Mta-cooperative prmt5 inhibitors

Abstract

The present invention relates to compounds that inhibit Protein Arginine N-Methyl Transferase 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.

Description

MTA-COOPERATIVE PRMT5 INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 62 / 899,575, filed September 12, 2019, U.S. Provisional Application No. 62 / 942,833, filed December 3, 2019, U.S. Provisional Application No. 62 / 961,371, filed January 15, 2020, U.S. Provisional Application No. 62 / 994,927, filed March 26, 2020, and U.S. Provisional Application No. 63 / 060,261, filed August 3, 2020, the disclosure of each of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The present invention relates to compounds that are MTA-cooperative inhibitors of Protein Arginine N-Methyl Transferase 5 (PRMT5). In particular, the present invention relates to compounds, pharmaceutical compositions comprising the compounds and methods for use therefor.BACKGROUND OF THE INVENTION

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

[0004] Homozygous deletions of pl6 / CDKN2a are prevalent in cancer and these mutations commonly involve the co-deletion of adjacent genes, including the gene encoding methylthioadenosine phosphorylase (MTAP). It is estimated that approximately 15% of all human cancers have a homozygous deletion of the MTAP gene (e.g., see Firestone & Schramm (2017) J. Am. Chem Soc. 139(39):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), which is a potent inhibitor of PRMT5. Inhibition of PRMT5 activity results in reduced methylation activity and increased sensitivity of cellular proliferation to PRMT5 depletion or loss of activity. Hence, the loss of MTAP activity reduces methylation activity of PRMT5 making the cells selectively dependent on PRMT5 activity.SUMMARY OF THE INVENTION

[0006] Thus, we realized that MTA-cooperative inhibition of PRMT5 activity in MTAP deleted cancers will provide therapeutic benefit for a wide range of cancers. The compounds of the present invention provide this therapeutic benefit as MTA-cooperative inhibitors of PRMT5 that negatively modulate the activity of MTA-bound PRMT5 in a cell, particularly an MTAP-deficient cell, or for treating various forms of MTAP-associated cancer.

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

[0008] In one aspect of the invention, compounds are provided that are represented by Formula (I):Formula (I)

[0009] and pharmaceutically acceptable salts thereof:

[0010] wherein:

[0010] R1is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-C1 - C5 alkyl, -Y-cycloalkyl, -Y- heterocyclyl, -Y-aryl, -Y-arC1-C3 alkyl or -Y-heteroaryl, wherein the cycloalkyl, theheterocyclyl, the aryl, and the heteroaryl portions are each optionally substituted with one or more R2;

[0011] each Y is independently a bond or -NR4-;

[0012] each R2is independently hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SO2C1 – C3alkyl, -X-arC1-C3alkyl, 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 the heterocyclyl, the cycloalkyl, the aryl and the heteroaryl are optionally substituted with one or more R5;

[0013] each X is independently a bond, O, S, -NR4- or -NR4C(O)-

[0014] each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-;

[0015] each L is independently a bond or C1 – C3 alkylene;

[0016] R3aand R3bare each independently hydrogen or deuterium, or R3aand R3btogether are oxo;

[0017] each R4is independently hydrogen or C1 – C3 alkyl;

[0018] each R5is independently cyano, oxo, halogen, C1 – C3 alkyl, hydroxyalkyl, alkoxy, - X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3alkyl, X-arC1-C3alkyl substituted with cyano -X-L- cycloalkyl, -X-L-heteroaryl optionally substituted with one or more C1-C3alkyl or oxo, or -X- aryl; and

[0019] R6is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

[0020] In one aspect of the invention, compounds are provided that are represented by Formula (I-A):Formula (I-A)or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R3b, R4, R5, R6, Y, X, Z and L are as each defined for Formula I.

[0021] In one aspect of the invention, compounds are provided that are represented by Formula (I-B):Formula (I-B) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R3b, R4, R5, R6, Y, X, Z and L are as each defined for Formula I.

[0022] In one aspect of the invention, compounds are provided that are represented by Formula (I-C):Formula (I-C) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R3b, R4, R5, R6, Y, X, Z and L are as each defined for Formula I.

[0023] In another aspect of the invention, compounds are provided that are represented by Formula (I-D):or a pharmaceutically acceptable salt thereof: wherein: each Y is independently a bond or -NR4-; each R2is independently hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SO2CI - 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 the heterocyclyl, the cycloalkyl, the aryl and the heteroaryl are optionally substituted with one or more R5, or; each X is independently a bond, O, S, -NR4- or -NR4C(0)-; each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-; each L is independently a bond or C1 - C3 alkylene; each R4is independently hydrogen or C1 - C3 alkyl; each R5is independently cyano, oxo, halogen, C1 - C3 alkyl, hydroxyalkyl, alkoxy, - X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, X-arC1-C3 alkyl substituted with cyano, -X-L-cycloalkyl, -X-L-heteroaryl optionally substituted with one or more C1-C3alkyl or oxo, or -X-aryl; andR6is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

[0024] In another aspect of the invention, intermediates are provided that are useful for the preparation of compounds of Formula (I), Formula (I-A), Formula (I-B) and Formula (I-C).

[0025] In another aspect of the invention, pharmaceutical compositions are provided comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0026] In yet another aspect of the invention, methods for inhibiting PRMT5 activity in a in a cell, comprising contacting the cell with a compound of Formula (I), Formula (I-A), Formula (I-B) and Formula (I-C). In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0027] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (I-C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. In one embodiment, the cell is an MTAP-deficient cell.

[0028] Also provided are methods for treating cancer in a patient comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0029] Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with 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 (I-A), Formula (I-B), Formula (I-C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention relates to MTA-cooperative PRMT5 inhibitors. In particular, the present invention relates to compounds that inhibit PRMT5 activity in the presence of bound MTA, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of use therefor.DEFINITIONS

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference to the extent they are consistent with the present disclosure. Terms and ranges have their generally defined definition unless expressly defined otherwise.

[0032] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety generally refers to a monovalent radical (e.g. CH3-CH2-), in certain circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term “alkylene.” (Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).

[0033] As used herein, “PRMT5” refers to a mammalian Protein Arginine N-Methyl Transferase 5 (PRMT5) enzyme.

[0034] As used herein, a “PRMT5 inhibitor” or “MTA-cooperative PRMT5 inhibitor” refers to compounds of the present invention that are represented by Formula (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of the PRMT5 in the presence of bound MTA in vitro or in vivo, or in cells expressing elevated levels of MTA.

[0035] As used herein, “MTAP” refers to a mammalian methylthioadenosine phosphorylase (MTAP) enzyme.

[0036] An “MTAP-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a loss of MTAP activity resulting in sensitizing the disorder to selective inhibition of PRMT5 activity. A non-limiting example of an MTAP-associated disease or disorder is an MTAP-associated cancer.

[0037] The term “amino” refers to –NH2.

[0038] The term “acetyl” refers to “-C(O)CH3.

[0039] As herein employed, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.

[0040] The term "alkyl" as employed herein refers to saturated straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, “alkyl” encompasses C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11and C12groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0041] The term "alkenyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, “alkenyl” encompasses C2, C3, C4, C5, C6, C7, C8, C9, C10, C11and C12groups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0042] The term "alkynyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms. As such, “alkynyl” encompasses C2, C3, C4, C5, C6, C7, C8, C9, C10, C11and C12groups. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0043] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Exemplary alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Exemplary alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.

[0044] The term “alkoxy” refers to –OC1 – C6 alkyl.

[0045] The term "cycloalkyl" as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. As such, “cycloalkyl” includes C3, C4, C5, C6, C7, C8, C9, C10, C11and C12cyclic hydrocarbon groups. Examples of cycloalkyl groupsinclude, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0046] The term "heteroalkyl" refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced O, S, or NRx, wherein Rxis hydrogen or C1 – C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl and methoxypropyl.

[0047] An "aryl" group is a C6-C14aromatic moiety comprising one to three aromatic rings. As such, “aryl” includes C6,C10, C13, and C14cyclic hydrocarbon groups. An exemplary aryl group is a C6-C10aryl group. Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An “aryl” group also includes fused multicyclic (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.

[0048] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group wherein the moiety is linked to another group via the alkyl moiety. An exemplary aralkyl group is –(C1 - C6)alkyl(C6 - C10)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. For example, an arC1-C3alkyl is an aryl group covalently linked to a C1-C3 alkyl.

[0049] A "heterocyclyl" or "heterocyclic" group is a mono- or bicyclic (fused or spiro) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently –C(O)-, N, NR4, O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons. Examples of heterocyclic groups include, without limitation, 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.

[0050] As used herein, “L-heterocyclyl” refers to a heterocyclyl group covalently linked to another group via an alkylene linker

[0051] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms; having 6, 10, or 14 p electrons shared in a cyclicarray; and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S. “Heteroaryl” also includes fused multicyclic ( 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 and at least one ring contains an N, O, or S ring atom.

[0052] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][l,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH- carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, lH-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, oxazolyl, 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, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0053] A "L-heteroaralkyl" or "L-heteroarylalkyl" group comprises a heteroaryl group covalently linked to another group via an alkylene linker. Examples of heteroalkyl groups comprise a C1- C6alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolyl ethyl, 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 O and / or S atoms.

[0054] An "arylene," " heteroaryl ene," or "heterocyclylene" group is a bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.

[0055] As employed herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as “optionally substituted” without expressly stating the substituents it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents.

[0056] The term "halogen" or "halo" as employed herein refers to chlorine, bromine, fluorine, or iodine.

[0057] The term “haloalkyl” refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, flurochloromethyl, chloromethyl, and fluorom ethyl.

[0058] The term “hydroxyalkyl” refers to -alkylene-OH.

[0059] As used herein, “an effective amount” of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of PRMT5 enzyme.

[0060] As used herein, a “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of PRMT5. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0061] As used herein, “treatment” means any manner in which the symptoms or pathology of a condition, disorder or disease in a patient are ameliorated or otherwise beneficially altered.

[0062] As used herein, “amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition” refers to any lessening, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.COMPOUNDS

[0063] In one aspect of the invention, compounds are provided that are represented by Formula (I):Formula (I)

[0064] or a pharmaceutically acceptable salt thereof:

[0065] wherein:

[0066] R1is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-C1 - C5 alkyl, -Y-cycloalkyl, -Y- heterocyclyl, -Y-aryl, -Y-arC1-C3 alkyl or -Y-heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl portions are each optionally substituted with one or more R2;

[0067] each Y is a bond or -NR4-;

[0068] each R2is independently hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SO2CI - 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 the heterocyclyl, the cycloalkyl, the aryl and the heteroaryl are optionally substituted with one or more R5;

[0069] each X is independently a bond, O, S, -NR4- or -NR4C(0)-;

[0070] each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-;

[0071] each L is independently a bond or C1 - C3 alkylene;

[0072] R3aand R3bare each independently hydrogen or deuterium, or R3aand R3btogether are oxo;

[0073] each R4is independently hydrogen or C1 - C3 alkyl;

[0074] each R5is independently cyano, oxo, halogen, C1 – C3 alkyl, hydroxyalkyl, alkoxy, - X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3alkyl, X-arC1-C3alkyl substituted with cyano, -X-L- cycloalkyl, -X-L-heteroaryl optionally substituted with one or more C1-C3alkyl or oxo, or -X- aryl; and

[0075] R6is hydrogen, halogen, haloalkyl, C1-C3 alkyl or alkoxy.

[0076] In one embodiment for compounds of Formula (I), R1is hydrogen.

[0077] In another embodiment for compounds of Formula (I), R1is halogen. In certain embodiments, the halogen is bromine.

[0078] In one embodiment for compounds of Formula (I), R1is -L-CN. In one embodiment, L is C1 – C3 alkylene. In certain embodiments, the C1 – C3 alkylene is methylene.

[0079] In one embodiment for compounds of Formula (I), R1is -Y-C1 – C5 alkyl. In one embodiment, Y is a bond and the C1 – C5 alkyl is methyl. In one embodiment, Y is -NR4- and the C1 – C5 alkyl is methyl, ethyl or propyl.

[0080] In one embodiment for compounds of Formula (I), R1is hydroxyalkyl.

[0081] In one embodiment for compounds of Formula (I), R1is -Y-heterocyclyl. In certain embodiments, Y is a bond and the heterocyclyl is azetidinyl, THFyl or morpholinyl.

[0082] In one embodiment for compounds of Formula (I), R1is -Y-aryl wherein the aryl is optionally substituted with one or more R2.

[0083] In certain embodiments, Y is a bond and the aryl is phenyl optionally substituted with one or two R2. In one embodiment, the one or two R2groups are each independently C1 – C3 alkyl, cyano or halogen.

[0084] In one embodiment for compounds of Formula (I), R1is -Y-cycloalkyl. In one embodiment, Y is a bond and the cycloalkyl is cyclopentyl.

[0085] In one embodiment for compounds of Formula (I), R1is -Y-heteroaryl optionally substituted with one or more R2. In certain embodiment, the heteroaryl is, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, oxidazolyl, pyridyl, pyridiazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrazolopyridinyl, 1H-pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridyl, tetrahydropyrazolopyrazinyl, 2H-4ƛ4-imidazopyrimidinyl, 2H-4ƛ4-imidazopyridazinyl, oxazolopyridyl or 5,6-dihydro-8H- imidazooxazinyl, each optionally substituted with one or more R2. In one embodiment, Y is a bond.

[0086] In one embodiment, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is azetidinyl and R2is -(NR4)2.

[0087] In one embodiment, R1is heteroaryl, Y is a bond and the heteroaryl is tetrahydropyrazolopyrazinyl, optionally substituted with one or more R2. In one embodiment, the tetrahydropyrazolopyrazinyl is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl optionally substituted with one or more R2. In one embodiment, the tetrahydropyrazolopyrazinyl is substituted with one R2. In one embodiment, R2is -X-C1-C5 alkyl, arC1-C3alkyl, -Z-C1-C5 alkyl, -Z-cycloalkyl or -X-aryl. In one embodiment, R2is -Z-cycloalkyl, wherein Z is a bond and the cycloalkyl is cyclopropyl. In one embodiment, R2is -Z-cycloalkyl, wherein Z is - C(O)- and the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl.

[0088] In one embodiment wherein R1is Y-heteroaryl, Y is a bond and the heteroaryl is pyrazolopyridinyl optionally substituted with one or more R2. In one embodiment, the pyrazolylpyridinyl is substituted with one R2, wherein the one R2is alkoxy or -X-aryl. In one embodiment, the alkoxy is methoxy or isopropyloxy. In certain embodiments, the -X-aryl, the X is O and the aryl is phenyl.

[0089] In one embodiment, Y is a bond and the R1heteroaryl is pyridyl, optionally substituted with one or two R2. In certain embodiments, the pyridyl is substituted with one R2, wherein R2is hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SO2C1 – C3alkyl, arC1-C3alkyl, 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 the heterocyclyl, the cycloalkyl, the aryl and the heteroaryl are optionally substituted with one or more R5.

[0090] In one embodiment, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is -X-C1 – C5 alkyl, X is a bond and the C1 – C5 alkyl is methyl, ethyl propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl.

[0091] In one embodiment, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is -X-haloalkyl, X is a bond and the haloalkyl is difluoromethyl or trifluoromethyl. Inanother embodiment, R2is -X-haloalkyl, wherein X is O, and wherein the haloalkyl is difluoromethyl or trifluoromethyl.

[0092] In one embodiment, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is -X-L-cycloalkyl, wherein X is a bond, L is a bond and the cycloalkyl is cyclopropyl or cyclohexyl. In another embodiment, R2is -X-L-cycloalkyl, wherein X is a bond, L is methylene and the cycloalkyl is cyclopropyl. In one embodiment, R2is -X-L-cycloalkyl, wherein X is O, L is methylene and the cycloalkyl is cyclopropyl.

[0093] In one embodiment, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is C2-C4 alkynyl, wherein the alkynyl is ethynyl or prop-2-ynyl.

[0094] In another embodiment, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is -SO2C1 – C3 alkyl, wherein the C1 – C3 alkyl is methyl.

[0095] In one embodiment, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is heterocyclyl, wherein the heterocyclyl is morpholinyl or tertrahydropyranyl.

[0096] In other embodiments, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is -X-heteroaryl, wherein the heteroaryl is optionally substituted with one or more R5. In one embodiment, X is a bond, the heteroaryl is pyrazolyl substituted with one R5, wherein R5is C1- C3 alkyl. In one embodiment, X is a bond, the heteroaryl is pyridyl or pyrimidinyl, each optionally substituted with one R5.

[0097] In one embodiment, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is arC1-C3alkyl, wherein the arC1-C3alkyl is benzyl.

[0098] In one embodiment wherein R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is -X-heteroaryl, wherein the X is O, and the heteroaryl is quinolinyl optionally substituted with one or more R5. In another embodiment, the X is -NR4-, and the heteroaryl is quinolinyl optionally substituted with one or more R5.

[0099] In one embodiment, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is -X-aryl, wherein X is O and the aryl is phenyl optionally substituted with one, two or three R5. In one embodiment, each of the one, two or three R5groups 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 phenyl optionally substituted with one R5, wherein R5is halogen or C1-C3 alkyl. In one embodiment, X is O and the aryl is phenyl optionallysubstituted with two R5groups, wherein each R5group is independently cyano. In one embodiment, X is -NR4- and the aryl is phenyl optionally substituted with two R5groups, wherein each R5group is independently alkoxy. In certain embodiments, each alkoxy is methoxy.

[0100] In one embodiment, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is halogen, wherein the halogen is chlorine or fluorine. In one embodiment, R1is -Y- heteroaryl, Y is a bond and the heteroaryl is pyridyl and R2is-X-L-cycloalkyl, heterocyclyl or -X-aryl, wherein the aryl is optionally substituted with one or more R5. In one embodiment, R2is-X-L-cycloalkyl, wherein X and L are each a bond and the cycloalkyl is cyclohexyl. In one embodiment, R2is heterocyclyl, wherein the heterocyclyl is tetrahydropyranyl. In one embodiment, R2is -X-aryl, wherein the aryl is phenyl substituted with two R5, wherein each R5is cyano.

[0101] In certain embodiments, R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl substituted with two R2. In one embodiment, each R2is independently -X-C1 – C5 alkyl or one R2is halogen or cycloalkyl and the second R2is -X-C1 – C5 alkyl, wherein X is a bond.

[0102] In one embodiment for compounds of Formula (I), R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyrimidinyl, optionally substituted with one or two R2. In one embodiment, the pyrimidinyl is substituted with one R2, wherein R2is -X-C1 – C5 alkyl or - X-haloalkyl. In one embodiment, each X is a bond.

[0103] In one embodiment for compounds of Formula (I), R1is -Y-heteroaryl, Y is a bond and the heteroaryl is quinolinyl, optionally substituted with one or two R2. In certain embodiments, the one R2group is cyano. In certain embodiments, one R2group is cyano and the second R2is halogen or -X-C1 C5 alkyl.

[0104] In one embodiment for compounds of Formula (I), R1is -Y-heteroaryl, Y is a bond and the heteroaryl is isothiazolyl, optionally substituted with one or two R2. In one embodiment, R2is -X-aryl optionally substituted with one R5, wherein the aryl is naphthyl substituted with one R5, wherein R5is cyano.

[0105] In one embodiment for compounds of Formula (I), R1is -Y-heteroaryl, Y is a bond and the heteroaryl is pyrazolyl, optionally substituted with one, two or three R2groups.

[0106] In certain embodiments, the pyrazolyl is substituted with one R2, wherein R2is cyano, -X-C1 – C5 alkyl, hydroxyalkyl, arC1-C3alkyl or -X-aryl, wherein the aryl is optionally substituted with one or more R5. In one embodiment, R2is -X-C1 – C5 alkyl, wherein X is a bond and the C1 - C5 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl.

[0107] In other embodiments, the pyrazolyl is substituted with two R2groups, wherein the two R2groups are independently (1) -X-C1 – C5 alkyl, (2) -X-C1 – C5 alkyl and halogen, (3) -X-C1 – C5 alkyl and alkoxy, (4) -X-C1 – C5 alkyl and -N(R4)2, -(5) X-C1 – C5 alkyl and -X- haloalkyl, (6) -X-C1 – C5 alkyl and arC1-C3alkyl, (7) -X-C1 – C5 alkyl and -X-L- cyclolalkyl, -(8) -X-C1 – C5 alkyl and -heterocyclyl, (9) -X-C1 – C5 alkyl and -X-aryl optionally substituted with one or more R5, (10) -X-C1 – C5 alkyl and -X-heteroaryl optionally substituted with one or more R5, (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-C3alkyl or X-arC1-C3alkyl substituted with cyano, and (21) halogen and -X-aryl.

[0108] In one embodiment wherein R1is pyrazolyl, the pyrazolyl is substituted with two R2, wherein one R2is -X-C1 – C5 alkyl and the second R2is -X-aryl optionally substituted with one or more R5. In one embodiment, each X is a bond and the aryl is phenyl substituted with two R5, wherein (1) each R5is independently -X-C1 – C5 alkyl, wherein X is a bond; (2) one R5is cyano and one R5is -X-C1 – C5 alkyl, wherein X is a bond; (3) one R5is cyano and one R5is -X-L-cycloalkyl, wherein X is a bond and L is a bond, methylene or ethylene; (4) one R5is cyano and one R5is halogen; (5) one R5is cyano and one R5is alkoxy; (6) each R5is independently cyano or (7) each R5is independently halogen.

[0109] In one embodiment wherein R1is pyrazolyl, the pyrazolyl is substituted with two R2, wherein one R2is -X-C1 – C5 alkyl and the second R2is -X-aryl optionally substituted with one or more R5. In one embodiment, the X is a bond and the aryl is naphthyl substituted with one R5, wherein R5is cyano or halogen. In one embodiment, the naphthyl is substituted with two R5groups, wherein one R5is cyano and the second R5is halogen, alkoxy or cyano. In one embodiment, the naphthyl is substituted with three R5groups, wherein one R5is cyano and the second R5is X-haloalkyl and the third R5is -X-L-cycloalkyl.

[0110] In one embodiment wherein R1is pyrazolyl, the pyrazolyl is substituted with two R2, wherein one R2is -X-C1 – C5 alkyl and the second R2is -X-aryl optionally substituted with one or more R5. In one embodiment, the X is a bond and the aryl is phenyl substituted with three R5, wherein (1) each R5is independently -X-C1 – C5 alkyl, wherein each X is a bond; (2) one R5is cyano and two R5are-X-C1 – C5 alkyl, wherein each X is a bond; (3) one R5is cyano, one R5is halogen, and one R5is -X-C1 – C5 alkyl, wherein X is a bond; (4) one R5is cyano and two R5are alkoxy, (5) one R5is cyano and two R5are halogens (6) one R5is cyano, one R5is halogen and one R5is alkoxy, (7) or one R5is cyano, one R5is halogen, and one R5is -X-L-cycloalkyl.

[0111] In one embodiment wherein R1is pyrazolyl, the pyrazolyl is substituted with two R2, wherein one R2is -X-C1 – C5 alkyl and the second R2is -X-heteroaryl optionally substituted with one or more R5. In one embodiment, each X is a bond and the heteroaryl is quinolinyl, pyrazolyl, chromanyl, indolizinyl, dihydrobenzylfuranyl or imidzaopyridinyl, each optionally substituted with one or more R5.

[0112] In one embodiment, the pyrazolyl is substituted with three R2, wherein each R2is independently -X-C1 – C5 alkyl and each X is a bond.

[0113] In one embodiment wherein R1is pyrazolyl, the pyrazolyl is substituted with three R2, wherein (1) one R2is cyano and two R2are halogen; (2) one R2is cyano, one R2is halogen and one R2is alkoxy. In other embodiments, one R2is alkoxy, and two R2are independently halogen

[0114] In one embodiment for compounds of Formula (I), R1is -Y-heteroaryl, Y is a bond and the heteroaryl is imidazolyl, 1H-pyrrolopyridyl, tetrahydropyrazolopyrazinyl, 2H-4ƛ4- imidazopyrimidinyl, 2H-4ƛ4-imidazopyridazinyl, or oxazolopyridyl, each substituted with one R2group, wherein R2is -X-C1 – C5 alkyl, wherein X is a bond. In one embodiment, the heteroaryl is 1H-pyrrolopyridyl substituted with one R2, wherein R2is cyano or -X-aryl. In certain embodiments, the X of the -X-aryl is a bond and the aryl is phenyl. In one embodiment, the heteroaryl is imidazolyl substituted with one R2, wherein R2is hydroxyalkyl or -X-aryl.

[0115] In one embodiment for compounds of Formula (I), R1is -Y-heteroaryl, Y is a bond and the heteroaryl is imidazopyridyl substituted with one R2group, wherein R2is cyano, alkoxy, halogen or -X-C1 – C5 alkyl. In other embodiments, the heteroaryl is imidazopyridylsubstituted with two R2groups, wherein one R2is halogen and the second R2group is -X-C1 – C5 alkyl or halogen.

[0116] In one embodiment for compounds of Formula (I), R1is -Y-aryl, Y is -NR4- and the aryl is phenyl optionally substituted with one or more R5.

[0117] In one embodiment, R1is -Y- arC1-C3alkyl. In one embodiment, Y is -NR4- and the arC1-C3alkyl is benzyl.

[0118] In one embodiment, R3aand R3bare each hydrogen. In another embodiment, R3aand R3bare each deuterium. In certain embodiments, one of R3aand R3bis hydrogen and the other is deuterium. In one embodiment, R3aand R3btaken together are oxo.

[0119] In one embodiment, each R4is hydrogen. In one embodiment, each R4is independently C1 – C3 alkyl. In one embodiment, one R4is hydrogen and the other R4is C1 – C3 alkyl.

[0120] In one embodiment, the cycloalkyl, aryl or heteroaryl rings are optionally substituted with one or more R5, wherein R5is cyano, oxo, halogen, C1 – C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3alkyl, -X-L-cycloalkyl or -X-aryl.

[0121] In one embodiment, R6is hydrogen. In one embodiment, R6is halogen. In certain embodiments, the halogen is chlorine or fluorine. In one embodiment, R6is C1 – C3 alkyl. In certain embodiments, the C1 – C3 alkyl is methyl or ethyl. In one embodiment, R6is alkoxy. In certain embodiments, the alkoxy is methoxy. In one embodiment, R6is haloalkyl. In certain embodiments, the haloalkyl is trifluoromethyl.

[0122] In one aspect of the invention, compounds are provided that are represented by Formula (I-A):Formula (I-A)

[0123] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R3b, R4, R5, R6, Y, X, Z, and L are as each defined for Formula I.

[0124] In one aspect of the invention, compounds are provided that are represented by Formula (I-B):Formula (I-B)

[0125] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R3b, R4, R5, R6, Y, X, Z, and L are as each defined for Formula I.

[0126] In one aspect of the invention, compounds are provided that are represented by Formula (I-C):Formula (I-C)

[0127] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R3b, R4, R5, R6, Y, X, Z and L are as each defined for Formula I.

[0128] In another aspect of the invention, compounds are provided that are represented by Formula (I-D):Formula (I-D) or a pharmaceutically acceptable salt thereof: wherein: each Y is independently a bond or -NR4-; each R2is independently hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SO2C1 – C3alkyl, -X-arC1-C3alkyl, 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 the heterocyclyl, the cycloalkyl, the aryl and the heteroaryl are optionally substituted with one or more R5, or; each X is independently a bond, O, S, -NR4- or -NR4C(O)-; each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-; each L is independently a bond or C1 – C3 alkylene; each R4is independently hydrogen or C1 – C3 alkyl; each R5is independently cyano, oxo, halogen, C1 – C3 alkyl, hydroxyalkyl, alkoxy, -X- haloalkyl, -Z-cycloalkyl, -X-arC1-C3alkyl, X-arC1-C3alkyl substituted with cyano, -X-L- cycloalkyl, -X-L-heteroaryl optionally substituted with one or more C1-C3alkyl or oxo, or - X-aryl; and  R6is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

[0129] In one embodiment, the compound of Formula (I), Formula (I-A), Formula (I- B),and / or Formula (I-C) is:,and pharmaceutically acceptable salts of the foregoing compounds.

[0130] In one embodiment, the compound of Formula (I) is:or a pharmaceutically acceptable salt of the foregoing compounds.

[0131] The compounds of Formula (I), Formula (I-A), Formula (I-B) and Formula (I-C) may be formulated into pharmaceutical compositions. PHARMACEUTICAL COMPOSITIONS

[0132] In another aspect, the invention provides pharmaceutical compositions comprising a PRMT5 inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain embodiments, compounds of the invention are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be by the oral route.

[0133] The characteristics of the carrier will depend on the route of administration. As used herein, the term “pharmaceutically acceptable” means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington’s Pharmaceutical Sciences, 18thEdition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0134] As used herein, the term “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as 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 can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula –NR+Z-,wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0135] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt / wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity 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.

[0136] The pharmaceutical compositions comprising compounds of the present invention may be used in the methods described herein. METHODS OF USE

[0137] In yet another aspect, the invention provides for methods for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity is desired in vitro with an effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B) or Formula (I-C), pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof. In one embodiment, the cell is an MTAP-deficient cell.

[0138] The compositions and methods provided herein are particularly deemed useful for inhibiting PRMT5 activity in a cell in vivo. In one embodiment, a cell in which inhibition of PRMT5 activity is desired is contacted in vivo with a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), or Formula (I-C), or a pharmaceutically acceptable salt thereof, to negatively modulate the activity of PRMT5. In other embodiments, a therapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing the compound of Formula (I), Formula (I-A), Formula (I-B) or Formula (I-C) may be used. In one embodiment, the cell is an MTAP-deficient cell. In one embodiment, the negatively modulating the activity of PRMT5 occurs in the presence of bound MTA.

