - 7.36 (m , 3H), 5.70 (s, 2H), LCMS [M+l]+351.0. Intermediate E: 4benzyloxy-6-bromo-l-chloro-phthalazine: NMRΧΗ (400 MHz, CDCI3) δ = 8.39 (d, J = 1.6 Hz, 1H), 8.10 - 8.01 (m, 2H), 7.61 - 7.54 (m, 2H), 7.48 - 7.35 (m, 3H), 5.70 (s, 2H), LCMS [M+l]+351.0. INTERMEDIARY F - Track 1 INTERMEDIARY F 106 Step 1: To a solution of 1-(5-bromo-2-methylophenyl)ethenone 8c (100 g, 445 mmol, 1.00 eq.) in water (1.00 L) potassium carbonate (92.4 g, 668 mmol, 1.50 eq.) and potassium permanganate (493 g, 3.12 mol, 7.00 eq.). The mixture was stirred at 50 °C for 3 hours before adding ethanol (1.00 L), and the resulting mixture was stirred at 50 °C for another 30 minutes. After that time, the solid was filtered, and the pH of the filtrate was adjusted to pH 2 with conc. hydrochloric acid. (500 mL). The mixture was then extracted with ethyl acetate (1.00 L), the organic layer was separated and then concentrated in vacuo to obtain 4-bromo-2-oxalo-benzoic acid 9c (278 g, 997 mmol, 75% yield) in the form of a white solid, which was used in the next step without further purification. LCMS [Mfl]+= 271.1. Step 2: To a solution of 4-bromo-2-oxalo-benzoic acid 9c (382 g, 1.27 mol) in ethyl alcohol (3.00 L) hydrazine hydrate (71.2 g, 1.39 mol, 69.1 mL). The mixture was stirred at 75 °C for 4 hours, and the precipitate formed was filtered, washed with ethyl alcohol (500 mL) and dried to obtain 7-bromo-4-oxo-3H-phthalazine-l-acid. carboxylic acid 10c (280 g, 1.03 mol, 81% yield) as a white solid, which was used in the next step without further purification. 4H NMR (400 MHz, DMSO-de) δ = 8.72-8.81 (m, 1H), 8.11-8.21 (m, 1H), 7.95-8.09 (m, 1H). Stage 3: To a solution of 7-bromo-4-oxo-3H acid 107 phthalazine-l-carboxylic acid 10c (200 g, 675 mmol) in methyl alcohol (2.00 L), sulfuric acid (131 g, 1.31 mol, 71.0 mL) was added, and the reaction mixture was stirred at 65°C for 24 hours. After that time, the cooled reaction mixture was filtered, and the filter cake was dried under reduced pressure in order to obtain methyl 7-bromo-4-oxo-3H-phthalazine-l-carboxylate 11b (216 g, crude) in form of a white solid, which was used in the next step without further purification. LCMS [M+l]+= 283, 0; RMNXH (400 MHz, DMSO-d6) δ = 13.31 (s, 1H), 8.72 (s, 1H), 8.16-8.18 (d, J = 8.4 Hz, 1H), 8 .03-8, 05 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H). Step 4: A stirred solution of methyl 7-bromo-4-oxo3H-phthalazine-l-carboxylate 11c (159 g, 494 mmol) in ethyl alcohol (1.50 L) was treated in portions with sodium borohydride (48.6 g, 1.29 mol, 2.60 eq) at 0 °C. To this mixture was added a solution of calcium chloride (65.8 g, 593 mmol, 1.20 eq). The mixture was then stirred for 2 hours at 0 °C, and a further 1 hour at 20 °C. After that time, the reaction mixture was concentrated under reduced pressure, and the residue was suspended in water (800 mL), the pH was adjusted to pH 5 with 1N hydrochloric acid (300 mL), and the precipitate was filtered, washed with water (300 mL x 3) and dried to obtain 6-bromo-4-(hydroxymethyl)-2Hphthalazin-l-one 12c (162 g, crude) as a yellow solid. LCMS [M+l]+= 255.0; 4H NMR (400 MHz, DMSO-d&) δ = 12.66 (s, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.16 (d, J = 8.8 108 Hz, 1H), 8.01 (dd, J = 8.4, 2.0 Hz, 1H), 5.58 (t, J = 5.6 Hz, 1H), 4.67 (d, J = 6 ,0 Hz, 2H). Step 5: 6-Bromo-4-(hydroxymethyl)-2H-phthalazin-l-one 12c (162 g, crude) was dissolved in thionyl chloride (1.00 L), and the mixture was stirred at 70 °C for 2 hours, then concentrated under reduced pressure (35 °C). The concentrated residue was dissolved in dichloromethane (1.00 L) and concentrated to dryness to obtain 6-bromo-4-(chloromethyl)-2H-phthalazin-l-one 13c (154 g, crude) as a white solid that was used in the next step without further purification. LCMS [M+l]+= 274.8; RMNXH (400 MHz, DMSO-de) δ = 12.92 (s, 1H), 8.30 (s, 1H), 8.18-8.20 (d, J = 7.6 Hz, 1H), 8 .06-8.08 (t, J = 8.8 Hz, 1H), 5.07 (s, 2H). Step 6: To a solution of 6-bromo-4-(chloromethyl)-2Hf talazin-l-one 13c (148 g, crude) in DMF (1.5 L) was added (1,3-dioxoisoindolin-2-yl )potassium (121 g, 653 mmol). The reaction mixture was stirred at 90 °C for 2 hours and then cooled to 25 °C. The precipitate formed was filtered and washed with DMF (200 mL x 2), and the filter cake was crushed with water (1.00 L), filtered and dried in order to obtain Intermediate F, 2[(7-bromo -4-oxo-3H-phthalazin-l-yl)methyl]isoindoline-1,3-dione (162 g, 413 mmol, 76% yield) as a white solid. RMNXH (400 MHz, DMSO-dg) δ = 12.59 (s, 1H), 8.43 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H) ), 8.07 (dd, J = 1.6, 8.4 Hz, 1H) , 7.97 - 7.93 (m, 2H) , 7.92 - 7.86 (m, 2H), 109 5.19 (s, 2H), LCMS [M+l]: 383.9. INTERMEDIARY F - Track 2 either INTERMEDIARY F Step 1: A mixture of 5-bromoisobenzofuran-l(3H)-one (50.0 g, 235 mmol, 1.00 eq), DMF-DMA (180 g, 1.51 mol, 201 mL, 6.44 eq ) and t-BuOK (2.63 g, 23.5 mmol, 0.10 eq) was degassed and purged with N23 times and then stirred at 110 °C for 20 h under N2 atmosphere. After that time, the reaction mixture was concentrated under reduced pressure in order to remove DMF-DMA, and the residue formed was stirred in petroleum ether (100 mL) at 25 °C for 30 min. The solid formed was filtered, and the filter cake was stirred in ethyl acetate (200 mL) at 80 °C for 12 h, filtered, and the filter cake was dried under reduced pressure in order to obtain (Z)-5-bromo -3((dimethylamino)methylene)isobenzofuran-1(3H)-one (39.0 g, 120 mmol, 51% yield, 82% purity) as a red solid. LCMS [M+l]+= 270.1; NMR (400 MHz, DMSQ-cW δ = 7.97 (d, J = 1.2 Hz, 1H), 7.61-7.59 (d, J = 8.0, 1H), 7.30 7.27 (dd, J= 8.0 &1.2 Hz, 1H), 3.10 (s, 6H). 110 Step 2: To a mixture of (Z)-5-bromo-3((dimethylamino)methylene)isobenzofuran-1(3H)-one (39.0 g, 119 mmol, 82.0% purity, 1.00 eg ) in EtOH (650 mL) ΝΗ2ΝΗ2·Η2Ο (12.5 g, 245 mmol, 12.1 mL, 2.05 eg) was added at 25 °C. The mixture was degassed with N2, then stirred at 25 °C for 0.5 h and then at 70 °C for 12 h. After that time, the reaction mixture was filtered, and the solid was dried to obtain 6-bromo-4-((dimethylamino)methyl)phthalazin-1(2H)-one (30.0 g, 105 mmol, 88% yield, 99% purity) as a yellow solid. LCMS [M+l]+= 282.1; 4H NMR (400 MHz, DMSO-de) δ 12.6 (s, 1H), 8.33 (s, 1H), 8.14-8.12 (d, J=8.4 Hz, 1H), 8, 00-7.98 (m, 1H), 3.61 (s, 1H), 2.18 (s, 1H). Step 3: A mixture of 6-bromo-4((dimethylamino)methyl)phthalazin-1(2H)-one (15.0 g, 53.2 mmol, 1.00 eq) in THF (187 mL) was degassed with N23 times before cooling to 0 °C. Isobutyl carbonhydrochloride (8.71 g, 63.80 mmol, 8.38 mL, 1.20 eq) was then added dropwise, and then the mixture was stirred at 25 °C for 6 h under N2. After that time, the mixture was cooled to 0 °C before adding HC1 (0.5 M, 250 mL) maintaining a temperature between 0 °C and 10 °C. After the addition was complete, the solid was filtered, washed with THF (30 mL x 3) and dried to give 6-bromo4-(chloromethyl)phthalazin-1(2H)-one (11.0 g, 37.56 mmol, 71% yield, 93% purity) as a yellow solid. LCMS [M+l]+= 256, 1; Η4NMR (400 MHz, DMSO-ds) δ 12.9 111 (s, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.19 - 8.17 (d, J= 8.0 Hz, 1H),8,O6 - 80.4 (dd, J= 8.0 Hz & 1.6 Hz, 1H), 5.06 (s, 2H). Step 4: To a mixture of 6-bromo-4-(chloromethyl)phthalazin 1(2H)-one (8.06 g, 27.5 mmol, 93% purity, 1.00 eq) in DMF (160 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (5, 61 g, 30.3 mmol, 1.10 eq) and stirred at 25 °C for 1 hr. After that time, the mixture was washed with HC1 (0.5 M, 100 mL), filtered, and the solid was washed with sat. NaHCCg. (30 mL x 2), pure water (30 mL x 2), and then triturated with EtOH (15 mL) at 70 °C for 1 hr. The solid was then filtered and dried in order to obtain Intermediate F (8.30 g, 17.9 mmol, 65.0% yield, 83% purity) as a yellow solid. LCMS [M+l]+= 384.1 / 386.1; RMNXH (400 MHz, DMSO-d6) δ 12.6 (s, 1H), 8.43 (s, 1H), 8.18 8.16 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.95 - 7.89 (m, 4H), 5.18 (s, 2H). INTERMEDIARY G with. H2SO4 KMnO4, K2CO3 H2O, 50 °C, 3 h Stage 1 n2h4*h2o EtOH, 75 °C, 4 h Stage 2 MeOl-I, reflux, 12 h Etana 3 SOCI2(as solvent) 0-20°C, overnight Etana 5 NaBH4, CaCI2 MeOH, 0-20 °C, 4 h Stage 4 DMF, 90 °C, 2 h Stage 6 INTERMEDIARY G 112 Step 1: Potassium carbonate (9) was added to a solution of 1-(4-bromo-2-methylophenyl)ethenone 8d (10.0 g, 46.9 mmol, 1.00 eq.) in water (50 mL). .73 g, 70.40 mmol, 1.50 eq.) and potassium permanganate (51.9 g, 329 mmol, 7.00 eq.). The mixture was stirred at 50 °C for 3 hours before adding ethanol (50 mL), and the resulting mixture was stirred at 50 °C for another 30 minutes. After that time, the solid was filtered, and the pH of the filtrate was adjusted to pH 2 with conc. hydrochloric acid. (5 mL). The mixture was then extracted with ethyl acetate (50 mL), the organic layer was separated and concentrated in vacuo to obtain 5-bromo-2-oxalo-benzoic acid 9d (10.0 g, crude) as a white solid that was used in the next step without further purification. LCMS [M+l]+= 273.0. Step 2: To a solution of 5-bromo-2-oxalo-benzoic acid 9d (10.0 g, crude) in ethyl alcohol (120 mL) was added hydrazine hydrate (1.87 g, 36.6 mmol, 1 .82 mL), and the mixture was stirred at 75 °C for 4 hours. After that time, the precipitate formed was filtered and washed with ethyl alcohol (5 mL) and dried to obtain 6-bromo-4-oxo-3H-phthalazine-1carboxylic acid lOd (7.50 g, 27. 9 mmol, 59% yield) as a white solid. LCMS [M+l]+= 269.0. Step 3: To a solution of 6-bromo-4-oxo-3Hphthalazine-l-carboxylic acid lOd (7.50 g, 27.9 mmol, 1.00 eq.) in methyl alcohol (40 mL) sulfuric acid was added (16.7 g, 167 mmol, 9.10 mL, 6.00 eq.), and the reaction mixture was stirred at 113°C for 12 hours. After that time, the reaction mixture was allowed to cool, and the precipitate formed was filtered and dried in order to obtain methyl 6-bromo-4-oxo-3H-phthalazine-1-carboxylate lid (7.00 g, 24.7 mmol, 89% yield) as a white solid. LCMS [M+1]+= 282.9. Step 4: A stirred solution of sodium borohydride (2.43 g, 64.29 mmol, 2.60 eq.) in ethyl alcohol (250 mL) was treated in portions with methyl 6-bromo-4-oxo-3H- phthalazine-1carboxylate lid (7.00 g, 24.7 mmol, 1.00 eq.) at 0 °C. To this mixture was added a solution of calcium chloride (3.29 g, 29.7 mmol, 1.20 eq.) in ethyl alcohol (250 mL) dropwise. The mixture was then stirred for 3 hours at 0 °C, and one hour at 20 °C. After that time, the mixture was concentrated under reduced pressure, and the concentrated residue was suspended in water (30 mL), and the pH was adjusted to pH 5 with hydrochloric acid (5 mL). The precipitate formed was filtered, washed with water (5 mL χ 3) and triturated with ethyl alcohol (50 mL), filtered and dried to obtain 7-bromo-4-(hydroxymethyl)-2H-phthalazin- l-one 12d (6.00 g, 23.5 mmol, 95% yield) as a white solid. LCMS [M+l]+= 255.0. Step 5: 7-Bromo-4-(hydroxymethyl)-2H-phthalazin-l-one 12d (6.00 g, 23.5 mmol) was dissolved in thionyl chloride (50 mL) at 0 °C. The reaction mixture was stirred at 20°C for 12 hours and then concentrated under reduced pressure (35°C). The concentrated residue was dissolved in dichloromethane (20 mL) and 114 was concentrated to obtain 7-bromo-4-(chloromethyl)-2Hphthalazin-l-one 13d (5.50 g, crude) as a white solid which was used in the next step without further purification. LCMS [M+l]+= 275.0. Step 6: To a solution of 7-bromo-4-(chloromethyl)-2Hphthalazin-l-one 13d (5.50 g, crude) in DMF (60.0 mL) was added (1,3-dioxoisoindolin-2- il)potassium (5.59 g, 30.2 mmol). The reaction mixture was stirred at 90 °C for 2 hours, then cooled to 25 °C, and the precipitate formed was filtered and triturated with ethyl alcohol (150 mL) to obtain Intermediate G, 2-[(6 -bromo-4-oxo-3H-phthalazin-1yl)methyl]isoindoline-1,3-dione (5.00 g, 13.0 mmol, 65% yield) as a white solid. RMNXH (400 MHz, DMSO-dg) δ = 12.66 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.22 - 8.18 (m, 1H), 8 .14 ​​- 8.10 (m, 1H), 7.97 - 7.93 (m, 2H), 7.91 - 7.87 (m, 2H), 5.18 (s, 2H), LCMS [M +l]: 386.1. INTERMEDIARY I Step 1: A solution of Intermediate F (3.00 g, 7.81 mmol, 1.00 eq.) and hydrazine hydrate (1.60 g, 31.2 mmol, 1.55 mL, 4.00 eq. ) was stirred at 80 °C for 2 hours, cooled and concentrated under reduced pressure. The concentrated residue is then 115 washed with water and triturated with ethyl alcohol at 25 °C to obtain 4-(aminomethyl)-6-bromo-2H-phthalazin-l-one 106 (1.95 g, 7.67 mmol, 98% performance) in the form of a white solid. LCMS [M+l]+= 256.1. Step 2 To a solution of 4-(aminomethyl)-6-bromo-2Hphthalazin-l-one 106 (1.90 g, 7.48 mmol, 1.00 eq.) and triethylamine (2.27 g, 22.4 mmol, 3.12 mL, 3.00 eq) in dichloromethane (40.0 mL) di-tert-butyl dicarbonate (3.26 g, 15.0 mmol, 3.44 mL, 2.00 eq.) was added. . The mixture was stirred at 25°C for 2 hours, filtered and concentrated under reduced pressure to obtain a residue. The concentrated residue was triturated with dichloromethane (40 mL), then filtered and dried to obtain t-butylN-[(7-bromo-4-oxo-3H-phthalazin-l-yl)methyl]carbamate, Intermediate I (1.97 g, 5.56 mmol, 74% yield) as a white solid. LCMS [M+l]+= 356, 1, NMR (400 MHz, DMSO-dg) δ = 12.71 (s, 1H), 8.26 (br s, 1H), 8.16 (br d, J = 8.0 Hz, 1H), 8.02 (br d, J = 8.0 Hz, 1H), 7.46 (br s, 1H), 4.41 (br d, J = 4.4 Hz, 2H), 1.40 (br s, 9H). INTERMEDIARY J or or INTERMEDIARY! INTERMEDIARY! A mixture of Intermediate I (130.0.275 mmol, 1.00 eq.), bis(pinacolato)diboron (BPD) (104.9 g, 412.9 mmol, 1.50 eq.), Pd(dppf)C12 (20.1 g, 27.5 mmol, 0.10 eq.), KOAc (81.0 g, 825 mmol, €116 > Π K C K N C 3.00 eg) in dioxane (2.60 L) was degassed and purged with N2. The mixture was then stirred at 100 °C for 2 hours. After that time, the mixture was filtered, concentrated, and the residue was triturated with 10 / 1 petroleum ether / ethyl acetate (400 mL) at 25 °C for 1 hr. The solid was then filtered and dried to obtain Intermediate J as a brown solid (68.0 g, 162 mmol, 59% yield). LCMS [M+l]+= 402.3; 4H NMR (400 MHz, CDC13) δ = 12.62 (s, 1H), 8.25 (s, 2H), 8.01-8.13 (m, 1H), 7.217.45 (m, 1H), 4 .34-4, 63 (m, 2H), 1.42 (s, 9H), 1.32 (s, 12H). INTERMEDIARY K Pd(OAc)2. DavePhos BmNac. pivalic acid NMP. IOO°C. 3 p.m. INTERMEDIARY K A solution of 4-bromo-l-methyl-pyrazole (500 mg, 3.11 mmol, 1.00 eg.) and l-bromo-3-fluoro-benzene (543 mg, 3.11 mmol, 346 pL, 1.00 eg) in N-methylopyrrolidone (10 mL) was degassed with nitrogen. Then, palladium acetate (7.0 mg, 31.1 pmol, 0.10 eg.) and 2-(2dicyclohexylphosphanylphenyl)-N,77-dimethyl-aniline (DavePhos) (24.0 mg, 62.1 pmol, 0.02 eg.). To the resulting dark brown solution, tetrabutylammonium acetate (1.87 g, 6.21 mmol, 2 mL, 2.00 eg) and pivalic acid (317 mg, 3.11 mmol, 357 uL, 1 .00 eg.), and the resulting solution was stirred at 100°C for 15 hours. After the reaction is complete, 117 the mixture was cooled. Ethyl acetate (100 mL) was added, and the resulting mixture was washed with brine (3*100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude oil. The crude oil was purified by silica gel chromatography (petroleum ether / ethyl acetate 0-10%) to obtain 4-bromo-5(3-fluorophenyl)-1-methyl-1H-pyrazole, Intermediate K (600 mg, 2.35 mmol, 76% yield) as a colorless oil. LCMS [M+1]+= 255.0. NMR (400 MHz, CDC13) δ = 7.56 (s, 1H), 7.50 (dt, J = 6.0, 8.0 Hz, 1H), 7.24 - 7.18 (m, 2H) , 7.18 7.13 (m, 1H), 3.85 (s, 3H). Intermediates A-l to A-32 set out in Table I-I were prepared following the teachings of the General Reaction Schemes and the method for the preparation of INTERMEDIATE K. Table I-I Intermediate Structure Spectral data A-1 zBr Cl i 4-bromo-5—(3—chlorophenyl)—1— methyl-1H—pyrazole LCMS [M+1]+ = 353.0; 1H NMR (400 MHz, CDCI3) δ = 7.54 (s, 1H), 7.47 - 7.43 (m, 2H), 7.42 - 7.40 (m, 1H), 7.30 (dt , J = 1.6,4.4 Hz, 1H), 3.83 (s, 3H) A-2 Br O / yy 4-bromo-5-(3-methoxyphenyl)-1-methyl-1H- pyrazole LCMS [M+1]+ = 267.0; 1H NMR (400 MHz, DMSO-d6) δ = 7.93 (s, 1H), 7.51 (s, 1H), 7.50 - 7.44 (t, J=8.4, 1H), 7 .11 - 7.07 (m, 1H), 7.05 - 7.03 (m, 1H), 3.83 (s, 3H), 3.82 (s, 3H) 118 A-3 βιO Λ 4—bromo—5—(3—methylophenyl)—1—methyl—1H—pyrazole LCMS [M+1]+ = 251.0; 1H NMR (400 MHz, CDCI3) δ = 7.50 (s, 1H), 7.39 - 7.33 (m, 1H), 7.25 (br d, J = 7.6 Hz, 1H), 7 .21 - 7.14 (m, 2H), 3.79 (s, 3H), 2.41 (s, 3H) A-4 Br l / j 4-bromo-5—(4—fluorophenyl)—1— methyl-1H-pyrazole 1H NMR (400 MHz, DMSO-d6) δ = 7.65 (s, 1H), 7.58 7.54 (m, 2H), 7.42 - 7.38 (m, 2H) , 3.35 (s, 3H) A-5 Br Nnf / N [Π 4-bromo-5—(4—chlorophenyl)—1— methyl-1H-pyrazole LCMS [M+1]+ = 272.9; 1H NMR (400 MHz, CDCI3) δ = 3.82 (s, 3 H) 7.34 - 7.38 (d, J = 8.8 Hz, 2 H) 7.48 - 7.52 (d, J = 8.8 Hz, 2 H) 7.55 (s, 1 H) A-6 Br nY XX 4—bromo—5—(4—methylophenyl)—1—methyl—1H—pyrazole LCMS [M+1]+ = 251.0 A-7 Br Nnf xl 4-bromo-5-(4-methoxyphenyl)-1-methyl-1H-pyrazole LCMS [M+1]+ = 269.0; 1H NMR (400 MHz, CDCI3- d) δ = 7.53 (s, 1H), 7.36 - 7.32 (m, 2H), 7.05 - 7.01 (m, 2H), 3.88 (s, 3H), 3.81 (s, 3H) A-8 Br Nnf / N lX 5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2methylopyridine LCMS [M+1]+ = 252.0; 1H NMR (400 MHz, CDCI3) δ = 8.56 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 2.4, 8.0 Hz, 1H), 7.56 ( s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 2.65 (s, 3H) A-9 Br NXÍ / N jO 2—(4 —bromo—1—methyl—1 H-pyrazol-5—yl)—benzonitrile 1H NMR (400 MHz, CDCI3) δ = 7.86 (dd, J = 0.8, 7.6 Hz, 1H), 7, 76 (dt, J = 1.2, 7.6 Hz, 1H), 7.63 (dt, J = 1.2, 7.6 Hz, 1H), 7.60 (s, 1H), 7.49 (dd, J = 0.8, 7.6 Hz, 1H), 3.81 (s, 3H) QRzzcn / zznz / q / υιλι 119 A-10 „Br N A jTl 2—(4—bromo—1—methyl—1H—pyrazole—5—¡I)—5— chlorobenzonitrile LCMS [M+1]+ = 297.9; 1H NMR (400 MHz, CDCI3) δ = 7.84 (d, J = 2.0 Hz, 1 H) 7.73 (dd, J = 8.4, 2.0 Hz, 1 H) 7.60 ( s, 1 H) 7.43 (d, J = 8.4 Hz, 1 H) 3.81 (s, 3 H) A—11 zBr <1 Cl / II Ί 2—(4—bromo—1—methyl —1H—pyrazole—5—¡I)—4— chlorobenzonitrile 1H NMR (400 MHz, DMSO-d6) δ = 8.13 (d, J = 8.4 Hz, 1H), 7.93 - 7.90 ( d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.0, 8.4 Hz, 1H), 7.76 (s, 1H),3.75 (s, 3H) A -12 Br nHÍ 0 / N 1Ύ' 2—(4—bromo—1—methyl—1H—pyrazole—5—¡I)—4— methoxybenzonitrile LCMS [M+1]+ = 294.1; 1H NMR (400 MHz, CDCI3) δ = 7.77 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.09 (dd, J = 2.8, 8.8 Hz, 1H), 6.95 (d, J = 2.8 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H) A-13 Br N^X _ / N ΎΥ 2 —(4—bromo—1—methyl—1H—pyrazole—5—¡I)—4— methylbenzonitrile LCMS [M+1]+ = 276.0; 1H NMR (400 MHz, CDCI3) δ = 7.73 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.42 (dd, J = 0.8, 8.0 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 3.80 (s, 3H), 2.51 (s, 3H) A-14 Br ζχ _ / N λΧ N 2— (4—bromo—1—methyl—1H—pyrazole—5—¡I)—5—methylbenzonitrile LCMS [M+1]+ = 276.1; 1H NMR (400 MHz, CDCI3) δ = 7.58 (s, 1H), 7.50 (s, 1H), 7.48 (br d, J = 8.0 Hz, 1H), 7.28 (d , J = 8.0 Hz, 1H), 3.72 (s, 3H), 2.42 (s, 3H) QRzzrn / zznz / zi / υιλι 120 A-15 Br / N jO 2—(4—bromo—1—methyl—1H—pyrazole—5—¡1)—6— methoxybenzonitrile LCMS [M+1]+ = 292.1; 1H NMR (400 MHz, DMSO-de) δ = 7.87 - 7.80 (m, 1H), 7.74 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 3.99 (s, 3H), 3.71 (s, 3H) A-16 _ ,Br / N jn 2—(4—bromo—1 —methyl—1H—pyrazole—5—¡I)—5— methoxybenzonitrile LCMS [M+1]+ = 294.1; 1H NMR (400 MHz, CDCI3) δ = 7.50 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 2.8 Hz, 1H) , 7.21-7.17 (m, 1H), 3.84 (s, 3H), 3.71 (s, 3H), A-17 Br FY CN n II I 2-(4-bromo-1- methyl-1 H—pyrazole—5—¡I)—6— methylbenzonitrile LCMS [Μ+ψ = 278.0; 1H NMR (400 MHz, DMSO-cfe) δ = 7.80 (t, J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.48 (d, J= 7.6 Hz, 1H), 3.70 (s, 3H), 2.58 (s, 3H) A-18 Br .__ / CN ¿XA / 1 1 U 2—(4—bromo—1—methyl—1H—pyrazole—5—¡I)—6— chlorobenzonitrile LCMS [M+1]+ = 298.0; 1H NMR (400 MHz, DMSO-d6) δ = 7.98 (dd, J = 1.2, 6.8 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7, 77 (s, 1H), 7.69 (dd, J = 1.2 Hz, 1H), 3.75 (s, 3H) A-19 Br 4—bromo—5—(4—ethylophenyl)—1—methyl —1H—pyrazole LCMS [M+1]+ = 265.1; 1H NMR (400 MHz, CDCI3) δ = 7.54 (s, 1H), 7.33 (m, 4H), 3.82 (s, 3H), 2.81 - 2.71 (m, 2H), 1.31 (t, 1=7.6 Hz, 3H) A-20 Br 1 4—bromo—5-(4—cyclopropoxyphenyl)-1—methyl—1H—pyrazole LCMS [M+1]+ =295 ,0; 1H NMR (400 MHz, CDCI3) δ = 7.58 (s, 1H), 7.36 - 7.33 (m, 2H), 7.21-7.18 (m, 2H), 3.84 (s , 3H), 3.83 - 3.78 (m, 1H), 0.87 - 0.84 (m, 2H), 0.83 (m, 2H) 121 A-21 —Ί CD O v) 4—bromo—1—methyl—5—(naphthalen—2—¡I)—1H—pyrazole LCMS [M+1]+ = 289.1; 1H NMR (400 MHz, CDCI3) δ = 7.98 (d, 1 = 8.4 Hz, 1H), 7.95 - 7.87 (m, 3H), 7.63 - 7.55 (m, 3H ), 7.50 (dd, J = 1.6, 8.4 Hz, 1H), 3.88 (s, 3H) A-22 Br ΠΙ ' ^Í^CI 4-bromo-5—(3.4 —dichlorophenyl)—1-methyl-1H-pyrazole LCMS [M+1]+ = 306.8; 1H NMR (400 MHz, CDCI3) δ = 7.60 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H) , 7.27 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H), 3.83 (s, 3H) A-23 Br and Cl 4-bromo-5—(3,5—dichlorophenyl )—1-methyl-1H-pyrazole LCMS [M+1]+ =306.9; 1H NMR (400 MHz, CDCh) δ = 7.55 (s, 1H), 7.48 (t, J =1.8 Hz, 1H), 7.31 (d, J =2.0 Hz, 2H) , 3.84 (s, 3H) A-24 Br ___ / F fxlsi V1 4—bromo—5-(2—fluorophenyl)—1—methyl—1H—pyrazole LCMS [M+1]+ = 255.0; 1H NMR (400 MHz, CDCI3) δ = 7.57 (s, 1H), 7.54 - 7.47 (m, 1H), 7.41 - 7.37 (m, 1H), 7.30 (br t, J = 8.0 Hz, 1H), 7.26 - 7.20 (m, 1H), 3.79 (s, 3H) A-25 ,Br 6—(4—bromo—1—methyl—1H —pyrazole—5—yl)quinoline—5—carbonitrile LCMS [M+1]+ = 313.0; 1H NMR (400 MHz, CDCI3) δ = 9.15 (dd, J = 1.6, 4.0 Hz, 1H), 8.67 (dd, J = 0.8, 8.4 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.73 (dd, 1 = 4.0, 8.4 Hz, 1H ), 7.67 (s, 1H), 3.88 (s, 3H) A-26 Br νΠ / ” jO F 4-bromo-5-(2-(difluoromethyl)phenyl)-1-methyl-1Hpyrazole LCMS [ M+1]+ = 287.0; 1H NMR (400 MHz, CDCI3) δ = 7.86 - 7.80 (m, 1H), 7.69 - 7.60 (m, 2H), 7.58 (s, 1H), 7.32 - 7 .28 (m, 1H), 6.59 - 6.27 (m, 1H), 3.65 (s, 3H) QRzzcn / zznz / q / υιλι 122 A-27 ^.Br nA 2—(4—bromo—1—methyl—1H—pyrazole—5—¡1)—5— methoxybenzonitrile LCMS [M+1]+ = 294.1; 1H NMR (400 MHz, CDCI3) δ = 7.50 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 2.8 Hz, 1H) , 7.21-7.17 (m, 1H), 3.84 (s, 3H), 3.71 (s, 3H), A-28 Cl ^Ν'Νλ 4—bromo—5—(1—chloronaphthalen —2—yl)—1—methyl—1H—pyrazole LCMS [M+1]+ = 323.2; 1H NMR (400 MHz, CDCI3) δ = 8.41 (d, J = 8.4 Hz, 1H), 8.00 - 7.87 (m, 2H), 7.77 - 7.62 (m, 3H ), 7.37 (d, J= 8.4 Hz, 1H), 3.77 (s, 3H) A-29 cnxnA oca 7—(4—bromo-1—methyl—1H—pyrazole—5—¡l )quinoline—8—carbonitrile LCMS [Μ+ψ = 313.2; 1H NMR (400 MHz, CDCI3) δ = 9.19 (dd, J = 1.6, 4.0 Hz, 1H), 8.34 (dd, J = 1.6, 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.72 - 7.60 (m, 3H), 3.89 (s, 3H) A-30 m rí / b b o ó 2—(4— bromo-1—(2—((tetrahydro—2H—pyran—2—¡l)oxy)ethyl)— 1H-pyrazole-5- II) benzon ytrile LCMS [M-83]+ = 292.1; 1H NMR (400 MHz, CDCI3) δ = = 7.84 (d, J = 7.9 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.65 (s, 1H), 7 .63-7.58 (m, 1H), 7.58-7.51 (m, 1H), 4.49-4.40 (m, 1H), 4.31 - 4.03 (m, 3H) , 4.01 - 3.81 (m, 1H), 3.76 3.62 (m, 1H), 3.48 - 3.36 (m, 1H), 1.60 - 1.38 (m, 6H ) A-31 Λ CN^N-A u1^ 2—(4—bromo—1—methyl—1H—pyrazole—5—¡I)—6— cyclopropylbenzonitrile LCMS [M+1]+ =397.3; 1H NMR (400 MHz, CD3OD) δ = 8.23 ​​(d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 7.81 - 7.75 (m, 1H), 7, 70 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.50 - 7.45 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H ), 3.85 (s, 2H), 3.80 (s, 3H), 2.36 -2.19(m, 1H), 1.24 -1.17 (m, 2H), 0.98- 0.86 (m, 2H) 123 A-32 Ll_ 2—(4—bromo—3—fluoro—1—methyl—1H—pyrazole—5—¡I)—1— naphthonitrile LCMS [M + 1]+ = 330.0; 1H NMR (400 MHz, CDCh) δ = 8.33 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.80 (dt, J = 1.2, 7.6 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.50 (d, J = 8 .4 Hz, 1H), 3.72 (s, 3H) AA INTERMEDIARY AA INTERMEDIARY To a solution of 3-bromo-5-fluoro-pyridine (2.20 g, 12.5 mmol, 1.00 eq.) in dimethylformamide (50 mL) was added sodium phenylosulfanyl (1.98 g, 15.0 mmol , 1.20 eg) followed by stirring at 110 °C for 12 hours. After that time, the reaction mixture was diluted with water (700 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SIO2, petroleum ether: 0-10% ethyl acetate) to obtain 3-bromo-5-phenylsulfanyl-pyridine, Intermediate AA (1.31 g, 4.48 mmol, 35% yield) in the form of a yellow oil. LCMS [M+l]+= 268.0; 4H NMR (400 MHz, MeOD) δ = 8.44 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.73 124 (t, J= 2.0 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.45 - 7.41 (m, 3H). AB INTERMEDIARY AB INTERMEDIARY To a solution of 2-chlorobenzenethiol (296 mg, 2.05 mmol, 233 pL, 1.20 eq.) in DMF (2 mL) were added sodium hydride (82 mg, 2.05 mmol, 60% purity, 1.20 eq.) and 3-bromo-5-fluoropyridine (300 mg, 1.70 mmol, 1.00 eg.), and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was then quenched by adding water (10 mL) and then extracted with ethyl acetate (30 mL χ 3). The combined organic layers were washed with brine (50 mL χ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep TLC. (petroleum ether: ethyl acetate 20%) in order to obtain 3-bromo-5-(2chlorophenyl)sulfanyl-pyridine, Intermediate AB (280 mg, 931 pmol, 54% yield) in the form of a white solid. LCMS [M+l]+= 302.0; 4H NMR (400 MHz, CDCl3-d) δ = 8.56 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.33 - 7.28 (m, 2H), 7.26 - 7.22 (m, 1H). The AC to AG INTERMEDIARIES shown in Table IIla were prepared following the teachings of the General Reaction Schemes and the method for the preparation of INTERMEDIARY AB. Table I-IIa Intermediate Structure Characterization AC m q ω 0 O 3-bromo-5-((4-chlorophenyl)thio)pyrádine LCMS [M+1]+ = 302.0 AD ω O O 3-bromo-5-((3 -chlorophenyl)t¡o)pyr¡dina LCMS [M+1]+ = 302.0; 1H NMR (400 MHz, CDCI3) δ = 8.55 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.40 - 7.38 (m, 1H), 7.34 - 7.30 (m, 2H), 7.29 - 7.27 (m, 1H) CD AE — 3 -bromo-5-(0-tolylthio)pyridine LCMS [M+1]+ = 280.0; 1H NMR (400 MHz, CDCI3) δ = 8.45 (br s, 1H), 8.29 (br s, 1H), 7.48 (s, 1H), 7.44 (d, J =7.6 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.26 - 7.21 (m, 1H), 2.40 (s, 3H) AF TI 1JL 3-bromo-5-(p -tolylthio)p¡r¡dina LCMS [M+1]+ = 281.0; 1H NMR (400 MHz, DMSO-d6) δ = 8.53 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.82 (q, J = 2.4 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.31 - 7.23 (m, 2H), 7.11 - 7.06 (m, 1H) AG 3 —bromo—5—(m—tolylthio)pyridine LCMS [M+1]+ = 279.9; 1H NMR (400 MHz, CDCI3) δ = 8.48 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.67 - 7.61 ( m, 1H), 7.34 - 7.28 (m, 3H), 7.21 - 7.19 (m, 1H), 2.38 (s, 3H) INTERMEDIARY AH CL K2CO3, DMF, 50 °C, 10 h * Stage 1 NBS, ACN, 0 0.5 hM Stage 2 INTERMEDIARY AH Step 1: To a solution of 2-methyl-lH-imidazole (1.00 g, 126 12.2 mmol, 1.00 eq.) in DMF (10 mL) potassium carbonate (1.68 g, 12.2 mmol, 1.00 eq.) and 2-chloroacetonitrile (920 mg, 12.2 mmol, 773 pL, 1.00 eq.), and the mixture was stirred at 50 °C for 5 hours. After that time, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phases were washed with brine (20 mL), dried over sodium sulfate anhydrous, filtered and concentrated. The residue was purified by column chromatography (SiCh, petroleum ether: ethyl acetate 10-100%) to obtain 2-(2-methylomidazol-lyl) acetonitrile (460 mg, 3.80 mmol, 31% performance) in the form of a yellow oil. RMNXH (400 MHz, CDC13) δ = 6.98 (d, J = 1.2 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H), 4.79 (s, 2H), 2.47 (s, 3H). Step 2: A solution of N-bromosuccinimide (542 mg, 3.05 mmol, 0.90 eq.) in acetonitrile (10 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and after that time, the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (2 mL χ 3). The combined organic phases were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a residue. The residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 127 10-100%) followed by a second column (S1O2, petroleum ether: ethyl acetate: methanol 1: 1: 0.4) in order to obtain 2(5-bromo-2-methyl-imidazol-l-yl)acetonitrile, Intermediate HA (460 mg, 2.30 mmol, 67% yield) as a brown solid. 