MTA-cooperative PRMT5 inhibitor

Abstract

The present invention relates to compounds that inhibit protein arginine N-methyltransferase 5 (PRMT5) activity. In particular, the present invention relates to compounds, pharmaceutical compositions, and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention. [Formula 1] JPEG2022548255000379.jpg4234

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 899,575, filed September 12, 2019, U.S. Provisional Patent Application No. 62 / 942,833, filed December 3, 2019, U.S. Provisional Patent Application No. 62 / 961,371, filed January 15, 2020, U.S. Provisional Patent Application No. 62 / 994,927, filed March 26, 2020, and U.S. Provisional Patent Application No. 63 / 060,261, filed August 3, 2020, the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] The present invention relates to compounds that are MTA-cooperative inhibitors of protein arginine N-methyltransferase 5 (PRMT5). In particular, the present invention relates to compounds, pharmaceutical compositions containing those compounds, and methods of their use. [Background technology]

[0003] Protein arginine N-methyltransferase (PRMT5) is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the ω-nitrogen of the guanidino functional group of L-arginine residues in proteins (ω-monomethylation), and the transfer of a second methyl group to the other ω-nitrogen, resulting in symmetric dimethylarginine (sDMA). PRMT5 forms a complex with MEP50 (methylosomal protein 50), which is required for substrate reorganization and orientation, as well as for PRMT5-catalyzed histone 2A and histone 4 methyltransferase activity (see, e.g., Ho et al., (2013) PLOS ONE 8(8):10.1371 / annotation / e6b5348e-9052-44ab-8f06-90d01dc88fc2).

[0004] Homozygous deletions of p16 / CDKN2a are common in cancer, and these mutations are commonly associated with co-deletions of adjacent genes, including the gene encoding methylthioadenosine phosphorylase (MTAP). It is estimated that approximately 15% of all human cancers have homozygous deletions of the MTAP gene (see, e.g., Firestone & Schramm (2017) J. Am. Chem Soc. 139(39):13754-13760. doi:10.1021 / jacs.7b05803. Epub 2017 Sep 20).

[0005] Cells lacking MTAP activity have elevated levels of the MTAP substrate, methylthioadenosine (MTA), a potent inhibitor of PRMT5. Inhibition of PRMT5 activity results in decreased methylation activity and increased sensitivity of cell proliferation to PRMT5 depletion or loss of activity. Thus, loss of MTAP activity reduces the methylation activity of PRMT5 and renders cells selectively dependent on PRMT5 activity. Summary of the Invention

[0006] Thus, the present inventors have recognized that MTA-cooperative inhibition of PRMT5 activity in MTAP-deficient cancers provides therapeutic benefit against a wide range of cancers. The compounds of the present invention provide this therapeutic benefit as MTA-cooperative inhibitors of PRMT5 to negatively regulate the activity of MTA-bound PRMT5 in cells, particularly MTAP-deficient cells, or to treat various forms of MTAP-associated cancers.

[0007] There is a need to develop new MTA-cooperative PRMT5 inhibitors that can inhibit PRMT5 activity in the presence of elevated MTA concentrations, especially in MTAP-deficient cells.

[0008] In one aspect of the present invention, a compound of formula (I): [ka] and pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-C1-C5 alkyl, -Y-cycloalkyl, -Y-heterocyclyl, -Y-aryl, -Y-arC1-C3 alkyl, or -Y-heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl moieties are each selected from one or more R 2 is optionally replaced by each Y is independently a bond or -NR 4 - and Each R 2 are independently selected from hydroxy, halogen, cyano, cyanomethyl, -(NR 4 )2, hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, -X-arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclyl, -XL-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl, or -X-heteroaryl, wherein the heterocyclyl, cycloalkyl, aryl, and heteroaryl are independently selected from one or more R 5 is optionally replaced by Each X is independently a bond, O, S, or -NR 4 -or-NR 4 C(O)-, each Z is independently a bond, —SO—, —SO2—, —CH(OH)—, or —C(O)—; each L is independently a bond or C1-C3 alkylene; R 3a and R 3b are each independently hydrogen or deuterium, or R 3a and R 3b But together, it is Oxo, Each R 4 are independently hydrogen or C1-C3 alkyl; Each R 5are independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, X-arC1-C3 alkyl substituted with cyano, -XL-cycloalkyl, -XL-heteroaryl optionally substituted with one or more C1-C3 alkyl or oxo, or -X-aryl; R 6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl, or alkoxy.

[0009] In one aspect of the present invention, a compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , Y, X, Z, and L are each as defined for formula I.

[0010] In one aspect of the present invention, a compound represented by formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , Y, X, Z, and L are each as defined for formula I.

[0011] In one aspect of the present invention, a compound represented by formula (IC), s [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , Y, X, Z, and L are each as defined for formula I.

[0012] In another aspect of the present invention, a compound of formula (ID): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, each Y is independently a bond or -NR 4 - and Each R 2 are independently selected from hydroxy, halogen, cyano, cyanomethyl, -(NR 4 )2, hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, -X-arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclyl, -XL-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl, or -X-heteroaryl, wherein the heterocyclyl, cycloalkyl, aryl, and heteroaryl are independently selected from one or more R 5 optionally replaced by, or Each X is independently a bond, O, S, or -NR 4 -or-NR 4 C(O)-, each Z is independently a bond, —SO—, —SO2—, —CH(OH)—, or —C(O)—; each L is independently a bond or C1-C3 alkylene; Each R 4 are independently hydrogen or C1-C3 alkyl; Each R 5are independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, X-arC1-C3 alkyl substituted with cyano, -XL-cycloalkyl, -XL-heteroaryl optionally substituted with one or more C1-C3 alkyl or oxo, or -X-aryl; R 6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl, or alkoxy.

[0013] In another aspect of the present invention, intermediates useful in the preparation of compounds of formula (I), formula (IA), formula (IB), and formula (IC) are provided.

[0014] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0015] In yet another aspect of the present invention, there is provided a method for inhibiting PRMT5 activity in a cell, the method comprising contacting the cell with a compound of Formula (I), Formula (IA), Formula (IB), and Formula (IC). In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0016] Also provided herein are methods of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), Formula (IA), Formula (IB), and Formula (IC), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the cell is an MTAP-deficient cell.

[0017] Also provided is a method for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention, or a pharmaceutically acceptable salt thereof.

[0018] Also provided herein are methods of treating cancer in a patient in need thereof, the methods comprising: (a) determining that the cancer is associated with an MTAP double deletion (e.g., an MTAP-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (IA), Formula (IB), and Formula (IC), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention relates to MTA-associated PRMT5 inhibitors. In particular, the present invention relates to compounds that inhibit PRMT5 activity in the presence of bound MTA, pharmaceutical compositions containing therapeutically effective amounts of the compounds, and methods of using them.

[0020] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs.All patents, patent applications and publications mentioned in this specification are incorporated by reference to the extent that they are consistent with this disclosure.Unless otherwise explicitly defined, terms and scopes have the definitions that are generally defined.

[0021] For brevity, chemical moieties are defined and referred to throughout primarily as monovalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under appropriate structural circumstances apparent to one of ordinary skill in the art. For example, an "alkyl" moiety generally refers to a monovalent radical (e.g., CH3-CH2-), but in certain circumstances, a divalent linking moiety can be "alkyl," in which case one of ordinary skill in the art would understand alkyl to be the divalent radical equivalent to the term "alkylene" (e.g., -CH2-CH2-). (Similarly, in situations where a divalent moiety is required and is described as "aryl," one of ordinary skill in the art would understand the term "aryl" to refer to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal valence numbers for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of S).

[0022] As used herein, "PRMT5" refers to the mammalian protein arginine N-methyltransferase 5 (PRMT5) enzyme.

[0023] As used herein, "PRMT5 inhibitor" or "MTA-associated PRMT5 inhibitor" refers to a compound of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of PRMT5 in the presence of bound MTA in vitro or in vivo, or in cells expressing elevated levels of MTA.

[0024] As used herein, "MTAP" refers to the mammalian methylthioadenosine phosphorylase (MTAP) enzyme.

[0025] As used herein, "MTAP-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a loss of MTAP activity that sensitizes the disorder to selective inhibition of PRMT5 activity. A non-limiting example of an MTAP-associated disease or disorder is an MTAP-associated cancer.

[0026] The term "amino" refers to -NH2.

[0027] The term "acetyl" refers to -C(O)CH3.

[0028] As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent, where the alkyl and aryl moieties are as defined herein.

[0029] The term "alkyl" as used herein refers to saturated straight- and branched-chain aliphatic groups having 1 to 12 carbon atoms. Thus, "alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C 10 , C 11 and C 12 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0030] As used herein, the term "alkenyl" refers to an unsaturated straight- or branched-chain aliphatic group having 2 to 12 carbon atoms and one or more carbon-carbon double bonds. Thus, "alkenyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C5 10 , C 11 and C 12 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0031] As used herein, the term "alkynyl" refers to an unsaturated straight- or branched-chain aliphatic group having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. Thus, "alkynyl" refers to any of C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52 10 , C 11 and C 12 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0032] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is positioned between and functions to link two other chemical groups, as defined herein above. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Exemplary alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0033] The term "alkoxy" refers to -OC1-C6 alkyl.

[0034] The term "cycloalkyl" as used herein refers to saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons. Thus, "cycloalkyl" refers to C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C5 10 , C 11 , and C 12 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0035] The term "heteroalkyl" refers to an alkyl group, as defined herein above, wherein one or more carbon atoms in the chain are independently O, S, or NRx is replaced by R x refers to an alkyl group where R is hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0036] An "aryl" group is a C6-C aryl group containing one to three aromatic rings. 14 It is an aromatic moiety. Therefore, "aryl" includes C6, C 10 , C 13 , and C 14 Cyclic hydrocarbon groups are included. Exemplary aryl groups include C-C 10 It is an aryl group. Particular aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. "Aryl" groups also include fused polycyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic, such as indenyl.

[0037] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently bonded to an alkyl group, which is linked to another group via the alkyl portion. Exemplary aralkyl groups are -(C1-C6)alkyl(C6-C10)aryl, including, but not limited to, benzyl, phenethyl, and naphthylmethyl. For example, arC1-C3alkyl is an aryl group covalently bonded to a C1-C3 alkyl.

[0038] A "heterocyclyl" or "heterocyclic" group is a monocyclic or bicyclic (fused or spiro) ring structure having 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms), e.g., 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR 4, O, or S, with the remainder of the ring atoms being quaternary or carbonyl carbons. Examples of heterocyclic groups include, but are not limited to, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, THFyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0039] As used herein, "L-heterocyclyl" refers to a heterocyclyl group covalently linked to another group via an alkylene linker.

[0040] 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, with 6, 10, or 14 pi electrons shared in a cyclic arrangement, and having, in addition to carbon atoms, 1 to 3 heteroatoms, each independently N, O, or S. "Heteroaryl" also includes fused polycyclic (e.g., bicyclic) ring systems in which at least one ring is aromatic and one or more fused rings are non-aromatic, provided that at least one ring contains an N, O, or S ring atom.

[0041] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(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, cinnolinyl, furanyl, furanyl, and the like. Zanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 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, oxazo Allyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclinyl thiazinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0042] 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 C1-C6 alkyl groups and heteroaryl groups 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, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent ring oxygen and / or sulfur atoms.

[0043] An "arylene," "heteroarylene," or "heterocyclylene" group is a divalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined herein above, that is positioned between and serves to connect two other chemical groups.

[0044] As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as "optionally substituted" without explicitly reciting the substituents, it means that the group optionally has 1 to 4, preferably 1 to 3, and more preferably 1 or 2 non-hydrogen substituents.

[0045] The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine, or iodine.

[0046] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogen. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0047] The term "hydroxyalkyl" refers to -alkylene-OH.

[0048] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of the PRMT5 enzyme.

[0049] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to alleviate or in any way reduce symptoms, or to stop or reverse the progression of a condition, or to negatively regulate or inhibit the activity of PRMT5. Such an amount can be administered as a single dose or according to a dosing regimen, whereby the amount is effective.

[0050] As used herein, treatment refers to any manner in which the symptoms or pathology of a condition, disorder, or disease are alleviated or beneficially altered in a patient.

[0051] As used herein, alleviation of symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any relief, whether permanent or temporary, persistent or transient, that can result from or be associated with the administration of the composition.

[0052] compound In one aspect of the present invention, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-C1-C5 alkyl, -Y-cycloalkyl, -Y-heterocyclyl, -Y-aryl, -Y-arC1-C3 alkyl, or -Y-heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl moieties are each selected from one or more R 2is optionally replaced by Each Y is a bond or -NR 4 - and Each R 2 are independently selected from hydroxy, halogen, cyano, cyanomethyl, -(NR 4 )2, hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, -X-arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclyl, -XL-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl, or -X-heteroaryl, wherein the heterocyclyl, cycloalkyl, aryl, and heteroaryl are independently selected from one or more R 5 is optionally replaced by Each X is independently a bond, O, S, or -NR 4 -or-NR 4 C(O)-, each Z is independently a bond, —SO—, —SO2—, —CH(OH)—, or —C(O)—; each L is independently a bond or C1-C3 alkylene; R 3a and R 3b are each independently hydrogen or deuterium, or R 3a and R 3b But together, it is Oxo, Each R 4 are independently hydrogen or C1-C3 alkyl; Each R 5 are independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, X-arC1-C3 alkyl substituted with cyano, -XL-cycloalkyl, -XL-heteroaryl optionally substituted with one or more C1-C3 alkyl or oxo, or -X-aryl; R 6 is hydrogen, halogen, haloalkyl, C1-C3 alkyl, or alkoxy.

[0053] In one embodiment for compounds of formula (I), R 1 is hydrogen.

[0054] In another embodiment for compounds of formula (I), R 1 is a halogen. In certain embodiments, the halogen is bromine.

[0055] In one embodiment for compounds of formula (I), R 1 is -L-CN. In one embodiment, L is C1-C3 alkylene. In certain embodiments, C1-C3 alkylene is methylene.

[0056] In one embodiment for compounds of formula (I), R 1 is -Y-C1-C5 alkyl. In one embodiment, Y is a bond and C1-C5 alkyl is methyl. In one embodiment, Y is -NR 4 -, and C1-C5 alkyl is methyl, ethyl, or propyl.

[0057] In one embodiment for compounds of formula (I), R 1 is hydroxyalkyl.

[0058] In one embodiment for compounds of formula (I), R 1 is -Y-heterocyclyl. In certain embodiments, Y is a bond and heterocyclyl is azetidinyl, THFyl, or morpholinyl.

[0059] In one embodiment for compounds of formula (I), R 1 is -Y-aryl, and aryl is one or more R 2 is optionally replaced by

[0060] In certain embodiments, Y is a bond and the aryl is selected from one or two R 2 In one embodiment, one or two R 2The groups are each independently C1-C3 alkyl, cyano, or halogen.

[0061] In one embodiment for compounds of formula (I), R 1 is -Y-cycloalkyl. In one embodiment, Y is a bond and cycloalkyl is cyclopentyl.

[0062] In one embodiment for compounds of formula (I), R 1 is one or more R 2 In certain embodiments, heteroaryl is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, oxidazolyl, pyridyl, pyridiazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrazolopyridinyl, 1H-pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridyl, tetrahydropyrazolopyrazinyl,

number

number

[0063] In one embodiment, R 1 is -Y-heteroaryl, Y is a bond, heteroaryl is azetidinyl, and R 2 is -(NR 4 )2.

[0064] In one embodiment, R 1 is heteroaryl, Y is a bond, and the heteroaryl is selected from one or more R 2In one embodiment, the tetrahydropyrazolopyrazinyl is a tetrahydropyrazolopyrazinyl optionally substituted with one or more R 2 In one embodiment, the tetrahydropyrazolopyrazinyl is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl optionally substituted with one R 2 In one embodiment, R 2 is -X-C1-C5 alkyl, arC1-C3 alkyl, -Z-C1-C5 alkyl, -Z-cycloalkyl, or -X-aryl. 2 is -Z-cycloalkyl, where Z is a bond and cycloalkyl is cyclopropyl. 2 is -Z-cycloalkyl, where Z is -C(O)-, and cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[1.1.1]pentyl.

[0065] R 1 In one embodiment where Y-heteroaryl, Y is a bond and the heteroaryl is selected from one or more R 2 In one embodiment, the pyrazolylpyridinyl is a pyrazolopyridinyl optionally substituted with one R 2 and one R 2 is alkoxy or -X-aryl. In one embodiment, alkoxy is methoxy or isopropyloxy. In certain embodiments, -X-aryl, where X is O and aryl is phenyl.

[0066] In one embodiment, Y is a bond and R 1 Heteroaryl is a heteroaryl group consisting of one or two R 2 In certain embodiments, pyridyl is optionally substituted with one R 2 is substituted with R 2 is hydroxy, halogen, cyano, cyanomethyl, -(NR 4)2, hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclyl, -XL-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl, or -X-heteroaryl, wherein heterocyclyl, cycloalkyl, aryl, and heteroaryl are selected from the group consisting of one or more R 5 is optionally replaced by

[0067] In one embodiment, R 1 is Y-heteroaryl, Y is a bond, heteroaryl is pyridyl, and R 2 is -X-C1-C5 alkyl, where X is a bond and C1-C5 alkyl is methyl, ethylpropyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl.

[0068] In one embodiment, R 1 is -Y-heteroaryl, where Y is a bond, heteroaryl is pyridyl, and R 2 is -X-haloalkyl, where X is a bond and haloalkyl is difluoromethyl or trifluoromethyl. 2 is -X-haloalkyl, where X is O and haloalkyl is difluoromethyl or trifluoromethyl.

[0069] In one embodiment, R 1 is -Y-heteroaryl, Y is a bond, heteroaryl is pyridyl, and R 2 is -XL-cycloalkyl, X is a bond, L is a bond, and cycloalkyl is cyclopropyl or cyclohexyl. 2 is -XL-cycloalkyl, where X is a bond, L is methylene, and cycloalkyl is cyclopropyl. 2is -XL-cycloalkyl, X is O, L is methylene and cycloalkyl is cyclopropyl.

[0070] In one embodiment, R 1 is -Y-heteroaryl, Y is a bond, heteroaryl is pyridyl, and R 2 is a C2-C4 alkynyl, wherein the alkynyl is ethynyl or prop-2-ynyl.

[0071] In another embodiment, R 1 is -Y-heteroaryl, Y is a bond, heteroaryl is pyridyl, and R 2 is —SO 2 C 1 -C 3 alkyl, where C 1 -C 3 alkyl is methyl.

[0072] In one embodiment, R 1 is -Y-heteroaryl, Y is a bond, heteroaryl is pyridyl, and R 2 is heterocyclyl, wherein the heterocyclyl is morpholinyl or tetrahydropyranyl.

[0073] In other embodiments, R 1 is -Y-heteroaryl, Y is a bond, heteroaryl is pyridyl, and R 2 is -X-heteroaryl, where heteroaryl is one or more R 5 In one embodiment, X is a bond and the heteroaryl is optionally substituted with one R 5 and R is a pyrazolyl substituted with 5 is C1-C3 alkyl. In one embodiment, X is a bond and the heteroaryl is each one R 5 and pyridyl or pyrimidinyl optionally substituted with

[0074] In one embodiment, R 1 is Y-heteroaryl, Y is a bond, heteroaryl is pyridyl, and R 2is arC1-C3 alkyl, and arC1-C3 alkyl is benzyl.

[0075] R 1 In one embodiment where is -Y-heteroaryl, Y is a bond, heteroaryl is pyridyl, and R 2 is -X-heteroaryl, where X is O and heteroaryl is one or more R 5 In another embodiment, X is -NR 4 -, and heteroaryl is one or more R 5 and quinolinyl optionally substituted with

[0076] In one embodiment, R 1 is -Y-heteroaryl, Y is a bond, heteroaryl is pyridyl, and R 2 is -X-aryl, where X is O and aryl is one, two, or three R 5 In one embodiment, one, two, or three R 5 Each of the groups is independently selected from the group consisting of cyano, halogen, C1-C3 alkyl, and alkoxy. In one embodiment, X is S and the aryl is selected from one R 5 phenyl optionally substituted with R 5 is halogen or C1-C3 alkyl. In one embodiment, X is O and aryl is selected from two R 5 phenyl optionally substituted with a group, and each R 5 In one embodiment, X is -NR 4 -, and the aryl is a group consisting of two R 5 phenyl optionally substituted with a group, and each R 5 The groups are independently alkoxy. In certain embodiments, each alkoxy is methoxy.

[0077] In one embodiment, R 1 is -Y-heteroaryl, Y is a bond, heteroaryl is pyridyl, and R 2is a halogen, the halogen being chlorine or fluorine. In one embodiment, R 1 is -Y-heteroaryl, Y is a bond, heteroaryl is pyridyl, and R 2 is -XL-cycloalkyl, heterocyclyl, or -X-aryl, and the aryl is selected from one or more R 5 In one embodiment, R 2 is -XL-cycloalkyl, where X and L are each a bond, and cycloalkyl is cyclohexyl. 2 is heterocyclyl, wherein the heterocyclyl is tetrahydropyranyl. In one embodiment, R 2 is -X-aryl, where aryl is a group consisting of two R 5 and each R 5 is cyano.

[0078] In certain embodiments, R 1 is -Y-heteroaryl, where Y is a bond and the heteroaryl is a heteroaryl group consisting of two R 2 In one embodiment, each R 2 are independently -X-C1-C5 alkyl or one R 2 is halogen or cycloalkyl, and the second R 2 is -X-C1-C5 alkyl, where X is a bond.

[0079] In one embodiment for compounds of formula (I), R 1 is -Y-heteroaryl, where Y is a bond and the heteroaryl is selected from one or two R 2 In one embodiment, pyrimidinyl is a pyrimidinyl optionally substituted with one R 2 wherein R 2 is -X-C1-C5 alkyl, or -X-haloalkyl. In one embodiment, each X is a bond.

[0080] In one embodiment for compounds of formula (I), R1 is -Y-heteroaryl, where Y is a bond and the heteroaryl is selected from one or two R 2 In certain embodiments, one R 2 In certain embodiments, one R 2 The group is cyano and the second R 2 is halogen or -X-C1C5 alkyl.

[0081] In one embodiment for compounds of formula (I), R 1 is -Y-heteroaryl, where Y is a bond and the heteroaryl is selected from one or two R 2 In one embodiment, R 2 is one R 5 -X-aryl optionally substituted with 5 naphthyl substituted with R 5 is cyano.

[0082] In one embodiment for compounds of formula (I), R 1 is -Y-heteroaryl, where Y is a bond, and the heteroaryl is selected from one, two, or three R 2 and pyrazolyl, optionally substituted with a group.

[0083] In certain embodiments, pyrazolyl is a compound having one R 2 is substituted with R 2 is cyano, -X-C1-C5 alkyl, hydroxyalkyl, arC1-C3 alkyl, or -X-aryl, and aryl is selected from one or more R 5 In one embodiment, R 2 is -X-C1-C5 alkyl, where X is a bond and C1-C5 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl.

[0084] In other embodiments, the pyrazolyl is selected from the group consisting of two R2 groups and two R 2 The groups are independently selected from the group consisting of: (1) —X—C1-C5 alkyl; (2) —X—C1-C5 alkyl and halogen; (3) —X—C1-C5 alkyl and alkoxy; and (4) —X—C1-C5 alkyl and —N(R 4 )2, (5) -X-C1-C5 alkyl and -X-haloalkyl, (6) -X-C1-C5 alkyl and -C1-C3 alkyl, (7) -X-C1-C5 alkyl and -X-L-cycloalkyl, (8) -X-C1-C5 alkyl and -heterocyclyl, (9) -X-C1-C5 alkyl and one or more R 5 (10)-X-C1-C5 alkyl optionally substituted with, and one or more R 5 (11) -X-C1-C5 alkyl and cyanomethyl, (12) -X-C1-C5 alkyl and cyano, (13) cyano and halogen (wherein halogen is chlorine or fluorine), (14) 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-arC1-C3 alkyl or X-arC1-C3 alkyl substituted with cyano, and (21) halogen and -X-aryl.

[0085] R 1 In one embodiment, wherein R is pyrazolyl, the pyrazolyl is selected from two R 2 and one R 2 is -X-C1-C5 alkyl, and the second R 2 is one or more R 5 In one embodiment, each X is a bond and the aryl is selected from two R 5 wherein (1) each R 5 are independently -X-C1-C5 alkyl, where X is a bond; (2) one of R 5 is cyano, while R 5is -X-C1-C5 alkyl, X is a bond, (3) one of R 5 is cyano, while R 5 is -XL-cycloalkyl, X is a bond, L is a bond, methylene, or ethylene, (4) one of R 5 is cyano, while R 5 is a halogen, and (5) one of R 5 is cyano, while R 5 is alkoxy, (6) each R 5 is independently cyano, or (7) each R 5 are independently halogen.

[0086] R 1 In one embodiment, wherein R is pyrazolyl, the pyrazolyl is selected from two R 2 and one R 2 is -X-C1-C5 alkyl, and the second R 2 is one or more R 5 In one embodiment, X is a bond and aryl is selected from the group consisting of one R 5 naphthyl substituted with R 5 is cyano or halogen. In one embodiment, naphthyl is a group having two R 5 substituted with one R 5 is cyano and the second R 5 is halogen, alkoxy, or cyano. In one embodiment, naphthyl has three R 5 group and one R 5 is cyano and the second R 5 is X-haloalkyl, and the third R 5 is -XL-cycloalkyl.

[0087] R 1 In one embodiment, wherein R is pyrazolyl, the pyrazolyl is selected from two R 2 and one R 2 is -X-C1-C5 alkyl, and the second R 2 is one or more R 5In one embodiment, X is a bond and aryl is selected from the group consisting of three R 5 wherein (1) each R 5 are independently -X-C1-C5 alkyl, each X is a bond, (2) one R 5 is cyano and two R 5 is -X-C1-C5 alkyl, each X is a bond; (3) one R 5 is cyano and one R 5 is a halogen and one R 5 is -X-C1-C5 alkyl, X is a bond, (4) one R 5 is cyano and two R 5 is alkoxy, (5) one R 5 is cyano and two R 5 is a halogen, and (6) one R 5 is cyano and one R 5 is a halogen and one R 5 is alkoxy, (7) or one R 5 is cyano and one R 5 is a halogen and one R 5 is -XL-cycloalkyl.

[0088] R 1 In one embodiment, wherein R is pyrazolyl, the pyrazolyl is selected from two R 2 and one R 2 is -X-C1-C5 alkyl, and the second R 2 is one or more R 5 In one embodiment, each X is a bond and the heteroaryl is each one or more R 5 quinolinyl, pyrazolyl, chromanyl, indolizinyl, dihydrobenzylfuranyl, or imizaopyridinyl optionally substituted by

[0089] In one embodiment, the pyrazolyl is selected from the group consisting of three R 2 and each R 2is independently —X—C1-C5 alkyl, and each X is a bond.

[0090] R 1 In one embodiment, wherein R is pyrazolyl, the pyrazolyl is selected from three R 2 wherein (1) one R 2 is cyano and two R 2 is halogen or (2) one R 2 is cyano and one R 2 is a halogen and one R 2 is alkoxy. In other embodiments, one R 2 is alkoxy, and two R 2 are independently halogen.

[0091] In one embodiment for compounds of formula (I), R 1 is -Y-heteroaryl, wherein Y is a bond, and heteroaryl is imidazolyl, 1H-pyrrolopyridyl, tetrahydropyrazolopyrazinyl,

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[0092] In one embodiment for compounds of formula (I), R 1 is -Y-heteroaryl, where Y is a bond and the heteroaryl is selected from one R 2 is an imidazopyridyl substituted with a group, 2 is cyano, alkoxy, halogen, or -X-C1-C5 alkyl. In other embodiments, heteroaryl is a heteroaryl having two R 2 imidazopyridyl substituted with one R 2 is a halogen and the second R 2 The group is -X-C1-C5 alkyl or halogen.

[0093] In one embodiment for compounds of formula (I), R 1 is -Y-aryl, and Y is -NR 4 -, and aryl is one or more R 5 is phenyl optionally substituted with

[0094] In one embodiment, R 1 is -Y-arC1-C3 alkyl. In one embodiment, Y is -NR 4 - and arC1-C3 alkyl is benzyl.

[0095] In one embodiment, R 3a and R 3b Each is hydrogen. In another embodiment, R 3a and R 3b Each R is deuterium. 3a and R 3b One of R is hydrogen and the other is deuterium. 3a and R 3b are, together, oxo.

[0096] In one embodiment, each R 4 is hydrogen. In one embodiment, each R 4 is independently C1-C3 alkyl. In one embodiment, one R 4 is hydrogen, and the other R 4 is C1-C3 alkyl.

[0097] In one embodiment, the cycloalkyl, aryl, or heteroaryl ring contains one or more R 5 and optionally substituted with R 5 is cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, -XL-cycloalkyl, or -X-aryl.

[0098] In one embodiment, R 6 is hydrogen. In one embodiment, R 6 is a halogen. In certain embodiments, the halogen is chlorine or fluorine. In one embodiment, R 6 is C1-C3 alkyl. In certain embodiments, C1-C3 alkyl is methyl or ethyl. In one embodiment, R 6 is alkoxy. In certain embodiments, alkoxy is methoxy. In one embodiment, R 6 is haloalkyl. In certain embodiments, haloalkyl is trifluoromethyl.

[0099] In one aspect of the present invention, a compound of formula (IA): [ka]

[0100] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , Y, X, Z, and L are each as defined for formula I.

[0101] In one aspect of the present invention, a compound represented by formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , Y, X, Z, and L are each as defined for formula I.

[0102] In one aspect of the present invention, a compound represented by formula (IC): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , Y, X, Z, and L are each as defined for formula I.

[0103] In another aspect of the present invention, a compound of formula (ID): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, each Y is independently a bond or -NR 4 - and Each R 2 are independently selected from hydroxy, halogen, cyano, cyanomethyl, -(NR 4)2, hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, -X-arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclyl, -XL-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl, or -X-heteroaryl, wherein the heterocyclyl, cycloalkyl, aryl, and heteroaryl are independently selected from one or more R 5 optionally replaced by, or Each X is independently a bond, O, S, or -NR 4 -or-NR 4 C(O)-, each Z is independently a bond, —SO—, —SO2—, —CH(OH)—, or —C(O)—; each L is independently a bond or C1-C3 alkylene; Each R 4 are independently hydrogen or C1-C3 alkyl; Each R 5 are independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, X-arC1-C3 alkyl substituted with cyano, -XL-cycloalkyl, -XL-heteroaryl optionally substituted with one or more C1-C3 alkyl or oxo, or -X-aryl; R 6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl, or alkoxy.

[0104] In one embodiment, the compound of formula (I), formula (IA), formula (IB), and / or formula (IC) is [ka] [ka] [ka]

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[0105] In one embodiment, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt of the above compound.

[0106] The compounds of formula (I), formula (IA), formula (IB), and formula (IC) may be formulated into pharmaceutical compositions.

[0107] Pharmaceutical Compositions In another aspect, the present invention provides a pharmaceutical composition comprising a PRMT5 inhibitor according to the present invention and a pharmaceutically acceptable carrier, excipient, or diluent.The compounds of the present invention can be formulated by any method known in the art and prepared for administration by any route, including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.In certain embodiments, the compounds of the present invention are administered intravenously in a hospital environment.In certain other embodiments, administration may be preferably by oral route.

[0108] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic material that is compatible with a biological system, such as a cell, cell culture, tissue, or organism, and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, in addition to the inhibitor, the composition according to the present invention may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other substances well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18 th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0109] As used herein, the term " pharmaceutically acceptable salt " refers to a salt that retains the desired biological activity of the above-identified compound and exhibits minimal or no undesired toxic effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and acids formed with organic acids such as 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, including, in particular, quaternary ammonium salts of the formula -NRZ-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0110] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient without causing serious toxic effects to the patient being treated. For all of the above conditions, the dose of the active compound ranges from about 0.01 to 300 mg / kg per day, preferably 0.1 to 100 mg / kg per day, and more commonly from 0.5 to about 25 mg per kilogram of recipient body weight per day. Typical topical dosages 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 is active in 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.

[0111] Pharmaceutical compositions containing the compounds of the invention can be used in the methods described herein.

[0112] How to use In yet another aspect, the present invention provides a method for inhibiting PRMT5 activity in a cell, the method comprising contacting a cell in which in vitro inhibition of PRMT5 activity is desired with an effective amount of a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the cell is an MTAP-deficient cell.

[0113] The compositions and methods provided herein are considered to be particularly useful for inhibiting PRMT5 activity in cells in vivo. In one embodiment, cells for which inhibition of PRMT5 activity is desired are contacted in vivo with a therapeutically effective amount of a compound of formula (I), formula (IA), formula (IB), or formula (IC), or a pharmaceutically acceptable salt thereof, to negatively regulate PRMT5 activity. In other embodiments, a pharmaceutical composition containing a therapeutically effective amount of a pharmaceutically acceptable salt or a compound of formula (I), formula (IA), formula (IB), or formula (IC) can be used. In one embodiment, the cells are MTAP-deficient cells. In one embodiment, negatively regulating PRMT5 activity occurs in the presence of bound MTA.

[0114] By negatively regulating PRMT5 activity, particularly in cells lacking MTAP activity, this method is designed to inhibit PRMT5 activity and prevent cell proliferation. Cells can be contacted with a single dose or multiple doses according to a specific treatment regimen to affect the desired negative regulation of PRMT5. The degree of PRMT5 inhibition can be monitored in vitro against the enzyme in cells in the presence and absence of MTA and using well-known methods, including those described in Example B below, to assess the effectiveness and dosage of treatment.