[0139] By negatively modulating the activity of PRMT5, particularly in cases for cells that lack MTAP activity, the methods are designed to inhibit PRMT5 activity to block cellular proliferation. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to affect the desired negative modulation of PRMT5. The degree PRMT5 inhibition may be monitored in vitro against the enzyme in the presence and absence of MTA and in the cell using well known methods, including those described in Example B below, to assess the effectiveness of treatment and dosages.

[0140] In another aspect, methods of treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula (I), Formula (I- A), Formula (I-B) of Formula (I-C), pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided. In one embodiment, the cancer is an MTAP-associated cancer.

[0141] The compositions and methods provided herein may be used for the treatment of a wide variety of cancer including tumors such as prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: 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, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm’s tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cellcarcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder 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, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli- Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin’s disease, non-Hodgkin’s lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0142] 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.

[0143] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. GENERAL REACTION SCHEMES, INTERMEDIATES AND EXAMPLES GENERAL REACTION SCHEMES

[0144] The compounds of the present 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.

[0145] For instance, intermediates for preparing compounds and compounds of Formula (I), Formula (I-A), Formula (I-B) or Formula (I-C) of the present invention may be prepared according to General Reaction Schemes I - XVI: GENERAL REACTION SCHEME I

[0146] Compounds of Formula (I) wherein R1is aryl or heteroaryl, may be prepared according to General Reaction Scheme I. Compounds 7a and 7b are both examples of Formula (I) wherein R1is aryl or heteroaryl and R3aand R3bare H. A haloaryl cyclic anhydride 1 is treated with bis(nucleophile) such as hydrazine hydrate in acetic acid at elevated temperature, to form a phthalhydrazide 2 which is treated with a halogenating agent, for example POCl3to afford the trihalophthalazine 3. Treatment of the trihalophthalazine 3 withan alcohol, for example benzyl alcohol and NaH in THF at 0ºC, furnishes dihaloalkoxyphthalazine 4a and 4b as a mixture of regioisomers. The mixture of 4a and 4b is subjected to palladium catalyzed cross coupling conditions, such as the Stille coupling or the Suzuki coupling with aryl / heteroaryl metal reactants, for example with the corresponding aryl / heteroaryl-tributyltin or aryl / heteroaryl boronic acids / esters to provide substituted haloalkoxyphthalazine 5a and 5b as a mixture of regioisomers. The substituted haloalkoxyphthalazine mixture 5a and 5b is subjected to metal-mediated cyanation conditions with for example, Pd2(dba)3, dppf, Zn and ZnCN2 in DMF at elevated temperature and the resulting cyanoalkoxyphthalazine mixture 6a and 6b is subjected to hydrogenation conditions, for example with Pd / C, HCl and H2in 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 furnish the desired compounds 7a and 7b of Formula (I). GENERAL REACTION SCHEME II

[0147] Compounds of Formula (I) wherein R1is aryl or heteroaryl, may be prepared according to General Reaction Scheme II. Compounds 7a and 7b are both examples of Formula (I) wherein R1is aryl or heteroaryl and R3aand R3bare H. The mixture ofregioisomers 4a and 4b are separated by chromatography, such as supercritical fluid chromatography (SFC) giving isomerically pure dihaloalkoxyphthalazines 4a and 4b.4a or 4b is then subjected to metal-mediated cross coupling conditions, for example Suzuki conditions, with aryl / heteroaryl boronic acids / esters to provide the substituted haloalkoxyphthalazine 5a or 5b. The substituted haloalkoxyphthalazine 5a or 5b is subjected to metal-mediated cyanation conditions with for example, Pd2(dba)3, dppf, Zn and ZnCN2in DMF at elevated temperature to furnish cyanoalkoxyphthalazine 6a or 6b. Cyanoalkoxyphthalazine 6a or 6b is subjected to hydrogenation conditions, for example with Pd / C, HCl and H2in methanol to give the phthalazinone 7a or 7b to furnish the desired compounds of Formula (I). GENERAL REACTION SCHEME III-A

[0148] Compounds of Formula (I) wherein R1is aryl, heteroaryl, heterocyclyl or alkyl, may be prepared according to General Reaction Scheme III-A. Compound 7a is an example of Formula (I) wherein R1is aryl, heteroaryl, heterocyclyl or alkyl and R3aand R3bare H.1-(5- halo-2-methylphenyl)ethenone 8a is treated with an oxidant, for example KMnO4in water at 50ºC to furnish 2-(carboxycarbonyl)-4-halobenzoic acid 9a. Condensation of 9a, for example with hydrazine hydrate in ethanol at elevated temperature, yields 7-halo-4-oxo-3,4- dihydrophthalazine-1-carboxylic acid 10a which is then esterified with acid and alcohol, for example sulfuric acid and methanol. Methyl 7-halo-4-oxo-3,4-dihydrophthalazine-1- carboxylate 11a is reduced via hydride reduction, for example with sodium borohydride andCaCl2in methanol, to afford the 6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12a, which is then treated with halogenating agent, for example thionyl chloride for 12 hours to provide 6- halo-4-(halomethyl)phthalazin-1(2H)-one 13a. Nucleophilic SN2 displacement of 13a with a nitrogen nucleophile for example, potassium phthalimide in DMF at elevated temperature furnishes 14a which is subjected to metal-mediated cross coupling conditions, for example Suzuki conditions, with aryl / heteroaryl / heterocyclyl / alkyl boronic acids / esters to provide phthalazinone coupling product 15a. The phthalimide protecting group of 15a is removed under solvolysis conditions, for example with hydrazine hydrate in ethanol to furnish the desired compound 7a of Formula (I). GENERAL REACTION SCHEME III-B

[0149] Compounds of Formula (I) wherein R1is aryl, heteroaryl, heterocyclyl or alkyl, may be prepared according to General Reaction Scheme III-B. Compound 7b is an example of Formula (I) wherein R1is aryl, heteroaryl, heterocyclyl or alkyl and R3aand R3bare H.1-(5- halo-2-methylphenyl)ethenone 8b is treated with an oxidant, for example KMnO4in water at 50ºC to furnish 2-(carboxycarbonyl)-4-halobenzoic acid 9b. Condensation of 9b, for example with hydrazine hydrate in ethanol at elevated temperature, yields 7-halo-4-oxo-3,4- dihydrophthalazine-1-carboxylic acid 10b which is then esterified with acid and alcohol, for example sulfuric acid and methanol. Methyl 7-halo-4-oxo-3,4-dihydrophthalazine-1- carboxylate 11b is reduced via hydride reduction, for example with sodium borohydride and CaCl2in methanol, to afford the 6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12b, whichis then treated with halogenating agent, for example thionyl chloride for 12 hours to provide 6-halo-4-(halomethyl)phthalazin-1(2H)-one 13b. Nucleophilic SN2 displacement of 13b with a nitrogen nucleophile for example, potassium phthalimide in DMF at elevated temperature furnishes 14b which is subjected to metal-mediated cross coupling conditions, for example Suzuki conditions, with aryl / heteroaryl / heterocyclyl / alkyl boronic acids / esters to provide phthalazinone coupling product 15b. The phthalimide protecting group of 15b is removed under solvolysis conditions, for example with hydrazine hydrate in ethanol to furnish the desired compound 7b of Formula (I). GENERAL REACTION SCHEME IV-A

[0150] Compounds of Formula (I) wherein R1is pyridyl and R2is -O-aryl or -O-heteroaryl, may be prepared according to General Reaction Scheme IV-A. Compound 29 is an example of Formula (I) wherein R1is pyridyl, R2is -O-aryl or -O-heteroaryl, and R3aand R3bare 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 furnish 3-halo-5-R2-oxypyridine 27.3-halo-5-R2- pyridine 27 is coupled to boronic acid, Intermediate AN under palladium catalyzed cross coupling conditions, for example the Suzuki coupling, to generate R2-pyridyl coupling product 28. R2-pyridyl coupling product 28 is subjected to solvolysis conditions, for example with hydrazine hydrate in ethanol, to furnish the free amine 29 of Formula (I).GENERAL REACTION SCHEME IV-B

[0151] Compounds of Formula (I) wherein R1is pyridyl and R2is -O-aryl or -O-heteroaryl, may be prepared according to General Reaction Scheme IV-B. Compound 29 is an example of Formula (I) wherein R1is pyridyl, R2is -O-aryl or -O-heteroaryl, and R3aand R3bare H.5- bromopyridin-3-ol 25 is heated with aryl / heteroaryl halide 26, for example in a mixture of DMF and NaH, to furnish 3-bromo-5-R2-pyridine 27.3-bromo-5-R2-pyridine 27 is coupled to boronic acid Intermediate J under palladium catalyzed cross coupling conditions, for example Suzuki conditions, to generate coupling product 28-Boc. Coupling product 28-Boc is subjected to acidic conditions, for example with TFA, to furnish the desired compound 29 of Formula (I). GENERAL REACTION SCHEME IV-C

[0152] Compounds of Formula (I) wherein R1is 5-R2-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-3-yl and R2is -C1 - C5 alkyl, heterocyclyl, -L-cycloalkyl, -CH2-aryl and -CH2- heteroaryl where L is a bond or C1 - C3 alkylene, may be prepared according to General Reaction Scheme IV-C. Compound 34 is an example of Formula (I) wherein R1is 5-R2-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl, R2is -C1 - C5 alkyl, heterocyclyl, -L-cycloalkyl, - CH2-aryl and -CH2-heteroaryl where L is a bond or C1 - C3 alkylene and R3aand R3bare H.3- Bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 30 is reacted with aldehyde or ketone 31under reductive amination conditions, for example with sodium borohydride in methanol, to form R2-substituted product 32. Amination product 32 is coupled to boronic ester Intermediate AN under palladium catalyzed cross-coupling, for example Suzuki conditions, furnishing coupling product 33. Coupling product 33 is then exposed to solvolysis conditions, for example with hydrazine hydrate, to deliver free amine 34 of Formula (I). GENERAL REACTION SCHEME IV-D

[0153] Compounds of Formula (I) wherein R1is aryl or heteroaryl, may be prepared according to General Reaction Scheme IV-D. Compound 94 is an example of Formula (I) wherein R1is an appropriately substituted aryl or heteroaryl and R3aand R3bare H. N-Boc boronic ester Intermediate J is coupled to an aryl / heteroaryl-substituted halide 92 under palladium catalyzed cross coupling conditions, for example Suzuki coupling conditions, to generate N-Boc-R1-substituted coupling product 90. N-Boc-R1-substituted coupling product 90 is subjected to acidic conditions to remove the Boc group, for example TFA, to afford R1- substituted amine 94 of Formula (I). GENERAL REACTION SCHEME IV-E

[0154] Compounds of Formula (I) wherein R1is 5-R2-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-3-yl and R2is -C1 - C5 alkyl, heterocyclyl, -L-cycloalkyl, -CH2-aryl and -CH2- heteroaryl where L is a bond or C1 - C3 alkylene, may be prepared according to GeneralReaction Scheme IV-E. Compound 34 is an example of Formula (I) wherein R1is 5-R2-6,7- dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl, R2is -C1 - C5 alkyl, heterocyclyl, -L-cycloalkyl, - CH2-aryl and -CH2-heteroaryl where L is a bond or C1 - C3 alkylene and R3aand R3bare H.3- Bromo-5-R2-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine 32 is borylated, for example with Miyaura conditions, to supply boronate ester 32a-Bpin. Borylation product 32a-Bpin is coupled to Intermediate F under palladium catalyzed cross-coupling conditions, for example Suzuki conditions, furnishing coupling product 33a. Coupling product 33a is deprotected under acidic conditions, for example TFA, to deliver amine 34a of Formula (I). GENERAL REACTION SCHEME IV-F

[0155] Compounds of Formula (I) wherein R1is 5-R2-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-3-yl and R2is aryl or heteroaryl, may be prepared according to General Reaction Scheme IV-F. Compound 34 is an example of Formula (I) wherein R1is 5-R2-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-3-yl, R2is aryl or heteroaryl and R3aand R3bare H.3-Bromo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine 30 is reacted with aryl / heteroaryl halide 26, under copper catalyst mediated Ullman coupling conditions, for example with Cu(I)I, Cs2CO3, L-proline in DMF, at elevated temperature, to form amination product 32. R2-substituted amination product 32 is coupled to Intermediate AN under palladium catalyzed cross-coupling conditions, for example Suzuki conditions, furnishing coupling product 33. Coupling product 33 is subjected to solvolysis conditions, for example hydrazine hydrate, to deliver amine 34 of Formula (I).GENERAL REACTION SCHEME IV-G

[0156] Compounds of Formula (I) wherein R1is 5-R2-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-3-yl and R2is -C(O)- aryl or -C(O)- heteroaryl, may be prepared according to General Reaction Scheme IV-G. Compound 40 is an example of Formula (I) wherein R1is 5- R2-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-yl, R2is -C(O)- aryl or -C(O)- heteroaryl and R3aand R3bare H.3-Bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 30 is coupled to carboxylic acid 37 with a coupling reagent, for example 1-[bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid 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 the Suzuki coupling, to yield coupling product 39. R2-coupling product 39 is subjected to solvolysis conditions, for example with hydrazine monohydrate, to remove the phthalimide moiety and provide amine compound 40 of Formula (I). GENERAL REACTION SCHEME IV-H

[0157] Compounds of Formula (I) wherein R1is 1-methyl-5-R2-1H-pyrazole-4-yl and R2is alkyl, aryl or heteroaryl, may be prepared according to General Reaction Scheme IV-H. Compound 45 is an example of Formula (I) wherein R1is 1-methyl-5-R2-1H-pyrazole-4-yl, R2is alkyl, aryl or heteroaryl and R3aand R3bare H.4-bromo-1-methyl-1H-pyrazole 41 is coupledto alkyl / aryl / heteroaryl-substituted halide 42, for example with palladium acetate, DavePhos, tetrabutylammoniumacetate, pivalic acid in NMP at elevated temperature to furnish R2- substituted-bromopyrazole 43. R2-substituted-bromopyrazole 43 is coupled to Intermediate AN under palladium-mediated cross coupling conditions, for example Suzuki conditions, to provide R2-substituted coupling product 44. The coupling product 44 is subjected to solvolysis conditions, for example with hydrazine hydrate to furnish amine 45 of Formula (I). GENERAL REACTION SCHEME IV-I

[0158] Compounds of Formula (I) wherein R1is pyridyl, R2is -S-aryl or -S-heteroaryl, may be prepared according to General Reaction Scheme IV-I. Compound 57 is an example of Formula (I) wherein R1is pyridyl, R2is -S-aryl or -S-heteroaryl and R3aand R3bare H.3- bromo-5-fluoropyridine 53a is subjected to SNAr substitution conditions, for example sodium aryl / heteroaryl thiolate 54, NaH in DMF at elevated temperature, to provide 3-bromo-5- (aryl / heteroarylthio)pyridine 55.3-bromo-5-(aryl / heteroarylthio)pyridine 55 is coupled with boronic ester Intermediate AN under palladium cross coupling conditions, for example Suzuki conditions, to furnish R2-pyridyl-cross coupling product 56. R2-pyridyl-cross coupling product 56 is subjected to solvolysis conditions, with for example hydrazine hydrate, to produce amine 57 of Formula (I). GENERAL REACTION SCHEME IV-J

[0159] Compounds of Formula (I) wherein R1is pyridyl, R2is -S(O)-aryl or -S(O)- heteroaryl, may be prepared according to General Reaction Scheme IV-J. Compound 94 is an example of Formula (I) wherein R1is pyridyl, R2is -S(O)-aryl or -S(O)-heteroaryl and R3aand R3bare H.3-bromo-5-(R2-thio)pyridine 55 is subjected to oxidation conditions, for example mCPBA in dichloromethane at ambient temperature, to afford 3-bromo-5-(R2- sulfinyl)pyridine 92.3-bromo-5-(R2-sulfinyl)pyridine 92 is coupled with boronic ester intermediate AN under palladium catalyzed cross-coupling conditions, for example Suzuki conditions, to provide R2-substituted sulfinylpyridyl product 93. R2-substituted sulfinylpyridyl product 93 is subjected to solvolysis conditions, for example with hydrazine hydrate, to procure the R2-substituted sulfinylpyridyl amine 94 of Formula (I). GENERAL REACTION SCHEME IV-K

[0160] Compounds of Formula (I) wherein R1is 1-methyl-5-R2-1H-pyrazole-4-yl and R2is alkyl, aryl or heteroaryl, may be prepared according to General Reaction Scheme IV-K. Compound 111 is an example of Formula (I) wherein R1is 1-methyl-5-R2-1H-pyrazole-4-yl, R2is alkyl, aryl or heteroaryl and R3aand R3bare H. H-R2107 is halogenated, for example with a halogenating agent such N-bromosuccinimide or N-chlorosuccinimide under palladium catalyzed conditions such as palladium acetate in the presence of an acid such as p- toluenesulfonic acid in a solvent such as dichloroethane under elevated temperature for example 70ºC to give halide 108.4-bromo-1-methyl-1H-pyrazole 41 is coupled to alkyl / aryl / heteroaryl-substituted halide 108, for example with palladium acetate, DavePhos, tetrabutylammoniumacetate, pivalic acid in NMP at elevated temperature to furnish R2- substituted-bromopyrazole 109. R2-substituted-bromopyrazole 109 is coupled to IntermediateJ under palladium-mediated cross coupling conditions, for example Suzuki conditions, to provide N-Boc-R2-substituted coupling product 110. The coupling product 110 is subjected to acidic conditions to remove the Boc group, for example TFA, to afford R2-substituted amine 111 of Formula (I). GENERAL REACTION SCHEME V

[0161] Compounds of Formula (I) wherein R1is cycloalkyl or heterocyclyl, may be prepared according to General Reaction Scheme V. Compound 7a is an example of Formula (I) wherein R1is cycloalkyl or heterocyclyl and R3aand R3bare H.2-((7-bromo-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione Intermediate F is coupled to a 4-6 membered ring olefin boronic acid 17 under palladium catalyzed coupling conditions, for example Suzuki coupling conditions to provide the appropriate olefinic coupling product 18. The olefin coupling product 18 is then subjected to hydrogenation conditions, for example Pd / C and H2, to furnish the appropriate hydrogenation product 19. The hydrogenation product is then subjected to hydrazine solvolysis conditions, for example with hydrazine hydrate to provide the primary amine compound 7a of Formula (I).GENERAL REACTION SCHEME VI-A

[0162] Compounds of Formula (I) wherein R1is N-linked heteroaryl or N-linked heterocyclyl, may be prepared according to General Reaction Scheme VI-A. Compound 22 is an example of Formula (I) wherein R1is N-linked heteroaryl or N-linked heterocyclyl and R3aand R3bare H. Boronic ester intermediate AN, is subjected to metal catalyzed cross-coupling conditions, for example Ullman, Buchwald-Hartwig or Chan-Lam conditions with a nitrogen containing heterocyclyl or a nitrogen containing heteroaryl 20 to provide the appropriate N- coupled product 21. This N-coupled product 21 is subjected to solvolysis conditions, for example with hydrazine hydrate to remove the phthalimide to furnish the desired primary amine 22 of Formula (I). GENERAL REACTION SCHEME VI-B

[0163] Compounds of Formula (I) wherein R1is N-linked heteroaryl or N-linked heterocyclyl, may be prepared according to General Reaction Scheme VI-B. Compound 23 is an example of Formula (I) wherein R1is N-linked heteroaryl or N-linked heterocyclyl and R3aand R3bare H.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, for example Ullman, Buchwald-Hartwig or Chan-Lam conditions with a nitrogen containing heterocyclyl or nitrogen containing heteroaryl 20 to provide the appropriate N-coupled product 21a. ThisN-coupled product 21a is then subjected to solvolysis conditions, for example with hydrazine hydrate to furnish the desired primary amine 91a of Formula (I). GENERAL REACTION SCHEME VI-C

[0164] Compounds of Formula (I) wherein R1is N-linked heteroalkyl, N-linked arylheteroalkyl or N-linked aralkyl, may be prepared according to General Reaction Scheme VI-C. Compound 24 is an example of Formula I wherein R1is N-linked heteroalkyl, N-linked arylheteroalkyl or N-linked aralkyl and R3aand R3bare H.2-((6-bromo-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione intermediate F, is subject to metal catalyzed cross-coupling conditions, for example Ullman, Buchwald-Hartwig or Chan-Lam conditions with an heteroalkyl / arylheteroalkyl / aralkyl amine 20 to provide the appropriate N-coupled product 21b. This N-coupled product 21b is then subject to solvolysis conditions, for example with hydrazine hydrate to furnish the desired R1substituted product 91b of Formula (I). GENERAL REACTION SCHEME VII

[0165] Compounds of Formula (I) wherein R1is pyridyl and R2is O-aryl or O-heteroaryl, may be prepared according to General Reaction Scheme VII. Compound 29 is an example of Formula (I) wherein R1is pyridyl, R2is O-aryl or O-heteroaryl and R3aand R3bare H.3- bromo-5-hydroxypyridine 25 is coupled to boronic ester Intermediate AN under palladium catalyzed cross coupling conditions, for example the Suzuki coupling conditions Pd(dppf)Cl2, NaHCO3, dioxane / water at 80ºC, to generate coupling product 28-OH. Coupling product 28- OH was subjected to SNAr reaction conditions for example K2CO3in DMF at 110ºC with R2- substituted aryl / heteroaryl halide 26, to furnish R2-substituted aryl / heteroaryl pyridyl ether 28. R2-substituted aryl / heteroaryl pyridyl ether 28 was subjected to solvolysis conditions, for example hydrazine hydrate to furnish free amine 29 of Formula (I). GENERAL REACTION SCHEME VIII-A

[0166] Compounds of Formula (I) wherein R1is pyridyl and R2is aryl or heteroaryl, may be prepared according to General Reaction Scheme VIII-A. Compound 85 is an example of Formula (I) wherein R1is pyridyl, R2is aryl or heteroaryl and R3aand R3bare H. Intermediate CB is borylated under Miyaura conditions, for example with bis(pinacolato)diboron, Pd(dppf)Cl2, KOAc in dioxane at elevated temperature to provide boronic acid 86. Boronic acid 86 is coupled with R2halide 26 under palladium catalyzed cross coupling conditions, for example Suzuki conditions, to yield R2-pyridyl coupling product 84. R2-pyridyl coupling product 84 is subjected to solvolysis conditions, for example with hydrazine hydrate, to provide primary amine 85 of Formula (I).GENERAL REACTION SCHEME VIII-B

[0167] Compounds of Formula (I) wherein R1is pyridyl and R2is aryl or heteroaryl, may be prepared according to General Reaction Scheme VIII-B. Compound 85 is an example of Formula (I) wherein R1is pyridyl, R2is aryl or heteroaryl and R3aand R3bare H. Intermediate AN is coupled to 3-bromo-5-iodopyridine 53b under palladium catalyzed cross coupling conditions, for example Suzuki conditions, to give 3-bromo-pyridyl coupling product Intermediate CB. Intermediate CB is then coupled to aryl / heteroaryl-substituted boronic ester under palladium catalyzed cross-coupling conditions, for example Suzuki coupling conditions, to provide R2-substituted pyridyl coupling product 84. Coupling product 84 undergoes solvolysis, for example with hydrazine hydrate, to provide primary amine 85 of Formula (I).GENERAL REACTION SCHEME IX-A

[0168] Compounds of Formula (I), wherein R1is aryl or heteroaryl, R3ais alkyl and R3bis H, may be prepared according to General Reaction Scheme IX-A. Compound 100 is an example of Formula (I) wherein R1is aryl or heteroaryl, R3ais alkyl and R3bis H. Methyl 7-halo-4-oxo- 3,4-dihydrophthalazine-1-carboxylate 11a is reduced using a hydride reducing conditions, for example sodium borohydride, CaCl2in methanol at 0ºC, to afford primary alcohol 6-halo-4- (hydroxymethyl)phthalazin-1(2H)-one 12a.6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12a is reacted with an oxidant, for example MnO2in dichloroethane to furnish 7-halo-4-oxo- 3,4-dihydrophthalazine-1-carbaldehyde 95.7-halo-4-oxo-3,4-dihydrophthalazine-1- carbaldehyde 95 is converted to the sulfinamide compound 96 by for example, adding t- butanesulfinamide, titanium tetra-iso-propoxide in THF and heating to 60ºC for 12 hours. t- Butyl sulfonamide 96 is then reacted with alkylmagnesium halide in THF at -78ºC to generate methyl sulfonamide 97. Methyl sulfonamide 97 is coupled to an appropriate R1-substituted boronic ester under palladium catalyzed cross coupling conditions, for example Suzuki conditions, to supply R1-substituted coupling product 99. R1-substituted coupling product 99 is desulfinylated under acidic conditions, for example HCl / dioxane to furnish R1-substituted primary amine 100 of Formula (I).GENERAL REACTION SCHEME IX-B

[0169] Compounds of Formula (I), wherein R1is aryl or heteroaryl, R3ais alkyl and R3bis H, may be prepared according to General Reaction Scheme IX-B. Compounds 9-5a and 9-5b are examples of Formula (I) wherein R1is aryl or heteroaryl, R3ais alkyl and R3bis H. t-Butyl sulfinamide intermediate 97 is borylated under Miyaura conditions, for example with bis(pinacolato)diboron, Pd(dppf)Cl2, KOAc in dioxane at elevated temperature to provide boronic ester 9-2 which is then reacted coupled to an appropriate R1-substituted halide under palladium catalyzed cross coupling conditions, for example Suzuki conditions, to supply R1- substituted coupling product 9-3. R1-substituted coupling product 9-3 is desulfinylated under acidic conditions, for example HCl / dioxane to furnish R1-substituted primary amine 9-4 of Formula (I). The racemic mixture of 9-4 is then separated into the corresponding pure enantiomers via chiral prep HPLC and or chiral SFC to give chiral amines 9-5a and 9-5b examples of compounds of Formula (I).GENERAL REACTION SCHEME X

[0170] Compounds of Formula (I) wherein R1is aryl, heteroaryl, heterocyclyl or alkyl, may be prepared according to General Reaction Scheme X. Compound 10-10 is an example of Formula (I) wherein R1is aryl, heteroaryl, heterocyclyl or alkyl, R3aand R3bare H and R6is hydrogen, halogen, C1-C3 alkyl or alkoxy.1-(5-bromo-2-methyl-3-substituted phenyl)ethanone 10-1 is treated with an oxidant, for example KMnO4in water at 50ºC to furnish 4-bromo-2-(carboxycarbonyl)-6-substituted-benzoic acid 10-2. Condensation of 10-2, for example with hydrazine hydrate in ethanol at elevated temperature, yields 7-bromo-4-oxo- 3,4-dihydrophthalazine-5-substituted-1-carboxylic acid 10-3 which is then esterified with acid and alcohol, for example 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 via hydride reduction, for example with sodium borohydride and CaCl2in methanol, to afford the 6- bromo-4-(hydroxymethyl)-8-substituted-phthalazin-1(2H)-one 10-5, which is then treated with halogenating agent, for example thionyl chloride for 12 hours to provide 6-halo-4- (chloromethyl)-8-substituted-phthalazin-1(2H)-one 10-6. Nucleophilic SN2 displacement of 10-6 with a nitrogen nucleophile for example, potassium phthalimide in DMF at elevated temperature furnishes 10-7 which is borylated, for example with Miyaura conditions, to give boronate ester 10-8. Palladium-mediated cross coupling conditions, for example Suzuki conditions, with boronic ester 10-8 and aryl / heteroaryl / heterocyclyl / alkyl halides provides 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 furnish the desired compound 10-10 of Formula (I). GENERAL REACTION SCHEME XI

[0171] Compounds of Formula (I) wherein R1is aryl, heteroaryl, heterocyclyl or alkyl, may be prepared according to General Reaction Scheme XI. Compound 11-7 is an example of Formula (I) wherein R1is aryl, heteroaryl, heterocyclyl or alkyl, R3aand R3bare D and R6is hydrogen, halogen, C1-C3 alkyl or alkoxy. Methyl 7-bromo-4-oxo-3,4-dihydrophthalazine-5- substituted-1-carboxylate 10-4 is reduced via deuteride reduction, for example with sodium borodeuteride and CaCl2in methanol-d4, to afford the 6-bromo-4-((hydroxy-d)methyl-d2)-8- substituted-phthalazin-1(2H)-one 11-2, which is then treated with halogenating agent, for example thionyl chloride for 12 hours to provide 6-bromo-4-(chloromethyl-d2)-8-substituted- phthalazin-1(2H)-one 11-3. Nucleophilic SN2 displacement of 11-3 with a nitrogen nucleophile for example, potassium phthalimide in DMF at elevated temperature furnishes 11-4 which is borylated, for example with Miyaura conditions, to give boronate ester 11-5. Palladium-mediated cross coupling conditions, for example Suzuki conditions, with boronic ester 11-5 and aryl / heteroaryl / heterocyclyl / alkyl halides provides 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 furnish the desired compound 11-7 of Formula (I). GENERAL REACTION SCHEME XII

[0172] Compounds of Formula (I) wherein R2is aryl or heteroaryl, may be prepared according to General Reaction Scheme XII. Compound 12-3 is an example of Formula (I) wherein R2is aryl or heteroaryl, R3aand R3bare H, R6is hydrogen, halogen, C1-C3 alkyl or alkoxy and substituent is alkyl, aryl or heteroaryl. Bromo or chloro compound 12-1 is subjected to palladium-mediated cross coupling conditions, for example Suzuki conditions, with an alkyl / aryl / heteroaryl boronic acid / ester to give substituent coupled product 12-2. The BOC group is then removed with acidiemc conditions, for example TFA, to afford R2- substituted amine 12-3 of Formula (I).GENERAL REACTION SCHEME XIII