1H NMR (400 MHz, CDCI3) δ = 6.97 (s, 1H), 4.82 (s, 2H), 2.53 (s, 3H). AI INTERMEDIARY 1. NaNO2, HCl, H2O, 0°C, 10 min 2. CuCI, HCI, 0-25°C, h N^1 AI INTERMEDIARY To a solution of 4-bromo-2-methyl-pyrazole-3-amine (0.20 g, 1.14 mmol, 1.00 eq.) in hydrochloric acid (12 M, 2 mL, 21.1 eq.) A solution of sodium nitrite (86 mg, 1.25 mmol, 1.10 eq.) in water (1.8 mL) was slowly added at 0 °C. After stirring for 10 minutes, the mixture was added portionwise to a solution of cuprous chloride (112 mg, 1.14 mmol, 27.2 pL, 1.00 eq.) in hydrochloric acid (12 M, 1.00 mL , 10.6 eq. ) . The reaction mixture was stirred at 25 °C for 3 hours. After that time, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL χ 3). The combined organic phases were washed with aq. sodium bicarbonate. (5 mL), with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep TLC. (petroleum ether:ethyl acetate 25%) in order to obtain 4-bromo-5-chloro-l-methyl-pyrazole, Intermediate AI (92 128 mg, 363 pmol, 31% yield) as a white solid. LCMS [M+l]+= 197.0; NMR (400 MHz, CDCl3-d) δ =7.48 (s, 1H), 3.88 (s, 3H). INTERMEDIARY AJ NaBH4, EtOH, 25 °C, 1 hr INTERMEDIARY AJ Sodium borohydride (22 mg, 572 pmol, 1.50 eq.) was slowly added to a solution of (5-bromo-3-pyridyl)phenyl-methanone (100 mg, 381 pmol, 1.00 eq.) in ethyl alcohol (5 mL). After stirring at 25 °C for 2 h, the reaction was quenched with water (2 mL) and concentrated in vacuo. The residue was diluted with ethyl acetate (10 mL), washed with brine (10 χ 3 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain (5-bromopyridin-3yl) (phenyl). methanol, Intermediate AJ (97 mg, 367 pmol, 96% yield) as a colorless oil. LCMS [M+l]+= 263, 9. 4H NMR (400 MHz, CDC13) δ = 8.53 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 7.89 (t, J = 2.0 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.38 - 7.31 (m, 4H), 5.85 (s , 1H), 2.85 (s, 1H). AK INTERMEDIARY N m-CPBA, DCM, |sj ίι ί < 25 °C, 1hr íi ί íT |l 1 II 1 -----------------------► H I II 1 AA INTERMEDIARY AK INTERMEDIARY To a solution of 3-bromo-5-(phenylthio)pyridine, Intermediary AA (200 mg 751 pmol, 1.00 eq.) in dichloromethane 129 (4 mL) 3-chloroperoxybenzoic acid (153 mg, 751 pmol, 85.0% purity, 1.00 eq.) was added. The resulting mixture was stirred at 25 °C under nitrogen for 1 hour. After that time, aq sodium hydroxide solution was added. (4 N, 40 mL), and the mixture was extracted with dichloromethane (20 mL χ 2). The combined organic layers were washed with brine (5 mL*2), dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (SiCh, petroleum ether: ethyl acetate 5-20%) to obtain 3-bromo5-(phenylosulfinyl)pyridine, Intermediate AK (150 mg, 532 pmol, 70% performance) in the form of a white solid. Η4NMR (400 MHz, CDC13) δ = 8.72 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.16 (t, J = 2 .0 Hz, 1H), 7.72 - 7.68 (m, 2H), 7.55-7.2 7 (m, 3H) . INTERMEDIARY TO / / \\ o o INTERMEDIARY AA INTERMEDIARY AL A solution of oxone (2.10 g, 3.42 mmol, 2.00 eq.) in water (10 mL) was added to a solution of 3-bromo-5phenylsulfanyl-pyridine intermediate AA (500 mg, 1.71 mmol , 1.00 eq.) in THE (10 mL) and methyl alcohol (10 mL) at 0 °C. The resulting mixture was stirred at 35 °C for 12 hours and after that time it was filtered, and the filtrate was concentrated under reduced pressure. The residue formed was purified by HPLC 130 reverse phase (0.1% FA condition) in order to obtain 3 (benzenesulfonyl)-5-bromo-pyridine, AL Intermediate (300 mg, 1.01 mmol, 59% yield) as a white solid. 4H NMR (400MHz, DMSO-d6) δ = 9.13 (d, J = 2.0 Hz, 1H), 9.01 (d, J = 2.0 Hz, 1H), 8.66 (t, J = 2.0 Hz, 1H), 8.12 - 8.08 (m, 2H), 7.77 - 7.72 (m, 1H), 7.69 - 7.64 (m, 2H). AM INTERMEDIARY Step 1: Phosphorus oxychloride (4.71 g, 30.7 mmol, 2.9 mL, 1.23 eq.) was added dropwise to DMF (6 mL) at 0°C, and then the mixture was stirred at 0 °C for 10 minutes. After that time, a solution of 1-phenyloethanone (3.00 g, 25.0 mmol, 2.91 mL, 1.00 eq.) in DMF (25 mL) was added dropwise with stirring. The reaction mixture was then heated for 3 hours at 60 °C. After that time, the solution was cooled to room temperature and slowly poured into an aqueous sodium acetate solution (10%, 100 mL). The pH was adjusted to 4 with an additional amount of sodium acetate solution (10 mL) and extracted with ethyl acetate (20 mL χ 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain (Z)-3-chloro-3-phenyl-prop-2-enal (2, 50 g, 14.1 mmol, 56% yield) in the form of an oil 131 yellow. LCMS [M+l]+= 167.1, NMR (400 MHz, CDC13) δ = 10.24 (d, J = 6.8 Hz, 1H), 7.49 (m, 5H), 6.69 ( d, J = 6.8 Hz, 1H). Stage 2: Hydrogen cyanide (HCN) is produced as a byproduct in this reaction. Appropriate safety procedures and precautions must be employed. A mixture of (Z)-3chloro-3-phenyl-prop-2-enal (1.76 g, 10.6 mmol, 1.00 eq.), ammonium thiocyanate (1.61 g, 21.1 mmol, 1.61 mL, 2.00 eg) in acetone (25 mL) was degassed and purged with nitrogen and stirred at 80 °C for 1 hour. After that time, the cooled mixture was poured into saturated aqueous sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (100 mL χ 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue formed was purified by column chromatography (SIO2, petroleum ether / ethyl acetate 0-50%) in order to obtain 5-phenyloisothiazole (1.00 g, 6.20 mmol, 58% yield) in form of a yellow oil. LCMS [M+l] + = 162.2, NMR2Η (400 MHz, CDCI3) δ = 8.49 (d, J = 2.0 Hz, 1H), 7.64 - 7.60 (m, 2H), 7.48 - 7.43 (m, 3H), 7.42 (d, J = 2.0 Hz, 1H). Step 3: Bromine (952 mg, 5.95 mmol, 307 pL, 3.20 eg.) was added dropwise over a period of 30 min to a stirred mixture of 5-phenyloisothiazole (300 mg, 1.86 mmol, 1 .00 eg), potassium acetate (365 mg, 3.72 mmol, 2.00 eg.) and acetic acid (12 mL). 132 The reaction mixture was stirred at 25 °C for 5 hours and after that time, it was treated with aq sodium bisulfite. (33%, 10 mL). The solution was made basic with aq sodium hydroxide. (20%, 10 mL), extracted with dichloromethane (3 χ 80 mL). The combined organic extracts were dried (anhydrous sodium sulfate), filtered and concentrated to obtain 4-bromo-5-phenyloisothiazole, AM Intermediate (300 mg, 1.25 mmol, 67% yield) as a colorless oil. LCMS [M+l]+= 240.9, NMR (400 MHz, CDC13) δ = 8.39 (s, 1H), 7.69 - 7.65 (m, 2H), 7.52 - 7.47 (m, 3H), 13C NMR (400 MHz, CDCI3) δ = 161.0, 159.5, 129.9, 129.3, 129.0, 128.5, 106.0. AN INTERMEDIARY or or INTERMEDIARY I INTERMEDIARY AN A mixture of intermediate I (160 g, 416 mmol, 1.00 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l, 3,2dioxaborolan-2- il)-1,3,2-dioxaborolane (BPD) (158 g, 624 mmol, 1.50 eq.), Pd(dppf)CI2 (30.4 g, 41.6 mmol, 0.10 eq.), Potassium acetate (122 g, 1.25 mol, 3.00 eq.) in dioxane (2.0 L) was purged with nitrogen and stirred at 100 °C for 3 hrs. After that time, the reaction mixture was filtered and concentrated under reduced pressure. The residue was triturated with MeOH (1.0 L) at 133 °C for 2 h, filtered and dried to obtain 2-((4oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3, 4dihydrophthalazin-l-yl)methyl)isoindoline-1,3-dione, Intermediate ΆΝ (93.0 g, 209 mmol, 50% yield) as a gray solid. LCMS [M+l]+= 432.4. i-H: (400 MHz DMSO-cU δ: 12.54 (s, 1H), 8.24-8.37 (m, 2H), 8.13 (d, J = 7.6 Hz, 1H), 7, 93-7, 99 (m, 2H), 7.87-7.93 (m, 2H), 5.22 (s, 2H), 1.36 (s, 12H). INTERMEDIATE AO NaH, DMF, 0-100 °C, 2 h AO INTERMEDIARY To a solution of 3,5-dibromopyridine (1.00 g, 4.22 mmol, 1.00 eq.) in DMF (10 mL) was added sodium hydride (270 mg, 6.75 mmol, 60% purity , 1.60 eq.) at 0 °C for 10 min, followed by N-methylaniline (452 ​​mg, 4.22 mmol, 458 pL, 1.00 eq.). The resulting mixture was stirred at 100 °C for 2 hours. After that time, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL χ 3). The combined organic layers were washed with brine (50 mL χ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (400 g SÍO2, water / acetonitrile, 0-100% 70 mL / min) to obtain 5-bromo-77-methyl-7V-phenyl-pyridine. -3-amine, Intermediary A.O. 134 (50.0 mg, 190 pmol, 5% yield) as a yellow solid. LCMS [M+l]+262.9. RMNXH (400 MHz, CDC13d) δ = 8.12 (br d, J = 6.4 Hz, 2H), 7.44 - 7.35 (m, 2H), 7.26 - 7.24 (m, 1H) ), 7.23 - 7.19 (m, 1H), 7.19 - 7.17 (m, 1H), 7.17 - 7.14 (m, 1H), 3.33 (s, 3H). INTERMEDIARY APPindina’ Cu(OAc)2,NC 4A MS, O2, DCM,r\ °C, 12 hrs Βιχb,°hγγ OHN AP INTERMEDIARY A mixture of (5-bromo-3-pyridyl) boronic acid (325 mg, 1.61 mmol, 1.50 eq.), lH-pyrazole-5-carbonitrile (100 mg, 1.07 mmol, 1.00 eq. .), pyridine (255 mg, 3.22 mmol, 260 pL, 3.00 eq.), 4Á molecular sieves (20.0 mg, 1.07 mmol) and copper acetate (585 mg, 3, 22 mmol, 3.00 eg) in dichloromethane (5 mL) was degassed with nitrogen and stirred at 20 °C for 12 hours under an oxygen atmosphere (103.4 kPa (15 psi)). After that time, the reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 5-20%) in order to obtain 2- (5-bromo-3-pyridyl)pyrazole-3carbonitrile, AP Intermediate (150 mg, 602 pmol, 56% yield) as a white solid. LCMS [M+l]+249.0. 4H NMR (400 MHz, DMSO-de) δ = 9.15 (d, J = 2.4 Hz, 1H), 8.91 (d, J = 2.4 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.63 (t, J = 2.0 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H). 135 AS INTERMEDIARY 0H, NaH MeOH, t. to. 4 hours Stage 2 Pd / C, H2(15 psi) ^ci, NaHOO^ MeOH, H:O, 70°C2 h Step 3 THF, 0”C to 20”C, 2 h Stage 1 HINTERMEDIARIO AS Step 1: To a solution of cyclopropanol (450 mg, 7.74 mmol, 1.10 eq.) in THF (10 mL) was added sodium hydride (310 mg, 7.74 mmol, 60.0% purity, 1.10 eg) at 0 °C, followed by 5-fluoro-2-nitro-pyridine (1.00 g, 7.04 mmol, 1.00 eq.), and the mixture was warmed to 20 °C and stirred for 2 hours. After completion, the mixture was filtered and concentrated in vacuo, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 20-80%) to obtain 5-(cyclopropoxy) -2-nitro-pyridine (1.10 g, 6.11 mmol, 86% yield) as a white solid. LCMS [M+l]+= 181.1. Step 2: To a solution of 5-(cyclopropoxy)-2-nitropyridine (200 mg, 1.11 mmol, 1.00 eq.) in methyl alcohol (4 mL), palladium on activated carbon (100 mg, 1.00 eq.) was added. 11 mmol, 10% purity, 1.00 eq.), and the mixture was stirred at 30 °C for 4 hours under a hydrogen atmosphere (103.4 kPa (15 psi)). After completion, the reaction mixture was filtered, washed with methanol (5 mL χ 2) and concentrated to obtain 5-(cyclopropoxy)pyridin-2-amine (120 mg, 799 pmol, 72% 136 yield) in the form of a black oil, which was used for the next step without further purification. LCMS [M+l]+= 151.1. Step 3: To a solution of 5-(cyclopropoxy)pyridine-2amine (120 mg, 799 pmol, 1.00 eq.) in methyl alcohol (2 mL) and water (1.0 mL), 2-chloroacetaldehyde (313) was added. mg, 1.60 mmol, 257 pL, 2.00 eq.) and sodium bicarbonate (70.5 mg, 839 pmol, 1.05 eq.). The mixture was stirred at 70 °C for 2 hours. After that time, the solvent was removed under reduced pressure, the mixture was diluted with ethyl acetate (3 mL) and water (12 mL), and extracted with ethyl acetate (5 mL χ 3). The combined organic layers were washed with brine (10 mL χ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6(cyclopropoxy)imidazo[1,2-a]pyridine (220 mg, crude) as a yellow solid that was used for the next step without further purification. LCMS [M+l]+= 175.2. Step 4: To a solution of 6-(cyclopropoxy)imidazo[1,2a]pyridine (220 mg, crude) in acetonitrile (2 mL) was added Nyodosuccinimide (313 mg, 1.39 mmol). The mixture was stirred at 20 °C for 1 hour. At the end, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiC®, petroleum ether: ethyl acetate 20-80%) in order to obtain 6-(cyclopropoxy)- 3-iodoimidazo[1,2-a]pyridine, AS Intermediate (220 mg, 733 pmol, 137 58% yield) in the form of a white solid. LCMS [M+l]+= 300, 9. 4H NMR (400 MHz, DMSO-d6) δ = 8.03 (d, J = 2.0 Hz, 1H), 7.76 (s, 1H), 7, 60 (d, J = 9.6 Hz, 1H), 7.17 (dd, J = 2.4, 9.6 Hz, 1H), 4.08 - 4.05 (m, 1H), 0. 88 - 0.82 (m, 2H), 0.80 - 0.72 (m, 2H). AT INTERMEDIARY or Stage 1 Stage 2 AT INTERMEDIARY Step 1: To a solution of 5-(trifluoromethoxy)pyridin-2amine (250 mg, 1.40 mmol, 1.00 eg.) in methanol (5 mL) and water (2.5 mL) 2-chloroacetaldehyde ( 289 mg, 1.47 mmol, 237 pL, 1.05 eq.) and sodium bicarbonate (118 mg, 1.41 mmol, 54.8 pL, 1.00 eq.). The mixture was stirred at 70 °C for 2 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were concentrated to obtain 6-(trifluoromethoxy)imidazo[1,2a]pyridine (250 mg, crude) as a colorless oil which was used for the next step without further purification. Step 2: To a solution of 6(trifluoromethoxy)imidazo[1,2-a]pyridine (238 mg, crude) in acetonitrile (10 mL) was added N-iodosuccinimide (291 mg, 1.30 mmol) in acetonitrile (5 mL) at 0 °C, and the resulting yellow suspension was allowed to warm to 20 °C for 2 138 hours. The reaction mixture was then diluted with water (10 mL), extracted with ethyl acetate (10 mL χ 3), and the combined organic extracts were washed with brine (10 mL), dried, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate 10-15%) to obtain 3-iodo-6(trifluoromethoxy)imidazo[1,2-a]pyridine, Intermediate a ( 180 mg, 548 pmol, 46% yield) as a yellow solid. LCMS [M+l]+= 329.0. RMNXH (400 MHz, CDC13) δ = 8.23 ​​- 8.19 (s, 1H), 7.80 (s, 1H), 7.71 (d, J = 9.6 Hz, 1H), 7.27 (m, 1H). AU INTERMEDIARY AU INTERMEDIARY Step 1: A mixture of 6-iodoimidazo[1,2-a]pyridine (500 mg, 2.05 mmol, 1.00 eq.), phenyl boronic acid (275 mg, 2.25 mmol, 1.10 eq. ), Pd(dppf)C12 (150 mg, 205 pmol, 0.10 eq.), sodium bicarbonate (344 mg, 4.10 mmol, 159 pL, 2.00 eq.) in dioxane (5 mL) and water (1.00 mL) was degassed with nitrogen and stirred at 80 °C for 1 hour. After that time, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl alcohol (5 mL), and the solution was then concentrated. The residue was purified by prep TLC. 139 (dichloromethane: methyl alcohol, 10%) in order to obtain 6phenyloimidazo[1,2-a]pyridine (250 mg, 1.29 mmol, 62% yield) as a white solid. LCMS [M+l]+= 195.1. Step 2: To a solution of 6-phenyloimidazo[1,2a]pyridine (100 mg, 515 pmol, 1.00 eq.) in acetonitrile (2 mL) was added N-iodosuccinimide (127 mg, 566 pmol, 1.10 eq.), and the mixture was stirred at 0 °C for 1 hour. After that time, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl alcohol (2 mL), the supernatant was removed, and the remainder was concentrated under reduced pressure. The residue was purified by prep TLC. (petroleum ether: ethyl acetate 10%) in order to obtain 3-iodo-6-phenyl-imidazo[1,2a]pyridine, AU Intermediate (120 mg, 375 pmol, 72% yield) in the form of a solid yellow color. LCMS [M+l]+= 321.0, 2H NMR (400 MHz, DMSO-cU δ = 8.40 (br s, 1H), 7.77 (m, 3H), 7.73 - 7.62 (m , 2H) , 7.58 - 7.49 (m, 2H) , 7.45 (m, 1H) AV INTERMEDIATE AV INTERMEDIARY Formaldehyde (610 mg, 20.3 mmol, 559 pL, 2.00 eq.) e 140 sodium hydroxide (812 mg, 20.3 mmol, 2.00 eq.), and the mixture was stirred at 20 ° C for 2 hours. After completion, the reaction mixture was then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5-20%), then by prep TLC. (petroleum ether: ethyl acetate 20%) in order to obtain 5-bromo-3-(methoxymethyl)-IH-pyrrolo[2,3-b]pyridine, AV intermediate (120 mg, 498 pmol, 5% yield) as a white solid. LCMS [M+l]+= 243.0. Η4NMR (400 MHz, DMSO-d6) δ = 11.83 (br s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 4.53 (s, 2H), 3.25 (s, 3H). AX INTERMEDIARY (CH3)3CCOCH2COC(CH3)3, ,N Cul , Cs2CO3, DMF, 100 °C, £ 1 °5^ ΗΟ'^Έγ AX INTERMEDIARY To a solution of 5-bromopyridin-3-ol (500 mg, 2.87 mmol, 1.00 eq.) in DMF (10 mL) was added cesium carbonate (1.87 g, 5.75 mmol, 2, 00 eq.), 2-iodopyridine (707 mg, 3.45 mmol, 366 pL, 1.20 eg.), 2,2,6,6-tetramethyloheptane-3,5-dione (212 mg, 1.15 mmol , 237 pL, 0.40 eg.) and cuprous iodide (109 mg, 575 pmol, 0.20 eg.). The mixture was stirred at 100 °C for 0.5 hours. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (70.0 mL x3). The organic layers The combined 141 were washed with brine (100 mL), dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SIO2, petroleum ether: 0-20% ethyl acetate) to obtain 3-bromo-5(2-pyridyloxy)pyridine, Intermediate AX (600 mg, 1.45 mmol, 50% yield) in the form of a yellow oil. LCMS [M+l]+= 250.8. RMNXH (400 MHz, DMSO-d&) δ = 8.57 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.16 (ddd, J = 0.8, 2.0, 4.8 Hz, 1H), 8.02 (s, 1H), 7.91 (ddd, J = 2.0, 7.2, 8.0 Hz, 1H), 7.21 - 7.15 (m, 2H). INTERMEDIARY AY INTERMEDIARY AY To a solution of 2-chloropyrimidine (300 mg, 2.62 mmol, 1.00 eq.) in DMF (2 mL) were added potassium carbonate (724 mg, 5.24 mmol, 2.00 eq.) and 5 -bromopyridin-3-ol (479 mg, 2.75 mmol, 1.05 eq.). The mixture was stirred at 110 °C for 5 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (80 mL x3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-[(5-bromo-3pyridyl)oxy]pyrimidine, Intermediate AY ( 523 mg, crude) as a red solid, which was used in the following 142 stage without further purification. LCMS [M+l]+= 252.0; RMNXH (400 MHz, DMSO-d6) δ = 8.70 (s, 1H), 8.69 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.57 (d , J = 2.4 Hz, 1H), 8.17 (t, J = 2.0 Hz, 1H), 7.34 (t, J = 4.8 Hz, 1H). INTERMEDIARY AY-1 INTERMEDIARY AY-1 Step 1: To a solution of 2-methylopyrazole-3-ol (500 mg, 5.10 mmol, 1.00 eq.), (bromomethyl)benzene (1.05 g, 6.12 mmol, 726 pL, 1, 20 eq.) in DMF (6.00 mL) potassium carbonate (1.06 g, 7.65 mmol, 1.50 eq.) was added. The mixture was stirred at 120 °C for 4 hours. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 50 / 1 to 6 / 1) to obtain 5-benzyloxy1-methyl-pyrazole (450 mg, 2.39 mmol, 47% performance) in the form of a colorless oil. LCMS [M+l]+= 189.2; NMRΧΗ (400 MHz, CDCI3) δ = 7.43 - 7.41 (m, 3H), 7.40 - 7.35 (m, 2H), 7.31 (d, J = 2.0 Hz, 1H) , 7.24 - 7.21 (d, J = 2.0 Hz, 1H), 5.08 (s, 2H), 3.67 (s, 3H). 143 Step 2: To a solution of 5-benzy 1oxy-1-methi 1opyrazole (400 mg, 2.13 mmol, 1.00 eq.) in acetonitrile (6 mL) was added NBS (416 mg, 2.34 mmol, 1 .10 eq.). The mixture was stirred at 0°C for 0.5 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiCh, petroleum ether / ethyl 1 acetate = 100 / 1 to 20 / 1) to obtain 5-benzyloxy -4-brorno-1-methi 1opyrazole (320 mg, 1.20 mmol, 56% yield) as a yellow oil. LCMS [M+l]+= 266.9; NMR (400 MHz, CDC13) δ = 7.39 (s, 5H), 7.32 (s, 1H), 5.28 (s, 2H), 3.45 (s, 3H). Intermediate AY-2 set forth in Table IIlb was prepared following the teachings of the General Reaction Schemes and the method for the preparation of Intermediate AY-1. Table I-IIb Intermediate Structure Spectral data AY-2 Br 4—bromo—5—(cyclopropylmethoxy)—1—methyl—1 H—pyrazole LCMS [M+1]+ = 233.1; 1H NMR (400 MHz, CDCI3) δ =7.32 7.28 (s, 1H), 4.11 -4.07 (m, 2H), 3.74-3.68 (s, 3H), 1.251, 16 (m, 1H), 0.67 - 0.57 (m, 2H), 0.37 - 0.28 (m, 2H) 144 GENERAL PROCEDURE FOR INTERMEDIARIES B-l A B-15 Aryl / Heteroaryl-OH n NaH, DMF, 0^100 °C, n p |Ί 12 hrs.p |l Aryl / l-Ieteroaryl To the corresponding aryl / heteroaryl phenol (3.89 mmol, 1.00 eq.) in DMF (10 mL) was added sodium hydride (4.28 mmol, 60% purity, 1.10 eq.) at 0 °C low nitrogen. After the addition was complete, the mixture was stirred at 25 °C for 0.5 hour, followed by the addition of 3-bromo-5-fluoro-pyridine (3.89 mmol, 1.00 eq.), and the mixture It was stirred at 100 °C for another 12 hours. After that time, the reaction mixture was quenched by adding water (10 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL χ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was used directly in the next step without further purification. Following the teachings of the General Reaction Schemes and the general procedure for Intermediates B-1 to B-15, the intermediates of Table IIII were prepared. Intermediate Structure Characterization B-1 Μ 3-Bromo-5-(pyridin—3- ¡loxy)pyrádina LCMS [M+1]+ = 250.9; 1H NMR (400 MHz, CDCI3) δ = 8.51 8.48 (m, 2H), 8.48 - 8.45 (m, 1H), 8.36 (d, J = 2.8 Hz, 1H) , 7.47(t, J = 2.0 Hz 1H), 7.40 - 7.35 (m, 2H) 145 B-2 ΑΛ. 3-Bromo-5-(3-fluorophenoxy)pyridine LCMS [M+1] + = 268.0; 1H NMR (400 MHz, DMSO-d6) δ = 8.53 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.81 (t, J = 2.0 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.08 - 7.03 (m, 2H), 6.97 - 6.92 (m, 1H) B- 3 AA 3-Bromo-5-(m-tolyloxy)pyridine LCMS [M+1 ]+ = 265.9; 1H NMR (400 MHz, CDCI3) δ = 8.40 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.41 (t, J = 2.0 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.92 - 6.81 (m, 2H), 2.37 (s, 3H) B-4 Αλ 3-Bromo-5-(3-chlorophenoxy)pindine LCMS [M+1] + = 286.0; 1H NMR (400 MHz, DMSO-dc) δ = 8.53 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.82 (q, J = 2.4 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.31 - 7.23 (m, 2H), 7.11 - 7.06 (m,1H) B- 5 Αλ 3-Bromo-5-(3-methoxyphenoxy)p¡r¡d¡na LCMS [M+1]+ = 279.9; 1H NMR (400 MHz, CDCI3) δ = 8.42 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.44 (t, J = 2.4 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 6.79 - 6.74 (m, 1H), 6.64 - 6.59 (m, 2H), 3.81 (s, 3H) B-6 3—((5—Bromopyridin—3—yl)oxy)benzonitrile LCMS [M+1 ]+ = 277.0; 1H NMR (400 MHz, DMSO-d6) δ = 8.55 (d, J = 1.6 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 7.86 (t, J = 2.4 Hz, 1H), 7.69 - 7.66 (m, 2H), 7.62 (t, J = 8.4 Hz, 1H), 7.47 (ddd, J = 1.2 , 2.4.8.0 Hz, 1H) B-7 CA 3—Bromo—5—(2-fluorophenoxy)pyridine LCMS [M+1 ]+ = 269.9; 1H NMR (400 MHz, DMSO-d6) δ = 8.50 (d, J = 1.6 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.48 - 7.39 (m, 1H), 7.36 - 7.27 (m, 3H) 146 B-8 CXX 3-Bromo-5-(2-chlorophenoxy)pyridine LCMS [M+1] + = 286.0; 1H NMR (400 MHz, DMSO-d6) δ = 8.49 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.66 - 7, 62 (m, 2H), 7.43 (td, J = 1.6, 8.0 Hz, 1H), 7.34 - 7.28 (m, 2H) B-9 oxx 3-Bromo-5-( o- tolyloxy)p¡r¡dina LCMS [M+1]+ = 266.0; 1H NMR (400 MHz, CDCI3) δ = 8.37 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 0.8, 7.2 Hz, 1H), 7.29 (s, 1H), 7.27-7.22 (td, J = 1.6,7.6 Hz, 1H), 7.20 - 7 .14 ​​(td, J = 1.2, 7.6 Hz, 1H), 6.96 (dd, J = 1.2, 8.0 Hz, 1H), 2.23 (s, 3H) B-10 3-Bromo-5-(2,4-dimet¡lofenox¡)pyr¡dina LCMS [M+1]+ = 278.0; 1H NMR (400 MHz, CDCI3) δ = 8.35 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.26 - 7.24 ( t, J = 2.4 Hz, 1H), 7.10 (s, 1H), 7.04 (dd, J = 1.2, 8.4 Hz, 1H), 6.86 (d, J = 8 ,4 Hz, 1H), 2.35 (s,3H), 2.17 (s, 3H) B—11 ΟΟ,Χι. 3—Bromo—5—(3—chloro—4—methylophenoxy)pyridine LCMS [M+1]+ = 299.9; 1H NMR (400 MHz, CDCI3) δ = 8.43 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.44 - 7.41 ( t, J = 2.4.1H), 7.26 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 1.6,4.4 Hz, 1H), 2.38 (s, 3H), B-12 . / A 3—Bromo—5—(3—chloro—2—methylophenoxy)pyridine LCMS [M+ 1]+ = 299.9; 1H NMR (400 MHz, CDCI3) δ = 8.41 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.32 - 7.31 ( t, J = 2.0 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.88 (dd, J = 0.8, 8.0 Hz, 1H), 6, 69 (dd, J = 1.6, 7.6 Hz, 1H), 2.31 (s, 3H) B-13 XuX 3-Bromo-5-(4-methoxyphenoxy)pyridine LCMS [M+1] + = 280.1; 1H NMR (400 MHz, CDCI3) δ = 8.36 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.35 - 7.33 ( m, 1H), 7.04 - 6.99 (m, 2H), 6.96 - 6.91 (m, 2H), 3.84 (s, 3H) QRzzcn / zznz / q / υιλι 147 B-14 n A 3-Bromo-5-(2-methoxyphenoxy¡)pyridine LCMS [M+1]+ = 280.1; 1H NMR (400 MHz, CDCI3) δ = 8.35 (d, J = 1.6 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 2.0, 2.4 Hz, 1H), 7.08 - 7.01 (m, 2H), 6.95 - 6.86 (m, 2H), 3.82 (s, 3H) B-15 m p di p 3—bromo—5—(2,4—dimethoxyphenoxy)pyridine LCMS [M+1 ]+ = 312.0; 1H NMR (400 MHz, CDCI3) δ = 8.32 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.24 (t, J = 2.0 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.60 (d, J = 2.8 Hz, 1H), 6.49 (dd, J = 2, 8, 8.8 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H) BN INTERMEDIARY K2CO3, DMF, 110’C, 12 hrsy Stage 3 CL BN INTERMEDIARY To a solution of 3-bromo-5-fluoro-pyridine (210 mg, 1.19 mmol, 0.95 eg.) in DMF (10 mL) was added potassium carbonate (347 mg, 2.51 mmol, 2, 00 eg.) and 3-chloro-2, 4-dimethyl-phenol (197 mg, 1.26 mmol, 1.00 eq.). The mixture was stirred at 110 °C for 12 hours. After that time, the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were then washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-20% petroleum ether:ethyl acetate) to obtain 3-bromo 148 5-(3-chloro-2, 4-dimethyl-phenoxy) pyridine, BN Intermediate (178 mg, 569 pmol, 45% yield) as a colorless oil. LCMS [M+l]+= 314.0. RMNXH (400 MHz, DMSO-d6) δ = 8.45 (d, J = 2.0 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.57 (t, J = 2.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 2.34 (s, 3H), 2.22 (s, 3H) . BP INTERMEDIARY 'BP INTERMEDIARY To a solution of 3-bromo-4,5,6,7tetrahydropyrazolo[1,5-a]pyrazine (300 mg, 949 pmol, 1.00 eq., TEA) and benzaldehyde (131 mg, 1.23 mmol, 125 pL, 1.30 eg.) in dichloromethane (10 mL) sodium triacetoxyborohydride (402 mg, 1.90 mmol, 2.00 eg.) and acetic acid (114 mg, 1.90 mmol, 109 pL, 2) were added .00 eg.). The mixture was then stirred at 25 °C for 4 hours. After that time, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL χ 3). The combined organic layers were washed with brine (50 mL χ 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep TLC. (SiO2, petroleum ether: ethyl acetate 25%) in order to obtain 5-benzyl-3-bromo-6,7-dihydro-4H-pyrazolo[1,5a]pyrazine, Intermediate BP (170 mg, 582 pmol, 61 % yield) in the form of a colorless oil. LCMS [M+l]+= 149 294.0. 4H NMR (400 MHz, CD3OD) δ = 7.45 (s, 1H), 7.41 - 7.32 (m, 5H), 4.12 (t, J = 5.6 Hz, 2H), 3.77 (s, 2H), 3.57 (s, 2H), 2.96 (t, J = 5.6 Hz, 2H). INTERMEDIARY BQ ''^ο NaBH3CN, ZnCI2MeOH, 20°C, 2 hr Br Br BQ INTERMEDIARY A mixture of 3-bromo-4,5,6,7tetrahydropyrazolo[1,5-a]pyrazine (400 mg, 1.27 mmol, 1.00 eq.), acetaldehyde (5.0 M, 508 uL, 2, 01 eq.), sodium cyanoborohydride (160 mg, 2.54 mmol, 2.01 eq.), zinc chloride (1.0 M, 2.53 mL, 2.00 eq.) in methanol (8 mL) It was stirred at 25 °C for 2 hours. After that time, the solvent was evaporated, and the residue was purified by column chromatography (SÍO2, dichloromethane: 0-10% methanol). The product was further purified by prep HPLC. (Waters ethyl-6,7-dihydro-4Hpyrazolo[1,5-a]pyrazine, intermediate BQ (100 mg, 434 pmol, 34% yield) as a colorless oil. 3H NMR (400 MHz, CD3OD) δ = 7.47 (s, 1H), 4.21 - 4.11 (t, J = 6.0 Hz, 2H), 3.61 (s, 2H), 3.03 - 2.94 (t, J = 6.0 Hz, 2H), 2.69 (q, J=7.2 Hz, 2H), 1.20 (t, J=7.2 Hz, 3H). 150 BR INTERMEDIARY Br -^0 NaBH(OAc)3, DCM, 20°C, 14 hrs BR INTERMEDIARY Step 1: To a mixture of 3-bromo-4,5,6,7tetrahydropyrazolo[1,5-a]pyrazine (200 mg, 990 pmol, 1.00 eq.) and acetone (862 mg, 14.9 mmol, 1.09 mL, 15.0 eq.) in dichloromethane (1.00 mL), sodium triacetoxyborohydride (420 mg, 1.98 mmol, 2.00 eq.) was added. After stirring at 25 °C for 14 hours, the mixture was extracted with dichloromethane (5 mL χ 3), washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep TLC. (SÍO2, dichloromethane: methyl alcohol 10%) in order to obtain 3-bromo-5-isopropyl-6,7dihydro-4H-pyrazolo[1,5-a]pyrazine (150 mg, 531 pmol, 54% yield) in form of a yellow oil. LCMS [M+l] + = 244.0. 4H NMR (400 MHz, CDCI3) δ = 7.35 (s, 1H), 4.12 - 4.06 (t, J = 5.2 Hz, 2H), 3.59 (s, 2H), 2.96 - 2.90 (m, 1H), 2.89 - 2.86 (t, J = 5.2 Hz, 2H), 1.09 (s, 3H), 1.07 (s, 3H), Step 2: A mixture of 3-bromo-5-isopropyl-6,7-dihydro4H-pyrazolo[1,5-a]pyrazine (80.0 mg, 328 pmol, 1.00 eq.), 4,4,4 ',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (166 mg, 655 pmol, 2.00 eq.), potassium acetate ( 113 mg, 1.15 151 mmol, 3.50 eq. ) and PdC12[P(Cy) 3] 2 (24.2 mg, 32.8 pmol, 0.10 eq.) in dimethylaminopyridine (1 mL) was purged with nitrogen, then stirred at 90 °C for 20 hours. The mixture was then concentrated under reduced pressure to obtain 5-isopropyl-3(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7-dihydro-4Hpyrazolo[1 ,5-a]pyrazine, Intermediate BR (700 mg, 303 umol, 92% yield) as a black solid. LCMS [M+l]+= 292.2. BS INTERMEDIARY TMS,oXo^\ HN. ►ZN. ÁM \ NaBH4, THF / MeOH, \ / \ Br 25°C, 12 hrvBr BS INTERMEDIARY A pressure tube was charged with 3-bromo-4,5,6,7tetrahydropyrazolo[1,5-a]pyrazine (260 mg, 1.29 mmol, 1.00 eq.), (1-ethoxycyclopropoxy)trimethi 1osi1ane ( 673 mg, 3.86 mmol, 776 pL, 3.00 eq.), sodium cyanoborohydride (243 mg, 3.86 mmol, 3.00 eq.) and acetic acid (773 mg, 12.9 mmol, 73 6 pL, 10.0 eg.) in THE (5 mL) and ethyl alcohol (5 mL). The resulting solution was stirred for 2 hours at 60 °C, then the reaction mixture was concentrated to obtain a residue. The residue was purified by prep TLC. (SiO2, petroleum ether: ethyl acetate 20%) in order to obtain 3-br omo-5-ci c lopr opi lo-6, 7-dihydro-4 Jipi ra z olo [ 1 , 5 - a ] pi ra z ina, BS Intermediate (150 mg, 620 pmol, 48% yield) as a colored solid 152 yellow. NMR (400MHz, CD3OD) δ = 7.45 (s, 1H), 4.14 - 4.09 (m, 2H), 3.75 (s, 2H), 3.20 - 3.10 (m, 2H ), 2.02 - 1.96 (m, 1H), 0.65 - 0.57 (m, 2H), 0.56 - 0.44 (m, 2H). BT INTERMEDIARY BT INTERMEDIARY A mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5a]pyrazine (500 mg, 1.58 mmol, 1.00 eq.), iodobenzene (1.29 g, 6.33 mmol, 705 pL, 4.00 eg.), copper iodide (60.3 mg, 316 pmol, 0.20 eg.), (2S)-pyrrolidine-2-carboxylic acid (72.9 mg, 633 pmol, 0.40 eg.) . ) and cesium carbonate (1.03 g, 3.16 mmol, 2.00 eg.) in DMF (10 mL) was degassed and purged with nitrogen, then stirred at 100 °C for 1.5 hours. After that time, the mixture was cooled, extracted with ethyl acetate (5 mL x 3), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue formed was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 5-10%) in order to obtain 3-bromo-5-phenyl-6,7-dihydro-4H-pyrazolo[1, 5-a]pyrazine, BT Intermediate (55 mg, 197 pmol, 12% yield) as a yellow solid. LCMS [M+l]1= 278.2. 