MTA-Synergistic PRMT5 Inhibitors

Abstract

The present invention relates to compounds that inhibit the activity of protein arginine N-methyltransferase 5 (PRMT5). In particular, the invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the invention. # imgabs0 #

Description

[0001] This application is a divisional application of Chinese Patent Application for Invention (filing date: September 11, 2020; application number: 202080073827.9 (International Application Number: PCT / US2020 / 050457); invention title: MTA-Cooperative PRMT5 Inhibitor).

[0002] Cross-reference to related applications

[0003] This application claims the benefit of priority of U.S. Provisional Application No. 62 / 899,575, filed on September 12, 2019; U.S. Provisional Application No. 62 / 942,833, filed on December 3, 2019; U.S. Provisional Application No. 62 / 961,371, filed on January 15, 2020; U.S. Provisional Application No. 62 / 994,927, filed on March 26, 2020; and U.S. Provisional Application No. 63 / 060,261, filed on August 3, 2020, the disclosures of each of which are hereby incorporated by reference in their entirety. Technical Field

[0004] The present invention relates to compounds that are MTA cooperative inhibitors of protein arginine N-methyltransferase 5 (PRMT5). In particular, the present invention relates to compounds, pharmaceutical compositions comprising the compounds, and methods of using the same. Background Art

[0005] Protein arginine N-methyltransferase (PRMT5) is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the ω-nitrogen of the guanidino function of a protein L-arginine residue (ω-monomethylation) and the transfer of a second methyl group to another ω-nitrogen, resulting in symmetric dimethylarginine (sDMA). PRMT5 forms a complex with MEP50 (methylosome protein 50), which is necessary for substrate recognition and orientation and is also necessary for the histone 2A and histone 4 methyltransferase activities catalyzed by PRMT5 (e.g., see Ho et al., (2013) PLOS ONE 8(8): 10.1371 / annotation / e6b5348e-9052-44ab-8f06-90d01dc88fc2).

[0006] Homozygous deletions of p16 / CDKN2a are common in cancers, and these mutations often involve co-deletions of adjacent genes, including the gene encoding methylthioadenosine phosphorylase (MTAP). It is estimated that homozygous deletions of the MTAP gene occur in approximately 15% of all human cancers (see, e.g., Firestone & Schramm (2017) J. Am. Chem. Soc. 139(39):13754-13760. doi:10.1021 / jacs.7b05803. Epub Sep 20, 2017).

[0007] Cells lacking MTAP activity have elevated levels of the MTAP substrate methylthioadenosine (MTA), which is a potent inhibitor of PRMT5. Inhibition of PRMT5 activity results in reduced methylation activity and increased sensitivity of cell proliferation to PRMT5 depletion or loss of activity. Thus, loss of MTAP activity reduces the methylation activity of PRMT5, rendering cells selectively dependent on PRMT5 activity. SUMMARY OF THE INVENTION

[0008] Accordingly, we have recognized that in MTAP-deficient cancers, co-inhibition of PRMT5 activity by MTA will provide therapeutic benefits for a wide range of cancers. The compounds of the present invention provide such therapeutic benefits as MTA co-inhibitors of PRMT5, which negatively regulate the activity of MTA-bound PRMT5 in cells, particularly MTAP-deficient cells, or for treating various forms of MTAP-related cancers.

[0009] There is a need to develop new MTA co-PRMT5 inhibitors that are capable of inhibiting PRMT5 activity in the presence of elevated MTA concentrations, particularly in MTAP-deficient cells.

[0010] In one aspect of the invention, there is provided a compound represented by formula (I):

[0011]

[0012] and pharmaceutically acceptable salts thereof:

[0013] wherein:

[0014] R 1 is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-C1-C5 alkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, -Y-arC1-C3 alkyl or -Y-heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties are each optionally substituted with one or more R 2 substituents;

[0015] Each Y is independently a bond or -NR4 -;

[0016] Each R 2 is independently hydroxy, halogen, cyano, cyanomethyl, -(NR 4 )2, hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, -X-arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclic group, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl or -X-heteroaryl, where the heterocyclic group, cycloalkyl, aryl and heteroaryl are optionally substituted by one or more R 5 substituents;

[0017] Each X is independently a bond, O, S, -NR 4 -, or -NR 4 C(O)-;

[0018] Each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-;