[0115] In another aspect, a method of treating cancer is provided, comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula (I), Formula (IA), Formula (IB), or Formula (IC), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is an MTAP-associated cancer.

[0116] The compositions and methods provided herein can be used for the treatment of a wide variety of cancers, including, for example, tumors such as prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer, as well as sarcoma. 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, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous tumor), adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), Bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct: gallbladder cancer, ampullary carcinoma, bile duct carcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid, and giant cell tumor;Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenoma) Cancer, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL);

[0117] 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.

[0118] The dosage concentration and route of administration to the patient will vary depending on the cancer being treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts can also be co-administered with other anti-neoplastic compounds, for example, chemotherapeutic agents, or used as pre- or post-operative adjuvants in combination with other treatments, such as radiation or surgical intervention.

[0119] General Reaction Schemes, Intermediates and Examples General reaction scheme The compounds of the invention may be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or may be prepared using other reagents and conventional methods well known to those skilled in the art.

[0120] For example, compounds of formula (I), formula (IA), formula (IB) or formula (IC) of the present invention and intermediates for preparing the compounds can be prepared according to general reaction schemes I-XVI: [ka]

[0121] R 1 Compounds of formula (I) where R is aryl or heteroaryl may be prepared according to General Reaction Scheme I. Compounds 7a and 7b are both examples of formula (I), where R 1 is aryl or heteroaryl, and R 3a and R 3bis H. Treatment of haloaryl cyclic anhydride 1 with a bis(nucleophile), such as hydrazine hydrate in acetic acid, at elevated temperature forms phthalhydrazide 2, which is treated with a halogenating agent, such as POCl, to give trihalophthalazine 3. Treatment of trihalophthalazine 3 with an alcohol, such as benzyl alcohol in THF, and NaH at 0°C affords dihaloalkoxyphthalazines 4a and 4b as a mixture of regioisomers. Subjecting the mixture of 4a and 4b to palladium-catalyzed cross-coupling conditions, such as Stille or Suzuki coupling, with an aryl / heteroaryl metal reactant, such as the corresponding aryl / heteroaryl-tributyltin or aryl / heteroaryl boronic acid / ester, provides substituted haloalkoxyphthalazines 5a and 5b as a mixture of regioisomers. The substituted haloalkoxyphthalazine mixture 5a and 5b is subjected to metal-mediated cyanation conditions using, for example, Pd(dba) 3 , dppf, Zn, and ZnCN in DMF at elevated temperature, and the resulting cyanoalkoxyphthalazine mixture 6a and 6b is subjected to hydrogenation conditions using, for example, Pd / C, HCl, and H 2 in methanol to give the phthalazinone methylamine mixture 7a and 7b. The regioisomeric mixture of 7a and 7b is separated by chromatography, such as supercritical fluid chromatography (SFC), to give the desired compounds of Formula (I) 7a and 7b. [ka]

[0122] R 1 Compounds of formula (I) where R is aryl or heteroaryl can be prepared according to General Reaction Scheme II. Compounds 7a and 7b are both examples of formula (I), where R 1 is aryl or heteroaryl, and R 3a and R 3bis H. The mixture of regioisomers 4a and 4b is separated by chromatography, e.g., supercritical fluid chromatography (SFC), to give isomerically pure dihaloalkoxyphthalazines 4a and 4b. 4a or 4b is then subjected to metal-mediated cross-coupling conditions, e.g., Suzuki conditions, with an aryl / heteroaryl boronic acid / ester to provide substituted haloalkoxyphthalazine 5a or 5b. Substituted haloalkoxyphthalazine 5a or 5b is subjected to metal-mediated cyanation conditions, e.g., with Pd(dba) , dppf, Zn, and ZnCN in DMF at elevated temperature to give cyanoalkoxyphthalazine 6a or 6b. Cyanoalkoxyphthalazine 6a or 6b is subjected to hydrogenation conditions, e.g., with Pd / C, HCl, and H in methanol, to give phthalazinone 7a or 7b, providing the desired compound of Formula (I). [ka]

[0123] R 1 Compounds of formula (I) where R 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 R 1 is aryl, heteroaryl, heterocyclyl, or alkyl, and R 3a and R 3bis H. 1-(5-Halo-2-methylphenyl)ethenone 8a is treated with an oxidizing agent, such as KMnO in water at 50° C., to provide 2-(carboxycarbonyl)-4-halobenzoic acid 9a. Condensation of 9a with, for example, hydrazine hydrate in ethanol at elevated temperature provides 7-halo-4-oxo-3,4-dihydrophthalazine-1-carboxylic acid 10a, which is then esterified with an acid and an alcohol, such as sulfuric acid and methanol. Methyl 7-halo-4-oxo-3,4-dihydrophthalazine-1-carboxylate 11a is reduced by hydride reduction, for example, with sodium borohydride and CaCl in methanol, to give 6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12a, which is then treated with a halogenating agent, for example, thionyl chloride, for 12 hours to give 6-halo-4-(halomethyl)phthalazin-1(2H)-one 13a. Nucleophilic S-reaction of 13a with a nitrogen nucleophile, for example, potassium phthalimide in DMF, at elevated temperature can be performed. N Displacement of 2 provides 14a which is subjected to metal-mediated cross-coupling conditions, such as Suzuki conditions, with an aryl / heteroaryl / heterocyclyl / alkylboronic acid / ester to provide the phthalazinone coupling product 15a. The phthalimide protecting group of 15a is removed under solvolysis conditions, such as with hydrazine hydrate in ethanol, to give the desired compound of formula (I) 7a. [ka]

[0124] R 1 Compounds of formula (I) where R 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 R 1 is aryl, heteroaryl, heterocyclyl, or alkyl, and R 3a and R 3bis H. 1-(5-Halo-2-methylphenyl)ethenone 8b is treated with an oxidizing agent, such as KMnO in water at 50° C., to provide 2-(carboxycarbonyl)-4-halobenzoic acid 9b. Condensation of 9b with, for example, hydrazine hydrate in ethanol at elevated temperature provides 7-halo-4-oxo-3,4-dihydrophthalazine-1-carboxylic acid 10b, which is then esterified with an acid and an alcohol, such as sulfuric acid and methanol. Methyl 7-halo-4-oxo-3,4-dihydrophthalazine-1-carboxylate 11b is reduced by hydride reduction, for example, with sodium borohydride and CaCl in methanol, to give 6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12b, which is then treated with a halogenating agent, for example, thionyl chloride, for 12 hours to give 6-halo-4-(halomethyl)phthalazin-1(2H)-one 13b. Nucleophilic S-reaction of 13b with a nitrogen nucleophile, for example, potassium phthalimide in DMF, at elevated temperature can be performed. N Displacement of 14b provides 14b, which is subjected to metal-mediated cross-coupling conditions, such as Suzuki conditions, with an aryl / heteroaryl / heterocyclyl / alkylboronic acid / ester to provide the phthalazinone coupling product 15b. The phthalimide protecting group of 15b is removed under solvolysis conditions, such as with hydrazine hydrate in ethanol, to give the desired compound of formula (I), 7b. [ka]

[0125] R 1 is pyridyl and R 2 Compounds of formula (I) where R is -O-aryl or -O-heteroaryl can be prepared according to General Reaction Scheme IV-A. Compound 29 is an example of formula (I) where R 1 is pyridyl and R 2 is -O-aryl or -O-heteroaryl, and R 3a and R 3bis H. 5-Bromopyridin-3-ol 25 is heated with an appropriately substituted aryl / heteroaryl halide 26, for example, in a mixture of DMF and NaH, to give the 3-halo-5-R 2 3-halo-5-R 2 -pyridine 27 is coupled to a boronic acid, intermediate An, under palladium-catalyzed cross-coupling conditions, e.g., in a Suzuki coupling, to form R 2 -pyridyl coupling product 28. 2 The -pyridyl coupling product 28 is subjected to solvolysis conditions, for example using hydrazine hydrate in ethanol, to provide the free amine 29 of formula (I). [ka]

[0126] R 1 is pyridyl and R 2 Compounds of formula (I) where R is -O-aryl or -O-heteroaryl can be prepared according to General Reaction Scheme IV-B. Compound 29 is an example of formula (I) where R 1 is pyridyl and R 2 is -O-aryl or -O-heteroaryl, and R 3a and R 3b is H. 5-Bromopyridin-3-ol 25 is heated with aryl / heteroaryl halide 26, for example, in a mixture of DMF and NaH, to give 3-bromo-5-R 2 -pyridine 27. 3-Bromo-5-R 2 Pyridine 27 is coupled under palladium-catalyzed cross-coupling conditions, for example Suzuki conditions, to a boronic acid, intermediate J, to generate the coupled product 28-Boc, which is subjected to acidic conditions, for example with TFA, to provide the desired compound of formula (I) 29. [ka]

[0127] R 1 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, and R 2 Compounds of Formula (I) where R is -C1-C5 alkyl, heterocyclyl, -L-cycloalkyl, -CH2-aryl, and -CH2-heteroaryl, and 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) where R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, and R 2 is —C1-C5 alkyl, heterocyclyl, -L-cycloalkyl, —CH2-aryl, and —CH2-heteroaryl, L is a bond or C1-C3 alkylene, and R 3a and R 3b is H. 3-Bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 30 can be reacted with aldehydes or ketones 31 under reductive amination conditions, for example with sodium borohydride in methanol, to give R 2 -substituted product 32. The amination product 32 is coupled to the boronic ester intermediate AN under palladium-catalyzed cross-coupling, e.g., Suzuki conditions, to provide the coupled product 33. The coupled product 33 is then subjected to solvolysis conditions, e.g., with hydrazine hydrate, to give the free amine 34 of formula (I). [ka]

[0128] R 1 Compounds of Formula (I) where R is aryl or heteroaryl can be prepared according to General Reaction Scheme IV-D. Compound 94 is an example of Formula (I) where R 1 is an appropriately substituted aryl or heteroaryl, and R 3a and R 3bis H. The N-Boc boronate intermediate J is coupled to an aryl / heteroaryl substituted halide 92 under palladium-catalyzed cross-coupling conditions, e.g., Suzuki coupling conditions, to give the N-Boc-R 1 -substituted coupling product 90. 1 The -substituted coupling product 90 is subjected to acidic conditions to remove the Boc group, e.g., TFA, to form the R 1 -substituted amine 94 is obtained. [ka]

[0129] R 1 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, and R 2 Compounds of Formula (I) where R is -C1-C5 alkyl, heterocyclyl, -L-cycloalkyl, -CH2-aryl, and -CH2-heteroaryl, and 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 R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, and R 2 is —C1-C5 alkyl, heterocyclyl, -L-cycloalkyl, —CH2-aryl, and —CH2-heteroaryl, L is a bond or C1-C3 alkylene, and R 3a and 3b is H. 3-Bromo-5-R 2 4H-6,7-Dihydro-4H-pyrazolo[1,5-a]pyrazine 32 is boronated using, for example, Miyaura conditions to give boronate ester 32a-Bpin. The boronated product 32a-Bpin is coupled to intermediate F under palladium-catalyzed cross-coupling conditions, for example, Suzuki conditions, to provide coupled product 33a. The coupled product 33a is deprotected under acidic conditions, for example, TFA, to give amine 34a of Formula (I). [ka]

[0130] R 1 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, and R 2 Compounds of Formula (I) where R is aryl or heteroaryl can be prepared according to General Reaction Scheme IV-F. Compound 34 is an example of Formula (I) where R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, and R 2 is aryl or heteroaryl, and R 3a and R 3b is H. 3-Bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 30 is reacted with aryl / heteroaryl halides 26 under copper-catalyzed Ullmann coupling conditions, for example, with Cu(I)I, CsCO, L-proline in DMF at elevated temperature to form aminated products 32. 2 The -substituted amination product 32 is coupled to intermediate AN under palladium catalyzed cross-coupling, e.g., Suzuki conditions, to provide the coupling product 33. The coupling product 33 is subjected to solvolysis conditions, e.g., with hydrazine hydrate, to give the amine 34 of formula (I). [ka]

[0131] R 1 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, and R 2 Compounds of Formula (I) where R is -C(O)-aryl or -C(O)-heteroaryl can be prepared according to General Reaction Scheme IV-G. Compound 40 is an example of Formula (I) where R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, and R2 is —C(O)-aryl or —C(O)-heteroaryl, and R 3a and R 3b is H. 3-Bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 30 is coupled to carboxylic acid 37 using a coupling reagent, such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), with a base such as triethylamine in DMF to form amide 38. Amide 38 is coupled to boronic ester intermediate AN under palladium-catalyzed cross-coupling conditions, for example, in a Suzuki coupling, to give coupled product 39. R 2 The -coupling product 39 is subjected to solvolysis conditions, for example with hydrazine monohydrate, to remove the phthalimide moiety and provide the amine compound 40 of formula (I). [ka]

[0132] R 1 1-methyl-5-R 2 -1H-pyrazol-4-yl, and R 2 Compounds of Formula (I) where R is alkyl, aryl, or heteroaryl can be prepared according to General Reaction Scheme IV-H. Compound 45 is an example of Formula (I) where R 1 is 1-methyl-5-R 2 -1H-pyrazol-4-yl, and R 2 is alkyl, aryl, or heteroaryl, and R 3a and R 3b is H. 4-Bromo-1-methyl-1H-pyrazole 41 can be coupled to alkyl / aryl / heteroaryl substituted halides 42 using, for example, palladium acetate, DavePhos, tetrabutylammonium acetate, pivalic acid in NMP at elevated temperature to give R 2 -substituted bromopyrazole 43 is obtained. 2The -substituted bromopyrazole 43 is coupled to intermediate AN under palladium-mediated cross-coupling conditions, e.g., Suzuki conditions, to afford R 2 -substituted coupling product 44. The coupling product 44 is subjected to solvolysis conditions, for example, using hydrazine hydrate, to provide the amine 45 of formula (I). [ka]

[0133] R 1 is pyridyl and R 2 Compounds of formula (I) where R 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 R 1 is pyridyl and R 2 is -S-aryl or -S-heteroaryl, and R 3a and R 3b is H. 3-Bromo-5-fluoropyridine 53a is S N Ar substitution conditions, such as sodium aryl / heteroaryl thiolate 54, are subjected to NaH in DMF at elevated temperature to give 3-bromo-5-(aryl / heteroarylthio)pyridine 55. 3-Bromo-5-(aryl / heteroarylthio)pyridine 55 is coupled with the boronic ester intermediate AN under palladium cross-coupling conditions, such as Suzuki conditions, to give R 2 -pyridyl cross-coupling product 56. 2 The -pyridyl cross-coupling product 56 is subjected to solvolysis conditions, for example with hydrazine hydrate, to produce the amine 57 of formula (I). [ka]

[0134] R 1 is pyridyl and R 2Compounds of Formula (I) where R is -S(O)-aryl or -S(O)-heteroaryl can be prepared according to General Reaction Scheme IV-J. Compound 94 is an example of Formula (I) where R 1 is pyridyl and R 2 is —S(O)-aryl or —S(O)-heteroaryl, and R 3a and R 3b is H. 3-Bromo-5-(R 2 -thio)pyridine 55 is subjected to oxidation conditions, such as mCPBA in dichloromethane at ambient temperature, to afford 3-bromo-5-(R 2 -sulfinyl)pyridine 92 is obtained. 2 (-sulfinyl)pyridine 92 can be coupled under palladium-catalyzed cross-coupling conditions, e.g., Suzuki conditions, with the boronic ester intermediate AN to afford R 2 -substituted sulfinylpyridyl product 93. 2 The -substituted sulfinylpyridyl product 93 is subjected to solvolysis conditions, for example, using hydrazine hydrate, to give the R 2 -substituted sulfinylpyridylamine 94 is obtained. [ka]

[0135] R 1 1-methyl-5-R 2 -1H-pyrazol-4-yl, and R 2 Compounds of Formula (I) where R is alkyl, aryl, or heteroaryl can be prepared according to General Reaction Scheme IV-K. Compound 111 is an example of Formula (I) where R 1 is 1-methyl-5-R 2 -1H-pyrazol-4-yl, and R 2 is alkyl, aryl, or heteroaryl, and R 3a and R 3b is H. HR 2107 is halogenated using a halogenating agent such as N-bromosuccinimide or N-chlorosuccinimide under palladium catalyzed conditions such as palladium acetate in a solvent such as dichloroethane in the presence of an acid such as p-toluenesulfonic acid at elevated temperatures such as 70° C. to give halide 108. 4-Bromo-1-methyl-1H-pyrazole 41 is coupled to alkyl / aryl / heteroaryl substituted halides 108 using, for example, palladium acetate, DavePhos, tetrabutylammonium acetate, pivalic acid in NMP at elevated temperatures to give R 2 -substituted bromopyrazole 109. 2 The N-substituted bromopyrazole 109 is coupled to intermediate J under palladium-mediated cross-coupling conditions, e.g., Suzuki conditions, to afford N-Boc-R 2 -substituted coupling product 110. The coupling product 110 is subjected to acidic conditions to remove the Boc group, e.g., TFA, to provide the R 2 -substituted amine 111 is obtained. [ka]

[0136] R 1 Compounds of formula (I) where R is cycloalkyl or heterocyclyl can be prepared according to General Reaction Scheme V. Compound 7a is an example of a compound of formula (I) where R 1 is cycloalkyl or heterocyclyl, and R 3a and R 3bis H. 2-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione intermediate F is coupled to a 4- to 6-membered olefin boronic acid 17 under palladium-catalyzed coupling conditions, such as Suzuki coupling conditions, to provide the appropriate olefin-coupled product 18. The olefin-coupled product 18 is then subjected to hydrogenation conditions, such as Pd / C and H2, to provide the appropriate hydrogenated product 19. The hydrogenated product is then subjected to hydrazine solvolysis conditions, such as using hydrazine hydrate, to provide the primary amine compound 7a of Formula (I). [ka]

[0137] R 1 Compounds of Formula (I) where R is an 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 R 1 is an N-linked heteroaryl or an N-linked heterocyclyl, and R 3a and R 3b is H. The boronic ester intermediate AN is subjected to metal-catalyzed cross-coupling conditions, such as Ullman, Buchwald-Hartwig, or Chan-Lam conditions, with a nitrogen-containing heterocyclyl or nitrogen-containing heteroaryl 20 to give the appropriate N-coupled product 21. This N-coupled product 21 is subjected to solvolysis conditions, for example, using hydrazine hydrate, to remove the phthalimide and provide the desired primary amine 22 of formula (I). [ka]

[0138] R 1 Compounds of Formula (I) where R is an 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 R 1is an N-linked heteroaryl or an N-linked heterocyclyl, and R 3a and R 3b is H. The 2-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione intermediate F is subjected to metal-catalyzed cross-coupling conditions, such as Ullman, Buchwald-Hartwig, or Chan-Lam conditions, with a nitrogen-containing heterocyclyl or nitrogen-containing heteroaryl 20 to give the appropriate N-coupled product 21a. This N-coupled product 21a is then subjected to solvolysis conditions, for example, using hydrazine hydrate, to provide the desired primary amine 91a of Formula (I). [ka]

[0139] R 1 Compounds of Formula (I) where R is an N-linked heteroalkyl, N-linked arylheteroalkyl, or N-linked aralkyl can be prepared according to General Reaction Scheme VI-C. Compound 24 is an example of Formula I, where R 1 is an N-linked heteroalkyl, an N-linked arylheteroalkyl, or an N-linked aralkyl; R 3a and R 3b is H. The 2-((6-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione intermediate F is subjected to metal-catalyzed cross-coupling conditions, such as Ullman, Buchwald-Hartwig, or Chan-Lam conditions, with heteroalkyl / arylheteroalkyl / aralkylamine 20 to provide the appropriate N-coupled product 21b. This N-coupled product 21b is then subjected to solvolysis conditions, such as with hydrazine hydrate, to afford the desired R 1 To provide the substitution product 91b. [ka]

[0140] R1 is pyridyl and R 2 Compounds of Formula (I) where R is O-aryl or O-heteroaryl can be prepared according to General Reaction Scheme VII. Compound 29 is an example of Formula (I) where R 1 is pyridyl and R 2 is O-aryl or O-heteroaryl, and R 3a and R 3b is H. 3-Bromo-5-hydroxypyridine 25 is coupled to the boronate ester intermediate AN under palladium-catalyzed cross-coupling conditions, for example, Suzuki coupling conditions, Pd(dppf)Cl, NaHCO, dioxane / water at 80° C., to generate the coupled product 28-OH. The coupled product 28-OH is then reacted with R 2 -substituted aryl / heteroaryl halide 26 at 110 °C, N Ar reaction conditions, e.g., K2CO3 in DMF, and R 2 -substituted aryl / heteroaryl pyridyl ether 28 was obtained. 2 -substituted aryl / heteroaryl pyridyl ether 28 was subjected to solvolysis conditions, such as hydrazine hydrate, to give the free amine 29 of formula (I). [ka]

[0141] R 1 is pyridyl and R 2 Compounds of Formula (I) where R is aryl or heteroaryl can be prepared according to General Reaction Scheme VIII-A. Compound 85 is an example of a compound of Formula (I) where R 1 is pyridyl and R 2 is aryl or heteroaryl, and R 3a and R 3b is H. Intermediate CB can be boronated under Miyaura conditions, e.g., with bis(pinacolato)diboron, Pd(dppf)Cl2, and KOAc in dioxane at elevated temperature, to give boronic acid 86. Boronic acid 86 can be converted to R under palladium-catalyzed cross-coupling conditions, e.g., under Suzuki conditions.2 coupled with halide 26 to give R 2 The pyridyl coupling product 84 is obtained. 2 The -pyridyl coupling product 84 is subjected to solvolysis conditions, for example, hydrazine hydrate, to provide the primary amine 85 of formula (I). [ka]

[0142] R 1 is pyridyl and R 2 Compounds of Formula (I) where R is aryl or heteroaryl can be prepared according to General Reaction Scheme VIII-B. Compound 85 is an example of a compound of Formula (I) where R 1 is pyridyl and R 2 is aryl or heteroaryl, and R 3a and R 3b is H. Intermediate AN is coupled to 3-bromo-5-iodopyridine 53b under palladium-catalyzed cross-coupling conditions, e.g., Suzuki conditions, to give the 3-bromo-pyridyl coupling product intermediate CB. Intermediate CB is then coupled to an aryl / heteroaryl-substituted boronic ester under palladium-catalyzed cross-coupling conditions, e.g., Suzuki conditions, to give R 2 This provides the substituted pyridyl coupling product 84. The coupling product 84 undergoes solvolysis, for example with hydrazine hydrate, to give the primary amine 85 of formula (I). [ka]

[0143] R 1 is aryl or heteroaryl, and R 3a is alkyl, and R 3b Compounds of formula (I) where R is H can be prepared according to General Reaction Scheme IX-A. Compound 100 is an example of a compound of formula (I) where R 1 is aryl or heteroaryl, and R 3ais alkyl, and R 3b is H. Methyl 7-halo-4-oxo-3,4-dihydrophthalazine-1-carboxylate 11a is reduced using hydride reduction conditions, such as sodium borohydride, CaCl in methanol at 0° C., to give the primary alcohol, 6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12a. Reaction of 6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12a with an oxidizing agent, such as MnO in dichloroethane, gives 7-halo-4-oxo-3,4-dihydrophthalazine-1-carbaldehyde 95. 7-Halo-4-oxo-3,4-dihydrophthalazine-1-carbaldehyde 95 is converted to sulfinamide compound 96, for example, by adding t-butanesulfinamide, titanium tetraisopropoxide in THF, and heating to 60° C. for 12 hours. t-Butylsulfonamide 96 is then reacted with an alkyl magnesium halide in THF at −78° C. to produce methylsulfonamide 97. Methylsulfonamide 97 can be converted to the appropriate R-sulfonamide under palladium-catalyzed cross-coupling conditions, for example, Suzuki conditions. 1 -substituted boronic ester, 1 - to provide the substituted coupling product 99. 1 The -substituted coupling product 99 is desulfinylated under acidic conditions, e.g., HCl / dioxane, to give the R 1 -substituted primary amine 100. [ka]

[0144] R 1 is aryl or heteroaryl, and R 3a is alkyl, and R 3b Compounds of formula (I) where R is H can be prepared according to General Reaction Scheme IX-B. Compounds 9-5a and 9-5b are examples of compounds of formula (I) where R 1 is aryl or heteroaryl, and R 3a is alkyl, and R 3bis H. The t-butylsulfinamide intermediate 97 is boronated under Miyaura conditions, for example, using bis(pinacolato)diboron, Pd(dppf)Cl, KOAc in dioxane at elevated temperature, to give the boronate ester 9-2. This can then be converted to the appropriate R 1 -substituted halide under palladium catalyzed cross-coupling conditions, e.g., Suzuki conditions, to couple to form R 1 -substituted coupling product 9-3. 1 The -substituted coupling product 9-3 is desulfinylated under acidic conditions, for example, HCl / dioxane, to give the R 1 -substituted primary amine 9-4. The racemic mixture of 9-4 is then separated into the corresponding pure enantiomers via chiral preparative HPLC and / or chiral SFC to provide examples of chiral amines 9-5a and 9-5b of compounds of Formula (I). [ka]

[0145] R 1 Compounds of formula (I) where R is aryl, heteroaryl, heterocyclyl, or alkyl can be prepared according to general reaction scheme X. Compound 10-10 is an example of formula (I) where R 1 is aryl, heteroaryl, heterocyclyl, or alkyl, and R 3a and R 3b is H and R 6is hydrogen, halogen, C-C alkyl, or alkoxy. 1-(5-bromo-2-methyl-3-substituted phenyl)ethanone 10-1 is treated with an oxidizing agent, such as KMnO, in water at 50°C to give 4-bromo-2-(carboxycarbonyl)-6-substituted benzoic acid 10-2. Condensation of 10-2 with, for example, hydrazine hydrate in ethanol at elevated temperature gives 7-bromo-4-oxo-3,4-dihydrophthalazine-5-substituted-1-carboxylic acid 10-3, which is then esterified using an acid and alcohol, such as sulfuric acid and methanol, to give ester 10-4. Methyl 7-bromo-4-oxo-3,4-dihydrophthalazine-5-substituted-1-carboxylate 10-4 is reduced by hydride reduction, for example, with sodium borohydride and CaCl in methanol, to give 6-bromo-4-(hydroxymethyl)-8-substituted-phthalazin-1(2H)-one 10-5, which is then treated with a halogenating agent, for example, thionyl chloride, for 12 hours to give 6-halo-4-(chloromethyl)-8-substituted-phthalazin-1(2H)-one 10-6. Nucleophilic S-reaction of 10-6 with a nitrogen nucleophile, for example, potassium phthalimide in DMF at elevated temperature, affords N Displacement affords 10-7, which can be boronated, for example, using Miyaura conditions, to afford the boronate ester 10-8. Palladium-mediated cross-coupling conditions, for example, Suzuki conditions, using the boronate ester 10-8 and an aryl / heteroaryl / heterocyclyl / alkyl halide provides the phthalazinone coupling product 10-9. The phthalimide protecting group of 10-9 is removed under solvolysis conditions, for example, with hydrazine hydrate in ethanol, to afford the desired compound of Formula (I), 10-10. [ka]

[0146] R 1 Compounds of Formula (I) where R 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 R 1is aryl, heteroaryl, heterocyclyl or alkyl, and R 3a and R 3b is D and R 6 is hydrogen, halogen, C1-C3 alkyl, or alkoxy. 7-Bromo-4-oxo-3,4-dihydrophthalazine-5-substituted-1-methyl carboxylate 10-4 is reduced by deuterium reduction, for example, with sodium borodeuteride and CaCl2 in methanol-d4, to give 6-bromo-4-(hydroxy-d)methyl-d2)-8-substituted-phthalazin-1(2H)-one 11-2, which is then treated with a halogenating agent, for example, thionyl chloride, for 12 hours to give 6-bromo-4-(chloromethyl-d2)-8-substituted-phthalazin-1(2H)-one 11-3. The nucleophilic S-reaction of 11-3 with a nitrogen nucleophile, for example, potassium phthalimide in DMF at elevated temperature, affords 6-bromo-4-(hydroxymethyl-d2)-8-substituted-phthalazin-1(2H)-one 11-3. N Displacement affords 11-4, which can be boronated, for example, using Miyaura conditions, to afford the boronate ester 11-5. Palladium-mediated cross-coupling conditions, for example, Suzuki conditions, using the boronate ester 11-5 and an aryl / heteroaryl / heterocyclyl / alkyl halide provides the phthalazinone coupling product 11-6. The phthalimide protecting group of 11-6 is removed under solvolysis conditions, for example, with hydrazine hydrate in ethanol, to afford the desired compound of Formula (I), 11-7. [ka]

[0147] R 2 Compounds of formula (I) where R is aryl or heteroaryl can be prepared according to General Reaction Scheme XII. Compound 12-3 is an example of formula (I) where R 2 is aryl or heteroaryl, and R 3a and R 3b is H and R 6is hydrogen, halogen, C1-C3 alkyl, or alkoxy, and the substituent is alkyl, aryl, or heteroaryl. The bromo or chloro compound 12-1 is subjected to palladium-mediated cross-coupling conditions, e.g., Suzuki conditions, with alkyl / aryl / heteroaryl boronic acids / esters to give the substituent coupling product 12-2. The BOC group is then removed under acidic conditions, e.g., TFA, to give the R of formula (I). 2 -substituted amine 12-3. [ka]

[0148] R 1 Compounds of Formula (I) where R is alkyl-cyano can be prepared according to General Reaction Scheme XIII. Compound 13-3 is an example of Formula (I) where R 1 is -CHCN. The bromo or chloro compound 13-1 is subjected to palladium-mediated cross-coupling conditions, e.g., Suzuki conditions, with an isoxazole boronic acid / ester to give the substituent coupling product 13-2. The isoxazole is then subjected to hydrazine hydrate in an alcoholic solvent, such as hot ethanol, followed by an acidic workup, e.g., with HCl at pH 1, to give the nitrile product 13-3 of formula (I). [ka]

[0149] R 2 is aryl or heteroaryl, and R 6 Compounds of Formula (I) where R is alkoxy can be prepared according to General Reaction Scheme XIV. Compound 14-3 is an example of Formula (I) where R is alkoxy. 2 is aryl or heteroaryl, and R 6 For example, the fluoro compound 14-1, bearing an amine suitably protected with a BOC group or a phthalimide group, can be reacted with an aromatic S-group having -F as the leaving group and the corresponding oxyanion as the nucleophile. NThe protecting group is then removed under appropriate conditions. For example, heat with sodium alkyloxide in a polar solvent is used to give the substituted product 14-2. The protecting group is then removed under appropriate conditions. For example, BOC is removed under acidic conditions such as HCl or TFA in dioxane, or the phthalimide group is removed by heat under basic nucleophilic conditions such as hydrazine hydrate in ethanol, to give the R 6 -substituted amine 14-3. [ka]

[0150] R 2 is aryl or heteroaryl, and R 6 Compounds of Formula (I) where R is C1-C3 alkyl can be prepared according to General Reaction Scheme XV. Compound 15-3 is an example of Formula (I) where R 2 is aryl or heteroaryl, and R 6 is C1-C3 alkyl. Chloro compound 15-1, where the amine is suitably protected, for example with a BOC group or a phthalimide group, is coupled to an appropriate C1-C3 trialkylborane under palladium-catalyzed cross-coupling conditions, for example, Suzuki-Miyaura coupling conditions, to give the corresponding R 6 The protecting groups are then removed under appropriate conditions. For example, BOC is removed under acidic conditions such as HCl in dioxane or TFA in dioxane, and the phthalimide group is removed by heat under basic nucleophilic conditions such as hydrazine hydrate in ethanol to give the R 6 -substituted amine 15-3. [ka]

[0151] R 1 1-methyl-5-R 2 -1H-pyrazol-4-yl, and R 2Compounds of Formula (I) where R is alkyl, aryl, or heteroaryl can be prepared according to General Reaction Scheme XVI. Compound 16-6 is an example of a compound of Formula (I) where R 1 1-methyl-5-R 2 -1H-pyrazol-4-yl, and R 2 is alkyl, aryl, or heteroaryl, and R 3a and R 3b is H. HR 2 16-1 is halogenated using a halogenating agent such as N-bromosuccinimide or N-iodosuccinimide under palladium catalyzed conditions such as palladium acetate in a solvent such as dichloroethane in the presence of an acid such as p-toluenesulfonic acid at elevated temperatures such as 70°C to give halide 16-2. The bromo or iodo compound 16-2 is subjected to palladium-mediated cross-coupling conditions, e.g., Suzuki conditions, using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give the coupled product 16-3. For example, 1-methyl-5-R is halogenated using a halogenating agent such as N-bromosuccinimide or N-iodosuccinimide in a polar solvent such as acetonitrile to give the bromo or iodo compound 16-2. 2 -1H-pyrazole 16-3 was halogenated to give 4-halo-1-methyl-5-R 2 4-Bromo-1-methyl-5-R 2 -1H-pyrazole 16-4 is coupled to intermediate J under palladium-mediated cross-coupling conditions, e.g., Suzuki conditions, to afford N-Boc-R 2 -substituted coupling product 16-5. The coupling product 16-5 is subjected to acidic conditions to remove the Boc group, e.g., TFA, to provide the R 2 -substituted amine 16-6. [ka]

[0152] Step 1: A mixture of 5-bromoisobenzofuran-1,3-dione 1a (55.0 g, 242 mmol, 1.00 equiv.) and acetic acid (165 mL) was stirred at 125° C. for 1 hour. The mixture was then cooled to 10° C., and hydrazine hydrate (12.7 g, 254 mmol, 12.4 mL, 1.05 equiv.) was added dropwise, forming a thick white precipitate. Additional acetic acid (55 mL) was added, and the mixture was stirred at 125° C. for an additional 30 minutes. The mixture was then cooled, diluted with acetic acid (150 mL), and filtered. The filter cake was washed with acetic acid (50 mL × 3), dried, and then dissolved in 5% (w / w) sodium hydroxide solution (800 mL). The solution was acidified with acetic acid (200 mL), resulting in a thick white precipitate, which was filtered. The filter cake was washed with water (50 mL × 3), followed by methanol, and then dried in vacuo to give 6-bromo-2,3-dihydrophthalazine-1,4-dione 2a (45.6 g, crude) as a white solid, which was then used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ = 8.17 (d, J = 2.0 Hz, 1H), 8.01-7.97 (m, 1H), 7.95-7.89 (m, 1H).