153 BU INTERMEDIARY DMAP, DCM, 40 °C, 3 hrs Br Stage 2 BU INTERMEDIARY A mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5a]pyrazine (200 mg, 633 pmol, 1.00 eq.), acetyl acetate (96.9 mg, 94 9 pmol, 88, 9 pL, 1.5 0 eq.) and DMAP (7.73 mg, 63.3 pmol, 0.10 eq.) in dichloromethane (10 mL) was degassed and purged with nitrogen, then stirred at 40 °C during 3 hours. At the end, the reaction mixture was concentrated under reduced pressure, in order to obtain 1-(3-bromo-6,7-dihydro-4Hpyrazolo[1,5-a]pyrazin-5-yl)ethenone, Intermediate BU (100 mg, crude) as a white solid. LCMS [M+l]+= 244.2. BV INTERMEDIARY Stage 2 HATU.TEA. DMF,i,a, 1 h Triethylamine (240 mg, 2.37 mmol, 330 pL, 3.00 eq.), HATU (601 mg, 1.58 mmol, 2.0 0 eq.), and cyclopropane carboxylic acid (102 mg, 1.19 mmol, 93.7 pL, 1.50 eq.). The mixture was stirred at 35°C for 1 hour. 154 After that time, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30.0 mL * 3), and the combined organic layers were washed with brine (50 mL), dried over sulfate of anhydrous sodium, filtered and concentrated under reduced pressure. The residue formed was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 0-50%) in order to obtain (3-bromo-6,7dihydro-4H-pyrazolo[1,5-a]pyrazin -5-yl)-cyclopropylmethanone, Intermediate BV (139 mg, 515 pmol, 65% yield) as a colorless oil. 4H NMR (400 MHz, CDC13) δ = 7.48 (s, 1H), 4.89 - 4.68 (m, 2H), 4.33 - 4.05 (m, 4H), 1.87 - 1, 79 (m, 1H), 1.09 - 1.04 (m, 2H), 0.93 - 0.84 (m, 2H). Following the teachings of the General Reaction Schemes and the procedure for INTERMEDIATE BV, INTERMEDIARIES C-l to C-5 were prepared as set forth in Table I-IV: Table I-IV Intermediate Structure Characterization C-1 O Br (3—Bromo—6,7-dihydroprázolo[1,5—a]pyrazin-5(4H)-yl)(cyclobutyl)methanone LCMS [M+1] + = 286, 1 1H NMR (400 MHz, DMSO-d6) δ = 7.59 (s, 1H), 4.60 - 4.49 (m, 2H), 4.14 - 4.05 (m, 2H), 3, 96 - 3.79 (m, 2H), 3.55 - 3.47 (m, 1H), 2.25 - 2.10 (m, 4H), 1.98 -1.88 (m, 1H), 1.81 -1.70 (m, 1H) C-2 ir Q (3-Bromo-6,7-dihydroprázolo[1,5-a]pyrazin-5(4H)yl)(cyclopentyl)methanone LCMS [M+1]+ = 297.9 C -3 <Ί ΡνΛ O Br (3—Bromo—6,7—dihydropyrazolo[1,5—a]pyrazin—5(4H)— ¡l)(cyclohexyl)methanone 1H NMR (400 MHz, DMSO-d6) δ = 7.59 (s, 1H), 4.78 - 4.50 (m, 2H), 4.16 (m, 1H), 4.06-3.91 (m, 3H), 2.79-2, 70 (m, 1H), 1.77 -1.58 (m, 5H), 1.44-1.17 (m, 5H) O Br bicyclo[1,1,1]pentan-1- yl(3- bromo-6,7-dihydrop¡razolo[1,5a]pyrazin-5(4H)-yl)methanone LCMS [M+1] + = 298.1 C-5 or Br (3-Bromo-6,7-dihydrop ¡razolo[1,5-a]pyrazin-5(4H)yl)(phenyl)methanone LCMS [M+1] + = 308.0 CB INTERMEDIARY INTERMEDIARY ΑΝ Pd(dppf)CI2, NaHCO3, dioxane, H2O, 80°C, 1 h A mixture of 3-bromo-5-iodo-pyridine (3.00 g, 10.6 mmol, 1.00 eq.), AN intermediate (2.28 g, 5.28 mmol, 0.50 eq.), sodium bicarbonate (1.78 g, 21.1 mmol, 822 pL, 2.00 eg.), Pd(dppf)CI2 (773 mg, 1.06 mmol, 0.10 eg.) in dioxane (50 mL) and water (10 mL) was degassed with nitrogen 3, then stirred at 80 °C for 1 hour. The cooled reaction mixture was then concentrated under reduced pressure, diluted with water (200 mL), filtered, and the filter cake was triturated with dichloromethane: 156 methyl alcohol (10%, 150 mL) . The solid was filtered, dried, and the solid was triturated a second time in methyl alcohol (100 mL), then filtered and dried to obtain 2-[[7-(5-bromo-3pyridyl)-4- oxo-3H-phthalazin-l-yl]methyl]isoindoline-1,3dione, Intermediate CB (775 mg, crude) as a gray solid. NMR (400 MHz, DMSO-d6) δ = 12.54 (s, 1H), 9.16 (d, J = 1.2 Hz, 1H), 8.82 (d, J = 1.6 Hz, 1H) ), 8.73 (s, 1H) , 8.52 (s, 1H) , 8.38 - 8.28 (m, 2H) , 7.98 - 7.95 (m, 2H) , 7.90 ( m, 2H), 5.38 (s, 2H) . CC INTERMEDIARY CC INTERMEDIARY Step 1: To a solution of pyrazolo[1,5-a]pyridin-5ol (250 mg, 1.86 mmol, 1.00 eq.) in DMF (2 mL) was added potassium carbonate (773 mg, 5, 59 mmol, 3.00 eq.), and the mixture was stirred at 30 °C for 0.5 hour. Iodoethane (872 mg, 5.59 mmol, 447 pL, 3.00 eq.) was then added, and the resulting mixture was stirred at 30 °C for 12 hours. After that time, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL χ 3), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate anhydrous, filtered and concentrated under reduced pressure. The residue was purified by 157 middle of the TLC prep. (S1O2, petroleum ether / Ethyl acetate 20%) in order to obtain 5-ethoxypyrazolo[1,5-a]pyridine (272 mg, 1.68 mmol, 90% yield) as a white solid. LCMS [M+1]+= 163.2; Η2NMR (400 MHz, DMSOd6) δ = 8.50 (d, J= 7.6 Hz, 1H), 7.86 (d, J= 2.0 Hz, 1H), 6.98 (d, J = 2 .8 Hz, 1H), 6.52 (dd, J = 2.8, 7.6 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H), 4.06 (q, J = 6.8 Hz, 2H), 1.35 (t, J = 6.8 Hz, 3H). Step 2: To a solution of 5-ethoxypyrazolo[1,5a]pyridine (260 mg, 1.60 mmol, 1.00 eq.) in acetonitrile (1.0 mL) was added NIS (397 mg, 1.76 mmol , 1.10 eq.). The mixture was stirred at 25 °C for 1 hour, before diluting the mixture with water (30 mL) and extracting with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep TLC. (SÍO2, petroleum ether / ethyl acetate 20%) in order to obtain 5-ethoxy-3-iodo-pyrazolo[1,5-a]pyridine (369 mg, 1.28 mmol, 80% yield) as a solid pink color. LCMS [M+1]+= 289.1; 2H NMR (400 MHz, DMSO-d6) δ = 8.57 (d, J= 7.6 Hz, 1H), 7.96 (s, 1H), 6.67 (d, J = 2.4 Hz, 1H ), 6.59 (dd, J = 2.4, 7.6 Hz, 1H), 4.14 (q, J = 6.8 Hz, 2H), 1.37 (t, J= 6.8 Hz , 3H). 158 CD INTERMEDIARY Stage 1 Stage 2 CD INTERMEDIARY CD intermediate, 3-iodo-5-isopropoxy-pyrazolo[1,5a]pyridine was prepared as a yellow solid (299 mg, 0.99 mmol, 87% yield in 2 steps) using 2-iodopropane following the same procedure than that used for the preparation of CC Intermediate. LCMS [M+1]+= 303.0; NMR (400 MHz, DMSO-d6) δ = 8.56 (d, J = 7.6 Hz, 1H), 7.96 (s, 1H), 6.67 (d, J= 2.8 Hz, 1H), 6.57 (dd, J= 2.8, 7.6 Hz, 1H), 4.77 (td, J= 6.0, 12.0 Hz, 1H), 1.32 (s, 3H), 1.30 (s, 3H). CE INTERMEDIARY Step 1: A mixture of pyrazolo[1,5-a]pyridin-5-ol (300 mg, 2.24 mmol, 1.00 eq.), phenyl boronic acid (545 mg, 4.47 mmol, 2.00 eg.), 4Á MS (30 mg), copper acetate (812 mg, 4.47 mmol, 2.00 eq.) and triethylamine (1.13 g, 11.2 mmol, 1.56 mL, 5.00 eg) in dichloromethane (10 mL) was degassed with oxygen and stirred at 25 °C for 10 hours under an oxygen atmosphere (103.4 kPa (15 psi)). After that time, the mixture 159 reaction was filtered, concentrated, and the residue formed was purified by means of column chromatography (SÍO2, petroleum ether / ethyl acetate 0-20%) in order to obtain 5phenoxypyrazolo[1,5-a]pyridine ( 200 mg, 0.95 mmol, 43% yield) in the form of a yellow oil. LCMS [M+1] + = 211.2. Step 2: To a solution of 5-phenoxypyrazolo[1,5a]pyridine (180 mg, 0.86 mmol, 1.00 eq.) in acetonitrile (2 mL) was added NIS (212 mg, 0.94 mmol, 1 .10 eq.). The mixture was stirred at 0°C for 1 hour. The reaction mixture was then concentrated, and the residue was purified by column chromatography (SiO2, 0-5% petroleum ether / ethyl acetate) to obtain 3-iodo-5-phenoxy-pyrazolo[1, 5-a]pyridine (170 mg, 0.51 mmol, 59% yield) as a yellow oil. LCMS [M+1]+= 336.9. CE INTERMEDIARY CF INTERMEDIARY Step 1: A mixture of l-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyrazole (1.50 g, 7.21 mmol, 1.00 eq. ), [(E)-2-bromovinyl]benzene (2.90 g, 15.8 mmol, 2.03 mL, 2.20 eq.), Pd(PPh3)2C12 (506 mg, 721 umol, 0.10 eq.), carbonate 160 potassium (1.30 g, 9.41 mmol, 1.30 eg.) in ethyl alcohol (3.8 mL) and DMF (7.5 mL) was degassed with nitrogen and then stirred at 75 °C for 2 hours. After that time, the mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (80 mL χ 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SIO2, 0-20% petroleum ether / ethyl acetate) to obtain l-methyl-5-[(E)-styryl]pyrazole (990 mg, 5.37 mmol, 74% yield) as a yellow solid. LCMS [M+l]+= 185.2; RMNXH (400 MHz, DMSO-d6) δ = 7.65 (d, J = 7.2 Hz, 2H), 7.42 - 7.36 (m, 3H), 7.32 - 7.25 (m, 2H), 7.12 (d, J = 16.0 Hz, 1H), 6.63 (d, J= 2.0 Hz, 1H), 3.91 (s, 3H). Step 2: To a solution of l-methyl-5-[(E)styryl]pyrazole (400 mg, 2.17 mmol, 1.00 eq.) in ethyl alcohol (3 mL) Pd / C (10, 0 mg, 10% Pd) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times, and the mixture was then stirred under hydrogen (103.4 kPa (15 psi)) at 25 °C for 12 hours. After that time, the reaction mixture was filtered and concentrated under reduced pressure to obtain l-methyl-5-(2-phenylethyl)pyrazole (385 mg, 1.93 mmol, 89% yield) as a yellow oil, which was used in the next stage without further 161 LCMS purification [M+l]+= 187.2. Step 3: To a solution of l-methyl-5-(2f enylethyl)pyrazole (385 mg, 1.93 mmol, 1.00 eq.) in acetonitrile (10 mL) was added N-bromosuccinimide (343 mg, 1.00 eq.). 93 mmol, 1.00 eq.). The mixture was then stirred at 0 °C for 0.5 hour. After that time, the reaction mixture was concentrated under reduced pressure, and the residue was purified by prep TLC. (SÍO2, petroleum ether / ethyl acetate 20%) in order to obtain 4-bromo-l-methyl-5-(2-phenylethyl)pyrazole (430 mg, 1.62 mmol, 84% yield) in the form of a yellow oil. NMRΤΗ (400 MHz, DMSO-d6) δ = 7.43 (s, 1H), 7.31 7.24 (m, 2H), 7.23 - 7.18 (m, 1H), 7.17 - 7 .11 (m, 2H) , 3.58 (s, 3H) , 2.97 - 2.89 (t, J = 7.2 Hz, 2H) , 2.84 - 2.77 (t, J = 7 ,2Hz, 2H). CG INTERMEDIARY Br CG INTERMEDIARY Step 1: A mixture of l-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyrazole (1.00 g, 4.81 mmol, 1.00 eq. ), 2-bromopyridine (911 mg, 5.77 mmol, 0.55 mL, 1.20 eq.), cesium carbonate (3.13 g, 9.61 mmol, 2.00 eq.) and Pd(dppf )C12 (352 mg, 0.48 mmol, 0.10 eq.) in dioxane (10 mL) and water (2 mL) was degassed and purged with nitrogen, and then the mixture was 162 stirred at 100 °C for 1 hour. After that time, the cooled reaction mixture was concentrated under reduced pressure, and purified by column chromatography (SiO2, 0-20% petroleum ether / ethyl acetate) to obtain 2-(2-methylopyrazole-3 -yl)pyridine (860 mg, crude) in the form of a red oil, which was used in the next step directly without further purification. NMRΧΗ (400 MHz, DMSO-de) δ = 8.69 - 8.66 (m, 1H), 7.89 (dt, J= 1.6, 7.6 Hz, 1H), 7.78 (td, 0=1.2, 8.0 Hz, 1H), 7.48 (d, 0= 2.0 Hz, 1H), 7.37 (ddd, 0=1.2, 4.8, 7.6 Hz , 1H), 6.78 (d, 0 = 1.6 Hz, 1H), 4.14 (s, 3H). Step 2: To a solution of 2-(2-methylopyrazol-3yl)pyridine (760 mg, crude) in acetonitrile (10 mL) was added N-bromosuccinimide (850 mg, 4.77 mmol). The mixture was stirred at 0°C for 0.5 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by prep TLC. (SiO2, petroleum ether / ethyl acetate 20%) in order to obtain 2- (4-bromo-2-methyl-pyrazol-3-yl)pyridine (507 mg, 2.13 mmol, 44% yield) in the form of a whitish solid. 4H NMR (400 MHz, DMSO-d6) δ = 8.77 (td, J = 0.8, 4.0 Hz, 1H), 8.01 (dt, 0= 2.0, 7.6 Hz, 1H) , 7.76. Step 3: To a solution of 2-(4-bromo-2-methyl-pyrazol3-yl)pyridine (150 mg, 0.63 mmol, 1.00 eq.) in dichloroethane (3 mL) meta-chloroperbenzoic acid was added (435 mg, 2.14 mmol, 85% purity, 3.40 eq.). The mixture was stirred at 60 °C for 5 163 hours. The reaction mixture was then quenched by adding saturated sodium sulfite solution (20 mL) and extracted with dichloromethane (20 mL χ 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by prep TLC. (3ίΟ2, petroleum ether / ethyl acetate 50%) in order to obtain 2-(4-bromo-l-methyl-lH-pyrazol5-yl)pyridine 1-oxide (185 mg, crude) as a colored solid yellow, which was used in the next step directly without further purification. LCMS [M+l]+= 254.1; 2H NMR (400 MHz, DMSO-d6) δ = 8.46 (d, J= 6.4 Hz, 1H), 7.70 (s, 1H), 7.5 (dt, J= 1.2, 7, 6 Hz, 2H), 7.52 - 7.47 (m, 1H), 3.74 (s, 3H). CH INTERMEDIARY CH INTERMEDIARY Step 1: A mixture of quinolin-8-ol (454 mg, 3.13 mmol, 0.54 mL, 1.10 eq.), 3-bromo-5-fluoro-pyridine (500 mg, 2.84 mmol, 1.00 eq.), potassium carbonate (785 mg, 5.68 mmol, 2.00 eq.) in DMF (6 mL) was degassed with nitrogen, then stirred at 110 °C for 3 hours. After that time, the mixture was extracted with ethyl acetate (5 mL χ 3), and the combined extracts were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 8 -[(5-bromo-3-pyridyl)oxy]quinoline (0.30 g, 0.75 mmol, 26% 164 yield) in the form of a yellow oil. LCMS [M+l]+= 301.0; 2H NMR (400 MHz, CDC13) δ = 8.95 (dd, J= 2.0, 4.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.39 (d , J = 2.4 Hz, 1H) , 8.25 (dd, J = 2.0, 8.4 Hz, 1H) , 7.73 (dd, J = 1.6, 8.4 Hz, 1H) , 7.55 (t, J= 8.0 Hz, 1H), 7.50 (dd, J= 4.0, 8.4 Hz, 1H), 7.47 - 7.43 (m, 2H). CI INTERMEDIARY CI INTERMEDIARY Step 1: A mixture of 3,5-dibromopyridine (1.48 g, 6.25 mmol, 1.00 eq.), quinolin-8-amine (901 mg, 6.25 mmol, 1.00 eq.), sodium tert-butoxide (901 mg, 9.37 mmol, 1.50 eg.), Pd2(dba)3 (57.2 mg, 62.5 pmol, 0.01 eg.) and Xantphos (72.3 mg , 125 pmol, 0.02 eg) in dioxane (10 mL) was degassed with nitrogen, then stirred at 100 °C for 2 hours. After that time, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL χ 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by reverse phase HPLC (0.1% formic acid condition ( FA)) in order to obtain N-(5-bromo-3-pyridyl)quinoline-8-amine (160 mg, 486 pmol, 7% yield) in 165 form of a yellow solid. LCMS [M+l]+= 300.0; RMNTH (400 MHz, CDC13) δ = 8.82 (dd, J= 1.6, 4.0 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.40 (br s, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.17 (dd, J= 1.6, 8.4 Hz, 1H), 7.92 (t, J= 2 .0 Hz, 1H), 7.51 - 7.46 (m, 3H), 7.37 (dd, J= 1.6, 8.0 Hz, 1H). Step 2: N-(5-bromo-3-pyridyl)quinolin-8-amine (130 mg, 394 pmol, 1.00 eq.) was dissolved in DMF (2 mL), then, sodium hydride (32 mg, 790 pmol, 60.0% purity, 2.00 eq.) at 0 °C, and the mixture was stirred at 0 °C for 10 minutes. After that time, methyl iodide (224 mg, 1.58 mmol, 98 pL, 4.00 eq.) was added, and the resulting mixture was stirred at 20 °C for 1 hour. The reaction mixture was then quenched with water (10 mL), extracted with ethyl acetate (20 mL χ 3), and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain N-(5-bromo-3-pyridyl)-N-methyl-quinolin-8-amine (150 mg, 334 pmol, 85% yield) as a yellow oil. LCMS [M+l]+= 314.1; 4H NMR (400 MHz, CDC13) δ = 8.90 (dd, J= 1.6, 4.4 Hz, 1H), 8.24 (dd, J= 1.6, 8.4 Hz, 1H), 8 .01 (d, J = 2.0 Hz, 1H) , 7.92 (d, J= 2.8 Hz, 1H) , 7.82 (dd, J = 1.6, 8.0 Hz, 1H) , 7.65 - 7.62 (m, 1H) , 7.61 - 7.57 (m, 1H) , 7.46 (dd, J= 4.4, 8.4 Hz, 1H) , 7.10 (t, J= 2.4 Hz, 1H), 3.49 (s, 3H) . 6 CJ INTERMEDIARY CJ INTERMEDIARY Step 1: A mixture of 2-ethylbenzonitrile (500 mg, 3.81 mmol, 0.51 mL, 1.00 eq.), p-toluenesulfonic acid (363 mg, 1.91 mmol, 0.50 eq.), N-Bromosuccinimide (746 mg, 4.19 mmol, 1.10 eq.) and palladium acetate (85.6 mg, 0.38 mol, 0.10 eq.) in 1,2-dichloroethane (10 mL) were degassed with nitrogen, then stirred at 70 °C for 12 hours. After that time, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SIO2, 0-5% petroleum ether / ethyl acetate) to obtain 2-bromo-6-ethyl -benzonitrile (446 mg, 1.15 mmol, 30% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.76 (dd, J= 0.8, 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.60 - 7.54 (m, 1H), 2.81 (m, 2H), 1.22 (m, 3H) . Step 2: A mixture of 2-bromo-6-ethyl-benzonitrile (446 mg, 1.15 mmol, 1.00 eq.), 4-bromo-l-methyl-pyrazole (203 mg, 1.26 mmol, 1 .10 eq.), palladium acetate (2.57 mg, 0.12 mmol, 0.01 eq.), DavePhos (9.0 mg, 0.23 mmol, 0.02 eq.), 2-methylpropanoic acid or ( 30.3 mg, 0.34 mmol, 31.9 uL, 0.30 eq.) and tetrabutyl ammonium acetate (691 mg, 2.29 mmol, 0.70 mL, 2.00 167 eq. ) in 77-methyl pyrrolidone (10 mL) was degassed with nitrogen, then stirred at 100 °C for 12 hours. After that time, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (60 mL χ 3), and the combined organic layers were washed with brine (80 mL), dried over sodium sulfate anhydrous, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SIO2, 10-20% petroleum ether / ethyl acetate) to obtain 2-(4-bromo-2methyl-pyrazol-3-yl)-6-ethyl-benzonitrile. (310 mg, 0.44 mmol, 39% yield) as a yellow solid. LCMS [M+l]+= 290.1; Η2NMR (400 Hz, DMSO-d6) δ = 7.83 - 7.78 (m, 1H), 7.73 (s, 1H), 7.68 (d, J= 7, 6 Hz, 1H), 7 .50 - 7.47 (m, 1H), 3.71 (s, 3H), 2.90 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). INTERMEDIARIES D-l to D-20 set out in Table I-V were prepared following the teachings of the General Reaction Schemes and the method for the preparation of INTERMEDIATE CJ. Table I-V Intermit. Structure Spectral data D-1 Br / χ ? 2-(4-bromo-1 —methyl-1 H-pyrazol-5-yl)-5-ethylbenzonitol LCMS [M+1]+ = 289.9; 1H NMR (400 MHz, CDCI3) δ = 7.67 (d, J= 1.2 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 5.30 (s, 1H), 3.80 (s, 3H), 2.79 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H) 168 D-21 __ / BrNC nXAAa n \ y 1 A7 2-(4- bromo-1- methyl-1H-pyrazole-5- ¡I)-4-ethylbenzonitrile LCMS [M+1]+ = 290.0; 1H NMR (400 MHz, CDCI3) δ = 7.67 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.36 (dd, J = 2.0, 8.0 Hz, 1H), 7.22 (d, J = 1.2 Hz, 1H), 3.72 (s, 3H), 2.72 (q, J = 7.6 Hz, 2H), 1.23 ( t, J = 7.6 Hz, 3H) D-3 Br N1 2—(4—bromo—1—methyl—1H—pyrazol—5—yl)—5—cyclopropylbenzonitrile LCMS [M+1 ]+ = 304.1 ; 1H NMR (400 MHz, CDCI3) δ = 7.58 (s, 1H), 7.51 (d, J =2.0 Hz, 1H), 7.43 - 7.39 (m, 1H), 7, 36 - 7.31 (m, 1H), 3.79 (s, 3H), 2.01 (tt, J =5.2, 8.4 Hz, 1H), 1.18 - 1.11 (m, 2H), 0.86 - 0.78 (m, 2H) D-4 __ / BrNC νΑΑΧ N \ \\ i Cl 2—(4—bromo—1—methyl-1 H-pyrazole—5—yl)—4 —chloro-5-methylobenzonitrile LCMS [M+1]+ =312.0; 1H NMR (400 MHz, CDCI3) δ = 7.71 (s, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 3.81 (s, 3H), 2.51 ( s, 3H) D-5 —Zz J Z °\ / o o 3-(4-bromo-1-methyl-1 H—pyrazole—5—¡I)—2—naphtonitrile LCMS [M+1] + = 312.1 ; 1H NMR (400 MHz, CDCI3) δ = 8.43 (s, 1H), 8.04 7.96 (m, 2H), 7.95 (s, 1H), 7.79 - 7.70 (m, 2H), 7.64 (s, 1H), 3.85 (s, 3H) D-6 Br ¡XA / NC?^° 2-(4-bromo-1 -methyl-1 H-pyrazole-5-¡ l)-4,5-d¡methoxybenzon¡trilo LCMS [M+1 ]+ = 324.0; 1H NMR (400 MHz, CDCI3) δ = 7.59 (s, 1H), 7.23 (s, 1H), 6.87 (s, 1H), 3.99 (s, 3H), 3.97 ( s, 3H), 3.83 (s, 3H) D-7 N=, Y Br NC / Ó / x0 Cl 2- (4- bromo-1- methyl-1H-pyrazole-5- ¡I)-5- chloro-4-methoxybenzonitrile LCMS [M+1 ]+ = 327.9; 1H NMR (400 MHz, CDCI3) δ = 7.83 (s, 1H), 7.61 (s, 1H), 6.96 (s, 1H), 4.01 (s, 3H), 3.84 ( s, 3H) D-8 Br / ' NC 2-(4- bromo-1-methyl-1H-pyrazol-5-yl)-4,5-dimethylobenzonítrilo LCMS [M+1] + = 292, 0; 1H NMR (400 MHz, CDCI3) δ = 7.60 (s, 1H), 7.58 (s, 1H), 7.22 (s, 1H), 3.79 (s, 3H), 2.40 ( s, 3H), 2.39 (s, 3H) D-9 Br ία NC^X^CI 2—(4—bromo—1—methyl-1 H—pyrazole—5—yl)—5—chloro—4— methylbenzonitrile LCMS [M+1 ]+ = 312.0; 1H NMR (400 MHz, CDCI3) δ = 7.82 (s, 1H), 7.59 (s, 1H), 7.34 (s, 1H), 3.81 (s, 3H), 2.53 ( s, 3H) D-10 Br ÓAW A kr\ \ 4—bromo—5—(4—isopropylphenyl)—1—methyl—1H—pyrazole LCMS [M+1 ]+ = 281.1; 1H NMR (400 MHz, CDCI3) δ = 7.54 (s, 1H), 7.39 - 7.32 (m, 4H), 3.83 (s, 3H), 1.31 (d, J =6 ,8Hz, 6H) QRZZQn / ZZnZ / q / ΥΙΛΙ 169 D—11 Br ^ / ^Cl n'n 2-(4- bromo-1- methyl-1H-pyrazole—5- ¡I)-4-chloro-5-methoxybenzonitrile LCMS [M+1]+ = 328.0 ; 1H NMR (400 MHz, MeOD) δ = 7.67 (s, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 4.03 (s, 3H), 3.77 ( s, 3H) D-12 Br CN N-d W 2—(4—bromo—1—methyl—1H—pyrazol—5—yl)—5—ethoxyterephthalonitrile LCMS [Μ+ψ = 306.1; 1H NMR (400 MHz, CDCI3) δ = 7.53 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 2.4, 8.8 Hz, 1H), 7.44 ( s, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.73 (s, 3H), 1.45 ( t, J = 7.2 Hz, 3H) D-13 Br íTV+C^Vc| n-n NC Cl 6-(4- bromo-1- methyl-1 H-pyrazole-5- ¡I)- 2,3-dichlorobenzonitrile LCMS [Μ+ψ = 392.3; 1H NMR (400 MHz, CDCI3) δ = 7.83 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H) , 3.82 (s, 3H) D-14 m o \ 2 o 2—(4—bromo—1—methyl—1H—pyrazole—5—¡I)—6—chloro—4—methylobenzonitrile LCMS [M+1 ] + = 311.9; 1H NMR (400 MHz, CDCI3) δ = 7.83 (s, 1H), 7.61 (s, 1H), 6.96 (s, 1H), 4.01 (s, 3H), 3.84 ( s, 3H) D-15 N=, di Y Br N<\ / ciCC 2—(4—bromo—1—methyl—1H—pyrazole—5—¡I)—6—chloro—5—methylobenzonitrile LCMS [M+ 1 ]+ = 312; 1H NMR (400 MHz, CDCh) δ = 7.62 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.31 - 7.26 ( m, 1H), 3.81 (d, J = 1.2 Hz, 3H),2.54 (s, 3H) D-16 N=> --n / A γ Br NC '' ζ) 2—( 4—bromo—1—methyl—1H—pyrazole—5—¡I)—4—cyclopropylbenzonitrile LCMS [M+1]+ = 304.1; 1H NMR (400 MHz, CDCI3) δ = 7.71 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.26-7.23 (dd, J= 1.6 , 8.4, 1H), 7.11 (d, J = 1.6 Hz, 1H), 3.81 (s, 3H), 2.03- 1.99 (m, 1H), 1.20 - 1.17 (m, 2H), 0.87 0.82 (m,2H) D-17 N=, and Br NC / / Cl Cl 2—(4—bromo—1—methyl—1H—pyrazole—5— I)—4,5—dichlorobenzonitrile LCMS [M+1 ]+ = 329.9; 1H NMR (400 MHz, CDCI3) δ = 7.93 (s, 1H), 7.60 (m, 2H), 3.83 (s, 3H) D-18 N=, --n' zk and Br NC JO Cl 6—(4—bromo—1—methyl—1H—pyrazol—5—yl)—3—chloro—2—methylobenzonitrile LCMS [Μ+ψ = 312.0; 1H NMR (400 MHz, CDCI3) δ = 7.71 (d, J = 8.4Hz, 1H), 7.59 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H), 2.71 (s, 3H) 170 D-19 N=a Y Br NC, / Jo Cl 2-(4- bromo-1-methyl-1H-pyrazole—5- ¡I)-4-chloro-6-methylobenzonitrile LCMS [M+1 ]+ = 312 ,0; 1H NMR (400 MHz, CDCI3) δ = 7.59 (s, 1H), 7.48 (d, J = 1.2 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H) , 3.81 (s, 3H) D-20 Br / Ύ ?N / N 2—(4—bromo—1—methyl—1H—pyrazol—5—yl)—6—propylbenzonitrile LCMS [M+1]+ = 305.9; 1H NMR (400 MHz, DMSO-d6) δ = 7.84 - 7.77 (m, 1H), 7.74 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 3.71 (s, 3H), 2.89 - 2.83 (m, 2H), 1.75 - 1.64 (m, 2H) , 0.98 - 0.92 (m, 3H) INTERMEDIARY DA INTERMEDIARY DA Step 1: A mixture of 3-bromophenol (1.00 g, 5.78 mmol, 1.00 eq.), bromocyclobutane (1.17 g, 8.65 mmol, 0.82 mL, 1.50 eq.) and potassium carbonate (3.20 g, 23.1 mmol, 4.00 eq.) in DMF (10 mL) was stirred at 120°C for 6 hours. The reaction mixture was diluted with water (80 mL) and extracted with (petroleum ether / 20% ethyl acetate) (50 mL χ 3), and the combined extracts were washed with aq. sodium hydroxide. (1.00 M, 50 mL), with brine (50 mL), and dried over sodium sulfate and concentrated, in order to obtain l-bromo-3(cyclobutoxy)benzene (1.20 g, 5.27 mmol, 91% yield) in the form of a colorless oil. 4H NMR (400 MHz, CDCI3) δ = 7.04 - 6.93 (m, 2H), 6.86 (t, J = 2.4 Hz, 1H), 6.64 (ddd, J = 1.2, 2.4, 8.0 Hz, 1H), 4.60 - 4.44 (m, 1H), 2.34 (tddd, J = 171 2.8, 6.8, 8.0, 9.6 Hz, 2H), 2.14 - 1.98 (m, 2H), 1.83 - 1.71 (m, 1H), 1.66 - 1.50 (m, 1H) . Step 2: l-Bromo-3-(cyclobutoxy)benzene (300 mg, 1.32 mmol, 1.00 eq.), 4-bromo-l-methyl-pyrazole (213 mg, 1.32 mmol, 1, 00 eq.), palladium acetate (2.97 mg, 13.2 pmol, 0.01 eg.), tetrabutylammonium acetate (224 mg, 2.91 mmol, 2.20 eg.), 2-methylpropanoic acid (34 .9 mg, 396 pmol, 36.8 pL, 0.30 eg.) and DavePhos (10.4 mg, 26.4 pmol, 0.02 eg.) in NMP (5 mL) were degassed with nitrogen and heated up to 100°C for 12 hours. The reaction mixture was then diluted with water (20 mL), extracted with ethyl acetate (30 mL χ 3), and the combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SIO2, petroleum ether / ethyl acetate 1-5%) to obtain 4-bromo-5-[3(cyclobutoxy)phenyl]-1-methyl-pyrazole (40 .0 mg) in the form of a yellow oil. RMNXH (400 MHz, CDCI3) δ = 7.54 (s, 1H), 7.45 (s, 1H), 6.98 - 6.90 (m, 2H), 6.86 - 6.83 (m, 1H), 4.68 (t, J= 7.2 Hz, 1H), 3.83 (s, 3H), 2.54 - 2.40 (m, 2H), 2.27 - 2.14 (m , 2H), 1.95 - 1.66 (m, 2H) . The INTERMEDIARIES E-l and E-2 shown in Table I-VI were prepared following the teachings of the General Reaction Schemes and the method for the preparation of DA Intermediary. 172 Table I-VI Intermediate Structure Spectral data E-1 Br ΐ u 0 4—bromo—5—(4—cyclobutoxyphenyl)—1—methyl—1H—pyrazole LCMS [M+1]+ = 307.1; 1H NMR (400 MHz, CDCI3) δ = 7.52 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H) , 4.70 (quin, J = 7.2 Hz, 1H), 3.81 (s, 3H), 2.54 - 2.47 (m, 2H), 2.28 2.19 (m, 2H) , 1.94- 1.87 (m, 1H), 1.78- 1.72 (m, 1H) E-2 Br NC__ ΥΐΛΓθ 2—(4-bromo—1—methyl—1H—pyrazole—5—yl )—5—ethoxybenzonitrile LCMS [M+1]+ = 307.9; 1H NMR (400 MHz, CDCI3) δ = 7.58 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H) , 7.26 7.21 (dd, J = 2.8, 8.8 Hz, 1H), 4.16-4.10 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H) DB INTERMEDIARY Br DB INTERMEDIARY Step 1: A mixture of l-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyrazole (1.50 g, 7.21 mmol, 1.00 eq. ), l-bromo-2-chloro-benzene (1.38 g, 7.21 mmol, 0.84 mL, 1.00 eq.), sodium carbonate (2.29 g, 21.6 mmol, 3, 00 eq.), Pd(dppf)C12 (528 mg, 0.72 mmol, 0.10 eq.) in water (2.4 mL) and dioxane (12 mL) was degassed with nitrogen, then stirred at 80 ° C for 2 hours. After that time, the mixture was concentrated under reduced pressure and purified by means of column chromatography (SIO2, Petroleum ether / ethyl acetate 10-20%) in order to 173 to obtain 5-(2-chlorophenyl)-1-methyl-pyrazole (0.56 g, 2.88 mmol, 40% yield) as a yellow solid. LCMS [M+1]+= 193.1; Η2NMR (400 MHz, CDC13) δ = 7.56 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 1.2, 7.6 Hz, 1H), 7.43 7, 33 (m, 3H), 6.30 (d, J = 2.0 Hz, 1H), 3.74 (s, 3H). Step 2: A mixture of 5-(2-chlorophenyl)-1-methylopyrazole (200 mg, 1.04 mmol, 1.00 eq.), N-bromo-succinimide (203 mg, 1.14 mmol, 1.10 eq.) in acetonitrile (2 mL) was degassed with nitrogen, then stirred at 0 °C for 2 hours. After that time, the mixture was concentrated under reduced pressure, and the residue was purified by prep TLC. (Petroleum ether / ethyl acetate 20%) to obtain 4-bromo-5-(2chlorophenyl)-1-methyl-pyrazole (220 mg, 0.77 mmol, 74% yield) as a colored solid yellow. LCMS [M+1]+= 273, 1; NMR (400 MHz, CDC13) δ = 7.59 - 7.55 (m, 2H), 7.50 - 7.40 (m, 2H), 7.36 - 7.33 (m, 1H), 3, 74 (s, 3H). INTERMEDIARIES F-l to F-22 set forth in Table I-VII were prepared following the teachings of the General Reaction Schemes and the method for the preparation of INTERMEDIATE DB. Table I-VII Intermediate Structure Spectral data F-1 A or XA 0 4—bromo—5—(2,6—dichlorophenyl)—1—methyl—1 H—pyrazole LCMS [M+1]+ = 306.9; 1H NMR (400 MHz, CDCI3) δ = 7.59 (s, 1H), 7.53-7.51 (m, 1H), 7.50-7.47 (m, 1H), 7.46-7 .35 (m, 1H), 174 3.70 (s, 3H) F-2 ώ LL qp 2-(4-bromo-1- methyl-1H-pyrazol-5-yl)-3—fluorobenzonitrile LCMS [M+1]+ = 282.0; 1H NMR (400 MHz, CDCI3) δ = 7.72 7.64 (m, 2H), 7.63 (s, 1H), 7.55 - 7.49 (m, 1H), 3.80 (s, 3H) F-3 N=a ^-N = 331.9; 1H NMR (400 MHz, CDCI3) δ = 7.70 (d, J = 2.0 Hz, 1H), 7.61 (s, 1H), 7.39 (d, J = 2.0 Hz, 1H) , 3.84 (s, 3H) F-4 / " o_ \ o 2-(4-bromo-1-methyl-1H-pyrazole-5-II)-4-chloro-6methoxybenzonitrile LCMS [M+1+] = 327.9; 1H NMR (400 MHz, CDCI3) δ = 7.57 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 4.02 (s, 3H), 3.82 (s, 3H) F-5 N=i Y Br yXcn oÁX / Cl 2-(4-bromo-1- methyl-1H-pyrazole-5 -I)-4-methoxy-6chlorobenzonitrile LCMS [M+1]+ = 328.0; 1H NMR (400 MHz, DMSO-d6) δ = 7.75 (s, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H), 3.75 (s, 3H) F-6 " or 7 \ υ ΐΑλΧ 2-(4-bromo-1-methyl-1H-p¡razol-5-yl)-5-methoxy¡-6chlorobenzonitrile LCMS [M+1 ]+ = 328.1; 1H NMR (400 MHz, CDCI3) δ = 7.58 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H) , 4.03 (s, 3H), 3.80 (s, 3H) F-7 ¿ or 2—(4—bromo—1—methyl—1H—pyrazol—5—yl)-5—methoxy—6—methylbenzonitrile LCMS [M+1]+ = 308.0; 1H NMR (400 MHz, CDCI3) δ = 7.58 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H) , 4.03 (s, 3H), 3.80 (s, 3H), 2.50 (s, 3H) F-8 N=n y Br N^y y^ J ÍY 2—(4—bromo—1—methyl—1H—pyrazole—5—yl)quinoline LCMS [M+1]+ = 290.0; 1H NMR (400 MHz, CDCI3) δ = 8.21 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.70 (dt, J = 1.2, 7.6 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.50 (s, 1H), 4.08 (s, 3H) F-9 N=n miA Y Br n<\7 JO 2—(4—bromo—1—methyl—1H—pyrazol—5—yl)—4—methoxy—1— naphthonitrile LCMS [M+1]+ = 344.0; 1H NMR (400 MHz, CDCI3) δ = 8.40 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.79 (ddd, J = 1.2, 7.2, 8.4 Hz, 1H), 7.70 (ddd, J = 1.2, 7.2, 8.4 Hz, 1H), 7.64 (s, 1H), 6 .80 (s, 1H), 4.12 (s, 3H), 3.88 (s, 3H) F-10 N=, ^yA Y Br nc / Y 6—(4—bromo—1—methyl—1H —pyrazole—5—yl)-2—ethyl—3— methoxybenzonitrile LCMS [M+1]+ = 322.1; 1H NMR (400 MHz, CDCI3) δ = 7.56 (s, 1H), 7.26 - 7.22 (m, 1H), 7.18 - 7.11 (m, 1H), 3.94 (s , 3H), 3.77 (s, 3H), 2.96 (q, J = 7.6 Hz, 2H), 1.28 - 1.24 (m, 3H) F—11 N=r ^n / A Y Br NC / yy-ci A Γ (Jj 2—(4—bromo—1—methyl—1H—pyrazol—5—yl)-3—chloro—1— naphthonitrile LCMS [M+1]+ = 346.0, 348.0; 1H NMR (400 MHz, DMSO-d6) δ = 8.78 (s, 1H), 8.23 ​​(t, J = 9.2, 2H), 7.95 - 7.90 (m, 2H), 7.85 (s, 1H), 3.74 (s, 1H) F-12 and ro T—benzyl-4-bromo—5'—chloro—2—methyl-TH,2H—3,4' — bipyrazole LCMS [M+1]+ = 353.0; 1H NMR (400 MHz, CDCI3) δ = 7.67 (s, 1H), 7.54 (s, 1H), 7.41 - 7.33 ( m, 3H), 7.31 - 7.27 (m, 2H), 5.43 (s, 2H), 3.79 (s, 3H) F-13 m YA H 4—bromo—T,2-dimethyl —TH,2H-[3,4'—bipyrazole]—5'— carbonitrile LCMS [M+1]+ =265.9; 1H NMR (400 MHz, CDCI3) δ = 7.70 (s, 1H), 7 .56 (s, 1H), 4.16 (s, 3H), 3.87 (s, 3H) QAzzcn / zznz / q / υιλι F-14 —n TI Αβγ JJLA'N T—benzyl—4—bromo—2—methyl—TH,2H—[3,4'—bipyrazole]—5'— carbonitrile LCMS [M+1]+ = 342.0 F-15 N^, —N 3\ Y 'Br rVcN T-benzyl—4-bromo-2-methyl- TH,2H-[3,4-bipyrazole]-3'carbonitrile LCMS [M+1] + = 342 ,0; 1H NMR (400 MHz, CDCI3-d) δ = 7.61 (s, 1H), 7.54 (s, 1H), 7.47-7.39 (m, 1H), 7.36-7.30 (m, 2H), 5.43 (s, 2H), 3.87 (s, 3H) F-16 —N 31 AAr CI^J r An ZA 4-bromo-5'-chloro-1',2— dimethyl—TH,2H-[3,4'—bipyrazole]-3carbonitrile LCMS [M+1]+ = 302.0; 1H NMR (400 MHz, CDCI3) δ = 7.59 (s, 1H), 4.04 (s,3H), 3.84 (s, 3H) F—17 o 'Xa CD -1 4-bromo-5 '-chloro-1 ',2-dimethyl—1Ή.2Η—3,4'- bipyrazole LCMS [M+1]+ =277.0; 1H NMR (400 MHz, CDCI3) δ = 7.60 (s, 1H), 7.53 (s, 1H), 3.94 (s, 3H), 3.79 (s, 3H) F-18 o A / \ flA AAA in 4-bromo-5-(1,3-dihydroisobenzofuran—4—yl)—1 —methyl—1Hpyrazole LCMS [M+1]+ = 280.9; 1H NMR (400 MHz, CDCI3) δ = 7.54 (s, 1H), 7.45 - 7.35 (m, 2H), 7.18 (d, J = 7.2 Hz, 1H), 5, 26 - 5.11 (m, 3H), 4.88 - 4.83 (m, 1H), 3.72 (s, 3H) F-19 N=i A A V Br °AA. 4-bromo-5-(isochroman-8-¡l)-1-methyl-1H-pyrazole LCMS [M+1]+ = 293.0; 1H NMR (400 MHz, CDCI3) δ = 7.54 (s, 1H), 7.34 - 7.26 (m, 2H), 7.04 (d, J = 6.8 Hz, 1H), 4, 65 - 4.57 (m, 1H), 4.34 - 4.28 (m, 1H), 4.07 - 3.92 (m, 2H), 3.65 (s, 3H), 3.05- 2.88 (m, 2H) F-20 N=i -A A Y Br nc / Jo N-N \ 5-(4-bromo-1-methyl-1 H-pyrazol-5-yl)-1 -methyl-1H- indazole —4-carbonitrile LCMS [M+1]+ = 318.0 QRzzcn / zznz / q / υιλι F-21 Y Y Br NC / zN-n 5-(4-bromo-1-methyl-1H-pyrazole-5-¡I)-2-methyl-2Hindazol—4-carbonitrile LCMS [M+1]+ = 318, 0 F-22 N=a ^-N Y y Br nc, j \ >7 S-N 5-(4-bromo-1- methyl-1H-pyrazole-5-¡l)benzo[c]isothiazol-4carbonitrile LCMS [M+ 1]+ =318.9; 1H NMR (400 MHz, CDCI3,) δ = 9.62 (d, J = 0.8 Hz, 1H), 8.22 (dd, J = 1.2, 9.2 Hz, 1H), 7.65 (s, 1H), 7.50 (d, J = 9.2 Hz, 1H), 3.88 (s, 3H) DC INTERMEDIARY DC INTERMEDIARY Step 1: To a solution of 2-bromonaf talene-1carbaldehyde (220 mg, 0.94 mmol, 1.00 eq.) in water (5 mL) was added amino hydrogen sulfate (212 mg, 1.87 mmol, 2, 00 eg. ) . The mixture was stirred at 50 °C for 12 hours. The suspension was then filtered, and the filter cake was dried under reduced pressure to obtain (1E)-2-bromonaphthalene-l-carbaldehyde oxime (220 mg, 0.88 mmol, 94% yield) as a solid. white in color, which was used without further purification. NMR A (400 MHz, DMSO-cU δ = 11.79 (s, 1H), 8.58 (s, 1H), 8.55 (dd, J = 1.6, 8.0 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.67 - 7.57 (m, 2H). To a solution of (1E)-2-bromonaphthalene-l-carbaldehyde oxime (220 178 mg, crude) in THF (5 mL), triethylamine (890 mg, 8.80 mmol, 1.22 mL) and trifluoroacetic anhydride (924 mg, 4.40 mmol, 0.61 mL) were added, and the mixture was stirred at 20 °C for 1 hour. After that time, the reaction mixture was concentrated under reduced pressure, and the residue was purified by prep TLC. (SÍO2, petroleum ether / ethyl acetate 10%) in order to obtain 2-bromonaphthalene-l-carbonitrile (190 mg, 0.82 mmol, 93% yield) as a white solid. GCMS [M+l]+= 230.9; NMR (400 MHz, DMSO-d6) δ = 8.26 (d, J = 8.8 Hz, 1H), 8.16 (d, J= 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H) , 7.93 (d, J = 8.8 Hz, 1H) , 7.85 (dt, J = 1.2, 8.4 Hz, 1H) , 7.79 7, 71 (m, 1H). Step 2: A mixture of 2-bromonaphthalene-lcarbonitrile (190 mg, 0.82 mmol, 1.00 eq.), 4-bromo-lmethyl-pyrazole (132 mg, 0.82 mmol, 1.00 eq.), tetrabutylammonium acetate (494 mg, 1.64 mmol, 0.50 mL, 2.00 eq.), DavePhos (6.4 mg, 16 pmol, 0.02 eq.), 2methylpropanoic acid (22 mg, 246 pmol, 23 pL, 0.30 eq.) and palladium acetate (1.8 mg, 8.2 pmol, 0.01 eq.) in N-methyl pyrrolidone (NMP) (6 mL) was degassed with nitrogen, then the mixture was stirred at 100 °C for 12 hours. After that time, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL χ 3). The combined organic layers were washed with brine (100 mL χ 2), dried over anhydrous sodium sulfate, filtered, and 179 were concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid condition) to obtain 2-(4-bromo-2-methyl-pyrazol3-i 1)naphthalene-1-carbonitrilo (190 mg, 0.61 mmol, 74% yield) as a yellow oil. LCMS [M+l] + = 314.1; NMR (400 MHz, DMSO-d6) δ = 8.49 (d, J = 8.4 Hz, 1H), 8.24 (t, J = 8.4 Hz, 2H), 7.92 (dt, J = 1.2, 8.4 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.81 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H) , 3.79 (s, 3H). DD INTERMEDIARY DD INTERMEDIARY Step 1: To a solution of ethyl alcohol (207 mg, 4.50 mmol, 0.26 mL, 3.00 eq.) in THF (3 mL) sodium hydride (180 mg, 4.50 mmol, 60 eq.) was added. .0% purity, 3.00 eq.), followed by a solution of 2-bromo-6-fluoro-benzonitrile (300 mg, 1.50 mmol, 1.00 eq.) in THF (1 mL), by drip,. After the addition was complete, the mixture was stirred at 25°C for 3 hours. After that time, the reaction was quenched with water (0.2 mL) and concentrated in vacuo, and the residue was purified by column chromatography (SIO2, petroleum ether / ethyl acetate 10%) in order to obtain 2-brorno-6-ethoxy-benzonitrile (200 mg, 0.89 mmol, 180 59% yield) in the form of a white solid. 4H NMR (400 MHz, CDC13) δ = 7.38 - 7.32 (t, J = 8.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.90 (d , J = 8.4 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H). Step 2: A mixture of 2-bromo-6-ethoxy-benzonitrile (200 mg, 0.89 mmol, 1.00 eq.), 4-bromo-l-methyl-pyrazole (185 mg, 1.15 mmol, 1 .30 eg.), palladium acetate (2.0 mg, 8.9 pmol, 0.01 eg.), DavePhos (7.0 mg, 17.7 pmol, 0.02 eg.), 2-methylpropanoic acid (23.4 mg, 265 pmol, 25 pL, 0.30 eg.) and tetrabutylammonium acetate (533 mg, 1.77 mmol, 2.00 eg.) were degassed with nitrogen, then the mixture was stirred at 100 °C for 15 hours. After that time, the mixture was diluted with ethyl acetate (20 mL), washed with water (20 mL χ 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was then purified by prep TLC. (SIO2, petroleum ether / ethyl acetate 20%) in order to obtain 2-(4-bromo-l-methyl-lH-pyrazol-5-yl)-6ethoxybenzonitrile (60.0 mg, 0.20 mmol, 22% of performance) in the form of a white solid. LCMS [M+l]+= 306.1; 4H NMR (400 MHz, CDC13) δ = 7.56 (dd, J= 7.6, 8.4 Hz, 1H), 7.49 (s, 1H), 7.02 (d, J = 8.4 Hz , 1H) , 6.91 (d, J = 7.6 Hz, 1H) , 4.15 (q, J = 7.2 Hz, 2H) , 3.73 (s, 3H) , 1.46 (t , J = 7.2 Hz, 3H). 181 INTERMEDIARY OF INTERMEDIARY OF A mixture of 4-bromo-2-methyl-pyrazole-3-ol (300 mg, 1.69 mmol, 1.00 eq.), 1-(bromomethyl)-2-chloro-benzene (348 mg, 1.69 mmol, 0.22 mL, 1.00 eq.) and potassium carbonate (469 mg, 3.39 mmol, 2.00 eq.) in DMF (8 mL) was stirred at 18 °C for 2 hours. After that time, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL χ 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (0.1% FA condition). ) in order to obtain 4-bromo-5-[(2-chlorophenyl)methoxy]-1-methyl-pyrazole (220 mg, 0.72 mmol, 42% yield) as a yellow solid. LCMS [M+l] + = 303.0; 4H NMR (400 MHz, CDC13) δ = 7.48 - 7.43 (m, 2H), 7.37 - 7.27 (m, 3H), 5.40 (s, 2H), 3.55 (s, 3H). The INTERMEDIARIES a G-l to G-4 shown in Table I-VIII were prepared following the teachings of the General Reaction Schemes and the method for the preparation of INTERMEDIARY OF. 182 Table I-VIII Intermediary Structure Spectral data G-1 Br N 0 ]| ] ' w 4—bromo—5—((3—chlorobenzyl)ox¡)—1—methyl—1H—pyrazole LCMS [M+1]+ = 303.0; 1H NMR (400 MHz, CDCI3) δ = 7.43 (d, J = 1.6 Hz, 1H), 7.37 - 7.35 (m, 1H), 7.34 - 7.30 (m, 2H ), 7.28 (t, J = 1.6 Hz, 1H), 5.26 (s, 2H), 3.54 (s, 3H) G-2 Br No. || | 4—bromo—5—((4—chlorobenzyl)oxy)—1—methyl-1 H—pyrazole LCMS [M+1]+ = 303.0; 1H NMR (400 MHz, CDCh) δ = 7.43 7.35 (m, 2H), 7.35 - 7.29 (m, 3H), 5.25 (s, 2H), 3.49 (s, 3H) G-3 Br No. II I 1 4—bromo—5—((2—cyanobenzyl)oxy)—1 -methyl-1 H—pyrazole LCMS [M+1]+ = 294.1; 1H NMR (400 MHz, CDCb) δ = 7.75 (d, J = 7.6 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.55 - 7.49 (m, 1H ), 7.32 (s, 1H), 5.46 (s, 2H), 3.64 (s, 3H) G-4 Br íVa N ° || | Cl 2-(((4-bromo-1-methyl-1H-pyrazol-5-yl)oxy)methyl)—3chlorobenzonitrile LCMS [M+1]+ = 327.9; 1H NMR (400 MHz, CDCh) δ = 7.63 7.58 (m, 1H), 7.58 - 7.54 (m, 2H), 7.34 - 7.30 (m, 1H), 5, 46 (s, 2H), 3.68 (s, 3H) H-1 INTERMEDIARY H-1 INTERMEDIARY Step 1: A mixture of 2-bromo-6-fluoro-benzonitrile (600 mg, 3.00 mmol, 1.00 eq.), propan-2-ol (225 mg, 3.75 mmol, 0.29 mL, 1.25 eq.), cesium carbonate (1.47 g, 4.50 mmol, 1.50 eq.) in DMF (6 mL) was stirred at 75 °C for 1 hour. After that time, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL χ 3). The organic layers The combined 183 were washed with brine (100 mL χ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid condition) to obtain 2-bromo-6-isopropoxy-benzonitrile (540 mg, 2.25 mmol, 75% yield) in form of a white solid. LCMS [M+1]+= 241.9; 2H NMR (400 MHz, DMSO~d6) δ = 7.56 (t, J = 8.4 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.90 - 4.75 (m, 1H), 1.32 (d, J= 6.0 Hz, 6H). Step 2: A mixture of 2-bromo-6-isopropoxy-benzonitrile (500 mg, 2.08 mmol, 1.00 eq.), 4-bromo-l-methyl-pyrazole (335 mg, 2.08 mmol, 1 .00 eq.), diacetoxypalladium (4.7 mg, 0.021 mmol, 0.01 eq.), DavePhos (16 mg, 0.042 mmol, 0.02 eq.), tetrabutylammonium acetate (1.26 g, 4.16 mmol , 2.00 eq.) and 2-methylpropanoic acid (55 mg, 0.63 mmol, 0.06 mL, 0.30 eq.) in 1methyl-2-pyrrolidinone (7 mL) was degassed with nitrogen, then stirred at 100 °C for 12 hours. After that time, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL χ 3). The combined organic layers were washed with brine (100 mL χ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid condition) to obtain 2(4-bromo-2-methyl-pyrazol-3-yl)-6-isopropoxy-benzonitrile (160 mg, 0.50 mmol, 24% yield) of a colored solid 184 white. LCMS [M+l]+= 319.9; RMNLH (400 MHz, DMSO-d6) δ = 7.81 - 7.76 (m, 1H), 7.72 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7 .14 ​​(d, J = 7.2 Hz, 1H), 4.88 (td, J = 6.0, 12.0 Hz, 1H), 3.71 (s, 3H), 1.36 (d, J= 6.0 Hz, 6H). INTERMEDIARIES H-2 to H-8 set forth in Table I-IX were prepared following the teachings of the General Reaction Schemes and the method for the preparation of INTERMEDIATE H-1. Table I-IX Intermediate Structure Spectral data H-2 N=\ z+y~Br 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-6-c¡clopropoxy¡benzon¡trilo LCMS [M+1] + = 318.0; 1H NMR (400 MHz, CDCI3) δ = 7.71 - 7.64 (m, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7, 05 - 7.01 (m, 1H), 3.92 (td, J = 2.8, 5.6 Hz, 1H), 0.96 - 0.91 (m, 4H) H-3 .y m o p íVo \ 2—(4—bromo—1—methyl—1H—pyrazole—5—yl)—6—cyclobutoxybenzonitrile LCMS [M+1 ]+ = 334.0; 1H NMR (400 MHz, CDCI3) δ = 7.65 - 7.59 (m, 1H), 7.59 (s, 1H), 7.00 - 6.93 (m, 2H), 4.80 (q , J = 7.2 Hz, 1H), 3.82 - 3.79 (s, 3H), 2.61 - 2.48 (m, 2H), 2.39 - 2.27 (m, 2H), 2.03 -1.91 (m, 1H), 1.84-1.70 (m, 1H) H-4 N=\ 2—(4—bromo—1—methyl—1H—pyrazol—5—yl) —6—propoxybenzonitrile LCMS [M+1 ]+ = 320.0; 1H NMR (400 MHz, DMSO-d6) δ = 7.80 (dd, J = 8.0, 8.4 Hz, 1H), 7.73 (s, 1H), 7.43 (d, J = 8 .4 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 4.18 (dt, J = 2.0, 6.4 Hz, 2H), 1.81 (q, J = 7.6 Hz, 2H), 1.02 (t, J = 7.6 Hz, 3H) H-5 R \ by? O gold V 2—(4—bromo—1—methyl—1H—pyrazole—5—¡I)—4—chloro—6— cyclopropoxybenzonitrile LCMS [M+1] += 353.9; 1H NMR (400 MHz, CDCI3) δ = 7.57 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H) , 3.95 - 3.90 (m, 1H), 3.81 (s, 3H), 0.99- 0.94 (m, 4H) H-6 N=\ 1H NMR (400 MHz, CDCI3) δ = 7.73 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H) , 4.61 (m, 1H), 3.82 (s, 3H), 1.11 - 1.04 (m, 2H), 0.80-0.72 (m, 2H) H-7 Br £ T Λ 2—(4—bromo—1—methyl—1H—pyrazole—5—¡I)—6—cyclopropoxy—4— (trifluoromethyl)benzonitrile 1H (500 MHz, CDCI3) δ = 7.69 (d , J= 1.2 Hz, 1 H), 7.59 (s, 1 H),7.29 (d, J = 1.2 Hz, 1 H), 4.01- 3.97 (m, 1 H), 3.81 (s, 3 H), 1.01- 0.97 (m,4H) H-8 O O” K 3—(4—bromo—1—methyl—1H—pyrazol—5—yl) —1—cyclopropoxy—2— naphtonitrile 1H NMR (400 MHz, CDCI3) δ = 8.26 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.70 - 7.65 (m, 1H), 7.63 (s, 1H), 7.57 (s, 1H), 4.74 (tt, J = 2.8, 6.0 Hz, 1H), 3.86 (s, 3H), 1.13-1.07 (m,2H), 0.95- 0.87 (m,2H) INTERMEDIARY 1-1 Stage 1 Stage 1: To a solution 6-hydroxychromane-5carbonitrile (150 mg, 0.86 mmol, 1.00 eq.) and triethylamine (2.57 mmol, 0.36 mL, 3.00 eq.) in dichloromethane (2 mL) a solution of trifluoromethanesulfonic anhydride (0.86 mmol, 0.141 mL, 1.00 eq.) in dichloromethane (1 mL), dropwise, at 0 °C. The mixture was then stirred at 0 °C for 0.5 h. After that time, the mixture was diluted with ethyl acetate (50 mL), washed with brine (50 mLx3) and dried over sodium sulfate. 186 anhydrous sodium, filtered and concentrated. The residue was purified by prep TLC. (SÍO2, petroleum ether / ethyl acetate 10%) in order to obtain (5-cyanochroman-6-yl) trifluoromethanesulfonate (80 mg, 0.26 mmol, 30% yield) in the form of a colorless liquid. RMNXH (400 MHz, CDCI3) δ = 7.21 - 7.15 (m, 1H), 7.09 - 7.04 (m, 1H), 4.31 - 4.20 (m, 2H), 3, 00 (t, J = 6.4 Hz, 2H), 2.18 - 2.02 (m, 2H). Step 2: A mixture of (5-cyanochroman-6-yl)trifluoromethanesulfonate (70 mg, 0.23 mmol, 1.00 eq.), 1methyl-5-(4,4,5,5-tetramethyl-l,3 ,2-dioxaborolan-2-yl)pyrazole (71 mg, 0.34 mmol, 1.50 eq.), Pd(dtbpf)Cl2(15 mg, 0.23 mmol, 0.10 eq.), sodium bicarbonate (38 mg, 0.46 mmol, 2.00 eq.) in DMF (2 mL) was degassed with nitrogen. The mixture was then stirred at 80 °C for 1 hour, cooled to 25 °C, diluted with ethyl acetate (30 mL) and washed with brine (30 mL χ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep TLC. (SiO2, petroleum ether / ethyl acetate 30%) in order to obtain 6-(2-methylopyrazol-3-yl)chroman-5-carbonitrile (40 mg, 0.17 mmol, 73% yield) in the form of a solid white. LCMS [M+l]+= 240.0; NMR (400 MHz, CDC13) =7.57 (d, J = 1.6 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.12 - 7.06 (m, 1H), 6.40 (d, J = 2.0 Hz, 1H), 4.30 - 4.24 (m, 2H), 3.82 (s, 3H), 3.03 (t, J = 6.4 Hz , 2H), 2.17 2.09 (m, 2H) . 187 Step 3: To a solution of 6-(2-methylopyrazole-3yl)chroman-5-carbonitrile (30 mg, 0.125 mmol, 1.00 eq.) in acetonitrile (1.5 mL) was added NBS (34 mg, 0 .19 mmol, 1.50 eq.). The mixture was stirred at 25 °C for 1 hour, then concentrated. The residue was purified by prep TLC. (SÍO2, petroleum ether / ethyl acetate 30%) in order to obtain 6(4-bromo-2-methyl-pyrazol-3-yl)chroman-5-carbonitrile (25 mg, 0.79 mmol, 63% yield ) in the form of a yellow solid. LCMS [M+l]+= 320.1; RMNXH (400 MHz, CDCI3) δ = 7.57 (s, 1H), 7.18 - 7.11 (m, 2H), 4.29 (dd, J = 4.4, 6.0 Hz, 2H) , 3.79 (s, 3H) , 3.05 (dt, J = 2.0, 6.4 Hz, 2H) , 2.15 (dq, J = 4.4, 6.4 Hz, 2H) . INTERMEDIARIES 1-2 to 1-4 set forth in Table I-X were prepared following the teachings of the General Reaction Schemes and the method for the preparation of INTERMEDIATE 1-1 Table I-X Intermediate Structure Spectral data 1-2 CN N'N F 2-(4-bromo-1-methyl-1 H-pyrazol-5-yl)-5-fluoro— 1- naphthonitrile LCMS [M+1] = 329.9 ; 1H NMR (400 MHz, CDCI3) δ = 8.49 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.75 (dt, J = 5.2, 8.0 Hz, 1H), 7.66 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 7.2.9 .2 Hz, 1H), 3.86 (s, 3H) 1-3 CN 't / ri 2—(4—bromo—1—methyl—1H—pyrazole—5—yl)—7—fluoro—1—naphtonitrile LCMS [M+1] = 329.9; 1H NMR (400 MHz, CDCI3) δ = 8.21 (d, J = 8.4 Hz, 1H), 8.04 (dd, J = 5.4, 9.1 Hz, 1H), 8.00 ( dd, J = 2.4, 9.5 Hz, 1H), 7.65 (s, 1H), 7.56 - 7.47 (m, 2H), 3.86 (s, 3H) 188 1-4 F CN Ai 2—(4—bromo—1—methyl—1H—pyrazol—5—yl)—8—fluoro—1—naphtonitrile 1H NMR (400 MHz, CDCh) δ = 8.22 (dd, J = 1.6, 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.71 - 7.66 (m, 1H), 7.65 (s, 1H) , 7.55 (d, J = 8.4 Hz, 1H), 7.49 - 7.42 (m, 1H), 3.87 (s, 3H) DF INTERMEDIARY B.O.C. DF INTERMEDIARY A mixture of tero-butyl 5-bromo-3-iodo-pyrrolo[2,Ιό] pyridine-l-carboxylate (120 mg, 0.28 mmol, 1 eg), (2cyanophenyl)boronic acid (83 mg, 0.57 mmol, 2 eg), Pd(dppf)C12 (21 mg, 0.03 mmol, 0.1 eg), NaHCOa (71 mg, 0.85 mmol) in DMF (2 mL) was degassed with nitrogen, then stirred at 80 °C for 3 hr. After that time, the mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL x 3). The organic phase was concentrated, and the residue was purified by prep TLC. (SÍO2, petroleum ether / ethyl acetate 15%) in order to obtain intermediate E-l, tere-butyl 5-bromo-3-(2cyanophenyl)pyrrolo[2,3-b]pyridine-l-carboxylate (50 mg, 0. 13 mmol, 44% yield) as a white solid. LCMS [M-55]+= 342.1; NMR (400 MHz, CDC13) δ = 8.62 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 8.03 (s, 1H), 7.84 (dd, J = 1.2, 8.0 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7 .52 (dt, J= 1.2, 7.6 Hz, 1H), 1.70 (s, 9H) . 189 DG INTERMEDIARY DO INTERMEDIARY Step 1: A mixture of mg, 0.420 mmol, 1.00 eq.), 1,3,2-dioxaborolan-2-yl)pyraz eq.), Pd(dtbpf)C12 (27 mg, 0, sodium (89 mg , 0.840 mmol, 2.0( 6-bromo-7-methoxy-quinoline (100 l-methyl-5-(4,4,5,5-tetramethylod 1 (105 mg, 0.504 mmo1, 1.20)42 mmol, 0.10 eq.) carbonate I eq.) in dioxane (1.0 mL) and water (0.2 mL) was degassed with nitrogen. The mixture was then stirred at 80 °C for 2 hours, concentrated under reduced pressure, and the residue was purified by prep TLC. (SiO2, ethyl acetate) to obtain 7-methoxy-6-(2-methylopyrazol-3yl)quinoline (80 mg, 0.334 mmol, 80% yield) as a yellow solid. LCMS [M+l]+= 240.2; i-H NMR (400 MHz, CDC13) δ = 8.82 (dd, J = 1.6, 4.4 Hz, 1H), 8.04 (d, J= 8.0 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.48 (s, 1H), 7.27 (dd, J= 4.4, 8.0 Hz, 1H), 6.28 (d, J = 1.6 Hz, 1H), 3.91 (s, 3H), 3.70 (s, 3H). Step 2: A mixture of 7-methoxy-6-(2-methylopyrazol-3yl)quinoline (500 mg, 2.09 mmol, 1.00 eq.) and pyridine hydrochloride (2.41 g, 20.9 mmol, 10.0 eq.) was stirred at 160 °C 190 for 0.5 hours. After that time, the residue was purified by reverse prep HPLC. (0.1% formic acid) in order to obtain 6-(2-methylopyrazol-3-yl)quinolin-7-ol (260 mg, 1.07 mmol, 51% yield, 92% purity) in the form of a yellow solid. LCMS [M+l] + = 226.1. Step 3: To a solution of 6-(2-methylopyrazole-3yl)quinolin-7-ol (260 mg, 1.15 mmol, 1.00 eq.) and triethylamine (0.32 mL, 2.31 mmol, 2 .00 eq.) in dichloromethane (5 mL) trifluoromethanesulfonic anhydride (0.29 mL, 1.73 mmol, 1.50 eq.) was added dropwise at 0 °C. The mixture was stirred at 20°C for 1 hour, quenched with water (12 mL), and extracted with dichloromethane (15 mL χ 3). The combined organic extracts were washed with brine (12 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (SIO2, petroleum ether / ethyl acetate 10- 100%) in order to obtain [6-(2-methylopyrazole-3yl)-7-quinolyl] trifluoromethanesulfonate (0.97 g, 0.706 mmol, 61%) in the form of a yellow oil. LCMS [M+l]+= 358.1. Step 4: A mixture of [6-(2-methylopyrazole-3-i1)-7quinolyl] trifluoromethanesulfonate (970 mg, 0.668 mmol, 1.00 eq.), zinc cyanide (157 mg, 1.34 mmol, 2 .00 eq.), Pd3(dba)3(61 mg, 0.67 mmol, 0.1 eq.), DPPF (74 mg, 0.134 191 mmol, 0.20 eq.) and zinc powder (4.3 mg, 0.67 mmol, 0.10 eq.) in DMF (10 mL) was degassed with nitrogen, then stirred at 100 °C for 2 hours. After that time, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL χ 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by HPLC (0.1% formic acid condition) to obtain 6-(2-methylopyrazole-3yl)quinoline-7-carbonitrile (100 mg, 0.249 mmol, 37% yield) as a brown solid. LCMS [M+1]+= 235.2. Step 5: To a solution of 6-(2-methylopyrazole-3yl)quinoline-7-carbonitrile (90 mg, 0.384 mmol, 1.00 eq.) in acetonitrile (5 mL) was added N-bromosuccinimide (103 mg, 0.576 mmol, 1.50 eq.). The mixture was stirred at 20 °C for 0.5 h, then concentrated under reduced pressure, and the residue was purified by prep TLC. (dichloromethane / methyl alcohol 10%) in order to obtain 6-(4bromo-2-methyl-pyrazol-3-yl)quinoline-7-carbonitrile (50 mg, 0.160 mmol, 41% yield) as a solid of yellow color. LCMS [M+1]+= 315.1; 2H NMR (400 MHz, CDC13) δ = 9.14 (dd, J = 1.6, 4.4 Hz, 1H), 8.68 (s, 1H), 8.31 (d, J = 8.4 Hz , 1H), 7.96 (s, 1H), 7.69 - 7.65 (m, 1H), 7.65 (s, 1H), 3.86 (s, 3H). 192 DH INTERMEDIARY DH INTERMEDIARY Step 1: A mixture of 6-bromo-7-methoxy-quinoline (100 mg, 0.420 mmol, 1.00 eq.), zinc cyanide (98 mg, 0.840 mmol, 2.00 eq.), Pd3(dba) 3 ( 38 mg, 0.042 mmol, 0.10 eq.), DPPF (47 mg, 0.084 mmol, 0.20 eq.) and zinc powder (2.8 mg, 0.042 mmol, 0.10 eq.) in DMF (2 mL) was degassed and purged with nitrogen. The mixture was then stirred at 100 °C for 2 h, then diluted with water (2 mL) and extracted with ethyl acetate (2 mL χ 3). The combined organic extracts were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by HPLC (0.1% formic acid) to obtain 7-methoxyquinoline-6carbonitrile (56 mg, 0.304 mmol, 72% yield) as a white solid. LCMS [M+l]+= 185.2; 4H NMR (400 MHz, CDCI3) δ = 8.97 (dd, J= 1.6, 4.0 Hz, 1H), 8.17 (s, 1H), 8.15 (dd, J = 1.2, 8.4 Hz, 1H), 7.53 (s, 1H), 7.40 (dd, J = 4.0, 8.4 Hz, 1H), 4.09 (s, 3H). Step 2: To a solution of 7-methoxyquinoline-6carbonitrile (1.40 g, 7.60 mmol, 1.00 eq) in toluene (20 193 mL) aluminum trichloride (3.04 g, 22.8 mmol, 1.25 mL, 3.00 eq) was added. The mixture was stirred at 100 °C for 1 hour, and then the reaction mixture was diluted with water (3 mL), and the pH was adjusted to 4-5 with sodium hydroxide (2N, 0.1 mL). The solid formed was filtered and dried under reduced pressure to obtain 7-hydroxyquinoline-6-carbonitrile (1.20 g, crude) as a black solid, which was used in the next step directly without further purification. . LCMS [M+1]+= 171.1. Step 3: To a solution of 7-hydroxyquinoline-6carbonitrile (500 mg, 2.94 mmol, 1 eg.) and triethylamine (0.82 mL, 5.88 mmol, 2.00 eg.) in dichloromethane (10 mL) Trifluoromethanesulfonic anhydride (0.73 mL, 4.41 mmol, 1.50 eg.) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 1 hour and after that time, the reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (50 mL χ 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SIO2, petroleum ether / ethyl acetate 10-50%) to obtain (6-cyano-7-quinoli1)trifluoromethanesulfonate (250 mg, 0.570 mmol, 19% performance) in the form of a yellow oil. LCMS [M+1]+= 303, 0; RMNXH (400 MHz, CDCI3) δ = 9.15 (dd, J = 1.6, 4.0 Hz, 1H), 8.37 (s, 194 1Η), 8.32 - 8.30 (d, J = 8.4 Hz 1H), 8.23 ​​(s, 1H), 7.65 (dd, J = 4.0, 8.4 Hz, 1H) . Step 4: A mixture of (6-cyano-7-quinolyl)trifluorornetethanesulfonate (237 mg, 0.541 mmol, 1.00 eq.), 1methyl-5-(4,4,5,5-tetramethyl-l,3,2 -dioxaborolan-2yl)pyrazole (135 mg, 0.649 mmol, 1.20 eq.), sodium bicarbonate (91 mg, 1.08 mmol, 2.00 eq.) and Pd(dtbpf)C12 (35 mg, 0.054 mmol , 0.10 eg.) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and stirred at 80 °C for 1 hour. After that time, the mixture was concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10-100%) in order to obtain 7(2-methylopyrazole-3-i1) guiñoline-6-carbonitrile (120 mg, 0.498 mmol, 92% yield) as a yellow solid. LCMS [M+l]+= 235.2. Step 5: A mixture of 7-(2-methylopyrazole-3yl)quinoline-6-carbonitrile (120 mg, 0.512 mmol, 1.00 eq.) and N-bromosuccinimide (164 mg, 0.922 mmol, 1.80 eq. . ) in acetonitrile (4 mL) was degassed with nitrogen and stirred at 20 °C for 2 hours. After that time, the mixture was concentrated, and the residue was purified by prep TLC. (SiO2, dichloromethane / methyl alcohol 10%) in order to obtain 7-(4-bromo-2-methyl-pyrazol-3-yl)quinoline-6carbonitrile (121 mg, 0.385 mmol, 75% yield) as a yellow solid. LCMS [M+l]+= 314.9; 195 3H NMR (400 MHz, CDC13) δ = 9.15 (dd, J = 2.0, 4.4 Hz, 1H), 8.43 (s, 1H), 8.33 (dd, J = 0.8, 8.4 Hz, 1H), 8.23 ​​(s, 1H), 7.68 - 7, 63 (m, 2H), 3.87 (s, 3H). DI INTERMEDIARY DI INTERMEDIARY To a solution of N-(4-bromo-2-methyl-pyrazol-3yl)benzamide (500 mg, 1.78 mmol, 1.00 eq.) in DMF (5 mL) at 0 °C was added sodium hydride (143 mg, 3.57 mmol, 60.0% purity, 2.00 eg.), and the mixture was stirred at 0 °C for 30 minutes. After that time, iodomethane (0.133 mL, 2.14 mmol, 1.20 eg) in DMF (1 mL) was added, and the mixture was stirred at 0°C for another 10 minutes. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (40 mL χ 3), and the combined organic extracts were washed with brine (70 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SIO2, petroleum ether / ethyl acetate 0-30%) to obtain N-(4bromo-2-methyl-pyrazol-3-yl)-¿V-methyl- benzamide (400 mg, 1.36 mmol, 76% yield) as a white solid. 3H NMR (400 MHz, DMSO-d6) δ = 7.44 (s, 1H), 7.36 - 7.41 (m, 1H), 7.26 - 7.33 (m, 4H), 3.72 ( s, 3H), 3.23 (s, 3H). 196 DJ INTERMEDIARY DJ INTERMEDIARY Step 1: To a stirred solution of methyl 7-bromo-4-oxo3H-phthalazine-l-carboxylate (1.00 g, 3.53 mmol, 1.00 eq.), sodium borodeuteride (347 mg, 9.18 mmol, 2.60 eq.) in methanol-d4 (30 mL) at 0 °C, calcium chloride (470 mg, 4.24 mmol, 1.20 eq.) was added. The mixture was then stirred at 0 °C for 3 hours, then at 20 °C for 1 hour. After that time, the reaction mixture was concentrated. The residue was diluted with water (30 mL), the pH was adjusted to 5 with hydrochloric acid (1 N, 5 mL), the mixture was filtered, and the filter cake was washed with water (5 mL χ 3), then Triturated with ethyl alcohol (20 mL) to obtain 6-bromo-4-((hydroxy-d)methyl-d2)phthalazin-1(2H)-one (463 mg, 1.61 mmol, 46% yield) in the form of a white solid. LCMS [M+l]+= 259.0; 4H NMR (400 MHz, DMSOd6) δ = 12.66 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.02 (dd, J= 2.0, 8.4 Hz, 1H), 5.53 (s, 1H). 197 Step 2: A mixture of 6-bromo-4-((hydroxy-d)methylodi)phthalazin-1(2H)-one (463 mg, 1.61 mmol, 1.00 eq.) and thionyl chloride (10 mL ) was stirred at 30 °C for 12 hours. After that time, the mixture was concentrated, and the residue was dissolved in dichloromethane and concentrated 3 times (2 mL χ 3) in order to obtain 6-bromo-4-(chloromethyl-d2)phthalazin-1(2H)- one (450 mg, 1.43 mmol, 88% yield) as a yellow solid. LCMS [M+1]+= 277.0. Step 3: To a solution of 6-bromo-4-(chloromethylod2)phthalazin-1 (2H)-one (450 mg, 1.63 mmol, 1.00 eq.) in DMF (3 mL) was added (1, 3-dioxoisoindolin-2-yl)potassium (454 mg, 2.45 mmol, 1.50 eq.), and the mixture was stirred at 90 °C for 2 hours. After that time, the cooled reaction mixture was filtered, and the collected solid was triturated with ethyl alcohol (5 mL), filtered and dried to obtain 2-((7-bromo-4-oxo3,4- dihydrophthalazin-l-yl)methyl-d2)isoindo1ine-1,3-dione (30 0 mg, crude) as a white solid. LCMS [M+1]+= 386, 0; NMR (400 MHz, DMSQ-d6) δ = 12.60 (s, 1H), 8.43 (d, J= 1.6 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H ), 8.09 - 8.05 (m, 1H), 7.97 - 7.92 (m, 2H), 7.92 - 7.87 (m, 2H). Step 4: A mixture of 2-((7-bromo-4-oxo-3,4dihydrophthalazin-l-yl)methyl-d2)isoindoline-1,3-dione (200 mg, crude), 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l, 3,2dioxaborolan-2-yl)-1,3,2-dioxaborolane (197 mg, 0.78 mmol), Pd(dppf)C12 (38 mg, 0.052 mmol) and potassium acetate (152 mg, 198 1.55 mmol) in dioxane (10 mL) was degassed with nitrogen. The mixture was stirred at 100 °C for 2 hours, and after that time, the mixture was concentrated, and the residue was triturated with methyl alcohol (3 mL), filtered and dried to obtain 2((4- oxo-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4dihydrophthalazin-l-yl)methyl-d2)isoindoline-1,3-dione (200 mg , 0.303 mmol, 59% yield in 2 steps) as a white solid. LCMS [M+1]+= 352.1; NMR A (400 MHz, DMSO-de) δ = 12.70 - 12.28 (m, 1H), 8.35 - 8.25 (m, 2H), 8.13 (br s, 1H), 7, 93 (br d, J = 17.0 Hz, 4H), 1.34 (br s, 12H). DK INTERMEDIARY DK INTERMEDIARY Step 1: To a solution of K2CO3 (44.7 g, 323 mmol) in water (500 mL) was added 1-(5-bromo-3-chloro-2methylophenyl)ethan-l-one (40.0 g, 162 mmol) and warmed to 50 °C. KMnOq was then added carefully, in 10 batches (165 g, 1.04 mol), and the temperature was kept below 80 °C to avoid a runaway exothermic peak. After completion of the addition, the mixture was stirred at 60 °C for 199 hrs. After that time, the mixture was cooled to 0 °C and quenched by dropwise addition of saturated sodium sulfite solution (200 mL), while maintaining the temperature below 10 °C. The mixture was then stirred for 30 min at 0 °C. After that time, the transparent colorless mixture was filtered with celatom, the filter cake was washed with water (100 mL), and the aqueous phase was washed with MTBE (200 mL). The aqueous phase was then acidified to pH 2 by the addition of 3M HC1 followed by extraction with ethyl acetate (300 mL χ 3). The combined organic phases were washed with brine (300 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to obtain 4-bromo-2(carboxycarbonyl)-6-chlorobenzoic acid compound (20.0 g, 65.0 mmol, 36% yield) as a white solid. LCMS [M-l] - = 306.8; bHNMR (400 MHz, DMSO-d6) δ 12.7 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H). Step 2: To a solution of 4-bromo-2(carboxycarbonyl)-6-chlorobenzoic acid compound (20.0 g, 65.0 mmol) in EtOH (200 mL) was added NH2NH2*H2O (4.30 g, 85 .9 mmol) in one serving, under N2. The mixture was then stirred at 70 °C for 1 hr. After that time, the cooled reaction mixture was filtered, washed, and the solid was dried under vacuum to obtain 7bromo-5-chloro-4-oxo-3,4-dihydrophthalazine-l-carboxylic acid (14, 0 g, 46.1 mmol, 71% yield) as a white solid. LCMS [M+l]+= 305.2; NMR (400 MHz, DMSO-d6) δ 200 7.77 (d, J =2.0 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H). Step 3: To a mixture of 7-bromo-5-chloro-4-oxo3,4-dihydrophthalazine-l-carboxylic acid (14.0 g, 46.1 mmol) in MeOH (250 mL) was added conc. H2SO4. (9.23 g, 92.2 mmol) in one serving under nitrogen. The mixture was then heated to 70 °C for 16 hrs, then allowed to cool to room temperature, filtered and dried to provide methyl 7-bromo5-chloro-4-oxo-3,4-dihydrophthalazine-l-carboxylate ( 7.50 g, 23.6 mmol, 51% yield) as a white solid. RMNXH (400 MHz, DMSO-d6) δ 13.2 (s, 1H), 6.68 (d, J =1.6 Hz, 1H), 8.18 (d, J =1.6 Hz, 1H) . Step 4: To a solution of methyl 7-bromo-5-chloro-4-oxo3,4-dihydrophthalazine-l-carboxylate (7.50 g, 23.6 mmol) in EtOH (70 mL) was added NaBH4(2, 32 g, 61.4 mmol) at 0 °C, followed by the careful and slow addition of CaC12 (3.15 g, 28.3 mmol) at 0 °C for 2 hours. The mixture was then allowed to warm to 15 °C and stirred for another 2 hours. After that time, the reaction was poured onto sat. NH4C1. (100 mL), and the solid was filtered, washed with water (10 mL) then with EtOH (10 mL) and dried to obtain 6-bromo-8-chloro-4(hydroxymethyl)phthalazin-1(2H). )-one (4.00 g, 13.8 mmol, 54% yield) as a white solid. LCMS [M+1]+= 291.0; 3H NMR (400 MHz, DMSO-d6) δ 12.6 (s, 1H), 8.24 (d, J =1.6 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H) , 5.61- 5.58 (t, J =2 Hz, 1H) , 4.65 -4,, 63 (d, J =8 Hz, 2H) . 