[0173] Compounds of Formula (I) wherein R1is alkyl-cyano, may be prepared according to General Reaction Scheme XIII. Compound 13-3 is an example of Formula (I) wherein R1is - CH2CN. Bromo or chloro compound 13-1 is subjected to palladium-mediated cross coupling conditions, for example Suzuki conditions, with an isoxazole boronic acid / ester to give substituent coupled product 13-2. The isoxazole is then subjected to hydrazine hydrate in an alcoholic solvent such as ethanol at elevated temperature followed by acidic work up, for example with HCl at pH 1 to give nitrile product 13-3 of Formula (I). GENERAL REACTION SCHEME XIV

[0174] Compounds of Formula (I) wherein R2is aryl or heteroaryl and R6is alkoxy may be prepared according to General Reaction Scheme XIV. Compound 14-3 is an example of Formula (I) wherein R2is aryl or heteroaryl, and R6is alkoxy. Fluoro compound 14-1 with the amine suitably protected with for example, a BOC group or phthalimide group is subjected to aromatic SN2 conditions with -F as the leaving group and the corresponding oxy anion as the nucleophile. For example, with a sodium alkyl oxide in a polar solvent with heat to give substituent substituted product 14-2. The protecting group is then removed under appropriate conditions. For example, the BOC is removed under acidic conditions such as HCl or TFA in dioxane or the phthalimide group is removed under basic nucleophilic conditions such as hydrazine hydrate in ethanol with heat to afford R6-substituted amine 14-3 of Formula (I).GENERAL REACTION SCHEME XV

[0175] Compounds of Formula (I) wherein R2is aryl or heteroaryl and R6is C1-C3 alkyl may be prepared according to General Reaction Scheme XV. Compound 15-3 is an example of Formula (I) wherein R2is aryl or heteroaryl, and R6is C1-C3 alkyl. Chloro compound 15-1 with the amine suitably protected with for example, a BOC group or phthalimide group, is coupled to the appropriate C1-C3 trialkylborane under palladium catalyzed cross coupling conditions, for example Suzuki-Miyaura coupling conditions, to supply the corresponding R6- substituted coupling product 15-2. The protecting group is then removed under appropriate conditions. For example, the BOC is removed under acidic conditions such as HCl in dioxane or TFA in dioxane and the phthalimide group is removed under basic nucleophilic conditions such as hydrazine hydrate in ethanol with heat to afford R6-substituted amine 15-3 of Formula (I). GENERAL REACTION SCHEME XVI

[0176] Compounds of Formula (I) wherein R1is 1-methyl-5-R2-1H-pyrazole-4-yl and R2is alkyl, aryl or heteroaryl, may be prepared according to General Reaction Scheme XVI. Compound 16-6 is an example of Formula (I) wherein R1is 1-methyl-5-R2-1H-pyrazole-4-yl,R2is alkyl, aryl or heteroaryl and R3aand R3bare H. H-R216-1 is halogenated, for example with a halogenating agent such N-bromosuccinimide or N-iodosuccinimide under palladium catalyzed conditions such as palladium acetate in the presence of an acid such as p- toluenesulfonic acid in a solvent such as dichloroethane under elevated temperature for example 70 ºC to give halide 16-2. Bromo or iodo compound 16-2 is subjected to palladium- mediated cross coupling conditions, for example Suzuki conditions, with 1-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give coupled product 16-3.1-methyl-5- R2-1H-pyrazole 16-3 is halogenated for example with a halogenating agent such N- bromosuccinimide or N-iodosuccinimide in a polar solvent such as acetonitrile to give 4-halo- 1-methyl-5-R2-1H-pyrazole compound 16-4.4-bromo-1-methyl-5-R2-1H-pyrazole 16-4 is coupled to Intermediate J under palladium-mediated cross coupling conditions, for example Suzuki conditions, to provide N-Boc-R2-substituted coupling product 16-5. The coupling product 16-5 is subjected to acidic conditions to remove the Boc group, for example TFA, to afford R2-substituted amine 16-6 of Formula (I). INTERMEDIATES C, D and E

[0177] Step 1: A mixture of 5-bromoisobenzofuran-1,3-dione 1a (55.0 g, 242 mmol, 1.00 eq.) and acetic acid (165 mL) was stirred at 125°C for 1 hour. After such time the mixture was cooled to 10 °C and hydrazine hydrate (12.7 g, 254 mmol, 12.4 mL, 1.05 eq.) was addeddropwise, resulting in the formation of a thick white precipitate. Additional acetic acid (55 mL) was added and the mixture stirred at 125 °C for a further 30 mins. After such time time the mixture was 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 a 5% (w / w) sodium hydroxide solution (800 mL). The solution was acidified with acetic acid (200 mL) to give a thick white precipitate which was filtered. The filter cake was washed with water (50 mL × 3) followed by methanol then dried in vacuo to give 6-bromo-2,3-dihydrophthalazine-1,4-dione 2a (45.6 g, crude) as a white solid. This solid was then used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) d = 8.17 (d, J = 2.0 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.95 - 7.89 (m, 1H).

[0178] 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. After such time the reaction mixture was concentrated under reduced pressure and the residue 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 sodium bicarbonate aqueous solution (200 mL × 5), brine (200 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-bromo-1,4- dichloro-phthalazine 3a (14.5 g, crude) as a yellow solid. This solid was then used in the next step without further purification.1H NMR (400 MHz, CDCl3) d = 8.49 (d, J = 1.2 Hz, 1H), 8.23 - 8.15 (m, 2H).

[0179] 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 hour. 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 hour. After such time the reaction mixture was 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 (SiO2, 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.1H NMR (400 MHz, CDCl3) d = 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).

[0180] 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 × 30 mm, 10 µm); : [0.1% NH3H2O MeOH]; B%: 0%-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) as a white solid. Intermediate D: 4-benzyloxy-7-bromo-1-chloro-phthalazine:1H NMR (400 MHz, CDCl3) d  = 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-bromo-1-chloro-phthalazine:1H NMR (400 MHz, CDCl3) d = 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. INTERMEDIATE F – Route 1

[0181] Step 1: To a solution of 1-(5-bromo-2-methyl-phenyl)ethenone 8c (100 g, 445 mmol, 1.00 eq.) in water (1.00 L) was added potassium carbonate (92.4 g, 668 mmol, 1.50 eq.) and potassium permanganate (493 g, 3.12 mol, 7.00 eq.). The mixture was stirred at 50 °C for 3 hours before ethanol (1.00 L) was added and the resulting mixture stirred at 50 °Cfor a further 30 minutes. After such time the solid was filtered and the filtrate pH adjusted to pH 2 with conc. hydrochloric acid (500 mL). The mixture was then extracted with ethyl acetate (1.00 L), the organic layer separated 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.

[0182] Step 2: To a solution of 4-bromo-2-oxalo-benzoic 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 hours 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.1H NMR (400 MHz, DMSO-d6) d = 8.72-8.81 (m, 1H), 8.11-8.21 (m, 1H), 7.95-8.09 (m, 1H).

[0183] 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 stirred at 65 °C for 24 hours. After such time the cooled reaction mixture was filtered and the filter cake 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;1H NMR (400 MHz, DMSO-d6) d = 13.31 (s, 1H), 8.72 (s, 1H), 8.16-8.18 (d, J = 8.4 Hz, 1H), 8.03-8.05 (d, J = 8.4 Hz,, 1H), 3.91 (s, 3H).

[0184] 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 treated portion wise with sodium borohydride (48.6 g, 1.29 mol, 2.60 eq) at 0 °C. To this mixture was added a solution of calcium chloride (65.8 g, 593 mmol, 1.20 eq). The mixture was then stirred for 2 hours at 0 °C and a further 1 hour at 20 °C. After such time the reaction mixture was concentrated under reduced pressure, and the residue was suspended in water (800 mL), the pH was adjusted to pH 5 with 1N hydrochloric acid (300 mL) and the precipitate was filtered, washed with water (300 mL × 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;1H NMR (400 MHz, DMSO-d6) d = 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).

[0185] 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;1H NMR (400 MHz, DMSO-d6) d = 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).

[0186] 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 hours and then cooled to 25 °C. The formed precipitate was filtered and washed with DMF (200 mL x 2) and the filter cake 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.1H NMR (400 MHz, DMSO-d6) d = 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. INTERMEDIATE F – Route 2

[0187] Step 1: A mixture of 5-bromoisobenzofuran-1(3H)-one (50.0 g, 235 mmol, 1.00 eq), DMF-DMA (180 g, 1.51 mol, 201 mL, 6.44 eq) and t-BuOK (2.63 g, 23.5 mmol, 0.10 eq) was degassed and purged with N23 times and then stirred at 110 °C for 20 h under a N2atmosphere. After such time the reaction mixture concentrated under reduced pressure to remove the DMF-DMA and the formed residue was stirred in petroleum ether (100 mL) at 25°C for 30 mins. The formed solid was filtered and the filter cake stirred in ethyl acetate (200 mL) at 80 °C for 12 h, 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) d = 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).

[0188] 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 eq) in EtOH (650 mL) was added NH2NH2•H2O (12.5 g, 245 mmol, 12.1 mL, 2.05 eq) at 25 °C. The mixture was degassed with N2then stirred at 25 °C for 0.5 h and then at 70 °C for 12 h. After such time the reaction mixture was 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;1H NMR (400 MHz, DMSO-d6) d 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).

[0189] Step 3: A mixture of 6-bromo-4-((dimethylamino)methyl)phthalazin-1(2H)-one (15.0 g, 53.2 mmol, 1.00 eq) in THF (187 mL) and degassed with N23 times before being cooled to 0 °C. Isobutyl carbonochloridate (8.71 g, 63.80 mmol, 8.38 mL, 1.20 eq) was then added dropwise and then the mixture stirred at 25 °C for 6 h under N2. After such time the mixture was cooled to 0 °C before HCl (0.5 M, 250 mL) was added maintaining a temperature between 0 °C and 10 °C. After the addition was complete the solid was filtered, washed with THF (30 mL x 3) and dried to afford a 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) d 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).

[0190] Step 4: To a mixture of 6-bromo-4-(chloromethyl)phthalazin-1(2H)-one (8.06 g, 27.5 mmol, 93% purity, 1.00 eq) in DMF (160 mL) was added (1,3-dioxoisoindolin-2- yl)potassium (5.61 g, 30.3 mmol, 1.10 eq) and stirred at 25 °C for 1 hr. After such time the mixture was washed with HCl (0.5 M, 100 mL), filtered and the solid washed with sat. NaHCO3. (30 mL x 2), pure water (30 mL x 2) and then triturated with EtOH (15 mL) at 70 °C for 1 hr. The solid was then filtered and dried 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;1H NMR (400MHz, DMSO-d6) d 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). INTERMEDIATE G

[0191] Step 1: To a solution of 1-(4-bromo-2-methyl-phenyl)ethenone 8d (10.0 g, 46.9 mmol, 1.00 eq.) in water (50 mL) was added potassium carbonate (9.73 g, 70.40 mmol, 1.50 eq.) and potassium permanganate (51.9 g, 329 mmol, 7.00 eq.). The mixture was stirred at 50 °C for 3 hours before ethanol (50 mL) was added and the resulting mixture stirred at 50 °C for a further 30 minutes. After such time the solid was filtered and the filtrate pH adjusted to pH 2 with conc. hydrochloric acid (5 mL). The mixture was then extracted with ethyl acetate (50 mL), the organic layer 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.

[0192] Step 2: To a solution of 5-bromo-2-oxalo-benzoic acid 9d (10.0 g, crude) in ethyl alcohol (120 mL) was added hydrazine hydrate (1.87 g, 36.6 mmol, 1.82 mL) and the mixture was stirred at 75 °C for 4 hours. After such time the formed precipitate was filtered and 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.

[0193] Step 3: To a solution of 6-bromo-4-oxo-3H-phthalazine-1-carboxylic acid 10d (7.50 g, 27.9 mmol, 1.00 eq.) in methyl alcohol (40 mL) was added sulfuric acid (16.7 g, 167 mmol, 9.10 mL, 6.00 eq.) and the reaction mixture stirred at 65 °C for 12 hours. After such time the reaction mixture was allowed to cool and the formed precipitate 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.

[0194] Step 4: A stirred solution of sodium borohydride (2.43 g, 64.29 mmol, 2.60 eq.) in ethyl alcohol (250 mL) was treated portion wise with methyl 6-bromo-4-oxo-3H-phthalazine- 1-carboxylate 11d (7.00 g, 24.7 mmol, 1.00 eq.) at 0 °C. To this mixture was added a solution of calcium chloride (3.29 g, 29.7 mmol, 1.20 eq.) in ethyl alcohol (250 mL) in a dropwise fashion. The mixture was then stirred for 3 hours at 0 °C and an additional hour at 20 °C. After such time the mixture was concentrated under reduced pressure and the concentrated residue was suspended in water (30 mL) and the pH adjusted to pH 5 with 1N hydrochloric acid (5 mL). The formed precipitate was filtered, washed with water (5 mL × 3) and 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.

[0195] 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.

[0196] 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 and 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.1H NMR (400 MHz, DMSO-d6) d = 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.INTERMEDIATE I

[0197] Step 1: A solution of Intermediate F (3.00 g, 7.81 mmol, 1.00 eq.) and hydrazine hydrate (1.60 g, 31.2 mmol, 1.55 mL, 4.00 eq.) was stirred at 80 °C for 2 hours, cooled and concentrated under reduced pressure. The concentrated residue 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.

[0198] Step 2 To a solution of 4-(aminomethyl)-6-bromo-2H-phthalazin-1-one 106 (1.90 g, 7.48 mmol, 1.00 eq.) and triethylamine (2.27 g, 22.4 mmol, 3.12 mL, 3.00 eq) in dichloromethane (40.0 mL) was added di-tert-butyl dicarbonate (3.26 g, 15.0 mmol, 3.44 mL, 2.00 eq.). 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) then 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]+= 356.1.1H NMR (400 MHz, DMSO-d6) d = 12.71 (s, 1H), 8.26 (br s, 1H), 8.16 (br d, J = 8.0 Hz, 1H), 8.02 (br d, J = 8.0 Hz, 1H), 7.46 (br s, 1H), 4.41 (br d, J = 4.4 Hz, 2H), 1.40 (br s, 9H). INTERMEDIATE J

[0199] A mixture of Intermediate I (130.0, 275 mmol, 1.00 eq.), bis(pinacolato)diboron (BPD) (104.9 g, 412.9 mmol, 1.50 eq.), Pd(dppf)Cl2(20.1 g, 27.5 mmol, 0.10 eq.), KOAc (81.0 g, 825 mmol, 3.00 eq.) in dioxane (2.60 L) was degassed and purged with N2. Themixture was then stirred at 100 °C for 2 hours. After such time the mixture was filtered, concentrated and the residue triturated with petroleum ether / ethyl acetate 10 / 1 (400 mL) at 25 °C for 1 hr. 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) d = 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). INTERMEDIATE K

[0200] A solution of 4-bromo-1-methyl-pyrazole (500 mg, 3.11 mmol, 1.00 eq.) and the 1- bromo-3-fluoro-benzene (543 mg, 3.11 mmol, 346 µL, 1.00 eq.) in N-methylpyrrolidone (10 mL) was degassed with nitrogen. Then, palladium acetate (7.0 mg, 31.1 µmol, 0.10 eq.) and 2-(2-dicyclohexylphosphanylphenyl)-N,N-dimethyl-aniline (DavePhos) (24.0 mg, 62.1 µmol, 0.02 eq.) was added. To the resulting dark brown solution, tetrabutylammonium acetate (1.87 g, 6.21 mmol, 2 mL, 2.00 eq.) and pivalic acid (317 mg, 3.11 mmol, 357 µL, 1.00 eq.) were added and the resulting solution stirred at 100°C for 15 hours. After the reaction was completed, the mixture was cooled. Ethyl acetate (100 mL) was added and the resulting mixture was washed with brine (3 × 100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to 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]+= 255.0.1H NMR (400 MHz, CDCl3) d = 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).

[0201] The Intermediates A-1 to A-32 shown in Table I-I were prepared following the teachings of the General Reaction Schemes and the method to prepare INTERMEDIATE K.INTERMEDIATE AA

[0100] To a solution of 3-bromo-5-fluoro-pyridine (2.20 g, 12.5 mmol, 1.00 eq.) in dimethylformamide (50 mL) was added phenylsulfanylsodium (1.98 g, 15.0 mmol, 1.20 eq.) followed by stirring at 110 °C for 12 hours. After such time the reaction mixture was 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 give 3-bromo-5-phenylsulfanyl-pyridine, Intermediate AA (1.31 g, 4.48 mmol, 35% yield) as a yellow oil. LCMS [M+1]+= 268.0;1H NMR (400 MHz, MeOD) d = 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).INTERMEDIATE AB

[0202] To a solution of 2-chlorobenzenethiol (296 mg, 2.05 mmol, 233 µL, 1.20 eq.) in DMF (2 mL) was added sodium hydride (82 mg, 2.05 mmol, 60% purity, 1.20 eq.) and 3- bromo-5-fluoro-pyridine (300 mg, 1.70 mmol, 1.00 eq.) and stirred at 25 °C for 2 hours. The reaction mixture was then quenched by addition 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 prep-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;1H NMR (400 MHz, CDCl3-d) d = 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).

[0203] The INTERMEDIATES AC to AG shown in Table I-IIa were prepared following the teachings of the General Reaction Schemes and the method to prepare INTERMEDIATE AB.INTERMEDIATE AH

[0204] Step 1: To a solution of 2-methyl-1H-imidazole (1.00 g, 12.2 mmol, 1.00 eq.) in DMF (10 mL) was added potassium carbonate (1.68 g, 12.2 mmol, 1.00 eq.) and 2- chloroacetonitrile (920 mg, 12.2 mmol, 773 µL, 1.00 eq.) and the mixture stirred at 50 °C for 5 hours. After such time the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3) and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10-100%) to give 2-(2- methylimidazol-1-yl)acetonitrile (460 mg, 3.80 mmol, 31% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) d = 6.98 (d, J = 1.2 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H), 4.79 (s, 2H), 2.47 (s, 3H).

[0205] Step 2: To a solution of 2-(2-methylimidazol-1-yl)acetonitrile (410 mg, 3.38 mmol, 1.00 eq.) in acetonitrile (10 mL) was added a solution of N-bromosuccinimide (542 mg, 3.05 mmol, 0.90 eq.) in acetonitrile (10 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and after such time the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic phases were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered and concentrated to a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 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.1H NMR (400 MHz, CDCl3) d = 6.97 (s, 1H), 4.82 (s, 2H), 2.53 (s, 3H).INTERMEDIATE AI

[0206] To a solution of 4-bromo-2-methyl-pyrazol-3-amine (0.20 g, 1.14 mmol, 1.00 eq.) in hydrochloric acid (12 M, 2 mL, 21.1 eq.) was slowly added a solution of sodium nitrite (86 mg, 1.25 mmol, 1.10 eq.) in water (1.8 mL) at 0 °C. After stirring for 10 minutes, the mixture was added in portions to a solution of cuprous chloride (112 mg, 1.14 mmol, 27.2 µL, 1.00 eq.) in hydrochloric acid (12 M, 1.00 mL, 10.6 eq.). The reaction mixture was stirred at 25 °C for 3 hours. After such time the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). Combined organic phases were washed with aqueous sodium bicarbonate (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-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;1H NMR (400 MHz, CDCl3-d) d = 7.48 (s, 1H), 3.88 (s, 3H). INTERMEDIATE AJ

[0207] Sodium borohydride (22 mg, 572 µmol, 1.50 eq.) was added slowly to a solution of (5-bromo-3-pyridyl)-phenyl-methanone (100 mg, 381 µmol, 1.00 eq.) in ethyl alcohol (5 mL). After stirring at 25 °C for 2 hours the reaction was quenched with water (2 mL) and concentrated under vacuum. 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) d = 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).INTERMEDIATE AK

[0208] To a solution of 3-bromo-5-(phenylthio)pyridine, Intermediate AA (200 mg, 751 µmol, 1.00 eq.) in dichloromethane (4 mL) was added 3-chloroperoxybenzoic acid (153 mg, 751 µmol, 85.0% purity, 1.00 eq.). The resulting mixture was stirred at 25 °C under nitrogen for 1 hour. After such time sodium hydroxide aqueous solution (4 N, 40 mL) was added and the mixture 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 (SiO2, petroleum ether: ethyl acetate 5-20%) to give 3- bromo-5-(phenylsulfinyl)pyridine, Intermediate AK (150 mg, 532 µmol, 70% yield) as a white solid.1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE AL

[0209] A solution of oxone (2.10 g, 3.42 mmol, 2.00 eq.) in water (10 mL) was added to a solution of 3-bromo-5-phenylsulfanyl-pyridine intermediate AA (500 mg, 1.71 mmol, 1.00 eq.) in THF (10 mL) and methyl alcohol (10 mL) at 0 °C. The resulting mixture was stirred at 35 °C for 12 hours and after such time was filtered and the filtrate concentrated under reduced pressure. The formed residue was purified by reversed-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.1H NMR (400MHz, DMSO-d6) d = 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).INTERMEDIATE AM

[0210] Step 1: Phosphorus oxychloride (4.71 g, 30.7 mmol, 2.9 mL, 1.23 eq.) was added dropwise to DMF (6 mL) at 0°C, and then the mixture was stirred at 0 °C for 10 minutes. After such time a solution of 1-phenylethanone (3.00 g, 25.0 mmol, 2.91 mL, 1.00 eq.) in DMF (25 mL) was added dropwise with stirring. The reaction mixture was then heated 3 hours at 60 °C. After such time the solution was cooled to room temperature and poured slowly into an aqueous sodium acetate solution (10%, 100 mL). The pH was adjusted to 4 with additional sodium acetate solution (10 mL) and extracted with ethyl acetate (20 mL × 3).  The combined organic phases were 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]+= 167.1.1H NMR (400 MHz, CDCl3) d =  10.24 (d, J = 6.8 Hz, 1H), 7.49 (m, 5H), 6.69 (d, J = 6.8 Hz, 1H).

[0211] Step 2: Hydrogen Cyanide (HCN) is produced as a byproduct in this reaction. Appropriate safety precaution and procedures should be employed. A mixture of (Z)-3- chloro-3-phenyl-prop-2-enal (1.76 g, 10.6 mmol, 1.00 eq.), ammonium thiocyanate (1.61 g, 21.1 mmol, 1.61 mL, 2.00 eq.) in acetone (25 mL) was degassed and purged with nitrogen and stirred at 80 °C for 1 hour. After such time the cooled mixture was poured into saturated sodium bicarbonate aqueous solution (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The formed 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]+= 162.2.1H NMR (400 MHz, CDCl3) d = 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).

[0212] Step 3: Bromine (952 mg, 5.95 mmol, 307 µL, 3.20 eq.) was added dropwise over a period of 30 min to a stirred mixture of 5-phenylisothiazole (300 mg, 1.86 mmol, 1.00 eq), potassium acetate (365 mg, 3.72 mmol, 2.00 eq.) and acetic acid (12 mL). The reaction mixture was stirred at 25 °C 5 hours and after such time treated with aqueous sodium bisulfite (33%, 10 mL). The solution was made basic with aqueous sodium hydroxide (20%, 10 mL),extracted with dichloromethane (3 × 80 mL). The combined organic extracts were dried (anhydrous sodium sulfate), filtered and concentrated to give to 4-bromo-5-phenyl- isothiazole, Intermediate AM (300 mg, 1.25 mmol, 67% yield) as colorless oil. LCMS [M+1]+= 240.9.1H NMR (400 MHz, CDCl3) d = 8.39 (s, 1H), 7.69 - 7.65 (m, 2H), 7.52 - 7.47 (m, 3H).13C NMR (400 MHz, CDCl3) d = 161.0, 159.5, 129.9, 129.3, 129.0, 128.5, 106.0. INTERMEDIATE AN

[0213] A mixture of intermediate I (160 g, 416 mmol, 1.00 eq.), 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 eq.), Pd(dppf)Cl2(30.4 g, 41.6 mmol, 0.10 eq.), potassium acetate (122 g, 1.25 mol, 3.00 eq.) in dioxane (2.0 L) was purged with nitrogen and stirred at 100 °C for 3 hrs. After such time the reaction mixture was filtered and concentrated under reduced pressure. The residue was triturated with MeOH (1.0 L) at 25 °C for 2 h, 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]+= 432.4.1H NMR: (400 MHz DMSO-d6) d: 12.54 (s, 1H), 8.24-8.37 (m, 2H), 8.13 (d, J = 7.6 Hz, 1H), 7.93-7.99 (m, 2H), 7.87-7.93 (m, 2H), 5.22 (s, 2H), 1.36 (s, 12H). INTERMEDIATE AO

[0214] To a solution of 3,5-dibromopyridine (1.00 g, 4.22 mmol, 1.00 eq.) in DMF (10 mL) was added sodium hydride (270 mg, 6.75 mmol, 60% purity, 1.60 eq.) at 0 °C over 10 min followed by N-methylaniline (452 mg, 4.22 mmol, 458 µL, 1.00 eq.). The resulting mixture was stirred at 100 °C for 2 hours. After such time the reaction mixture was 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 SiO2, 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]+262.9.1H NMR (400 MHz, CDCl3-d) d = 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). INTERMEDIATE AP

[0215] A mixture of (5-bromo-3-pyridyl)boronic acid (325 mg, 1.61 mmol, 1.50 eq.), 1H- pyrazole-5-carbonitrile (100 mg, 1.07 mmol, 1.00 eq.), pyridine (255 mg, 3.22 mmol, 260 µL, 3.00 eq.), 4Å molecular sieves (20.0 mg, 1.07 mmol) and copper acetate (585 mg, 3.22 mmol, 3.00 eq) in dichloromethane (5 mL) was degassed with nitrogen and stirred at 20 °C for 12 hours under an oxygen atmosphere (15 psi). After such time the reaction mixture was filtered and concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 5-20%) 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]+249.0.1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE AS

[0216] Step 1: To a solution of cyclopropanol (450 mg, 7.74 mmol, 1.10 eq.) in THF (10 mL) was added sodium hydride (310 mg, 7.74 mmol, 60.0% purity, 1.10 eq.) at 0 °C, followed by 5-fluoro-2-nitro-pyridine (1.00 g, 7.04 mmol, 1.00 eq.) and the mixture was warmed to 20 °C and stirred for 2 hours. After completion, the mixture was filtered and concentrated in vacuum and the residue purified by column chromatography (SiO2, petroleum ether: ethyl acetate 20-80%) to give 5-(cyclopropoxy)-2-nitro-pyridine (1.10 g, 6.11 mmol, 86% yield) as a white solid. LCMS [M+1]+= 181.1.

[0217] Step 2: To a solution of 5-(cyclopropoxy)-2-nitro-pyridine (200 mg, 1.11 mmol, 1.00 eq.) in methyl alcohol (4 mL) was added palladium on activated carbon (100 mg, 1.11 mmol, 10% purity, 1.00 eq.) and the mixture was stirred at 30 °C for 4 hours undera hydrogen (15 psi) atmosphere. After completion, the reaction mixture was filtered, washed with methanol (5 mL × 2) and concentrated to give 5-(cyclopropoxy)pyridin-2-amine (120 mg, 799 µmol, 72% yield) as a black oil which used for the next step without further purification. LCMS [M+1]+= 151.1.

[0218] Step 3: To a solution of 5-(cyclopropoxy)pyridin-2-amine (120 mg, 799 µmol, 1.00 eq.) in methyl alcohol (2 mL) and water (1.0 mL) was added 2-chloroacetaldehyde (313 mg, 1.60 mmol, 257 µL, 2.00 eq.) and sodium bicarbonate (70.5 mg, 839 µmol, 1.05 eq.). The mixture was stirred at 70 °C for 2 hours. After such time the solvent was 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 used for the next step without further purification. LCMS [M+1]+= 175.2.

[0219] 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 hour. Upon completion the reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (SiO2, petroleum ether: ethyl acetate 20-80%) to give 6-(cyclopropoxy)-3-iodo-imidazo[1,2-a]pyridine, Intermediate AS (220 mg, 733 µmol, 58% yield) as a white solid. LCMS [M+1]+= 300.9.1H NMR (400 MHz, DMSO-d6) d = 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).INTERMEDIATE AT

[0220] Step 1: To a solution of 5-(trifluoromethoxy)pyridin-2-amine (250 mg, 1.40 mmol, 1.00 eq.) in methanol (5 mL) and water (2.5 mL) was added 2-chloroacetaldehyde (289 mg, 1.47 mmol, 237 µL, 1.05 eq.) and sodium bicarbonate (118 mg, 1.41 mmol, 54.8 µL, 1.00 eq.). The mixture was stirred at 70 °C for 2 hours. The reaction mixture was then concentrated under reduced pressure and the residue 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 used for the next step without further purification.

[0221] Step 2: To a solution of 6-(trifluoromethoxy)imidazo[1,2-a]pyridine (238 mg, crude) in acetonitrile (10 mL) was added N-iodosuccinimide (291 mg, 1.30 mmol) in acetonitrile (5 mL) at 0 °C, and the resulting yellow suspension was allowed to warm to 20 °C for 2 hours. The reaction mixture was then diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3) and the combined organic extracts were washed with brine (10 mL), dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate 10-15%) to give 3-iodo-6-(trifluoromethoxy)imidazo[1,2- a]pyridine, Intermediate AT (180 mg, 548 µmol, 46% yield) as yellow solid. LCMS [M+1]+= 329.0.1H NMR (400 MHz, CDCl3) d = 8.23 - 8.19 (s, 1H), 7.80 (s, 1H), 7.71 (d, J = 9.6 Hz, 1H), 7.27 (m, 1H).