[0153] Step 2: A solution of 6-bromo-2,3-dihydrophthalazine-1,4-dione 2a (20.0 g, crude) in phosphorus oxychloride (330 g, 2.15 mol, 200 mL) was stirred at 120 °C for 12 hours. The reaction mixture was then 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 × 3), and the combined organic layers were washed with aqueous sodium bicarbonate (200 mL × 5), brine (200 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 6-bromo-1,4-dichlorophthalazine 3a (14.5 g, crude) as a yellow solid. This solid was then used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ=8.49 (d, J=1.2 Hz, 1H), 8.23-8.15 (m, 2H).

[0154] 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 THF (30 mL) was stirred at 0° C. for 0.5 h. The mixture was then added dropwise to a solution of 6-bromo-1,4-dichloro-phthalazine 3a (13.1 g, crude) in THF (80 mL) at 0° C. The reaction mixture was warmed to 10° C. and stirred at 10° C. for 1 h. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (150 mL×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 (SiO, petroleum ether:ethyl acetate 10–25%) to give intermediate C, a 1:1 mixture of 4-benzyloxy-7-bromo-1-chloro-phthalazine 4c and 4-benzyloxy-6-bromo-1-chloro-phthalazine 4d (9.79 g, 28.0 mmol, 66% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)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).

[0155] 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 x 30 mm, 10 μm); mobile phase: [0.1% NH3HO MeOH]; B%: 0% to 60%; 40 min) to give intermediate D, 4-benzyloxy-7-bromo-1-chloro-phthalazine (2.40 g, 6.86 mmol) as a white solid, and intermediate E, 4-benzyloxy-6-bromo-1-chloro-phthalazine (2.54 g, 7.27 mmol) as a white solid. Intermediate D: 4-benzyloxy-7-chloro-phthalazine: 1H NMR(400 MHz,CDCl3)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+1] + 351.0. Intermediate E: 4-benzyloxy-6-chloro-phthalazine: 1 H NMR (400 MHz, CDCl3) 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+1] + 351.0. [ka]

[0156] Step 1: To a solution of 1-(5-bromo-2-methyl-phenyl)ethenon 8c (100 g, 445 mmol, 1.00 equiv.) in water (1.00 L) was added potassium carbonate (92.4 g, 668 mmol, 1.50 equiv.) and potassium permanganate (493 g, 3.12 mol, 7.00 equiv.). The mixture was stirred at 50 °C for 3 h, after which ethanol (1.00 L) was added, and the resulting mixture was stirred at 50 °C for an additional 30 min. The solid was then filtered, and the filtrate pH was adjusted to pH 2 with concentrated hydrochloric acid (500 mL). The mixture was then extracted with ethyl acetate (1.00 L), and the organic layer was separated and then concentrated in vacuo to give 4-bromo-2-oxalo-benzoic acid 9c (278 g, 997 mmol, 75% yield) as a white solid, which was used in the next step without further purification. LCMS [M+1] + =271.1.

[0157] Step 2: To a solution of 4-bromo-2-oxalobenzoic acid 9c (382 g, 1.27 mol) in ethyl alcohol (3.00 L) was added hydrazine hydrate (71.2 g, 1.39 mol, 69.1 mL). The mixture was stirred at 75 °C for 4 h, and the formed precipitate was filtered, washed with ethyl alcohol (500 mL), and dried to give 7-bromo-4-oxo-3H-phthalazine-1-carboxylic acid 10c (280 g, 1.03 mol, 81% yield) as a white solid, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ = 8.72-8.81 (m, 1H), 8.11-8.21 (m, 1H), 7.95-8.09 (m, 1H).

[0158] Step 3: To a solution of 7-bromo-4-oxo-3H-phthalazine-1-carboxylic acid 10c (200 g, 675 mmol) in methyl alcohol (2.00 L) was added sulfuric acid (131 g, 1.31 mol, 71.0 mL), and the reaction mixture was stirred at 65° C. for 24 h. The cooled reaction mixture was then filtered, and the filter cake was dried under reduced pressure to give methyl 7-bromo-4-oxo-3H-phthalazine-1-carboxylate 11b (216 g, crude) as a white solid, which was used in the next step without further purification. LCMS [M+1] + =283.0, 1 H NMR (400MHz, DMSO-d6) δ = 13.31 (s, 1H), 8.72 (s, 1H), 8.16-8.18 (d, J = 8.4Hz, 1H), 8.03-8.05 (d, J = 8.4Hz, 1H), 3.91 (s, 3H).

[0159] Step 4: A stirred solution of methyl 7-bromo-4-oxo-3H-phthalazine-1-carboxylate 11c (159 g, 494 mmol) in ethyl alcohol (1.50 L) was partially treated with sodium borohydride (48.6 g, 1.29 mol, 2.60 equiv.) at 0 °C. To this mixture was added a solution of calcium chloride (65.8 g, 593 mmol, 1.20 equiv.). The mixture was then stirred at 0 °C for 2 h and then at 20 °C for 1 h. The reaction mixture was then concentrated under reduced pressure, the residue was suspended in water (800 mL), and the pH was adjusted to pH 5 with 1 N hydrochloric acid (300 mL). The precipitate was filtered, washed with water (300 mL × 3), and dried to give 6-bromo-4-(hydroxymethyl)-2H-phthalazin-1-one 12c (162 g, crude) as a yellow solid. LCMS [M+1] + =255.0; 1 H NMR(400 MHz,DMSO-d6)δ=12.66(s,1H),8.30(d,J=1.6 Hz,1H),8.16(d,J=8.8 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).

[0160] Step 5: 6-Bromo-4-(hydroxymethyl)-2H-phthalazin-1-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 give 6-bromo-4-(chloromethyl)-2H-phthalazin-1-one 13c (154 g, crude) as a white solid, which was used in the next step without further purification. LCMS [M+1] += 274.8; 1 H NMR (400 MHz, DMSO-d6) 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).

[0161] Step 6: To a solution of 6-bromo-4-(chloromethyl)-2H-phthalazin-1-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 h and then cooled to 25 °C. The formed precipitate was filtered and washed with DMF (200 mL × 2). The filter cake was triturated with water (1.00 L), filtered, and dried to give intermediate F, 2-[(7-bromo-4-oxo-3H-phthalazin-1-yl)methyl]isoindoline-1,3-dione (162 g, 413 mmol, 76% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)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), 5.19 (s, 2H). LCMS[M+1]:383.9. [ka]

[0162] Step 1: A mixture of 5-bromoisobenzofuran-1(3H)-one (50.0 g, 235 mmol, 1.00 equiv), DMF-DMA (180 g, 1.51 mol, 201 mL, 6.44 equiv), and t-BuOK (2.63 g, 23.5 mmol, 0.10 equiv) was degassed and purged with N three times, then stirred under N atmosphere at 110° C. for 20 h. The reaction mixture was then concentrated under reduced pressure to remove DMF-DMA, and the formed residue 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 hours, filtered, and the filter cake was dried under reduced pressure to give (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+1] + =270.1; 1H NMR(400 MHz,DMSO-d6)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).

[0163] 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 equiv.) in EtOH (650 mL) was added NHNH·H0 (12.5 g, 245 mmol, 12.1 mL, 2.05 equiv.) at 25 °C. The mixture was degassed with N and then stirred at 25 °C for 0.5 h and then at 70 °C for 12 h. The reaction mixture was then filtered and the solid was dried to give 6-bromo-4-((dimethylamino)methyl)phthalazin-1(2H)-one (30.0 g, 105 mmol, 88% yield, 99% purity) as a yellow solid. LCMS [M+1] + =282.1; 1 H NMR(400 MHz,DMSO-d6)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).

[0164] Step 3: A mixture of 6-bromo-4-((dimethylamino)methyl)phthalazin-1(2H)-one (15.0 g, 53.2 mmol, 1.00 equiv) in THF (187 mL) was degassed three times with N and then cooled to 0 °C. Isobutyl carbonochloridate (8.71 g, 63.80 mmol, 8.38 mL, 1.20 equiv) was then added dropwise, and the mixture was stirred at 25 °C under N for 6 h. The mixture was then cooled to 0 °C, after which HCl (0.5 M, 250 mL) was added, maintaining the 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-bromo-4-(chloromethyl)phthalazin-1(2H)-one (11.0 g, 37.56 mmol, 71% yield, 93% purity) as a yellow solid. LCMS [M+1] + =256.1; 1H NMR(400 MHz,DMSO-d6)δ 12.9(s,1H),8.29(d,J=1.6 Hz,1H),8.19-8.17(d,J=8.0 Hz,1H),8.06-80.4(dd,J=8.0 Hz&1.6 Hz,1H),5.06(s,2H).

[0165] Step 4: To a mixture of 6-bromo-4-(chloromethyl)phthalazin-1(2H)-one (8.06 g, 27.5 mmol, 93% purity, 1.00 equiv.) in DMF (160 mL), (1,3-dioxoisoindolin-2-yl)potassium (5.61 g, 30.3 mmol, 1.10 equiv.) was added and stirred at 25 °C for 1 h. The mixture was then washed with HCl (0.5 M, 100 mL), filtered, and the solid was washed with saturated NaHCO (30 mL × 2), purified water (30 mL × 2), and then triturated with EtOH (15 mL) at 70 °C for 1 h. The solid was then filtered and dried to give intermediate F (8.30 g, 17.9 mmol, 65.0% yield, 83% purity) as a yellow solid. LCMS [M+1] + =384.1 / 386.1; 1 H NMR(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). [ka]

[0166] Step 1: To a solution of 1-(4-bromo-2-methyl-phenyl)ethenon 8d (10.0 g, 46.9 mmol, 1.00 equiv.) in water (50 mL) was added potassium carbonate (9.73 g, 70.40 mmol, 1.50 equiv.) and potassium permanganate (51.9 g, 329 mmol, 7.00 equiv.). The mixture was stirred at 50 °C for 3 h, after which ethanol (50 mL) was added, and the resulting mixture was stirred at 50 °C for an additional 30 min. The solid was then filtered, and the filtrate pH was adjusted to pH 2 with concentrated hydrochloric acid (5 mL). The mixture was then extracted with ethyl acetate (50 mL), and the organic layer was separated and concentrated in vacuo to give 5-bromo-2-oxalo-benzoic acid 9d (10.0 g, crude) as a white solid, which was used in the next step without further purification. LCMS [M+1] + =273.0.

[0167] 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 h. The precipitate formed was then filtered, washed with ethyl alcohol (5 mL), and dried to give 6-bromo-4-oxo-3H-phthalazine-1-carboxylic acid 10d (7.50 g, 27.9 mmol, 59% yield) as a white solid. LCMS [M+1] + =269.0.

[0168] Step 3: To a solution of 6-bromo-4-oxo-3H-phthalazine-1-carboxylic acid 10d (7.50 g, 27.9 mmol, 1.00 equiv) in methyl alcohol (40 mL) was added sulfuric acid (16.7 g, 167 mmol, 9.10 mL, 6.00 equiv), and the reaction mixture was stirred at 65° C. for 12 h. The reaction mixture was then allowed to cool, and the precipitate that formed was filtered and dried to give methyl 6-bromo-4-oxo-3H-phthalazine-1-carboxylate 11d (7.00 g, 24.7 mmol, 89% yield) as a white solid. LCMS [M+1] + =282.9.

[0169] Step 4: A stirred solution of sodium borohydride (2.43 g, 64.29 mmol, 2.60 equiv) in ethyl alcohol (250 mL) was treated in portions with methyl 6-bromo-4-oxo-3H-phthalazine-1-carboxylate 11d (7.00 g, 24.7 mmol, 1.00 equiv) at 0° C. To this mixture was added dropwise a solution of calcium chloride (3.29 g, 29.7 mmol, 1.20 equiv) in ethyl alcohol (250 mL). The mixture was then stirred at 0° C. for 3 hours and at 20° C. for an additional 1 hour. The mixture was then concentrated under reduced pressure, and the concentrated residue was suspended in water (30 mL), and the pH was adjusted to pH 5 with 1 N hydrochloric acid (5 mL). The precipitate that formed was filtered, washed with water (5 mL x 3), triturated with ethyl alcohol (50 mL), filtered, and dried to give 7-bromo-4-(hydroxymethyl)-2H-phthalazin-1-one 12d (6.00 g, 23.5 mmol, 95% yield) as a white solid. LCMS [M+1] + =255.0.

[0170] Step 5: 7-Bromo-4-(hydroxymethyl)-2H-phthalazin-1-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 concentrated to give 7-bromo-4-(chloromethyl)-2H-phthalazin-1-one 13d (5.50 g, crude) as a white solid, which was used in the next step without further purification. LCMS [M+1] + =275.0.

[0171] Step 6: To a solution of 7-bromo-4-(chloromethyl)-2H-phthalazin-1-one 13d (5.50 g, crude) in DMF (60.0 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (5.59 g, 30.2 mmol). The reaction mixture was stirred at 90° C. for 2 hours, then cooled to 25° C. The formed precipitate was filtered and triturated with ethyl alcohol (150 mL) to give intermediate G, 2-[(6-bromo-4-oxo-3H-phthalazin-1-yl)methyl]isoindoline-1,3-dione (5.00 g, 13.0 mmol, 65% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)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+1]:386.1. [ka]

[0172] Step 1: A solution of intermediate F (3.00 g, 7.81 mmol, 1.00 equiv) and hydrazine hydrate (1.60 g, 31.2 mmol, 1.55 mL, 4.00 equiv) was stirred at 80 °C for 2 hours, cooled, and concentrated under reduced pressure. The concentrated residue was then washed with water and triturated with ethyl alcohol at 25 °C to give 4-(aminomethyl)-6-bromo-2H-phthalazin-1-one 106 (1.95 g, 7.67 mmol, 98% yield) as a white solid. LCMS [M+1] + =256.1.

[0173] Step 2: To a solution of 4-(aminomethyl)-6-bromo-2H-phthalazin-1-one 106 (1.90 g, 7.48 mmol, 1.00 equiv) and triethylamine (2.27 g, 22.4 mmol, 3.12 mL, 3.00 equiv) in dichloromethane (40.0 mL) was added di-tert-butyl dicarbonate (3.26 g, 15.0 mmol, 3.44 mL, 2.00 equiv). The mixture was stirred at 25 °C for 2 hours, filtered, and concentrated under reduced pressure to give a residue. The concentrated residue was triturated with dichloromethane (40 mL), filtered, and dried to give t-butyl-N-[(7-bromo-4-oxo-3H-phthalazin-1-yl)methyl]carbamate, Intermediate I (1.97 g, 5.56 mmol, 74% yield) as a white solid. LCMS[M+1] += 356.1. 1 H NMR(400 MHz,DMSO-d6)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(brs,9H). [ka]

[0174] A mixture of Intermediate I (130.0 g, 275 mmol, 1.00 equiv.), bis(pinacolato)diboron (BPD) (104.9 g, 412.9 mmol, 1.50 equiv.), Pd(dppf)Cl (20.1 g, 27.5 mmol, 0.10 equiv.), and KOAc (81.0 g, 825 mmol, 3.00 equiv.) in dioxane (2.60 L) was degassed and purged with N. The mixture was then stirred at 100 °C for 2 h. The mixture was then filtered and concentrated, and the residue was triturated with petroleum ether / ethyl acetate 10 / 1 (400 mL) at 25 °C for 1 h. The solid was then filtered and dried to give Intermediate J as a brown solid (68.0 g, 162 mmol, 59% yield). LCMS [M+1] + =402.3; 1H NMR (400 MHz, CDCl3) δ=12.62(s,1H),8.25(s,2H),8.01-8.13(m,1H),7.21-7.45(m,1H),4.34-4.63(m,2H),1.42(s,9H),1.32(s,12H). [ka]

[0175] A solution of 4-bromo-1-methyl-pyrazole (500 mg, 3.11 mmol, 1.00 equiv.) and 1-bromo-3-fluoro-benzene (543 mg, 3.11 mmol, 346 μL, 1.00 equiv.) in N-methylpyrrolidone (10 mL) was degassed with nitrogen. Palladium acetate (7.0 mg, 31.1 μmol, 0.10 equiv.) and 2-(2-dicyclohexylphosphanylphenyl)-N,N-dimethyl-aniline (DavePhos) (24.0 mg, 62.1 μmol, 0.02 equiv.) were then added. To the resulting dark brown solution, tetrabutylammonium acetate (1.87 g, 6.21 mmol, 2 mL, 2.00 equiv.) and pivalic acid (317 mg, 3.11 mmol, 357 μL, 1.00 equiv.) were added, and the resulting solution was stirred at 100 °C for 15 h. Upon completion of the reaction, 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 under reduced pressure to give a crude oil. The crude oil was purified by silica gel chromatography (petroleum ether / ethyl acetate 0–10%) to give 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. 1 H NMR (400 MHz, CDCl3) 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).

[0176] Intermediates A-1 through A-32 shown in Table II were prepared following the teachings of the general reaction scheme and method for preparing intermediate K. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [ka]

[0177] To a solution of 3-bromo-5-fluoro-pyridine (2.20 g, 12.5 mmol, 1.00 equiv.) in dimethylformamide (50 mL) was added phenylsulfanylsodium (1.98 g, 15.0 mmol, 1.20 equiv.), followed by stirring at 110 °C for 12 h. The reaction mixture was then diluted with water (700 mL) and extracted with ethyl acetate (150 mL × 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:ethyl acetate 0-10%) to afford 3-bromo-5-phenylsulfanyl-pyridine, intermediate AA (1.31 g, 4.48 mmol, 35% yield) as a yellow oil. LCMS [M+1] + =268.0; 1 H NMR (400 MHz,MeOD)δ=8.44(d,J=2.0 Hz,1H),8.31(d,J=2.0 Hz,1H),7.73(t,J=2.0 Hz,1H),7.50-7.46(m,2H),7.45-7.41(m,3H). [ka]

[0178] To a solution of 2-chlorobenzenethiol (296 mg, 2.05 mmol, 233 μL, 1.20 equiv.) in DMF (2 mL), sodium hydride (82 mg, 2.05 mmol, 60% purity, 1.20 equiv.) and 3-bromo-5-fluoropyridine (300 mg, 1.70 mmol, 1.00 equiv.) were added and 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×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 20%) to give 3-bromo-5-(2-chlorophenyl)sulfanyl-pyridine, intermediate AB (280 mg, 931 μmol, 54% yield) as a white solid. LCMS [M+1] + =302.0; 1 H 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).

[0179] Intermediates AC-AG shown in Tables I-IIa were prepared using the teachings of the General Reaction Scheme and the method for preparing Intermediate AB. [Table 2] [ka]

[0180] Step 1: To a solution of 2-methyl-1H-imidazole (1.00 g, 12.2 mmol, 1.00 equiv) in DMF (10 mL), potassium carbonate (1.68 g, 12.2 mmol, 1.00 equiv) and 2-chloroacetonitrile (920 mg, 12.2 mmol, 773 μL, 1.00 equiv) were added, and the mixture was stirred at 50 °C for 5 h. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 10–100%) to afford 2-(2-methylimidazo-1-yl)acetonitrile (460 mg, 3.80 mmol, 31% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) 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).

[0181] Step 2: To a solution of 2-(2-methylimidazol-1-yl)acetonitrile (410 mg, 3.38 mmol, 1.00 equiv) in acetonitrile (10 mL) was added dropwise a solution of N-bromosuccinimide (542 mg, 3.05 mmol, 0.90 equiv) in acetonitrile (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, after which the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (2 mL×3). The combined organic phase was washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 10–100%) followed by a second column (SiO2, petroleum ether:ethyl acetate:methanol 1:1:0.4) to give 2-(5-bromo-2-methyl-imidazol-1-yl)acetonitrile, intermediate AH (460 mg, 2.30 mmol, 67% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ = 6.97 (s, 1H), 4.82 (s, 2H), 2.53 (s, 3H). [ka]

[0182] To a solution of 4-bromo-2-methyl-pyrazol-3-amine (0.20 g, 1.14 mmol, 1.00 equiv.) in hydrochloric acid (12 M, 2 mL, 21.1 equiv.) was slowly added a solution of sodium nitrite (86 mg, 1.25 mmol, 1.10 equiv.) in water (1.8 mL) at 0 °C. After stirring for 10 min, the mixture was added in portions to a solution of copper chloride (112 mg, 1.14 mmol, 27.2 μL, 1.00 equiv.) in hydrochloric acid (12 M, 1.00 mL, 10.6 equiv.). The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was then diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with aqueous sodium bicarbonate (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 25%) to give 4-bromo-5-chloro-1-methyl-pyrazole, intermediate AI (92 mg, 363 μmol, 31% yield) as a white solid. LCMS [M+1] + =197.0; 1 H NMR (400 MHz, CDCl3-d) δ=7.48(s,1H),3.88(s,3H). [ka]

[0183] Sodium borohydride (22 mg, 572 μmol, 1.50 equiv.) was slowly added to a solution of (5-bromo-3-pyridyl)-phenyl-methanone (100 mg, 381 μmol, 1.00 equiv.) in ethyl alcohol (5 mL). After stirring at 25° C. for 2 hours, the reaction was quenched with water (2 mL) and concentrated in vacuo. The residue was diluted with ethyl acetate (10 mL), washed with brine (10×3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (5-bromopyridin-3-yl)(phenyl)methanol, intermediate AJ (97 mg, 367 μmol, 96% yield) as a colorless oil. LCMS [M+1] + =263.9. 1H NMR(400 MHz,CDCl3)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). [ka]

[0184] To a solution of 3-bromo-5-(phenylthio)pyridine, Intermediate AA (200 mg, 751 μmol, 1.00 equiv.) in dichloromethane (4 mL) was added 3-chloroperoxybenzoic acid (153 mg, 751 μmol, 85.0% purity, 1.00 equiv.). The resulting mixture was stirred under nitrogen at 25 °C for 1 h. Aqueous sodium hydroxide (4 N, 40 mL) was then added, and the mixture was extracted with dichloromethane (20 mL × 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 (SiO, petroleum ether:ethyl acetate, 5–20%) to afford 3-bromo-5-(phenylsulfinyl)pyridine, Intermediate AK (150 mg, 532 μmol, 70% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) 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),7.55-7.27(m,3H). [ka]

[0185] A solution of oxone (2.10 g, 3.42 mmol, 2.00 equiv) in water (10 mL) was added to a solution of 3-bromo-5-phenylsulfanyl-pyridine, Intermediate AA (500 mg, 1.71 mmol, 1.00 equiv) in THF (10 mL) and methyl alcohol (10 mL) at 0° C. The resulting mixture was stirred at 35° C. for 12 hours, then filtered, and the filtrate was concentrated under reduced pressure. The formed residue was purified by reverse-phase HPLC (0.1% FA condition) to give 3-(benzenesulfonyl)-5-bromo-pyridine, Intermediate AL (300 mg, 1.01 mmol, 59% yield) as a white solid. 1 H 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). [ka]

[0186] Step 1: Phosphorus oxychloride (4.71 g, 30.7 mmol, 2.9 mL, 1.23 equiv) was added dropwise to DMF (6 mL) at 0° C., and the mixture was then stirred at 0° C. for 10 minutes. A solution of 1-phenylethanone (3.00 g, 25.0 mmol, 2.91 mL, 1.00 equiv) in DMF (25 mL) was then added dropwise with stirring. The reaction mixture was then heated at 60° C. for 3 hours. The solution was then cooled to room temperature and slowly poured into aqueous sodium acetate (10%, 100 mL). The pH was adjusted to 4 with additional sodium acetate (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (Z)-3-chloro-3-phenyl-prop-2-enal (2.50 g, 14.1 mmol, 56% yield) as a yellow oil. LCMS [M+1] + =167.1. 1 H NMR (400MHz, CDCl3) δ=10.24(d,J=6.8 Hz,1H),7.49(m,5H),6.69(d,J=6.8 Hz,1H).

[0187] Step 2: This reaction generates hydrogen cyanide (HCN) as a by-product. Appropriate safety precautions and procedures should be used. A mixture of (Z)-3-chloro-3-phenylprop-2-enal (1.76 g, 10.6 mmol, 1.00 equiv.) and ammonium thiocyanate (1.61 g, 21.1 mmol, 1.61 mL, 2.00 equiv.) in acetone (25 mL) was degassed and purged with nitrogen and stirred at 80 °C for 1 h. The cooled mixture was then poured into saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 0-50%) to give 5-phenylisothiazole (1.00 g, 6.20 mmol, 58% yield) as a yellow oil. LCMS [M+1] + =162.2. 1 H NMR (400 MHz, CDCl3) 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).

[0188] Step 3: Bromine (952 mg, 5.95 mmol, 307 μL, 3.20 equiv) was added dropwise over 30 minutes to a stirred mixture of 5-phenylisothiazole (300 mg, 1.86 mmol, 1.00 equiv), potassium acetate (365 mg, 3.72 mmol, 2.00 equiv), and acetic acid (12 mL). The reaction mixture was stirred at 25° C. for 5 hours and then treated with sodium bisulfite (33%, 10 mL). The solution was made basic with aqueous sodium hydroxide (20%, 10 mL) and extracted with dichloromethane (3×80 mL). The combined organic extracts were dried (anhydrous sodium sulfate), filtered, and concentrated to give 4-bromo-5-phenyl-isothiazole, intermediate AM (300 mg, 1.25 mmol, 67% yield) as a colorless oil. LCMS [M+1] + =240.9. 1H NMR (400 MHz, CDCl3) δ = 8.39 (s, 1H), 7.69-7.65 (m, 2H), 7.52-7.47 (m, 3H). 13 C NMR(400 MHz,CDCl3)δ=161.0,159.5,129.9,129.3,129.0,128.5,106.0. [ka]

[0189] A mixture of Intermediate I (160 g, 416 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (BPD) (158 g, 624 mmol, 1.50 equiv), Pd(dppf)Cl (30.4 g, 41.6 mmol, 0.10 equiv), and potassium acetate (122 g, 1.25 mol, 3.00 equiv) in dioxane (2.0 L) was purged with nitrogen and stirred at 100° C. for 3 h. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was triturated with MeOH (1.0 L) at 25° C. for 2 hours, filtered, and dried to give 2-((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione, intermediate AN (93.0 g, 209 mmol, 50% yield) as a gray solid. LCMS [M+1] + =432.4. 1 H NMR:(400MHz DMSO-d6)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). [ka]

[0190] To a solution of 3,5-dibromopyridine (1.00 g, 4.22 mmol, 1.00 equiv.) in DMF (10 mL) was added sodium hydride (270 mg, 6.75 mmol, 60% purity, 1.60 equiv.) over 10 min at 0 °C, followed by N-methylaniline (452 ​​mg, 4.22 mmol, 458 μL, 1.00 equiv.). The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (400 g SiO, water / acetonitrile, 0-100% 70 mL / min) to give 5-bromo-N-methyl-N-phenyl-pyridin-3-amine, intermediate AO (50.0 mg, 190 μmol, 5% yield) as a yellow solid. LCMS [M+1] + 262.9. 1 H NMR(400 MHz,CDCl3-d)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). [ka]

[0191] A mixture of (5-bromo-3-pyridyl)boronic acid (325 mg, 1.61 mmol, 1.50 equiv), 1H-pyrazole-5-carbonitrile (100 mg, 1.07 mmol, 1.00 equiv), pyridine (255 mg, 3.22 mmol, 260 μL, 3.00 equiv), 4 Å molecular sieves (20.0 mg, 1.07 mmol), and copper acetate (585 mg, 3.22 mmol, 3.00 equiv) in dichloromethane (5 mL) was degassed with nitrogen and stirred under an oxygen atmosphere (15 psi) at 20° C. for 12 hours. The reaction mixture was then filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 5-20%) to give 2-(5-bromo-3-pyridyl)pyrazole-3-carbonitrile, intermediate AP (150 mg, 602 μmol, 56% yield) as a white solid. LCMS [M+1] + 249.0. 1 H NMR(400 MHz,DMSO-d6)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). [ka]

[0192] Step 1: To a solution of cyclopropanol (450 mg, 7.74 mmol, 1.10 equiv) in THF (10 mL) was added sodium hydride (310 mg, 7.74 mmol, 60.0% purity, 1.10 equiv) at 0° C., followed by 5-fluoro-2-nitro-pyridine (1.00 g, 7.04 mmol, 1.00 equiv), and the mixture was warmed to 20° C. and stirred for 2 h. Upon completion, the mixture was filtered, concentrated in vacuo, and the residue was purified by column chromatography (SiO 2、 Purification with petroleum ether:ethyl acetate (20-80%) gave 5-(cyclopropoxy)-2-nitropyridine (1.10 g, 6.11 mmol, 86% yield) as a white solid. LCMS [M+1] + =181.1.

[0193] Step 2: To a solution of 5-(cyclopropoxy)-2-nitro-pyridine (200 mg, 1.11 mmol, 1.00 equiv.) in methyl alcohol (4 mL), palladium on activated carbon (100 mg, 1.11 mmol, 10% purity, 1.00 equiv.) was added, and the mixture was stirred at 30° C. for 4 hours under an atmosphere of hydrogen (15 psi). Upon completion, the reaction mixture was filtered, washed with methanol (5 mL×2), and concentrated to afford 5-(cyclopropoxy)pyridin-2-amine (120 mg, 799 μmol, 72% yield) as a black oil, which was used in the next step without further purification. LCMS [M+1] + =151.1.

[0194] Step 3: To a solution of 5-(cyclopropoxy)pyridin-2-amine (120 mg, 799 μmol, 1.00 equiv.) in methyl alcohol (2 mL) and water (1.0 mL), 2-chloroacetaldehyde (313 mg, 1.60 mmol, 257 μL, 2.00 equiv.) and sodium bicarbonate (70.5 mg, 839 μmol, 1.05 equiv.) were added. The mixture was stirred at 70° C. for 2 hours. The solvent was then removed under reduced pressure, diluted with ethyl acetate (3 mL) and water (2 mL), and extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 6-(cyclopropoxy)imidazo[1,2-a]pyridine (220 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS [M+1] + =175.2.

[0195] Step 4: To a solution of 6-(cyclopropoxy)imidazo[1,2-a]pyridine (220 mg, crude) in acetonitrile (2 mL) was added N-iodosuccinimide (313 mg, 1.39 mmol). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 20-80%) to afford 6-(cyclopropoxy)-3-iodo-imidazo[1,2-a]pyridine, intermediate AS (220 mg, 733 μmol, 58% yield) as a white solid. LCMS [M+1] + =300.9. 1 H 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). [ka]

[0196] Step 1: To a solution of 5-(trifluoromethoxy)pyridin-2-amine (250 mg, 1.40 mmol, 1.00 equiv) in methanol (5 mL) and water (2.5 mL), 2-chloroacetaldehyde (289 mg, 1.47 mmol, 237 μL, 1.05 equiv) and sodium bicarbonate (118 mg, 1.41 mmol, 54.8 μL, 1.00 equiv) were added. 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×2). The combined organic layers were concentrated to give 6-(trifluoromethoxy)imidazo[1,2-a]pyridine (250 mg, crude) as a colorless oil, which was used in the next step without further purification.

[0197] Step 2: To a solution of 6-(trifluoromethoxy)imidazo[1,2-a]pyridine (238 mg, crude) in acetonitrile (10 mL) at 0 °C, N-iodosuccinimide (291 mg, 1.30 mmol) in acetonitrile (5 mL) was added, and the resulting yellow suspension was warmed to 20 °C for 2 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). 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 afford 3-iodo-6-(trifluoromethoxy)imidazo[1,2-a]pyridine, intermediate AT (180 mg, 548 μmol, 46% yield) as a yellow solid. LCMS [M+1] + =329.0. 1 H NMR (400 MHz, CDCl3) δ = 8.23-8.19 (s, 1H), 7.80 (s, 1H), 7.71 (d, J = 9.6 Hz, 1H), 7.27 (m, 1H). [ka]

[0198] Step 1: A mixture of 6-iodoimidazo[1,2-a]pyridine (500 mg, 2.05 mmol, 1.00 equiv.), phenylboronic acid (275 mg, 2.25 mmol, 1.10 equiv.), Pd(dppf)Cl (150 mg, 205 μmol, 0.10 equiv.), and sodium bicarbonate (344 mg, 4.10 mmol, 159 μL, 2.00 equiv.) in dioxane (5 mL) and water (1.00 mL) was degassed with nitrogen and stirred at 80° C. for 1 hour. The reaction mixture was then 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 preparative TLC (dichloromethane:methyl alcohol, 10%) to afford 6-phenylimidazo[1,2-a]pyridine (250 mg, 1.29 mmol, 62% yield) as a white solid. LCMS[M+1] + =195.1.