201 Step 5: A mixture of 6-bromo-8-chloro-4(hydroxymethyl)phthalazin-1(2H)-one (4.00 g, 13.8 mmol) and SOCI2 (36.4 g, 306 mmol) was stirred. at 65 °C for 1 hr. After that time, the mixture was concentrated, and the crude residue was triturated with MTBE (30 mL) at 25°C for 30 min. The solid was then filtered and dried to obtain 6-bromo-8-chloro-4(chloromethyl)phthalazin-1(2H)-one (3.50 g, 11.4 mmol, 82% yield) as of a light yellow solid. LCMS [M+1]+= 309.1; NMR (400 MHz, DMSO-dg) δ 12.9 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 5.06 (s, 1H). Step 6: To a mixture of potassium phthalimide (2.53 g, 13.6 mmol) in DMF (5 mL) was added a solution of 6-bromo-8chloro-4-(chloromethyl)phthalazin-1(2H)- one (3.50 g, 11.3 mmol) in DMF (35 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 hrs. After that time, the mixture was poured into ice water (200 mL), stirred for 30 min, filtered, then the solid was dried and then triturated with MeOH (30 mL) at 15°C for 30 min. The solid was filtered and dried to obtain 2-((7-bromo-5chloro-4-oxo-3,4-dihydrophthalazin-l-yl)methyl)isoindoline-1,3dione (1.30 g, 3, 10 mmol, 27% yield) as a light yellow solid. LCMS [M+1]+= 420.0; F NMR (400 MHz, DMSO-d6) δ 12.5 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7.97 - 7.94 (m, 2H) , 7, 92 - 7.89 (m, 2H) , 5.14 (s, 2H) . Step 7: A mixture of 2-((7-bromo-5-chloro-4-oxo-3,4dihydrophthalazin-l-yl)methyl)isoindoline-1,3-dione (1.30 g, 202 3.10 mmol), bis(pinacolato)diboron (1.20 g, .66 mmol) and potassium acetate (762 mg, 7.76 mmol) in dioxane (20 mL) were degassed with nitrogen. Pd(dppf)CI2 (114 mg, 0.16 mmol) was then added, and the mixture was stirred at 70 °C for 2.5 hrs. After that time, the mixture was cooled to room temperature, filtered, and the concentrated residue was triturated with MeOH (30.0 mL) at 15 °C for 30 min. The solid was then filtered, washed with MTB and dried to obtain 2-((5-chloro-4-oxo-7-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2- yl)-3,4-dihydrophthalazin-1yl)methyl)isoindoline-1,3-dione (910 mg, 1.95 mmol, 63% yield) as a light yellow solid. LCMS [M+l]+= 383.9; NMR (400 MHz, DMSO-d6) δ 12.5 (s, 1H), 8.20 (s, 1H), 7.79 (s, 1H), 7.96 -7.94 (m, 2H), 7.91 - 7.89 (m, 2H), 5.17 (s, 2H), 1.35 (s, 12H). DL INTERMEDIARY DL INTERMEDIARY Following the same procedure as for the synthesis of DK intermediate, 2-((5-fluoro-4-oxo-7-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1yl)methyl was prepared )isoindoline-1,3-dione, DL Intermediate, as a white solid (200 mg, 0.42 mmol, 2.1% yield) in 7 steps, starting from 1-(5-bromo- 3-fluoro-2 203 methylphenyl)ethan-l-one. LCMS [M+l] = 368.1; 4H NMR (400 MHz, DMSO-d6) δ = 12.,51 (s, 1H), 8.09 (s, 1H), 7.96 - 7.89 (m, 4H), 7.40 (d, 1H), 5.17 (s, 2H), 1.36 (s, 12H). DM INTERMEDIARY DM INTERMEDIARY Step 1: To a solution of 5-bromo-2-methyl-3pivalamidobenzoic acid (120 g, 382 mmol) in DMF (1.20 L) were added DIEA (98.7 g, 764 mmol, 133 mL), HATU ( 189 g, 497 mmol), followed by N,O-dimethylhydroxylamine (55.9 g, 573 mmol, HC1) at 20°C. The resulting solution was stirred at 20°C for 2 hrs, and after that time, the reaction mixture was poured into ice water (5.0 L). The mixture was extracted with ethyl acetate (2.0 L χ 3), and the combined organic phase was washed with brine (1.0 L), dried with anhydrous Na2SÜ4, filtered, and the filtrate was concentrated under reduced pressure to dry, order to achieve 5-bromo-N-methoxy-N,2-dimethyl-3-pivalamidobenzamide (135 g, 204 378 mmol, 99% yield) as a brown oil.2Η: 400 MHz, DMSO-dd <5 9.06 (s, 1H), 7.45 (d, J = 2.0 Hz, 1H ), 7.35 (d, J = 2.0 Hz, 1H), 3.43 (s, 3H), 3.27 (s, 3H), 2.01 (s, 3H), 1.23 (s , 9H). Step 2: To a solution of 5-bromo-N-methoxy-N,2dimethyl-3-pivalamidobenzamide (135 g, 378 mmol) in THF (1.5 L) MeMgBr (3.0 M, 315 mL) was added to 0°C. The resulting solution was allowed to warm to 20°C and stirred for 12 hrs. After that time, an additional aliquot of MeMgBr (3 M, 63.0 mL) was added, and the mixture was stirred for another 4 hr. The mixture was then diluted with NH4C1 (1.5 L), extracted with ethyl acetate (1.0 L * 3), and the combined organic phases were washed with brine (1.0 L), dried with anhydrous Na2SO4 and they leaked. The filtrate was concentrated to give N-(3acetyl-5-bromo-2-methylophenyl)pivalamide (115 g, 368 mmol, 98% yield) as a yellow solid.2Η 400 MHz, DMSO-dd δ 9.10 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 2.55 (s, 3H) , 2.10 (s, 3H) , 1.23 (s, 9H) . Step 3: To a solution of N-(3-acetyl-5-bromo-2methylophenyl)pivalamide (57.5 g, 184 mmol) in H2O (600 mL) were added K2CO3 (50.9 g, 368 mmol) and KMnCy (204 g, 1.29 mol) at 50 °C. The resulting solution was stirred at 50°C for 17 hrs. After that time, the reaction mixture was quenched with saturated sodium thiosulfate solution and filtered through 205 diatomite. The pH was adjusted to 2 with 2 N HC1, and the mixture was extracted with ethyl acetate:THF, 10:1 (1.00 L χ 3), washed with brine (500 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure to obtain 4bromo-2-(carboxycarbonyl)-6-pivalamidobenzoic acid (58.0 g, crude) as a light yellow oil.2H 400 MHz, DMSO-dd δ 9.87 (s, 1H), 8.63 (d, 0= 2.0 Hz, 1H), 7.54 (d, J= 2.0 Hz, 1H), 1.27 (s, 9H) . Step 4: To a solution of 4-bromo-2(carboxycarbonyl)-6-pivalamidobenzoic acid (110 g, 296 mmol) in EtOH (1.10 L) was added NH2NH2.H2O (18.1 g, 355 mmol, 17 .6 mL), and the solution was stirred at 75 °C for 3 hrs. After that time, the reaction mixture was filtered, and the filter cake was dried in order to obtain 7-bromo-4-oxo-5-pivalamido-3,4dihydrophthalazine-l-carboxylic acid (30.0 g, 81. 5 mmol, 28% yield) as a white solid. 400 MHz, DMSO-d6 δ 13.0 (s, 1H), 9.06 (d, J= 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 1, 27 (s, 9H). Step 5: To a solution of 7-bromo-4-oxo-5pivalamido-3,4-dihydrophthalazine-l-carboxylic acid (30.0 g, 81.5 mmol) in MeOH (400 mL) was added a solution of HCl / MeOH (4 M, 400 mL). The reaction mixture was warmed to 70 °C and stirred for 36 hrs to form a yellow solid. The reaction was concentrated, diluted with water (100 mL), and the pH was adjusted to pH 8 with 1 N NaOH, stirred for 206 0.5 hr, then filtered. The filter cake was washed with water (50 mL), then with EtOH (100 mL), and dried to obtain the crude product methyl 5-amino-7-bromo-4-oxo-3,4dihydrophthalazine-l- carboxylate (20.0 g, crude) as a yellow solid. Step 6: To a solution of methyl 5-amino-7-bromo-4-oxo3,4-dihydrophthalazine-l-carboxylate (15.0 g, 50.3 mmol) in MeCN (500 mL) was added TosOH (34, 6 g, 200 mmol) at 0 °C under N2. To this solution was added a solution of NaNO2 (8.68 g, 125 mmol) in H2O (20 mL), and the mixture was stirred at 0 °C for 10 minutes; then a solution of KI (25.0 g, 150 mmol) in H2O (20.0 mL) was added dropwise. The mixture was stirred at 20 °C for 1 hr, and the reaction was quenched by Na2S2O3. The mixture was concentrated to remove MeCN, then diluted with water (200 mL) and filtered. The filter cake was washed with water (50 mL), then with EtOH (100 mL), and dried, in order to obtain methyl 7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazine-l -carboxylate (15.0 g, crude) as a yellow solid. Step 7: In 8 batches, to a solution of methyl 7-bromo-5iodo-4-oxo-3,4-dihydrophthalazine-l-carboxylate (4.00 g, 9.78 mmol) in EtOH (60 mL) was added NaBH4 (740 mg, 19.6 mmol) in batches, at 0 °C, followed by the addition of CaCl2 (1.30 g, 11.7 mmol) in batches, at 0 °C. The reaction was stirred at 20"C for 1 hr. The 8 batches were then combined and quenched with NH4C1 (200 mL). The mixture was concentrated to remove EtOH, diluted 207 with water (200 mL) and then filtered, and the filter cake was washed with water (100 mL) and dried. The residue was triturated in MeOH (200 mL) for 10 hrs, filtered and dried to obtain 6bromo-4-(hydroxymethyl)-8-iodophthalazin-l(2H)-one (19.0 g, 38.0 g). 9 mmol, 50% yield) as a yellow solid. 8.29 (d, J = 1.88 Hz, 1H), 5.62 - 5.54 (m, 1H), 4.62 (d, J = 5.70 Hz, 2H). Step 8: in three batches, to a mixture of 6-bromo-4(hydroxymethyl)-8-iodophthalazin-1(2H)-one (2.00 g, 5.25 mmol) in dioxane (40 mL) solution of 2,4,6-trimethyl1,3,5,2,4,6-trioxatriborinane in THF (3.67 mL, 13.1 mmol, 50% purity), CS2CO3 (4.28 g, 13.1 mmol) and Pd(dppf)C12 (384 mg, 524 pmol). The reaction was stirred at 100 °C for 10 hrs. The three batches were combined and filtered through diatomite. The filtrate was concentrated, and the residue was purified by prep HPLC. (Phenomenex luna C18 250 x 150 mm x 15 pm; mobile phase: [water (0.1% TFA) - MeOH]; B%: 30% - 60%, 20 min) in order to obtain the 6-bromo-4 -(hydroxymethyl)-8-methylophthalazinl(2H)-one (1.1 g, 4.06 mmol, 26% yield) as a light yellow solid. LCMS [M+l]+= 271;1H 400 MHz, DMSO-dd δ 12.44 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 4.63 (s , 3H) , 2, 81 (s, 3H) . Step 9: A solution of 6-bromo-4-(hydroxymethyl)-8methylophthalazin-1(2H)-one (1.20 g, 4.46 mmol) in SOCl2 (13 mL) 208 was stirred at 70°C for 2 hr. After that time, the mixture was concentrated, and the residue was triturated in petroleum ether for 0.5 hr, filtered and dried to obtain 6-bromo4-(chloromethyl)-8-methylophthalazin-1(2H). -one (1.20 g, 4.17 mmol, 94% yield) as a light yellow solid. LCMS [M+l] + = 289;4H 400 MHz, DMSO-dh δ 12.70 (s, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 5.03 (s , 2H), 2.81 (s, 3H). Step 10: To a mixture of 6-bromo-4-(chloromethyl)-8methylophthalazin-1(2H)-one (1.10 g, 3.83 mmol) in DMF (30 mL) was added isoindoline-1,3- potassium dione (850 mg, 4.59 mmol) in one serving at 0 °C under N3. The mixture was stirred at 25 °C for 1 hr, and after that time, the mixture was slowly poured into ice water (100 mL), and the white solid formed was filtered, washed with water and dried in order to obtain the crude product 2-((7-bromo-5-methyl-4-oxo-3,4-dihydrophthalazin-1yl)methyl)isoindoline-1,3-dione (1.10 g, 2.32 mmol, 61% performance) in the form of a white solid. LCMS [M+l]+= 400;4H 400 MHz, DMSO-dh δ 12.37 (s, 1H), 8.20 (d, J = 1.32 Hz, 1H), 7. 97 - 7.87 (m, 5H), 5.12 (s, 2H), 2.81 (s, 3H) . Step 11: 2-((7-bromo-5-methyl-4-oxo-3,4dihydrophthalazin-l-yl)methyl)isoindoline-1,3-dione (1.10 g, 2.76 mmol), Pd (dppf)C12 (202 mg, 276 pmol), KOAc (542 mg, 5.52 mmol) and bis(pinacolato)diboron (1.05 g, 4.14 mmol) in dioxane (20 mL) were then degassed with nitrogen heated at 80 °C for 10 hours. After that time, the reaction 209 filtered through diatomite, the cake was washed with MeOH (10 mL), and the filtrate was concentrated. The residue was then triturated with MeOH (10 mL) for 1 hr, filtered, and the filter cake was washed with MeOH and dried to obtain 2-((5-methyl-4-oxo-7(4.4 ,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4dihydrophthalazin-l-yl)methyl)isoindoline-1,3-dione, DM Intermediate (510 mg, 1.15 mmol, 42 % yield) in the form of a gray solid. LCMS: Boronic acid [M+1]+= 364; boronate ester [M+1]+= 446).ΧΗ 400 MHz, DMSO-dh δ 12.27 (s, 1H), 8.06 (s, 1H), 7.92 - 7.82 (m, 5H) , 5.11 (s, 2H), 2.80 (s, 3H), 1.31 (s, 12H) . INTERMEDIARY DN INTERMEDIARY DN Step 1: To a solution of 5-(chloromethyl)-1-methylopyrazole (584 mg, 3.50 mmol, 1.00 eq.) and 2-phenylacetonitrile (819 mg, 6.99 mmol, 2.00 eq.) in DMF (10 mL) potassium carbonate (966 mg, 6.99 mmol, 2.00 eq.) was added. The mixture was stirred at 120 °C for 4 hours, then concentrated under reduced pressure. The residue was purified by column chromatography (SIO2, petroleum ether / ethyl acetate 10-50%) to obtain 3-(2-methylopyrazol-3-yl)-2-phenyl-propanenitrile (300 mg, 1.42 mmol, 41% yield) as a brown oil. 210 LCMS [M+1]+= 212.0; Y NMR (400 MHz, CDC13) δ =7.35 7.22 (m, 4H), 7.18 - 7.10 (m, 2H), 6.11 (d, J= 1.6 Hz, 1H) , 3.98 (t, J = 6.8 Hz, 1H), 3.41 (s, 3H), 3.26 3.18 (m, 1H), 3.16 - 3.05 (m, 1H) . Step 2: To a mixture of 3-(2-methi 1opyrazo1-3 - i 1) 2-pheni1o-propanonitri 1o (160 mg, 0.76 mmol, 1.00 eq.) in dry acetonitrile (2.0 mL) NBS (121 mg, 0.68 mmol, 0.90 eg.) was added in various portions. The mixture was stirred at 15 °C for 2 hours. After that time, ethyl acetate (40 mL) and water (40 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL χ 2), and the combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep HPLC. (Phenomenex Gemini-NX C18 75 * 30 mm x 3 pm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30% - 60%, 8 min) in order to obtain 3-(4-bromo -2-methylopyrazo1-3-i 1)-2-pheni1o-propanonitri 1 or (90.0 mg, 0.31 mmol, 41% yield) as a yellow oil. LCMS [M+1]+= 289.8; NMR (400 MHz, CDC13) δ = 7.37 (s, 1H), 7.35 7.26 (m, 3H), 7.20 - 7.14 (m, 2H), 4.04 (t, J = 7.6 Hz, 1H), 3.40 (s, 3H), 3.30 (dd, J = 7.2, 14.8 Hz, 1H), 3.07 (dd, J = 8.0, 14.8 Hz, 1H). 211 DO INTERMEDIARY eq.) was added dropwise over 5 minutes to a solution of 2,2,6,6-tetramethylpiperidine (2.40 mmol, 407 pL, 1.50 eq.) in THF (3 mL), kept at 0 °C. After 30 minutes, the reaction mixture was cooled to -78°C, and a solution of 5chloronaphthalene-l-carbonitrile (300 mg, 1.60 mmol, 1.00 eg) in THF (1.00 mL) was added. added drip for 10 minutes. The resulting dark solution was kept at −78 °C for 2 hours. A solution of iodine (609 mg, 2.40 mmol, 1.50 eq.) in THF (3 mL) was then added dropwise over 10 minutes. The reaction mixture was held at −78°C for 2 hours, then allowed to warm to 20°C over 3 hours. The reaction mixture was quenched with water (1 mL), and the resulting mixture was diluted with ethyl acetate (150 mL). The mixture was washed successively with aq sodium thiosulfate. sat. (3 * 150 mL), 1 M HCl (2 * 150 mL), and brine (1 χ 150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SIO2, petroleum ether: 5% ethyl acetate) to obtain 5-chloro-2-iodo-l-naphtonitrile (180 mg, 574 pmol, 36% yield) in 212 form of a yellow solid. GCMS [M+H]+= 312.9; RMNXH (400 MHz, CDC13) δ = 8.55 (d, J= 8.8 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.73 - 7.69 (m, 1H) , 7, 67 - 7.64 (m, 1H) , 7.63 - 7.58 (m, 1H) . Step 2: A mixture of l-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-IH-pyrazole (104 mg, 498 pmol, 1.30 eq.) , 5-chloro-2-iodo-l-naphtonitrile (120 mg, 383 pmol, 1.00 eq.), Pd(dtbpf)C12 (25 mg, 38 pmol, 0.10 eq.) and sodium carbonate (81 mg, 766 pmol, 2.00 eg) in dioxane (3 mL) and water (0.6 mL) was degassed with nitrogen, then stirred at 80 °C for 1 hour. The mixture was then concentrated, and the residue was purified by prep TLC. (SiO2, petroleum ether:ethyl acetate 30%) in order to obtain 5-chloro-2-(2-methylopyrazole-3yl)naphthalene-l-carbonitrile (90 mg, 336 pmol, 87% yield) in the form of a yellow solid. LCMS [M+l]+= 268.2; Η2NMR (400 MHz, CDCI3) δ = 8.62 (d, J = 8.8 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.81 - 7.77 (m , 1H), 7.73 7.67 (m, 1H) , 7.67 - 7.63 (m, 2H) , 6.61 (d, J = 2.0 Hz, 1H) , 3.91 (s , 3H). Step 3: To a solution of 5-chloro-2-(2-methylopyrazol-3yl)naphthalene-l-carbonitrile (170 mg, 635 pmol, 1.00 eq.) in acetonitrile (3 mL) was added NBS (124 mg , 699 pmol, 1.10 eg. ) . The mixture was stirred at 35°C for 2 hours, then concentrated to obtain a residue. The residue was purified by prep TLC. (SiO2, petroleum ether / ethyl acetate 30%) in order 213 to obtain 2-(4-bromo-l-methyl-lH-pyrazol-5-yl)-5-chloro-lnaphtonitrile, Intermediate DO (130 mg, 375 pmol, 59% yield) as a colored solid white. LCMS [M+l]+= 347.8; 4H NMR (400 MHz, CDC13) δ = 8.67 (dd, J = 0.8, 8.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.83 (dd , J= 1.2, 7.6 Hz, 1H) , 7.75 - 7.69 (m, 1H) , 7.66 (s, 1H) , 7.64 (d, J= 8.8 Hz, 1H), 3.86 (s, 3H). DP INTERMEDIARY DP INTERMEDIARY Step 1: To a solution of 2,2,6,6-tetramethylopiperidine (553 mg, 3.92 mmol, 0.67 mL, 1.20 eq.) in THE (7 mL) was added n-butyl lithium (2 .50 M, 1.57 mL, 1.20 eg.) at -10 °C under a nitrogen atmosphere. The mixture was stirred for 10 minutes, cooled to -65°C, and triisopropyl borate (859 mg, 4.57 mmol, 1.05 mL, 1.40 eg.) was added. After 5 minutes, a solution of 1-naphtonitrile (500 mg, 3.26 mmol, 1.00 eq.) in THE (3 mL) was added dropwise, and the reaction was then allowed to warm slowly to 25 °C, and then stirred for 16 hours. After that time, acetic acid (392 mg, 6.53 mmol, 0.37 mL, 2.00 eg.) was added, followed by the addition of propane1,3-diol (994 mg, 13.1 mmol, 0 .95 mL, 4.00 eg.), then the mixture was stirred at 25 °C for 1 hour. The reaction then 214 quenched by adding sat. ammonium chloride solution. (20 mL), and then diluted with water (10 mL) and extracted with ethyl acetate (30 mL χ 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 2-(1,3,2dioxaborinan-2-yl)-1-naphthonitrile (600 mg, 2.53 mmol, 78% yield) as a light yellow solid. Η4NMR (400 MHz, CDC13) δ = 8.40 (d, J = 8.0 Hz, 1H), 8.04 8.00 (m, 1H), 7.90 (d, J= 8.0 Hz, 2H), 7.71 - 7.60 (m, 2H), 4.30 (t, J = 5.6 Hz, 4H), 2.17 (quin, J = 5.6 Hz, 2H). Step 2: To a solution of 5-bromoisothiazole (150 mg, 0.915 mmol, 1.00 eq.) and 2-(1,3,2-dioxaborinan-2-yl)-1naphthonitrile (217 mg, 0.915 mmol, 1, 00 eq.) in toluene (8 mL) and ethyl alcohol (0.8 mL), potassium carbonate was added aq. (2.00 M, 0.915 mL, 2.00 eg.) and Pd(PPh3)4(106 mg, 0.091 mmol, 0.10 eg.) at 20 °C under a nitrogen atmosphere. The mixture was stirred at 100 °C for 16 hours, concentrated to dryness, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 10-15%) to obtain 2-( isothiazol-5-yl)-1-naphtonitrile (200 mg, 0.85 mmol, 93% yield) as a light yellow solid. Η2NMR (400 MHz, CDC13) δ = 8.62 (d, J = 1.6 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.15 (d, J= 8 .8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.79 (dt, J = 1.2 , 7.6 Hz, 1H), 7.74 - 7.66 (m, 2H). 215 Step 3: To a solution of 2-(isothiazol-5-yl)-1naphthonitrile (100 mg, 0.42 mmol, 1.00 eq.) in acetonitrile (2 mL) N-bromo-succinimide (753 mg, 4.23 mmol, 10.0 eq.) at 20 °C, and the mixture was stirred at 100 °C for 48 hours in a sealed tube. The mixture was then concentrated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL) and washed with water (30 mL χ 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then purified by prep HPLC. (Waters -yl)-1-naphtonitrile (50 mg, 0.16 mmol, 38% yield) as a white solid. RMNXH (400 MHz, CDCI3) δ = 8.51 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.81 (dt, J = 1.2, 7.6 Hz, 1H), 7.77 - 7. 69 (m, 1H), 7 .59 (d, J= 8.4 Hz, 1H). DQ INTERMEDIARY DQ INTERMEDIARY Step 1: To a solution of LDA (2.00 M, 0.587 mL, 1.10 eq.) in THE (10 mL), a solution of 4chloro-2-naphtonitrile (200 mg, 1.07 mmol, 1.00 eq) in THE (5 mL) at -78 °C. The mixture was then stirred at −78 °C for 1 hour. 216 After that time, a solution of iodine (285 mg, 1.12 mmol, 1.05 eg.) in THF (2 mL) was added dropwise at -78 °C. The mixture was then allowed to warm to room temperature and stirred at 20 °C for 2 hours. After that time, the reaction mixture was quenched by adding saturated ammonium chloride solution (15 mL) and sat sodium hyposulfite solution. (10 mL χ 3). The mixture was then extracted with ethyl acetate (20 mL χ 2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by flash chromatography (SiOz, ether petroleum: ethyl acetate 0-5%) in order to obtain 4-chloro-3-iodo-2-naphtonitrile (200 mg, 0.606 mmol, 30% yield) in the form of a white solid. RMNXH (400 MHz, CDCI3) δ = 8.35 (d, J= 8.4 Hz, 1H), 8.13 (s, 1H), 7.93 7.87 (m, 1H), 7.77 ( ddd, J= 1.2, 7.2, 8.4 Hz, 1H), 7.72 - 7.65 (m, 1H) . Step 2: To a solution of 4-chloro-3-iodo-2-naphtonitrile (320 mg, 1.02 mmol, 1.00 eq.) and l-methyl-5-(4,4,5,5tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole (319 mg, 1.53 mmol, 1.50 eg.) in dioxane (30 mL) and water (6 mL) potassium carbonate (283 mg, 2, 04 mmol, 2.00 eg) and Pd(dppf)CI2 (75 mg, 0.102 mmol, 0.10 eg) at 25 °C. The mixture was degassed with nitrogen, then stirred at 100 °C for 16 hours. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (30 mL χ 4). The combined organic layers 217 were washed with brine (25 mL χ 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by flash chromatography (S1O2, petroleum ether: ethyl acetate 0-5% ) in order to obtain 4-chloro3-(l-methyl-lH-pyrazol-5-yl)-2-naphtonitrile (50 mg, 0.178 mmol, 30% yield) as a yellow solid. LCMS [M+l]+= 268.0 / 270.0; 4H NMR (400 MHz, CDC13) δ = 8.48 - 8.39 (m, 1H), 8.34 - 8.27 (m, 1H), 8.04 - 7.95 (m, 1H), 7, 90 - 7.81 (m, 1H) , 7.78 (br t, J = 7.6 Hz, 1H) , 7.70 7.63 (m, 1H) , 6.52 - 6.43 (m, 1H), 3.80 - 3.72 (m, 3H). Step 3: To a solution of 4-chloro-3-(1-methyl-1Hpyrazol-5-yl)-2-naphtonitrile (100 mg, 0.374 mmol, 1.00 eq.) in acetonitrile (10 mL) was added N -iodosuccinimide (504 mg, 2.24 mmol, 6.00 eq.) at 25 °C, and the mixture was stirred at 80 °C for 16 hours. After that time, the reaction mixture was quenched with water (2 mL) at 0 °C, and then extracted with ethyl acetate (3 mL χ 3). The combined organic layers were washed with brine (5 mL χ 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue formed was purified by prep TLC. (SIO2, petroleum ether: ethyl acetate 30%) in order to obtain 4-chloro-3-(4-iodo-l-methyl-lH-pyrazol-5yl)-2-naphthonitrile (50 mg, 0.121 mmol, 32% of performance) in the form of a white solid. LCMS [M+l]+= 393.9 / 395.9; 4H NMR (400 MHz, CDCI3) δ = 8.46 (d, J= 8.4 Hz, 1H), 8.35 (s, 1H), 8.04 (d, J= 8.0 Hz, 1H), 7.92 - 7.86 (m, 1H), 7.84 - 7.79 218 (m, 1H), 7.71 (s, 1H), 3.81 (s, 3H). DR INTERMEDIARY Step 1: A mixture of 4-chloro-2,5-difluoro-benzonitrile (2.00 g, 11.5 mmol, 1.00 eq.), N-bromosuccinimide (4.10 g, 23.1 mmol, 2 .00 eg.), palladium acetate (259 mg, 1.15 mmol, 0.10 eg.) and p-toluenesulfonic acid (992 mg, 5.76 mmol, 0.50 eg.) in dichloroethane (50 mL) It was degassed with nitrogen, then stirred at 75 °C for 12 hours. After that time, the cooled mixture was extracted with dichloromethane (50 mL χ 3), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified. by means of column chromatography (SiO2, petroleum ether: ethyl acetate 0-3%) in order to obtain 2-bromo-4-chloro-3,6-difluoro-benzonitrile (1.10 g, 4.36 mmol , 38% yield) in the form of a white solid. RMNXH (400 MHz, CDC13) δ = 7.38 - 7.31 (m, 1H). Step 2: A mixture of 2-bromo-4-chloro-3,6-difluorobenzonitrile (1.10 g, 4.36 mmol, 1.00 eq.), cyclopropanol (380 219 mg, 6.54 mmol, 1.50 eq. ) and potassium carbonate (1.51 g, 10.9 mmol, 2.50 eg. ) in DMF (10 mL) was degassed with nitrogen, then stirred at 75 °C for 2 hours. After that time, the mixture was concentrated, and the residue was purified by prep TLC. (SÍO2, petroleum ether: ethyl acetate 7%) in order to obtain 2-bromo-4-chloro-6-(cyclopropoxy)-3-fluorobenzonitrile (600 mg, 2.07 mmol, 47% yield) as a white solid. Η2NMR (400 MHz, CDCI3) δ = 7.36 (d, J= 5.6 Hz, 1H), 3.88 - 3.79 (m, 1H), 0.91 (d, J = 4.8 Hz , 4H). Step 3: A mixture of l-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyrazole (1.29 g, 6.20 mmol, 3.00 eg. ), 2-bromo-4-chloro-6-(cyclopropoxy)-3-fluoro-benzonitrile (600 mg, 2.07 mmol, 1.00 eq.), sodium bicarbonate aq. (694 mg, 8.26 mmol, 0.321 mL, 4.00 eq.), ditertbutyl(cyclopentyl)phosphane; Dichloropalladium-iron (135 mg, 0.207 mmol, 0.10 eg.) in dioxane (20 mL) and water (4 mL) was degassed with nitrogen, and the mixture was stirred at 80 °C for 16 hours. After that time, the mixture was concentrated, and the residue was purified by column chromatography (S1O2, petroleum ether: ethyl acetate 5-20%) in order to obtain 4-chloro-6-(cyclopropoxy)- 3-fluoro-2-(2-methylopyrazol-3yl)benzonitrile (180 mg, 0.524 mmol, 25% yield) as a yellow solid. LCMS [M+l]+= 292.1; NMR !Η (400 MHz, CDCI3) δ = 7.62 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 220 6.0 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 3.92 - 3.85 (m, 1H), 3.81 (d, J = 1.2 Hz, 3H), 0.96 - 0.92 (m, 4H). Step 4: A mixture of 4-chloro-6-(cyclopropoxy)-3fluoro-2-(2-methylopyrazol-3-yl)benzonitrile (180 mg, 0.617 mmol, 1.00 eq) and N-bromosuccinimide (220 mg, 1.23 mmol, 2.00 eg) in acetonitrile (10 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. After that time, the mixture was concentrated, and the residue was purified by prep TLC. (SICA, petroleum ether: ethyl acetate 20%) in order to obtain 2- (4-bromo-2-methyl-pyrazol-3-yl)-4-chloro-6(cyclopropoxy)-3-fluoro-benzonitrile (170 mg, 0.455 mmol, 74% yield) as a white solid. LCMS [M+1]+= 371.8; iR NMR (400 MHz, CDC13) δ = 7.61 (s, 1H), 7.55 (d, J = 6.0 Hz, 1H), 3.93 - 3.85 (m, 1H), 3, 80 (s, 4H) , 0.97 0.94 (m, 4H) . DS INTERMEDIARY DC INTERMEDIARY A mixture of 2-(4-bromo-2-methyl-pyrazol-3yl)naphthalene-l-carbonitrile (150 mg, 0.48 mmol, 1.00 eq.), 4,4,5,5-tetramethyl-2 -(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (134 mg, 0.528 mmol, 221 1.10 eg.), potassium acetate (141 mg, 1.44 mmol, 3.00 eg.) and ditero-butyl(cyclopentyl)phosphane; Dichloropalladium-iron (31.3 mg, 0.048 mmol, 0.10 eg.) in dioxane (3 mL) was degassed with nitrogen, and then stirred at 80 °C for 2 hours. After that time, the reaction mixture was concentrated under reduced pressure, in order to obtain 2-[2-methyl-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyrazole -3-yl]naphthalene-l-carbonitrile (160 mg, crude) as a brown liquid, which was used in the next step without further purification. LCMS [M+l]+= 360.2. DT INTERMEDIARY DT INTERMEDIARY Step 1: To a solution of 4-bromo-2-methyl-pyrazole-3carbaldehyde (1.00 g, 5.29 mmol, 1.00 eq.) and nitromethane (420 mg, 6.88 mmol, 0.37 mL , 1.30 eg.) in methanol (10 mL) a solution of sodium hydroxide (466 mg, 11.6 mmol, 2.20 eg.) in water (1 mL) was added dropwise at 0 °C. The reaction mixture was then stirred at 0 °C for 0.5 h. After that time, the reaction mixture was quenched by the addition of HC1 (1.00 M, 5 mL), filtered, and the filtrate was concentrated under reduced pressure in order to obtain 4-bromo-l-methyl-5 -[(E)-2222 nitrovinyl]pyrazole (627 mg, crude) as a yellow solid, which was used in the next step without further purification. A NMR (400 MHz, CDCI3) δ = 8.10 (d, J = 13.6 Hz, 1H), 7.93 (d, J= 13.6 Hz, 1H), 7.57 (s, 1H) , 4.03 (s, 3H). Step 2: A suspension of 2-pyridin-l-io-lylacetonitrile chloride (627 mg) and 4Á MS (1.00 g, 0.215 mmol) in dichloroethane (30 mL) was cooled to 0 °C, then added 2,6-lutidine (1.45 g, 13.5 mmol, 1.57 mL, 5.00 eq.). After stirring for 15 minutes, 4-bromo-l-methyl-5[(E)-2-nitrovinyl]pyrazole (627 mg, 2.70 mmol, 1.00 eq.) was added, followed by the addition of acetate. cupric (736 mg, 4.05 mmol, 1.50 eq.). This mixture was then stirred at 0 °C for 15 minutes, then warmed to 25 °C and stirred at 25 °C for 5 hours. After that time, the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 10-20%) to obtain 2- (4-bromo2-methyl-pyrazol-3-yl)indolizine-3-carbonitrile (380 mg, 1.26 mmol, 47% yield) as a yellow solid. LCMS [M + 1]+= 301.0; 4H NMR (400 MHz, CDC13) δ = 8.34 (d, J = 6.0 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.18 - 7.11 (m, 1H) , 6.96 (dt, J = 1.2, 6.8 Hz, 1H) , 6.62 (s, 1H) , 3.91 (s, 3H) . 