[0222] Step 1: A mixture of 6-iodoimidazo[1,2-a]pyridine (500 mg, 2.05 mmol, 1.00 eq.), phenylboronic acid (275 mg, 2.25 mmol, 1.10 eq.), Pd(dppf)Cl2(150 mg, 205 µmol, 0.10 eq.),sodium bicarbonate (344 mg, 4.10 mmol, 159 µL, 2.00 eq.) in dioxane (5 mL) and water (1.00 mL) was degassed with nitrogen and stirred at 80 °C for 1 hour. After such time the reaction mixture was concentrated under reduced pressure and the residue diluted with ethyl alcohol (5 mL) and the solution was then concentrated. The residue was purified by prep-TLC (dichloromethane: methyl alcohol, 10%) to give 6-phenylimidazo[1,2-a]pyridine (250 mg, 1.29 mmol, 62% yield, ) as a white solid. LCMS [M+1]+= 195.1.

[0223] Step 2: To a solution of 6-phenylimidazo [1,2-a]pyridine (100 mg, 515 µmol, 1.00 eq.) in acetonitrile (2 mL) was added N-iodosuccinimide (127 mg, 566 µmol, 1.10 eq.) and the mixture was stirred at 0 °C for 1 hour. After such time the reaction mixture was concentrated under reduced pressure and the residue diluted with ethyl alcohol (2 mL) and the supernatant removed and concentrated under reduced pressure. The residue was purified by prep-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]+= 321.0.1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE AV

[0224] To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.00 g, 10.2 mmol, 1.00 eq.) in methyl alcohol (10 mL) was added formaldehyde (610 mg, 20.3 mmol, 559 µL, 2.00 eq.) and sodium hydroxide (812 mg, 20.3 mmol, 2.00 eq.) and the mixture was stirred at 20 °C for 2 hours. After completion the reaction mixture was then filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5-20%) then by prep-TLC (petroleum ether: ethyl acetate 20%) to give 5-bromo- 3-(methoxymethyl)-1H-pyrrolo[2,3-b]pyridine, Intermediate AV (120 mg, 498 µmol, 5% yield) as white solid. LCMS [M+1]+= 243.0.1H NMR (400 MHz, DMSO-d6) d = 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).INTERMEDIATE AX

[0225] To a solution of 5-bromopyridin-3-ol (500 mg, 2.87 mmol, 1.00 eq.) in DMF (10 mL) was added cesium carbonate (1.87 g, 5.75 mmol, 2.00 eq.), 2-iodopyridine (707 mg, 3.45 mmol, 366 µL, 1.20 eq.), 2,2,6,6-tetramethylheptane-3,5-dione (212 mg, 1.15 mmol, 237 µL, 0.40 eq.) and cuprous iodide (109 mg, 575 µmol, 0.20 eq.). The mixture was stirred at 100 °C for 0.5 hour. 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 (SiO2, 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]+= 250.8.1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE AY

[0226] To a solution of 2-chloropyrimidine (300 mg, 2.62 mmol, 1.00 eq.) in DMF (2 mL) was added potassium carbonate (724 mg, 5.24 mmol, 2.00 eq.) and 5-bromopyridin-3-ol (479 mg, 2.75 mmol, 1.05 eq.). The mixture was stirred at 110 °C for 5 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (80 mL ×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 and used into the next step directly without further purification. LCMS [M+1]+= 252.0;1H NMR (400 MHz,DMSO-d6) d = 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). INTERMEDIATE AY-1

[0227] Step 1: To a solution of 2-methylpyrazol-3-ol (500 mg, 5.10 mmol, 1.00 eq.), (bromomethyl)benzene (1.05 g, 6.12 mmol, 726 ^L, 1.20 eq.) in DMF (6.00 mL) was added potassium carbonate (1.06 g, 7.65 mmol, 1.50 eq.). The mixture was stirred at 120 °C for 4 hours. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 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) d = 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).

[0228] Step 2: To a solution of 5-benzyloxy-1-methyl-pyrazole (400 mg, 2.13 mmol, 1.00 eq.) in acetonitrile (6 mL) was added NBS (416 mg, 2.34 mmol, 1.10 eq.). The mixture was stirred at 0 °C for 0.5 hours. The reaction mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give 5-benzyloxy-4-bromo-1-methyl-pyrazole (320 mg, 1.20 mmol, 56% yield) as a yellow oil. LCMS [M+1]+= 266.9;1H NMR (400 MHz, CDCl3) d = 7.39 (s, 5H), 7.32 (s, 1H), 5.28 (s, 2H), 3.45 (s, 3H).

[0229] Intermediate AY-2 shown in Table I-IIb was prepared following the teachings of the General Reaction Schemes and the method to prepare Intermediate AY-1.GENERAL PROCEDURE FOR INTERMEDIATES B-1 to B-15

[0230] To the corresponding aryl / heteroaryl phenol (3.89 mmol, 1.00 eq.) in DMF (10 mL) was added sodium hydride (4.28 mmol, 60% purity, 1.10 eq.) at 0 °C under nitrogen. After the addition was complete the mixture was stirred at 25 °C for 0.5 hour, followed by addition with 3-bromo-5-fluoro-pyridine (3.89 mmol, 1.00 eq.) and stirred at 100 °C for a further 12 hours. After such time the reaction mixture was quenched by the addition water (10 mL) and then 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 which was used directly in the next step without further purification.

[0231] Following the teachings of the General Reaction Schemes and the general procedure for Intermediates B-1 to B-15 the intermediates in Table I-III were prepared.INTERMEDIATE BN

[0232] To a solution of 3-bromo-5-fluoro-pyridine (210 mg, 1.19 mmol, 0.95 eq.) in DMF (10 mL) was added potassium carbonate (347 mg, 2.51 mmol, 2.00 eq.) and 3-chloro-2, 4- dimethyl-phenol (197 mg, 1.26 mmol, 1.00 eq.). The mixture was stirred at 110 °C for 12 hours. After such time the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were then washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether:ethyl acetate 0- 20%) to give 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]+= 314.0.1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE BP

[0233] To a solution of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (300 mg, 949 µmol, 1.00 eq., TFA) and benzaldehyde (131 mg, 1.23 mmol, 125 µL, 1.30 eq.) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (402 mg, 1.90 mmol, 2.00 eq.) and acetic acid (114 mg, 1.90 mmol, 109 µL, 2.00 eq.). The mixture was then stirred at25 °C for 4 hours. After such time the reaction mixture was 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 prep-TLC (SiO2, 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]+= 294.0.1H NMR (400 MHz, CD3OD) d = 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). INTERMEDIATE BQ

[0234] A mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (400 mg, 1.27 mmol, 1.00 eq.), acetaldehyde (5.0 M, 508 uL, 2.01 eq.), sodium cyanoborohydride (160 mg, 2.54 mmol, 2.01 eq.), zinc chloride (1.0 M, 2.53 mL, 2.00 eq.) in methanol (8 mL) was stirred at 25 °C for 2 hours. After such time the solvent was evaporated and the residue purified by column chromatography (SiO2, dichloromethane: methanol 0-10%). The product was further purified by prep-HPLC (Waters Xbridge C18150 × 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 an colorless oil.1H NMR (400 MHz, CD3OD) d = 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). INTERMEDIATE BR

[0235] Step 1: To a mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (200 mg, 990 µmol, 1.00 eq.) and acetone (862 mg, 14.9 mmol, 1.09 mL, 15.0 eq.) in dichloromethane (1.00 mL), was added sodium triacetoxyborohydride (420 mg, 1.98 mmol, 2.00 eq.). 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 prep-TLC (SiO2, 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]+= 244.0.1H NMR (400 MHz, CDCl3) d  = 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).

[0236] Step 2: A mixture of 3-bromo-5-isopropyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine (80.0 mg, 328 µmol, 1.00 eq.), 4,4,4¢,4¢,5,5,5¢,5¢-octamethyl-2,2¢-bi(1,3,2- dioxaborolane) (166 mg, 655 µmol, 2.00 eq.), potassium acetate (113 mg, 1.15 mmol, 3.50 eq.) and PdCl2[P(Cy)3]2(24.2 mg, 32.8 µmol, 0.10 eq.) in dimethylaminopyridine (1 mL) was purged with nitrogen then stirred at 90 °C for 20 hours. The mixture was then concentrated under reduced pressure to 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. INTERMEDIATE BS

[0237] A pressure tube was charged with 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine (260 mg, 1.29 mmol, 1.00 eq.), (1-ethoxycyclopropoxy)trimethylsilane (673 mg, 3.86 mmol, 776 µL, 3.00 eq.), sodium cyanoborohydride (243 mg, 3.86 mmol, 3.00 eq.) and acetic acid (773 mg, 12.9 mmol, 736 µL, 10.0 eq.) in THF (5 mL) and ethyl alcohol (5 mL). The resulting solution was stirred for 2 hours at 60 °C, then the reaction mixture was concentrated to give a residue. The residue was purified by prep-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 yellow solid.1H NMR(400MHz, CD3OD) d = 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). INTERMEDIATE BT

[0238] A mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (500 mg, 1.58 mmol, 1.00 eq.), iodobenzene (1.29 g, 6.33 mmol, 705 µL, 4.00 eq.), copper iodide (60.3 mg, 316 µmol, 0.20 eq.), (2S)-pyrrolidine-2-carboxylic acid (72.9 mg, 633 µmol, 0.40 eq.) and cesium carbonate (1.03 g, 3.16 mmol, 2.00 eq.) in DMF (10 mL) was degassed and purged with nitrogen then stirred at 100 °C for 1.5 hours. After such time the mixture was cooled, extracted with ethyl acetate (5 mL × 3), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The formed residue was purified by column chromatography (SiO2, 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 yellow solid. LCMS [M+1]+= 278.2. INTERMEDIATE BU

[0239] A mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (200 mg, 633 µmol, 1.00 eq.), acetyl acetate (96.9 mg, 949 µmol, 88.9 µL, 1.50 eq.) and DMAP (7.73 mg, 63.3 µmol, 0.10 eq.) in dichloromethane (10 mL) was degassed and purged with nitrogen then stirred at 40 °C for 3 hours. Upon completion the reaction mixture was concentrated under reduced pressure to give 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.INTERMEDIATE BV

[0240] To a solution of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (250 mg, 791 µmol, 1.00 eq.) in dimethylformamide (2 mL) was added triethylamine (240 mg, 2.37 mmol, 330 µL, 3.00 eq.), HATU (601 mg, 1.58 mmol, 2.00 eq.), and cyclopropane carboxylic acid (102 mg, 1.19 mmol, 93.7 µL, 1.50 eq.). The mixture was stirred at 35 °C for 1 hour. After such time the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30.0 mL × 3) and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The formed residue was purified by column chromatography (SiO2, 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.1H NMR (400 MHz, CDCl3) d = 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).

[0241] Following the teachings of the General Reaction Schemes, and the procedure for INTERMEDIATE BV, INTERMEDIATES C-1 to C-5 were prepared as shown in Table I-IV:INTERMEDIATE CB

[0242] A mixture of 3-bromo-5-iodo-pyridine (3.00 g, 10.6 mmol, 1.00 eq.), intermediate AN (2.28 g, 5.28 mmol, 0.50 eq.), sodium bicarbonate (1.78 g, 21.1 mmol, 822 µL, 2.00 eq.), Pd(dppf)Cl2(773 mg, 1.06 mmol, 0.10 eq.) in dioxane (50 mL) and water (10 mL) was degassed with nitrogen 3 then stirred at 80 °C for 1 hour. The cooled reaction mixture was then concentrated under reduced, diluted with water (200 mL), filtered and the filter cake was triturated with dichloromethane: methyl alcohol (10%, 150 mL). The solid was filtered, dried and the solid was triturated a second time in methyl alcohol (100 mL), then filtered and dried to 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.1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE CC

[0243] Step 1: To a solution of pyrazolo[1,5-a]pyridin-5-ol (250 mg, 1.86 mmol, 1.00 eq.) in DMF (2 mL) was added potassium carbonate (773 mg, 5.59 mmol, 3.00 eq.) and the mixture stirred at 30 °C for 0.5 hour. Iodoethane (872 mg, 5.59 mmol, 447 ^L, 3.00 eq.) was then added and the resulting mixture stirred at 30 °C for 12 hours. After such time the reaction mixture was diluted with water (50 mL) extracted with ethyl acetate (20 mL × 3) and 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 prep- TLC (SiO2, Petroleum ether / Ethyl acetate 20%) to give 5-ethoxypyrazolo[1,5-a]pyridine (272 mg, 1.68 mmol, 90% yield) as a white solid. LCMS [M+1]+= 163.2;1H NMR (400 MHz, DMSO-d6) d = 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).

[0244] Step 2: To a solution of 5-ethoxypyrazolo[1,5-a]pyridine (260 mg, 1.60 mmol, 1.00 eq.) in acetonitrile (1.0 mL) was added NIS (397 mg, 1.76 mmol, 1.10 eq.). The mixture was stirred at 25 °C for 1 hour before 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 prep-TLC (SiO2, 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) d = 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). INTERMEDIATE CD

[0245] Intermediate CD, 3-iodo-5-isopropoxy-pyrazolo[1,5-a]pyridine was prepares as a yellow solid (299 mg, 0.99 mmol, 87% yield over 2 steps) using 2-iodopropane following the same procedure as used for the preparation of Intermediate CC. LCMS [M+1]+= 303.0;1HNMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE CE

[0246] Step 1: A mixture of pyrazolo[1,5-a]pyridin-5-ol (300 mg, 2.24 mmol, 1.00 eq.), phenylboronic acid (545 mg, 4.47 mmol, 2.00 eq.), 4Å MS (30 mg), copper acetate (812 mg, 4.47 mmol, 2.00 eq.) and triethylamine (1.13 g, 11.2 mmol, 1.56 mL, 5.00 eq.) in dichloromethane (10 mL) was degassed with oxygen and stirred at 25 °C for 10 hours under an oxygen (15 psi) atmosphere. After such time the reaction mixture was filtered, concentrated and the formed residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 0-20%) to give 5-phenoxypyrazolo[1,5-a]pyridine (200 mg, 0.95 mmol, 43% yield) as a yellow oil. LCMS [M+1]+= 211.2.

[0247] Step 2: To a solution of 5-phenoxypyrazolo[1,5-a]pyridine (180 mg, 0.86 mmol, 1.00 eq.) in acetonitrile (2 mL) was added NIS (212 mg, 0.94 mmol, 1.10 eq.). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was then concentrated and the residue purified by column chromatography (SiO2, petroleum ether / ethyl acetate 0-5%) to give 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. INTERMEDIATE CF

[0248] 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 eq.), [(E)-2-bromovinyl]benzene (2.90 g, 15.8 mmol,2.03 mL, 2.20 eq.), Pd(PPh3)2Cl2(506 mg, 721 umol, 0.10 eq.), potassium carbonate (1.30 g, 9.41 mmol, 1.30 eq.) in ethyl alcohol (3.8 mL) and DMF (7.5 mL) was degassed with nitrogen and then stirred at 75 °C for 2 hours. After such time the mixture was cooled to ambient temperature, diluted with water (100 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. The residue was purified by column chromatography (SiO2, Petroleum ether / ethyl acetate 0-20%) to give 1-methyl-5-[(E)- styryl]pyrazole (990 mg, 5.37 mmol, 74% yield) as a yellow solid. LCMS [M+1]+= 185.2;1H NMR (400 MHz, DMSO-d6) d = 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).

[0249] Step 2: To a solution of 1-methyl-5-[(E)-styryl]pyrazole (400 mg, 2.17 mmol, 1.00 eq.) in ethyl alcohol (3 mL) was added Pd / C (10.0 mg, 10% Pd) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times and the mixture was then stirred under hydrogen (15.0 psi) at 25 °C for 12 hours. After such time the reaction mixture was filtered and concentrated under reduced pressure to give 1-methyl-5-(2- phenylethyl)pyrazole (385 mg, 1.93 mmol, 89% yield) as a yellow oil and used into the next step without further purification. LCMS [M+1]+= 187.2.

[0250] Step 3: To a solution of 1-methyl-5-(2-phenylethyl)pyrazole (385 mg, 1.93 mmol, 1.00 eq.) in acetonitrile (10 mL) was added N-bromosuccinimide (343 mg, 1.93 mmol, 1.00 eq.). The mixture was then stirred at 0 °C for 0.5 hour. After such time the reaction mixture was concentrated under reduced pressure and the residue purified by prep-TLC (SiO2, Petroleum ether / ethyl acetate 20%) to give 4-bromo-1-methyl-5-(2-phenylethyl)pyrazole (430 mg, 1.62 mmol, 84% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE CG

[0251] 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 eq.), 2-bromopyridine (911 mg, 5.77 mmol, 0.55 mL, 1.20 eq.), cesium carbonate (3.13 g, 9.61 mmol, 2.00 eq.) and Pd(dppf)Cl2(352 mg, 0.48 mmol, 0.10 eq.) in dioxane (10 mL) and water (2 mL) was degassed and purged with nitrogen and then the mixture was stirred at 100 °C for 1 hour. After such time the cooled reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 0-20%) to give 2-(2-methylpyrazol-3-yl)pyridine (860 mg, crude) as a red oil which used into the next step directly without further purification.1H NMR (400 MHz, DMSO-d6) d = 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).

[0252] 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 hour. The reaction mixture was then concentrated under reduced pressure and the residue purified by prep-TLC (SiO2, 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.1H NMR (400 MHz, DMSO-d6) d = 8.77 (td, J = 0.8, 4.0 Hz, 1H), 8.01 (dt, J = 2.0, 7.6 Hz, 1H), 7.76 –

[0253] Step 3: To a solution of 2-(4-bromo-2-methyl-pyrazol-3-yl)pyridine (150 mg, 0.63 mmol, 1.00 eq.) in dichloroethane (3 mL) was added meta-chloroperbenzoic acid (435 mg, 2.14 mmol, 85% purity, 3.40 eq.). The mixture was stirred at 60 °C for 5 hours. The reaction mixture was then quenched by addition saturated sodium sulfite solution (20 mL) and 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 purified by prep-TLC (SiO2, 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 into the next step directly without further purification. LCMS [M+1]+= 254.1;1H NMR (400 MHz, DMSO-d6) d = 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).INTERMEDIATE CH

[0254] Step 1: A mixture of quinolin-8-ol (454 mg, 3.13 mmol, 0.54 mL, 1.10 eq.), 3- bromo-5-fluoro-pyridine (500 mg, 2.84 mmol, 1.00 eq.), potassium carbonate (785 mg, 5.68 mmol, 2.00 eq.) in DMF (6 mL) was degassed with nitrogen then stirred at 110 °C for 3 hours. After such time the mixture was 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;1H NMR (400 MHz, CDCl3) d = 8.95 (dd, J = 2.0, 4.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.25 (dd, J = 2.0, 8.4 Hz, 1H), 7.73 (dd, J = 1.6, 8.4 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.50 (dd, J = 4.0, 8.4 Hz, 1H), 7.47 - 7.43 (m, 2H). INTERMEDIATE CI

[0255] Step 1: A mixture of 3,5-dibromopyridine (1.48 g, 6.25 mmol, 1.00 eq.), quinolin-8- amine (901 mg, 6.25 mmol, 1.00 eq.), sodium tert-butoxide (901 mg, 9.37 mmol, 1.50 eq.), Pd2(dba)3 (57.2 mg, 62.5 mmol, 0.01 eq.) and Xantphos (72.3 mg, 125 mmol, 0.02 eq.) in dioxane (10 mL) was degassed with nitrogen then stirred at 100 °C for 2 hours. After such time the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by reversed-phase HPLC (0.1% formic acid (FA) condition) to give N-(5-bromo-3-pyridyl) quinolin-8-amine (160 mg, 486 mmol, 7% yield) as a yellow solid. LCMS [M+1]+= 300.0;1H NMR (400 MHz, CDCl3) d = 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).

[0256] Step 2: N-(5-bromo-3-pyridyl)quinolin-8-amine (130 mg, 394 mmol, 1.00 eq.) was dissolved in DMF (2 mL), then sodium hydride (32 mg, 790 mmol, 60.0% purity, 2.00 eq.) was added at 0 °C and the mixture was stirred at 0 °C for 10 minutes. After such time methyl iodide (224 mg, 1.58 mmol, 98 ^L, 4.00 eq.) was added and the resulting mixture was stirred at 20 °C for 1 hour. The reaction mixture was then quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3) and the combined organic phases were 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 mmol, 85% yield) as a yellow oil. LCMS [M+1]+= 314.1;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE CJ

[0257] Step 1: A mixture of 2-ethylbenzonitrile (500 mg, 3.81 mmol, 0.51 mL, 1.00 eq.), p- toluenesulfonic acid (363 mg, 1.91 mmol, 0.50 eq.), N-Bromosuccinimide (746 mg, 4.19 mmol, 1.10 eq.) and palladium acetate (85.6 mg, 0.38 mol, 0.10 eq.) in 1,2-dichloroethane (10 mL) was degassed with nitrogen then stirred at 70 °C for 12 hours. After such time the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 0-5%) to give 2-bromo-6-ethyl- benzonitrile (446 mg, 1.15 mmol, 30% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) d = 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).

[0258] Step 2: A mixture of 2-bromo-6-ethyl-benzonitrile (446 mg, 1.15 mmol, 1.00 eq.), 4-bromo-1-methyl-pyrazole (203 mg, 1.26 mmol, 1.10 eq.), palladium acetate (2.57 mg, 0.12mmol, 0.01 eq.), DavePhos (9.0 mg, 0.23 mmol, 0.02 eq.), 2-methylpropanoic acid (30.3 mg, 0.34 mmol, 31.9 uL, 0.30 eq.) and tetrabutylammonium acetate (691 mg, 2.29 mmol, 0.70 mL, 2.00 eq.) in N-methyl pyrrolidone (10 mL) was degassed with nitrogen then stirred at 100 °C for 12 hours. After such time the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (60 mL × 3) and 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;1H NMR (400 Hz, DMSO- d6) d = 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).

[0259] The INTERMEDIATES D-1 to D-20 shown in Table I-V were prepared following the teachings of the General Reaction Schemes and the method to prepare INTERMEDIATE CJ.INTERMEDIATE DA

[0260] Step 1: A mixture of 3-bromophenol (1.00 g, 5.78 mmol, 1.00 eq.), bromocyclobutane (1.17 g, 8.65 mmol, 0.82 mL, 1.50 eq.) and potassium carbonate (3.20 g, 23.1 mmol, 4.00 eq.) in DMF (10 mL) and 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) and 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) d = 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).

[0261] Step 2: 1-bromo-3-(cyclobutoxy)benzene (300 mg, 1.32 mmol, 1.00 eq.), 4-bromo- 1-methyl-pyrazole (213 mg, 1.32 mmol, 1.00 eq.), palladium acetate (2.97 mg, 13.2 mmol, 0.01 eq.), tetrabutylammonium acetate (224 mg, 2.91 mmol, 2.20 eq.), 2-methylpropanoic acid (34.9 mg, 396 mmol, 36.8 ^L, 0.30 eq.) and DavePhos (10.4 mg, 26.4 mmol, 0.02 eq.) in NMP (5 mL) was degassed with nitrogen and heated to 100°C for 12 hours. The reaction mixture was then diluted with water (20 mL), extracted with ethyl acetate (30 mL × 3) and the combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 1-5%) to give 4-bromo-5-[3- (cyclobutoxy)phenyl]-1-methyl-pyrazole (40.0 mg) as a yellow oil.1H NMR (400 MHz, CDCl3) d = 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).

[0262] The INTERMEDIATES E-1 and E-2 shown in Table I-VI were prepared following the teachings of the General Reaction Schemes and the method to prepare Intermediate DA.INTERMEDIATE DB

[0263] 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 eq.), 1-bromo-2-chloro-benzene (1.38 g, 7.21 mmol, 0.84 mL, 1.00 eq.), sodium carbonate (2.29 g, 21.6 mmol, 3.00 eq.), Pd(dppf)Cl2(528 mg, 0.72 mmol, 0.10 eq.) in water (2.4 mL) and dioxane (12 mL) was degassed with nitrogen then stirred at 80 °C for 2 hours. After such time the mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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).

[0264] Step 2: A mixture of 5-(2-chlorophenyl)-1-methyl-pyrazole (200 mg, 1.04 mmol, 1.00 eq.), N-bromo-succinimide (203 mg, 1.14 mmol, 1.10 eq.) in acetonitrile (2 mL) was degassed with nitrogen then stirred at 0 °C for 2 hours. After such time the mixture was concentrated under reduced pressure and the residue was purified by prep-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) d = 7.59 - 7.55 (m, 2H), 7.50 - 7.40 (m, 2H), 7.36 - 7.33 (m, 1H), 3.74 (s, 3H).

[0265] The INTERMEDIATES F-1 to F-22 shown in Table I-VII were prepared following the teachings of the General Reaction Schemes and the method to prepare INTERMEDIATE DB.INTERMEDIATE DC

[0266] Step 1: To a solution of 2-bromonaphthalene-1-carbaldehyde (220 mg, 0.94 mmol, 1.00 eq.) in water (5 mL) was added amino hydrogen sulfate (212 mg, 1.87 mmol, 2.00 eq.). The mixture was stirred at 50 °C for 12 hours. The suspension was then filtered and the filter cake dried under reduced pressure to give (1E)-2-bromonaphthalene-1-carbaldehyde oxime (220 mg, 0.88 mmol, 94% yield) as a white solid which used without further purification.1H NMR (400 MHz, DMSO-d6) d = 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 stirred at 20 °C for 1 hour. After such time the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (SiO2, 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;1H NMR (400 MHz, DMSO-d6) d = 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).

[0267] Step 2: A mixture of 2-bromonaphthalene-1-carbonitrile (190 mg, 0.82 mmol, 1.00 eq.), 4-bromo-1-methyl-pyrazole (132 mg, 0.82 mmol, 1.00 eq.), tetrabutylammonium acetate (494 mg, 1.64 mmol, 0.50 mL, 2.00 eq.), DavePhos (6.4 mg, 16 mmol, 0.02 eq.), 2- methylpropanoic acid (22 mg, 246 mmol, 23 ^L, 0.30 eq.) and palladium acetate (1.8 mg, 8.2 mmol, 0.01 eq.) in N-methyl pyrrolidone (NMP) (6 mL) was degassed with nitrogen then themixture was stirred at 100 °C for 12 hours. After such time the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) 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;1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE DD

[0268] Step 1: To a solution of ethyl alcohol (207 mg, 4.50 mmol, 0.26 mL, 3.00 eq.) in THF (3 mL) was added sodium hydride (180 mg, 4.50 mmol, 60.0% purity, 3.00 eq.), followed by a solution of 2-bromo-6-fluoro-benzonitrile (300 mg, 1.50 mmol, 1.00 eq.) in THF (1 mL) in a dropwise fashion. After the addition was complete the mixture was stirred at 25 °C for 3 hours. After such time the reaction was quenched with water (0.2 mL) and concentrated in vacuum and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10%) to give 2-bromo-6-ethoxy-benzonitrile (200 mg, 0.89 mmol, 59% yield) as a white solid.1H NMR (400 MHz, CDCl3) d = 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).

[0269] Step 2: A mixture of 2-bromo-6-ethoxy-benzonitrile (200 mg, 0.89 mmol, 1.00 eq.), 4-bromo-1-methyl-pyrazole (185 mg, 1.15 mmol, 1.30 eq.), palladium acetate (2.0 mg, 8.9 mmol, 0.01 eq.), DavePhos (7.0 mg, 17.7 mmol, 0.02 eq.), 2-methylpropanoic acid (23.4 mg, 265 mmol, 25 ^L, 0.30 eq.) and tetrabutylammonium acetate (533 mg, 1.77 mmol, 2.00 eq.) was degassed with nitrogen then the mixture was stirred at 100 °C for 15 hours. After such time the mixture was diluted with ethyl acetate (20 mL), washed with water (20 mL × 3) and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was then purified by prep-TLC (SiO2, petroleumether / 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) d = 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). INTERMEDIATE DE

[0270] A mixture of 4-bromo-2-methyl-pyrazol-3-ol (300 mg, 1.69 mmol, 1.00 eq.), 1- (bromomethyl)-2-chloro-benzene (348 mg, 1.69 mmol, 0.22 mL, 1.00 eq.), and potassium carbonate (469 mg, 3.39 mmol, 2.00 eq.) in DMF (8 mL) was was stirred at 18 °C for 2 hours. After such time the reaction mixture was 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, concentrated under reduced pressure and the residue purified by reversed-phase HPLC (0.1% FA condition) 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;1H NMR (400 MHz, CDCl3) d = 7.48 - 7.43 (m, 2H), 7.37 - 7.27 (m, 3H), 5.40 (s, 2H), 3.55 (s, 3H).

[0271] The INTERMEDIATES to G-1 to G-4 shown in Table I-VIII were prepared following the teachings of the General Reaction Schemes and the method to prepare INTERMEDIATE DE.INTERMEDIATE H-1

[0272] Step 1: A mixture of 2-bromo-6-fluoro-benzonitrile (600 mg, 3.00 mmol, 1.00 eq.), propan-2-ol (225 mg, 3.75 mmol, 0.29 mL, 1.25 eq.), cesium carbonate (1.47 g, 4.50 mmol, 1.50 eq.) in DMF (6 mL) was stirred at 75 °C for 1 hour. After such time the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 2-bromo-6-isopropoxy-benzonitrile (540 mg, 2.25 mmol, 75% yield) as a white solid. LCMS [M+1]+= 241.9;1H NMR (400 MHz, DMSO-d6) d = 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).