[0199] Step 2: To a solution of 6-phenylimidazo[1,2-a]pyridine (100 mg, 515 μmol, 1.00 equiv.) in acetonitrile (2 mL), N-iodosuccinimide (127 mg, 566 μmol, 1.10 equiv.) was added, and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure, the residue was diluted with ethyl alcohol (2 mL), the supernatant was removed, and the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 10%) to give 3-iodo-6-phenyl-imidazo[1,2-a]pyridine, intermediate AU (120 mg, 375 μmol, 72% yield) as a yellow solid. LCMS [M+1] + =321.0. 1 H NMR (400 MHz, DMSO-d6) 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). [ka]

[0200] To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.00 g, 10.2 mmol, 1.00 equiv.) in methyl alcohol (10 mL), formaldehyde (610 mg, 20.3 mmol, 559 μL, 2.00 equiv.) and sodium hydroxide (812 mg, 20.3 mmol, 2.00 equiv.) were added, and the mixture was stirred at 20 °C for 2 h. 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%) followed by preparative TLC (petroleum ether:ethyl acetate 20%) to afford 5-bromo-3-(methoxymethyl)-1H-pyrrolo[2,3-b]pyridine, intermediate AV (120 mg, 498 μmol, 5% yield) as a white solid. LCMS [M+1] + =243.0. 1H NMR (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). [ka]

[0201] To a solution of 5-bromopyridin-3-ol (500 mg, 2.87 mmol, 1.00 equiv.) in DMF (10 mL), cesium carbonate (1.87 g, 5.75 mmol, 2.00 equiv.), 2-iodopyridine (707 mg, 3.45 mmol, 366 μL, 1.20 equiv.), 2,2,6,6-tetramethylheptane-3,5-dione (212 mg, 1.15 mmol, 237 μL, 0.40 equiv.), and copper iodide (109 mg, 575 μmol, 0.20 equiv.) were added. 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 × 3). The combined organic layers were washed with brine (100 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 0-20%) to give 3-bromo-5-(2-pyridyloxy)pyridine, intermediate AX (600 mg, 1.45 mmol, 50% yield) as a yellow oil. LCMS [M+1] + =250.8. 1 H NMR(400 MHz,DMSO-d6)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). [ka]

[0202] To a solution of 2-chloropyrimidine (300 mg, 2.62 mmol, 1.00 equiv) in DMF (2 mL) was added potassium carbonate (724 mg, 5.24 mmol, 2.00 equiv) and 5-bromopyridin-3-ol (479 mg, 2.75 mmol, 1.05 equiv). 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×3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-[(5-bromo-3-pyridyl)oxy]pyrimidine, intermediate AY (523 mg, crude) as a red solid, which was used directly in the next step without further purification. LCMS [M+1] + =252.0; 1 H NMR(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). [ka]

[0203] Step 1: To a solution of 2-methylpyrazol-3-ol (500 mg, 5.10 mmol, 1.00 equiv.), (bromomethyl)benzene (1.05 g, 6.12 mmol, 726 μL, 1.20 equiv.) in DMF (6.00 mL) was added potassium carbonate (1.06 g, 7.65 mmol, 1.50 equiv.). The mixture was stirred at 120 °C for 4 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (50 mL × 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 give 5-benzyloxy-1-methyl-pyrazole (450 mg, 2.39 mmol, 47% yield) as a colorless oil. LCMS [M+1] + =189.2; 1H NMR (400 MHz, CDCl3) 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).

[0204] Step 2: To a solution of 5-benzyloxy-1-methylpyrazole (400 mg, 2.13 mmol, 1.00 equiv) in acetonitrile (6 mL) was added NBS (416 mg, 2.34 mmol, 1.10 equiv). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to afford 5-benzyloxy-4-bromo-1-methyl-pyrazole (320 mg, 1.20 mmol, 56% yield) as a yellow oil. LCMS [M+1] + =266.9; 1 H NMR (400 MHz, CDCl3) δ = 7.39 (s, 5H), 7.32 (s, 1H), 5.28 (s, 2H), 3.45 (s, 3H).

[0205] Intermediate AY-2 shown in Tables I-IIb was prepared following the teachings of the General Reaction Scheme and the method for preparing Intermediate AY-1. [Table 3] [ka]

[0206] To the corresponding aryl / heteroarylphenol (3.89 mmol, 1.00 equiv.) in DMF (10 mL) was added sodium hydride (4.28 mmol, 60% purity, 1.10 equiv.) under nitrogen at 0° C. After the addition was complete, the mixture was stirred at 25° C. for 0.5 h, followed by the addition of 3-bromo-5-fluoro-pyridine (3.89 mmol, 1.00 equiv.) and stirring at 100° C. for an additional 12 h. The reaction mixture was then quenched by the addition of water (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was used directly in the next step without further purification.

[0207] Following the teachings of the general reaction scheme and general procedures for intermediates B-1 through B-15, the intermediates in Tables I through III were prepared. [Table 4-1] [Table 4-2] [ka]

[0208] To a solution of 3-bromo-5-fluoro-pyridine (210 mg, 1.19 mmol, 0.95 equiv) in DMF (10 mL) was added potassium carbonate (347 mg, 2.51 mmol, 2.00 equiv) and 3-chloro-2,4-dimethyl-phenol (197 mg, 1.26 mmol, 1.00 equiv). The mixture was stirred at 110 °C for 12 h. The reaction mixture was then diluted with water (80 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate, 0-20%) to afford 3-bromo-5-(3-chloro-2,4-dimethyl-phenoxy)pyridine, intermediate BN (178 mg, 569 μmol, 45% yield) as a colorless oil. LCMS [M+1] + =314.0. 1 H NMR(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). [ka]

[0209] To a solution of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (300 mg, 949 μmol, 1.00 equiv., TFA) and benzaldehyde (131 mg, 1.23 mmol, 125 μL, 1.30 equiv.) in dichloromethane (10 mL), sodium triacetoxyborohydride (402 mg, 1.90 mmol, 2.00 equiv.) and acetic acid (114 mg, 1.90 mmol, 109 μL, 2.00 equiv.) were added. The mixture was then stirred at 25° C. for 4 hours. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 25%) to give 5-benzyl-3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine, intermediate BP (170 mg, 582 μmol, 61% yield) as a colorless oil. LCMS [M+1] + =294.0. 1 H 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). [ka]

[0210] A mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (400 mg, 1.27 mmol, 1.00 equiv.), acetaldehyde (5.0 M, 508 μL, 2.01 equiv.), sodium cyanoborohydride (160 mg, 2.54 mmol, 2.01 equiv.), and zinc chloride (1.0 M, 2.53 mL, 2.00 equiv.) in methanol (8 mL) was stirred for 2 h at 25 °C. The solvent was then evaporated, and the residue was purified by column chromatography (SiO, dichloromethane:methanol 0–10%). The product was further purified by preparative HPLC (Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 16%–46%, 11.5 min) to give 3-bromo-5-ethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine, intermediate BQ (100 mg, 434 μmol, 34% yield) as a colorless oil. 1 H 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). [ka]

[0211] Step 1: To a mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (200 mg, 990 μmol, 1.00 equiv.) and acetone (862 mg, 14.9 mmol, 1.09 mL, 15.0 equiv.) in dichloromethane (1.00 mL), sodium triacetoxyborohydride (420 mg, 1.98 mmol, 2.00 equiv.) was added. After stirring at 25° C. for 14 hours, the mixture was extracted with dichloromethane (5 mL×3), washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, dichloromethane:methyl alcohol 10%) to give 3-bromo-5-isopropyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine (150 mg, 531 μmol, 54% yield) as a yellow oil. LCMS [M+1] + =244.0. 1 H NMR(400 MHz,CDCl3)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).

[0212] Step 2: 3-Bromo-5 in dimethylaminopyridine (1 mL) - A mixture of isopropyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine (80.0 mg, 328 μmol, 1.00 equiv.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (166 mg, 655 μmol, 2.00 equiv.), potassium acetate (113 mg, 1.15 mmol, 3.50 equiv.), and PdCl2[P(Cy)3]2 (24.2 mg, 32.8 μmol, 0.10 equiv.) was purged with nitrogen and then stirred at 90 °C for 20 h. The mixture was then concentrated under reduced pressure to give 5-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine, intermediate BR (700 mg, 303 umol, 92% yield) as a black solid. LCMS [M+1] +=292.2. [ka]

[0213] A pressure tube was charged with 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (260 mg, 1.29 mmol, 1.00 equiv), (1-ethoxycyclopropoxy)trimethylsilane (673 mg, 3.86 mmol, 776 μL, 3.00 equiv), sodium cyanoborohydride (243 mg, 3.86 mmol, 3.00 equiv), and acetic acid (773 mg, 12.9 mmol, 736 μL, 10.0 equiv) in THF (5 mL) and ethyl alcohol (5 mL). The resulting solution was stirred at 60° C. for 2 hours, and then the reaction mixture was concentrated to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 20%) to give 3-bromo-5-cyclopropyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine, intermediate BS (150 mg, 620 μmol, 48% yield) as a yellow solid. 1 H 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). [ka]

[0214] A mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (500 mg, 1.58 mmol, 1.00 equiv), iodobenzene (1.29 g, 6.33 mmol, 705 μL, 4.00 equiv), copper iodide (60.3 mg, 316 μmol, 0.20 equiv), (2S)-pyrrolidine-2-carboxylic acid (72.9 mg, 633 μmol, 0.40 equiv), and cesium carbonate (1.03 g, 3.16 mmol, 2.00 equiv) in DMF (10 mL) was degassed and purged with nitrogen, then stirred at 100° C. for 1.5 h. The mixture was then cooled, extracted with ethyl acetate (5 mL × 3), washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate 5-10%) to give 3-bromo-5-phenyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine, intermediate BT (55 mg, 197 μmol, 12% yield) as a yellow solid. LCMS [M+1] + =278.2. [ka]

[0215] A mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (200 mg, 633 μmol, 1.00 equiv.), acetyl acetate (96.9 mg, 949 μmol, 88.9 μL, 1.50 equiv.), and DMAP (7.73 mg, 63.3 μmol, 0.10 equiv.) in dichloromethane (10 mL) was degassed and purged with nitrogen before stirring at 40° C. for 3 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to afford 1-(3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)ethenone, Intermediate BU (100 mg, crude) as a white solid. LCMS [M+1] + =244.2. [ka]

[0216] To a solution of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (250 mg, 791 μmol, 1.00 equiv) in dimethylformamide (2 mL) was added triethylamine (240 mg, 2.37 mmol, 330 μL, 3.00 equiv), HATU (601 mg, 1.58 mmol, 2.00 equiv), and cyclopropanecarboxylic acid (102 mg, 1.19 mmol, 93.7 μL, 1.50 equiv). The mixture was stirred at 35 °C for 1 h. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The formed residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 0-50%) to give (3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-cyclopropyl-methanone, intermediate BV (139 mg, 515 μmol, 65% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) 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).

[0217] Following the teachings of the General Reaction Scheme and the procedure of Intermediate BV, Intermediates C-1 through C-5 were prepared as shown in Tables I-IV. [Table 5] [ka]

[0218] A mixture of 3-bromo-5-iodo-pyridine (3.00 g, 10.6 mmol, 1.00 equiv), Intermediate AN (2.28 g, 5.28 mmol, 0.50 equiv), sodium bicarbonate (1.78 g, 21.1 mmol, 822 μL, 2.00 equiv), Pd(dppf)Cl (773 mg, 1.06 mmol, 0.10 equiv) in dioxane (50 mL) and water (10 mL) was degassed with nitrogen and then stirred at 80° C. for 1 h. The cooled reaction mixture was then concentrated under reduced pressure, diluted with water (200 mL), filtered, and the filter cake was triturated with dichloromethane:methyl alcohol (10%, 150 mL). The solid was filtered and dried, and the solid was triturated a second time in methyl alcohol (100 mL), then filtered and dried to give 2-[[7-(5-bromo-3-pyridyl)-4-oxo-3H-phthalazin-1-yl]methyl]isoindoline-1,3-dione, intermediate CB (775 mg, crude) as a gray solid. 1 H 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). [ka]

[0219] Step 1: To a solution of pyrazolo[1,5-a]pyridin-5-ol (250 mg, 1.86 mmol, 1.00 equiv) in DMF (2 mL) was added potassium carbonate (773 mg, 5.59 mmol, 3.00 equiv), and the mixture was stirred at 30 °C for 0.5 h. Iodoethane (872 mg, 5.59 mmol, 447 μL, 3.00 equiv) was then added, and the resulting mixture was stirred at 30 °C for 12 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate 20%) to afford 5-ethoxypyrazolo[1,5-a]pyridine (272 mg, 1.68 mmol, 90% yield) as a white solid. LCMS[M+1] + =163.2; 1 H NMR(400 MHz,DMSO-d6)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).

[0220] Step 2: To a solution of 5-ethoxypyrazolo[1,5-a]pyridine (260 mg, 1.60 mmol, 1.00 equiv.) in acetonitrile (1.0 mL) was added NIS (397 mg, 1.76 mmol, 1.10 equiv.). The mixture was stirred at 25° C. for 1 hour, after which the mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL×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 preparative TLC (SiO, petroleum ether / ethyl acetate 20%) to give 5-ethoxy-3-iodo-pyrazolo[1,5-a]pyridine (369 mg, 1.28 mmol, 80% yield) as a pink solid. LCMS [M+1] + =289.1; 1H 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). [ka]

[0221] Intermediate CD, 3-iodo-5-isopropoxy-pyrazolo[1,5-a]pyridine, was prepared as a yellow solid (299 mg, 0.99 mmol, 87% yield over two steps) using 2-iodopropane following the same procedure used to prepare intermediate CC. LCMS [M+1] + =303.0; 1 H 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). [ka]

[0222] Step 1: A mixture of pyrazolo[1,5-a]pyridin-5-ol (300 mg, 2.24 mmol, 1.00 equiv.), phenylboronic acid (545 mg, 4.47 mmol, 2.00 equiv.), 4Å MS (30 mg), copper acetate (812 mg, 4.47 mmol, 2.00 equiv.), and triethylamine (1.13 g, 11.2 mmol, 1.56 mL, 5.00 equiv.) in dichloromethane (10 mL) was degassed with oxygen and stirred at 25 °C under an oxygen (15 psi) atmosphere for 10 h. The reaction mixture was then filtered and concentrated, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 0-20%) to afford 5-phenoxypyrazolo[1,5-a]pyridine (200 mg, 0.95 mmol, 43% yield) as a yellow oil. LCMS [M+1] + =211.2.

[0223] Step 2: To a solution of 5-phenoxypyrazolo[1,5-a]pyridine (180 mg, 0.86 mmol, 1.00 equiv.) in acetonitrile (2 mL) was added NIS (212 mg, 0.94 mmol, 1.10 equiv.). The mixture was stirred at 0 °C for 1 h. The reaction mixture was then concentrated, and the residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate 0-5%) to afford 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. [ka]

[0224] Step 1: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.50 g, 7.21 mmol, 1.00 equiv.), [(£)-2-bromovinyl]benzene (2.90 g, 15.8 mmol, 2.03 mL, 2.20 equiv.), Pd(PPh3)2Cl2 (506 mg, 721 µmol, 0.10 equiv.), potassium carbonate (1.30 g, 9.41 mmol, 1.30 equiv.) in ethyl alcohol (3.8 mL) and DMF (7.5 mL) was degassed with nitrogen and then stirred at 75° C. for 2 hours. The mixture was then cooled to ambient temperature, diluted with water (100 mL), and extracted with ethyl acetate (80 mL x 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 (SiO, petroleum ether / ethyl acetate 0-20%) to afford 1-methyl-5-[(E)-styryl]pyrazole (990 mg, 5.37 mmol, 74% yield) as a yellow solid. LCMS [M+1] + =185.2; 1 H NMR(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).

[0225] Step 2: To a solution of 1-methyl-5-[(E)-styryl]pyrazole (400 mg, 2.17 mmol, 1.00 equiv) in ethyl alcohol (3 mL) under nitrogen was added Pd / C (10.0 mg, 10% Pd). The suspension was degassed under vacuum and purged with hydrogen several times, and the mixture was stirred under hydrogen (15.0 psi) at 25° C. for 12 h. The reaction mixture was then filtered and concentrated under reduced pressure to afford 1-methyl-5-(2-phenylethyl)pyrazole (385 mg, 1.93 mmol, 89% yield) as a yellow oil, which was used in the next step without further purification. LCMS [M+1] + =187.2.

[0226] Step 3: To a solution of 1-methyl-5-(2-phenylethyl)pyrazole (385 mg, 1.93 mmol, 1.00 equiv) in acetonitrile (10 mL) was added N-bromosuccinimide (343 mg, 1.93 mmol, 1.00 equiv). The mixture was then stirred at 0° C. for 0.5 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate 20%) to afford 4-bromo-1-methyl-5-(2-phenylethyl)pyrazole (430 mg, 1.62 mmol, 84% yield) as a yellow oil. 1 H NMR(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=7.2 Hz,2H). [ka]

[0227] Step 1: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.00 g, 4.81 mmol, 1.00 equiv), 2-bromopyridine (911 mg, 5.77 mmol, 0.55 mL, 1.20 equiv), cesium carbonate (3.13 g, 9.61 mmol, 2.00 equiv) and Pd(dppf)Cl (352 mg, 0.48 mmol, 0.10 equiv) in dioxane (10 mL) and water (2 mL) was degassed and purged with nitrogen, then the mixture was stirred at 100 °C for 1 h. The cooled reaction mixture was then concentrated under reduced pressure and purified by column chromatography (SiO, petroleum ether / ethyl acetate 0-20%) to afford 2-(2-methylpyrazol-3-yl)pyridine (860 mg, crude) as a red oil, which was used directly in the next step without further purification. 1H NMR(400 MHz,DMSO-d6)δ=8.69-8.66(m,1H),7.89(dt,J=1.6,7.6 Hz,1H),7.78(td,J=1.2,8.0 Hz,1H),7.48(d,J=2.0 Hz,1H),7.37(ddd,J=1.2,4.8,7.6 Hz,1H),6.78(d,J=1.6 Hz,1H),4.14(s,3H).

[0228] Step 2: To a solution of 2-(2-methylpyrazol-3-yl)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 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate 20%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)pyridine (507 mg, 2.13 mmol, 44% yield) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6)δ=8.77(td,J=0.8,4.0 Hz,1H),8.01(dt,J=2.0,7.6 Hz,1H),7.76 -

[0229] Step 3: To a solution of 2-(4-bromo-2-methyl-pyrazol-3-yl)pyridine (150 mg, 0.63 mmol, 1.00 equiv.) in dichloroethane (3 mL) was added meta-chloroperbenzoic acid (435 mg, 2.14 mmol, 85% purity, 3.40 equiv.). The mixture was stirred at 60° C. for 5 hours. The reaction mixture was then quenched by adding saturated sodium sulfite solution (20 mL) and then extracted with dichloromethane (20 mL × 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 preparative TLC (SiO, petroleum ether / ethyl acetate 50%) to give 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)pyridine 1-oxide (185 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LCMS[M+1] + =254.1; 1H 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). [ka]

[0230] Step 1: A mixture of quinolin-8-ol (454 mg, 3.13 mmol, 0.54 mL, 1.10 equiv.), 3-bromo-5-fluoro-pyridine (500 mg, 2.84 mmol, 1.00 equiv.), and potassium carbonate (785 mg, 5.68 mmol, 2.00 equiv.) in DMF (6 mL) was degassed with nitrogen and then stirred at 110° C. for 3 hours. The mixture was then extracted with ethyl acetate (5 mL×3), and the combined extracts were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 8-[(5-bromo-3-pyridyl)oxy]quinoline (0.30 g, 0.75 mmol, 26% yield) as a yellow oil. LCMS [M+1] + =301.0; 1 H NMR(400 MHz,CDCl3)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=8.0Hz,1H),7.50(dd,J=4.0,8.4Hz,1H),7.47-7.43(m,2H). [ka]

[0231] Step 1: A mixture of 3,5-dibromopyridine (1.48 g, 6.25 mmol, 1.00 equiv), quinolin-8-amine (901 mg, 6.25 mmol, 1.00 equiv), sodium tert-butoxide (901 mg, 9.37 mmol, 1.50 equiv), Pd(dba) (57.2 mg, 62.5 μmol, 0.01 equiv), and XantPhos (72.3 mg, 125 μmol, 0.02 equiv) in dioxane (10 mL) was degassed with nitrogen and then stirred at 100° C. for 2 h. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by reverse-phase HPLC (0.1% formic acid (FA)) to give N-(5-bromo-3-pyridyl)quinolin-8-amine (160 mg, 486 μmol, 7% yield) as a yellow solid. LCMS [M+1] + =300.0; 1 H NMR(400 MHz,CDCl3)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).

[0232] Step 2: N-(5-Bromo-3-pyridyl)quinolin-8-amine (130 mg, 394 μmol, 1.00 equiv) was dissolved in DMF (2 mL), and then sodium hydride (32 mg, 790 μmol, 60.0% purity, 2.00 equiv) was added at 0° C., and the mixture was stirred at 0° C. for 10 minutes. Subsequently, methyl iodide (224 mg, 1.58 mmol, 98 μL, 4.00 equiv) 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×3), and the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give N-(5-bromo-3-pyridyl)-N-methyl-quinolin-8-amine (150 mg, 334 μmol, 85% yield) as a yellow oil. LCMS[M+1] + =314.1; 1 H NMR(400 MHz,CDCl3)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). [ka]

[0233] Step 1: A mixture of 2-ethylbenzonitrile (500 mg, 3.81 mmol, 0.51 mL, 1.00 equiv), p-toluenesulfonic acid (363 mg, 1.91 mmol, 0.50 equiv), N-bromosuccinimide (746 mg, 4.19 mmol, 1.10 equiv), and palladium acetate (85.6 mg, 0.38 mol, 0.10 equiv) in 1,2-dichloroethane (10 mL) was degassed with nitrogen and then stirred at 70 °C for 12 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate 0–5%) to afford 2-bromo-6-ethyl-benzonitrile (446 mg, 1.15 mmol, 30% yield) as a yellow oil. 1 H 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).

[0234] Step 2: A mixture of 2-bromo-6-ethyl-benzonitrile (446 mg, 1.15 mmol, 1.00 equiv), 4-bromo-1-methyl-pyrazole (203 mg, 1.26 mmol, 1.10 equiv), palladium acetate (2.57 mg, 0.12 mmol, 0.01 equiv), DavePhos (9.0 mg, 0.23 mmol, 0.02 equiv), 2-methylpropanoic acid (30.3 mg, 0.34 mmol, 31.9 uL, 0.30 equiv), and tetrabutylammonium acetate (691 mg, 2.29 mmol, 0.70 mL, 2.00 equiv) in N-methylpyrrolidone (10 mL) was degassed with nitrogen and then stirred at 100° C. for 12 hours. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10-20%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-ethyl-benzonitrile (310 mg, 0.44 mmol, 39% yield) as a yellow solid. LCMS [M+1] +=290.1; 1 H NMR(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).

[0235] Intermediates D-1 through D-20, shown in Tables I through V, were prepared following the teachings of the general reaction scheme and method for preparing intermediate CJ. [Table 6-1] [Table 6-2] [Table 6-3] [ka]

[0236] Step 1: A mixture of 3-bromophenol (1.00 g, 5.78 mmol, 1.00 equiv), bromocyclobutane (1.17 g, 8.65 mmol, 0.82 mL, 1.50 equiv), and potassium carbonate (3.20 g, 23.1 mmol, 4.00 equiv) 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 / ethyl acetate 20%) (50 mL × 3), and the combined extracts were washed with aqueous sodium hydroxide (1.00 M, 50 mL), brine (50 mL), dried over sodium sulfate, and concentrated to give 1-bromo-3-(cyclobutoxy)benzene (1.20 g, 5.27 mmol, 91% yield) as a colorless oil. 1H NMR(400 MHz,CDCl3)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=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).

[0237] Step 2: 1-Bromo-3-(cyclobutoxy)benzene (300 mg, 1.32 mmol, 1.00 equiv), 4-bromo-1-methyl-pyrazole (213 mg, 1.32 mmol, 1.00 equiv), palladium acetate (2.97 mg, 13.2 μmol, 0.01 equiv), tetrabutylammonium acetate (224 mg, 2.91 mmol, 2.20 equiv), 2-methylpropanoic acid (34.9 mg, 396 μmol, 36.8 μL, 0.30 equiv), and DavePhos (10.4 mg, 26.4 μmol, 0.02 equiv) in NMP (5 mL) was degassed with nitrogen and heated to 100 °C for 12 h. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). 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 (SiO, petroleum ether / ethyl acetate 1-5%) to give 4-bromo-5-[3-(cyclobutoxy)phenyl]-1-methyl-pyrazole (40.0 mg) as a yellow oil. 1 H NMR(400 MHz,CDCl3)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).

[0238] Intermediates E-1 and E-2 shown in Tables I-VI were prepared following the teachings of the general reaction scheme and method for preparing intermediate DA. [Table 7] [ka]

[0239] Step 1: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.50 g, 7.21 mmol, 1.00 equiv), 1-bromo-2-chloro-benzene (1.38 g, 7.21 mmol, 0.84 mL, 1.00 equiv), sodium carbonate (2.29 g, 21.6 mmol, 3.00 equiv), Pd(dppf)Cl (528 mg, 0.72 mmol, 0.10 equiv) in water (2.4 mL) and dioxane (12 mL) was degassed with nitrogen and then stirred at 80° C. for 2 h. The mixture was then concentrated under reduced pressure and purified by column chromatography (SiO, petroleum ether / ethyl acetate 10-20%) to give 5-(2-chlorophenyl)-1-methyl-pyrazole (0.56 g, 2.88 mmol, 40% yield) as a yellow solid. LCMS [M+1] + =193.1; 1 H NMR (400 MHz, CDCl3) 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).

[0240] Step 2: A mixture of 5-(2-chlorophenyl)-1-methyl-pyrazole (200 mg, 1.04 mmol, 1.00 equiv.), N-bromo-succinimide (203 mg, 1.14 mmol, 1.10 equiv.) in acetonitrile (2 mL) was degassed with nitrogen and then stirred at 0° C. for 2 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by preparative TLC (petroleum ether / ethyl acetate 20%) to give 4-bromo-5-(2-chlorophenyl)-1-methyl-pyrazole (220 mg, 0.77 mmol, 74% yield) as a yellow solid. LCMS [M+1] + =273.1; 1H NMR (400 MHz, CDCl3) δ = 7.59-7.55 (m, 2H), 7.50-7.40 (m, 2H), 7.36-7.33 (m, 1H), 3.74 (s, 3H).

[0241] Intermediates F-1 to F-22, shown in Tables I to VII, were prepared following the teachings of the General Reaction Scheme and the method for preparing Intermediate DB. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [ka]

[0242] Step 1: To a solution of 2-bromonaphthalene-1-carbaldehyde (220 mg, 0.94 mmol, 1.00 equiv.) in water (5 mL) was added amine hydrogen sulfate (212 mg, 1.87 mmol, 2.00 equiv.). 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 afford (1E)-2-bromonaphthalene-1-carbaldehyde oxime (220 mg, 0.88 mmol, 94% yield) as a white solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) 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-1-carbaldehyde oxime (220 mg, crude) in THF (5 mL) was added triethylamine (890 mg, 8.80 mmol, 1.22 mL) and trifluoroacetic anhydride (924 mg, 4.40 mmol, 0.61 mL), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate 10%) to give 2-bromonaphthalene-1-carbonitrile (190 mg, 0.82 mmol, 93% yield) as a white solid. GCMS [M+1] + =230.9; 1 H 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).

[0243] Step 2: A mixture of 2-bromonaphthalene-1-carbonitrile (190 mg, 0.82 mmol, 1.00 equiv.), 4-bromo-1-methyl-pyrazole (132 mg, 0.82 mmol, 1.00 equiv.), tetrabutylammonium acetate (494 mg, 1.64 mmol, 0.50 mL, 2.00 equiv.), DavePhos (6.4 mg, 16 μmol, 0.02 equiv.), 2-methylpropanoic acid (22 mg, 246 μmol, 23 μL, 0.30 equiv.), and palladium acetate (1.8 mg, 8.2 μmol, 0.01 equiv.) in N-methylpyrrolidone (NMP) (6 mL) was degassed with nitrogen and then stirred at 100° C. for 12 hours. The reaction mixture was then diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% formic acid) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)naphthalene-1-carbonitrile (190 mg, 0.61 mmol, 74% yield) as a yellow oil. LCMS [M+1] + =314.1; 1 H 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). [ka]

[0244] Step 1: To a solution of ethyl alcohol (207 mg, 4.50 mmol, 0.26 mL, 3.00 equiv) in THF (3 mL) was added sodium hydride (180 mg, 4.50 mmol, 60.0% purity, 3.00 equiv), followed by the dropwise addition of a solution of 2-bromo-6-fluoro-benzonitrile (300 mg, 1.50 mmol, 1.00 equiv) in THF (1 mL). After the addition was complete, the mixture was stirred at 25 °C for 3 h. The reaction was then quenched with water (0.2 mL), concentrated in vacuo, and the residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate 10%) to afford 2-bromo-6-ethoxy-benzonitrile (200 mg, 0.89 mmol, 59% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) 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).

[0245] Step 2: A mixture of 2-bromo-6-ethoxybenzonitrile (200 mg, 0.89 mmol, 1.00 equiv.), 4-bromo-1-methyl-pyrazole (185 mg, 1.15 mmol, 1.30 equiv.), palladium acetate (2.0 mg, 8.9 μmol, 0.01 equiv.), DavePhos (7.0 mg, 17.7 μmol, 0.02 equiv.), 2-methylpropanoic acid (23.4 mg, 265 μmol, 25 μL, 0.30 equiv.), and tetrabutylammonium acetate (533 mg, 1.77 mmol, 2.00 equiv.) was degassed with nitrogen and then stirred at 100° C. for 15 hours. The mixture was then diluted with ethyl acetate (20 mL) and washed with water (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was then purified by preparative TLC (SiO, petroleum ether / ethyl acetate 20%) to give 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-6-ethoxybenzonitrile (60.0 mg, 0.20 mmol, 22% yield) as a white solid. LCMS [M+1] + =306.1; 1H NMR(400 MHz,CDCl3)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). [ka]

[0246] A mixture of 4-bromo-2-methyl-pyrazol-3-ol (300 mg, 1.69 mmol, 1.00 equiv.), 1-(bromomethyl)-2-chloro-benzene (348 mg, 1.69 mmol, 0.22 mL, 1.00 equiv.), and potassium carbonate (469 mg, 3.39 mmol, 2.00 equiv.) in DMF (8 mL) was stirred at 18 °C for 2 h. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% FA conditions) to give 4-bromo-5-[(2-chlorophenyl)methoxy]-1-methyl-pyrazole (220 mg, 0.72 mmol, 42% yield) as a yellow solid. LCMS [M+1] + =303.0; 1 H NMR (400 MHz, CDCl3) δ=7.48-7.43(m,2H),7.37-7.27(m,3H),5.40(s,2H),3.55(s,3H).

[0247] Intermediates G-1 to G-4 shown in Tables I to VIII were prepared according to the teachings of the General Reaction Scheme and the method for preparing Intermediate DE. [Table 9] [ka]

[0248] Step 1: A mixture of 2-bromo-6-fluorobenzonitrile (600 mg, 3.00 mmol, 1.00 equiv.), propan-2-ol (225 mg, 3.75 mmol, 0.29 mL, 1.25 equiv.), and cesium carbonate (1.47 g, 4.50 mmol, 1.50 equiv.) in DMF (6 mL) was stirred at 75 °C for 1 hour. The reaction mixture was then diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL x 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 give 2-bromo-6-isopropoxybenzonitrile (540 mg, 2.25 mmol, 75% yield) as a white solid. LCMS [M+1] + =241.9; 1 H 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).

[0249] Step 2: A mixture of 2-bromo-6-isopropoxy-benzonitrile (500 mg, 2.08 mmol, 1.00 equiv), 4-bromo-1-methyl-pyrazole (335 mg, 2.08 mmol, 1.00 equiv), diacetoxypalladium (4.7 mg, 0.021 mmol, 0.01 equiv), DavePhos (16 mg, 0.042 mmol, 0.02 equiv), tetrabutylammonium acetate (1.26 g, 4.16 mmol, 2.00 equiv), and 2-methylpropanoic acid (55 mg, 0.63 mmol, 0.06 mL, 0.30 equiv) in 1-methyl-2-pyrrolidinone (7 mL) was degassed with nitrogen and then stirred at 100° C. for 12 hours. The reaction mixture was then diluted with water (30 mL) and extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% formic acid) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-isopropoxy-benzonitrile (160 mg, 0.50 mmol, yield 24) as a white solid. LCMS [M+1] + =319.9; 1 H NMR(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).