223 DU INTERMEDIARY INTERMEDIARY A-25 Step 1: A mixture of 6-(4-bromo-l-methyl-lH-pyrazol5-yl)quinoline-5-carbonitrile, Intermediate A-25 (120 mg, 0.38 mmol, 1.00 eq.), N -iodosuccinimide (517 mg, 2.30 mmol, 6.00 eq.) in acetic acid (5 mL) was stirred at 80 °C for 48 hours under a nitrogen atmosphere. The mixture was then concentrated, and saturated sodium sulfite solution (10 mL) was added to the residue. The mixture was then extracted with ethyl acetate (5 mL), and the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep TLC. (SÍO2, petroleum ether: ethyl acetate 50%) in order to obtain 6-(4-bromol-methyl-1H-pyrazol-5-yl)-3-iodoquinoline-5-carbonitrile (38 mg, 0.086 mmol, 22% of performance) in the form of a white solid. LCMS [M+1]+= 441.1; A NMR (400 MHz, CDC13) δ = 9.26 (d, J = 2.0 Hz, 1H), 9.03 (dd, J= 0.8, 2.0 Hz, 1H), 8.43 ( dd, J = 0.8, 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 3.87 (s, 3H). Step 2: A mixture of 6-(4-bromo-l-methyl-lH-pyrazol5-yl)-3-iodoquinoline-5-carbonitrile (35 mg, 0.080 mmol, 1.00 eq.), sodium methoxide (13 mg, 0.24 mmol, 3.00 eg.), cuprous iodide (1.5 mg, 0.008 mmol, 0.10 eg.) in methanol (1 224 mL) was degassed with nitrogen, then stirred at 105 °C for 16 hours. After that time, the mixture was filtered, the filtrate was concentrated, and the residue was purified by prep TLC. (SiO2, petroleum ether: ethyl acetate 50%) in order to obtain 6-(4-bromo-l-methyl-lH-pyrazol-5-yl)-3methoxyquinoline-5-carbonitrile (12 mg, 0.035 mmol, 44% of performance) in the form of a white solid. LCMS [M+l]+= 345.1; Η2NMR (400 MHz, CDC13) δ = 8.86 (d, J = 2.8 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.76 (d, J= 2 .8 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 4.07 (s, 3H), 3.87 (s, 3H). DV INTERMEDIARY INTERMEDIARY D-18 To a mixture of 6-(4-bromo-2-methyl-pyrazol-3-yl)-3chloro-2-methyl-benzonitriIo, Intermediate D-18 (400 mg, 1.29 mmol, 1.00 eq.) in THE (5 mL) lithium diisopropyl amine (2.00 M, 1.29 mL, 2.00 eq.) was added at -78 °C, and stirred at -78 °C for 30 minutes. Methyl iodide (5.15 mmol, 0.32 mL, 4.00 eq.) was then added at -78 °C, and the mixture was stirred for 2 hours. The reaction mixture was then quenched with ammonium chloride solution (10 mL) and extracted with dichloromethane (20 mL χ 3), and the combined organic extracts were washed with 225 brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep TLC. (S1O2, petroleum ether: ethyl acetate 20%) in order to obtain 6-(4-bromo-2-methyl-pyrazol-3-yl)-3chloro-2-ethyl-benzonitrile (280 mg, 0.86 mmol, 67% yield) in the form of a yellow oil. LCMS [M+1]+= 326, 0; 4H NMR (400 MHz, CDC13) δ = 7.71 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.24 (d, J= 8.4 Hz, 1H), 3.80 (s, 3H), 3.14 - 3.11 (m, 2H), 1.35 - 1.32 (m, 3H). DW INTERMEDIARY INTERMEDIARY D-19 2-(4-Bromo-l-methyl-lH-pyrazol-5-yl)-4-chloro6-ethylbenzonitrile was prepared using the same method as for the preparation of Intermediate DV, using Intermediate D-19 instead of Intermediate D -18, as a white solid (30 mg, 0.074 mmol, 23%). LCMS [M+1]+= 419.2; 2H NMR (400 MHz, DMSO-d6) δ = 12.88 (s, 1H), 8.38 (br s, 3H), 8.28 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.42 (dd, J = 1.6, 8.4 Hz, 1H), 4.39 - 4.22 (m, 2H), 3.75 (s, 3H), 2.83 (q , J= 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). 226 DX INTERMEDIARY DW INTERMEDIARY To a mixture of 2-(4-bromo-2-methyl-pyrazol-3-yl)-4chloro-6-ethyl-benzonitrile. DW intermediate (270 mg, 0.83 mmol, 1.00 eq.) in methanol (2 mL) sodium methoxide (449 mg, 8.32 mmol, 10.0 eq.) was added in one portion, at 20° C under nitrogen atmosphere. The mixture was stirred at 100 °C for 2 hours in a sealed tube, and a light yellow solution was formed. The mixture was then concentrated, and the residue was taken up in ethyl acetate (10 mL) and water (5 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (5 mL χ 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep TLC. (SiO2, Petroleum ether: Ethyl acetate 25%) in order to obtain 2(4-bromo-2-methyl-pyrazol-3-yl)-6-ethyl-4-methoxy-benzonitrile (220 mg, -70% purity) in the form of a white solid. LCMS [M+1]+= 321.9; NMRΧΗ (400 MHz, CDC13) δ = 7.58 (s, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 2.97 - 2.92 (m, 2H), 1.37 - 1.34 (t, J = 6.8Hz 3H). 227 DY INTERMEDIARY Step 1: A mixture of 2-bromo-5-methoxy-naphthalen-l-ol (2.60 g, 10.3 mmol, 1.00 eq.), l-methyl-5-(4,4,5, 5tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.21 g, 15.4 mmol, 1.50 eq.), ditertbutyl(cyclopentyl)phosphane;dichloropalladium;iron (670 mg, 1.03 mmol , 0.10 eq.) and sodium carbonate (2.18 g, 20.6 mmol, 2.00 eq.) in dioxane (30 mL) and water (6 mL) were degassed with nitrogen, then stirred at 100 °C for 0.5 hours. After that time, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 10-100%) in order to obtain 5-methoxy-2 -(2-methylopyrazole-3yl)naphthalen-l-ol (720 mg, 2.83 mmol, 28% yield) as a yellow solid. RMNXH (400 MHz, DMSOd6) δ = 9.57 (s, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H) , 7.48 - 7.42 (m, 1H) , 7.26 (d, J = 8.6 Hz, 1H) , 7.03 (d , J = 7.6 Hz, 1H), 6.33 (d, J = 1.6 Hz, 1H), 3.97 (s, 3H), 3.69 (s, 3H). Step 2: To a solution of 5-methoxy-2-(2methylopyrazol-3-yl)naphthalen-l-ol (650 mg, 2.56 mmol, 1.00 228 eq.), 4Á molecular sieves (1.00 g) and triethylamine (7.67 mmol, 1.07 mL, 3.00 eg.) in dichloromethane (20 mL) Tf2O (3.83 mmol, 0. 63 mL, 1.50 eg.) dropwise at -40 °C under nitrogen. The reaction mixture was stirred at -40 °C for 0.5 hours, then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 0-15%) in order to obtain [5-methoxy-2-(2-methylopyrazol-3-yl)-1-naphthyl] trifluoromethanesulfonate (341 mg, 0.79 mmol, 30% yield) as a yellow oil. LCMS [M+l]+= 387, 1; RMNXH (400 MHz, CDC13) δ = 8.40 (dd, J = 0.8, 8.8 Hz, 1H), 7.76 (d, J= 8.8 Hz, 1H), 7.64 (d , J = 8.0 Hz, 1H) , 7.61 (d, J = 2.0 Hz, 1H) , 7.43 (d, J = 8.8 Hz, 1H) , 7.00 (d, J = Ί,6 Hz, 1H), 6.45 (d, J = 2.0 Hz, 1H), 4.07 (s, 3H), 3.82 (s, 3H). Step 3: A mixture of [5-methoxy-2-(2-methylopyrazol3-yl)-1-naphthyl] trifluoromethanesulfonate (290 mg, 0.67 mmol, 1.00 eq.), zinc cyanide (0.81 mmol , 51.1 pL, 1.20 eg.), Pd2(dba)3 (612 mg, 0.067 mmol, 0.10 eg.), DPPF (74 mg, 0.134 mmol, 0.20 eg.) and powder Zinc (4.4 mg, 0.067 mmol, 0.10 eg.) in DMF (10 mL) was degassed with nitrogen, then stirred at 120 °C for 1 hour. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (100 mL χ 3). The combined organic layers were washed with brine (200 mL), dried 229 on anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 10-50%) in order to obtain 5-methoxy2- (2-methylopyrazole-3-í1)naphthalene-l-carbonitrile (156 mg, 0.59 mmol, 88% yield) as an off-white solid. LCMS [M+1]+= 264 , 1; RMNXH (400 MHz, CDC13) δ = 8.59 (dd, J = 0.8, 8.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.68 (t , J = 8.4 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.49 (d, J= 8.4 Hz, 1H) , 7.01 (d, J =7.6 Hz, 1H), 6.58 (d, J= 2.0 Hz, 1H), 4.07 (s, 3H), 3.89 (s, 3H). Step 4: To a solution of 5-methoxy-2-(2-methylpyrazol-3-yl)naphthalene-l-carbonitrile (180 mg, 0.68 mmol, 1.00 eq.) in acetonitrile (2 mL) was added Nbromosuccinimide (146 mg, 0.82 mmol, 1.20 eq.). The mixture was stirred at 35 °C for 0.5 h, then concentrated under reduced pressure, and the residue was purified by prep TLC. (SÍO2, petroleum ether: ethyl acetate 30%) in order to obtain 2-(4-bromo-2-methyl-pyrazol-3-yl)-5-methoxynaphthalene-l-carbonitrile (174 mg, 0.51 mmol, 74% yield) in the form of a whitish solid. LCMS [M + 1]+= 342.0; RMNXH (400 MHz, CDC13) δ = 8.64 (dd, J= 0.8, 8.8 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.70 (t , J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.47 (d, J= 8.8 Hz, 1H), 7.04 (d, J= 7.6 Hz, 1H ), 4.08 (s, 3H), 3.84 (s, 3H). 230 DZ INTERMEDIARY DZ Intermediary 1 DZ intermediate, 2-(4-bromo-l-methyl-lH-pyrazol-5-yl) 4-chloro-l-naphtonitrile was prepared as a yellow solid (25 mg, 0.072 mmol, 2% performance in 4 steps) starting from 2-bromo-4-chloro-naphthalen-l-ol according to the method described for the preparation of Intermediate DX. LCMS [M+l]+= 347.8; NMR (400 MHz, CDC13d) δ = 8, 48 - 8.43 (m, 1H), 8.42 - 8.38 (m, 1H), 7.91 - 7.82 (m, 2H), 7, 65 (d, J= 4.4 Hz, 2H), 3.88 (s, 3H). EA INTERMEDIARY Cl CN CN Intermediary DZ-1 Step 1: A mixture of [4-chloro-2-(2-methylopyrazol-3yl)-1-naphthyl] trifluoromethanesulfonate (38 mg, 0.097 mmol, 1.00 eg.), zinc cyanide (22 mg, 190 pmol, 12.4 pL, 2.00 eq.), DPPF (5.4 mg, 9.7 pmol, 0.10 eq.), zinc powder (640 pg, 9.7 pmol, 0.10 eq.) and Pd2(dba)3(4.5 mg, 4.86 pmol, 0.05 eq.) in DMF (1.0 mL) was degassed with nitrogen, then stirred at 100 °C for 4 hours. The mixture was then concentrated, and the residue was purified by prep TLC. (SiO2, ether 231 petroleum: ethyl acetate 20%) in order to obtain 2-(2methylopyrazol-3-yl)naphthalene-1,4-dicarbonitrile (30 mg, 93.4 pmol, 96% yield) as a colored solid yellow. LCMS [M+l]+= 259.0; 4H NMR (400 MHz, CDC13) δ = 8.48 - 8.44 (m, 1H), 8.44 - 8.39 (m, 1H), 7.96 (s, 1H), 7.96 - 7, 94 (m, 1H) , 7.94 - 7.92 (m, 1H) , 7.67 (d, J = 2.0 Hz, 1H) , 6.62 (d, J = 2.0 Hz, 1H) ), 3.92 (s, 3H). Step 2: A mixture of 2-(2-methylopyrazole-3yl)naphthalene-1,4-dicarbonitrile (30 mg, 0.093 mmol, 1.00 eq.), N-bromosuccinimide (41 mg, 0.23 mmol, 2, 00 eq.) in acetonitrile (2.0 mL) was degassed with nitrogen, then stirred at 35 °C for 2 hours. The mixture was then concentrated, and the residue was purified by prep TLC. (SIO2, petroleum ether: ethyl acetate 25%) in order to obtain 2-(4-bromo-2-methyl-pyrazol3-yl)naphthalene-1,4-dicarbonitrile (25 mg, 0.067 mmol, 58% yield) in the form of a yellow solid. LCMS [M+l]+= 339, 0; Η2NMR (400 MHz, CDCl3-d) δ = 8.52 - 8.41 (m, 2H), 8.01 - 7.96 (m, 2H), 7.95 (s, 1H), 7.68 ( s, 1H), 3.88 (s, 3H). EB INTERMEDIARY Step 1: A solution of n-butyl lithium (2.50 M, 1.87 mL, 232 1.00 eq.) was added dropwise over 30 min to a solution of 2,2,6,6-tetramethylopiperidine (660 mg, 4.67 mmol, 0.79 mL, 1.00 eq.) in THF (10 mL) at 0 °C, and the mixture was then cooled to -78 °C, and a solution of 4-fluoronaphthalene-l-carbonitrile (0.80 g, 4.67 mmol, 1.00 eq.) in THF ( 3 mL) was added over a period of 15 min. The mixture was then stirred at −78 °C for 2 hours. After that time, a solution of iodine (1.19 g, 4.67 mmol, 1.00 eq.) in THF (3 mL) was added over a period of 30 min, and the reaction mixture was stirred at - 78°C for 2 hours, then allowed to warm to 25°C and stirred for another 12 hours. The reaction mixture was then quenched with water (50 mL) and extracted with ethyl acetate (30 mL χ 2). The combined organic layers were washed with sat. sodium thiosulfate. (30 mL χ 3), 1 M hydrochloride (30 mL χ 3) and brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (ethyl acetate: 0-5% petroleum ether) to obtain 4-fluoro-3-iodonaphthalene-l-carbonitrile (1, 00 g, 3.37 mmol, 72% yield) as a white solid. RMNXH (400 MHz, CDC13) δ = 8.15 (d, J= 8.4 Hz, 1H), 8.13 - 8.07 (m, 2H), 7.72 (dt, J= 1.2, 7.7 Hz, 1H), 7.68 - 7.61 (m, 1H). Step 2: To a solution of 4-fluoro-3-iodo-naphthalene-lcarbonitrile (900 mg, 3.03 mmol, 1.00 eq.), l-methyl-5(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazole (1.58 g, 233 7.57 mmol, 2.50 eq.) and potassium phosphate (1.29 g, 6.06 mmol, 2.00 eq.) in dioxane (10 mL) and water (2 mL) diterobutyl (cyclopentyl)phosphane was added; dichloropalladium-iron (197 mg, 0.30 mmol, 0.10 eg.). The reaction was stirred at 80 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was then partitioned between water (20 mL) and ethyl acetate (10 mL), extracted with ethyl acetate (10 mL χ 2), and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and They concentrated. The residue was then purified by flash chromatography on silica gel (gradient 0-25% ethyl acetate: petroleum ether) to obtain 4-fluoro-3(2-methylopyrazol-3-yl)naphthalene-l- carbonitrile (0.80 g, 2.87 mmol, 95% yield) as a white solid. Η2NMR (400 MHz, CDC13) δ = 8.33 - 8.25 (m, 2H), 7.91 (s, 1H), 7.88 - 7.82 (m, 1H), 7.82 - 7, 75 (m, 1H) , 7.63 (d, J = 2.0 Hz, 1H) , 6.46 (d, J= 2.0 Hz, 1H) , 3.89 (d, J= 1.6 Hz, 3H). Step 3: To a solution of 4-fluoro-3-(2-methylopyrazol3-yl)naphthalene-l-carbonitrile (200 mg, 0.80 mmol, 1.00 eq.) in acetonitrile (5 mL) was added l- bromopyrrolidine-2,5-dione (212 mg, 1.19 mmol, 1.50 eg.), and the reaction was stirred at 25 °C for 12 hours. The reaction was then concentrated, and the residue was purified by flash chromatography on silica gel (0-15% ethyl acetate: petroleum ether) to obtain 3-(4-bromo-2-methyl-pyrazole- 3-yl)-4-fluoro-naphthalenol-carbonitrile (0.20 g, 0.61 mmol, 76% yield) in the form 234 of a solid gray color. LCMS [M+l]+= 332.1 / 300.1; RMNXH (400 MHz, CDC13) δ = 8.32 (dd, J = 8.4, 13.1 Hz, 2H), 7.95 7.86 (m, 2H), 7.84 - 7.76 (m , 1H), 7.64 (s, 1H), 3.85 (d, J = 1.2 Hz, 3H). EC INTERMEDIARY EC INTERMEDIARY Step 1: To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol, 1.00 eq.) and l-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan -2-yl)-IH-pyrazole (1.12 g, 5.38 mmol, 1.00 eq.) in dioxane (15 mL) and aqua (3 mL) potassium carbonate (1.49 g, 10 eq.) was added .8 mmol, 2.00 eq.) and Pd(dppf)C12 (393 mg, 0.538 mmol, 0.10 eq.) at 20 °C under a nitrogen atmosphere. The mixture was then stirred at 80 °C for 6 hours. After that time, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL χ 2). The combined organic layers were washed with brine (15 mL χ 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether : ethyl acetate 25-50%) in order to obtain 6-(l-methyl-lH-pyrazol-5yl)picolinaldehyde (800 mg, 4.27 mmol, 80% yield) in the form of a yellow solid. RMNXH (400 MHz, CDC13) 235 δ = 10.13 (d, J = 0.8 Hz, 1H), 7.99 - 7.89 (m, 2H), 7.83 (dd, J = 1.6, 7.2 Hz, 1H ), 7.55 (d, J = 2.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 4.35 (s, 3H). Step 2: To a solution of 6-(l-methyl-lH-pyrazol-5yl)picolinaldehyde (800 mg, 4.27 mmol, 1.00 eq.) in acetonitrile (12 mL) was added N-bromo-succinimide ( 1.14 g, 6.41 mmol, 1.50 eq.) at 20 °C, and the mixture was stirred for 16 hours. After that time, the mixture was concentrated, and the residue was purified by prep TLC. (SÍO2, petroleum ether: ethyl acetate 25%) in order to obtain 6-(4-bromo-lmethyl-1H-pyrazol-5-yl)picolinaldehyde (750 mg, 2.82 mmol, 66% yield) in the form of a white solid, NMR2Η (400 MHz, CDCI3) δ = 10.13 (s, 1H), 8.08 - 7.98 (m, 3H), 7.58 (s, 1H), 4.15 (s, 3H) . Step 3: To a solution of 6-(4-bromo-l-methyl-lHpyrazol-5-yl)picolinaldehyde (250 mg, 0.94 mmol, 1.00 eq.) in DMF (3 mL) acid 2 was added -amino acid (78 mg, 1.03 mmol, 1.10 eg), iodine (238 mg, 0.94 0 mmol, 0.19 mL, 1.0 0 eg), sodium bicarbonate (158 mg, 1. 88 mmol, 2.00 eg) at 20 °C. The mixture was then stirred at 60 °C for 6 h, then diluted with water (20 mL) and extracted with ethyl acetate (20 mL χ 2). The combined organic layers were washed with brine (10 mL χ 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by prep TLC. (SÍO2, ethyl acetate) in order to obtain 5- (4-bromo-l 236 methyl-lH-pyrazol-5-yl)imidazo[1,5-a]pyridine (35 mg, 0.126 mmol, 13% yield) as a yellow solid. A NMR (400 MHz, CDC13) δ = 7.77 (s, 1H), 7.68 (s, 1H), 7.64 - 7.59 (m, 2H), 6.87 (dd, J = 6 ,4, 9.2 Hz, 1H), 6.66 (d, J = 6.4 Hz, 1H), 3.79 (s, 3H). ED INTERMEDIARY ED INTERMEDIARY Step 1: To a solution of 4-bromo-5-chloro-lH-pyrazole (1.00 g, 5.51 mmol, 1.00 eq.) 2-(bromomethyl)benzonitrile (1.08 g, 5.51 mmol, 1.00 eq.) in acetonitrile (20 mL), potassium carbonate (914 mg, 6.61 mmol, 1.20 eq.) was added, and the mixture was stirred at 80 °C for 10 hours under an atmosphere of nitrogen. After that time, the reaction was quenched with water (200 mL) and then extracted with ethyl acetate (150 mL χ 3). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue formed was purified by column chromatography (SIO2, petroleum ether: ethyl acetate = 10: 1) in order to obtain 2-((4-bromo-3-chloro-lH-pyrazole-li1)methyl)benzonitrile (1.00 g, 3.37 mmol, 61% yield) as a solid White color. LCMS 237 [M+l]+= 297, 9; 4H NMR (400 MHz, DMSO-d6) δ = 8.27 (s, 1H), 7.89 (dd, J=0.8, 7.6 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.61 7.49 (m, 1H), 7.37 (d, J=7.6 Hz, 1H), 5.52 (s, 2H). Step 2: Ά a solution of 2-((4-bromo-3-chloro-lHpyrazol-l-yl)methyl)benzonitrile (400 mg, 1.35 mmol, 1.00 eg.), 1-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)-lH-pyrazole (561 mg, 2.70 mmol, 2.00 eg.) and sodium bicarbonate (227 mg, 2, 70 mmol, 2.00 eg.) in dioxane (10 mL) and water (1 mL) Pd(dppf)C12 (99 mg, 0.135 mmol, 0.10 eg.) was added under a nitrogen atmosphere. The mixture was stirred at 110 °C for 10 hours, and then the reaction was quenched by the addition of water (200 mL); then it was extracted with ethyl acetate (150 mL χ 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 30% ) in order to obtain 2-((3'-chloro-2-methyl-l'H,2H-[3,4'bipyrazol]-1'-yl)methyl)benzonitrile (200 mg, 0.672 mmol, 50% performance) in the form of a white solid. LCMS [M+l]+= 298.0; 4H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 1H) , 7.91 (d, J=7.6 Hz, 1H) , 7.79 - 7, 70 (m, 1H) , 7 .62 - 7.52 (m, 1H) , 7.50 - 7.42 (m, 2H) , 6.42 (d, J=2.0 Hz, 1H) , 5.58 (s, 2H) , 3.81 (s, 3H). Step 3: To a solution of 2-((3'-chloro-2-methyl-l' H, 2H[3,4'-bipyrazol]-1'-yl)methyl)benzonitrile (200 mg, 0.672 238 mmol, 1.00 eq.) in acetonitrile (10 mL), Nbromosuccinimide (132 mg, 0.739 mmol, 1.10 eq.) was added, and the mixture was stirred at 25 °C for 10 hours under a nitrogen atmosphere. After that time, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (40 mL χ 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue purified by column chromatography (SIO2, petroleum ether: 5% ethyl acetate). ) in order to obtain 2((4-bromo-3'-chloro-2-methyl-l'H,2H-[3,4'-bipyrazol]-1'yl)methyl)benzonitrile (130 mg, 0.345 mmol, 51% yield) in the form of a yellow solid. LCMS [M+1]+= 377, 9; NMR (400 MHz, DMSO-d6) δ = 8.37 (s, 1H) , 7.92 (d, J=7, 6 Hz, 1H) , 7.83 - 7.71 (m, 1H) , 7 .67 (s, 1H), 7.62 - 7.55 (m, 1H), 7.45 (d, J=8.0 Hz, 1H), 5.61 (s, 2H), 3.73 ( s, 3H). Step 4: To a solution of tere-butyl ((4-oxo-7-(4,4,5trimethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-lyl)methyl) carbamate ( 256 mg, 0.637 mmol, 2.00 eq.), 2—( (4 — bromo-3'-chloro-2-methyl-l'H,2H-[3,4'-bipyrazol]-1'yl)methyl )benzonitrile (120 mg, 0.319 mmol, 1.00 eq.), sodium bicarbonate (54 mg, 0.637 mmol, 25 pL, 2.00 eq.) in water (0.5 mL) and dioxane (5.0 mL ) Pd(dtbpf)Cl2(21 mg, 32 pmol, 0.10 eq.) was added under a nitrogen atmosphere, and then the mixture was stirred at 110 °C for 10 hours. The reaction was then quenched with water (50 mL), extracted with ethyl acetate (40 mL 239 χ 3), and the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 15%) to obtain tere-butyl ((7(3'-chloro-1'-(2-cyanobenzyl)-2- methyl-1'H,2H-[3,4'bipyrazole]-4-yl)-4-oxo-3,4-dihydrophthalazin-1yl)methyl)carbamate (115 mg, 0.201 mmol, 63% yield) as of a black and brown oil. LCMS [M+l]+= 571.1; 2H NMR (400 MHz, DMSO-d6) δ = 12.48 (s, 1H), 11.94 (s, 1H), 8.42 (s, 1H), 8.13 - 8.05 (m, 2H) , 7.92 (d, J=7.6 Hz, 1H) , 7.80 - 7.72 (m, 1H) , 7.62 - 7.55 (m, 2H) , 7.47 (d, J =8.0 Hz, 1H) , 7.40 - 7.31 (m, 1H) , 5.64 (s, 2H) , 4.36 (br d, J=5, 6 Hz, 2H) , 3, 74 (s, 3H), 1.38 (s, 9H). EE INTERMEDIARY INTERMEDIARY EE-1 INTERMEDIARY EE Step 1: To a mixture of phenyl boronic acid (1.92 g, 15.8 mmol, 2.00 eg.) and 3-chloro-4-iodo-lH-pyrazole (1.80 g, 7.88 mmol, 1.00 eq.) in dichloromethane (30 mL), pyridine (1.86 g, 23.5 mmol, 1.90 mL, 2.99 eg.) and copper acetate (1.72 g, 9.46 eg.) were added. mmol, 1.20 eg.) in one serving. The mixture was stirred at 20 °C for 16 hours, then filtered and concentrated, and the The residue was purified by flash chromatography on silica gel (0-5% ethyl acetate: petroleum ether) to obtain 3-chloro-4-iodo-l-phenyl-pyrazole (1.50 g, 4 .93 mmol, 63% yield) as a yellow liquid. LCMS [M+1]+= 305.0; NMR (400 MHz, CDC13) δ 7.91 (s, 1H), 7.63-7.59 (m, 2H), 7.49-7.43 (m, 2H), 7.36-7.30 (m, 1H). Step 2: l-methyl-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyrazole (1.23 g, 5.91 mmol, 1.50 eq.), 3chloro -4-iodo-l-phenyl-pyrazole (1.20 g, 3.94 mmol, 1.00 eq.), potassium phosphate (1.67 g, 7.88 mmol, 2.00 eq.) and ditertbutyl (cyclopentyl)phosphane;dichloropalladium-iron (256 mg, 0.39 mmol, 0.10 eq.) in dioxane (20 mL) and water (4 mL) were degassed and then heated to 80 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was then concentrated, and the residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL χ 3), dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified. by means of column chromatography (SÍO2, petroleum ether: ethyl acetate 10-15%) in order to obtain 3-chloro-4(2-methylopyrazol-3-yl)-1-phenyl-pyrazole, Intermediate EE-1 (0.80 g, 3.09 mmol, 79% yield) as a yellow oil. LCMS [M+1]+= 258.9; Η3NMR (400 MHz, CDC13) δ 7.97 (s, 1H), 7.71-7.67 (m, 2H), 7.55 (d, J = 2.0 Hz, 1H), 7.49 ( t, J = 8.0 Hz, 2H), 7.39-7.34 (m, 1H), 6.43 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H). 241 Step 3: A mixture of 3-chloro-4-(2-methylopyrazol-3-yl)1-phenyl-pyrazole (210 mg, 0.811 mmol, 1.00 eq.), tetrapotassiumohexacyanoiron (4-) trihydrate (1.03 g, 2.44 mmol, 3.00 eg.) and [2-(2-aminophenyl)phenyl]-methylosulfonyloxy-palladiodicyclohexyl-[3,6-dimethoxy-2-(2,4,6triisopropylphenyl)phenyl]phosphane (73 .6 mg, 0.081 mmol, 0.10 eg) in dimethylacetamide (6 mL) and water (3 mL) was heated to 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL χ 3). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 10-15%) in order to obtain 4-(2-methylopyrazol-3-yl)-1-phenyl-pyrazole-3-carbonitrile (200 mg, 0.80 mmol, 99% yield) as a solid of yellow color. LCMS [M+1]+= 249.9; 1H NMR (400 MHz, CDC13) δ = 8.09 (s, 1H), 7.76-7.72 (m, 2H), 7.56 (d, J= 2.0 Hz, 1H), 7.51 -7.56 (m, 2H), 7.43-7.48 (m, 1H), 6.59 (d, J = 2.0 Hz, 1H), 3.98 (s, 3H). Step 4: To a mixture of 4-(2-methylopyrazol-3-yl)-1phenyl-pyrazole-3-carbonitrile (180 mg, 0.722 mmol, 1.00 eq.) in acetonitrile (5 mL) was added N-bromosuccinimide (192 mg, 1.08 mmol, 1.50 eg.). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was then quenched with sodium sulfite. 242 saturated sodium (15 mL), extracted with ethyl acetate (15 mL χ 3), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10-20%) in order to obtain 4-(4-bromo-2-methyl-pyrazol-3-yl)-1-phenyl-pyrazol-3carbonitrile (220 mg, 0.67 mmol, 93% yield) in the form of a yellow solid. LCMS [M+1]+= 327.9;ΧΗ (500 MHz, CDC13) I = 8.17 (s, 1H), 7.78-7.74 (m, 2H), 7.59 (s, 1H) ), 7.58-7.54 (m, 2H), 7.49-7.45 (m, 1H), 3.95 (s, 3H). EF INTERMEDIARY N==N== óÁ YV^Br \\ / -----*1 7 N-n N-n t) X INTERMEDIARY EE-1 INTERMEDIARY EF To a mixture of 3-chloro-4-(2-methylopyrazol-3-yl)-1phenyl-pyrazole, Intermediate EE-1 (200 mg, 0.773 mmol, 1.00 eq.) in acetonitrile (1 mL), l -bromopyrrolidine-2,5dione (165 mg, 0.927 mmol, 1.20 eg.) in one serving, at 20 °C. The mixture was stirred at 200C for 16 hours. The reaction mixture was then concentrated, and the residue was purified by flash chromatography on silica gel (0-17% ethyl acetate: petroleum ether) to obtain 4-bromo-5-(3-chloro1- phenyl-pyrazol-4-yl)-1-methyl-pyrazole (200 mg, 0.592 mmol, 77% yield) as a yellow oil. !H (500 MHz, CDCI3) δ = 8.07 - 8.04 (m, 1H), 7.72 (dd, J - 1.2, 243 8.4 Hz, 2H), 7.58 (s, 1H), 7.54 - 7.49 (m, 2H), 7.42 - 7.35 (m, 1H), 3.88 (s, 3H) ). INTERMEDIARY EG INTERMEDIARY EG Steps 1-6: 2-((7-bromo-4-oxo-5-(trifluoromethyl)-3,4dihydrophthalazin-l-yl)methyl)isoindoline-1,3-dione was prepared as a white solid (0.50 g, 1.11 mmol, 6% yield in 6 steps) starting from l-(5-bromo2-methyl-3-(trifluoromethyl)phenyl)ethan-l-one, following the same procedure as the one described for the first 6 stages of DK Intermediary. LCMS [M+l]+= 454.0; NMR (400 MHz, DMSO-d6) δ = 12.75 (s, 1H), 8.74 (d, J= 1.6 Hz, 1H), 8.41 (s, 1H), 7. 97 - 7 , 92 (m, 2H) , 7.91 - 7.86 (m, 2H) , 5.22 (s, 2H) . Step 7: A mixture of 2-((7-bromo-4-oxo-5(trifluoromethyl)-3,4-dihydrophthalazin-1yl)methyl)isoindoline-1,3-dione (50 mg, 0.111 mmol, 1.00 eq.), bis(pinacolato)diboron (34 mg, 0.133 mmol, 1.20 eq.), Pd(dppf)C12 (8 mg, 0.011 mmol, 0.10 eg.) and potassium acetate (22 mg, 0.221 mmol, 2.00 eg) in dioxane (2 mL) was degassed with nitrogen and stirred at 100 °C for 1 hour. The reaction mixture was then concentrated under reduced pressure to obtain [4-[(1,3-dioxoisoindolin-2-yl)methyl]-l-oxo-8 acid. 244(trifluoromethyl)-2H-phthalazin-6-yl] boronic acid (46.0 mg, crude) as a brown solid. LCMS [M-81]+= 418.1. INTERMEDIARY EH 7-(4-bromo-l-methyl-lH-pyrazol-5-yl)chroman-8carbonitrile, Intermediate EH was prepared as a white solid (21 mg, 0.049 mmol, 84% yield) using the same 4-step procedure as that used for the preparation of Intermediate DY, but starting with 7bromocroman-8-ol. LCMS [M+l]+= 413.2; NMR (400 MHz, DMSOd6) δ = 12.40 (br s, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.70 (dd, J= 1.6, 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.58 (d, J= 1.6 Hz, 1H), 7.14 (d, J= 7.6 Hz, 1H), 4.35 (br t, J = 4.8 Hz, 2H), 3 .72 (s, 3H) , 3.68 (d, J = 2.0 Hz, 2H) , 2.89 (br t, J = 6.0 Hz, 2H), 2.05 - 2.00 (m, 2H). INTERMEDIARY The F INTERMEDIARY The 2-(4-bromo-l-methyl-lH-pyrazol-5-yl)-6-fluoro-lnaphtonitrile, Intermediate El, was prepared as a 245 white solid (60 mg, 0.182 mmol, 31% yield in 2 steps) following the same procedure as that described for the preparation of DC Intermediate, starting from 2-bromo-6fluoro-1-naphtha1 due. LCMS [M+l]+= 32 9 , 8 / 331 , 8 ; NMR (400MHz, CCDCl3-d) δ = 8.39 (dd, J = 5.2, 9.2 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7, 68 - 7, 63 (m, 2H), 7.62 - 7.56 (m, 1H), 7.54 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H). EX INTERMEDIARY EX INTERMEDIARY 3-(4-bromo-l-methyl-lH-pyrazol-5-yl)-1-chloro2-naphthonitri 1o, Intermediate EJ, was prepared as a light yellow solid (35 mg, 0.101 mmol, 18 % yield in 2 stages), following the same procedure as that described for the preparation of DC Intermediate, starting from 3-bromo-lchloro-2-naphthaldehyde. NMR (4 00MHz, CCDCl3-d) δ = 10.60 (s, 1H), 8.47 - 8.41 (m, 1H), 8.11 (s, 1H), 7.89 - 7.77 (m, 1H), 7.74 - 7.66 (m, 2H) . 246 INTERMEDIARY ΕΚ Stage 1: To a solution 6-bromoquinoline-5carbonitrile (1.00 g, 4.29 mmol, 1.00 eq.) in acetic acid (20 mL) was added N-chlorosuccinimide (5.73 g, 42.9 mmol, 10.0 eq. ). The mixture was stirred at 135 °C for 24 hours. The pH of the reaction mixture was then adjusted to pH 7 with 2 N aqueous sodium hydroxide solution (5 mL), diluted with water (50 mL), and extracted with dichloromethane (30 mL χ 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether: 10-ethyl acetate). 15%) in order to obtain 6-bromo-3-chloro-quinoline-5carbonitrile (512 mg, 1.91 mmol, 45% yield) as an off-white solid. LCMS [M + 1]+= 269.0; RMNXH (400 MHz, CDC13) δ = 8.94 (s, 1H), 8.49 (dd, J = 0.8, 2.4 Hz, 1H), 8.18 (s, 1H), 7.93 (d, J= 9.2 Hz, 1H) . Step 2: A mixture of 6-bromo-3-chloro-quinoline-5carbonitrile (512 mg, 1.91 mmol, 1.00 eq.), l-methyl-5(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrazole (398 mg, 247 1.91 mmol, 1.00 eq.), diterobutyl (cyclopentyl)phosphane; dichloropalladium iron (125 mg, 0.19 mmol, 0.10 eg.), sodium bicarbonate (322 mg, 3.83 mmol, 0 .15 mL, 2.00 eg) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and stirred at 80 °C for 0.5 hour. After that time, the reaction mixture was concentrated under reduced pressure, and the residue was purified by prep TLC. (SÍO2, petroleum ether: ethyl acetate 30%) in order to obtain 3-chloro-6-(2-methylopyrazol-3-yl)quinoline-5carbonitrile (250 mg, 0.930 mmol, 49% yield) in the form of a yellow solid. LCMS [M + 1]+= 269.1; 1H NMR (400 MHz, CDCI3) δ = 9.00 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 8 .8 Hz, 1H) , 7.78 (d, J= 8.8 Hz, 1H) , 7.66 (d, J = 1.6 Hz, 1H) , 6.63 (d, J = 1.6 Hz, 1H), 3.92 (s, 3H).