[0273] Step 2: A mixture of 2-bromo-6-isopropoxy-benzonitrile (500 mg, 2.08 mmol, 1.00 eq.), 4-bromo-1-methyl-pyrazole (335 mg, 2.08 mmol, 1.00 eq.), diacetoxypalladium (4.7 mg, 0.021 mmol, 0.01 eq.), DavePhos (16 mg, 0.042 mmol, 0.02 eq.), tetrabutylammonium;acetate (1.26 g, 4.16 mmol, 2.00 eq.) and 2-methylpropanoic acid (55 mg, 0.63 mmol, 0.06 mL, 0.30 eq.) in 1-methyl-2-pyrrolidinone (7 mL) was degassed with nitrogen then stirred at 100 °C for 12 hours. After such time the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (0.1% formic acid condition) to give 2-(4- bromo-2-methyl-pyrazol-3-yl)-6-isopropoxy-benzonitrile (160 mg, 0.50 mmol, 24 yield) as awhite solid. LCMS [M+1]+= 319.9;1H NMR (400 MHz, DMSO-d6) d = 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).

[0274] The INTERMEDIATES to H-2 to H-8 shown in Table I-IX were prepared following the teachings of the General Reaction Schemes and the method to prepare INTERMEDIATE H-1.INTERMEDIATE I-1

[0275] Step 1: To a solution of 6-hydroxychromane-5-carbonitrile (150 mg, 0.86 mmol, 1.00 eq.) and triethylamine (2.57 mmol, 0.36 mL, 3.00 eq.) in dichloromethane (2 mL) was added a solution of trifluoromethanesulfonic anhydride (0.86 mmol, 0.141 mL, 1.00 eq.) in dichloromethane (1 mL) dropwise at 0 °C, The mixture was then stirred at 0 °C for 0.5 hour. After such time the mixture was diluted with ethyl acetate (50 mL), washed with brine (50 mL × 3) and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate 10%) to give (5-cyanochroman-6- yl) trifluoromethanesulfonate (80 mg, 0.26 mmol, 30% yield) as a colorless liquid.1H NMR (400 MHz, CDCl3) d = 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).

[0276] Step 2: A mixture of (5-cyanochroman-6-yl) trifluoromethanesulfonate (70 mg, 0.23 mmol, 1.00 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (71.mg, 0.34 mmol, 1.50 eq.), Pd(dtbpf)Cl2(15 mg, 0.23 mmol, 0.10 eq.), sodium bicarbonate (38 mg, 0.46 mmol, 2.00 eq.) in DMF (2 mL) was degassed with nitrogen. The mixture was then stirred at 80 °C for 1 hour, cooled to 25 °C, diluted with ethyl acetate (30 mL) and washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate 30%) 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).

[0277] Step 3: To a solution of 6-(2-methylpyrazol-3-yl)chromane-5-carbonitrile (30 mg, 0.125 mmol, 1.00 eq.) in acetonitrile (1.5 mL) was added NBS (34 mg, 0.19 mmol, 1.50 eq.). The mixture was stirred at 25 °C for 1 hour then concentrated. The residue was purified by prep-TLC (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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).

[0278] The INTERMEDIATES to I-2 to I-4 shown in Table I-X were prepared following the teachings of the General Reaction Schemes and the method to prepare INTERMEDIATE I-1INTERMEDIATE DF

[0279] A mixture of tert-butyl 5-bromo-3-iodo-pyrrolo[2,3-b]pyridine-1-carboxylate (120 mg, 0.28 mmol, 1 eq) , (2-cyanophenyl)boronic acid (83 mg, 0.57 mmol, 2 eq) , Pd(dppf)Cl2(21 mg, 0.03 mmol, 0.1 eq) , NaHCO3(71 mg, 0.85 mmol) in DMF (2 mL) was degassed with nitrogen then stirred at 80 °C for 3 hr. After such time mixture was diluted with ethyl acetate (20 mL) and washed by water (20 mL x 3). The organic phase was concentrated and the residue purified by by prep-TLC (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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).INTERMEDIATE DG

[0280] Step 1: A mixture of 6-bromo-7-methoxy-quinoline (100 mg, 0.420 mmol, 1.00 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (105 mg, 0.504 mmol, 1.20 eq.), Pd(dtbpf)Cl2(27 mg, 0.042 mmol, 0.10 eq.) and sodium carbonate (89 mg, 0.840 mmol, 2.00 eq.) in dioxane (1.0 mL) and water (0.2 mL) was degassed with nitrogen. The mixture was then stirred at 80 °C for 2 hours, concentrated under reduced pressure and the residue purified by prep-TLC (SiO2,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;1H NMR (400 MHz, CDCl3) d = 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).

[0281] Step 2: A mixture of 7-methoxy-6-(2-methylpyrazol-3-yl)quinoline (500 mg, 2.09 mmol, 1.00 eq.) and pyridine hydrochloride (2.41 g, 20.9 mmol, 10.0 eq.) was stirred at 160 °C for 0.5 hour. After such time the residue was purified by reverse prep-HPLC (0.1% formic acid) to give 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.

[0282] Step 3: To a solution of 6-(2-methylpyrazol-3-yl)quinolin-7-ol (260 mg, 1.15 mmol, 1.00 eq.) and triethylamine (0.32 mL, 2.31 mmol, 2.00 eq.) in dichloromethane (5 mL) was added trifluoromethanesulfonic anhydride (0.29 mL, 1.73 mmol, 1.50 eq.) in a dropwise fashion 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 and concentrated and the residue purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10-100%) to give [6-(2-methylpyrazol-3-yl)-7-quinolyl] trifluoromethanesulfonate (0.97 g, 0.706 mmol, 61%) as a yellow oil. LCMS [M+1]+= 358.1.

[0283] Step 4: A mixture of [6-(2-methylpyrazol-3-yl)-7-quinolyl] trifluoromethanesulfonate (970 mg, 0.668 mmol, 1.00 eq.), zinc cyanide (157 mg, 1.34 mmol, 2.00 eq.), Pd2(dba)3(61 mg, 0.67 mmol, 0.1 eq.), DPPF (74 mg, 0.134 mmol, 0.20 eq.) and zinc powder (4.3 mg, 0.67 mmol, 0.10 eq.) in DMF (10 mL) was degassed with nitrogen then stirred at 100 °C for 2 hours. After such time the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by HPLC (0.1% formic acid condition) 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.

[0284] Step 5: To a solution of 6-(2-methylpyrazol-3-yl)quinoline-7-carbonitrile (90 mg, 0.384 mmol, 1.00 eq.) in acetonitrile (5 mL) was added N-bromosuccinimide (103 mg, 0.576 mmol, 1.50 eq.). The mixture was stirred at 20 °C for 0.5 hours then concentrated under reduced pressure and the residue was purified by prep-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;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE DH

[0285] Step1: A mixture of 6-bromo-7-methoxy-quinoline (100 mg, 0.420 mmol, 1.00 eq.), zinc cyanide (98 mg, 0.840 mmol, 2.00 eq.), Pd2(dba)3 (38 mg, 0.042 mmol, 0.10 eq.), DPPF (47 mg, 0.084 mmol, 0.20 eq.) and zinc powder (2.8 mg, 0.042 mmol, 0.10 eq.) in DMF (2 mL) was degassed and purged with nitrogen. The mixture was then stirred at 100 °C for 2 hours then diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). Thecombined 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) d = 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).

[0286] Step 2: To a solution of 7-methoxyquinoline-6-carbonitrile (1.40 g, 7.60 mmol, 1.00 eq) in toluene (20 mL) was added aluminum trichloride (3.04 g, 22.8 mmol, 1.25 mL, 3.00 eq). The mixture was stirred at 100 °C for 1 hour and then the reaction mixture was diluted with water (3 mL) and pH adjusted to 4-5 with sodium hydroxide (2N, 0.1 mL). The formed solid was filtered and dried under reduced pressure to give 7-hydroxyquinoline-6-carbonitrile (1.20 g, crude) as a black solid which used into next step directly without further purification. LCMS [M+1]+= 171.1.

[0287] Step 3: To a solution of 7-hydroxyquinoline-6-carbonitrile (500 mg, 2.94 mmol, 1 eq.) and triethylamine (0.82 mL, 5.88 mmol, 2.00 eq.) in dichloromethane (10 mL) was added trifluoromethanesulfonic anhydride (0.73 mL, 4.41 mmol, 1.50 eq.) in a dropwise fashion at 0 °C. The mixture was stirred at 20 °C for 1 hour and after such time 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 (SiO2, petroleum ether / ethyl acetate 10-50%) to give (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) d = 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).

[0288] Step 4: A mixture of (6-cyano-7-quinolyl) trifluoromethanesulfonate (237 mg, 0.541 mmol, 1.00 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (135 mg, 0.649 mmol, 1.20 eq.), sodium bicarbonate (91 mg, 1.08 mmol, 2.00 eq.) and Pd(dtbpf)Cl2(35 mg, 0.054 mmol, 0.10 eq.) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and stirred at 80 °C for 1 hour. After such time the mixture was concentrated and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10- 100%) to give 7-(2-methylpyrazol-3-yl)quinoline-6-carbonitrile (120 mg, 0.498 mmol, 92% yield) as a yellow solid. LCMS [M+1]+= 235.2.

[0289] Step 5: A mixture of 7-(2-methylpyrazol-3-yl)quinoline-6-carbonitrile (120 mg, 0.512 mmol, 1.00 eq.) and N-bromosuccinimide (164 mg, 0.922 mmol, 1.80 eq.) in acetonitrile (4 mL) was degassed with nitrogen and stirred at 20 °C for 2 hours. After such time the mixture was concentrated and the residue was purified by prep-TLC (SiO2, 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) d = 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). INTERMEDIATE DI

[0290] To a solution of N-(4-bromo-2-methyl-pyrazol-3-yl)benzamide (500 mg, 1.78 mmol, 1.00 eq.) in DMF (5 mL) at 0 °C was added sodium hydride (143 mg, 3.57 mmol, 60.0% purity, 2.00 eq.) and the mixture stirred at 0 °C for 30 minutes. After such time iodomethane (0.133 mL, 2.14 mmol, 1.20 eq.) in DMF (1 mL) was added and the mixture was stirred at 0 °C for a further 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.1H NMR (400 MHz, DMSO-d6) d = 7.44 (s, 1H), 7.36 - 7.41 (m, 1H), 7.26 - 7.33 (m, 4H), 3.72 (s, 3H), 3.23 (s, 3H).INTERMEDIATE DJ

[0291] Step 1: To a stirred solution of methyl 7-bromo-4-oxo-3H-phthalazine-1- carboxylate (1.00 g, 3.53 mmol, 1.00 eq.), sodium borodeuteride (347 mg, 9.18 mmol, 2.60 eq.) in methanol-d4 (30 mL) at 0 °C was added calcium chloride (470 mg, 4.24 mmol, 1.20 eq.). The mixture then stirred at 0 °C for 3 hours then at 20 °C for 1 hour. After such time the reaction mixture was concentrated. The residue was diluted with water (30 mL), the pH adjusted to 5 with hydrochloric acid (1N, 5 mL) and the mixture filtered and the filter cake washed with water (5 mL × 3) 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;1H NMR (400 MHz, DMSO-d6) d = 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).

[0292] Step 2: A mixture of 6-bromo-4-((hydroxy-d)methyl-d2)phthalazin-1(2H)-one (463 mg, 1.61 mmol, 1.00 eq.) and thionyl chloride (10 mL) was stirred at 30 °C for 12 hours. After such time the mixture was concentrated and the residue dissolved in dichloromethane and concentrated 3 times (2 mL × 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.

[0293] Step 3: To a solution of 6-bromo-4-(chloromethyl-d2)phthalazin-1(2H)-one (450 mg, 1.63 mmol, 1.00 eq.) in DMF (3 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (454 mg, 2.45 mmol, 1.50 eq.) amd the mixture stirred at 90 °C for 2 hours. After such time the cooled reaction mixture was 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; 1H NMR (400 MHz, DMSO-d6) d = 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).

[0294] 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 and after such time the mixture was concentrated and the residue 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 2 steps) as a white solid. LCMS [M+1]+= 352.1;1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE DK

[0295] Step1: 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. KMnO4was then added carefully in 10 batches (165 g, 1.04 mol) and the temperature maintained below 80 °C to avoid an uncontrolled exotherm. After completion of the addition the mixture was stirred at 60 °C for 6 hrs. After such time the mixture was 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 for 30 min at 0 °C. After such time the clear colorless mixture was filtrated with celatom and the filter cake was washed with water (100 mL) and the aqueous phase washed with MTBE (200 mL). The aqueous phase was then acidified to pH 2 by the addition of 3M HCl followed by extractionwith ethyl acetate (300 mL × 3). The combined organic phases were washed with brine (300 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 4- bromo-2-(carboxycarbonyl)-6-chlorobenzoic acid (20.0 g, 65.0 mmol, 36% yield) as white solid. LCMS [M-1] - = 306.8;1H NMR (400 MHz, DMSO-d6) d 12.7 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H).

[0296] 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 NH2NH2•H2O (4.30 g, 85.9 mmol) in one portion under N2. The mixture was then stirred at 70 °C for 1 hr. After such time the cooled reaction mixture was filtered, washed and the solid dried in vacuum to give 7-bromo- 5-chloro-4-oxo-3,4-dihydrophthalazine-1-carboxylic acid (14.0 g, 46.1 mmol, 71% yield) as white solid. LCMS [M+1]+= 305.2;1H NMR (400 MHz, DMSO-d6) d 7.77 (d, J =2.0 Hz, 1H), 7.59 (d, J =2.0 Hz, 1H).

[0297] 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 conc. H2SO4(9.23 g, 92.2 mmol) in one portion under nitrogen. The mixture was then heated to 70 °C for 16 hrs then allowed to cool to ambient temperature, filtered and dried gave methyl 7-bromo-5-chloro-4- oxo-3,4-dihydrophthalazine-1-carboxylate (7.50 g, 23.6 mmol, 51% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) d 13.2 (s, 1H), 6.68 (d, J =1.6 Hz, 1H), 8.18 (d, J =1.6 Hz, 1H).

[0298] Step 4: 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) was added NaBH4 (2.32 g, 61.4 mmol) at 0 °C followed by the careful, slow addition of CaCl2(3.15 g, 28.3 mmol) at 0 °C over 2 hours. The mixture was then allowed to warm to 15 °C and stirred for a further 2 hours. After such time the reaction was poured onto sat. NH4Cl (100 mL) and the solid 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 white solid. LCMS [M+1]+= 291.0;1H NMR (400 MHz, DMSO-d6) d 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: A mixture of 6-bromo-8-chloro-4-(hydroxymethyl)phthalazin-1(2H)-one (4.00 g, 13.8 mmol) and SOCl2(36.4 g, 306 mmol) was stirred at 65 °C for 1 hr. After such time the mixture was concentrated, and the crude residue 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 light yellow solid.LCMS [M+1]+= 309.1;1H NMR (400 MHz, DMSO-d6) d 12.9 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 5.06 (s, 1H).

[0299] 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 stirred at 0 °C for 2 hrs. After such time the mixture was poured onto ice-water (200 mL), stirred for 30 min., filtered then the solid was dried and then triturated with MeOH (30 mL) at 15 °C for 30 min. The solid was filtered and dried to 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 light yellow solid. LCMS [M+1]+= 420.0;1H NMR (400 MHz, DMSO-d6) d 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).

[0300] 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. Then Pd(dppf)Cl2(114 mg, 0.16 mmol) was added and the mixture stirred at 70 °C for 2.5 hrs. After such time the mixture was cooled to room temperature, filtered and the concentrated residue 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 light yellow solid. LCMS [M+1]+= 383.9;1H NMR (400 MHz, DMSO- d6) d 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). INTERMEDIATE DL

[0301] 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 as a white solid (200 mg,0.42 mmol, 2.1% yield) in 7 steps from 1-(5-bromo-3-fluoro-2-methylphenyl)ethan-1-one. LCMS [M+1] = 368.1;1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE DM

[0302] 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 hrs and after such time 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 with anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to dry to afford 5-bromo-N- methoxy-N,2-dimethyl-3-pivalamidobenzamide (135 g, 378 mmol, 99% yield) as brown oil.1H NMR: 400 MHz, DMSO-d6 d 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).

[0303] 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 allowed to warm to 20°C and stirred for 12 hrs. After such time an additional aliquot of MeMgBr (3 M, 63.0 mL) was added and the mixture stirred for a further4 hrs. The mixture was then diluted with NH4Cl (1.5 L), extracted with ethyl acetate (1.0 L × 3) and the combined organic phases were washed with brine (1.0 L), dried with anhydrous Na2SO4and filtered. The filtrate was concentrated to afford N-(3-acetyl-5-bromo-2- methylphenyl)pivalamide (115 g, 368 mmol, 98% yield) as yellow solid.1H NMR 400 MHz, DMSO-d6 d 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).

[0304] Step 3: To a solution of N-(3-acetyl-5-bromo-2-methylphenyl)pivalamide (57.5 g, 184 mmol) in H2O (600 mL) was added K2CO3 (50.9 g, 368 mmol) and KMnO4(204 g, 1.29 mol) at 50 °C. The result solution was stirred at 50°C for 17 hrs. After such time the reaction mixture was quenched by saturated sodium thiosulfate solution and filtered through diatomite. The pH was adjusted to 2 with 2N HCl and the mixture extracted with an ethyl acetate:THF 10:1 mixture (1.00 L × 3), washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-bromo-2-(carboxycarbonyl)-6- pivalamidobenzoic acid (58.0 g, crude) as light yellow oil.1H NMR 400 MHz, DMSO-d6 d 9.87 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 1.27 (s, 9H).

[0305] Step 4: To a solution of 4-bromo-2-(carboxycarbonyl)-6-pivalamidobenzoic acid (110 g, 296 mmol) in EtOH (1.10 L) was added NH2NH2•H2O (18.1 g, 355 mmol, 17.6 mL) and the solution was stirred at 75 °C for 3 hrs. After such time the reaction mixture was filtered and the filter cake dried to give 7-bromo-4-oxo-5-pivalamido-3,4-dihydrophthalazine- 1-carboxylic acid (30.0 g, 81.5 mmol, 28% yield) as white solid.1H NMR 400 MHz, DMSO- d6 d 13.0 (s, 1H), 9.06 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 1.27 (s, 9H).

[0306] 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 for 36 hrs to form a yellow solid. The reaction was concentrated, diluted with water (100 mL) and the pH adjusted to pH 8 with 1 N NaOH, stirred for 0.5 hr 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.

[0307] 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) at 0 °C under N2. To this solution was added a solution of NaNO2(8.68 g, 125 mmol) in H2O (20 mL) and the mixture was stirred at 0 °C for 10 minutes then a solution of KI (25.0 g, 150mmol) in H2O (20.0 mL) was added dropwise. The mixture was stirred at 20 °C for 1 hr and the reaction was quenched by Na2S2O3. The mixture was concentrated to remove the 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 the methyl 7-bromo-5-iodo-4-oxo-3,4- dihydrophthalazine-1-carboxylate (15.0 g, crude) as a yellow solid.

[0308] Step 7: In 8 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 NaBH4(740 mg, 19.6 mmol) in batches at 0 °C followed by the addition of CaCl2(1.30 g, 11.7 mmol) in batches at 0 °C. The reaction was stirred at 20 °C for 1 hr. The 8 batches were then combined and quenched with NH4Cl (200 mL). The mixture was concentrated to remove EtOH, diluted with water (200 mL) and then filtered and the filter cake was washed with water (100 mL) and dried. The residue was triturated in MeOH (200 mL) for 10 hrs, filtered and dried to give the 6-bromo-4-(hydroxymethyl)-8-iodophthalazin-1(2H)-one (19.0 g, 38.9 mmol, 50% yield) as a yellow solid.1H NMR 400 MHz, DMSO-d6 d 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).

[0309] 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 in THF (3.67 mL, 13.1 mmol, 50% purity), Cs2CO3(4.28 g, 13.1 mmol) and Pd(dppf)Cl2(384 mg, 524 mmol). The reaction was stirred at 100 °C for 10 hrs. The three batches were combined and filtered through diatomite. The filtrate was concentrated and the residue purified by Prep-HPLC (Phenomenex luna C18250 x 150 mm x 15 mm; mobile phase: [water (0.1% TFA) - MeOH]; B%: 30% - 60%, 20 min) to give the 6-bromo-4-(hydroxymethyl)-8-methylphthalazin-1(2H)-one (1.1 g, 4.06 mmol, 26% yield) as a light yellow solid. LCMS [M+1]+= 271;1H NMR 400 MHz, DMSO-d6 d 12.44 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 4.63 (s, 3H), 2.81 (s, 3H).

[0310] Step 9: A solution of 6-bromo-4-(hydroxymethyl)-8-methylphthalazin-1(2H)-one (1.20 g, 4.46 mmol) in SOCl2(13 mL) was stirred at 70°C for 2 hr. After such time the mixture was concentrated and the residue triturated in petroleum ether for 0.5 hr, filtered and dried to give 6-bromo-4-(chloromethyl)-8-methylphthalazin-1(2H)-one (1.20 g, 4.17 mmol, 94% yield) as a light yellow solid. LCMS [M+1]+= 289;1H NMR 400 MHz, DMSO-d6 d 12.70 (s, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 5.03 (s, 2H), 2.81 (s, 3H).

[0311] Step 10: To a mixture of give 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 N2. The mixture was stirred at 25 °C for 1 hr and after such time the mixture was slowly poured into ice water (100 mL) and the formed white solid was filtrated, 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;1H NMR 400 MHz, DMSO-d6 d 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).

[0312] 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)Cl2(202 mg, 276 mmol), KOAc (542 mg, 5.52 mmol) and bis(pinacolato)diboron (1.05 g, 4.14 mmol) in dioxane (20 mL) was de-gassed with nitrogen then heated at 80 °C for 10 hours. After such time the reaction was filtered through diatomite and the cake washed with MeOH (10 mL) and the filtrate concentrated. The residue was then triturated with MeOH (10 mL) for 1 hr, filtered and the filter cake 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; boronate ester [M+1]+= 446).1H NMR 400 MHz, DMSO-d6 d 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). INTERMEDIATE DN

[0313] Step 1: To a solution of 5-(chloromethyl)-1-methyl-pyrazole (584 mg, 3.50 mmol, 1.00 eq) and 2-phenylacetonitrile (819 mg, 6.99 mmol, 2.00 eq.) in DMF (10 mL) was added potassium carbonate (966 mg, 6.99 mmol, 2.00 eq.). The mixture was stirred at 120 °C for 4 hours then and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10-50%) to give 3-(2-methylpyrazol-3- yl)-2-phenyl-propanenitrile (300 mg, 1.42 mmol, 41% yield) as a brown oil. LCMS [M+1]+=212.0;1H NMR (400 MHz, CDCl3) d =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).

[0314] Step 2: To a mixture of 3-(2-methylpyrazol-3-yl)-2-phenyl-propanenitrile (160 mg, 0.76 mmol, 1.00 eq.) in dry acetonitrile (2.0 mL) was added NBS (121 mg, 0.68 mmol, 0.90 eq.) in several portions. The mixture was stirred at 15 °C for 2 hours. After such time ethyl acetate (40 mL) and water (40 mL) were added and the layers 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 vacuum. The residue was purified by prep-HPLC (Phenomenex Gemini-NX C1875 × 30 mm × 3 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30% - 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;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE DO

[0315] Step 1: n-Butyllithium (2.5 M in hexane, 959 ^L, 1.50 eq.) was added dropwise over 5 minutes to a solution of 2,2,6,6-tetramethylpiperidine (2.40 mmol, 407 ^L, 1.50 eq.) 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 eq.) 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 eq.) in THF (3 mL) was then added dropwise over 10 minutes. The reaction mixture was maintained at -78 °C for 2 hours then allowed to warm to 20°C for 3 hours. The reaction mixture was quenched with water (1 mL) and the resulting mixture 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 sodiumsulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 5%) to give 5-chloro-2-iodo-1-naphthonitrile (180 mg, 574 mmol, 36% yield) as a yellow solid. GCMS [M+H]+= 312.9;1H NMR (400 MHz, CDCl3) d = 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).

[0316] Step 2: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (104 mg, 498 mmol, 1.30 eq.), 5-chloro-2-iodo-1-naphthonitrile (120 mg, 383 mmol, 1.00 eq.), Pd(dtbpf)Cl2(25 mg, 38 mmol, 0.10 eq.) and sodium carbonate (81 mg, 766 mmol, 2.00 eq.) in the dioxane (3 mL) and water (0.6 mL) was degassed with nitrogen then stirred at 80 °C for 1 hour. The mixture was then concentrated and the residue purified by prep-TLC (SiO2, petroleum ether:ethyl acetate 30%) to give 5-chloro-2-(2-methylpyrazol-3- yl)naphthalene-1-carbonitrile (90 mg, 336 mmol, 87% yield) as a yellow solid. LCMS [M+1]+= 268.2;1H NMR (400 MHz, CDCl3) d = 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).

[0317] Step 3: To a solution of 5-chloro-2-(2-methylpyrazol-3-yl)naphthalene-1- carbonitrile (170 mg, 635 mmol, 1.00 eq.) in acetonitrile (3 mL) was added NBS (124 mg, 699 mmol, 1.10 eq.). The mixture was stirred at 35 °C for 2 hours then concentrated to give a residue. The residue was purified by prep-TLC (SiO2, 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 mmol, 59% yield) as a white solid. LCMS [M+1]+= 347.8;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE DP

[0318] Step 1: To a solution of 2,2,6,6-tetramethylpiperidine (553 mg, 3.92 mmol, 0.67 mL, 1.20 eq.) in THF (7 mL) was added n-butyl lithium (2.50 M, 1.57 mL, 1.20 eq.) at -10 °Cunder 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 eq.) was added. After 5 minutes, a solution of 1-naphthonitrile (500 mg, 3.26 mmol, 1.00 eq.) in THF (3 mL) was added in a dropwise fashion and the reaction was then allowed to warm slowly to 25 °C and then stirred for 16 hours. After such time acetic acid (392 mg, 6.53 mmol, 0.37 mL, 2.00 eq.) was added followed by the addition of propane-1,3-diol (994 mg, 13.1 mmol, 0.95 mL, 4.00 eq.) then the mixture was stirred at 25 °C for 1 hour. The reaction was then quenched by the addition of 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 light-yellow solid.1H NMR (400 MHz, CDCl3) d = 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).

[0319] Step 2: To a solution of 5-bromoisothiazole (150 mg, 0.915 mmol, 1.00 eq.) and 2- (1,3,2-dioxaborinan-2-yl)-1-naphthonitrile (217 mg, 0.915 mmol, 1.00 eq.) in toluene (8 mL) and ethyl alcohol (0.8 mL) were added aqueous potassium carbonate (2.00 M, 0.915 mL, 2.00 eq.) and Pd(PPh3)4(106 mg, 0.091 mmol, 0.10 eq.) at 20 °C under a nitrogen atmosphere. The mixture was stirred at 100 °C for 16 hours, concentrated to dryness and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10-15%) to give 2- (isothiazol-5-yl)-1-naphthonitrile (200 mg, 0.85 mmol, 93% yield) as a light yellow solid.1H NMR (400 MHz, CDCl3) d = 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).

[0320] Step 3: To a solution of 2-(isothiazol-5-yl)-1-naphthonitrile (100 mg, 0.42 mmol, 1.00 eq.) in acetonitrile (2 mL) was added N-bromo-succinimide (753 mg, 4.23 mmol, 10.0 eq.) at 20 °C and the mixture was stirred at 100 °C for 48 hours in a sealed tube. The mixture was then concentrated under reduced pressure and the residue diluted with ethyl acetate (30 mL) and washed with water (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was then purified by prep-HPLC (Waters Xbridge BEH C18100 × 30 mm × 10 mm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 45% - 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) d = 8.51 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.8Hz, 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). INTERMEDIATE DQ

[0321] Step 1: To a solution of LDA (2.00 M, 0.587 mL, 1.10 eq.) in THF (10 mL) was added in a dropwise fashion a solution of 4-chloro-2-naphthonitrile (200 mg, 1.07 mmol, 1.00 eq) in THF (5 mL) at -78 °C. Then the mixture was stirred at -78 °C for 1 hour. After such time a solution of iodine (285 mg, 1.12 mmol, 1.05 eq.) in THF (2 mL) was added dropwise at -78 °C. The mixture was then allowed to warm to room temperature and stirred at 20 °C for 2 hours. After such time the reaction mixture was 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 purified by flash chromatography (SiO2, 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.1H NMR (400 MHz, CDCl3) d = 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).

[0322] Step 2: To a solution of 4-chloro-3-iodo-2-naphthonitrile (320 mg, 1.02 mmol, 1.00 eq.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (319 mg, 1.53 mmol, 1.50 eq.) in dioxane (30 mL) and water (6 mL) was added potassium carbonate (283 mg, 2.04 mmol, 2.00 eq.) and Pd(dppf)Cl2(75 mg, 0.102 mmol, 0.10 eq.) at 25 °C. The mixture was degassed with nitrogen then stirred at 100 °C for 16 hours. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (30 mL × 4). The combined organic layers were washed with brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated and the residue 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;1H NMR (400 MHz, CDCl3) d = 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).