[0250] Intermediates H-2 to H-8 shown in Tables I to IX were prepared following the teachings of the General Reaction Scheme and the method for preparing Intermediate H-1. [Table 10] [ka]

[0251] Step 1: To a solution of 6-hydroxychroman-5-carbonitrile (150 mg, 0.86 mmol, 1.00 equiv.) and triethylamine (2.57 mmol, 0.36 mL, 3.00 equiv.) in dichloromethane (2 mL) was added dropwise a solution of trifluoromethanesulfonic anhydride (0.86 mmol, 0.141 mL, 1.00 equiv.) in dichloromethane (1 mL) at 0 °C. The mixture was then stirred at 0 °C for 0.5 h. The mixture was then diluted with ethyl acetate (50 mL), washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate 10%) to give (5-cyanochroman-6-yl)trifluoromethanesulfonate (80 mg, 0.26 mmol, 30% yield) as a colorless liquid. 1 H NMR (400 MHz, CDCl3)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).

[0252] Step 2: A mixture of (5-cyanochroman-6-yl)trifluoromethanesulfonate (70 mg, 0.23 mmol, 1.00 equiv.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (71 mg, 0.34 mmol, 1.50 equiv.), Pd(dtbpf)Cl (15 mg, 0.23 mmol, 0.10 equiv.), and sodium bicarbonate (38 mg, 0.46 mmol, 2.00 equiv.) in DMF (2 mL) was degassed with nitrogen. The mixture was then stirred at 80 °C for 1 h, cooled to 25 °C, diluted with ethyl acetate (30 mL), washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate 30%) to give 6-(2-methylpyrazol-3-yl)chromane-5-carbonitrile (40 mg, 0.17 mmol, 73% yield) as a white solid. LCMS [M+1] += 240.0; 1H NMR(400 MHz,CDCl3)=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).

[0253] Step 3: To a solution of 6-(2-methylpyrazol-3-yl)chromane-5-carbonitrile (30 mg, 0.125 mmol, 1.00 equiv.) in acetonitrile (1.5 mL) was added NBS (34 mg, 0.19 mmol, 1.50 equiv.). The mixture was stirred at 25° C. for 1 h and then concentrated. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate 30%) to give 6-(4-bromo-2-methyl-pyrazol-3-yl)chromane-5-carbonitrile (25 mg, 0.79 mmol, 63% yield) as a yellow solid. LCMS [M+1] += 320.1; 1 H NMR(400 MHz,CDCl3)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).

[0254] Intermediates I-2 to I-4 shown in Table IX were prepared following the teachings of the General Reaction Scheme and the method for preparing intermediate I-1. [Table 11] [ka]

[0255] A mixture of tert-butyl 5-bromo-3-iodo-pyrrolo[2,3-b]pyridine-1-carboxylate (120 mg, 0.28 mmol, 1 equiv.), (2-cyanophenyl)boronic acid (83 mg, 0.57 mmol, 2 equiv.), Pd(dppf)Cl (21 mg, 0.03 mmol, 0.1 equiv.), and NaHCO (71 mg, 0.85 mmol) in DMF (2 mL) was degassed with nitrogen and then stirred at 80° C. for 3 h. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with water (20 mL × 3). The organic phase was concentrated and the residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate 15%) to give intermediate E-1, tert-butyl 5-bromo-3-(2-cyanophenyl)pyrrolo[2,3-b]pyridine-1-carboxylate (50 mg, 0.13 mmol, 44% yield) as a white solid. LCMS [M-55] + =342.1; 1 H NMR(400 MHz,CDCl3)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). [ka]

[0256] Step 1: A mixture of 6-bromo-7-methoxy-quinoline (100 mg, 0.420 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (105 mg, 0.504 mmol, 1.20 equiv), Pd(dtbpf)Cl (27 mg, 0.042 mmol, 0.10 equiv) and sodium carbonate (89 mg, 0.840 mmol, 2.00 equiv) in dioxane (1.0 mL) and water (0.2 mL) was degassed with nitrogen. The mixture was then stirred at 80° C. for 2 h, concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO, ethyl acetate) to give 7-methoxy-6-(2-methylpyrazol-3-yl)quinoline (80 mg, 0.334 mmol, 80% yield) as a yellow solid. LCMS [M+1] + =240.2; 1 H NMR(400 MHz,CDCl3)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).

[0257] Step 2: A mixture of 7-methoxy-6-(2-methylpyrazol-3-yl)quinoline (500 mg, 2.09 mmol, 1.00 equiv) and pyridine hydrochloride (2.41 g, 20.9 mmol, 10.0 equiv) was stirred at 160° C. for 0.5 h. The residue was then purified by reverse preparative HPLC (0.1% formic acid) to afford 6-(2-methylpyrazol-3-yl)quinolin-7-ol (260 mg, 1.07 mmol, 51% yield, 92% purity) as a yellow solid. LCMS [M+1] + =226.1.

[0258] Step 3: To a solution of 6-(2-methylpyrazol-3-yl)quinolin-7-ol (260 mg, 1.15 mmol, 1.00 equiv) and triethylamine (0.32 mL, 2.31 mmol, 2.00 equiv) in dichloromethane (5 mL) was added trifluoromethanesulfonic anhydride (0.29 mL, 1.73 mmol, 1.50 equiv) 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×3). The combined organic extracts were washed with brine (12 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate 10-100%) to afford [6-(2-methylpyrazol-3-yl)-7-quinolyl]trifluoromethanesulfonate (0.97 g, 0.706 mmol, 61%) as a yellow oil. LCMS [M+1] + =358.1.

[0259] Step 4: A mixture of [6-(2-methylpyrazol-3-yl)-7-quinolyl]trifluoromethanesulfonate (970 mg, 0.668 mmol, 1.00 equiv), zinc cyanide (157 mg, 1.34 mmol, 2.00 equiv), Pd(dba) (61 mg, 0.67 mmol, 0.1 equiv), DPPF (74 mg, 0.134 mmol, 0.20 equiv), and zinc powder (4.3 mg, 0.67 mmol, 0.10 equiv) in DMF (10 mL) was degassed with nitrogen and then stirred at 100° C. for 2 h. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by HPLC (0.1% formic acid) to give 6-(2-methylpyrazol-3-yl)quinoline-7-carbonitrile (100 mg, 0.249 mmol, 37% yield) as a brown solid. LCMS [M+1] + =235.2.

[0260] Step 5: To a solution of 6-(2-methylpyrazol-3-yl)quinoline-7-carbonitrile (90 mg, 0.384 mmol, 1.00 equiv.) in acetonitrile (5 mL) was added N-bromosuccinimide (103 mg, 0.576 mmol, 1.50 equiv.). The mixture was stirred at 20° C. for 0.5 hours, then concentrated under reduced pressure, and the residue was purified by preparative TLC (dichloromethane / methyl alcohol 10%) to give 6-(4-bromo-2-methyl-pyrazol-3-yl)quinoline-7-carbonitrile (50 mg, 0.160 mmol, 41% yield) as a yellow solid. LCMS [M+1] + =315.1; 1 H NMR(400 MHz,CDCl3)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). [ka]

[0261] Step 1: A mixture of 6-bromo-7-methoxyquinoline (100 mg, 0.420 mmol, 1.00 equiv.), zinc cyanide (98 mg, 0.840 mmol, 2.00 equiv.), Pd2(dba)3 (38 mg, 0.042 mmol, 0.10 equiv.), DPPF (47 mg, 0.084 mmol, 0.20 equiv.), and zinc powder (2.8 mg, 0.042 mmol, 0.10 equiv.) in DMF (2 mL) was degassed and purged with nitrogen. The mixture was then stirred at 100 °C for 2 h, after which it was diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 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 give 7-methoxyquinoline-6-carbonitrile (56 mg, 0.304 mmol, 72% yield) as a white solid. LCMS [M+1] + =185.2; 1H NMR(400 MHz,CDCl3)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).

[0262] Step 2: To a solution of 7-methoxyquinoline-6-carbonitrile (1.40 g, 7.60 mmol, 1.00 equiv.) in toluene (20 mL) was added aluminum trichloride (3.04 g, 22.8 mmol, 1.25 mL, 3.00 equiv.). The mixture was stirred at 100 °C for 1 h. The reaction mixture was then diluted with water (3 mL) and the pH was adjusted to 4-5 with sodium hydroxide (2 N, 0.1 mL). The solid formed was filtered and dried under reduced pressure to give 7-hydroxyquinoline-6-carbonitrile (1.20 g, crude) as a black solid, which was used directly in the next step without further purification. LCMS [M+1] + =171.1.

[0263] Step 3: To a solution of 7-hydroxyquinoline-6-carbonitrile (500 mg, 2.94 mmol, 1 equiv.) and triethylamine (0.82 mL, 5.88 mmol, 2.00 equiv.) in dichloromethane (10 mL), trifluoromethanesulfonic anhydride (0.73 mL, 4.41 mmol, 1.50 equiv.) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 1 h, after which the reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (50 mL × 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 (SiO, petroleum ether / ethyl acetate 10–50%) to afford (6-cyano-7-quinolyl)trifluoromethanesulfonate (250 mg, 0.570 mmol, 19% yield) as a yellow oil. LCMS[M+1] + =303.0; 1H NMR (400 MHz, CDCl3) δ=9.15(dd,J=1.6,4.0 Hz,1H),8.37(s,1H),8.32-8.30(d,J=8.4 Hz 1H),8.23(s,1H),7.65(dd,J=4.0,8.4 Hz,1H).

[0264] Step 4: (6-cyano-7-quinolyl)trifluoromethanesulfonate (237 mg, 0.541 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (135 mg, 0.649 mmol, 1.20 equiv), sodium bicarbonate (91 mg, 1.08 mmol, 2.00 equiv) and Pd(dtbpf)Cl in dioxane (10 mL) and water (2 mL). 2( A mixture of 35 mg, 0.054 mmol, 0.10 equiv. of HCl was degassed with nitrogen and stirred at 80° C. for 1 h. The mixture was then concentrated and the residue was purified by column chromatography (SiO 2、 Purification with petroleum ether / ethyl acetate (10-100%) gave 7-(2-methylpyrazol-3-yl)quinoline-6-carbonitrile (120 mg, 0.498 mmol, 92% yield) as a yellow solid. LCMS [M+1] + =235.2.

[0265] Step 5: A mixture of 7-(2-methylpyrazol-3-yl)quinoline-6-carbonitrile (120 mg, 0.512 mmol, 1.00 equiv) and N-bromosuccinimide (164 mg, 0.922 mmol, 1.80 equiv) in acetonitrile (4 mL) was degassed with nitrogen and stirred at 20 °C for 2 h. The mixture was then concentrated, and the residue was purified by preparative TLC (SiO, dichloromethane / methyl alcohol 10%) to give 7-(4-bromo-2-methyl-pyrazol-3-yl)quinoline-6-carbonitrile (121 mg, 0.385 mmol, 75% yield) as a yellow solid. LCMS [M+1] + =314.9; 1H NMR (400 MHz, CDCl3) 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). [ka]

[0266] To a solution of N-(4-bromo-2-methyl-pyrazol-3-yl)benzamide (500 mg, 1.78 mmol, 1.00 equiv) in DMF (5 mL) was added sodium hydride (143 mg, 3.57 mmol, 60.0% purity, 2.00 equiv) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. Then, iodomethane (0.133 mL, 2.14 mmol, 1.20 equiv) was added in DMF (1 mL), and the mixture was stirred at 0° C. for an additional 10 minutes. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (40 mL×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 give N-(4-bromo-2-methyl-pyrazol-3-yl)-N-methyl-benzamide (400 mg, 1.36 mmol, 76% yield) as a white solid. 1 H 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). [ka]

[0267] Step 1: To a stirred solution of methyl 7-bromo-4-oxo-3H-phthalazine-1-carboxylate (1.00 g, 3.53 mmol, 1.00 equiv), sodium borodeuteride (347 mg, 9.18 mmol, 2.60 equiv) in methanol-d4 (30 mL) at 0° C. was added calcium chloride (470 mg, 4.24 mmol, 1.20 equiv) at 0° C. The mixture was then stirred at 0° C. for 3 hours and then at 20° C. for 1 hour. The reaction mixture was then concentrated. The residue was diluted with water (30 mL), the pH was adjusted to 5 with 1N hydrochloric acid (5 mL), the mixture was filtered, and the filter cake was washed with water (5 mL x 3) and then triturated with ethyl alcohol (20 mL) to give 6-bromo-4-((hydroxy-d)methyl-d2)phthalazin-1(2H)-one (463 mg, 1.61 mmol, 46% yield) as a white solid. LCMS [M+1] + =259.0; 1 H NMR(400 MHz,DMSO-d6)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).

[0268] Step 2: A mixture of 6-bromo-4-((hydroxy-d)methyl-d2)phthalazin-1(2H)-one (463 mg, 1.61 mmol, 1.00 equiv) and thionyl chloride (10 mL) was stirred at 30 °C for 12 hours. The mixture was then concentrated, and the residue was dissolved in dichloromethane and concentrated three times (2 mL x 3) to give 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.

[0269] Step 3: To a solution of 6-bromo-4-(chloromethyl-d2)phthalazin-1(2H)-one (450 mg, 1.63 mmol, 1.00 equiv.) in DMF (3 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (454 mg, 2.45 mmol, 1.50 equiv.), and the mixture was stirred at 90° C. for 2 hours. The cooled reaction mixture was then filtered, and the collected solid was triturated with ethyl alcohol (5 mL), filtered, and dried to give 2-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl-d2)isoindoline-1,3-dione (300 mg, crude) as a white solid. LCMS [M+1] + =386.0; 1 H NMR(400 MHz,DMSO-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).

[0270] Step 4: A mixture of 2-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl-d2)isoindoline-1,3-dione (200 mg, crude), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (197 mg, 0.78 mmol), Pd(dppf)Cl2 (38 mg, 0.052 mmol) and potassium acetate (152 mg, 1.55 mmol) in dioxane (10 mL) was degassed with nitrogen. The mixture was stirred at 100° C. for 2 hours, after which the mixture was concentrated and the residue was triturated with methyl alcohol (3 mL), filtered, and dried to give 2-((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl-d2)isoindoline-1,3-dione (200 mg, 0.303 mmol, 59% yield over two steps) as a white solid. LCMS [M+1] + =352.1; 1H NMR (400 MHz, DMSO-d6) 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). [ka]

[0271] Step 1: To a solution of K2CO3 (44.7 g, 323 mmol) in water (500 mL) was added 1-(5-bromo-3-chloro-2-methylphenyl)ethan-1-one (40.0 g, 162 mmol) and warmed to 50 °C. KMnO4 was then carefully added in 10 batches (165 g, 1.04 mol), maintaining the temperature below 80 °C to avoid uncontrolled exotherm. After the addition was complete, the mixture was stirred at 60 °C for 6 h. The mixture was then cooled to 0 °C and quenched by the dropwise addition of saturated sodium sulfite solution (200 mL) while maintaining the temperature below 10 °C. The mixture was then stirred at 0 °C for 30 min. The clear, colorless mixture was then filtered through 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 HCl, followed by extraction with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give compound 4-bromo-2-(carboxycarbonyl)-6-chlorobenzoic acid (20.0 g, 65.0 mmol, 36% yield) as a white solid. LCMS [M-1] - =306.8; 1 H NMR (400 MHz, DMSO-d6) δ 12.7 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H).

[0272] Step 2: To a solution of compound 4-bromo-2-(carboxycarbonyl)-6-chlorobenzoic acid (20.0 g, 65.0 mmol) in EtOH (200 mL) was added NHNH under N. 2·HO (4.30 g, 85.9 mmol) was added in one portion. The mixture was then stirred at 70 °C for 1 h. The cooled reaction mixture was then filtered, washed, and the solid was dried in vacuo to give 7-bromo-5-chloro-4-oxo-3,4-dihydrophthalazine-1-carboxylic acid (14.0 g, 46.1 mmol, 71% yield) as a white solid. LCMS [M+1] + =305.2; 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H).

[0273] Step 3: To a mixture of 7-bromo-5-chloro-4-oxo-3,4-dihydrophthalazine-1-carboxylic acid (14.0 g, 46.1 mmol) in MeOH (250 mL) was added concentrated HSO (9.23 g, 92.2 mmol) in one portion under nitrogen. The mixture was then heated to 70 °C for 16 h, then cooled to ambient temperature, filtered, and dried to give methyl 7-bromo-5-chloro-4-oxo-3,4-dihydrophthalazine-1-carboxylate (7.50 g, 23.6 mmol, 51% yield) as a white solid. 1 H NMR (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).

[0274] Step 4: To a solution of methyl 7-bromo-5-chloro-4-oxo-3,4-dihydrophthalazine-1-carboxylate (7.50 g, 23.6 mmol) in EtOH (70 mL) at 0 °C was added NaBH (2.32 g, 61.4 mmol), followed by the careful slow addition of CaCl (3.15 g, 28.3 mmol) at 0 °C over 2 h. The mixture was then warmed to 15 °C and stirred for an additional 2 h. The reaction was then poured into saturated NH Cl (100 mL), and the solid was filtered, washed with water (10 mL), then EtOH (10 mL), and dried to give 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; 1 H 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). Step 5: 6-Bromo-8-chloro-4-(hydroxymethyl)phthalazin-1(2H)-one (4.00 g, 13.8 mmol) and SOCl 2( A mixture of 6-bromo-8-chloro-4-(chloromethyl)phthalazin-1(2H)-one (3.50 g, 11.4 mmol, 82% yield) was stirred at 65° C. for 1 h. The mixture was then 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 give 6-bromo-8-chloro-4-(chloromethyl)phthalazin-1(2H)-one (3.50 g, 11.4 mmol, 82% yield) as a pale yellow solid. LCMS [M+1] + =309.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 5.06 (s, 1H).

[0275] 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-8-chloro-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 hours. The mixture was then poured into ice water (200 mL) and stirred for 30 minutes. The solid was then filtered, dried, and triturated with MeOH (30 mL) at 15 °C for 30 minutes. The solid was filtered and dried to give 2-((7-bromo-5-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (1.30 g, 3.10 mmol, 27% yield) as a pale yellow solid. LCMS [M+1] + =420.0; 1 H 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).

[0276] Step 7: A mixture of 2-((7-bromo-5-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (1.30 g, 3.10 mmol), bis(pinacolato)diboron (1.20 g, 4.66 mmol), and potassium acetate (762 mg, 7.76 mmol) in dioxane (20 mL) was degassed with nitrogen. Pd(dppf)Cl (114 mg, 0.16 mmol) was then added, and the mixture was stirred at 70 °C for 2.5 h. The mixture was then 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 give 2-((5-chloro-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (910 mg, 1.95 mmol, 63% yield) as a pale yellow solid. LCMS [M+1] + =383.9; 1 H 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). [ka]

[0277] Following the same procedure for the synthesis of intermediate DK, 2-((5-fluoro-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione, intermediate DL, was prepared in seven steps from 1-(5-bromo-3-fluoro-2-methylphenyl)ethan-1-one as a white solid (200 mg, 0.42 mmol, 2.1% yield). LCMS [M+1]=368.1; 1H 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). [ka]

[0278] Step 1: To a solution of 5-bromo-2-methyl-3-pivalamidobenzoic acid (120 g, 382 mmol) in DMF (1.20 L) was added DIEA (98.7 g, 764 mmol, 133 mL), HATU (189 g, 497 mmol), followed by N,O-dimethylhydroxylamine (55.9 g, 573 mmol, HCl) at 20 °C. The resulting solution was stirred at 20 °C for 2 h, after which the reaction mixture was poured into ice water (5.0 L). The mixture was extracted with ethyl acetate (2.0 L × 3), and the combined organic phase was washed with brine (1.0 L), dried over anhydrous NaSO, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 5-bromo-N-methoxy-N,2-dimethyl-3-pivalamidobenzamide (135 g, 378 mmol, 99% yield) as a brown oil. 1 H NMR:400 MHz,DMSO-d6 δ 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).

[0279] Step 2: To a solution of 5-bromo-N-methoxy-N,2-dimethyl-3-pivalamidobenzamide (135 g, 378 mmol) in THF (1.5 L) was added MeMgBr (3.0 M, 315 mL) at 0 °C. The resulting solution was warmed to 20 °C and stirred for 12 h. An additional aliquot of MeMgBr (3 M, 63.0 mL) was then added, and the mixture was stirred for an additional 4 h. The mixture was then diluted with NHCl (1.5 L) and extracted with ethyl acetate (1.0 L × 3). The combined organic phases were washed with brine (1.0 L), dried over anhydrous NaSO, and filtered. The filtrate was concentrated to give N-(3-acetyl-5-bromo-2-methylphenyl)pivalamide (115 g, 368 mmol, 98% yield) as a yellow solid. 1 H NMR 400 MHz, DMSO-d6 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).

[0280] Step 3: To a solution of N-(3-acetyl-5-bromo-2-methylphenyl)pivalamide (57.5 g, 184 mmol) in HO (600 mL) was added KCO (50.9 g, 368 mmol) and KMnO (204 g, 1.29 mol) at 50 °C. The resulting solution was stirred at 50 °C for 17 h. The reaction mixture was then quenched with saturated sodium thiosulfate solution and filtered through diatomaceous earth. The pH was adjusted to 2 with 2 N HCl, and the mixture was extracted with a 10:1 mixture of ethyl acetate:THF (1.00 L × 3), washed with brine (500 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 4-bromo-2-(carboxycarbonyl)-6-pivalamidobenzoic acid (58.0 g, crude) as a pale yellow oil. 1 H NMR 400 MHz, DMSO-d6 δ 9.87(s,1H),8.63(d,J=2.0 Hz,1H),7.54(d,J=2.0 Hz,1H),1.27(s,9H).

[0281] Step 4: To a solution of 4-bromo-2-(carboxycarbonyl)-6-pivalamidobenzoic acid (110 g, 296 mmol) in EtOH (1.10 L) was added NH 2· HO (18.1 g, 355 mmol, 17.6 mL) was added and the solution was stirred at 75° C. for 3 h. The reaction mixture was then filtered and the filter cake was dried to give 7-bromo-4-oxo-5-pivalamido-3,4-dihydrophthalazine-1-carboxylic acid (30.0 g, 81.5 mmol, 28% yield) as a white solid. 1 H NMR 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).

[0282] Step 5: To a solution of 7-bromo-4-oxo-5-pivalamido-3,4-dihydrophthalazine-1-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 at room temperature for 36 hours, resulting in the formation of a yellow solid. The reaction was concentrated, diluted with water (100 mL), adjusted to pH 8 with 1 N NaOH, stirred for 0.5 hours, and then filtered. The filter cake was washed with water (50 mL), then EtOH (100 mL), and dried to give the crude product, methyl 5-amino-7-bromo-4-oxo-3,4-dihydrophthalazine-1-carboxylate (20.0 g, crude), as a yellow solid.

[0283] Step 6: To a solution of methyl 5-amino-7-bromo-4-oxo-3,4-dihydrophthalazine-1-carboxylate (15.0 g, 50.3 mmol) in MeCN (500 mL) was added TosOH (34.6 g, 200 mmol) under N at 0 °C. To this solution was added a solution of NaNO (8.68 g, 125 mmol) in HO (20 mL), and the mixture was stirred at 0 °C for 10 minutes. Then, a solution of KI (25.0 g, 150 mmol) in HO (20.0 mL) was added dropwise. The mixture was stirred at 20 °C for 1 hour, and the reaction was quenched with NaSO. 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 EtOH (100 mL) and dried to give methyl 7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazine-1-carboxylate (15.0 g, crude) as a yellow solid.

[0284] Step 7: In eight batches, a solution of methyl 7-bromo-5-iodo-4-oxo-3,4-dihydrophthalazine-1-carboxylate (4.00 g, 9.78 mmol) in EtOH (60 mL) was added in batches at 0 °C to NaBH (740 mg, 19.6 mmol), followed by CaCl (1.30 g, 11.7 mmol) in batches at 0 °C. The reaction was stirred at 20 °C for 1 h. The eight batches were then combined and quenched with NH Cl (200 mL). The mixture was concentrated to remove EtOH, diluted with water (200 mL), and then filtered. The filter cake was washed with water (100 mL) and dried. The residue was triturated in MeOH (200 mL) for 10 h, filtered, and dried to give 6-bromo-4-(hydroxymethyl)-8-iodophthalazin-1(2H)-one (19.0 g, 38.9 mmol, 50% yield) as a yellow solid. 1 H NMR 400 MHz,DMSO-d6 δ 12.64(s,1H),8.56(d,J=1.88 Hz,1H),8.29(d,J=1.88 Hz,1H),5.62-5.54(m,1H),4.62(d,J=5.70 Hz,2H).

[0285] 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) was added a solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, CsCO (4.28 g, 13.1 mmol), and Pd(dppf)Cl (384 mg, 524 μmol) in THF (3.67 mL, 13.1 mmol, 50% purity). The reaction was stirred at 100 °C for 10 h. The three batches were combined and filtered through diatomaceous earth. The filtrate was concentrated, and the residue was purified by preparative HPLC (Phenomenex luna C18 250 × 150 mm × 15 μm; mobile phase: [water (0.1% TFA)-MeOH], B%: 30% to 60%, 20 min) to give 6-bromo-4-(hydroxymethyl)-8-methylphthalazin-1(2H)-one (1.1 g, 4.06 mmol, 26% yield) as a pale yellow solid. LCMS [M+1] + =271; 1 H NMR 400 MHz, DMSO-d6 δ 12.44(s,1H),8.10(s,1H),7.82(s,1H),4.63(s,3H),2.81(s,3H).

[0286] Step 9: A solution of 6-bromo-4-(hydroxymethyl)-8-methylphthalazin-1(2H)-one (1.20 g, 4.46 mmol) in SOCl (13 mL) was stirred at 70 °C for 2 h. The mixture was then concentrated, and the residue was triturated with petroleum ether for 0.5 h, filtered, and dried to give 6-bromo-4-(chloromethyl)-8-methylphthalazin-1(2H)-one (1.20 g, 4.17 mmol, 94% yield) as a pale yellow solid. LCMS [M+1] + =289; 1 H NMR 400 MHz, DMSO-d6 δ 12.70(s,1H),8.08(s,1H),7.88(s,1H),5.03(s,2H),2.81(s,3H).

[0287] Step 10: To a mixture of 6-bromo-4-(chloromethyl)-8-methylphthalazin-1(2H)-one (1.10 g, 3.83 mmol) in DMF (30 mL) was added potassium isoindoline-1,3-dione (850 mg, 4.59 mmol) in one portion at 0° C. under N. The mixture was stirred at 25° C. for 1 hour, after which the mixture was slowly poured into ice-water (100 mL). The white solid that formed was filtered, washed with water, and dried to give the crude product 2-((7-bromo-5-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (1.10 g, 2.32 mmol, 61% yield) as a white solid. LCMS [M+1] + =400; 1 H NMR 400 MHz,DMSO-d6 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).

[0288] Step 11: 2-((7-bromo-5-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (1.10 g, 2.76 mmol), Pd(dppf)Cl (202 mg, 276 μmol), KOAc (542 mg, 5.52 mmol), and bis(pinacolato)diboron (1.05 g, 4.14 mmol) in dioxane (20 mL) was degassed with nitrogen and then heated at 80° C. for 10 h. The reaction was then filtered through diatomaceous earth, the cake washed with MeOH (10 mL), and the filtrate was concentrated. The residue was then triturated with MeOH (10 mL) for 1 h, filtered, and the filter cake was washed with MeOH and dried to give 2-((5-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione, intermediate DM (510 mg, 1.15 mmol, 42% yield) as a gray solid. LCMS: Boronic acid [M+1] + =364; Boronic acid ester [M+1] + =446). 1H NMR 400 MHz, DMSO-d6 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). [ka]

[0289] Step 1: To a solution of 5-(chloromethyl)-1-methylpyrazole (584 mg, 3.50 mmol, 1.00 equiv.) and 2-phenylacetonitrile (819 mg, 6.99 mmol, 2.00 equiv.) in DMF (10 mL) was added potassium carbonate (966 mg, 6.99 mmol, 2.00 equiv.). The reaction mixture was stirred at 120 °C for 4 h and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10-50%) to afford 3-(2-methylpyrazol-3-yl)-2-phenyl-propanenitrile (300 mg, 1.42 mmol, 41% yield) as a brown oil. LCMS [M+1] += 212.0; 1 H NMR(400 MHz,CDCl3)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).

[0290] Step 2: To a mixture of 3-(2-methylpyrazol-3-yl)-2-phenyl-propanenitrile (160 mg, 0.76 mmol, 1.00 equiv.) in dry acetonitrile (2.0 mL), NBS (121 mg, 0.68 mmol, 0.90 equiv.) was added portionwise. The mixture was stirred at 15° C. for 2 hours. Then, 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×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 preparative HPLC (Phenomenex Gemini-NX C18 75 x 30 mm x 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30% to 60%, 8 min) to give 3-(4-bromo-2-methyl-pyrazol-3-yl)-2-phenyl-propanenitrile (90.0 mg, 0.31 mmol, 41% yield) as a yellow oil. LCMS [M+1] += 289.8; 1 H NMR(400 MHz,CDCl3)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). [ka]

[0291] Step 1: n-Butyllithium (2.5 M in hexanes, 959 μL, 1.50 equiv.) was added dropwise over 5 minutes to a solution of 2,2,6,6-tetramethylpiperidine (2.40 mmol, 407 μL, 1.50 equiv.) in THF (3 mL) maintained at 0° C. After 30 minutes, the reaction mixture was cooled to −78° C., and a solution of 5-chloronaphthalene-1-carbonitrile (300 mg, 1.60 mmol, 1.00 equiv.) in THF (1.00 mL) was added dropwise over 10 minutes. The resulting dark solution was maintained at −78° C. for 2 hours. A solution of iodine (609 mg, 2.40 mmol, 1.50 equiv.) in THF (3 mL) was then added dropwise over 10 minutes. The reaction mixture was maintained at −78° C. for 2 hours, then warmed to 20° C. for 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 saturated aqueous sodium thiosulfate (3 × 150 mL), 1 M HCl (2 × 150 mL), and brine (1 × 150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 5%) to give 5-chloro-2-iodo-1-naphthonitrile (180 mg, 574 μmol, 36% yield) as a yellow solid. GCMS [M+H] += 312.9; 1 H NMR (400 MHz, CDCl3) 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).

[0292] Step 2: 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (104 mg, 498 μmol, 1.30 equiv.), 5-chloro-2-iodo-1-naphthonitrile (120 mg, 383 μmol, 1.00 equiv.), Pd(dtbpf)Cl in dioxane (3 mL) and water (0.6 mL). 2(A mixture of 5-chloro-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (25 mg, 38 μmol, 0.10 equiv.) and sodium carbonate (81 mg, 766 μmol, 2.00 equiv.) was degassed with nitrogen and then stirred at 80° C. for 1 h. The mixture was then concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 30%) to give 5-chloro-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (90 mg, 336 μmol, 87% yield) as a yellow solid. LCMS [M+1] += 268.2; 1 H NMR(400 MHz,CDCl3)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).

[0293] Step 3: To a solution of 5-chloro-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (170 mg, 635 μmol, 1.00 equiv.) in acetonitrile (3 mL) was added NBS (124 mg, 699 μmol, 1.10 equiv.). The mixture was stirred at 35° C. for 2 hours and then concentrated to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate 30%) to give 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-1-naphthonitrile, intermediate DO (130 mg, 375 μmol, 59% yield) as a white solid. LCMS [M+1] += 347.8; 1 H NMR(400 MHz,CDCl3)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). [ka]

[0294] Step 1: To a solution of 2,2,6,6-tetramethylpiperidine (553 mg, 3.92 mmol, 0.67 mL, 1.20 equiv) in THF (7 mL) was added n-butyllithium (2.50 M, 1.57 mL, 1.20 equiv) dropwise 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 equiv) was added. After 5 minutes, a solution of 1-naphthonitrile (500 mg, 3.26 mmol, 1.00 equiv) in THF (3 mL) was added dropwise, and the reaction was then allowed to warm slowly to 25° C. and stirred for 16 hours. Acetic acid (392 mg, 6.53 mmol, 0.37 mL, 2.00 equiv) was then added, followed by propane-1,3-diol (994 mg, 13.1 mmol, 0.95 mL, 4.00 equiv), and the mixture was then stirred at 25° C. for 1 hour. The reaction was then quenched by adding saturated ammonium chloride solution (20 mL), and then diluted with water (10 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(1,3,2-dioxaborinan-2-yl)-1-naphthonitrile (600 mg, 2.53 mmol, 78% yield) as a pale yellow solid. 1 H NMR(400 MHz,CDCl3)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).

[0295] Step 2: To a solution of 5-bromoisothiazole (150 mg, 0.915 mmol, 1.00 equiv) and 2-(1,3,2-dioxaborinan-2-yl)-1-naphthonitrile (217 mg, 0.915 mmol, 1.00 equiv) in toluene (8 mL) and ethyl alcohol (0.8 mL) was added aqueous potassium carbonate (2.00 M, 0.915 mL, 2.00 equiv) and Pd(PPh3)4 (106 mg, 0.091 mmol, 0.10 equiv) under a nitrogen atmosphere at 20 °C. The mixture was stirred at 100 °C for 16 h, concentrated to dryness, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 10–15%) to give 2-(isothiazol-5-yl)-1-naphthonitrile (200 mg, 0.85 mmol, 93% yield) as a pale yellow solid. 1 H NMR(400 MHz,CDCl3)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).