[0100] Step 3: To a solution of 3-chloro-6-(2-methylopyrazol-3yl)quinoline-5-carbonitrile (249 mg, 0.927 mmol, 1.00 eq.) in acetonitrile (5 mL) N was added -bromosuccinimide (214 mg, 1.20 mmol, 1.30 eg.). The mixture was stirred at 35 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10-15%) to obtain 6-(4-bromo-2-methyl -pyrazol-3-yl)-3-chloro-quinoline-5carbonitrile (289 mg, 0.831 mmol, 90% yield) as a yellow solid. LCMS [M + 1]+= 349, 0; ^-H NMR 248 (400 MHz, CDC13) δ = 9.04 (d, J = 2.4 Hz, 1H), 8.64 (dd, J = 0.8, 2.4 Hz, 1H), 8.49 - 8.46 (m, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 3.87 (s, 3H). INTERMEDIARIES EL-Ά and EL-B Step 1: To a solution of 1,3-dibromo-2-chloro-5-fluorobenzene (61.0 g, 212 mmol, 1.00 eq.) and 1-methylopyrrole (34.3 g, 423 mmol, 37, 7 mL, 2.00 eq.) in toluene (1500 mL) nbutyl lithium (2.50 M in THE, 88.9 mL, 1.05 eq.) was added dropwise at 30°C under nitrogen. The mixture was then stirred at −30 °C for 0.5 h, then allowed to warm to 25 °C and stirred for 12 h. After that time, the reaction mixture was quenched with water (20 mL) and concentrated under reduced pressure to obtain a residue. The residue was diluted with ethyl acetate (1000 mL), washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was 249 purified by column chromatography (S1O2, petroleum ether: ethyl acetate 10-50%) to obtain 3-bromo-5fluoro-ll-methyl-ll-azatricyclo[6.2.1.02,7]undeca-2 (7),3,5,9tetraene (30.0 g, 118 mmol, 56% yield) as a brown liquid. RMNXH (400 MHz, CDCI3) δ = 7.10 6.65 (m, 4H), 4.83 - 4.44 (m, 2H), 2.31 - 2.09 (m, 3H). Step 2: To a solution of 3-bromo-5-fluoro-ll-methyl11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5,9-tetraene (61.5 g, 242 mmol, 1.00 eq.) in chloroform (1300 mL) m-CFBA (98.2 g, 484 mmol, 85% purity, 2.00 eq.) was carefully added in portions, maintaining the internal temperature below 40 °C. After 2 hours, the brown solution turned yellow, and the mixture was stirred at 25°C for another 24 hours. After that time, the mixture was diluted with dichloromethane (1000 mL) and washed with saturated sodium sulfite (1500 mL χ 2), followed by brine (1500 mL), then dried over anhydrous sodium sulfate, filtered, was concentrated, and the residue was purified by column chromatography (SIO2, petroleum ether: 0-10% ethyl acetate) to obtain l-bromo-3-fluoro-naphthalene (37.8 g, 168 mmol , 70% yield) in the form of a colorless liquid. RMNXH (400 MHz, CDCI3) δ = 8.25 - 8.18 (m, 1H), 7.75 (br d, J = 3.2 Hz, 1H), 7.63 (dd, J = 2.4 , 8.0 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.47 7.40 (m, 1H). 250 Step 3: A mixture of l-bromo-3-fluoro-naphthalene (34.8 g, 155 mmol, 1.00 eq.), Pd2(dba)3 (14.2 g, 15.5 mmol, 0.10 eg.), zinc cyanide (45.4 g, 387 mmol, 24.5 mL, 2.50 eg.), DPPF (17.1 g, 30.9 mmol, 0.20 eg.) and Zn powder (1.01 g, 15.5 mmol, 0.10 eg.) in DMF (400 mL) was degassed with nitrogen, and then the mixture was stirred at 115 °C for 4 hours. After that time, the mixture was filtered, diluted with ethyl acetate (1000 mL), washed with brine (1000 mL χ 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified. by means of column chromatography (SiO2, petroleum ether: ethyl acetate 0-10%) in order to obtain 3fluoronaphthalene-l-carbonitrile (21.5 g, 126 mmol, 81% yield) as a solid of yellow color. 1H NMR (400 MHz, CDCI3) δ = 8.26 - 8.21 (m, 1H), 7.92 - 7.85 (m, 1H), 7.76 - 7.65 (m, 4H). Step 4: n-butyl lithium (2.50 M in hexane, 2.83 mL, 1.10 eg.) was added to a solution of N-isopropylpropan-2-amine (845 mg, 8.35 mmol, 1, 18 mL, 1.30 eg) in THF (15 mL) at -70°C, and the reaction mixture was stirred at -70°C for 15 minutes, and then, 3-fluoronaphthalene-l-carbonitrile ( 1.10 g, 6.43 mmol, 1.00 eq.) in THF (2 mL) to the mixture, and the reaction mixture was stirred for 30 minutes at -70 °C. A solution of iodine (2.12 g, 8.35 mmol, 1.30 eg.) in THF (2.00 mL) was then added to the reaction mixture at -70 °C, and the solution was stirred at - 70°C for another 30 minutes, and then 251 the mixture was warmed to 25 °C and stirred at 25 °C for 10 hours. After that time, the reaction was quenched with water (100 mL), and diluted with ethyl acetate (250 mL), washed with sat. sodium thiosulfate. (100 mL χ 2) and brine (250 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue formed was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 0-15%) in order to obtain 3- fluoro-2-iodo-naphthalene1-carbonitrile (1.70 g, 5.72 mmol, 89% yield) as a white solid. RMNXH (400 MHz, CDCI3) δ = 8.36 - 8.24 (m, 1H), 7.83 - 7.71 (m, 1H), 7.59 - 7.48 (m, 3H). Step 5: A mixture of 3-fluoro-2-iodo-naphthalene-1carbonitrile (800 mg, 2.69 mmol, 1.00 eq.), l-methyl-5(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrazole (1.23 g, 5.92 mmol, 2.20 eq.), Pd(dtbpf)C12 (176 mg, 0.269 mmol, 0.10 eq.), bicarbonate sodium (679 mg, 8.08 mmol, 3.00 eg.) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and stirred at 80 °C for 12 hours. After that time, the mixture was concentrated, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 5-50%) in order to obtain 3-fluoro-2-(2-methylopyrazole -3yl)naphthalene-l-carbonitrile (500 mg, 1.99 mmol, 74% yield) as a yellow solid. LCMS [M+l]+= 252.1; RMNXH (400 MHz, CDCI3) δ = 8.35 - 8.27 (m, 1H), 8.00 - 7.92 (m, 1H), 7.87 (d, J= 9.6 Hz, 1H) , 7.79 - 7.70 252 (m, 2H) , 7.68 (d, J= 2.0 Hz, 1H) , 6.62 (d, J = 2.0 Hz, 1H) , 3.85 (d, J = 1.2 Hz, 3H). Step 6: To a solution of 3-fluoro-2-(2-methylopyrazol3-yl)naphthalene-l-carbonitrile (500 mg, 1.99 mmol, 1.00 eq.) in acetonitrile (8 mL) was added N- bromosuccinimide (638 mg, 3.58 mmol, 1.80 eq.). The mixture was stirred at 25 °C for 3 hours. After that time, the mixture was concentrated, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 10-50%) in order to obtain 2-(4-bromo2-methyl-pyrazole -3-yl)-3-fluoro-naphthalene-l-carbonitrile (550 mg, 1.56 mmol, 78% yield) as a yellow solid. LCMS [M+l]+= 331.9; A NMR (400 MHz, CDC13) δ = 8.40 - 8.31 (m, 1H), 8.01 - 7.95 (m, 1H), 7.91 (d, J= 9.6 Hz, 1H) ), 7.79 - 7.73 (m, 2H), 7.68 (s, 1H), 3.84 (s, 3H). Step 7: To a solution of 3-fluoro-2-(2-methylopyrazol3-yl)naphthalene-l-carbonitrile (20.0 g, 79.6 mmol, 1.00 eg.) in acetonitrile (300 mL) was added 2V-iodosuccinimide (89.5 g, 398 mmol, 5.00 eq.). The mixture was stirred at 80 °C for 12 hours. After that time, the mixture was concentrated, and the residue was triturated with methyl alcohol (100 mL) at 25 °C for 30 min, and the mixture was filtered and dried in order to obtain 3-fluoro-2-(4iodo -2-methyl-pyrazol-3-yl)naphthalene-l-carbonitrile (25.2 g, 66.8 mmol, 84% yield) as a yellow solid. LCMS [M+l]+= 378.0; A NMR (400 MHz, CDC13) δ = 8.35 (br d, J = 8.4 Hz, 1H), 7.98 (br d, J = 8.4 Hz, 1H), 7.92 (d, 253 J = 9.2 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.74 - 7.67 (m, 1H), 3.92 - 3.82 (m, 3H). EM INTERMEDIARY A mixture of 2-(2-hydroxyphenyl)acetonitrile (182 mg, 1.36 mmol, 1.20 eq.), 3-bromo-5-fluoro-pyridine (200 mg, 1.14 mmol, 1.00 eq. ), potassium carbonate (393 mg, 2.84 mmol, 2.50 eg.) in DMF (10 mL) was stirred at 75 °C for 3 hours under a nitrogen atmosphere. The mixture was concentrated, and the residue was purified by prep TLC. (SÍO2, petroleum ether: ethyl acetate 15%) in order to obtain 2-[2-[(5-bromo-3pyridyl)oxy]phenyl]acetonitrile (200 mg, 0.43 mmol, 38% yield) in the form of a yellow oil. LCMS [M+l]+= 289.0. INTERMEDIARY IN cyclopropoxypicolinonitrile (800 mg, 3.35 mmol, 1.00 eq.) and 1methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1H254 pyrazole (732 mg , 3.51 mmol, 1.05 eq.) in dioxane (20 mL) and water (0.4 mL) ditero-butyl (cyclopentyl) phosphanedichloropalladium-iron (218 mg, 0.335 mmol, 0.10 eq.) was added. and sodium carbonate (709 mg, 6.69 mmol, 2.00 eq.) at 25 °C. The mixture was degassed and purged with nitrogen 3 times, and then stirred at 80 °C for 2 hours. After that time, the reaction mixture was quenched with water (20 mL) and then extracted with ethyl acetate (30 mL χ 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by flash chromatography on silica gel (SiO2, petroleum ether:ethyl acetate 0-10%) in order to obtain 3-cyclopropoxy-6-(l-methyl-lH-pyrazol-5yl)picolinonitrile (750 mg, 2.97 mmol, 89% yield) as a white solid . bHNMR (400 MHz, CD3OD) δ = 7.77 (s, 2H), 7.51 (d, J = 2.0 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 4.22 (s, 3H), 3.96 - 3.91 (m, 1H), 0.98 - 0.92 (m, 4H). Step 2: To a solution of 3-cyclopropoxy-6-(1-methylolH-pyrazol-5-yl)picolinonitrile (650 mg, 2.71 mmol, 1.00 eq.) in acetonitrile (20 mL) was added N- bromosuccinimide (723 mg, 4.06 mmol, 1.50 eq.) at 0 °C, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 mL χ 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, 255 were concentrated, and the residue was purified by prep TLC. (SiO2, petroleum ether: ethyl acetate = 1: 1) in order to obtain 6-(4-bromo-l-methyl-lH-pyrazol-5-yl) -3cyclopropoxypicolinonitrile (1.1 g, crude) as a yellow solid. LCMS [M+l] = 318.9 / 320.9; RMNXH (400 MHz, CDCI3) δ = 8.00 (d, J= 8.8 Hz, 1H), 7.84 (d, J= 9.2 Hz, 1H), 7.52 (s, 1H), 4.05 (s, 3H), 3.99 - 3.92 (m, 1H), 0.99 0.92 (m, 4H) . Step 3: To a solution of 6-(4-bromo-l-methyl-lHpyrazol-5-yl)-3-cyclopropoxypicolinonitrile (300 mg, 0.94 mmol, 1.00 eq.) in THF (20 mL) DIBAL-H (1.00 M, 5.64 mL, 6.00 eq.) was added at 25 °C, and the mixture was stirred at 25 °C for 3 hours. After that time, the reaction was quenched by the addition of sodium thiosulfate solution (20 mL). The mixture was extracted with ethyl acetate (30 mL χ 3), and the combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by means of the TLC prep. (SiO2, petroleum ether: ethyl acetate 1:1) in order to obtain (6-(4-bromo-lmethyl-lH-pyrazol-5-yl)-3-cyclopropoxypyridin-2-yl) methanamine (160 mg, 0.495 mmol) in the form of a yellow solid. A mixture of (6-(4-bromo-l-methyl-lH-pyrazol-5-yl)3-cyclopropoxypyridin-2-yl) methanamine (160 mg, 0.495 mmol, 1.00 eq.) in ethyl formate (3 mL) was stirred at 25 °C for 2 hours, followed by the addition of water (2 mL). The mixture then 256 was extracted with ethyl acetate (3 mL χ 3), and the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by means of TLC prep. (SiO2, petroleum ether: ethyl acetate 0-10%) in order to obtain N-((6-(4-bromol-methyl-lH-pyrazol-5-yl)-3-cyclopropoxypyridin-2-yl)methyl) Formamide (140 mg, 0.359 mmol, 73% yield) as a yellow solid. LCMS [M+l]+= 351.0 / 353.0; NMR (400 MHz, CDC13) δ = 8.36 (s, 1H), 7.68 - 7.61 (m, 2H), 7.55 7.52 (m, 1H), 7.03 (br s, 1H), 4.62 (d, J = 4.4 Hz, 2H), 3.99 (s, 3H), 3.85 (tt, J = 3.2, 5.6 Hz, 1H), 0, 92 - 0.85 (m, 4H). Step 4: To a solution of N-((6-(4-bromo-l-methyl-lHpyrazol-5-yl)-3-cyclopropoxypyridin-2-yl)methyl)formamide (140 mg, 0.359 mmol, 1.00 eq) and diisopropylethylamine (104 mg, 0.80 mmol, 0.14 mL, 2.00 eq.) in dichloromethane (8 mL) Tf2O (225 mg, 0.078 mmol, 0.13 mL, 2.00 eg.) was added. ) at -40 °C, then allowed to warm to room temperature and stirred at 25 °C for 6 hours. After that time, water (2 mL) was added, and the mixture was extracted with ethyl acetate (3 mL χ 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by prep TLC. (SiO2, petroleum ether: ethyl acetate 0-10%) in order to obtain 5- (4-bromo-l-methyl-lH-pyrazol-5-yl) -8cyclopropoxyimidazo[1,5-a]pyridine (110 mg , 0.314 mmol, 79% of 257 yield) in the form of a yellow solid. LCMS [M+l]+= 332.9 / 334.9; NMR (400 MHz, CDC13) δ = 7.72 - 7.60 (m, 3H), 6.61 (d, J = 7.6 Hz, 1H), 6.49 (d, J = 7.4 Hz , 1H) , 3.98 - 3.92 (m, 1H) , 3.77 (s, 3H) , 0.98 - 0.87 (m, 4H) . EO INTERMEDIARY C.N. Step 1: To a solution of 1-(2-methylopyrazol-3yl)ethanone (400 mg, 3.22 mmol, 1.00 eq.) in THE (6 mL) was added l-bromopyrrolidine-2,5-dione ( 1.43 g, 8.06 mmol, 2.50 eq.), and the mixture was stirred at 250 C for 12 hours. After that time, the reaction mixture was concentrated, and the residue was purified by prep TLC. (SÍO2, petroleum ether: ethyl acetate 20%) in order to obtain 2-bromo-l-(4-bromo-2-methylopyrazol-3-yl)ethanone (800 mg, 2.84 mmol, 88% yield) in the form of a yellow oil. LCMS [M+l]+= 282.9; 3H NMR (400 MHz, CDCI3) δ = 7.54 (s, 1H), 4.62 (s, 2H), 4.16 (s, 3H). Step 2: A solution of 2-bromo-l-(4-bromo-2-methylopyrazol-3-yl)ethanone (400 mg, 1.42 mmol, 1.00 eq.) and 2-(2pyridyl)acetonitrile (335 mg, 2.84 mmol, 0.31 mL, 2.00 eg) in acetonitrile (6 mL) was stirred at 70 °C for 11 hours, followed by the addition of triethylamine (431 mg, 4.26 mmol, 0 .59 258 mL, 3.00 eq.), and the mixture was stirred at 70 °C for another hour. The reaction mixture was then concentrated, and the residue was purified by prep TLC. (SÍO2, petroleum ether: ethyl acetate 30%) in order to obtain 2-(4-bromo-2-methyl-pyrazol3-yl)indolizine-l-carbonitrile (100 mg, 0.332 mmol, 23% yield) in the form of a yellow solid. LCMS [M+l]+= 301.0; RMNXH (400 MHz, CDC13) δ = 8.10 (d, J = 6.8 Hz, 1H), 7.72 (d, J= 9.2 Hz, 1H), 7.59 (s, 1H), 7.44 (s, 1H), 7.22 - 7.15 (m, 1H), 6.89 (t, J = 6.4 Hz, 1H), 3.96 (s, 3H). EP INTERMEDIARY To a solution of 4-chloro-2-(cyclopropoxy)-6-(2methylopyrazol-3-yl)benzonitrile (150 mg, 0.55 mmol, 1.00 eq.) in acetic acid (1.0 mL) was added N- iodosuccinimide (247 mg, 1.10 mmol, 2.00 eq.), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was then diluted with ethyl acetate (30 mL) and washed with brine (30 mL χ 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by TLC. prep (SÍO2, petroleum ether: ethyl acetate 20%) in order to obtain 4-chloro-2-(cyclopropoxy)-6(4-iodo-2-methyl-pyrazol-3-yl)benzonitrile (135 mg, 0.33 mmol, 61% yield) as a yellow solid. LCMS [Μ + H]+= 399.9; NMR (400 MHz, CDC13) δ = 7.53 (s, 259 1Η), 7.41 (d, J = 2.0 Hz, 1H) , 6.94 (d, J= 2.0 Hz, 1H) , 3.90 - 3.79 (m, 1H) , 3, 75 (s, 3H) , 0.99 - 0.76 (m, 4H) . EQ INTERMEDIARY Step 1: A mixture of 3-bromopyridine-2-carbaldehyde (1.00 g, 5.38 mmol, 1.00 eq.), l-methyl-5-(4,4,5,5tetramethyl-1,3, 2-dioxaborolan-2-yl)pyrazole (1.12 g, 5.38 mmol, 1.00 eq.), sodium bicarbonate (1.13 g, 13.4 mmol, 0.52 mL, 2.50 eq. . ) and triphenyl phosphine (141 mg, 0.54 mmol, 0.10 eq.) in DMF (10 mL) and water (2 mL) were degassed and purged with nitrogen 3 times, then palladium acetate (60 mg, 0.27 mmol, 0.05 eq. to the mixture, which was stirred at 80 ° C for 16 hours. After that time, the reaction solution was filtered, poured into water (2 mL) and extracted with ethyl acetate (10 mL χ 3).The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography. (SÍO2, petroleum ether: ethyl acetate 20-100%) in order to obtain 3-(2-methylopyrazole-3yl)pyridine-2-carbaldehyde (637 mg, 3.40 mmol, 63% yield) in the form of a solid brown color. LCMS [M+l]+= 188.0; 4H NMR (400 MHz, CDC13) δ = 10.14 - 10.06 (m, 1H), 8.93 (dd, J = 1.6, 4.8 Hz, 1H), 7.79 (dd, J = 1.2, 7.6Hz, 1H), 260, 64 - 7.58 (m, 2H), 6.30 (d, J = 2.0 Hz, 1H), 3.67 (s, 3H). Step 2: To a solution of 3-(2-methylopyrazole-3yl)pyridine-2-carbaldehyde (200 mg, 1.07 mmol, 1.00 eq.) in acetonitrile (5 mL) was added N-iodosuccinimide (480 mg , 2.14 mmol, 2.00 eq.), and the mixture was stirred at 20 ° C for 16 hours. The reaction was diluted with ethyl acetate (35 mL), washed with sat. sodium thiosulfate. (5 mL χ 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SÍO2, petroleum ether: ethyl acetate 20-100%) in order to obtain 3-(4-iodo2-methyl-pyrazole-3-ί1)pyridine-2-carbaldehyde (290 mg, 0.93 mmol, 87% yield) as a white solid. LCMS [M+l]+= 313.8; NMR A (400 MHz, CDC13) δ = 10.07 (s, 1H), 8.97 (dd, J= 1.6, 4.8 Hz, 1H), 7.79 - 7.73 (m, 1H) ), 7.68 (dd, J = 4.8, 7.6 Hz, 1H), 7.63 (s, 1H), 3.69 (s, 3H). Step 3: To a solution of 3-(4-iodo-2-methyl-pyrazol-3yl)pyridine-2-carbaldehyde (290 mg, 0.93 mmol, 1.00 eq.) in DMF (5 mL) was added 2-amino acetic acid (77 mg, 1.02 mmol, 1.10 eq.), iodine (235 mg, 0.93 mmol, 0.18 mL, 1.00 eq.) and sodium bicarbonate (155 mg, 1.85 mmol, 2.00 eq.). The mixture was then stirred at 60 °C for 6 hours. The reaction mixture was diluted with ethyl acetate (35 mL), washed with sat. of sodium thiosulfate (2 mL χ 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SÍO2, 261 petroleum ether: ethyl acetate 20-100%) in order to obtain 8-(4iodo-2-methyl-pyrazol-3-yl)imidazo[1,5-a]pyridine (100 mg, 0.31 mmol, 33 % yield) in the form of a yellow gum. LCMS [M-l] " = 324.9; NMR (400 MHz, CDC13) δ = 8.24 (s, 1H), 8.05 (d, J= 6.4 Hz, 1H), 7.65 (s, 1H), 7.19 (s, 1H), 6, 78 - 6, 69 (m, 2H), 3.82 (s, 3H). ER INTERMEDIARY Step 1: A mixture of 4-chloro-6-(cyclopropoxy)-3fluoro-2-(2-methylopyrazol-3-yl)benzonitrile (200 mg, 0.69 mmol, 1.00 eq.), methyl boronic acid ( 205 mg, 3.43 mmol, 5.00 eq.), ditere-butyl(cyclopentyl)phosphane-dichloropalladioiron (45 mg, 0.069 mmol, 0.10 eq.), and potassium carbonate (284 mg, 2.06 mmol, 3.00 eq.) in dioxane (2 mL) was degassed, purged with nitrogen 3 times and stirred at 100 °C for 2 hours. The mixture was then concentrated and purified by prep TLC. (SIO2, petroleum ether: ethyl acetate 25%) in order to obtain 6-(cyclopropoxy)-3-fluoro-4-methyl-2-(2methylopyrazol-3-yl)benzonitrile (35 mg, 0.10 mmol, 15 % yield) in the form of a yellow oil. LCMS [M+l]+= 274.3; Η2NMR (400 MHz, CDC13) δ = 7.60 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 6.0 Hz, 1H), 6.46 (d, J = 2 ,0Hz, 1H) , 262 3.86 (td, J = 2.8, 5.6 Hz, 1H), 3.80 (s, 3H), 2.43 (d, J = 2.0 Hz, 3H), 0.93 - 0 .88 (m, 4H). Step 2: A mixture of 6-(cyclopropoxy)-3-fluoro-4methyl-2-(2-methylopyrazol-3-yl)benzonitrile (35 mg, 0.13 mmol, 1.00 eq.), N-bromosuccinimide ( 46 mg, 0.26 mmol, 2.00 eq.) in acetonitrile (3 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. The mixture was then concentrated, and the residue was purified by prep TLC. (SIO2, petroleum ether: ethyl acetate 25%) in order to obtain 2-(4-bromo-2methyl-pyrazol-3-yl)-6-(cyclopropoxy)-3-fluoro-4-methylobenzonitrile (25 mg, 0.040 mmol, 31% yield) as a white solid. LCMS [M+l]+= 352.0; 1H NMR (400 MHz, CDCI3) δ = 7.59 (d, J = 2.8 Hz, 1H), 7.31 (br d, J = 2.8 Hz, 1H), 3.90 - 3.83 ( m, 1H), 3.78 (d, J = 2.8 Hz, 3H), 2.44 (br s, 3H), 0.92 (br dd, J = 3.2, 6.4 Hz, 4H ). INTERMEDIARY IS Step 1: To a mixture of 2-iodobenzothiof ene-3carbonitrile (280 mg, 0.98 mmol, 1.00 eq.), sodium carbonate (312 mg, 2.95 mmol, 3.00 eq.) and l- methyl-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (409 mg, 1.96 mmol, 2.00 eq.) in dioxane (4 mL) and water ( 1 mL) ditert-butyl(cyclopentyl)phosphane-dichloropalladium-iron was added (64 263 mg, 0.098 mmol, 0.10 eq.) and sodium carbonate (312 mg, 2.95 mmol, 3.00 eq.), and the mixture was stirred at 80 °C for 2 hours. After that time, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL χ 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by prep TLC. (SiO2, petroleum ether: ethyl acetate 10%) in order to obtain 2-(2-methylopyrazol-3-yl)benzothiophene-3carbonitrile (150 mg, 64% yield) as a yellow solid. 2H NMR (400 MHz, CDCI3) δ (ppm) = 8.06 8.01 (m, 1H), 7.94 - 7.89 (m, 1H), 7.64 - 7.61 (m, 1H), 7.61 7.51 (m, 2H), 6.79 (d, J= 1.6 Hz, 1H), 4.09 (s, 3H). Step 2: To a mixture of 2-(2-methylopyrazole-3yl)benzothiophene-3-carbonitrile (150 mg, 0.63 mmol, 1.00 eq.) in acetonitrile (2 mL) was added N-bromosuccinimide (112 mg , 0.63 mmol, 1.00 eg), and the mixture was stirred at 25 °C for 12 hours. After that time, the reaction mixture was added to a saturated sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (10 mL χ 3). The combined organic phases were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether: 0-ethyl acetate). 100%) to obtain 2-(4-bromo-2-methyl-pyrazol-3-yl)benzothiophene-3-carbonitrile (160 mg, 75% yield) as a colored solid 264 yellow. LCMS [M+l]+= 319.9; RMNXH (400 MHz, CDC13) δ (ppm) = 8.10 - 8.05 (m, 1H), 7.98 - 7.93 (m, 1H), 7.65 (s, 1H), 7.63 - 7.56 (m, 2H), 3.98 (s, 3H). ET INTERMEDIARY Stage 2 ES intermediate, 2-(4-bromo-2-methyl-pyrazol-3yl)thieno[2,3-b]pyridine-3-carbonitrile, was prepared as a yellow solid (80.0 mg, 0. 25 mmol, 22% yield in 2 steps) from thieno[2,3-b]pyridine-3carbonitrile in steps, following the procedure described for Intermediate ER. LCMS [M+l]+=320.9; RMNXH (400 MHz, CDCI3) δ (ppm) = 8.78 (dd, J= 1.6, 4.4 Hz, 1H), 8.34 (dd, J = 1.6, 8.0 Hz, 1H) ), 7.66 (s, 1H), 7.58 (dd, J = 4.4, 8.0 Hz, 1H), 3.99 (s, 3H). EU INTERMEDIARY Step 1: To a solution of 2-methylosulfonylethanol (569 mg, 4.58 mmol, 1.20 eq.) in DMF (30 mL) was added sodium hydride (183 mg, 4.58 mmol, 60.0% purity, 1.20 eg.) at 0 °C. After stirring for 0.5 hours, 4-chloro-2 was added 265 fluoro-6-(2-methylopyrazol-3-yl)benzonitrile (900 mg, 3.82 mmol, 1.00 eq.) in DMF (5 mL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. After that time, the mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL χ 3), the aqueous phase was adjusted to pH 1 with HC1 (10 mL) and further extracted with ethyl acetate ( 100 mL χ 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain 4-chloro-2-hydroxy-6-(2-methylopyrazol-3yl)benzonitrile (455 mg, crude) as a solid. yellow in color, which was used in the next step without further purification. LCMS [M]+= 234.1; RMNXH (400 MHz, DMSO-d6) δ = 11.96 (br s, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 3.76 (s, 3H). Step 2: To a solution of 4-chloro-2-hydroxy-6-(2methylopyrazol-3-yl)benzonitrile (150 mg, 0.642 mmol, 1.00 eq.) and 2-chloro-2,2-difluoro-acetate of sodium (392 mg, 2.57 mmol, 4.00 eq.) in DMF (2 mL) and water (0.2 mL) cesium carbonate (314 mg, 0.96 mmol, 1.50 eq.) was added. The mixture was stirred at 100 °C for 1 hour. The reaction mixture was then quenched by adding water (40 mL) and extracted with ethyl acetate (20 mL χ 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue 266 was purified by prep TLC. (S1O2, petroleum ether: ethyl acetate 25%) to obtain 4-chloro-2(difluoromethoxy)-6-(2-methylopyrazol-3-yl) benzonitrile (85 mg, 0.30 mmol, 47% yield ) in the form of a yellow solid. LCMS [M]+= 284.0; NMR (400 MHz, DMSQ-d6) δ (ppm) = 7.76 (s, 1H), 7.74 (d, J= 2.0 Hz, 1H), 7.72 - 7.71 (m, 1H ), 7.58 (d, J = 2.0 Hz, 1H) , 7.54 (s, 1H) , 7.36 (s, 1H) , 6.60 (d, J = 2.0 Hz, 1H) ), 3.80 (s, 3H). Step 3: To a solution of 4-chloro-2-(difluoromethoxy)-6(2-methylopyrazol-3-yl) benzonitrile (85 mg, 0.30 mmol, 1.00 eq.) in acetic acid (2 mL) N-iodide succinimide (135 mg, 0.60 mmol, 2.00 eq.) was added. The mixture was stirred at 25 °C for 1 hour, then the reaction mixture was quenched by adding water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by prep TLC. (SÍO2, petroleum ether: ethyl acetate 20%) in order to obtain 4-chloro-2-(difluoromethoxy)-6-(4-iodo-2-methylopyrazol-3-yl) benzonitrile (90 mg, 0.22 mmol , 73% yield) as a yellow solid. LCMS [M + H]+= 409, 9; RMNXH (400 MHz, CD3OD-d4) δ (ppm) = 7.72 - 7.68 (m, 1H), 7.67 (s, 1H), 7.52 (d, J= 2.0 Hz, 1H ), 7.42 - 7.02 (m, 1H), 3.83 (s, 3H). 267 EV INTERMEDIARY Step 1: A mixture of 7-bromo-l,3-benzothiazol-6-amine (2.00 g, 8.73 mmol, 1.00 eq.), zinc cyanide (1.54 g, 13.1 mmol , 1.50 eq.), Pd2(dba)3(80 mg, 0.87 mmol, 0.01 eq.), DPPF (97 mg, 0.175 mmol, 0.02 eq.) and zinc powder (5, 7 mg, 0.087 mmol, 0.01 eq.) in DMF (20 mL) was degassed, purged with nitrogen 3 times, and then stirred at 140 °C for 16 hours. After that time, the reaction mixture was extracted with 150 mL ethyl acetate (50 mL χ 3), and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated , and the residue formed was purified by means of column chromatography (SiO2, petroleum ether: ethyl acetate 10-25%) in order to obtain 6-amino-l,3-benzothiazol-7-carbonitrile (1.05 g , 4.66 mmol, 53% yield) as a yellow solid. LCMS [M+l]+= 176.1; NMR (400 MHz, CDC13-d) δ = 8.79 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H) ), 4.69 (br s, 2H). Step 2: A mixture of 6-amino-l,3-benzothiazol-7carbonitrile (500 mg, 2.85 mmol, 1.00 eq.), paratoluenesulfonic acid (590 mg, 3.42 mmol, 1.20 eq.) , tere-butyl 268 nitrite (353 mg, 3.42 mmol, 407 uL, 1.20 eq.), tetrabutylammonium bromide (1.84 g, 5.71 mmol, 2.00 eg.) and copper bromide (64 mg, 0.286 mmol, 0.10 eg) in acetonitrile (15 mL) was degassed with nitrogen and stirred at 25 °C for 6 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl acetate 10-25%) to obtain 6bromo-1,3-benzothiazol-7-carbonitrile. (300 mg, 1.25 mmol, 44% yield) as a yellow solid. LCMS [M+l]+= 240, 9; Η4NMR (400 MHz, CDCI3) δ = 9.11 (s, 1H), 8.20 (d, J= 8.8 Hz, 1H), 7.81 (d, J= 8.8 Hz, 1H). Step 3: A mixture of l-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyrazole (261 mg, 1.25 mmol, 1.00 eq.), 6-bromo-l,3-benzothiazol-7-carbonitrile (300 mg, 1.25 mmol, 1.00 eg), ditert-butyl(cyclopentyl)phosphane;dichloropalladium iron (82 mg, 0.125 mmol, 0.10 eg. .) and sodium bicarbonate (316 mg, 3.76 mmol, 3.00 eg.) in dioxane (10 mL) and water (2 mL) were degassed with nitrogen and then stirred at 80 °C for 3 hours under a nitrogen atmosphere. The mixture was then concentrated, and the residue was purified by column chromatography (S1O2, petroleum ether: ethyl acetate 5-25%) to obtain 6-(2-methylopyrazol-3-yl)-1, 3benzothiazol-7-carbonitrile (280 mg, 0.89 mmol, 71% yield) as a yellow solid. LCMS [M+l]+= 241.0; NMR A (400 MHz, CDCl3-d) δ = 9.21 (s, 1H), 269 8.43 (d, J = 8.4 Hz, 1H), 7.66 - 7.58 (m, 2H), 6.58 (d, J = 2.0 Hz, 1H), 3.91 (s , 3H). Step 4: A mixture of 6-(2-methylopyrazol-3-yl)-1,3benzothiazol-7-carbonitrile (140 mg, 0.58 mmol, 1.00 eq.), Nbromosuccinimide (207 mg, 1.17 mmol , 2.00 eg) in acetonitrile (3 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. The mixture was then concentrated, and the residue was purified by column chromatography (SIO2, petroleum ether: ethyl 5-20%) in order to obtain 6-(4-bromo-2-methylopyrazol-3-yl) -1,3-benzothiazol-7-carbonitrile (300 mg, 0.47 mmol, 81% yield) as a white solid. LCMS [M+1]+= 321.0; Η3NMR (400 MHz, CDCl3-d) δ = 9.25 (s, 1H), 8.48 (d, J= 8.4 Hz, 1H), 7.65 (s, 1H), 7.61 (d , J = 8.4 Hz, 1H), 3.85 (s, 3H). EW INTERMEDIARY Step 1: To a solution of 3-(hydroxymethyl)-1methylpyridin-2(1H)-one (650 mg, 4.67 mmol, 1.00 eq.) in dichloromethane (15 mL) was added thionyl chloride (667 mg , 5.61 mmol, 407 uL, 1.20 eg.), and the mixture was stirred at 25°C for 2 hrs. The mixture was concentrated in vacuo to obtain 3-(chloromethyl)-l-methyl-pyridin-2-one (650 mg, crude) in 270 form of a white solid. Step 2: To a solution of 3-(chloromethyl)-1-methylopyridin-2-one (650 mg, 4.12 mmol, 1.00 eq.), 4-bromo-5-chloroIH-pyrazole (747 mg, 4 .12 mmol, 1.00 eq.) in acetonitrile (20 mL), potassium carbonate (683 mg, 4.94 mmol, 1.20 eq.) was added, and the mixture was stirred at 80 °C for 12 hours. The reaction was then quenched with water (100 mL) and extracted with ethyl acetate (50 mL χ 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether: 5% ethyl acetate) to obtain 3-[(4-bromo-5-chloro-pyrazol-l-yl)methyl]-1- Methylpyridin-2-one (270 mg, 0.89 mmol, 51% yield) as a yellow solid. LCMS [M+l]+= 304.0. Step 3: To a solution of 3-[(4-bromo-5-chloro-pyrazol1-yl)methyl]-l-methyl-pyridin-2-one (270 mg, 0.89 mmol, 1.00 eq.) , 4-bromo-l-methyl-5-(4,4,5,5-tetramethyl-l, 3,2dioxaborolan-2-yl)pyrazole (512 mg, 1.78 mmol, 2.00 eq.) in dioxane (10 mL) and water (1 mL), Pd(dppf)Cl2 (65 mg, 0.089 mmol, 0.10 eq.) and sodium bicarbonate (150 mg, 1.78 mmol, 69 pL, 2.00 eq.) were added. . ) . The mixture was stirred at 110 °C for 10 hours. The reaction mixture was then quenched by the addition of water (50 mL) and extracted with ethyl acetate (30 mL χ 3). The combined organic layers were washed with brine (30 mL), 271 dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep HPLC. (Phenomenex Gemini-NX 80 mm χ 40 mm χ 3 pm; mobile phase: [water (10 mM NH4HCO3) -ACN]; B%: 5%-35%, 8 min) in order to obtain 3-[[5- chloro4-(2-methylopyrazole-3-yl)pyrazol-l-yl]methyl]-1-methylopyridin-2-one (60.0 mg, 0.198 mmol, 22% yield) as a gray solid. LCMS [M+1]+= 304.1; ^-H NMR (400 MHz, DMSO-de) δ = 8.24 (s, 1H), 7.73 (d, J= 2.0, 6.8 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H) , 7.32 (d, J= 5.2 Hz, 1H) , 6.39 (d, J= 2.0 Hz, 1H) , 6.25 (t, J= 6 .8 Hz, 1H), 5.14 (s, 2H), 3.79 (s, 3H), 3.45 (s, 3H). Step 4: To a solution of 3-((5'-chloro-2-methyl-l Ή, 2H[3,4'-bipyrazol]-1'-yl)methyl)-l-methylopy...