[0323] Step 3: To a solution of 4-chloro-3-(1-methyl-1H-pyrazol-5-yl)-2-naphthonitrile (100 mg, 0.374 mmol, 1.00 eq.) in acetonitrile (10 mL) was added N-iodosuccinimide (504 mg, 2.24 mmol, 6.00 eq.) at 25 °C and the mixture was stirred at 80 °C for 16 hours. After such time the reaction mixture was quenched with water (2 mL) at 0 °C, and then 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 prep-TLC (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE DR

[0324] Step 1: A mixture of 4-chloro-2,5-difluoro-benzonitrile (2.00 g, 11.5 mmol, 1.00 eq.), N-bromosuccinimide (4.10 g, 23.1 mmol, 2.00 eq.), palladium acetate (259 mg, 1.15 mmol, 0.10 eq.) and p-toluene sulphonic acid (992 mg, 5.76 mmol, 0.50 eq.) in dichloroethane (50 mL) was degassed with nitrogen then stirred at 75 °C for 12 hours. After such time the cooled mixture was extracted with dichloromethane (50 mL × 3), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue purified by column chromatography (SiO2, petroleum ether: ethylacetate 0-3%) to give 2-bromo-4-chloro-3,6-difluoro-benzonitrile (1.10 g, 4.36 mmol, 38% yield) as a white solid.1H NMR (400 MHz, CDCl3) d = 7.38 - 7.31 (m, 1H).

[0325] Step 2: A mixture of 2-bromo-4-chloro-3,6-difluoro-benzonitrile (1.10 g, 4.36 mmol, 1.00 eq.), cyclopropanol (380 mg, 6.54 mmol, 1.50 eq.) and potassium carbonate (1.51 g, 10.9 mmol, 2.50 eq.) in DMF (10 mL) was degassed with nitrogen then stirred at 75 °C for 2 hours. After such time the mixture was concentrated and the residue was purified by prep- TLC (SiO2, 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.1H NMR (400 MHz, CDCl3) d = 7.36 (d, J = 5.6 Hz, 1H), 3.88 - 3.79 (m, 1H), 0.91 (d, J = 4.8 Hz, 4H).

[0326] 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 eq.), 2-bromo-4-chloro-6-(cyclopropoxy)-3-fluoro- benzonitrile (600 mg, 2.07 mmol, 1.00 eq.), aqueous sodium bicarbonate (694 mg, 8.26 mmol, 0.321 mL, 4.00 eq.), ditert-butyl(cyclopentyl)phosphane;dichloropalladium-iron (135 mg, 0.207 mmol, 0.10 eq.) in dioxane (20 mL) and water (4 mL) was degassed with nitrogen and the mixture was stirred at 80 °C for 16 hours. After such time the mixture was concentrated and the residue purified by column chromatography (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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).

[0327] Step 4: A mixture of 4-chloro-6-(cyclopropoxy)-3-fluoro-2-(2-methylpyrazol-3- yl)benzonitrile (180 mg, 0.617 mmol, 1.00 eq) and N-bromosuccinimide (220 mg, 1.23 mmol, 2.00 eq.) in acetonitrile (10 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. After such time the mixture was concentrated and the residue was purified by prep-TLC (SiO2, 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) d = 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).INTERMEDIATE DS

[0328] A mixture of 2-(4-bromo-2-methyl-pyrazol-3-yl)naphthalene-1-carbonitrile (150 mg, 0.48 mmol, 1.00 eq.), 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 eq.), potassium acetate (141 mg, 1.44 mmol, 3.00 eq.) and ditert-butyl(cyclopentyl)phosphane;dichloropalladium-iron (31.3 mg, 0.048 mmol, 0.10 eq.) in dioxane (3 mL) was degassed with nitrogen and then stirred at 80 °C for 2 hours. After such time the reaction mixture was 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 brown liquid which used into the next step without further purification. LCMS [M+1]+= 360.2. INTERMEDIATE DT

[0329] Step 1: To a solution of 4-bromo-2-methyl-pyrazole-3-carbaldehyde (1.00 g, 5.29 mmol, 1.00 eq.) and nitromethane (420 mg, 6.88 mmol, 0.37 mL, 1.30 eq.) in methanol (10 mL) was added in a dropwise fashion a solution of sodium hydroxide (466 mg, 11.6 mmol, 2.20 eq.) in water (1 mL) at 0 °C. The reaction mixture was then stirred at 0 °C for 0.5 hour. After such time the reaction mixture was quenched by addition of HCl (1.00 M, 5 mL), filtered and the filtrate concentrated under reduced pressure to give 4-bromo-1-methyl-5-[(E)- 2-nitrovinyl]pyrazole (627 mg, crude) as a yellow solid which used into the next step withoutfurther purification.1H NMR (400 MHz, CDCl3) d = 8.10 (d, J = 13.6 Hz, 1H), 7.93 (d, J = 13.6 Hz, 1H), 7.57 (s, 1H), 4.03 (s, 3H).

[0330] Step 2: A suspension of 2-pyridin-1-ium-1-ylacetonitrile chloride (627 mg) and 4Å MS (1.00 g, o.215 mmol) in dichloroethane (30 mL) was cooled to 0 °C then 2,6-lutidine (1.45 g, 13.5 mmol, 1.57 mL, 5.00 eq.) was added. After stirring for 15 minutes, 4-bromo-1- methyl-5-[(E)-2-nitrovinyl]pyrazole (627 mg, 2.70 mmol, 1.00 eq.) was added, followed by the addition of cupric acetate (736 mg, 4.05 mmol, 1.50 eq.). This mixture was then stirred at 0 °C for 15 minutes then warmed to 25 °C and stirred at 25 °C for 5 hours. After such time the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10-20%) to 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) d = 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). INTERMEDIATE DU

[0331] 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 eq.), N-iodosuccinimide (517 mg, 2.30 mmol, 6.00 eq.) in acetic acid (5 mL) was stirred at 80 °C for 48 hours under a nitrogen atmosphere. The mixture was then concentrated and to the residue was added saturated sodium sulfite solution (10 mL). The mixture was then extracted with ethyl acetate (5 mL) and the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-TLC (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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).

[0332] 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 eq.), sodium methoxide (13 mg, 0.24 mmol, 3.00 eq.), cuprous iodide (1.5 mg, 0.008 mmol, 0.10 eq.) in methanol (1 mL) was degassed with nitrogen then stirred at 105 °C for 16 hours. After such time the mixture was filtered and the filtrate concentrated and the residue was purified by prep-TLC (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE DV

[0333] 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 eq.) in THF (5 mL) was added lithium diisopropyl amine (2.00 M, 1.29 mL, 2.00 eq.) at -78 °C and stirred at -78 °C for 30 minutes. Then methyl iodide (5.15 mmol, 0.32 mL, 4.00 eq.) was added at -78 °C and the mixture stirred for 2 hours. The reaction mixture was then quenched with ammonium chloride solution (10 mL) and extracted with dichloromethane (20 mL × 3) and the combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-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;1H NMR (400 MHz, CDCl3) d = 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).INTERMEDIATE DW

[0334] 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-ethylbenzonitrile was prepared using the same method as for the preparation of Intermediate DV using Intermediate D-19 in place of Intermediate D-18 as a white solid (30 mg, 0.074 mmol, 23%). LCMS [M+1]+= 419.2;1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE DX

[0335] 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 eq.) in methanol (2 mL) was added sodium methoxide (449 mg, 8.32 mmol, 10.0 eq.) in one portion at 20 °C under nitrogen atmosphere. The mixture was stirred at 100 °C for 2 hours in a sealed tube and a light-yellow solution was formed. The mixture was then concentrated and the residue taken up in ethyl acetate (10 mL) and water (5 mL). The layers were separated, and the aqueous phase 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 give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate 25%) to give 2- (4-bromo-2-methyl-pyrazol-3-yl)-6-ethyl-4-methoxy-benzonitrile (220 mg, ~70% purity) as a white solid. LCMS [M+1]+= 321.9;1H NMR (400 MHz, CDCl3) d = 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).INTERMEDIATE DY

[0336] Step 1: A mixture of 2-bromo-5-methoxy-naphthalen-1-ol (2.60 g, 10.3 mmol, 1.00 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.21 g, 15.4 mmol, 1.50 eq.), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (670 mg, 1.03 mmol, 0.10 eq.) and sodium carbonate (2.18 g, 20.6 mmol, 2.00 eq.) in dioxane (30 mL) and water (6 mL) was degassed with nitrogen then stirred at 100 °C for 0.5 hour. After such time the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 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.1H NMR (400 MHz, DMSO-d6) d = 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).

[0337] Step 2: To a solution of 5-methoxy-2-(2-methylpyrazol-3-yl)naphthalen-1-ol (650 mg, 2.56 mmol, 1.00 eq.), 4Å molecular sieves (1.00 g) and triethylamine (7.67 mmol, 1.07 mL, 3.00 eq.) in dichloromethane (20 mL) was added Tf2O (3.83 mmol, 0.63 mL, 1.50 eq.) in a dropwise fashion at -40 °C under nitrogen. The reaction mixture was stirred at -40 °C for 0.5 hour then concentrated under reduced pressure and the residue purified by column chromatography (SiO2, petroleum ether: ethyl acetate 0-15%) to give [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;1H NMR (400 MHz, CDCl3) d = 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).

[0338] Step 3: A mixture of [5-methoxy-2-(2-methylpyrazol-3-yl)-1-naphthyl] trifluoromethanesulfonate (290 mg, 0.67 mmol, 1.00 eq.), zinc cyanide (0.81 mmol, 51.1 ^L, 1.20 eq.), Pd2(dba)3(612 mg, 0.067 mmol, 0.10 eq.), DPPF (74 mg, 0.134 mmol, 0.20 eq.) and zinc powder (4.4 mg, 0.067 mmol, 0.10 eq.) in DMF (10 mL) was degassed with nitrogenthen stirred at 120 °C for 1 hour. 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 purified by column chromatography (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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).

[0339] Step 4: To a solution of 5-methoxy-2-(2-methylpyrazol-3-yl)naphthalene-1- carbonitrile (180 mg, 0.68 mmol, 1.00 eq.) in acetonitrile (2 mL) was added N- bromosuccinimide (146 mg, 0.82 mmol, 1.20 eq.). The mixture was stirred at 35 °C for 0.5 hour then concentrated under reduced pressure and the residue purified by prep-TLC (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE DZ

[0340] 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;1H NMR (400 MHz, CDCl3-d) d = 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).INTERMEDIATE EA

[0341] Step 1: A mixture of [4-chloro-2-(2-methylpyrazol-3-yl)-1-naphthyl] trifluoromethanesulfonate (38 mg, 0.097 mmol, 1.00 eq.), zinc cyanide (22 mg, 190 mmol, 12.4 ^L, 2.00 eq.), DPPF (5.4 mg, 9.7 mmol, 0.10 eq.), zinc powder (640 ^g, 9.7 mmol, 0.10 eq.) and Pd2(dba)3(4.5 mg, 4.86 mmol, 0.05 eq.) in DMF (1.0 mL) was degassed with nitrogen then stirred at 100 °C for 4 hours. The mixture was then concentrated and the residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate 20%) to give 2-(2- methylpyrazol-3-yl)naphthalene-1,4-dicarbonitrile (30 mg, 93.4 mmol, 96% yield) as a yellow solid. LCMS [M+1]+= 259.0;1H NMR (400 MHz, CDCl3) d = 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).

[0342] Step 2: A mixture of 2-(2-methylpyrazol-3-yl)naphthalene-1,4-dicarbonitrile (30 mg, 0.093 mmol, 1.00 eq.), N-bromosuccinimide (41 mg, 0.23 mmol, 2.00 eq.) in acetonitrile (2.0 mL) was degassed nitrogen then stirred at 35 °C for 2 hours. The mixture was then concentrated and the residue purified by prep-TLC (SiO2, petroleum ether: ethyl acetate 25%) to give 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;1H NMR (400 MHz, CDCl3-d) d = 8.52 - 8.41 (m, 2H), 8.01 - 7.96 (m, 2H), 7.95 (s, 1H), 7.68 (s, 1H), 3.88 (s, 3H). INTERMEDIATE EB

[0343] Step 1: A solution of n-butyl lithium (2.50 M, 1.87 mL, 1.00 eq.) was added dropwise over 30 min to a solution of 2,2,6,6-tetramethylpiperidine (660 mg, 4.67 mmol, 0.79 mL, 1.00 eq.) in THF (10 mL) at 0 ºC and the mixture was then was cooled to -78 °C and asolution of 4-fluoronaphthalene-1-carbonitrile (0.80 g, 4.67 mmol, 1.00 eq.) in THF (3 mL) was added over 15 min. The mixture was then stirred at -78 °C for 2 hours. After such time a solution of iodine (1.19 g, 4.67 mmol , 1.00 eq.) in THF (3 mL) was added over 30 min and the reaction mixture was stirred at -78 °C for 2 hours, then allowed to warm-up to 25 ºC and stirred for a further 12 hours. The reaction mixture was then quenched with water (50 mL) and extracted with ethyl acetate (30 mL × 2). The combine organic layers were washed with saturated sodium thiosulfate (30 mL × 3), 1 M hydrochloride (30 mL × 3) and brine (50 mL) and 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.1H NMR (400 MHz, CDCl3) d = 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).

[0344] Step 2: To a solution of 4-fluoro-3-iodo-naphthalene-1-carbonitrile (900 mg, 3.03 mmol, 1.00 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.58 g, 7.57 mmol, 2.50 eq.) and potassium phosphate (1.29 g, 6.06 mmol, 2.00 eq.) in dioxane (10 mL) and water (2 mL) was added ditert-butyl(cyclopentyl)phosphane;dichloropalladium-iron (197 mg, 0.30 mmol, 0.10 eq.). The reaction was stirred at 80 °C for 18 hours under nitrogen atmosphere. 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 the organic layers dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was then purified by flash silica gel chromatography (0-25% ethyl acetate: petroleum ether gradient) to give 4-fluoro-3-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (0.80 g, 2.87 mmol, 95% yield) as a white solid.1H NMR (400 MHz, CDCl3) d = 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).

[0345] Step 3: To a solution of 4-fluoro-3-(2-methylpyrazol-3-yl)naphthalene-1- carbonitrile (200 mg, 0.80 mmol, 1.00 eq.) in acetonitrile (5 mL) was added 1- bromopyrrolidine-2,5-dione (212 mg, 1.19 mmol, 1.50 eq.) and the reaction was stirred at 25 °C for 12 hours. The reaction was then concentrated and the residue purified by flash silica gel chromatography (0-15% ethyl acetate: petroleum ether) to give 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;1H NMR (400 MHz, CDCl3) d = 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).INTERMEDIATE EC

[0346] Step 1: To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol, 1.00 eq.) 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 eq.) in dioxane (15 mL) and water (3 mL) was added potassium carbonate (1.49 g, 10.8 mmol, 2.00 eq.) and Pd(dppf)Cl2(393 mg, 0.538 mmol, 0.10 eq.) at 20 °C under a nitrogen atmosphere. The mixture was then stirred at 80 °C for 6 hours. After such time the reaction mixture was 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 (SiO2, 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.1H NMR (400 MHz, CDCl3) d = 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).

[0347] Step 2: To a solution of 6-(1-methyl-1H-pyrazol-5-yl)picolinaldehyde (800 mg, 4.27 mmol, 1.00 eq.) in acetonitrile (12 mL) was added N-bromo-succinimide (1.14 g, 6.41 mmol, 1.50 eq.) at 20 °C and the mixture was stirred for 16 hours. After such time the mixture was concentrated and the residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate 25%) to give 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)picolinaldehyde (750 mg, 2.82 mmol, 66% yield) as a white solid.1H NMR (400 MHz, CDCl3) d = 10.13 (s, 1H), 8.08 - 7.98 (m, 3H), 7.58 (s, 1H), 4.15 (s, 3H).

[0348] Step 3: To a solution of 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)picolinaldehyde (250 mg, 0.94 mmol, 1.00 eq.) in DMF (3 mL) was added 2-aminoacetic acid (78 mg, 1.03 mmol, 1.10 eq.), iodine (238 mg, 0.940 mmol, 0.19 mL, 1.00 eq), sodium bicarbonate (158 mg, 1.88 mmol, 2.00 eq.) at 20 °C. The mixture was then stirred at 60 °C for 6 hours then 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 purified by prep-TLC (SiO2, 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.1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE ED

[0349] Step 1: To a solution of 4-bromo-5-chloro-1H-pyrazole (1.00 g, 5.51 mmol, 1.00 eq.) 2-(bromomethyl)benzonitrile (1.08 g, 5.51 mmol, 1.00 eq.) in acetonitrile (20 mL) was added potassium carbonate (914 mg, 6.61 mmol, 1.20 eq.) and the mixture was stirred at 80 °C for 10 hours under a nitrogen atmosphere. After such time the reaction was quenched by water (200 mL) and then 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 formed residue was purified by column chromatography (SiO2, 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;1H NMR (400 MHz, DMSO-d6) d = 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).

[0350] Step 2: To a solution of 2-((4-bromo-3-chloro-1H-pyrazol-1-yl)methyl)benzonitrile (400mg, 1.35 mmol, 1.00eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (561 mg, 2.70 mmol, 2.00 eq.) and sodium bicarbonate (227 mg, 2.70 mmol, 2.00 eq.) in dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl2(99 mg, 0.135 mmol, 0.10eq.) under a nitrogen atmosphere. The mixture was stirred at 110 °C for 10 hours and then the reaction was quenched by adding water (200 mL) then extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 30%) 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;1H NMR (400 MHz, DMSO-d6) d = 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).

[0351] 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 eq.) in acetonitrile (10 mL) was added N- bromosuccinimide (132 mg, 0.739 mmol, 1.10 eq.) and the mixture was stirred at 25 °C for 10 hours under nitrogen atmosphere. After such time the reaction was quenched with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by column chromatography (SiO2, 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;1H NMR (400 MHz, DMSO-d6) d = 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).

[0352] 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 eq.), 2-((4- bromo-3'-chloro-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)methyl)benzonitrile (120 mg, 0.319 mmol, 1.00 eq.), sodium bicarbonate (54 mg, 0.637 mmol, 25 ^L, 2.00 eq.) in water (0.5 mL) and dioxane (5.0 mL) was added Pd(dtbpf)Cl2(21 mg, 32 mmol, 0.10 eq.) under a nitrogen atmosphere and then the mixture was stirred at 110 °C for 10 hours. The reaction was then quenched with water (50 mL), extracted with ethyl acetate (40 mL × 3) and the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 15%) to give 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 black brown oil. LCMS [M+1]+= 571.1;1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE EE

[0353] Step 1: To a mixture of phenylboronic acid (1.92 g, 15.8 mmol, 2.00 eq.) and 3- chloro-4-iodo-1H-pyrazole (1.80 g, 7.88 mmol, 1.00 eq.) in dichloromethane (30 mL) was added pyridine (1.86 g, 23.5 mmol, 1.90 mL, 2.99 eq.) and copper acetate (1.72 g, 9.46 mmol, 1.20 eq.) in one portion. The mixture was stirred at 20 °C for 16 hours, then filtered and concentrated and the residue purified by flash silica gel chromatography (0-5% ethyl acetate: petroleum ether) to give 3-chloro-4-iodo-1-phenyl-pyrazole (1.50 g, 4.93 mmol, 63% yield) as a yellow liquid. LCMS [M+1]+= 305.0;1H NMR (400 MHz, CDCl3) d 7.91 (s, 1H), 7.63- 7.59 (m, 2H), 7.49-7.43 (m, 2H), 7.36-7.30 (m, 1H).

[0354] 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 eq.), 3-chloro-4-iodo-1-phenyl-pyrazole (1.20 g, 3.94 mmol, 1.00 eq.), potassium phosphate (1.67 g, 7.88 mmol, 2.00 eq.) and ditert- butyl(cyclopentyl)phosphane;dichloropalladium-iron (256 mg, 0.39 mmol, 0.10 eq.) in dioxane (20 mL) and water (4 mL) was de-gassed and then heated to 80 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was then concentrated, and the residue diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3), dried over sodium sulfate, concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 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) d 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).

[0355] Step 3: A mixture of 3-chloro-4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole (210 mg, 0.811 mmol, 1.00 eq.), tetrapotassium-hexacyanoiron(4-) trihydrate (1.03 g, 2.44 mmol, 3.00 eq.) 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 eq.) in dimethylacetamide (6 mL) and water (3 mL) was heated to 100 °C for 16 hours under nitrogen atmosphere. 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 purified by column chromatography (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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).

[0356] Step 4: To a mixture of 4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole-3-carbonitrile (180 mg, 0.722 mmol, 1.00 eq.) in acetonitrile (5 mL) was added N-bromosuccinimide (192 mg, 1.08 mmol, 1.50 eq.). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was then quenched with saturated sodium sulfite (15 mL), extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, concentrated and the residue purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10-20%) to give 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;1H NMR (500 MHz, CDCl3) d = 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). INTERMEDIATE EF

[0357] To a mixture of 3-chloro-4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole, Intermediate EE-1 (200 mg, 0.773 mmol, 1.00 eq.) in acetonitrile (1 mL) was added 1-bromopyrrolidine- 2,5-dione (165 mg, 0.927 mmol, 1.20 eq.) in one portion at 20 °C. The mixture was stirred at20 °C for 16 hours. The reaction mixture was then concentrated and the residue purified by flash silica gel chromatography (0-17% ethyl acetate: petroleum ether) to give 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) d = 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). INTERMEDIATE EG

[0358] 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 over 6 steps) starting from 1-(5-bromo-2-methyl-3-(trifluoromethyl)phenyl)ethan-1-one following the same procedure described for the first 6 steps of Intermediate DK. LCMS [M+1]+= 454.0;1H NMR (400 MHz, DMSO-d6) d = 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).

[0359] 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 eq.), bis(pinacolato)diboron (34 mg, 0.133 mmol, 1.20 eq.), Pd(dppf)Cl2(8 mg, 0.011 mmol, 0.10 eq.) and potassium acetate (22 mg, 0.221 mmol, 2.00 eq.) in dioxane (2 mL) was degassed with nitrogen and stirred at 100 °C for 1 hour. The reaction mixture was then concentrated under reduced pressure to 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. INTERMEDIATE EH

[0360] 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 4 step procedure as used for the preparation of Intermediate DY but starting with 7-bromochroman- 8-ol. LCMS [M+1]+= 413.2;1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE EI

[0361] 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 2 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;1H NMR (400MHz, CCDCl3-d) d = 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). INTERMEDIATE EJ

[0362] 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-1-chloro-2-naphthonitrile, Intermediate EJ was prepared as a light yellow solid (35 mg, 0.101 mmol, 18 % yield over 2 steps) following the same procedure as described for the preparation of Intermediate DC starting from 3-bromo-1-chloro-2-naphthaldehyde.1H NMR (400MHz, CCDCl3-d) d = 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). INTERMEDIATE EK

[0363] Step 1: To a solution of 6-bromoquinoline-5-carbonitrile (1.00 g, 4.29 mmol, 1.00 eq.) in acetic acid (20 mL) was added N-chlorosuccinimide (5.73 g, 42.9 mmol, 10.0 eq.). The mixture was stirred at 135 °C for 24 hours. The pH of the reaction mixture was then adjusted to pH 7 with 2 N sodium hydroxide aqueous solution (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, concentrated and 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;1H NMR (400 MHz, CDCl3) d = 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).

[0364] Step 2: A mixture of 6-bromo-3-chloro-quinoline-5-carbonitrile (512 mg, 1.91 mmol, 1.00 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (398 mg, 1.91 mmol, 1.00 eq.), ditert-butyl(cyclopentyl)phosphane;dichloropalladium-iron (125 mg, 0.19 mmol, 0.10 eq.), sodium bicarbonate (322 mg, 3.83 mmol, 0.15 mL, 2.00 eq.) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and stirred at 80 °C for 0.5 hour. After such time the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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).

[0365] Step 3: To a solution of 3-chloro-6-(2-methylpyrazol-3-yl)quinoline-5-carbonitrile (249 mg, 0.927 mmol, 1.00 eq.) in acetonitrile (5 mL) was added N-bromosuccinimide (214 mg, 1.20 mmol, 1.30 eq.). The mixture was stirred at 35 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10-15%) to give 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) d = 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). INTERMEDIATES EL-A and EL-B

[0366] Step 1: To a solution of 1,3-dibromo-2-chloro-5-fluoro-benzene (61.0 g, 212 mmol, 1.00 eq.) and 1-methylpyrrole (34.3 g, 423 mmol, 37.7 mL, 2.00 eq.) in toluene (1500 mL) was added n-butyl lithium (2.50 M in THF, 88.9 mL, 1.05 eq.) dropwise at -30°C under nitrogen. The mixture was then stirred at -30 °C for 0.5 hour then allowed to warm to 25 °C and stirred for 12 hours. After such time the reaction mixture was quenched with water (20 mL) and concentrated under reduced pressure to give 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 (SiO2,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.1H NMR (400 MHz, CDCl3) d = 7.10 - 6.65 (m, 4H), 4.83 - 4.44 (m, 2H), 2.31 - 2.09 (m, 3H).

[0367] 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 eq.) in chloroform (1300 mL) was carefully added m-CPBA (98.2 g, 484 mmol, 85% purity, 2.00 eq.) in portions maintaining the inner temperature below 40 °C. After 2 hours, the brown solution turned yellow and the mixture was stirred at 25°C for a further 24 hours. After such time the mixture was 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 (SiO2, petroleum ether: ethyl acetate 0-10%) to give 1-bromo-3-fluoro-naphthalene (37.8 g, 168 mmol, 70 % yield) as a colorless liquid.1H NMR (400 MHz, CDCl3) d = 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).

[0368] Step 3: A mixture of 1-bromo-3-fluoro-naphthalene (34.8 g, 155 mmol, 1.00 eq.), Pd2(dba)3(14.2g, 15.5 mmol, 0.10 eq.), zinc cyanide (45.4 g, 387 mmol, 24.5 mL, 2.50 eq.), DPPF (17.1 g, 30.9 mmol, 0.20 eq.) and Zn power (1.01 g, 15.5 mmol, 0.10 eq.) in DMF (400 mL) was degassed with nitrogen and then the mixture was stirred at 115 °C for 4 hours. After such time the mixture was 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 (SiO2, 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) d = 8.26 - 8.21 (m, 1H), 7.92 - 7.85 (m, 1H), 7.76 - 7.65 (m, 4H).

[0369] Step 4: n-butyl lithium (2.50 M in hexane, 2.83 mL, 1.10 eq.) was added to a solution of N-isopropylpropan-2-amine (845 mg, 8.35 mmol, 1.18 mL, 1.30 eq.) in THF (15 mL) at -70 °C and the reaction mixture was stirred at -70 °C for 15 minutes and then 3- fluoronaphthalene-1-carbonitrile (1.10 g, 6.43 mmol, 1.00 eq.) in THF (2 mL) was added to the mixture and the reaction mixture was stirred for 30 minutes at -70 °C. A solution of iodine (2.12 g, 8.35 mmol, 1.30 eq.) in THF (2.00 mL) was then added to the reaction mixture at -70 °C and the solution was stirred at -70 °C for a further 30 minutes and then the mixture was warmed to 25 °C and stirred at 25 °C for 10 hours. After such time the reaction was quenchedwith water (100 mL), and diluted with ethyl acetate (250 mL), washed with saturated sodium thiosulfate (100 mL × 2) and brine (250 mL). The organic phase was dried over anhydrous sodium sulfate filtered, concentrated and the formed residue was purified by column chromatography (SiO2, 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.1H NMR (400 MHz, CDCl3) d = 8.36 - 8.24 (m, 1H), 7.83 - 7.71 (m, 1H), 7.59 - 7.48 (m, 3H).

[0370] Step 5: A mixture of 3-fluoro-2-iodo-naphthalene-1-carbonitrile (800 mg, 2.69 mmol, 1.00 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.23 g, 5.92 mmol, 2.20 eq.), Pd(dtbpf)Cl2(176 mg, 0.269 mmol, 0.10 eq.), sodium bicarbonate (679 mg, 8.08 mmol, 3.00 eq.) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and stirred at 80 °C for 12 hours. After such time the mixture was concentrated and the residue purified by column chromatography (SiO2, petroleum ether: ethyl acetate 5-50%) to give 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;1H NMR (400 MHz, CDCl3) d = 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).

[0371] Step 6: To a solution of 3-fluoro-2-(2-methylpyrazol-3-yl)naphthalene-1- carbonitrile (500 mg, 1.99 mmol, 1.00 eq.) in acetonitrile (8 mL) was added N- bromosuccinimide (638 mg, 3.58 mmol, 1.80 eq.). The mixture was stirred at 25 °C for 3 hours. After such time the mixture was concentrated and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10-50%) to give 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) d = 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).

[0372] Step 7: To a solution of 3-fluoro-2-(2-methylpyrazol-3-yl)naphthalene-1- carbonitrile (20.0 g, 79.6 mmol, 1.00 eq.) in acetonitrile (300 mL) was added N- iodosuccinimide (89.5 g, 398 mmol, 5.00 eq.). The mixture was stirred at 80 °C for 12 hours. After such time the mixture was concentrated and the residue was triturated with methyl alcohol (100 mL) at 25oC for 30 min and the mixture 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;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE EM

[0373] A mixture of 2-(2-hydroxyphenyl)acetonitrile (182 mg, 1.36 mmol, 1.20 eq.), 3- bromo-5-fluoro-pyridine (200 mg, 1.14 mmol, 1.00 eq.), potassium carbonate (393 mg, 2.84 mmol, 2.50 eq.) in DMF (10 mL) was was stirred at 75 °C for 3 hours under a nitrogen atmosphere. The mixture was concentrated and the residue was purified by prep-TLC (SiO2, 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. INTERMEDIATE EN

[0374] Step 1: To a solution of 6-bromo-3-cyclopropoxypicolinonitrile (800 mg, 3.35 mmol, 1.00 eq.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (732 mg, 3.51 mmol, 1.05 eq.) in dioxane (20 mL) and water (0.4 mL) was added ditert- butyl(cyclopentyl)phosphane-dichloropalladium-iron (218 mg, 0.335 mmol, 0.10 eq.) and sodium carbonate (709 mg, 6.69 mmol, 2.00 eq.) at 25 °C. The mixture was degassed and purged with nitrogen for 3 times, and then stirred at 80 °C for 2 hours. After such time the reaction mixture was quenched with water (20 mL) and then extracted with ethyl acetate (30 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 flash silica gel chromatography (SiO2, petroleum ether: ethyl acetate 0-10%) to give 3-cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)picolinonitrile (750 mg, 2.97 mmol, 89% yield) as a white solid.1H NMR (400 MHz, CD3OD) d = 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).