[0296] Step 3: To a solution of 2-(isothiazol-5-yl)-1-naphthonitrile (100 mg, 0.42 mmol, 1.00 equiv) in acetonitrile (2 mL) was added N-bromo-succinimide (753 mg, 4.23 mmol, 10.0 equiv) at 20° C., and the mixture was stirred in a sealed tube at 100° C. for 48 hours. The mixture was then concentrated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL), washed with water (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was then purified by preparative HPLC (Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 45% to 75%, 8 min) to give 2-(4-bromoisothiazol-5-yl)-1-naphthonitrile (50 mg, 0.16 mmol, 38% yield) as a white solid. 1H NMR(400 MHz,CDCl3)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). [ka]

[0297] Step 1: To a solution of LDA (2.00 M, 0.587 mL, 1.10 equiv) in THF (10 mL) was added dropwise a solution of 4-chloro-2-naphthonitrile (200 mg, 1.07 mmol, 1.00 equiv) in THF (5 mL) at −78° C. The mixture was then stirred at −78° C. for 1 hour. After that, a solution of iodine (285 mg, 1.12 mmol, 1.05 equiv) in THF (2 mL) was added dropwise at −78° C. The mixture was then warmed to room temperature and stirred at 20° C. for 2 hours. The reaction mixture was then quenched by adding saturated ammonium chloride solution (15 mL) and saturated sodium hyposulfite solution (10 mL×3). The mixture was then extracted with ethyl acetate (20 mL × 2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by flash chromatography (SiO, petroleum ether:ethyl acetate 0-5%) to give 4-chloro-3-iodo-2-naphthonitrile (200 mg, 0.606 mmol, 30% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) 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).

[0298] Step 2: To a solution of 4-chloro-3-iodo-2-naphthonitrile (320 mg, 1.02 mmol, 1.00 equiv) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (319 mg, 1.53 mmol, 1.50 equiv) in dioxane (30 mL) and water (6 mL), potassium carbonate (283 mg, 2.04 mmol, 2.00 equiv) and Pd(dppf)Cl (75 mg, 0.102 mmol, 0.10 equiv) were added at 25 °C. The mixture was degassed with nitrogen and then stirred at 100 °C for 16 h. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (30 mL × 4). The combined organic layers were washed with brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by flash chromatography (SiO2, petroleum ether:ethyl acetate 0-5%) to give 4-chloro-3-(1-methyl-1H-pyrazol-5-yl)-2-naphthonitrile (50 mg, 0.178 mmol, 30% yield) as a yellow solid. LCMS [M+1] + =268.0 / 270.0; 1 H NMR(400 MHz,CDCl3)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).

[0299] Step 3: To a solution of 4-chloro-3-(1-methyl-1H-pyrazol-5-yl)-2-naphthonitrile (100 mg, 0.374 mmol, 1.00 equiv.) in acetonitrile (10 mL) was added N-iodosuccinimide (504 mg, 2.24 mmol, 6.00 equiv.) at 25 °C, and the mixture was stirred at 80 °C for 16 hours. Then, at 0 °C, the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The formed residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 30%) to give 4-chloro-3-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2-naphthonitrile (50 mg, 0.121 mmol, 32% yield) as a white solid. LCMS[M+1] + =393.9 / 395.9; 1 H NMR(400 MHz,CDCl3)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 (m, 1H), 7.71 (s, 1H), 3.81 (s, 3H). [ka]

[0300] Step 1: A mixture of 4-chloro-2,5-difluoro-benzonitrile (2.00 g, 11.5 mmol, 1.00 equiv), N-bromosuccinimide (4.10 g, 23.1 mmol, 2.00 equiv), palladium acetate (259 mg, 1.15 mmol, 0.10 equiv), and p-toluenesulfonic acid (992 mg, 5.76 mmol, 0.50 equiv) in dichloroethane (50 mL) was degassed with nitrogen and stirred at 75° C. for 12 hours. The cooled mixture was then extracted with dichloromethane (50 mL × 3), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 0–3%) to give 2-bromo-4-chloro-3,6-difluoro-benzonitrile (1.10 g, 4.36 mmol, 38% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ=7.38-7.31 (m, 1H).

[0301] Step 2: A mixture of 2-bromo-4-chloro-3,6-difluoro-benzonitrile (1.10 g, 4.36 mmol, 1.00 equiv), cyclopropanol (380 mg, 6.54 mmol, 1.50 equiv) and potassium carbonate (1.51 g, 10.9 mmol, 2.50 equiv) in DMF (10 mL) was degassed with nitrogen and then stirred at 75° C. for 2 h. The mixture was then concentrated and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 7%) to give 2-bromo-4-chloro-6-(cyclopropoxy)-3-fluoro-benzonitrile (600 mg, 2.07 mmol, 47% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 7.36 (d, J = 5.6 Hz, 1H), 3.88-3.79 (m, 1H), 0.91 (d, J = 4.8 Hz, 4H).

[0302] Step 3: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.29 g, 6.20 mmol, 3.00 equiv), 2-bromo-4-chloro-6-(cyclopropoxy)-3-fluoro-benzonitrile (600 mg, 2.07 mmol, 1.00 equiv), aqueous sodium bicarbonate (694 mg, 8.26 mmol, 0.321 mL, 4.00 equiv), di-tert-butyl(cyclopentyl)phosphane, dichloropalladium-iron (135 mg, 0.207 mmol, 0.10 equiv) in dioxane (20 mL) and water (4 mL) was degassed with nitrogen and the mixture was stirred at 80° C. for 16 h. The mixture was then concentrated and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 5-20%) to give 4-chloro-6-(cyclopropoxy)-3-fluoro-2-(2-methylpyrazol-3-yl)benzonitrile (180 mg, 0.524 mmol, 25% yield) as a yellow solid. LCMS [M+1] + =292.1; 1 H NMR(400 MHz,CDCl3)δ=7.62(d,J=2.0 Hz,1H),7.49(d,J=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).

[0303] Step 4: A mixture of 4-chloro-6-(cyclopropoxy)-3-fluoro-2-(2-methylpyrazol-3-yl)benzonitrile (180 mg, 0.617 mmol, 1.00 equiv.) and N-bromosuccinimide (220 mg, 1.23 mmol, 2.00 equiv.) in acetonitrile (10 mL) was stirred at 40° C. under a nitrogen atmosphere for 2 hours. The mixture was then concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 20%) to give 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; 1H NMR (400 MHz, CDCl3) 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). [ka]

[0304] A mixture of 2-(4-bromo-2-methyl-pyrazol-3-yl)naphthalene-1-carbonitrile (150 mg, 0.48 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (134 mg, 0.528 mmol, 1.10 equiv), potassium acetate (141 mg, 1.44 mmol, 3.00 equiv) and di-tert-butyl(cyclopentyl)phosphane; dichloropalladium-iron (31.3 mg, 0.048 mmol, 0.10 equiv) in dioxane (3 mL) was degassed with nitrogen and then stirred at 80° C. for 2 h. The reaction mixture was then concentrated under reduced pressure to give 2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]naphthalene-1-carbonitrile (160 mg, crude) as a brown liquid, which was used in the next step without further purification. LCMS [M+1] + =360.2. [ka]

[0305] Step 1: To a solution of 4-bromo-2-methyl-pyrazole-3-carbaldehyde (1.00 g, 5.29 mmol, 1.00 equiv) and nitromethane (420 mg, 6.88 mmol, 0.37 mL, 1.30 equiv) in methanol (10 mL) was added dropwise a solution of sodium hydroxide (466 mg, 11.6 mmol, 2.20 equiv) in water (1 mL) at 0° C. The reaction mixture was then stirred at 0° C. for 0.5 h. The reaction mixture was then quenched by the addition of HCl (1.00 M, 5 mL), filtered, and the filtrate was concentrated under reduced pressure to afford 4-bromo-1-methyl-5-[(E)-2-nitrovinyl]pyrazole (627 mg, crude) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) 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).

[0306] Step 2: A suspension of 2-pyridin-1-ium-1-ylacetonitrile chloride (627 mg) and 4Å MS (1.00 g, 0.215 mmol) in dichloroethane (30 mL) was cooled to 0° C., and then 2,6-lutidine (1.45 g, 13.5 mmol, 1.57 mL, 5.00 equiv.) was added. After stirring for 15 minutes, 4-bromo-1-methyl-5-[(E)-2-nitrovinyl]pyrazole (627 mg, 2.70 mmol, 1.00 equiv.) was added, followed by cupric acetate (736 mg, 4.05 mmol, 1.50 equiv.). The mixture was then stirred at 0° C. for 15 minutes, then heated to 25° C. and stirred at 25° C. for 5 hours. The reaction mixture was then 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 (SiO, petroleum ether:ethyl acetate 10-20%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)indolizine-3-carbonitrile (380 mg, 1.26 mmol, 47% yield) as a yellow solid. LCMS [M + 1] + =301.0; 1H NMR (400 MHz, CDCl3) 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). [ka]

[0307] Step 1: A mixture of 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)quinoline-5-carbonitrile, Intermediate A-25 (120 mg, 0.38 mmol, 1.00 equiv.), and N-iodosuccinimide (517 mg, 2.30 mmol, 6.00 equiv.) 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 preparative TLC (SiO, petroleum ether / ethyl acetate 50%) to give 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-iodoquinoline-5-carbonitrile (38 mg, 0.086 mmol, 22% yield) as a white solid. LCMS [M+1] + =441.1; 1 H NMR(400 MHz,CDCl3)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).

[0308] Step 2: A mixture of 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-iodoquinoline-5-carbonitrile (35 mg, 0.080 mmol, 1.00 equiv.), sodium methoxide (13 mg, 0.24 mmol, 3.00 equiv.), and cuprous iodide (1.5 mg, 0.008 mmol, 0.10 equiv.) in methanol (1 mL) was degassed with nitrogen and then stirred at 105 °C for 16 hours. The mixture was then filtered, the filtrate was concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 50%) to give 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-methoxyquinoline-5-carbonitrile (12 mg, 0.035 mmol, 44% yield) as a white solid. LCMS [M+1] + =345.1; 1 H NMR(400 MHz,CDCl3)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). [ka]

[0309] A mixture of 6-(4-bromo-2-methyl-pyrazol-3-yl)-3-chloro-2-methyl-benzonitrile, Intermediate D-18 (400 mg, 1.29 mmol, 1.00 equiv) in THF (5 mL) was added to lithium diisopropylamine (2.00 M, 1.29 mL, 2.00 equiv) at −78° C. and stirred at −78° C. for 30 minutes. Methyl iodide (5.15 mmol, 0.32 mL, 4.00 equiv) 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 × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 20%) to give 6-(4-bromo-2-methyl-pyrazol-3-yl)-3-chloro-2-ethyl-benzonitrile (280 mg, 0.86 mmol, 67% yield) as a yellow oil. LCMS [M+1] + =326.0; 1 H NMR (400 MHz, CDCl3) 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). [ka]

[0310] 2-(4-Bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-ethylbenzonitrile was prepared as a white solid (30 mg, 0.074 mmol, 23%) using the same method as for the preparation of intermediate DV, substituting intermediate D-19 for intermediate D-18. LCMS [M+1] + =419.2; 1H 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). [ka]

[0311] To a mixture of 2-(4-bromo-2-methyl-pyrazol-3-yl)-4-chloro-6-ethyl-benzonitrile, Intermediate DW (270 mg, 0.83 mmol, 1.00 equiv.) in methanol (2 mL) was added sodium methoxide (449 mg, 8.32 mmol, 10.0 equiv.) in one portion at 20° C. under a nitrogen atmosphere. The mixture was stirred in a sealed tube at 100° C. for 2 hours to form a pale yellow solution. The mixture was then concentrated, and the residue was dissolved in ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (5 mL×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 25%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-ethyl-4-methoxy-benzonitrile (220 mg, ca. 70% purity) as a white solid. LCMS [M+1] + =321.9; 1 H NMR(400 MHz,CDCl3)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=6.8 Hz 3H). [ka]

[0312] Step 1: A mixture of 2-bromo-5-methoxy-naphthalen-1-ol (2.60 g, 10.3 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.21 g, 15.4 mmol, 1.50 equiv), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (670 mg, 1.03 mmol, 0.10 equiv), and sodium carbonate (2.18 g, 20.6 mmol, 2.00 equiv) in dioxane (30 mL) and water (6 mL) was degassed with nitrogen and then stirred at 100° C. for 0.5 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 10–100%) to give 5-methoxy-2-(2-methylpyrazol-3-yl)naphthalen-1-ol (720 mg, 2.83 mmol, 28% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)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).

[0313] Step 2: To a solution of 5-methoxy-2-(2-methylpyrazol-3-yl)naphthalen-1-ol (650 mg, 2.56 mmol, 1.00 equiv), 4 Å molecular sieves (1.00 g), and triethylamine (7.67 mmol, 1.07 mL, 3.00 equiv) in dichloromethane (20 mL) was added TfO (3.83 mmol, 0.63 mL, 1.50 equiv) dropwise under nitrogen at −40° C. After stirring at −40° C. for 0.5 h, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 0–15%) to afford [5-methoxy-2-(2-methylpyrazol-3-yl)-1-naphthyl]trifluoromethanesulfonate (341 mg, 0.79 mmol, 30% yield) as a yellow oil. LCMS[M + 1] + =387.1; 1 H NMR(400 MHz,CDCl3)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=7.6 Hz,1H),6.45(d,J=2.0 Hz,1H),4.07(s,3H),3.82(s,3H).

[0314] Step 3: A mixture of [5-methoxy-2-(2-methylpyrazol-3-yl)-1-naphthyl]trifluoromethanesulfonate (290 mg, 0.67 mmol, 1.00 equiv.), zinc cyanide (0.81 mmol, 51.1 μL, 1.20 equiv.), Pd(dba) (612 mg, 0.067 mmol, 0.10 equiv.), DPPF (74 mg, 0.134 mmol, 0.20 equiv.), and zinc powder (4.4 mg, 0.067 mmol, 0.10 equiv.) in DMF (10 mL) was degassed with nitrogen and then stirred at 120° C. for 1 h. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 10-50%) to give 5-methoxy-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (156 mg, 0.59 mmol, 88% yield) as an off-white solid. LCMS [M + 1] + =264.1; 1 H NMR(400 MHz,CDCl3)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).

[0315] Step 4: To a solution of 5-methoxy-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (180 mg, 0.68 mmol, 1.00 equiv.) in acetonitrile (2 mL) was added N-bromosuccinimide (146 mg, 0.82 mmol, 1.20 equiv.). After stirring at 35° C. for 0.5 h, the mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 30%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)-5-methoxy-naphthalene-1-carbonitrile (174 mg, 0.51 mmol, 74% yield) as an off-white solid. LCMS [M + 1] + =342.0; 1 H NMR(400 MHz,CDCl3)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). [ka]

[0316] Intermediate DZ, 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-1-naphthonitrile, was prepared as a yellow solid (25 mg, 0.072 mmol, 2% yield over 4 steps) starting from 2-bromo-4-chloro-naphthalen-1-ol according to the method described for the preparation of intermediate DX. LCMS [M+1] + =347.8; 1 H NMR (400 MHz, CDCl3-d) 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). [ka]

[0317] Step 1: A mixture of [4-chloro-2-(2-methylpyrazol-3-yl)-1-naphthyl]trifluoromethanesulfonate (38 mg, 0.097 mmol, 1.00 equiv), zinc cyanide (22 mg, 190 μmol, 12.4 μL, 2.00 equiv), DPPF (5.4 mg, 9.7 μmol, 0.10 equiv), zinc powder (640 μg, 9.7 μmol, 0.10 equiv), and Pd(dba) (4.5 mg, 4.86 μmol, 0.05 equiv) in DMF (1.0 mL) was degassed with nitrogen and then stirred at 100 °C for 4 h. The mixture was then concentrated and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 20%) to give 2-(2-methylpyrazol-3-yl)naphthalene-1,4-dicarbonitrile (30 mg, 93.4 μmol, 96% yield) as a yellow solid. LCMS [M+1] + =259.0; 1 H NMR(400 MHz,CDCl3)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).

[0318] Step 2: A mixture of 2-(2-methylpyrazol-3-yl)naphthalene-1,4-dicarbonitrile (30 mg, 0.093 mmol, 1.00 equiv.), N-bromosuccinimide (41 mg, 0.23 mmol, 2.00 equiv.) in acetonitrile (2.0 mL) was degassed with nitrogen and stirred at 35° C. for 2 hours. The mixture was then concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 25%) to afford 2-(4-bromo-2-methyl-pyrazol-3-yl)naphthalene-1,4-dicarbonitrile (25 mg, 0.067 mmol, 58% yield) as a yellow solid. LCMS [M+1] + =339.0; 1 H NMR (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). [ka]

[0319] Step 1: A solution of n-butyllithium (2.50 M, 1.87 mL, 1.00 equiv.) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (660 mg, 4.67 mmol, 0.79 mL, 1.00 equiv.) in THF (10 mL) at 0° C. over 30 minutes. The mixture was then cooled to −78° C., and a solution of 4-fluoronaphthalene-1-carbonitrile (0.80 g, 4.67 mmol, 1.00 equiv.) in THF (3 mL) was added over 15 minutes. The mixture was then stirred at −78° C. for 2 hours. A solution of iodine (1.19 g, 4.67 mmol, 1.00 equiv.) in THF (3 mL) was then added over 30 minutes. The reaction mixture was stirred at −78° C. for 2 hours, then warmed to 25° C., and stirred for an additional 12 hours. The reaction mixture was then quenched with water (50 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated aqueous sodium thiosulfate (30 mL × 3), 1 M hydrochloric acid (30 mL × 3), and brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by flash silica gel chromatography (ethyl acetate:petroleum ether 0-5%) to give 4-fluoro-3-iodo-naphthalene-1-carbonitrile (1.00 g, 3.37 mmol, 72% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) 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).

[0320] Step 2: To a solution of 4-fluoro-3-iodo-naphthalene-1-carbonitrile (900 mg, 3.03 mmol, 1.00 equiv.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.58 g, 7.57 mmol, 2.50 equiv.), and potassium phosphate (1.29 g, 6.06 mmol, 2.00 equiv.) in dioxane (10 mL) and water (2 mL), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium-iron (197 mg, 0.30 mmol, 0.10 equiv.) was added. The reaction was stirred at 80° C. under a nitrogen atmosphere for 18 hours. The reaction mixture was then partitioned between water (20 mL) and ethyl acetate (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was then purified by flash silica gel chromatography (0 to 25% ethyl acetate:petroleum ether gradient) to afford 4-fluoro-3-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (0.80 g, 2.87 mmol, 95% yield) as a white solid. 1 H NMR(400 MHz,CDCl3)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).

[0321] Step 3: To a solution of 4-fluoro-3-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (200 mg, 0.80 mmol, 1.00 equiv) in acetonitrile (5 mL) was added 1-bromopyrrolidine-2,5-dione (212 mg, 1.19 mmol, 1.50 equiv) and the reaction was stirred at 25 °C for 12 h. The reaction was then concentrated and the residue was purified by flash silica gel chromatography (0-15% ethyl acetate:petroleum ether) to afford 3-(4-bromo-2-methyl-pyrazol-3-yl)-4-fluoro-naphthalene-1-carbonitrile (0.20 g, 0.61 mmol, 76% yield) as a gray solid. LCMS [M+1] +=332.1 / 300.1; 1 H NMR (400 MHz, CDCl3) 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). [ka]

[0322] Step 1: To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol, 1.00 equiv.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.12 g, 5.38 mmol, 1.00 equiv.) in dioxane (15 mL) and water (3 mL), potassium carbonate (1.49 g, 10.8 mmol, 2.00 equiv.) and Pd(dppf)Cl (393 mg, 0.538 mmol, 0.10 equiv.) were added under a nitrogen atmosphere at 20° C. The mixture was then stirred at 80° C. for 6 hours. The reaction mixture was then diluted with water (50 mL) and extracted with dichloromethane (50 mL × 2). The combined organic layers were washed with brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 25-50%) to give 6-(1-methyl-1H-pyrazol-5-yl)picolinaldehyde (800 mg, 4.27 mmol, 80% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3)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).

[0323] Step 2: To a solution of 6-(1-methyl-1H-pyrazol-5-yl)picolinaldehyde (800 mg, 4.27 mmol, 1.00 equiv) in acetonitrile (12 mL) was added N-bromo-succinimide (1.14 g, 6.41 mmol, 1.50 equiv) at 20° C., and the mixture was stirred for 16 h. The mixture was then concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 25%) to afford 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)picolinaldehyde (750 mg, 2.82 mmol, 66% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ=10.13(s,1H),8.08-7.98(m,3H),7.58(s,1H),4.15(s,3H).

[0324] Step 3: To a solution of 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)picolinaldehyde (250 mg, 0.94 mmol, 1.00 equiv) in DMF (3 mL) was added 2-aminoacetic acid (78 mg, 1.03 mmol, 1.10 equiv), iodine (238 mg, 0.940 mmol, 0.19 mL, 1.00 equiv), and sodium bicarbonate (158 mg, 1.88 mmol, 2.00 equiv) at 20° C. The mixture was then stirred at 60° C. for 6 hours, diluted with water (20 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (SiO, ethyl acetate) to give 5-(4-bromo-1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]pyridine (35 mg, 0.126 mmol, 13% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) 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). [ka]

[0325] Step 1: To a solution of 4-bromo-5-chloro-1H-pyrazole (1.00 g, 5.51 mmol, 1.00 equiv) and 2-(bromomethyl)benzonitrile (1.08 g, 5.51 mmol, 1.00 equiv) in acetonitrile (20 mL), potassium carbonate (914 mg, 6.61 mmol, 1.20 equiv) was added, and the mixture was stirred at 80° C. under a nitrogen atmosphere for 10 hours. The reaction was then quenched with water (200 mL) and extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate=10:1) to give 2-((4-bromo-3-chloro-1H-pyrazol-1-yl)methyl)benzonitrile (1.00 g, 3.37 mmol, 61% yield) as a white solid. LCMS [M+1] + =297.9; 1 H 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).

[0326] Step 2: To a solution of 2-((4-bromo-3-chloro-1H-pyrazol-1-yl)methyl)benzonitrile (400 mg, 1.35 mmol, 1.00 equiv.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (561 mg, 2.70 mmol, 2.00 equiv.), and sodium bicarbonate (227 mg, 2.70 mmol, 2.00 equiv.) in dioxane (10 mL) and water (1 mL), Pd(dppf)Cl (99 mg, 0.135 mmol, 0.10 equiv.) was added under a nitrogen atmosphere. The mixture was stirred at 110 °C for 10 hours, then the reaction was quenched by adding water (200 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 30%) to give 2-((3'-chloro-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)methyl)benzonitrile (200 mg, 0.672 mmol, 50% yield) as a white solid. LCMS [M+1] + =298.0; 1 H 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).

[0327] Step 3: To a solution of 2-((3'-chloro-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)methyl)benzonitrile (200 mg, 0.672 mmol, 1.00 equiv) in acetonitrile (10 mL) was added N-bromosuccinimide (132 mg, 0.739 mmol, 1.10 equiv) and the mixture was stirred under nitrogen atmosphere at 25°C for 10 hours. Then the reaction was quenched with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 5%) to give 2-((4-bromo-3'-chloro-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)methyl)benzonitrile (130 mg, 0.345 mmol, 51% yield) as a yellow solid. LCMS [M+1] + =377.9; 1 H 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).

[0328] Step 4: To a solution of tert-butyl ((4-oxo-7-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate (256 mg, 0.637 mmol, 2.00 equiv.), 2-((4-bromo-3′-chloro-2-methyl-1′H,2H-[3,4′-bipyrazol]-1′-yl)methyl)benzonitrile (120 mg, 0.319 mmol, 1.00 equiv.), sodium bicarbonate (54 mg, 0.637 mmol, 25 μL, 2.00 equiv.) in water (0.5 mL) and dioxane (5.0 mL) was added Pd(dtbpf)Cl 2(A solution of 21 mg, 32 μmol, 0.10 equiv.) was added under a nitrogen atmosphere, and the mixture was then stirred at 110° C. for 10 hours. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (40 mL×3). 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 (SiO, petroleum ether:ethyl acetate 15%) to afford tert-butyl ((7-(3′-chloro-1′-(2-cyanobenzyl)-2-methyl-1′H,2H-[3,4′-bipyrazol]-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (115 mg, 0.201 mmol, 63% yield) as a dark brown oil. LCMS [M+1] + =571.1; 1 H 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). [ka]

[0329] Step 1: To a mixture of phenylboronic acid (1.92 g, 15.8 mmol, 2.00 equiv.) and 3-chloro-4-iodo-1H-pyrazole (1.80 g, 7.88 mmol, 1.00 equiv.) in dichloromethane (30 mL), pyridine (1.86 g, 23.5 mmol, 1.90 mL, 2.99 equiv.) and copper acetate (1.72 g, 9.46 mmol, 1.20 equiv.) were added in one portion. The mixture was stirred at 20 °C for 16 h, then filtered and concentrated. The residue was purified by flash silica gel chromatography (0-5% ethyl acetate:petroleum ether) to afford 3-chloro-4-iodo-1-phenyl-pyrazole (1.50 g, 4.93 mmol, 63% yield) as a yellow liquid. LCMS [M+1] + =305.0; 1 H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.63-7.59 (m, 2H), 7.49-7.43 (m, 2H), 7.36-7.30 (m, 1H).

[0330] Step 2: 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.23 g, 5.91 mmol, 1.50 equiv), 3-chloro-4-iodo-1-phenyl-pyrazole (1.20 g, 3.94 mmol, 1.00 equiv), potassium phosphate (1.67 g, 7.88 mmol, 2.00 equiv), and di-tert-butyl(cyclopentyl)phosphane; dichloropalladium-iron (256 mg, 0.39 mmol, 0.10 equiv) in dioxane (20 mL) and water (4 mL) was degassed and then heated to 80° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was then concentrated, and the residue was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 10-15%) to give 3-chloro-4-(2-methylpyrazol-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; 1H NMR(400 MHz,CDCl3)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).

[0331] Step 3: A mixture of 3-chloro-4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole (210 mg, 0.811 mmol, 1.00 equiv.), tetrapotassium hexacyanoiron(4-) trihydrate (1.03 g, 2.44 mmol, 3.00 equiv.), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium-dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (73.6 mg, 0.081 mmol, 0.10 equiv.) in dimethylacetamide (6 mL) and water (3 mL) was heated to 100° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL×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 (SiO, petroleum ether:ethyl acetate 10-15%) to give 4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole-3-carbonitrile (200 mg, 0.80 mmol, 99% yield) as a yellow solid. LCMS [M+1] + =249.9; 1 H NMR(400 MHz,CDCl3)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).

[0332] Step 4: To a mixture of 4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole-3-carbonitrile (180 mg, 0.722 mmol, 1.00 equiv.) in acetonitrile (5 mL) was added N-bromosuccinimide (192 mg, 1.08 mmol, 1.50 equiv.). The mixture was stirred at 20 °C for 16 h. The reaction mixture was then quenched with saturated sodium sulfite (15 mL), extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 10-20%) to afford 4-(4-bromo-2-methyl-pyrazol-3-yl)-1-phenyl-pyrazole-3-carbonitrile (220 mg, 0.67 mmol, 93% yield) as a yellow solid. LCMS [M+1] + =327.9; 1 H NMR (500 MHz, CDCl3) δ=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). [ka]

[0333] To a mixture of 3-chloro-4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole, intermediate EE-1 (200 mg, 0.773 mmol, 1.00 equiv) in acetonitrile (1 mL) was added 1-bromopyrrolidine-2,5-dione (165 mg, 0.927 mmol, 1.20 equiv) in one portion at 20 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was then concentrated, and the residue was purified by flash silica gel chromatography (0 to 17% ethyl acetate:petroleum ether) to afford 4-bromo-5-(3-chloro-1-phenyl-pyrazol-4-yl)-1-methyl-pyrazole (200 mg, 0.592 mmol, 77% yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ=8.07-8.04(m,1H),7.72(dd,J=1.2,8.4 Hz,2H),7.58(s,1H),7.54-7.49(m,2H),7.42-7.35(m,1H),3.88(s,3H). [ka]

[0334] Steps 1-6: 2-((7-bromo-4-oxo-5-(trifluoromethyl)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione was prepared as a white solid (0.50 g, 1.11 mmol, 6% yield for 6 steps) starting from 1-(5-bromo-2-methyl-3-(trifluoromethyl)phenyl)ethan-1-one according to the same procedure as described for the first 6 steps of intermediate DK. LCMS [M+1] + =454.0; 1 H 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).

[0335] Step 7: A mixture of 2-((7-bromo-4-oxo-5-(trifluoromethyl)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (50 mg, 0.111 mmol, 1.00 equiv), bis(pinacolato)diboron (34 mg, 0.133 mmol, 1.20 equiv), Pd(dppf)Cl (8 mg, 0.011 mmol, 0.10 equiv), and potassium acetate (22 mg, 0.221 mmol, 2.00 equiv) in dioxane (2 mL) was degassed with nitrogen and stirred at 100 °C for 1 h. The reaction mixture was then concentrated under reduced pressure to give [4-[(1,3-dioxoisoindolin-2-yl)methyl]-1-oxo-8-(trifluoromethyl)-2H-phthalazin-6-yl]boronic acid (46.0 mg, crude) as a brown solid. LCMS [M-81] + =418.1. [ka]

[0336] 7-(4-Bromo-1-methyl-1H-pyrazol-5-yl)chromane-8-carbonitrile, intermediate EH, was prepared as a white solid (21 mg, 0.049 mmol, 84% yield) using the same four-step procedure used to prepare intermediate DY, but starting from 7-bromochroman-8-ol. LCMS [M+1] + =413.2; 1 H NMR(400 MHz,DMSO-d6)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). [ka]

[0337] 2-(4-Bromo-1-methyl-1H-pyrazol-5-yl)-6-fluoro-1-naphthonitrile, intermediate EI, was prepared as a white solid (60 mg, 0.182 mmol, 31% yield over two steps) following the same procedure as described for the preparation of intermediate DC, starting from 2-bromo-6-fluoro-1-naphthaldehyde. LCMS [M+1] + =329.8 / 331.8; 1 H 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). [ka]

[0338] 3-(4-Bromo-1-methyl-1H-pyrazol-5-yl)-1-chloro-2-naphthonitrile, intermediate EJ, was prepared as a pale yellow solid (35 mg, 0.101 mmol, 18% yield over two steps) following the same procedure as described for the preparation of intermediate DC, starting from 3-bromo-1-chloro-2-naphthaldehyde. 1 H NMR (400MHz, 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). [ka]

[0339] Step 1: To a solution of 6-bromoquinoline-5-carbonitrile (1.00 g, 4.29 mmol, 1.00 equiv.) in acetic acid (20 mL) was added N-chlorosuccinimide (5.73 g, 42.9 mmol, 10.0 equiv.). The mixture was stirred at 135 °C for 24 h. The pH of the reaction mixture was then adjusted to pH 7 with 2N aqueous sodium hydroxide (5 mL), diluted with water (50 mL), and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 10-15%) to give 6-bromo-3-chloro-quinoline-5-carbonitrile (512 mg, 1.91 mmol, 45% yield) as an off-white solid. LCMS [M + 1] + =269.0; 1 H NMR (400 MHz, CDCl3) 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).

[0340] Step 2: A mixture of 6-bromo-3-chloro-quinoline-5-carbonitrile (512 mg, 1.91 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (398 mg, 1.91 mmol, 1.00 equiv), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium-iron (125 mg, 0.19 mmol, 0.10 equiv), sodium bicarbonate (322 mg, 3.83 mmol, 0.15 mL, 2.00 equiv) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and stirred at 80° C. for 0.5 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 30%) to give 3-chloro-6-(2-methylpyrazol-3-yl)quinoline-5-carbonitrile (250 mg, 0.930 mmol, 49% yield) as a yellow solid. LCMS [M + 1] + =269.1; 1 H NMR(400 MHz,CDCl3)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).

[0341] Step 3: To a solution of 3-chloro-6-(2-methylpyrazol-3-yl)quinoline-5-carbonitrile (249 mg, 0.927 mmol, 1.00 equiv.) in acetonitrile (5 mL), N-bromosuccinimide (214 mg, 1.20 mmol, 1.30 equiv.) was added. The mixture was stirred at 35 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 10-15%) to afford 6-(4-bromo-2-methyl-pyrazol-3-yl)-3-chloro-quinoline-5-carbonitrile (289 mg, 0.831 mmol, 90% yield) as a yellow solid. LCMS [M + 1] + =349.0; 1H NMR (400 MHz, CDCl3)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). [ka]

[0342] Step 1: To a solution of 1,3-dibromo-2-chloro-5-fluoro-benzene (61.0 g, 212 mmol, 1.00 equiv) and 1-methylpyrrole (34.3 g, 423 mmol, 37.7 mL, 2.00 equiv) in toluene (1500 mL) was added n-butyllithium (2.50 M in THF, 88.9 mL, 1.05 equiv) dropwise at −30° C. under nitrogen. The mixture was stirred at −30° C. for 0.5 h, then heated to 25° C. and stirred for 12 h. The reaction mixture was then quenched with water (20 mL) and concentrated under reduced pressure to provide 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 purified by column chromatography (SiO, petroleum ether:ethyl acetate 10-50%) to give 3-bromo-5-fluoro-11-methyl-11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5,9-tetraene (30.0 g, 118 mmol, 56% yield) as a brown liquid. 1 H NMR (400 MHz, CDCl3) δ = 7.10-6.65 (m, 4H), 4.83-4.44 (m, 2H), 2.31-2.09 (m, 3H).