[0019] Each L is independently a bond or C1-C3 alkylene;

[0020] R 3a and R 3b are each independently hydrogen or deuterium, or R 3a and R 3b together are oxo;

[0021] Each R 4 is independently hydrogen or C1-C3 alkyl;

[0022] Each R 5 is independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, -X-arC1-C3 alkyl substituted by cyano, -X-L-cycloalkyl, -X-L-heteroaryl optionally substituted by one or more C1-C3 alkyl or oxo, or -X-aryl; and

[0023] R 6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

[0024] In one aspect of the present invention, there is provided a compound represented by formula (I-A):

[0025]

[0026] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3a , R3b and R 4 and R 5 and R 6 Y, X, Z, and L are as defined for formula I, respectively.

[0027] In one aspect of the present invention, there is provided a compound represented by formula (I-B):

[0028]

[0029] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 and R 3a and R 3b and R 4 and R 5 and R 6 Y, X, Z, and L are as defined for formula I, respectively.

[0030] In one aspect of the present invention, there is provided a compound represented by formula (I-C):

[0031]

[0032] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 and R 3a and R 3b and R 4 and R 5 and R 6 Y, X, Z, and L are as defined for formula I, respectively.

[0033] In another aspect of the present invention, there is provided a compound represented by formula (I-D):

[0034]

[0035] or a pharmaceutically acceptable salt thereof:

[0036] Wherein:

[0037] Each Y is independently a bond or -NR 4 -;

[0038] Each R 2 is independently hydroxy, halogen, cyano, cyanomethyl, -(NR 4)2. hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, -X-arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclic group, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl or -X-heteroaryl, wherein the heterocyclic group, cycloalkyl, aryl and heteroaryl are optionally substituted by one or more R 5 substituted, or;

[0039] Each X is independently a bond, O, S, -NR 4 -, or -NR 4 C(O)-;

[0040] Each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-;

[0041] Each L is independently a bond or C1-C3 alkylene;

[0042] Each R 4 is independently hydrogen or C1-C3 alkyl;

[0043] Each R 5 is 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 by one or more C1-C3 alkyl or oxo, or -X-aryl; and

[0044] R 6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

[0045] In another aspect of the present invention, there are provided intermediates useful for preparing the compounds of formula (I), formula (I-A), formula (I-B) and formula (I-C).

[0046] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0047] In another aspect of the present invention, a method for inhibiting PRMT5 activity in cells, comprising contacting the cells 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.

[0048] The present invention also provides a method for inhibiting cell proliferation in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of formula (I), formula (I-A), formula (I-B), formula (I-C) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the cell is an MTAP-deficient cell.

[0049] There is also provided a method for treating cancer in a patient, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound, a pharmaceutical composition, or a pharmaceutically acceptable salt thereof of the present invention.

[0050] The present invention also provides a method for treating cancer in a patient in need thereof, said method comprising (a) determining that the cancer is associated with MTAP double deletion (e.g., an MTAP-related 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

[0051] The present invention relates to MTA co-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 using the same.

[0052] Definitions

[0053] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference to the extent that they are consistent with the present disclosure. Terms and ranges have their ordinary defined meanings unless otherwise specifically defined.

[0054] For simplicity, the chemical moieties are mainly defined and referred to throughout the text as monovalent chemical moieties (e.g., alkyl, aryl, etc.). However, such terms can also be used to express the corresponding polyvalent moieties in a suitable structural context that is clear to those skilled in the art. For example, while the "alk" moiety typically refers to a monovalent radical (e.g., CH3-CH2-), in some cases, the divalent linking moiety can be "alkyl", in which case those skilled in the art will understand that alkyl is a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term "alkylene" (similarly, in cases where a divalent moiety is required and is referred to as "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 valence numbers for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of S).

[0055] As used herein, "PRMT5" refers to the mammalian protein arginine N-methyltransferase 5 (PRMT5) enzyme.

[0056] As used herein, "PRMT5 inhibitor" or "MTA-cooperative PRMT5 inhibitor" refers to the compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of PRMT5 in the presence of bound MTA in vitro or in vivo, or in cells expressing elevated levels of MTA.

[0057] As used herein, "MTAP" refers to the mammalian methylthioadenosine phosphorylase (MTAP) enzyme.