[0375] Step 2: To a solution of 3-cyclopropoxy-6-(1-methyl-1H-pyrazol-5- yl)picolinonitrile (650 mg, 2.71 mmol, 1.00 eq.) in acetonitrile (20 mL) was added N- bromosuccinimide (723 mg, 4.06 mmol, 1.50 eq.) at 0 °C and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by prep-TLC (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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).

[0376] Step 3: To a solution of 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3- cyclopropoxypicolinonitrile (300 mg, 0.94 mmol, 1.00 eq.) in THF (20 mL) was added DIBAL-H (1.00 M, 5.64 mL, 6.00 eq.) at 25 °C and the mixture was stirred at 25 °C for 3 hours. After such time the reaction was 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, concentrated and the residue was purified by prep-TLC (SiO2, 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 eq.) 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, concentrated and the residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate 0-10%) to give 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;1H NMR (400 MHz, CDCl3) d = 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).

[0377] 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 eq) and diisopropylethylamine (104 mg, 0.80 mmol, 0.14 mL, 2.00 eq.) in dichloromethane (8 mL) was added Tf2O (225 mg, 0.078 mmol, 0.13 mL, 2.00 eq.) at -40 °C then allowed to warm to ambient temperature and stirred at 25 °C for 6 hours. After such time water (2 mL) was added and the mixture 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 prep-TLC (SiO2, petroleum ether: ethyl acetate 0-10%) to give 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;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE EO

[0378] Step 1: To a solution of 1-(2-methylpyrazol-3-yl)ethanone (400 mg, 3.22 mmol, 1.00 eq.) in THF (6 mL) was added 1-bromopyrrolidine-2,5-dione (1.43 g, 8.06 mmol, 2.50 eq.) and the mixture was stirred at 25 °C for 12 hours. After such time the reaction mixture was concentrated and the residue purified by prep-TLC (SiO2, 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) d = 7.54 (s, 1H), 4.62 (s, 2H), 4.16 (s, 3H).

[0379] Step 2: A solution of 2-bromo-1-(4-bromo-2-methyl-pyrazol-3-yl)ethanone (400 mg, 1.42 mmol, 1.00 eq.) and 2-(2-pyridyl)acetonitrile (335 mg, 2.84 mmol, 0.31 mL, 2.00 eq.) in acetonitrile (6 mL) was stirred at 70 °C for 11 hours followed by the addition of triethylamine (431 mg, 4.26 mmol, 0.59 mL, 3.00 eq.) and stirred at 70 °C for a further 1 hour. The reaction mixture was then concentrated and the residue purified by prep-TLC (SiO2, petroleum ether: ethyl acetate 30%) to give 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;1HNMR (400 MHz, CDCl3) d = 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). INTERMEDIATE EP

[0380] To a solution of 4-chloro-2-(cyclopropoxy)-6-(2-methylpyrazol-3-yl)benzonitrile (150 mg, 0.55 mmol, 1.00 eq.) in acetic acid (1.0 mL) was added N-iodosuccinimide (247 mg, 1.10 mmol, 2.00 eq.) and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was then diluted with ethyl acetate (30 mL) and washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by prep-TLC (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE EQ

[0381] Step 1: A mixture of 3-bromopyridine-2-carbaldehyde (1.00 g, 5.38 mmol, 1.00 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.12 g, 5.38 mmol, 1.00 eq.), sodium bicarbonate (1.13 g, 13.4 mmol, 0.52 mL, 2.50 eq.) and triphenyl phosphine (141 mg, 0.54 mmol, 0.10 eq.) in DMF (10 mL) and water (2 mL) was degassed and purged with nitrogen 3 times, then palladium acetate (60 mg, 0.27 mmol, 0.05 eq.) was added to the mixture and stirred at 80 °C for 16 hours. After such time the reaction solution was 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, concentrated and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 20-100%) to give 3-(2-methylpyrazol-3-yl)pyridine-2-carbaldehyde (637 mg, 3.40 mmol, 63% yield) as a brown solid. LCMS [M+1]+= 188.0;1H NMR (400 MHz, CDCl3) d = 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).

[0382] Step 2: To a solution of 3-(2-methylpyrazol-3-yl)pyridine-2-carbaldehyde (200 mg, 1.07 mmol, 1.00 eq.) in acetonitrile (5 mL) was added N-iodosuccinimide (480 mg, 2.14 mmol, 2.00 eq.) and the mixture was stirred at 20 °C for 16 hours. The reaction was diluted by 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 give 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;1H NMR (400 MHz, CDCl3) d = 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).

[0383] Step 3: To a solution of 3-(4-iodo-2-methyl-pyrazol-3-yl)pyridine-2-carbaldehyde (290 mg, 0.93 mmol, 1.00 eq.) in DMF (5 mL) was added 2-aminoacetic acid (77 mg, 1.02 mmol, 1.10 eq.), iodine (235 mg, 0.93 mmol, 0.18 mL, 1.00 eq.) and sodium bicarbonate (155 mg, 1.85 mmol, 2.00 eq.). Then 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 (SiO2, 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) d = 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). INTERMEDIATE ER

[0384] Step 1: A mixture of 4-chloro-6-(cyclopropoxy)-3-fluoro-2-(2-methylpyrazol-3- yl)benzonitrile (200 mg, 0.69 mmol, 1.00 eq.), methylboronic acid (205 mg, 3.43 mmol, 5.00eq.), ditert-butyl(cyclopentyl)phosphane-dichloropalladium-iron (45 mg, 0.069 mmol, 0.10 eq.) and potassium carbonate (284 mg, 2.06 mmol, 3.00 eq.) in dioxane (2 mL) was degassed, purged with nitrogen 3 times and stirred at 100 °C for 2 hours. The mixture was then concentrated and purified by prep-TLC (SiO2, petroleum ether: ethyl acetate 25%) 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;1H NMR (400 MHz, CDCl3) d = 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, 5.6 Hz, 1H), 3.80 (s, 3H), 2.43 (d, J = 2.0 Hz, 3H), 0.93 - 0.88 (m, 4H).

[0385] Step 2: A mixture of 6-(cyclopropoxy)-3-fluoro-4-methyl-2-(2-methylpyrazol-3- yl)benzonitrile (35 mg, 0.13 mmol, 1.00 eq.), N-bromosuccinimide (46 mg, 0.26 mmol, 2.00 eq.) in acetonitrile (3 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. The mixture was then concentrated and the residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate 25%) 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;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE ES

[0386] Step 1: To a mixture of 2-iodobenzothiophene-3-carbonitrile (280 mg, 0.98 mmol, 1.00 eq.), sodium carbonate (312 mg, 2.95 mmol, 3.00 eq.) and 1-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (409 mg, 1.96 mmol, 2.00 eq.) in dioxane (4 mL) and water (1 mL) was added ditert-butyl(cyclopentyl)phosphane-dichloropalladium-iron (64 mg, 0.098 mmol, 0.10 eq.) and sodium carbonate (312 mg, 2.95 mmol, 3.00 eq.) and the mixture was stirred at 80 °C for 2 hours. After such time water (5 mL) was added and the mixture extracted with ethyl acetate (10 mL × 3). The combined organic phase were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate 10%) to give 2-(2-methylpyrazol-3-yl)benzothiophene-3-carbonitrile (150 mg, 64% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) d (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).

[0387] Step 2: To a mixture of 2-(2-methylpyrazol-3-yl)benzothiophene-3-carbonitrile (150 mg, 0.63 mmol, 1.00 eq.) in acetonitrile (2 mL) was added N-bromosuccinimide (112 mg, 0.63 mmol, 1.00 eq.) and the mixture was stirred at 25 °C for 12 hours. After such time the reaction mixture was added to a 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, concentrated and 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;1H NMR (400 MHz, CDCl3) d (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). INTERMEDIATE ET

[0388] Intermediate ES, 2-(4-bromo-2-methyl-pyrazol-3-yl)thieno[2,3-b]pyridine-3- carbonitrile, was prepared as a yellow solid (80.0 mg, 0.25 mmol, 22% yield over 2 steps) from thieno[2,3-b]pyridine-3-carbonitrile in steps following the procedure described for Intermediate ER. LCMS [M+1]+=320.9;1H NMR (400 MHz, CDCl3) d (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). INTERMEDIATE EU

[0389] Step 1: To a solution of 2-methylsulfonylethanol (569 mg, 4.58 mmol, 1.20 eq.) in DMF (30 mL) was added sodium hydride (183 mg, 4.58 mmol, 60.0% purity, 1.20 eq.) at 0 °C. After stirring for 0.5 hour 4-chloro-2-fluoro-6-(2-methylpyrazol-3-yl)benzonitrile (900 mg, 3.82 mmol, 1.00 eq.) in DMF (5 mL) was added in a dropwise fashion at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. After such time the mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), the aqueous phase 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 used into the next step without further purification. LCMS [M]+= 234.1;1H NMR (400 MHz, DMSO-d6) d = 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).

[0390] Step 2: To a solution of 4-chloro-2-hydroxy-6-(2-methylpyrazol-3-yl)benzonitrile (150 mg, 0.642 mmol, 1.00 eq.) and sodium 2-chloro-2,2-difluoro-acetate (392 mg, 2.57 mmol, 4.00 eq.) in DMF (2 mL) and water (0.2 mL) was added cesium carbonate (314 mg, 0.96 mmol, 1.50 eq.). The mixture was stirred at 100 °C for 1 hour. The reaction mixture was then quenched by addition water (40 mL) and 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 prep-TLC (SiO2, 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;1H NMR (400 MHz, DMSO-d6) d (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).

[0391] Step 3: To a solution of 4-chloro-2-(difluoromethoxy)-6-(2-methylpyrazol-3-yl) benzonitrile (85 mg, 0.30 mmol, 1.00 eq.) in acetic acid (2 mL) was added N-iodide succinimide (135 mg, 0.60 mmol, 2.00 eq.). The mixture was stirred at 25 °C for 1 hour then the reaction mixture was quenched by 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, concentrated and the residue was purified by prep- TLC (SiO2, 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;1H NMR (400 MHz, CD3OD-d4) d (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).INTERMEDIATE EV

[0392] Step 1: A mixture of 7-bromo-1,3-benzothiazol-6-amine (2.00 g, 8.73 mmol, 1.00 eq.), zinc cyanide (1.54 g, 13.1 mmol, 1.50 eq.), Pd2(dba)3 ( 80 mg, 0.87 mmol, 0.01 eq.), DPPF (97 mg, 0.175 mmol, 0.02 eq.) and zinc powder (5.7 mg, 0.087 mmol, 0.01 eq.) in DMF (20 mL) was degassed, purged with nitrogen 3 times, and then stirred at 140 °C for 16 hours. After such time the reaction mixture was extracted with ethyl acetate 150 mL (50 mL × 3) and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated and the formed residue 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;1H NMR (400 MHz, CDCl3-d) d = 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).

[0393] Step 2: A mixture of 6-amino-1,3-benzothiazole-7-carbonitrile (500 mg, 2.85 mmol, 1.00 eq.), para-toluenesulfonic acid (590 mg, 3.42 mmol, 1.20 eq.) , tert-butyl nitrite (353 mg, 3.42 mmol, 407 uL, 1.20 eq.), tetrabutylammonium bromide (1.84 g, 5.71 mmol, 2.00 eq.) and copper bromide (64 mg, 0.286 mmol, 0.10 eq.) in acetonitrile (15 mL) was degassed with nitrogen and stirred at 25 °C for 6 hours. The mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10-25%) to 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) d = 9.11 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H).

[0394] 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 eq.), 6-bromo-1,3-benzothiazole-7-carbonitrile (300 mg, 1.25 mmol, 1.00 eq.), ditert-butyl(cyclopentyl)phosphane;dichloropalladium iron (82 mg, 0.125 mmol, 0.10 eq.) and sodium bicarbonate (316 mg, 3.76 mmol, 3.00 eq.) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and then stirred at 80 °C for 3 hours under a nitrogen atmosphere. The mixture was then concentrated and the residue purified by column chromatography (SiO2, 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;1H NMR (400 MHz, CDCl3-d) d = 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).

[0395] Step 4: A mixture of 6-(2-methylpyrazol-3-yl)-1,3-benzothiazole-7-carbonitrile (140 mg, 0.58 mmol, 1.00 eq.), N-bromosuccinimide (207 mg, 1.17 mmol, 2.00 eq.) in acetonitrile (3 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. The mixture was then concentrated and the residue purified by column chromatography (SiO2, petroleum ether: ethyl 5-20%) to give 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;1H NMR (400 MHz, CDCl3-d) d = 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). INTERMEDIATE EW

[0396] Step 1: To a solution of 3-(hydroxymethyl)-1-methylpyridin-2(1H)-one (650 mg, 4.67 mmol, 1.00 eq.) in dichloromethane (15 mL) was added thionyl chloride (667 mg, 5.61 mmol, 407 uL, 1.20 eq.) and the mixture was stirred at 25°C for 2 hrs. The mixture was concentrated in vacuum to gvie 3-(chloromethyl)-1-methyl-pyridin-2-one (650 mg, crude) as a white solid.

[0397] Step 2: To a solution of 3-(chloromethyl)-1-methyl-pyridin-2-one (650 mg, 4.12 mmol, 1.00 eq.), 4-bromo-5-chloro-1H-pyrazole (747 mg, 4.12 mmol, 1.00 eq.) in acetonitrile (20 mL) was added potassium carbonate (683 mg, 4.94 mmol, 1.20 eq.) and the mixture was stirred at 80 °C for 12 hours. The reaction was then quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were 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.

[0398] 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 eq.), 4-bromo-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (512 mg, 1.78 mmol, 2.00 eq.) in dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl2(65 mg, 0.089 mmol, 0.10 eq.) and sodium bicarbonate (150 mg, 1.78 mmol, 69 mL, 2.00 eq.). The mixture was stirred at 110 °C for 10 hours. The reaction mixture was then quenched by addition 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 prep-HPLC (Phenomenex Gemini-NX 80 mm × 40 mm × 3 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 5%-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 grey solid. LCMS [M+1]+= 304.1;1H NMR (400 MHz, DMSO-d6) d = 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)

[0399] 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 eq.) in acetonitrile (1 mL) was added N-bromosuccinimide (26 mg, 0.147 mmol, 0.95 eq.). The mixture was stirred at 25 °C for 10 hours. The reaction mixture was then quenched by addition of water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by prep-TLC (SiO2, 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;1H NMR (400 MHz, DMSO-d6) d = 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). INTERMEDIATE EX

[0400] 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 over 6 steps) starting from 1-(5-bromo-2-methyl-3-(methoxy)phenyl)ethan-1-one following the same procedure described for the first 6 steps of Intermediate DK. LCMS [M+1]+=414.0.

[0401] 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 eq.), bis(pinacolato)diboron (3.88 g, 15.3 mmol, 1.5 eq.), Pd(dppf)Cl2•CH2Cl2(745 mg, 1.02 mmol, 0.1 eq.) and potassium acetate (3.00 g, 30.6 mmol, 3.0 eq.) in dioxane (60 mL) was degassed and purged with nitrogen 3 times, and stirred at 100 °C for 1 hour. The mixture was then concentrated, and the residue triturated with methanol, filtered and dried to give Intermediate EX as a grey solid (2.01 g, 43% yield). LCMS [M+1]+= 380.1 (boronic acid from loss of pinicol). INTERMEDIATE EY

[0402] 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;1H NMR (400 MHz, CDCl3) d = 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). INTERMEDIATE EZ

[0403] 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) d = 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). INTERMEDIATE FA

[0404] 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 eq.) in dioxane (10 mL) was added potassium carbonate (268 mg, 1.94 mmol, 3.00 eq.), ditert- butyl(cyclopentyl)phosphane;dichloropalladium-iron (42 mg, 0.064 mmol, 0.10 eq.) and methylboronic acid (194 mg, 3.23 mmol, 5.00 eq.). The mixture was stirred at 100 °C for 2 hours then 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 prep-TLC (SiO2, 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;1H NMR (400 MHz, CDCl3) d = 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).

[0405] Step 2: To a solution of 2-(cyclopropoxy)-4-methyl-6-(2-methylpyrazol-3- yl)benzonitrile (100 mg, 0.40 mmol, 1.00 eq.) in acetic acid (2 mL) was added N- iodosuccinimide (178 mg, 0.79 mmol, 2.00 eq.). The mixture was stirred at 25 °C for 1 hour then diluted with water (20 mL) and 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 purified by prep-TLC (SiO2, 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;1H NMR (400 MHz,CDCl3) d = 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). INTERMEDIATE FB

[0406] Step 1: To a solution of 2-fluoronaphthalen-1-ol (0.50 g, 3.08 mmol, 1.00 eq.) in dichloromethane (8 mL) was added NBS (521 mg, 2.93 mmol, 0.95 eq.) and the mixture was stirred at -50 °C for 0.25 hr. Water (10 mL) was then added and the separated organic phase was dried, concentrated and the residue purified by column chromatography (SiO2, petroleum ether / ethyl acetate 1%) to give 4-bromo-2-fluoro-naphthalen-1-ol (500 mg, 2.07 mmol, 67% yield) as a light yellow solid.1H NMR (400 MHz, CDCl3) d = 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).

[0407] Step 2: To a solution of 4-bromo-2-fluoro-naphthalen-1-ol (2.30 g, 9.54 mmol, 1.00 eq.), DIEA (21.0 mmol, 3.66 mL, 2.20 eq.) and DMAP (58 mg, 0.48 mmol, 0.05 eq.) in dichloromethane (40 mL) at 0 °C was added acetyl chloride (19.1 mmol, 1.36 mL, 2.00 eq.) in a dropwise fashion. The mixture was stirred at 28 °C for 1 hr before the mixture was concentrated and the formed residue purified by column chromatography (SiO2, pether / ethyl acetate 1%) to give (4-bromo-2-fluoro-1-naphthyl) acetate (2.50 g, 8.83 mmol, 93% yield) as a white solid.1H NMR (400 MHz, CDCl3) d = 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).

[0408] Step 3: A mixture of (4-bromo-2-fluoro-1-naphthyl) acetate (2.50 g, 8.83 mmol, 1.00 eq.), Pd2(dba)3(809 mg, 0.88 mmol, 0.10 eq.), Zn(CN)2(9.71 mmol, 0.62 mL, 1.10 eq.), Zn (29 mg, 0.442 mmol, 0.05 eq.) and DPPF (979 mg, 1.77 mmol, 0.20 eq.) in DMA (40 mL) was degassed with nitrogen 3 times then stirred at 120 °C for 3 hr. The reaction mixture was then diluted with ethyl acetate (100 mL), filtered and the filtrate was washed with brine (50 mL × 3), dried, concentrated and the residue was purified by column chromatography (SiO2,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.1H NMR (400 MHz, CDCl3) d = 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).

[0409] Step 4: To a solution of 3-fluoro-4-hydroxy-naphthalene-1-carbonitrile (880 mg, 4.70 mmol, 1.00 eq.) in dichloromethane (20 mL) was added triethylamine (9.40 mmol, 1.31 mL, 2.00 eq.) and Tf2O (8.46 mmol, 1.40 mL, 1.80 eq.) at 0 °C. The mixture was then stirred at 28 °C for 0.5 hr. The reaction mixture was then concentrated, and the residue purified by column chromatography (SiO2, petroleum ether / ethyl acetate 2%) to give (4-cyano-2-fluoro- 1-naphthyl) trifluoromethanesulfonate (1.15 g, 3.60 mmol, 77% yield) as a yellow solid.

[0410] Step 5: A mixture of (4-cyano-2-fluoro-1-naphthyl) trifluoromethanesulfonate (0.38 g, 1.19 mmol, 1.00 eq.), Pd(PPh3)4(138 mg, 0.12 mmol, 0.10 eq.), AlMe3 (2 M in PhMe, 1.79 mL, 3.00 eq.) in toluene (3.5 mL) was degassed with nitrogen 3 times and stirred at 120 °C for 2 hr. After such time the reaction was 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, concentrated and the residue purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate 5%) to give compound 3-fluoro-4-methyl-naphthalene-1-carbonitrile (90 mg, 0.49 umol, 41% yield) as a white solid.1H NMR (400 MHz, CDCl3) d = 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).

[0411] Step 6: To a solution of N-isopropylpropan-2-amine (0.86 mmol, 0.12 mL, 2.00 eq.) in THF (2 mL) was added n-BuLi (2.5 M in THF, 0.31 mL, 1.80 eq.) in a dropwise fashion at -70 °C. The mixture was then stirred at -70 °C for 0.5 hr, then 3-fluoro-4-methyl-naphthalene- 1-carbonitrile (80 mg, 0.43 mmol, 1 eq.) was added and stirred for a further 0.5 hr before iodine (0.87 mmol, 0.17 mL, 2.00 eq.) was added. After completion of the addition the mixture was stirred at 30 °C for 1 hr. The reaction mixture was then quenched by the addition of 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.

[0412] Step 7: A mixture of 3-fluoro-2-iodo-4-methyl-naphthalene-1-carbonitrile (110 mg, 0.35 mmol, 1.00 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (96 mg, 0.46 mmol, 1.30 eq.), [2-(2-aminophenyl)phenyl]palladium(1+)-bis(1-adamantyl)-butyl- phosphane-methanesulfonate (26 mg, 0.035 mmol, 0.10 eq.), K3PO4(1.50 M, 0.71 mL, 3.00 eq.) in n-butyl alcohol (2.8 mL) was degassed with nitrogen 3 times then stirred at 60 °C for 6hr. The reaction mixture was then filtered, concentrated and the residue was purified by prep- TLC (SiO2, 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.

[0413] 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 eq.) in acetic acid (2 mL) was added NIS (127 mg, 0.57 mmol, 3.00 eq.). The mixture was stirred at 30 °C for 12 hrs. The pH was then adjusted to pH 7 with saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate (10 mL × 3) and the combined organic phases were dried and concentrated. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate 20%) to give 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. INTERMEDIATE FC

[0414] Step 1: To a solution of 3-chloro-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile (200 mg, 0.747 mmol, 1.00 eq), potassium trifluoro(vinyl)borate (120 mg, 0.896 mmol, 1.20 eq), cesium carbonate (730 mg, 2.24 mmol, 3.00 eq) and dicyclohexyl(2',6'-diisopropoxy- [1,1'-biphenyl]-2-yl)phosphine (34.9 mg, 0.074 mmol, 0.10 eq) in THF (2 mL) and water (0.2 mL) was added palladium(II) chloride (13.3 mg, 0.074 mmol, 0.10 eq) under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 hours. The 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 light yellow solid. LCMS [M+1]+= 260.2.

[0415] Step 2: 2-(1-methyl-1H-pyrazol-5-yl)-3-vinyl-1-naphthonitrile (130 mg, 491 µmol, 1.00 eq) were dissolved in dichloromethane (20 mL) and cooled to -70 °C. Ozone wasbubbled into the reaction solution with stirring for 15 min. Dimethylsulfane (8.46 g, 136 mmol, 10 mL, 277 eq) was then added and the mixture stirred at -70 °C for 15 min. After such time the mixture was concentrated and then purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate 5-20%) to give 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.

[0416] Step 3: A solution of 3-formyl-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthonitrile (20 mg, 74.2 µmol, 1.00 eq) and (bis-(2-methoxyethyl)amino)sulfur trufluoride (41 mg, 185 µmol, 41 µL, 2.50 eq) in dichloromethane (1.0 mL) was stirred at 25 °C for 6 hours. The reaction was then quenched with saturated sodium bicarbonate aqueous (2 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed by brine (3 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by Prep- 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.

[0417] Step 4: To a solution of 3-(difluoromethyl)-2-(1-methyl-1H-pyrazol-5-yl)-1- naphthonitrile (11 mg, 38 µmol, 1.00 eq) in dichloromethane (1.0 mL) was added 1- bromopyrrolidine-2,5-dione (10 mg, 58 µmol, 1.50 eq). The mixture was stirred at 25 °C for 10 hours. The reaction mixture was the concentrated and purified by Prep-TLC (SiO2, 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. INTERMEDIATES FD and FE

[0418] Step 1: A mixture of sodium hidride (51 mg, 1.28 mmol, 60% purity, 1.20 eq.) and 2-methylsulfonylethanol (158 mg, 1.28 mmol, 1.20 eq.) in DMF (3 mL) at 0 °C under nitrogen was stirred 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 eq.) 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 colorless oil. LCMS [M+1]+=334.0;1H NMR (400 MHz, CDCl3) d = 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).

[0419] 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 eq.) in DMF (0.5 mL) was added sodium hydride (4.8 mg, 119 µmol, 60% purity, 2.00 eq.) at 0 °C under nitrogen and the mixture was stirred at 0 °C for 30 minutes. Then dibromo(difluoro)methane (38 mg, 180 µmol, 17 uL, 3.00 eq.) was 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 extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated under vacuum and the residue was purified by prep-TLC (SiO2, petroleum ether: ether acetate 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

[0420] 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 eq.) and sodium 2-chloro-2,2-difluoro-acetate (114 mg, 748 µmol, 2.50 eq.) in DMF (1.0 mL) and water (0.1 mL) was added cesium carbonate (146 mg, 449 µmol, 1.50 eq.). 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 phases were washed with brine (15 mL), dried with anhydrous sodium sulfate, filtered, concentrated in vacuum and the residue purified by column chromatography (SiO2, 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 colorless oil. LCMS [M+1]+=386.0;1H NMR (400 MHz, CDCl3) d = 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)

[0421] 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 eq.) and silver tetrafluoroborate (273 mg, 1.40 mmol, 6.50 eq.) in DCE (2. mL) was stirred at 65 °C for 3 hours. Then, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with brine (15 mL), dried with anhydrous sodium sulfate, filtered, concentrated in vacuum and the residue purified by reversed phase flash (0.1% FA condition) 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.

[0422] In one aspect of the invention, provided herein are Intermediates that mey be used in the preparation of compounds of Formula (I), Formula (I-A), Formula (I-B), Formula (I-C) and Formulat (1-D). In one embodiment, the intermediates include Intermediates A-1 through FE.

[0423] The following Examples are intended to illustrate further certain embodiments of the invention and are not intended to limit the scope of the invention. GENERAL REACTION METHODS FOR THE PREPARATION OF EXAMPLES 1-1 to 1-8 EXAMPLES 1-1 and 1-2

[0424] Step 1: A mixture of Intermediate C, a 1:1 mixture of 4c and 4d (587 mg, 1.68 mmol, 1.00 eq.), phenylboronic acid pinacol ester, Pd(dppf)Cl2(168 µmol, 0.10 eq.) and sodium carbonate (3.36 mmol, 2.00 eq.) in DMF (10 mL) was purged with nitrogen 3 times and stirred at 100 °C for 2 hours. After such time the reaction mixture was 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 prep-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.

[0425] 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 eq.) in DMF (10 mL) was added zinc cyanide (1.21 mmol, 1.50 eq.), 1,1'-bis(diphenylphosphino)ferrocene (80.6 µmol, 0.10 eq.), Pd2(dba)3(40.3 µmol, 0.05 eq.) and zinc powder (80.6 µmol, 0.10 eq.). The mixture was purged with nitrogen 3 times and stirred at 100 °C for 3 hours. After such time the reaction mixture was 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 a residue. The residue was purified by column chromatography (SiO2, 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.

[0426] 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 eq.) was added hydrochloric acid (6.00 M, 10.1 eq.) and methyl alcohol (3.00 mL) followed by palladium on activated carbon (29.6 µmol, 10% by mass) 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 hours. After such time the reaction mixture was filtered, concentrated under reduced pressure and the residue purified by prep-HPLC (Phenomenex Luna C18150 × 25 mm × 10 µm; mobile phase: [water (0.1%TFA)-ACN]; B%: 2%-25%, 10 min) followed by separation of the regioisomers by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm,10 µm); mobile phase: [0.1% NH3H2O MeOH]; B%: 60%-60%, 40 min] to give the desired compounds 4-(aminomethyl)-6- phenyl-phthalazin-1-ol, Example 1-1 (13.7 mg, 53.6 µmol, 26% yield) LCMS [M+1] = 252.2;1H NMR (400 MHz, MeOD) d = 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;1H NMR (400 MHz, MeOD) d = 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).

[0427] Following the teachings of the General Reaction Schemes, the synthesis procedure for Examples 1-1 & 1-2 and using the Intermediates disclosed herein, the Examples 1-3 to 1-8 were prepared as shown in Table 1: Table 1EXAMPLE 2-1

[0428] Step 1: A mixture of Intermediate D (150 mg, 429 µmol, 1.00 eq.), thiazol-4- ylboronic acid (66 mg, 515 µmol, 1.20 eq.), sodium carbonate (91 mg, 858 µmol, 2.00 eq.) and Pd(dppf)Cl2(31 mg, 42.9 µmol, 0.10 eq.) in DMF (1.00 mL) was purged with nitrogen 3 times and stirred at 100 °C for 12 hours under nitrogen. After such time the reaction mixture was 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 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).