[0343] Step 2: To a solution of 3-bromo-5-fluoro-11-methyl-11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5,9-tetraene (61.5 g, 242 mmol, 1.00 equiv) in chloroform (1300 mL) was carefully added m-CPBA (98.2 g, 484 mmol, 85% purity, 2.00 equiv) in portions, maintaining the internal temperature below 40° C. After 2 h, the brown solution turned yellow, and the mixture was stirred at 25° C. for an additional 24 h. The mixture was then diluted with dichloromethane (1000 mL) and washed with saturated sodium sulfite (1500 mL × 2) followed by brine (1500 mL), then dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 0–10%) to give 1-bromo-3-fluoro-naphthalene (37.8 g, 168 mmol, 70% yield) as a colorless liquid. 1 H NMR (400 MHz, CDCl3)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).

[0344] Step 3: A mixture of 1-bromo-3-fluoro-naphthalene (34.8 g, 155 mmol, 1.00 equiv), Pd(dba) (14.2 g, 15.5 mmol, 0.10 equiv), zinc cyanide (45.4 g, 387 mmol, 24.5 mL, 2.50 equiv), DPPF (17.1 g, 30.9 mmol, 0.20 equiv), and ZnO (1.01 g, 15.5 mmol, 0.10 equiv) in DMF (400 mL) was degassed with nitrogen, and then the mixture was stirred at 115 °C for 4 h. The mixture was then filtered, diluted with ethyl acetate (1000 mL), washed with brine (1000 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 0-10%) to give 3-fluoronaphthalene-1-carbonitrile (21.5 g, 126 mmol, 81% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ = 8.26-8.21 (m, 1H), 7.92-7.85 (m, 1H), 7.76-7.65 (m, 4H).

[0345] Step 4: n-Butyllithium (2.50 M in hexane, 2.83 mL, 1.10 equiv.) was added to a solution of N-isopropylpropan-2-amine (845 mg, 8.35 mmol, 1.18 mL, 1.30 equiv.) in THF (15 mL) at −70° C., and the reaction mixture was stirred at −70° C. for 15 minutes. Then, 3-fluoronaphthalene-1-carbonitrile (1.10 g, 6.43 mmol, 1.00 equiv.) in THF (2 mL) was added to the mixture, and the reaction mixture was stirred at −70° C. for 30 minutes. Then, a solution of iodine (2.12 g, 8.35 mmol, 1.30 equiv.) in THF (2.00 mL) was added to the reaction mixture at −70° C., and the solution was stirred at −70° C. for an additional 30 minutes. Then, the mixture was warmed to 25° C. and stirred at 25° C. for 10 hours. The reaction was then quenched with water (100 mL), diluted with ethyl acetate (250 mL), and washed with saturated sodium thiosulfate (100 mL × 2) and brine (250 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 0-15%) to give 3-fluoro-2-iodo-naphthalene-1-carbonitrile (1.70 g, 5.72 mmol, 89% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 8.36-8.24 (m, 1H), 7.83-7.71 (m, 1H), 7.59-7.48 (m, 3H).

[0346] Step 5: A mixture of 3-fluoro-2-iodo-naphthalene-1-carbonitrile (800 mg, 2.69 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.23 g, 5.92 mmol, 2.20 equiv), Pd(dtbpf)Cl (176 mg, 0.269 mmol, 0.10 equiv), sodium bicarbonate (679 mg, 8.08 mmol, 3.00 equiv) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and stirred at 80 °C for 12 h. The mixture was then concentrated, and the residue was purified by column chromatography (SiO 2、 Purification with petroleum ether:ethyl acetate (5-50%) gave 3-fluoro-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (500 mg, 1.99 mmol, 74% yield) as a yellow solid. LCMS [M+1] + =252.1; 1 H NMR(400 MHz,CDCl3)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(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).

[0347] Step 6: To a solution of 3-fluoro-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (500 mg, 1.99 mmol, 1.00 equiv.) in acetonitrile (8 mL), N-bromosuccinimide (638 mg, 3.58 mmol, 1.80 equiv.) was added. The mixture was stirred at 25 °C for 3 h. The mixture was then concentrated, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 10-50%) to afford 2-(4-bromo-2-methyl-pyrazol-3-yl)-3-fluoro-naphthalene-1-carbonitrile (550 mg, 1.56 mmol, 78% yield) as a yellow solid. LCMS [M+1] + =331.9; 1H NMR (400 MHz, CDCl3) 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).

[0348] Step 7: To a solution of 3-fluoro-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (20.0 g, 79.6 mmol, 1.00 equiv.) in acetonitrile (300 mL) was added N-iodosuccinimide (89.5 g, 398 mmol, 5.00 equiv.). The mixture was stirred at 80 °C for 12 hours. The mixture was then concentrated, and the residue was triturated with methyl alcohol (100 mL) at 25 °C for 30 minutes. The mixture was filtered and dried to give 3-fluoro-2-(4-iodo-2-methyl-pyrazol-3-yl)naphthalene-1-carbonitrile (25.2 g, 66.8 mmol, 84% yield) as a yellow solid. LCMS [M+1] + =378.0; 1 H NMR(400 MHz,CDCl3)δ=8.35(br d,J=8.4 Hz,1H),7.98(br d,J=8.4 Hz,1H),7.92(d,J=9.2 Hz, 1H), 7.82-7.74 (m, 2H), 7.74-7.67 (m, 1H), 3.92-3.82 (m, 3H). [ka]

[0349] A mixture of 2-(2-hydroxyphenyl)acetonitrile (182 mg, 1.36 mmol, 1.20 equiv.), 3-bromo-5-fluoro-pyridine (200 mg, 1.14 mmol, 1.00 equiv.), and potassium carbonate (393 mg, 2.84 mmol, 2.50 equiv.) in DMF (10 mL) was stirred at 75° C. under a nitrogen atmosphere for 3 h. The mixture was concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 15%) to give 2-[2-[(5-bromo-3-pyridyl)oxy]phenyl]acetonitrile (200 mg, 0.43 mmol, 38% yield) as a yellow oil. LCMS [M+1]+ =289.0. [ka]

[0350] Step 1: To a solution of 6-bromo-3-cyclopropoxypicolinonitrile (800 mg, 3.35 mmol, 1.00 equiv.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (732 mg, 3.51 mmol, 1.05 equiv.) in dioxane (20 mL) and water (0.4 mL), di-tert-butyl(cyclopentyl)phosphane-dichloropalladium-iron (218 mg, 0.335 mmol, 0.10 equiv.) and sodium carbonate (709 mg, 6.69 mmol, 2.00 equiv.) were added at 25° C. The mixture was then degassed and purged with nitrogen three times, then stirred at 80° C. for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by flash silica gel chromatography (SiO, petroleum ether:ethyl acetate 0–10%) to afford 3-cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)picolinonitrile (750 mg, 2.97 mmol, 89% yield) as a white solid. 1 H NMR (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).

[0351] Step 2: To a solution of 3-cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)picolinonitrile (650 mg, 2.71 mmol, 1.00 equiv) in acetonitrile (20 mL) was added N-bromosuccinimide (723 mg, 4.06 mmol, 1.50 equiv) 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 × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1) to give 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypicolinonitrile (1.1 g, crude) as a yellow solid. LCMS[M+1]=318.9 / 320.9; 1 H NMR (400 MHz, CDCl3) 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).

[0352] Step 3: To a solution of 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypicolinonitrile (300 mg, 0.94 mmol, 1.00 equiv) in THF (20 mL) was added DIBAL-H (1.00 M, 5.64 mL, 6.00 equiv) at 25° C., and the mixture was stirred for 3 h at 25° C. The reaction was then quenched by the addition of sodium thiosulfate solution (20 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 1:1) to give (6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypyridin-2-yl)methanamine (160 mg, 0.495 mmol) as a yellow solid. A mixture of (6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypyridin-2-yl)methanamine (160 mg, 0.495 mmol, 1.00 equiv) in ethyl formate (3 mL) was stirred at 25 °C for 2 hours, followed by the addition of water (2 mL). The mixture was then extracted with ethyl acetate (3 mL × 3), and the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 0-10%) to afford N-((6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypyridin-2-yl)methyl)formamide (140 mg, 0.359 mmol, 73% yield) as a yellow solid. LCMS [M+1] + =351.0 / 353.0; 1 H NMR(400 MHz,CDCl3)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).

[0353] Step 4: To a solution of N-((6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypyridin-2-yl)methyl)formamide (140 mg, 0.359 mmol, 1.00 equiv) and diisopropylethylamine (104 mg, 0.80 mmol, 0.14 mL, 2.00 equiv) in dichloromethane (8 mL) was added TfO (225 mg, 0.078 mmol, 0.13 mL, 2.00 equiv) at −40° C., warmed to ambient temperature, and stirred at 25° C. for 6 h. Then, water (2 mL) was added, and the mixture was extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 0-10%) to afford 5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-8-cyclopropoxyimidazo[1,5-a]pyridine (110 mg, 0.314 mmol, 79% yield) as a yellow solid. LCMS [M+1] + =332.9 / 334.9; 1 H NMR (400 MHz, CDCl3) 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). [ka]

[0354] Step 1: To a solution of 1-(2-methylpyrazol-3-yl)ethanone (400 mg, 3.22 mmol, 1.00 equiv) in THF (6 mL) was added 1-bromopyrrolidine-2,5-dione (1.43 g, 8.06 mmol, 2.50 equiv) and the mixture was stirred at 25 °C for 12 h. The reaction mixture was then concentrated and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 20%) to give 2-bromo-1-(4-bromo-2-methyl-pyrazol-3-yl)ethanone (800 mg, 2.84 mmol, 88% yield) as a yellow oil. LCMS [M+1] + =282.9; 1H NMR (400 MHz, CDCl3) δ = 7.54 (s, 1H), 4.62 (s, 2H), 4.16 (s, 3H).

[0355] Step 2: A solution of 2-bromo-1-(4-bromo-2-methyl-pyrazol-3-yl)ethanone (400 mg, 1.42 mmol, 1.00 equiv) and 2-(2-pyridyl)acetonitrile (335 mg, 2.84 mmol, 0.31 mL, 2.00 equiv) in acetonitrile (6 mL) was stirred at 70° C. for 11 h, followed by the addition of triethylamine (431 mg, 4.26 mmol, 0.59 mL, 3.00 equiv) and stirring at 70° C. for an additional 1 h. The reaction mixture was then concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 30%) to afford 2-(4-bromo-2-methyl-pyrazol-3-yl)indolizine-1-carbonitrile (100 mg, 0.332 mmol, 23% yield) as a yellow solid. LCMS [M+1] + =301.0; 1 H NMR(400 MHz,CDCl3)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). [ka]

[0356] To a solution of 4-chloro-2-(cyclopropoxy)-6-(2-methylpyrazol-3-yl)benzonitrile (150 mg, 0.55 mmol, 1.00 equiv.) in acetic acid (1.0 mL) was added N-iodosuccinimide (247 mg, 1.10 mmol, 2.00 equiv.), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was then diluted with ethyl acetate (30 mL), washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 20%) to give 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 [M + H] + =399.9; 1 H NMR (400 MHz, CDCl3) δ=7.53(s,1H),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). [ka]

[0357] Step 1: A mixture of 3-bromopyridine-2-carbaldehyde (1.00 g, 5.38 mmol, 1.00 equiv.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.12 g, 5.38 mmol, 1.00 equiv.), sodium bicarbonate (1.13 g, 13.4 mmol, 0.52 mL, 2.50 equiv.), and triphenylphosphine (141 mg, 0.54 mmol, 0.10 equiv.) in DMF (10 mL) and water (2 mL) was degassed and purged with nitrogen three times. Then, palladium acetate (60 mg, 0.27 mmol, 0.05 equiv.) was added to the mixture and stirred at 80° C. for 16 hours. The reaction solution was then filtered, poured into water (2 mL), and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 20-100%) to afford 3-(2-methylpyrazol-3-yl)pyridine-2-carbaldehyde (637 mg, 3.40 mmol, 63% yield) as a brown solid. LCMS [M+1] + =188.0; 1 H NMR(400 MHz,CDCl3)δ=10.14-10.06(m,1H),8.93(dd,J=1.6,4.8 Hz,1H),7.79(dd,J=1.2,7.6 Hz,1H),7.64-7.58(m,2H),6.30(d,J=2.0 Hz,1H),3.67(s,3H).

[0358] Step 2: To a solution of 3-(2-methylpyrazol-3-yl)pyridine-2-carbaldehyde (200 mg, 1.07 mmol, 1.00 equiv.) in acetonitrile (5 mL), N-iodosuccinimide (480 mg, 2.14 mmol, 2.00 equiv.) was added and the mixture was stirred at 20 °C for 16 h. The reaction was diluted with ethyl acetate (35 mL), washed with saturated sodium thiosulfate (5 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 20-100%) to afford 3-(4-iodo-2-methyl-pyrazol-3-yl)pyridine-2-carbaldehyde (290 mg, 0.93 mmol, 87% yield) as a white solid. LCMS [M+1] + =313.8; 1 H NMR(400 MHz, CDCl3)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).

[0359] Step 3: To a solution of 3-(4-iodo-2-methyl-pyrazol-3-yl)pyridine-2-carbaldehyde (290 mg, 0.93 mmol, 1.00 equiv.) in DMF (5 mL), 2-aminoacetic acid (77 mg, 1.02 mmol, 1.10 equiv.), iodine (235 mg, 0.93 mmol, 0.18 mL, 1.00 equiv.) and sodium bicarbonate (155 mg, 1.85 mmol, 2.00 equiv.) were added. The mixture was then stirred at 60° C. for 6 hours. The reaction mixture was diluted with ethyl acetate (35 mL), washed with saturated sodium thiosulfate solution (2 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 20-100%) to give 8-(4-iodo-2-methyl-pyrazol-3-yl)imidazo[1,5-a]pyridine (100 mg, 0.31 mmol, 33% yield) as a yellow gum. LCMS [M-1] - =324.9; 1H NMR (400 MHz, CDCl3) 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). [ka]

[0360] Step 1: A mixture of 4-chloro-6-(cyclopropoxy)-3-fluoro-2-(2-methylpyrazol-3-yl)benzonitrile (200 mg, 0.69 mmol, 1.00 equiv), methylboronic acid (205 mg, 3.43 mmol, 5.00 equiv), di-tert-butyl(cyclopentyl)phosphane-dichloropalladium-iron (45 mg, 0.069 mmol, 0.10 equiv) and potassium carbonate (284 mg, 2.06 mmol, 3.00 equiv) in dioxane (2 mL) was degassed and purged with nitrogen three times and stirred at 100° C. for 2 h. The mixture was then concentrated and purified by preparative TLC (SiO, petroleum ether:ethyl acetate 25%) to give 6-(cyclopropoxy)-3-fluoro-4-methyl-2-(2-methylpyrazol-3-yl)benzonitrile (35 mg, 0.10 mmol, 15% yield) as a yellow oil. LCMS [M+1] + =274.3; 1 H NMR(400 MHz,CDCl3)δ=7.60(d,J=2.0 Hz,1H),7.24(d,J=6.0 Hz,1H),6.46(d,J=2.0 Hz,1H),3.86(td,J=2.8,5.6Hz,1H),3.80(s,3H),2.43(d,J=2.0 Hz,3H),0.93-0.88(m,4H).

[0361] Step 2: A mixture of 6-(cyclopropoxy)-3-fluoro-4-methyl-2-(2-methylpyrazol-3-yl)benzonitrile (35 mg, 0.13 mmol, 1.00 equiv.), N-bromosuccinimide (46 mg, 0.26 mmol, 2.00 equiv.) in acetonitrile (3 mL) was stirred at 40° C. under a nitrogen atmosphere for 2 hours. The mixture was then concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 25%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-(cyclopropoxy)-3-fluoro-4-methyl-benzonitrile (25 mg, 0.040 mmol, 31% yield) as a white solid. LCMS [M+1] + =352.0; 1 H NMR(400 MHz,CDCl3)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). [ka]

[0362] Step 1: To a mixture of 2-iodobenzothiophene-3-carbonitrile (280 mg, 0.98 mmol, 1.00 equiv.), sodium carbonate (312 mg, 2.95 mmol, 3.00 equiv.), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (409 mg, 1.96 mmol, 2.00 equiv.) in dioxane (4 mL) and water (1 mL), di-tert-butyl(cyclopentyl)phosphane-dichloropalladium-iron (64 mg, 0.098 mmol, 0.10 equiv.) and sodium carbonate (312 mg, 2.95 mmol, 3.00 equiv.) were added, and the mixture was stirred at 80° C. for 2 hours. Then, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 10%) to afford 2-(2-methylpyrazol-3-yl)benzothiophene-3-carbonitrile (150 mg, 64% yield) as a yellow solid. 1 H NMR(400 MHz, CDCl3)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).

[0363] Step 2: To a mixture of 2-(2-methylpyrazol-3-yl)benzothiophene-3-carbonitrile (150 mg, 0.63 mmol, 1.00 equiv.) in acetonitrile (2 mL), N-bromosuccinimide (112 mg, 0.63 mmol, 1.00 equiv.) was added, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was then added to saturated sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 0-100%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)benzothiophene-3-carbonitrile (160 mg, 75% yield) as a yellow solid. LCMS [M+1] + =319.9; 1 H NMR (400 MHz, CDCl3) 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). [ka]

[0364] Intermediate ES, 2-(4-bromo-2-methyl-pyrazol-3-yl)thieno[2,3-b]pyridine-3-carbonitrile, was prepared from thieno[2,3-b]pyridine-3-carbonitrile in-process according to the procedure described for intermediate ER as a yellow solid (80.0 mg, 0.25 mmol, 22% yield over two steps). LCMS [M+1] + =320.9; 1 H NMR(400 MHz, CDCl3)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). [ka]

[0365] Step 1: To a solution of 2-methylsulfonylethanol (569 mg, 4.58 mmol, 1.20 equiv) in DMF (30 mL) was added sodium hydride (183 mg, 4.58 mmol, 60.0% purity, 1.20 equiv) at 0° C. After stirring for 0.5 h, 4-chloro-2-fluoro-6-(2-methylpyrazol-3-yl)benzonitrile (900 mg, 3.82 mmol, 1.00 equiv) in DMF (5 mL) was added dropwise at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The aqueous phase was adjusted to pH 1 with HCl (10 mL) and further extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 4-chloro-2-hydroxy-6-(2-methylpyrazol-3-yl)benzonitrile (455 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS [M] + =234.1; 1 H NMR(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).

[0366] Step 2: To a solution of 4-chloro-2-hydroxy-6-(2-methylpyrazol-3-yl)benzonitrile (150 mg, 0.642 mmol, 1.00 equiv.) and sodium 2-chloro-2,2-difluoroacetate (392 mg, 2.57 mmol, 4.00 equiv.) in DMF (2 mL) and water (0.2 mL), cesium carbonate (314 mg, 0.96 mmol, 1.50 equiv.) was added. The mixture was stirred at 100° C. for 1 hour. The reaction mixture was then quenched by adding water (40 mL) and then extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 25%) to give 4-chloro-2-(difluoromethoxy)-6-(2-methylpyrazol-3-yl)benzonitrile (85 mg, 0.30 mmol, 47% yield) as a yellow solid. LCMS [M] + =284.0; 1 H NMR(400 MHz,DMSO-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).

[0367] Step 3: To a solution of 4-chloro-2-(difluoromethoxy)-6-(2-methylpyrazol-3-yl)benzonitrile (85 mg, 0.30 mmol, 1.00 equiv.) in acetic acid (2 mL) was added N-iodosuccinimide (135 mg, 0.60 mmol, 2.00 equiv.). The mixture was stirred at 25 °C for 1 h, after which the reaction mixture was quenched by the addition of water (40 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 20%) to give 4-chloro-2-(difluoromethoxy)-6-(4-iodo-2-methyl-pyrazol-3-yl)benzonitrile (90 mg, 0.22 mmol, 73% yield) as a yellow solid. LCMS [M + H] + =409.9; 1 H NMR (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). [ka]

[0368] Step 1: A mixture of 7-bromo-1,3-benzothiazol-6-amine (2.00 g, 8.73 mmol, 1.00 equiv), zinc cyanide (1.54 g, 13.1 mmol, 1.50 equiv), Pd(dba) (80 mg, 0.87 mmol, 0.01 equiv), DPPF (97 mg, 0.175 mmol, 0.02 equiv) and zinc powder (5.7 mg, 0.087 mmol, 0.01 equiv) in DMF (20 mL) was degassed and purged with nitrogen three times, then stirred at 140 °C for 16 h. The reaction mixture was then extracted with 150 mL of ethyl acetate (50 mL × 3), and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 10-25%) to give 6-amino-1,3-benzothiazole-7-carbonitrile (1.05 g, 4.66 mmol, 53% yield) as a yellow solid. LCMS [M+1] + =176.1; 1 H NMR (400 MHz, CDCl3-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).

[0369] Step 2: A mixture of 6-amino-1,3-benzothiazole-7-carbonitrile (500 mg, 2.85 mmol, 1.00 equiv), para-toluenesulfonic acid (590 mg, 3.42 mmol, 1.20 equiv), tert-butyl nitrite (353 mg, 3.42 mmol, 407 uL, 1.20 equiv), tetrabutylammonium bromide (1.84 g, 5.71 mmol, 2.00 equiv) and copper bromide (64 mg, 0.286 mmol, 0.10 equiv) 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 (SiO, petroleum ether:ethyl acetate 10-25%) to give 6-bromo-1,3-benzothiazole-7-carbonitrile (300 mg, 1.25 mmol, 44% yield) as a yellow solid. LCMS [M+1] + =240.9; 1H NMR (400 MHz, CDCl3) δ = 9.11 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H).

[0370] Step 3: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (261 mg, 1.25 mmol, 1.00 equiv), 6-bromo-1,3-benzothiazole-7-carbonitrile (300 mg, 1.25 mmol, 1.00 equiv), di-tert-butyl(cyclopentyl)phosphane, iron dichloropalladium (82 mg, 0.125 mmol, 0.10 equiv) and sodium bicarbonate (316 mg, 3.76 mmol, 3.00 equiv) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and then stirred at 80° C. under a nitrogen atmosphere for 3 hours. The mixture was then concentrated, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 5-25%) to give 6-(2-methylpyrazol-3-yl)-1,3-benzothiazole-7-carbonitrile (280 mg, 0.89 mmol, 71% yield) as a yellow solid. LCMS [M+1] + =241.0; 1 H NMR (400 MHz, CDCl3-d) δ = 9.21 (s, 1H), 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).

[0371] Step 4: A mixture of 6-(2-methylpyrazol-3-yl)-1,3-benzothiazole-7-carbonitrile (140 mg, 0.58 mmol, 1.00 equiv.), N-bromosuccinimide (207 mg, 1.17 mmol, 2.00 equiv.) in acetonitrile (3 mL) was stirred at 40 °C under a nitrogen atmosphere for 2 h. The mixture was then concentrated, and the residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 5-20%) to afford 6-(4-bromo-2-methyl-pyrazol-3-yl)-1,3-benzothiazole-7-carbonitrile (300 mg, 0.47 mmol, 81% yield) as a white solid. LCMS [M+1]+ =321.0; 1 H NMR (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). [ka]

[0372] Step 1: To a solution of 3-(hydroxymethyl)-1-methylpyridin-2(1H)-one (650 mg, 4.67 mmol, 1.00 equiv) in dichloromethane (15 mL) was added thionyl chloride (667 mg, 5.61 mmol, 407 uL, 1.20 equiv) and the mixture was stirred for 2 hours at 25° C. The mixture was concentrated in vacuo to afford 3-(chloromethyl)-1-methyl-pyridin-2-one (650 mg, crude) as a white solid.

[0373] Step 2: To a solution of 3-(chloromethyl)-1-methyl-pyridin-2-one (650 mg, 4.12 mmol, 1.00 equiv.), 4-bromo-5-chloro-1H-pyrazole (747 mg, 4.12 mmol, 1.00 equiv.) in acetonitrile (20 mL), potassium carbonate (683 mg, 4.94 mmol, 1.20 equiv.) was added, and the mixture was stirred at 80° C. for 12 hours. The reaction mixture was then quenched with water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 5%) to give 3-[(4-bromo-5-chloro-pyrazol-1-yl)methyl]-1-methyl-pyridin-2-one (270 mg, 0.89 mmol, 51% yield) as a yellow solid. LCMS [M+1] + =304.0.

[0374] Step 3: To a solution of 3-[(4-bromo-5-chloro-pyrazol-1-yl)methyl]-1-methyl-pyridin-2-one (270 mg, 0.89 mmol, 1.00 equiv.), 4-bromo-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (512 mg, 1.78 mmol, 2.00 equiv.) in dioxane (10 mL) and water (1 mL), Pd(dppf)Cl (65 mg, 0.089 mmol, 0.10 equiv.) and sodium bicarbonate (150 mg, 1.78 mmol, 69 μL, 2.00 equiv.) were added. The mixture was stirred at 110° C. for 10 hours. The reaction mixture was then quenched by adding water (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini-NX 80 mm × 40 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 5% to 35%, 8 min) to give 3-[[5-chloro-4-(2-methylpyrazol-3-yl)pyrazol-1-yl]methyl]-1-methyl-pyridin-2-one (60.0 mg, 0.198 mmol, 22% yield) as a gray solid. LCMS [M+1] + =304.1; 1 H NMR(400 MHz,DMSO-d6)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).

[0375] Step 4: To a solution of 3-((5'-chloro-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)methyl)-1-methylpyridin-2(1H)-one (47.0 mg, 0.155 mmol, 1.00 equiv) in acetonitrile (1 mL) was added N-bromosuccinimide (26 mg, 0.147 mmol, 0.95 equiv). The mixture was stirred at 25°C for 10 hours. The reaction mixture was then quenched by adding water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (SiO, dichloromethane:methanol 10%) to give 3-((4-bromo-5'-chloro-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)methyl)-1-methylpyridin-2(1H)-one (45 mg, 0.118 mmol, 76% yield) as a white solid. LCMS [M+1] + =383.9; 1 H NMR(400 MHz,DMSO-d6)δ=7.89(s,1 H),7.71(d,J=6.8,1.2 Hz,1 H),7.67(s,1 H),6.93-6.96(m,1 H),6.23(t,J=6.8 Hz,1 H),5.22(s,2 H),3.74(s,3 H),3.47(s,3 H). [ka]

[0376] Steps 1-6: 2-((7-bromo-4-oxo-5-(methoxy)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione was prepared as a white solid (4.22 g, 10.2 mmol, 8% yield for 6 steps) starting from 1-(5-bromo-2-methyl-3-(methoxy)phenyl)ethan-1-one following the same procedure as described for the first 6 steps of intermediate DK. LCMS [M+1] + =414.0.

[0377] Step 7: A mixture of 2-((7-bromo-4-oxo-5-(methoxy)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (4.22 g, 10.2 mmol, 1.0 equiv), bis(pinacolato)diboron (3.88 g, 15.3 mmol, 1.5 equiv), Pd(dppf)Cl.CHCl (745 mg, 1.02 mmol, 0.1 equiv), and potassium acetate (3.00 g, 30.6 mmol, 3.0 equiv) in dioxane (60 mL) was degassed and purged with nitrogen three times and stirred at 100 °C for 1 h. The mixture was then concentrated, and the residue was triturated with methanol, filtered, and dried to afford intermediate EX as a gray solid (2.01 g, 43% yield). LCMS [M+1] + = 380.1 (boronic acid due to loss of pinicol. [ka]

[0378] 6-Cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile, intermediate EY, was prepared as a white solid (120 mg, 0.30 mmol, 20% over 3 steps) following the procedure described for the preparation of intermediate DQ. LCMS [M+1] += 383.8; 1 H NMR (400 MHz, CDCl3) δ=7.65(s,1H),7.51-7.40(m,2H),3.93-3.87(m,1H),3.83(s,3H),1.00-0.89(m,4H). [ka]

[0379] 6-Cyclopropoxy-3-chloro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile, intermediate EZ, was prepared as a yellow solid (160 mg, 0.40 mmol, 22% over 3 steps) following the procedure described for the preparation of intermediate DQ. LCMS [M+1] += 399.9; 1H NMR (400 MHz, CDCl3) δ=7.70(d,J=9.2 Hz,1H),7.64(s,1H),7.47(d,J=9.2 Hz,1H),3.92(td,J=2.8,5.6 Hz,1H),3.78(s,3H),0.99-0.90(m,4H). [ka]

[0380] Step 1: To a solution of 4-chloro-2-cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)benzonitrile (177 mg, 0.65 mmol, 1.00 equiv.) in dioxane (10 mL), potassium carbonate (268 mg, 1.94 mmol, 3.00 equiv.), di-tert-butyl(cyclopentyl)phosphane, dichloropalladium-iron (42 mg, 0.064 mmol, 0.10 equiv.), and methylboronic acid (194 mg, 3.23 mmol, 5.00 equiv.) were added. The mixture was stirred at 100° C. for 2 hours, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 25%) to give 2-(cyclopropoxy)-4-methyl-6-(2-methylpyrazol-3-yl)benzonitrile (111 mg, 0.44 mmol, 68% yield) as a white solid. LCMS [M+1] + =254.1; 1 H NMR(400 MHz,CDCl3)δ=7.98(d,J=2.0 Hz,1H),7.65(d,J=0.8 Hz,1H),7.27(s,1H),6.85(d,J=2.0 Hz,1H),4.35-4.29(m,1H),4.27(s,3H),2.91(s,3H),1.36-1.31(m,4H).

[0381] Step 2: To a solution of 2-(cyclopropoxy)-4-methyl-6-(2-methylpyrazol-3-yl)benzonitrile (100 mg, 0.40 mmol, 1.00 equiv.) in acetic acid (2 mL) was added N-iodosuccinimide (178 mg, 0.79 mmol, 2.00 equiv.). The mixture was stirred at 25 °C for 1 hour, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate 25%) to give 2-(cyclopropoxy)-6-(4-iodo-2-methyl-pyrazol-3-yl)-4-methyl-benzonitrile (94 mg, 0.25 mmol, 63% yield) as a yellow solid. LCMS [M+1] + =380.0; 1 H NMR(400 MHz,CDCl3)δ=7.66-7.55(m,1H),7.27(s,1H),6.80(s,1H),3.89(tt,J=3.2,6.0 Hz, 1H), 3.85-3.79 (m, 3H), 2.50 (s, 3H), 1.04-0.80 (m, 4H). [ka]

[0382] Step 1: To a solution of 2-fluoronaphthalen-1-ol (0.50 g, 3.08 mmol, 1.00 equiv) in dichloromethane (8 mL) was added NBS (521 mg, 2.93 mmol, 0.95 equiv) and the mixture was stirred at −50° C. for 0.25 h. Water (10 mL) was then added, the separated organic phase was dried and concentrated, and the residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate 1%) to give 4-bromo-2-fluoro-naphthalen-1-ol (500 mg, 2.07 mmol, 67% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3)δ=8.27-8.21(m,1H),8.19-8.11(m,1H),7.63(d,J=10.2 Hz,1H),7.61-7.54(m,2H),5.68(br d,J=4.0 Hz,1H).

[0383] Step 2: To a solution of 4-bromo-2-fluoro-naphthalen-1-ol (2.30 g, 9.54 mmol, 1.00 equiv.), DIEA (21.0 mmol, 3.66 mL, 2.20 equiv.), and DMAP (58 mg, 0.48 mmol, 0.05 equiv.) in dichloromethane (40 mL) was added acetyl chloride (19.1 mmol, 1.36 mL, 2.00 equiv.) dropwise at 0° C. The mixture was stirred at 28° C. for 1 hour, after which the mixture was concentrated, and the formed residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate 1%) to give (4-bromo-2-fluoro-1-naphthyl)acetate (2.50 g, 8.83 mmol, 93% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 8.26-8.18 (m, 1H), 7.94-7.86 (m, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.66-7.56 (m, 2H), 2.51 (s, 3H).

[0384] Step 3: A mixture of (4-bromo-2-fluoro-1-naphthyl)acetate (2.50 g, 8.83 mmol, 1.00 equiv), Pd(dba) (809 mg, 0.88 mmol, 0.10 equiv), Zn(CN) (9.71 mmol, 0.62 mL, 1.10 equiv), Zn (29 mg, 0.442 mmol, 0.05 equiv) and DPPF (979 mg, 1.77 mmol, 0.20 equiv) in DMA (40 mL) was degassed three times with nitrogen and then stirred at 120 °C for 3 h. The reaction mixture was then diluted with ethyl acetate (100 mL) and filtered, and the filtrate was washed with brine (50 mL × 3), dried and concentrated, and the residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate 2–10%) to give 3-fluoro-4-hydroxy-naphthalene-1-carbonitrile (980 mg, 5.24 mmol, 59% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ=8.36-8.27(m,1H),8.18(d,J=8.0 Hz,1H),7.76(d,J=9.6 Hz,1H),7.72-7.62(m,2H).

[0385] Step 4: To a solution of 3-fluoro-4-hydroxy-naphthalene-1-carbonitrile (880 mg, 4.70 mmol, 1.00 equiv) in dichloromethane (20 mL) was added triethylamine (9.40 mmol, 1.31 mL, 2.00 equiv) and TfO (8.46 mmol, 1.40 mL, 1.80 equiv) at 0 °C. The mixture was then stirred at 28 °C for 0.5 h. The reaction mixture was then concentrated, and the residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate 2%) to afford (4-cyano-2-fluoro-1-naphthyl)trifluoromethanesulfonate (1.15 g, 3.60 mmol, 77% yield) as a yellow solid.