Claims

1. A compound of Formula (I): or Formula (I) or one of its pharmaceutically acceptable salts: characterized in that: R1 is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-Cl-C5 alkyl, -Y-cycloalkyl, -Y-heterocyclyl, -Y-aryl, -YarCl-C3alkyl or -Y-heteroaryl, wherein the cycloalkyl portions, the heterocyclyl portions, the aryl portions, and the heteroaryl portions are each optionally substituted with one or more R2; each Y is independently a bond or -NR4-;each R2 is independently hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SCgCl C3alkyl, -X-arCl-C3alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-Cl-C5 alkyl, -Z-Cl-C5 alkyl, heterocyclyl, -XL-cycloalkyl, -Z-cycloalkyl, -X-aryl, Z-aryl, or -X-heteroaryl wherein the heterocyclyl, cycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R5s, or each X is independently a bond, O, S, -NR4 or -NR4C(O)-; each Z is independently a bond, -SO-, -SO2, -CH(OH)- or -C(O)-; each L is independently a C1-C3 alkyl linkage; R3a and R3b are each independently hydrogen or deuterium, or R3a and R3b together are oxo; each R4 is independently hydrogen or C1-C3 alkyl;each R5 is independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Zcycloalkyl, -X-arCl-C3alkyl, X-arCl-C3alkyl substituted with cyano, -XL-cycloalkyl, -XL-heteroaryl optionally substituted with one or more Cl-C3alkyl or oxo, or -X-aryl; and R6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

2. The compound according to claim 1, characterized in that R1 is -Y-heteroaryl optionally substituted with one or more R2s, Y is a linker, and the heteroaryl is pyrazolyl, imidazoyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, oxidazolyl, pyridyl, pyridiazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrazolopyridinyl, 1H-pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridyl, tetrahydropyrazolopyrazinyl, 2H-4L4-imidazopyrimidinyl, 2H-4X4-imidazopyridazinyl, oxazolopyridyl or 5,6-dihydro-8H-imidazooxazinyl, each optionally substituted with one or more R2s.

3. The compound according to claim 2, characterized in that the heteroaryl is pyrazolyl, optionally substituted with one, two or three R2 groups.

4. The compound according to claim 3, characterized in that the pyrazolyl is substituted with an R2.

5. The compound according to claim 3, characterized in that the pyrazolyl is substituted with two independently selected R2 groups.

6. The compound according to claim 5, characterized in that the two R2 groups are (1) independently -X-Cl-C5 alkyl, (2) -X-Cl-C5 alkyl and halogen, (3) -X-Cl-C5 alkyl and alkoxy, (4) -X-Cl-C5 alkyl and -N(R4)2, (5) X-Cl-C5 alkyl and -X-haloalkyl, (6) -X-Cl-C5 alkyl and arCl-C3alkyl, (7) -X-Cl-C5 alkyl and -XL-cyclolalkyl, (8) -X-Cl-C5 alkyl and -heterocyclyl, (9) -X-Cl-C5 alkyl and -X-aryl optionally substituted with one or more R5 groups, (10) -X-Cl-C5 alkyl and -X-heteroaryl optionally substituted with one or more R5, (11) -X-Cl - C5 alkyl and cyanomethyl, (12) -X-Cl - C5 alkyl and cyano, (13) cyano and halogen, wherein the halogen is chlorine or fluorine, (14) 521 cyano and -XL-cycloalkyl, (15) independently halogen, (16) cyano and alkoxy, wherein each X is a bond, (17) cyano and -X-aryl, (18) cyano and -X-heteroaryl, (19) cyano and heterocyclyl, (20) halogen and -X-arCl-C3alkyl or X-arClC3 alkyl substituted with cyano,and (21) halogen and -X-aryl., 7. A compound according to claim 1, characterized in that it has Formula (ID): or R6 Formula (ID) or one of its pharmaceutically acceptable salts: wherein R2 is hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SO2CI-C3alkyl, -X-arCl-C3alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-Cl-C5alkyl, -Z-Cl-C5alkyl, heterocyclyl, -XL-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl, or -X-heteroaryl, wherein the heterocyclyl, cycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R5s; each X is independently a bond, O, S, -NR4, or -NR4C(O)-; each Z is independently a bond, -SO-, -SO2522 , -CH(OH)- or -C(O)-; each L is independently a bond or Cl - C3 alkylene; each R4 is independently hydrogen or Cl - C3 alkyl;each R5 is independently cyano, oxo, halogen, C3-Cl alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Zcycloalkyl, -X-arCl-C3alkyl, X-arCl-C3alkyl substituted with cyano, -XL-cycloalkyl, -XL-heteroaryl optionally substituted with one or more C3-Cl alkyl or oxo, or -X-aryl; and R6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

8. The compound according to claim 1, characterized in that it is: Ρχ+Η 0 H2N uy„ o cA Aiyy 0 X\AN H2N xy 0 N H2N 0 Cl .N H2N 537 538 539 540 542 543 544 545 546 547 548 or one of its pharmaceutically acceptable salts.

9. The compound according to claim 1, characterized in that it is:

10. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound of Formula (I) according to claim 1 or a pharmaceutically acceptable salt or solvate of the compound, and a pharmaceutically acceptable excipient.

11. A method for treating cancer, characterized in that it comprises administering to a patient having cancer a therapeutically effective amount of a compound of Formula (I) according to claim 1 or a pharmaceutically acceptable salt or solvate of the compound, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent.

12. The method according to claim 11, characterized in that the cancer is selected from the group consisting of: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, lymphoma, lymphoma), stomach (carcinoma, lymphoma, lymphoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, lymphoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, lymphoma);genitourinary tract: kidney (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma;bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, chordoma of malignant giant cell tumor, osteochromomatoma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), neurofibroma of the spinal cord, meningioma, glioma, sarcoma);Gynecologic: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), fecal granulosa cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (carcinoma); hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi sarcoma, atypleus moles, dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and adrenal glands: neuroblastoma.; 13. The method according to claim 11, characterized in that the cancer is hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer.

14. The compound according to claim 1, characterized in that it is or one of its pharmaceutically acceptable salts.

15. A pharmaceutically acceptable salt of the compound according to claim 1, characterized in that the compound is 552 16. The method according to claim 11, characterized in that the compound of Formula (I) is or one of its pharmaceutically acceptable salts.

17. The method according to claim 11, characterized in that the compound of Formula (I) is 18. The method according to claim 11, characterized in that the compound of Formula (I) is a pharmaceutically acceptable salt of a compound of formula