[0429] Step 2: A mixture of 4-(1-(benzyloxy)-4-chlorophthalazin-6-yl)thiazole (76 mg, 214 µmol, 1.00 eq.), zinc cyanide (38 mg, 321 µmol, 20 µL, 1.50 eq.), DPPF (12 mg, 21 µmol, 0.10 eq.), Pd2(dba)3(10 mg, 10 µmol, 0.05 eq.) and zinc powder (1 mg, 21 µmol, 0.10 eq.) in DMF (1.00 mL) was degassed and purged with nitrogen 3 times. The mixture was then stirred at 105 °C for 2 hours under a nitrogen atmosphere. After such time the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3) and the combined organic layers washed with brine (30 mL), dried (Na2SO4anhydrous), 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).

[0430] Step 3: To a solution of 4-(benzyloxy)-7-(thiazol-4-yl)phthalazine-1-carbonitrile (103 mg, 299 µmol, 1.00 eq), HCl (6.0 M, 1.00 eq.) in MeOH (10 mL) was added palladiumon 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 stirred vigorously in a hydrogen atmosphere (50.0 psi) at 40 °C for 2 hours. After such time the reaction mixture was filtered, concentrated under reduced pressure and purified by prep- HPLC (Waters Xbridge 150 × 25 mm × 5 µm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 12%-42%, 10 min) to furnish 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) d = 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). GENERAL REACTION METHOD 2 FOR THE PREPARATION OF EXAMPLES 2-2 to 2-5

[0431] Step 1: A mixture of Intermediate E (429 µmol, 1.00 eq.), the appropriate aryl / heteroaryl-tributyltin reagent (644 µmol, 1.50 eq) and Pd(PPh3)4(43 µmol, 0.10 eq.) in toluene (2 mL) was purged with nitrogen 3 times and stirred at 100 °C for 12 hours. After such time the mixture was 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 a residue. The residue was then purified by column chromatography (SiO2, petroleum ether: ethyl acetate 5: 1 to 1: 1) to give appropriate R1-coupled product 5e.

[0432] Step 2: A mixture of the R1-coupled product 5e (214 µmol, 1.00 eq.), zinc cyanide (321 µmol, 20 µL, 1.50 eq.), DPPF (21 µmol, 0.10 eq.), Pd2(dba)3 (10 µmol, 0.05 eq.) and zinc powder (21 µmol, 0.10 eq.) in DMF (1.00 mL) was purged with nitrogen 3 times. The mixture was then stirred at 105 °C for 2 hours. After such time the mixture was 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 a residue. The concentrated residue was then purified by column chromatography (SiO2, petroleum ether: ethyl acetate 5: 1 to 1: 1) to give the appropriate R1-cyanide 6e which were used in the next step without further purification.

[0433] Step 3: To a solution of the appropriate R1-cyanide 6e (287 µmol, 1.00 eq), HCl (6.0 M, 1.00 eq.) 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 hours before being filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters Xbridge 150 × 25 mm × 5µm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 12% - 42%, 10 min) to return the desired compounds shown in Table 2.

[0434] Following the teachings of the General Reaction Schemes, the general reaction method 2 and the Intermediates disclosed herein, the Examples 2-2 to 2-5 are prepared as shown in Table 2. Table 2GENERAL COULPING METHODS (CM) AND PURIFICATION METHODS (PM) FOR THE PREPARATION OF EXAMPLES 3-1 to 3-61 CM 3A

[0435] Step 1: A mixture of the appropriate aryl / heteroaryl / alkyl-boronic ester (390 µmol, 1.5 eq.), intermediate F (260 µmol, 1.00 eq.), Pd(dppf)Cl2(26 µmol, 0.10 eq.), sodium bicarbonate (43 mg, 521 µmol, 20.3 µL, 2.00 eq.) in dioxane (1.00 mL) and water (0.20 mL) was purged with nitrogen 3 times. The mixture was then stirred at 80 °C for 2 hours. After such time the mixture was filtered, washed with a dichloromethane: methyl alcohol 10:1 mixture and the filtrate 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.

[0436] Step 2: To a solution of 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 hour, cooled and concentrated under reduced pressure. The concentrated residue was then purified by prep-HPLC according to one of the purification methods 3-1, 3- 2, 3-3 or 3-4 described herein to furnish 7a.CM 3B:

[0437] Step 1: Intermediate AN, the appropriate alkyl / aryl / heteroaryl bromide (464 µmol),  sodium bicarbonate (464 µmol, 18.0 µL, 2.00 eq.) and Pd(dppf)Cl2(17 mg, 23 µmol, 0.10 eq.) in dioxane (2 mL) and water (0.40 mL) was purged with nitrogen 3 times. The mixture was then stirred at 80 °C for 1 hour. After such time the reaction mixture was diluted with water (2 mL), filtered under reduced pressure and the filter cake triturated with ethyl alcohol (3 mL) to give the corresponding R1-Suzuki coupling product 15a as a black solid which was directly in the next step without further purification.

[0438] Step 2: To a solution of corresponding R1-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 hour. After such time the mixture was concentrated under reduced pressure and the residue purified by prep-HPLC according to one of the purification methods 3-1 to 3-4. CM 3C

[0439] Step 1: A mixture of Intermediate F (312 µmol, 1.00 eq.), the appropriate alkyl / aryl / heteroaryl tributyltin or alkyl / aryl / heteroaryl trimethyl silicon reagent (625 µmol, 2.00 eq.), Pd(PPh3)4(72 mg, 62 µmol, 0.20 eq.) in dioxane (3.00 mL) was purged with nitrogen 3 times. The mixture was then stirred at 100 °C for 1 hour. After such time the reaction mixture was diluted with a potassium fluoride solution (3.0 mL) to form a suspension. The suspension was filtered, and the filtrate 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 prep-TLC (SiO2, dichloromethane: methyl alcohol 10:1) to give the corresponding C-C bond formation compound 15a as a black solid.

[0440] 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. After such time the mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC according to one of the purification methods 3-1 to 3-4. Purification Methods (PM)

[0441] PM 3-1: column: Phenomenex Synergi C18150 × 25 × 10 mm; mobile phase: [water (0.05% HCl)-ACN]; B%: 5% - 25%, 11 min.

[0442] PM 3-2: column: Waters Xbridge 150 × 25 mm × 5 mm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 12% - 42%, 10 min.

[0443] PM 3-3: column: Waters Xbridge 150 × 25 mm × 5 mm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 2% - 32%, 10 min.

[0444] PM 3-4: column: Phenomenex Luna C1875 × 10mm × 3µm; mobile phase:[water (0.05%HCl)-ACN]; B%: 11%-31%, 6.5 min.

[0445] Following the teachings of the General Reaction Schemes, the coupling methods 3A, 3B and 3C and using purification methods 3-1, 3-2, 3-3 and 3-4 and the Intermediates disclosed herein, the Examples 3-1 to 3-61 are prepared as shown in Table 3. Table 3EXAMPLES 4-1 to 4-180^ COULPING METHODS (CM) AND PURIFICATION METHODS (PM) FOR THE PREPARATION OF EXAMPLES IN TABLE 4^ CM 4A:

[0446] Step 1: A mixture of the appropriate aryl / heteroaryl-halide 26 (390 µmol, 1.5 eq.), intermediate AN (260 µmol, 1.00 eq.), Pd(dppf)Cl2(26 µmol, 0.10 eq.), sodium bicarbonate (43.7 mg, 521 µmol, 20.3 µL, 2.00 eq.) in dioxane (1.0 mL) and water (0.2 mL) was purged with nitrogen 3 times. The mixture was then stirred at 80 °C for 2 hours. After such time the mixture was filtered, washed with a dichloromethane: methyl alcohol 10: 1 mixture and the filtrate concentrated under reduced pressure to give a residue. This concentrated residue wastriturated with methyl alcohol (3.0 mL), filtered and dried to give the corresponding coupling product 15a as a black solid.

[0447] Step 2: To a solution of 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 hour. After such time the mixture was concentrated in vacuo and the residue purified by prep- HPLC according to one of the purification methods 4-1 to 4-13. CM 4B:

[0448] Step 1: Intermediate J (189 mg, 470 µmol, 1.00 eq.), aryl / heteroaryl-halide 26 (564 µmol, 1.20 eq.), Pd(dppf)Cl2(34 mg, 47 µmol, 0.10 eq.), sodium bicarbonate (79 mg, 940 µmol, 37 µL, 2.00 eq.) in dioxane (1 mL) and water (0.20 mL) was purged with nitrogen 3 times, and stirred at 80 °C for 2 hours. Upon completion, the reaction mixture was poured into water (40 mL), filtered and the filter cake was dried under reduced pressure to give R2- Pyridyl-Suzuki coupling product 28-Boc (71 mg, crude) as a gray solid and used into the next step directly without further purification.

[0449] Step 2: To a solution of tert-butyl N-[[4-oxo-7-(5-pyrimidin-2-yloxy-3-pyridyl)- 3H-phthalazin-1-yl]methyl]carbamate R2-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 hour and upon completion concentrated to a residue under reduced pressure. The concentrated residue 29 was purified by prep-HPLC according to one of the purification methods 4-1 through 4-13.CM 4C

[0450] Step 1: A mixture of the appropriate aryl / heteroaryl boronic ester (303 µmol, 1.16 eq.), intermediate F (100 mg, 260 µmol, 1.00 eq.), Pd(dppf)Cl2(19 mg, 26 µmol, 0.10 eq.), sodium bicarbonate (66 mg, 781 µmol, 30 µL, 3.00 eq.) in dioxane (1 mL) and water (0.20 mL) was degassed and purged with nitrogen 3 times and stirred at 80 °C for 1 hour under a nitrogen atmosphere. After such time the mixture was filtered and concentrated under reduced pressure to give a residue. The concentrated residue was purified by column chromatography (SiO2, 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.

[0451] Step 2: To a solution of 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 hour, cooled and concentrated under reduced pressure. The concentrated residue 7a was then purified by prep-HPLC according to one of the purification methods 4-1 to 4-13 described herein. CM 4D

[0452] Step 1: Intermediate J (69 mg, 17 mmol, 1.30 eq.), aryl / heteroaryl-halide 26 (132 µmol, 1.0 eq.), Pd(dtbpf)Cl2(9 mg, 13 µmol, 0.10 eq.), sodium carbonate (28 mg, 263 µmol,2.00 eq.) in dioxane (1.5 mL) and water (0.30 mL) was purged with nitrogen 3 times, and stirred at 80 °C for 2 hours. After such time the mixture was concentrated and the residue purified by prep-TLC (SiO2, CH2Cl2: MeOH 20:1) to give R1-Suzuki coupling product 28-Boc and used into the next step directly without further purification.

[0453] Step 2: To a solution of tert-butyl N-[[4-oxo-7-(R1)-3H-phthalazin-1- yl]methyl]carbamate Suzuki coupling product 28-Boc (40 mg) 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 hour and upon completion concentrated to a residue under reduced pressure. The concentrated residue 29 was purified by prep-HPLC according to one of the purification methods 4-1 through 4-13. CM 4E

[0454] Step 1: Intermediate J (80 mg, 0.20 mmol, 1.00 eq.), aryl / heteroaryl-halide 26 (239 µmol, 1.2 eq.), [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6- dimethoxyphenyl)phenyl]phosphane (14.4 mg, 19.9 µmol, 0.10 eq.), sodium bicarbonate (34 mg, 398 µmol, 2.00 eq.) in 2-methyl-2-butanol (2.00 mL) and water (0.4 mL) was purged with nitrogen 3 times, and stirred at 80 °C for 3 hours. After such time the mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by prep-TLC (SiO2, petroleum ether: ethyl acetate = 1: 1.5) to give R1-Suzuki coupling product 28-Boc which was used in the next.

[0455] Step 2: A solution of tert-butyl N-[[4-oxo-7-(R1)-3H-phthalazin-1- yl]methyl]carbamate Suzuki coupling product 28-Boc (0.08 mmol, 1.00 eq) in HCl•dioxane (2.00 mL, 101 eq.) was stirred at 25 °C for 12 hours. The reaction was concentrated in vacuo and the residue purified by prep-HPLC according to one of the purification methods 4-1 through 4-13.CM 4F:

[0456] Step 1: Intermediate J (80 mg, 0.20 mmol, 1.00 eq.), aryl / heteroaryl-halide 26 (0.24 mmol, 1.2 eq.), 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 eq.), potassium phosphate, 0.40 mmol, 2.00 eq.) in n-butanol (2.0 mL) and water (0.4 mL) was purged with nitrogen 3 times, and stirred at 60 °C for 1 hour. After such time the mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by prep-TLC (SiO2, petroleum ether: ethyl acetate 20%) to give R1-Suzuki coupling product 28-Boc which was used in the next step.

[0457] Step 2: To a solution of tert-butyl N-[[4-oxo-7-(R1)-3H-phthalazin-1- yl]methyl]carbamate Suzuki coupling product 28-Boc (40.0 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (5.4 mmol, 0.40 mL). The mixture was stirred at 25 °C for 0.5 hour and upon completion concentrated to a residue under reduced pressure. The concentrated residue 29 was purified by prep-HPLC according to one of the purification methods 4-1 through 4-13. CM 4G:

[0458] Step 1: Intermediate J (40 mg, 0.10 mmol, 1.25 eq.), aryl / heteroaryl-halide 26 (0.076 mmol, 1.0 eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane methanesulfonate (8 µmol, 0.10 eq.), potassium phosphate, (0.23 mmol, 3.00 eq.) in dioxane (1.5 mL) and water (0.3 mL) was purged with nitrogen 3 times, and stirred at 90 °C for 2hours. After such time the mixture was filtered, concentrated and the residue was then purified by prep-TLC (SiO2, petroleum ether: ethyl acetate 60%) to give R1-Suzuki coupling product 28-Boc which was used in the next step.

[0459] Step 2: To a solution of tert-butyl N-[[4-oxo-7-(R1)-3H-phthalazin-1- yl]methyl]carbamate Suzuki coupling product 28-Boc (30.0 mg) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at 25 °C for 0.5 hour and upon completion concentrated to a residue under reduced pressure. The concentrated residue 29 was purified by prep-HPLC according to one of the purification methods 4-1 through 4-13. Purification Methods (PM)

[0460] PM 4-1: column: Phenomenex Synergi C18150 × 25 mm × 10 ^ mm; mobile phase: [water (0.05% HCl)-ACN]; B%: 5%-30%, 10 min.

[0461] PM 4-2: column: Waters Xbridge 150 × 25 mm × 5 mm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 5%-40%, 10 min.

[0462] PM 4-3: column: Waters Atlantis T3150 × 30 mm × 5 mm; mobile phase: [water (0.225% FA)-ACN];...

Claims

WE CLAIM:

1. A compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof: wherein: R1is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-C1 – C5 alkyl, -Y-cycloalkyl, -Y- heterocyclyl, -Y-aryl, -Y-arC1-C3alkyl or -Y-heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl portions are each optionally substituted with one or more R2; each Y is independently a bond or -NR4-; each R2is independently hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SO2C1 – C3alkyl, -X-arC1-C3alkyl, 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 the heterocyclyl, the cycloalkyl, the aryl and the heteroaryl are optionally substituted with one or more R5, or; each X is independently a bond, O, S, -NR4- or -NR4C(O)-; each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-; each L is independently a bond or C1 – C3 alkylene;R3aand R3bare each independently hydrogen or deuterium, or R3aand R3btogether are oxo; each R4is independently hydrogen or C1 – C3 alkyl; each R5is independently cyano, oxo, halogen, C1 – C3 alkyl, hydroxyalkyl, alkoxy, - X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3alkyl, X-arC1-C3alkyl substituted with cyano, -X-L-cycloalkyl, -X-L-heteroaryl optionally substituted with one or more C1-C3alkyl or oxo, or -X-aryl; and   R6is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

2. The compound according to claim 1, wherein R1is hydrogen.

3. The compound according to claim 1, wherein R1is halogen.

4. The compound according to claim 3, wherein the halogen is bromine.

5. The compound according to claim 1, wherein R1is -Y-C1 – C5 alkyl.

6. The compound of claim 5, wherein Y is a bond and the C1 – C5 alkyl is methyl.

7. The compound according to claim 1, wherein R1is hydroxyalkyl.

8. The compound according to claim 1, wherein R1is -L-CN.

9. The compound according to claim 8, wherein L is C1 – C3 alkylene.

10. The compound according to claim 1, wherein R1is -Y-heterocyclyl.

11. The compound according to claim 10, wherein Y is a bond and the heterocyclyl is azetidinyl, THFyl or morpholinyl.

12. The compound according to claim 1, wherein R1is -Y-aryl, wherein the aryl is optionally substituted with one or more R2.

13. The compound according to claim 12, wherein Y is a bond and the aryl is phenyl optionally substituted with one or two R2.

14. The compound according to claim 13, wherein the one or two R2groups are each independently cyano, halogen or -Y-C1 – C5 alkyl, wherein Y is a bond.

15. The compound according to claim 1, wherein R1is -Y-cycloalkyl.

16. The compound according to claim 15, wherein Y is a bond and the cycloalkyl is cyclopentyl.

17. The compound according to claim 1, wherein R1is -Y-heteroaryl optionally substituted with one or more R2.

18. The compound according to claim 17, wherein Y is a bond and the heteroaryl is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, oxidazolyl, pyridyl, pyridiazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrazolopyridinyl, 1H-pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridyl, tetrahydropyrazolopyrazinyl, 2H-4ƛ4-imidazopyrimidinyl, 2H-4ƛ4-imidazopyridazinyl, oxazolopyridyl or 5,6-dihydro-8H-imidazooxazinyl, each optionally substituted with one or more R2.

19. The compound according to claim 18, wherein the heteroaryl is tetrahydropyrazolopyrazinyl, optionally substituted with one or more R2.

20. The compound according to claim 19, wherein the tetrahydropyrazolopyrazinyl is substituted with one R2selected from the group consisting of -X-C1-C5 alkyl, arC1- C3alkyl, -Z-C1-C5 alkyl, -Z-cycloalkyl and -X-aryl.

21. The compound according to claim 20, wherein R2is -Z-cycloalkyl.

22. The compound according to claim 21, wherein Z is a bond and the cycloalkyl is cyclopropyl.

23. The compound according to claim 21, wherein Z is -C(O)- and the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl.

24. The compound according to claim 17, wherein the heteroaryl is pyridyl, optionally substituted with one or two R2.

25. The compound according to claim 24, wherein the pyridyl is substituted with one R2.

26. The compound according to claim 25, wherein R2is hydroxy, halogen, cyano, -(NR4)2, hydroxyalkyl, alkoxy, -SO2C1 – C3alkyl, arC1-C3alkyl, 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 the heterocyclyl, the cycloalkyl, the aryl and the heteroaryl are optionally substituted with one or more R5.

27. The compound according to claim 26, wherein R2is -X-C1 – C5 alkyl, and X is a bond and the C1 – C5 alkyl is methyl, ethyl, propyl, or isopropyl.

28. The compound according to claim 26, wherein R2is -X-haloalkyl, and X is a bond and the haloalkyl is difluoromethyl or trifluoromethyl.

29. The compound according to claim 26, wherein R2is -X-haloalkyl, X is O and the haloalkyl is difluoromethyl or trifluoromethyl.

30. The compound according to claim 26, wherein R2is -X-L-cycloalkyl, wherein X is a bond, L is a bond and the cycloalkyl is cyclopropyl.

31. The compound according to claim 26, wherein R2is -X-L-cycloalkyl, wherein X is a bond, L is a methylene and the cycloalkyl is cyclopropyl or cyclohexyl.

32. The compound according to claim 26, wherein R2is -X-L-cycloalkyl, wherein X is O, L is methylene and the cycloalkyl is cyclopropyl.

33. The compound according to claim 26, wherein R2is C2- C4 alkynyl, wherein the C2- C4 alkynyl is ethynyl or prop-2-ynyl.

34. The compound according to claim 26, wherein R2is -SO2C1 – C3 alkyl, wherein the C1 – C3 alkyl is methyl.

35. The compound according to claim 26, wherein R2is heterocyclyl, wherein the heterocyclyl is morpholinyl or tetrahydropryanyl.

36. The compound according to claim 26, wherein R2is -X-heteroaryl, wherein the heteroaryl is optionally substituted with one or more R5.

37. The compound according to claim 36, wherein X is a bond, and the heteroaryl is pyrazolyl substituted with one R5, wherein R5is C1 – C3 alkyl.

38. The compound according to claim 36, wherein the X is a bond, and the heteroaryl is pyridyl or pyrimidinyl, each optionally substituted with one or more R5.

39. The compound according to claim 36, wherein the X is a bond or O, and the heteroaryl is quinolinyl optionally substituted with one or more R5.

40. The compound according to claim 36, wherein the X is -NR4-, and the heteroaryl is quinolinyl optionally substituted with one or more R5.

41. The compound according to claim 36, wherein R2is -X-aryl, wherein the aryl is optionally substituted with one or more R5.

42. The compound according to claim 41, wherein X is a bond and the aryl is phenyl or naphthyl substituted with one, two or three R5.

43. The compound according to claim 42, wherein each R5is selected from the group consisting of cyano, halogen, -X-L-cycloalkyl, -X-haloalkyl, heterocyclyl, X- heteroaryl, C1 – C3 alkyl and alkoxy.

44. The compound according to claim 41, wherein X is O and the aryl is phenyl substituted with one or two R5.

45. The compound according to claim 44, wherein each R5is cyano, halogen, C1 – C3 alkyl or alkoxy.

46. The compound according to claim 41, wherein X is S, the aryl is phenyl substituted with one R5, wherein R5is halogen or C1 – C3 alkyl.

47. The compound according to claim 41, wherein the X is -NR4-, and the aryl is phenyl optionally substituted with one or more R5.

48. The compound according to claim 26, wherein R2is halogen, wherein the halogen is chlorine or fluorine.

49. The compound according to claim 18, wherein the heteroaryl is pyrazolopyridinyl, optionally substituted with one or more R2.

50. The compound of claim 49, wherein the pyrazolylpyridinyl is substituted with one R2, wherein the one R2is alkoxy or -X-aryl.

51. The compound of claim 45, wherein the alkoxy is methoxy or isopropyloxy.

52. The compound of claim 45, wherein the -X-aryl, the X is O and the aryl is phenyl.

53. The compound according to claim 1, wherein R1is -Y-aryl, wherein Y is -NR4- and the aryl is phenyl optionally substituted with one or more R5.

54. The compound according to claim 1, wherein R1is -Y-C1- C5 alkyl, wherein Y is - NR4- and the C1 – C5 alkyl is methyl, ethyl or propyl.

55. The compound according to claim 1, wherein R1is -Y-arC1-C3alkyl, wherein Y is - NR4- and the arC1-C3alkyl is benzyl.

56. The compound according to claim 24, wherein the pyridyl is substituted with two R2.

57. The compound according to claim 56, wherein each R2is -X-C1 – C5 alkyl or one R2is halogen or -X-L-cycloalkyl and the second R2is -X-C1 – C5 alkyl, wherein each X is a bond.

58. The compound according to claim 18, wherein the heteroaryl is pyrimidinyl, optionally substituted with one or more R2.

59. The compound according to claim 58, wherein the pyrimidinyl is substituted with one R2.

60. The compound according to claim 59, wherein R2is -X-C1 – C5 alkyl or -X-haloalkyl.

61. The compound according to claim 18, wherein the heteroaryl is pyrazolyl, optionally substituted with one, two or three R2groups.

62. The compound according to claim 61, wherein the pyrazolyl is substituted with one R2.

63. The compound according to claim 62, wherein R2is -X-C1 – C5 alkyl, hydroxyalkyl, arC1-C3alkyl, or -X-aryl optionally substituted with one or more R5.

64. The compound according to claim 63, wherein R2is -X-C1 – C5 alkyl, wherein the X is a bond, and the C1 - C5 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl.

65. The compound according to claim 61, wherein the pyrazolyl is substituted with two independently selected R2.

66. The compound according to claim 65, wherein the two R2groups are (1) independently -t -X-C1 – C5 alkyl, (2) -X-C1 – C5 alkyl and halogen, (3) -X-C1 – C5 alkyl and alkoxy, (4) -X-C1 – C5 alkyl and -N(R4)2, -(5) X-C1 – C5 alkyl and -X- haloalkyl, (6) -X-C1 – C5 alkyl and arC1-C3alkyl, (7) -X-C1 – C5 alkyl and -X-L- cyclolalkyl, -(8) -X-C1 – C5 alkyl and -heterocyclyl, (9) -X-C1 – C5 alkyl and -X-aryloptionally substituted with one or more R5, (10) -X-C1 – C5 alkyl and -X-heteroaryl optionally substituted with one or more R5, (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-C3alkyl or X- arC1-C3alkyl substituted with cyano, and (21) halogen and -X-aryl.

67. The compound according to claim 66, wherein the pyrazolyl is substituted with -X-C1 – C5 alkyl and -X-aryl optionally substituted with one or more R5, wherein the X is a bond and the aryl is phenyl substituted with two R5, wherein each R5is independently -X-C1 – C5 alkyl, wherein each X is a bond; one R5is cyano and one R5is -X-C1 – C5 alkyl, wherein each X is a bond; one R5is cyano and one R5is -X-L-cycloalkyl, wherein X is a bond and L is a bond, methylene or ethylene; one R5is cyano and one R5is halogen; one R5is cyano and one R5is alkoxy; or each R5is independently halogen.

68. The compound according to claim 66, wherein the pyrazolyl is substituted with -X-C1 – C5 alkyl and -X-aryl optionally substituted with one or more R5, wherein the X is a bond and the aryl is phenyl substituted with three R5, wherein each R5is -X-C1 – C5 alkyl, wherein each X is a bond; one R5is cyano and two R5are-X-C1 – C5 alkyl, wherein each X is a bond; one R5is cyano, one R5is halogen, and one R5is -X-C1 – C5 alkyl, wherein X is a bond; one R5is cyano and two R5are alkoxy, one R5is cyano and two R5are halogens, one R2is cyano and two R2are halogen; one R2is cyano, one R2is halogen and one R2is alkoxy, or one R2is alkoxy, and two R2are independently halogen.

69. The compound according to claim 18, wherein the heteroaryl is imidazolyl, 1H- pyrrolopyridyl, tetrahydropyrazolopyrazinyl, 2H-4ƛ4-imidazopyrimidinyl, 2H-4ƛ4- imidazopyridazinyl, or oxazolopyridyl, each substituted with one R2group, wherein each R2is -X-C1 – C5 alkyl, wherein X is a bond.

70. The compound according to claim 18, wherein the heteroaryl is imidazopyridyl substituted with one R2group, wherein R2is cyano, alkoxy, halogen or -X-C1 - C5 alkyl and X is a bond.

71. The compound according to claim 18, wherein the heteroaryl is imidazopyridyl substituted with two R2groups, wherein one R2group is halogen and the second R2group is -X-C1 - C5 alkyl, wherein X is a bond, or halogen.

72. The compound according to any of claims 2-71, wherein R3aand R3bare each hydrogen.

73. The compound according to any of claims 2-71, wherein R3aand R3bare each deuterium.

74. The compound according to any of claims 2-71, wherein one of R3aand R3bis hydrogen and the other is deuterium.

75. The compound according to any of claims 2-71, wherein R3aand R3btogether are oxo.

76. The compound according to any of claims 2-75, wherein R4is hydrogen.

77. The compound according to any of claims 2-75, wherein R4is methyl.

78. The compound according to any of claims 2-77, wherein R6is hydrogen.

79. The compound according to any of claims 2-77, wherein R6is halogen.

80. The compound of claim 79, wherein the halogen is chlorine or fluorine.

81. The compound according to any of claims 2-77, wherein R6is C1 - C3 alkyl.

82. The compound according to claim 81, wherein the C1 - C3 alkyl is methyl or ethyl.

83. The compound according to any of claims 2-77, wherein R6is alkoxy.

84. The compound according to claim 83, wherein the alkoxy is methoxy.

85. The compound according to any of claims 2-77, wherein R6is haloalkyl.

86. The compound according to claim 85, wherein the haloalkyl is trifiuorom ethyl.

87. A compound of Formula (I-D):Formula (I-D) or a pharmaceutically acceptable salt thereof: wherein: each Y is independently a bond or -NR4-; each R2is independently hydroxy, halogen, cyano, cyanomethyl, -(NR4)2, hydroxyalkyl, alkoxy, -SO2CI - 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 the heterocyclyl, the cycloalkyl, the aryl and the heteroaryl are optionally substituted with one or more R5, or; each X is independently a bond, O, S, -NR4- or -NR4C(O)-; each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-; each L is independently a bond or C1 - C3 alkylene; each R4is independently hydrogen or C1 - C3 alkyl;each R5is independently cyano, oxo, halogen, C1 - C3 alkyl, hydroxyalkyl, alkoxy, - X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, X-arC1-C3 alkyl substituted with cyano, -X-L-cycloalkyl, -X-L-heteroaryl optionally substituted with one or more C1-C3alkyl or oxo, or -X-aryl; andR6is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

88. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

89. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

90. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (I) according to any one of claims 1-89 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

91. A method for inhibiting PRMT5 activity in a cell, 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 1-89 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 90.

92. A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula (I) according to any one of claims 1-89 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents.

93. The method of claim 92, wherein the therapeutically effective amount of the compound is between about 0.01 to 300 mg / kg per day.

94. The method of claim 92, wherein the therapeutically effective amount of the compound is between about 0.1 to 100 g / kg per day.

95. The method according to any one of claims 91-94, wherein the cancer is selected from the group consisting of Cardiac: 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, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's 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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder 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, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial wcarcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

96. The method according to any one of claims 91-95, wherein the cancer is a MTAP- associated cancer.

7. The method of claim 95, wherein the cancer is hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.