[0386] Step 5: A mixture of (4-cyano-2-fluoro-1-naphthyl)trifluoromethanesulfonate (0.38 g, 1.19 mmol, 1.00 equiv.), Pd(PPh3)4 (138 mg, 0.12 mmol, 0.10 equiv.), and AlMe3 (2 M in PhMe, 1.79 mL, 3.00 equiv.) in toluene (3.5 mL) was degassed three times with nitrogen and stirred at 120 °C for 2 hours. The reaction was then quenched by the addition of water (5 mL), then diluted with ethyl acetate (40 ml), and filtered. The filtrate was washed with water (20 mL × 3), dried, and concentrated, and the residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate 5%) to give the compound 3-fluoro-4-methyl-naphthalene-1-carbonitrile (90 mg, 0.49 umol, 41% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 8.29-8.22 (m, 1H), 8.11-8.03 (m, 1H), 7.75-7.63 (m, 3H), 2.66 (d, J = 2.4 Hz, 3H).

[0387] Step 6: To a solution of N-isopropylpropan-2-amine (0.86 mmol, 0.12 mL, 2.00 equiv.) in THF (2 mL), n-BuLi (2.5 M in THF, 0.31 mL, 1.80 equiv.) was added dropwise at −70° C. The mixture was then stirred at −70° C. for 0.5 hours, followed by the addition of 3-fluoro-4-methyl-naphthalene-1-carbonitrile (80 mg, 0.43 mmol, 1 equiv.) and stirring for another 0.5 hours, followed by the addition of iodine (0.87 mmol, 0.17 mL, 2.00 equiv.). After the addition was complete, the mixture was stirred at 30° C. for 1 hour. The reaction mixture was then quenched by adding water (2 mL) and extracted with ethyl acetate (10 mL×2). The combined organic phases were dried and concentrated to give 3-fluoro-2-iodo-4-methyl-naphthalene-1-carbonitrile (110 mg, 0.35 mmol) as a brown solid.

[0388] Step 7: A mixture of 3-fluoro-2-iodo-4-methyl-naphthalene-1-carbonitrile (110 mg, 0.35 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (96 mg, 0.46 mmol, 1.30 equiv), [2-(2-aminophenyl)phenyl]palladium(1+)-bis(1-adamantyl)-butyl-phosphane-methanesulfonate (26 mg, 0.035 mmol, 0.10 equiv), KPO (1.50 M, 0.71 mL, 3.00 equiv) in n-butyl alcohol (2.8 mL) was degassed three times with nitrogen and then stirred at 60 °C for 6 h. The reaction mixture was then filtered and concentrated, and the residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate 20%) to give 3-fluoro-4-methyl-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (50 mg, 0.19 mmol, 53% yield) as a brown solid. LCMS [M+1] + 266.1.

[0389] Step 8: To a solution of 3-fluoro-4-methyl-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (50 mg, 0.19 mmol, 1.00 equiv.) in acetic acid (2 mL), NIS (127 mg, 0.57 mmol, 3.00 equiv.) was added. The mixture was stirred at 30 ° C. for 12 hours. The pH was then adjusted to pH 7 with saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate (10 mL × 3), and the combined organic phase was dried and concentrated. The residue was purified by preparative TLC (SiO 2 , petroleum ether / ethyl acetate 20%) to obtain the compound 3-fluoro-2-(4-iodo-2-methyl-pyrazol-3-yl)-4-methyl-naphthalene-1-carbonitrile (30 mg, 0.076 mmol, 41% yield) as a brown solid. LCMS [M+1] + 392.0. [ka]

[0390] Step 1: To a solution of 3-chloro-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile (200 mg, 0.747 mmol, 1.00 equiv.), potassium trifluorovinylborate (120 mg, 0.896 mmol, 1.20 equiv.), cesium carbonate (730 mg, 2.24 mmol, 3.00 equiv.), and dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (34.9 mg, 0.074 mmol, 0.10 equiv.) in THF (2 mL) and water (0.2 mL), palladium(II) chloride (13.3 mg, 0.074 mmol, 0.10 equiv.) was added under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 hours. The reaction mixture was then diluted with water (3 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 5-20%) to give 2-(1-methyl-1H-pyrazol-5-yl)-3-vinyl-1-naphthonitrile (130 mg, 0.049 mmol, 66% yield) as a pale yellow solid. LCMS [M+1] += 260.2.

[0391] Step 2: 2-(1-methyl-1H-pyrazol-5-yl)-3-vinyl-1-naphthonitrile (130 mg, 491 μmol, 1.00 equiv) was dissolved in dichloromethane (20 mL) and cooled to -70 °C. Ozone was bubbled through the reaction solution with stirring for 15 minutes. Dimethylsulfane (8.46 g, 136 mmol, 10 mL, 277 equiv) was then added, and the mixture was stirred at -70 °C for 15 minutes. The mixture was then concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 5-20%) to afford 3-formyl-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile (60 mg, 222 μmol, 45.3% yield) as a white solid. LCMS [M+1] += 262.2.

[0392] Step 3: A solution of 3-formyl-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile (20 mg, 74.2 μmol, 1.00 equiv.) and (bis-(2-methoxyethyl)amino)sulfur fluoride (41 mg, 185 μmol, 41 μL, 2.50 equiv.) in dichloromethane (1.0 mL) was stirred at 25° C. for 6 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (2 mL) and then extracted with ethyl acetate (5 mL×3). The combined organic layer was washed with brine (3 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate 20%) to give 3-(difluoromethyl)-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (11.0 mg, 38.4 μmol, 52% yield) as a white solid. LCMS[M+1] += 284.2.

[0393] Step 4: To a solution of 3-(difluoromethyl)-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile (11 mg, 38 μmol, 1.00 equiv.) in dichloromethane (1.0 mL) was added 1-bromopyrrolidine-2,5-dione (10 mg, 58 μmol, 1.50 equiv.). The mixture was stirred at 25° C. for 10 hours. The reaction mixture was concentrated and purified by preparative TLC (SiO, petroleum ether / ethyl acetate 20%) to give 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-(difluoromethyl)-1-naphthonitrile (12 mg, 33 μmol, 86% yield) as a colorless oil. LCMS [M+1] += 362.1. [ka]

[0394] Step 1: A mixture of sodium hydride (51 mg, 1.28 mmol, 60% purity, 1.20 equiv) and 2-methylsulfonylethanol (158 mg, 1.28 mmol, 1.20 equiv) in DMF (3 mL) was stirred under nitrogen at 0° C. for 30 minutes. Then, a solution of 2-(4-bromo-2-methyl-pyrazol-3-yl)-4-chloro-6-(cyclopropoxy)benzonitrile (375 mg, 1.06 mmol, 1 equiv) in DMF (2 mL) was added dropwise, and the reaction mixture was stirred at 25° C. for 2 hours. The mixture was then quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10-30%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-(cyclopropoxy)-4-hydroxy-benzonitrile (120 mg, 33% yield) as a colorless oil. LCMS [M+1] + =334.0; 1 H NMR(400 MHz,CDCl3)δ=9.77-9.37(m,1H),7.54(s,1H),6.98(d,J=2.0 Hz,1H),6.51(d,J=2.0 Hz, 1H), 3.85-3.82 (m, 1H), 3.80 (s, 3H), 0.94-0.84 (m, 5H).

[0395] Step 2A: To a mixture of 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-(cyclopropoxy)-4-hydroxy-benzonitrile (20 mg, 59 μmol, 1.00 equiv) in DMF (0.5 mL) was added sodium hydride (4.8 mg, 119 μmol, 60% purity, 2.00 equiv) at 0° C. under nitrogen, and the mixture was stirred at 0° C. for 30 minutes. Dibromo(difluoro)methane (38 mg, 180 μmol, 17 μL, 3.00 equiv) was then added to the mixture at 0° C., and the mixture was stirred at 25° C. for 1 hour. Water (3.00 mL) was then added, and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and the residue was purified by preparative TLC (SiO, petroleum ether:acetic ether 20%) to give 4-[bromo(difluoro)methoxy]-2-(4-bromo-2-methyl-pyrazol-3-yl)-6-(cyclopropoxy)benzonitrile (10.0 mg, 36% yield) as a white solid. LCMS [M+1] + =463.9.

[0396] Step 2B: To a mixture of 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-(cyclopropoxy)-4-hydroxy-benzonitrile (100 mg, 299 μmol, 1.00 equiv.) and sodium 2-chloro-2,2-difluoroacetate (114 mg, 748 μmol, 2.50 equiv.) in DMF (1.0 mL) and water (0.1 mL), cesium carbonate (146 mg, 449 μmol, 1.50 equiv.) was added. The mixture was stirred at 100° C. for 3 hours. The reaction mixture was then quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and the residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate 0-30%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-(cyclopropoxy)-4-(difluoromethoxy)benzonitrile (70 mg, 61% yield) as a colorless oil. LCMS [M+1] + =386.0; 1H NMR (400 MHz, CDCl3) δ=7.57(s,1H),7.23(d,J=2.4 Hz,1H),6.87-6.43(m,2H),3.95-3.87(m,1H),3.82(s,3H),0.99-0.90(m,4H).

[0397] Step 3: A mixture of 4-[bromo(difluoro)methoxy]-2-(4-bromo-2-methyl-pyrazol-3-yl)-6-(cyclopropoxy)benzonitrile (100 mg, 216 μmol, 1.00 equiv.) and silver tetrafluoroborate (273 mg, 1.40 mmol, 6.50 equiv.) in DCE (2 mL) was stirred at 65 °C for 3 hours. The reaction mixture was then quenched with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, and the residue was purified by reverse-phase flash (0.1% FA conditions) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-(cyclopropoxy)-4-(trifluoromethoxy)benzonitrile (55 mg, 63% yield) as a yellow solid. LCMS [M+1] + =402.1.

[0398] In one aspect of the present invention, provided herein are intermediates that can be used in the preparation of compounds of Formula (I), Formula (IA), Formula (IB), Formula (IC), and Formula (1-D). In one embodiment, the intermediates include intermediates A-1 through A-FE.

[0399] The following examples are intended to further illustrate certain embodiments of the present invention, but are not intended to limit the scope of the invention.

[0400] General reaction method for the preparation of Examples 1-1 to 1-8 Examples 1-1 and 1-2 [ka] Step 1: A mixture of a 1:1 mixture of intermediates C, 4c, and 4d (587 mg, 1.68 mmol, 1.00 equiv.), phenylboronic acid pinacol ester, Pd(dppf)Cl (168 μmol, 0.10 equiv.), and sodium carbonate (3.36 mmol, 2.00 equiv.) in DMF (10 mL) was purged with nitrogen three times and stirred at 100° C. for 2 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate 5:1) to give a 1:1 mixture of 4-(benzyloxy)-1-chloro-7-phenylphthalazine 5c and 5d 4-benzyloxy-1-chloro-6-phenyl-phthalazine (355 mg, 818 μmol, 48% yield) as a yellow solid.

[0401] Step 2: To a 1:1 mixture of 4-(benzyloxy)-1-chloro-6-phenylphthalazine 5c and 4-(benzyloxy)-1-chloro-7-phenylphthalazine 5d (350 mg, 806 μmol, 1.00 equiv.) in DMF (10 mL) was added zinc cyanide (1.21 mmol, 1.50 equiv.), 1,1′-bis(diphenylphosphino)ferrocene (80.6 μmol, 0.10 equiv.), Pd(dba) (40.3 μmol, 0.05 equiv.), and zinc powder (80.6 μmol, 0.10 equiv.). The mixture was purged with nitrogen three times and stirred at 100° C. for 3 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate 10:1 to 3:1) to give a 1:1 mixture of 4-(benzyloxy)-7-phenylphthalazine-1-carbonitrile 6c and 4-benzyloxy-6-phenyl-phthalazine-1-carbonitrile 6d (158 mg, 468 μmol, 58% yield) as a yellow solid.

[0402] Step 3: To a 1:1 mixture of 4-(benzyloxy)-7-phenylphthalazine-1-carbonitrile 6c and 4-(benzyloxy)-6,6-phenylphthalazine-1-carbonitrile 6d (100 mg, 296 μmol, 1.00 equiv.), hydrochloric acid (6.00 M, 10.1 equiv.) and methyl alcohol (3.00 mL) were added, followed by the addition of palladium on activated carbon (29.6 μmol, 10% by weight) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was then stirred under a hydrogen atmosphere (50 psi) at 40° C. for 2 h. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 150×25 mm×10 μm; mobile phase: [water (0.1% TFA)-ACN], B%: 2% to 25%, 10 min), followed by separation of regioisomers by SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm); mobile phase: [0.1% NH3HO MeOH]; B%: 60% to 60%, 40 min) to obtain the desired compound 4-(aminomethyl)-6-phenyl-phthalazin-1-ol, Example 1-1 (13.7 mg, 53.6 μmol, 26% yield). LCMS [M+1] = 252.2; 1 H NMR (400 MHz, MeOD) δ = 8.37 (d, J = 8.0 Hz, 1H), 8.09-8.02 (m, 2H), 7.76 (d, J = 7.2 Hz, 2H), 7.54-7.48 (m, 2H), 7.47-7.41 (m, 1H), 4.22 (s, 2H). LCMS [M+1]: 252.2 and 4-(aminomethyl)-7-phenyl-phthalazin-1-ol, Example 1-2 (23.6 mg, 91.8 μmol, 46% yield), LCMS [M+1]: 252.3; 1 H NMR(400 MHz,MeOD)δ=8.64(d,J=2.0 Hz,1H),8.28(dd,J=2.0,8.4 Hz,1H),8.01(d,J=8.4 Hz,1H),7.83-7.74(d,J=7.2 Hz,2H),7.58-7.51(m,2H),7.50-7.44(m,1H),4.61(s,2H)

[0403] Following the teachings of the General Reaction Scheme, the synthetic procedures for Examples 1-1 and 1-2, and using the intermediates disclosed herein, Examples 1-3 through 1-8 were prepared as shown in Table 1. [Table 12]

[0404] Example 2-1 [ka] Step 1: A mixture of intermediate D (150 mg, 429 μmol, 1.00 equiv), thiazol-4-ylboronic acid (66 mg, 515 μmol, 1.20 equiv), sodium carbonate (91 mg, 858 μmol, 2.00 equiv), and Pd(dppf)Cl (31 mg, 42.9 μmol, 0.10 equiv) in DMF (1.00 mL) was purged with nitrogen three times and stirred under nitrogen at 100° C. for 12 hours. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate 5:1 to 1:1) to give 4-(1-(benzyloxy)-4-chlorophthalazin-6-yl)thiazole (76 mg, 214 μmol, 50% yield).

[0405] Step 2: A mixture of 4-(1-(benzyloxy)-4-chlorophthalazin-6-yl)thiazole (76 mg, 214 μmol, 1.00 equiv.), zinc cyanide (38 mg, 321 μmol, 20 μL, 1.50 equiv.), DPPF (12 mg, 21 μmol, 0.10 equiv.), Pd(dba) (10 mg, 10 μmol, 0.05 equiv.), and zinc powder (1 mg, 21 μmol, 0.10 equiv.) in DMF (1.00 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 105° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (30 mL), dried (anhydrous NaSO), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=5:1 to 1:1) to give 4-(benzyloxy)-7-(thiazol-4-yl)phthalazine-1-carbonitrile (51 mg, 148 μmol, 69% yield).

[0406] Step 3: To a solution of 4-(benzyloxy)-7-(thiazol-4-yl)phthalazine-1-carbonitrile (103 mg, 299 μmol, 1.00 equiv.) and HCl (6.0 M, 1.00 equiv.) in MeOH (10 mL) was added palladium on activated carbon (296 μmol, 10.0% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was then vigorously stirred under a hydrogen atmosphere (50.0 psi) at 40° C. for 2 hours. The reaction mixture was then filtered, concentrated under reduced pressure, and purified by preparative HPLC (Waters Xbridge 150 x 25 mm x 5 μm; mobile phase: [water (0.05% v / v ammonium hydroxide)-ACN]; B%: 12%-42%, 10 min) to give 4-(aminomethyl)-6-(thiazol-4-yl)phthalazin-1(2H)-one, Example 2-1 (3 mg, 12 μmol, 4% yield, 97% purity) as a white solid. LCMS [M+1]: 259.2; 1H NMR (400 MHz, MeOD) δ = 9.17 (d, J = 2.0 Hz, 1H), 8.56 (s, 1H), 8.47-8.43 (m, 2H), 8.33 (d, J = 2.0 Hz, 1H), 4.29 (s, 2H).

[0407] General Reaction Method 2 for Preparation of Examples 2-2 to 2-5 [ka] Step 1: A mixture of intermediate E (429 μmol, 1.00 equiv.), the appropriate aryl / heteroaryl-tributyltin reagent (644 μmol, 1.50 equiv.), and Pd(PPh3)4 (43 μmol, 0.10 equiv.) in toluene (2 mL) was purged with nitrogen three times and stirred at 100 °C for 12 h. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate 5:1 to 1:1) to give the appropriate R 1 -coupling product 5e was obtained.

[0408] Step 2: R in DMF (1.00 mL) 1 A mixture of the coupling product 5e (214 μmol, 1.00 equiv.), zinc cyanide (321 μmol, 20 μL, 1.50 equiv.), DPPF (21 μmol, 0.10 equiv.), Pd(dba) (10 μmol, 0.05 equiv.), and zinc powder (21 μmol, 0.10 equiv.) was purged with nitrogen three times. The mixture was then stirred at 105°C for 2 h. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The concentrated residue was then purified by column chromatography (SiO, petroleum ether / ethyl acetate 5:1 to 1:1) to give the appropriate R 1-cyanide 6e was obtained, which was used in the next step without further purification

[0409] Step 3: Appropriate R 1 To a solution of cyanide 6e (287 μmol, 1.00 equiv.) and HCl (6.0 M, 1.00 equiv.) in MeOH (10 mL) was added palladium on activated carbon (296 μmol, 10% Pd) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was then vigorously stirred under a hydrogen atmosphere (50 psi) at 40°C for 2 h, after which it was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (0.05% v / v ammonium hydroxide)-ACN]; B%: 12%–42%, 10 min) to recover the desired compounds shown in Table 2.

[0410] Following the teachings of General Reaction Scheme, General Reaction Method 2, and the intermediates disclosed herein, Examples 2-2 through 2-5 are prepared as shown in Table 2. [Table 13]

[0411] General Coupling Method (CM) and Purification Method (PM) for Preparation of Examples 3-1 to 3-61 [ka] Step 1: A mixture of the appropriate aryl / heteroaryl / alkyl-boronic acid ester (390 μmol, 1.5 equiv.), intermediate F (260 μmol, 1.00 equiv.), Pd(dppf)Cl (26 μmol, 0.10 equiv.), and sodium bicarbonate (43 mg, 521 μmol, 20.3 μL, 2.00 equiv.) in dioxane (1.00 mL) and water (0.20 mL) was purged with nitrogen three times. The mixture was then stirred at 80° C. for 2 h. The mixture was then filtered, washed with a 10:1 mixture of dichloromethane:methyl alcohol, and the filtrate was concentrated under reduced pressure. The concentrated residue was then triturated with methyl alcohol (3.00 mL) to give the corresponding Suzuki coupling product 15a as a black solid.

[0412] Step 2: To a solution of the corresponding Suzuki coupling product 15a in ethyl alcohol (1.00 mL) was added hydrazine hydrate (242 μmol, 14 μL). The mixture was stirred at 80° C. for 1 h, cooled, and then concentrated under reduced pressure. The concentrated residue was then purified by preparative HPLC according to one of the purification methods 3-1, 3-2, 3-3, or 3-4 described herein to give 7a. [ka]

[0413] Step 1: Intermediate AN, the appropriate alkyl / aryl / heteroaryl bromide (464 μmol), sodium bicarbonate (464 μmol, 18.0 μL, 2.00 equiv.), and Pd(dppf)Cl (17 mg, 23 μmol, 0.10 equiv.) in dioxane (2 mL) and water (0.40 mL) were purged with nitrogen three times. The mixture was then stirred at 80° C. for 1 h. The reaction mixture was then diluted with water (2 mL), filtered under reduced pressure, and the filter cake was triturated with ethyl alcohol (3 mL) to give the corresponding R 1 The Suzuki coupling product 15a was obtained as a black solid, which was taken on directly to the next step without further purification.

[0414] Step 2: Dissolve the corresponding R in ethyl alcohol (1.00 mL) 1To a solution of the Suzuki coupling product 15a, hydrazine hydrate (242 μmol, 14 μL) was added. The mixture was stirred at 80° C. for 1 hour. The mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC according to one of purification methods 3-1 to 3-4. [ka]

[0415] Step 1: A mixture of intermediate F (312 μmol, 1.00 equiv.), the appropriate alkyl / aryl / heteroaryl tributyltin or alkyl / aryl / heteroaryl trimethylsilicon reagent (625 μmol, 2.00 equiv.), and Pd(PPh3)4 (72 mg, 62 μmol, 0.20 equiv.) in dioxane (3.00 mL) was purged with nitrogen three times. The mixture was then stirred at 100 °C for 1 h. The reaction mixture was then diluted with potassium fluoride solution (3.0 mL) to form a suspension. The suspension was filtered, and the filtrate was extracted with ethyl acetate (8 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane:methyl alcohol 10:1) to give the corresponding C-C bond-forming compound 15a as a black solid.

[0416] Step 2: To a solution of 15a in ethyl alcohol (1.0 mL) was added hydrazine hydrate (242 μmol, 14 μL). The mixture was stirred at 80° C. for 1 hour. The mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC according to one of purification methods 3-1 to 3-4.

[0417] Purification method (PM) PM3-1: Column: Phenomenex Synergi C18 150×25×10μm; Mobile phase: [Water (0.05%HCl)-ACN]; B%: 5%~25%, 11 minutes

[0418] PM 3-2: Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (0.05% v / v ammonium hydroxide)-ACN]; B%: 12%–42%, 10 min

[0419] PM 3-3: Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 2% to 32%, 10 min

[0420] PM 3-4: Column: Phenomenex Luna C18 75 x 10 mm x 3 μm; Mobile phase: [Water (0.05% HCl)-ACN]; B%: 11%~31%, 6.5 minutes.

[0421] Following the teachings of General Reaction Scheme, Coupling Methods 3A, 3B, and 3C, and using Purification Methods 3-1, 3-2, 3-3, and 3-4, and intermediates disclosed herein, Examples 3-1 through 3-61 are prepared as shown in Table 3. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6] [Table 14-7] [Table 14-8] [Table 14-9] [Table 14-10] [Table 14-11] [Table 14-12]

[0422] Examples 4-1 to 4-180 Coupling Methods (CM) and Purification Methods (PM) for the Preparation of the Examples in Table 4 [ka] Step 1: A mixture of the appropriate aryl / heteroaryl-halide 26 (390 μmol, 1.5 equiv.), intermediate AN (260 μmol, 1.00 equiv.), Pd(dppf)Cl (26 μmol, 0.10 equiv.), and sodium bicarbonate (43.7 mg, 521 μmol, 20.3 μL, 2.00 equiv.) in dioxane (1.0 mL) and water (0.2 mL) was purged with nitrogen three times. The mixture was then stirred at 80° C. for 2 h. The mixture was then filtered, washed with a 10:1 mixture of dichloromethane:methyl alcohol, and the filtrate was concentrated under reduced pressure to give a residue. The concentrated residue was then triturated with methyl alcohol (3.0 mL), filtered, and dried to give the corresponding coupling product 15a as a black solid.

[0423] Step 2: To a solution of the corresponding coupling product 15a in ethyl alcohol (1.00 mL) was added hydrazine hydrate (242 μmol, 14 μL). The mixture was stirred at 80° C. for 1 h. The mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC according to any of the purification methods 4-1 to 4-13. [ka]

[0424] Step 1: Intermediate J (189 mg, 470 μmol, 1.00 equiv.), aryl / heteroaryl-halide in dioxane (1 mL) and water (0.20 mL). A mixture of 26 (564 μmol, 1.20 equiv.), Pd(dppf)Cl (34 mg, 47 μmol, 0.10 equiv.), and sodium bicarbonate (79 mg, 940 μmol, 37 μL, 2.00 equiv.) was purged three times with nitrogen and stirred at 80° C. for 2 h. Upon completion, the reaction mixture was poured into water (40 mL), filtered, and the filter cake was dried under reduced pressure to give R 2 The -pyridyl-Suzuki coupling product 28-Boc (71 mg, crude) was obtained as a grey solid, which was used directly in the next step without further purification.

[0425] Step 2: tert-butyl N-[[4-oxo-7-(5-pyrimidin-2-yloxy-3-pyridyl)-3H-phthalazin-1-yl]methyl]carbamate R 2 To a solution of the -pyridyl-Suzuki coupling product 28-Boc (60 mg, crude) in dichloromethane (1 mL) was added trifluoroacetic acid (462 mg, 4.05 mmol, 0.30 mL). The mixture was stirred at 30 °C for 0.5 h and, upon completion, concentrated under reduced pressure to a residue. The concentrated residue 29 was purified by preparative HPLC according to any of the purification methods in 4-1 to 4-13. [ka]

[0426] Step 1: A mixture of the appropriate aryl / heteroaryl boronic acid ester (303 μmol, 1.16 equiv.), intermediate F (100 mg, 260 μmol, 1.00 equiv.), Pd(dppf)Cl (19 mg, 26 μmol, 0.10 equiv.), and sodium bicarbonate (66 mg, 781 μmol, 30 μL, 3.00 equiv.) in dioxane (1 mL) and water (0.20 mL) was degassed and purged with nitrogen three times and stirred at 80 °C under a nitrogen atmosphere for 1 h. The mixture was then filtered and concentrated under reduced pressure to give a residue. The concentrated residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate 10:1 to 0:1) to give the corresponding Suzuki coupling product 15a (12.0 mg, crude) as a yellow solid.

[0427] Step 2: To a solution of the corresponding Suzuki coupling product 15a (10 mg, crude) in ethyl alcohol (1.0 mL) was added hydrazine hydrate (10 mg, 207 μmol, 10 μL). The mixture was stirred at 80 °C for 1 h, cooled, and then concentrated under reduced pressure. The concentrated residue 7a was then purified by preparative HPLC according to one of the purification methods 4-1 to 4-13 described herein. [ka]

[0428] Step 1: Intermediate J (69 mg, 17 μmol, 1.30 equiv), aryl / heteroaryl-halide 26 (132 μmol, 1.0 equiv), Pd(dtbpf)Cl (9 mg, 13 μmol, 0.10 equiv), sodium carbonate (28 mg, 263 μmol, 2.00 equiv) in dioxane (1.5 mL) and water (0.30 mL) was purged three times with nitrogen and stirred at 80 °C for 2 h. The mixture was then concentrated and the residue was purified by preparative TLC (SiO, CHCl:MeOH 20:1) to give R 1 The -Suzuki coupling product 28-Boc was obtained, which was used directly in the next step without further purification.

[0429] Step 2: tert-Butyl N-[[4-oxo-7-(R1) To a solution of the Suzuki coupling product 28-Boc (40 mg) of 3H-phthalazin-1-ylmethylcarbamate in dichloromethane (1.5 mL) was added trifluoroacetic acid (5.4 mmol, 0.4 mL). The mixture was stirred at 25°C for 0.5 h and, upon completion, concentrated under reduced pressure to a residue. The concentrated residue 29 was purified by preparative HPLC according to any of the purification methods in 4-1 to 4-13. [ka]

[0430] Step 1: Intermediate J (80 mg, 0.20 mmol, 1.00 equiv), aryl / heteroaryl halide in 2-methyl-2-butanol (2.00 mL) and water (0.4 mL) A mixture of 26 (239 μmol, 1.2 equiv.), [2-(2-aminophenyl)phenyl]chloropalladium; dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (14.4 mg, 19.9 μmol, 0.10 equiv.), and sodium bicarbonate (34 mg, 398 μmol, 2.00 equiv.) was purged with nitrogen three times and stirred at 80 °C for 3 h. The mixture was then diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 1:1.5) to give R 1 -Suzuki coupling product 28-Boc was obtained, which was used further.

[0431] Step 2: tert-Butyl N-[[4-oxo-7-(R 1 A solution of the Suzuki coupling product 28-Boc (0.08 mmol, 1.00 equiv.) in HCl·dioxane (2.00 mL, 101 equiv.) was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC according to one of the purification methods described in 4-1 to 4-13. [ka]

[0432] Step 1: A solution of intermediate J (80 mg, 0.20 mmol, 1.00 equiv.), aryl / heteroaryl-halide 26 (0.24 mmol, 1.2 equiv.), methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (20 μmol, 0.10 equiv.), potassium phosphate 0.40 mmol, 2.00 equiv. in n-butanol (2.0 mL) and water...

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ is -L-CN, -Y-cycloalkyl, -Y-heterocyclyl, -Y-aryl, -Y-arC1-C3 alkyl, or -Y-heteroaryl, and said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl moieties each contain one or more R ２ is optionally replaced by Each Y is independently a bond or —NR ４ - and Each R ２ are independently selected from hydroxy, halogen, cyano, cyanomethyl, -(NR ４ ) ２ , hydroxyalkyl, alkoxy, -SO ２ C1-C3 alkyl, -X-arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclyl, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl, or -X-heteroaryl, wherein said heterocyclyl, said cycloalkyl, said aryl, and said heteroaryl are each independently selected from one or more R ５ optionally replaced by, or Each X is independently a bond, O, S, or —NR ４ -or-NR ４ C(O)—, Each Z is independently a bond, —SO—, or —SO ２ -, -CH(OH)-, or -C(O)-; each L is independently a bond or C1-C3 alkylene; R ３ａ and R ３ｂ are each independently hydrogen or deuterium, or R ３ａ and R ３ｂ But together, it is Oxo, Each R ４ are independently hydrogen or C1-C3 alkyl; Each R ５ are independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, —X-haloalkyl, -Z-cycloalkyl, —X-arC1-C3 alkyl, X-arC1-C3 alkyl substituted with cyano, —XL-cycloalkyl, —XL-heteroaryl optionally substituted with one or more C1-C3 alkyl or oxo, or —X-aryl; and R ６ is hydrogen, halogen, C1-C3 alkyl, haloalkyl, or alkoxy, or a pharmaceutically acceptable salt thereof.

2. R １ But there are one or more R ２ -Y-heteroaryl optionally substituted with Y is a bond and said heteroaryl is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, oxidazolyl, pyridyl, pyridiazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrazolopyridinyl, 1H-pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridyl, tetrahydropyrazolopyrazinyl, oxazolopyridyl, or 5,6-dihydro-8H-imidazooxazinyl, each of which is selected from one or more R ２ 2. The compound of claim 1, optionally substituted with

3. The heteroaryl may be one, two, or three R ２ The compound of claim 2, which is pyrazolyl optionally substituted with a group.

4. The pyrazolyl is one R ２ 4. The compound of claim 3 , substituted with:

5. The pyrazolyl is selected from two independently selected R ２ 4. The compound of claim 3 , substituted with:

6. The two R ２ The groups are (1) independently -t-X-C1-C5 alkyl, (2) -X-C1-C5 alkyl and halogen, (3) -X-C1-C5 alkyl and alkoxy, and (4) -X-C1-C5 alkyl and -N(R ４ ) ２ , (5) —X—C1-C5 alkyl and —X-haloalkyl, (6) —X—C1-C5 alkyl and arC1-C3 alkyl, (7) —X—C1-C5 alkyl and —XL-cycloalkyl, (8) —X—C1-C5 alkyl and -heterocyclyl, (9) —X—C1-C5 alkyl and one or more R ５ (10) —X—C1-C5 alkyl optionally substituted with —X-aryl, (11) —X—C1-C5 alkyl, and one or more R ５ (11) —X—C1-C5 alkyl and cyanomethyl, (12) —X—C1-C5 alkyl and cyano, (13) cyano and halogen, wherein the halogen is chlorine or fluorine, (14) cyano and —X-L-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-arC1-C3 alkyl, or X-arC1-C3 alkyl substituted with cyano, and (21) halogen and —X-aryl.

7. The compound of claim 1 having the formula (ID): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

8. The compound is 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 [Chemistry 3-4] [Transformation 3-5] [Chemistry 3-6] 【Chemistry 3-7】 【Transformation 3-8】 【Chemistry 3-9】 【Chemistry 3-10】 【Chemistry 3-11】 【Chemistry 3-12】 【Chemistry 3-13】 【Chemistry 3-14】 【Chemistry 3-15】 【Chemistry 3-16】 【Chemistry 3-17】 【Chemistry 3-18】 【Chemistry 3-19】 【Chemistry 3-20】 10. The compound of claim 1, which is:

9. The compound is 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

10. The compound of formula (I) 【Transformation 5】 2. The compound of claim 1, wherein:

11. The compound of formula (I) is represented by the formula 【Transformation 6】 2. The compound of claim 1, which is a pharmaceutically acceptable salt of the compound of formula:

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

13. 13. The pharmaceutical composition of claim 12 for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity is desired with the pharmaceutical composition.

14. A method for inhibiting PRMT5 activity in a cell in vitro, comprising contacting the cell in which inhibition of PRMT5 activity is desired with an effective amount of a compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 12.

15. The pharmaceutical composition according to claim 12 for treating cancer.

16. The cancer is cardiac: 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, chondroitin hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca sarcoma 16. The pharmaceutical composition of claim 15, wherein the therapeutic agent is selected from the group consisting of: cutaneous (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); cutaneous: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

17. The pharmaceutical composition of claim 15 or 16, wherein the cancer is an MTAP-associated cancer.

18. The pharmaceutical composition according to claim 15 or 16, wherein the cancer is hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.

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