[0058] As used herein, "MTAP-related disease or disorder" refers to a disease or disorder associated with, mediated by, or having a loss of MTAP activity, which results in the disorder being sensitive to the selective inhibition of PRMT5 activity. Non-limiting examples of MTAP-related diseases or disorders are MTAP-related cancers.

[0059] The term "amino" refers to –NH2.

[0060] The term "acetyl" refers to "-C(O)CH3.

[0061] As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent, where the alkyl and aryl moieties are as defined herein.

[0062] As used herein, the term "alkyl" refers to saturated straight-chain and branched-chain aliphatic groups having 1 to 12 carbon atoms. Thus, "alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C11 and C 12 groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0063] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched aliphatic group having one or more carbon-carbon double bonds and having 2 to 12 carbon atoms. Thus, "alkenyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 groups. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0064] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched aliphatic group having one or more carbon-carbon triple bonds and having 2 to 12 carbon atoms. Thus, "alkynyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 groups. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0065] An "alkylene", "alkenylene", or "alkynylene" group is an alkyl, alkenyl, or alkynyl group as defined above that is located between two other chemical groups and is used to link two other chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Exemplary alkenylene groups include, but are not limited to, vinylene, propenylene, and butenylene. Exemplary alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0066] The term "alkoxy" refers to -OC1-C6 alkyl.

[0067] As used herein, the term "cycloalkyl" is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. Thus, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 cyclic hydrocarbon groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0068] The term "heteroalkyl" refers to an alkyl group as defined above, wherein one or more carbon atoms in the chain are independently replaced by O, S, or NR x , where R xis hydrogen or a C1-C3 alkyl group. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0069] An "aryl" group is a C6-C containing one to three aromatic rings 14 aromatic moiety. Thus, "aryl" includes C6, C 10 , C 13 and C 14 cyclic hydrocarbon groups. Exemplary aryl groups are C6-C 10 aryl groups. Specific aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. An "aryl" group also includes fused polycyclic (e.g., bicyclic) ring systems where one or more of the fused rings are non-aromatic provided that at least one ring is aromatic, such as indenyl.

[0070] An "aralkyl" or "arylalkyl" group includes an aryl group covalently linked to an alkyl group, where the moiety is attached to another group through the alkyl moiety. Exemplary aralkyl groups are -(C1-C6)alkyl(C6-C10)aryl, including but not limited to benzyl, phenethyl, and naphthylmethyl. For example, arC1-C3 alkyl is an aryl group covalently linked to a C1-C3 alkyl group.

[0071] A "heterocyclic" or "heterocycle" group is a monocyclic or bicyclic (fused or spiro) ring structure having 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms), such as 4 to 8 atoms, where one or more of the ring atoms are independently -C(O)-, N, NR 4 , O, or S, and the remaining ring atoms are quaternary carbon or carbonyl carbon. Examples of heterocyclic groups include, but are not limited to, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, THFyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thialkyl, dithialkyl, trithialkyl, azathialkyl, oxathialkyl, dioxolanyl, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidinyl, 4-piperidinyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0072] As used herein, "L-heterocyclic" refers to a heterocyclic group covalently linked to another group through an alkylene linker.

[0073] 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 π electrons in a cyclic array; and having 1 to 3 heteroatoms each independently being N, O or S in addition to carbon atoms. "Heteroaryl" also encompasses fused polycyclic (e.g., bicyclic) ring systems in which one or more fused rings are non-aromatic provided that at least one ring is aromatic and at least one ring contains N, O or S ring atoms.

[0074] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzod[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, dihydroindolyl, 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, phenothiazinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridobenzimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolinyl, quinoxalinyl, quinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thiophenyl, thieno[2,3-d]thiazole, thieno[2,3-d]oxazole, thieno[2,3-d]imidazole, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

[0075] The "L - heteroaralkyl" or "L - heteroarylalkyl" group contains a heteroaryl group covalently linked to another group through an alkylene linker. Examples of heteroalkyl groups include C1 - C6 alkyl groups and heteroaryl groups having 5, 6, 9 or 10 ring atoms. Examples of heteroaralkyl include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl, isoquinolinylmethyl, isoindolylmethyl, cinnamylmethyl and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0076] The "arylene", "heteroarylene" or "heterocyclylene" group is a divalent aryl, heteroaryl or heterocyclic group as defined above that is located between two other chemical groups and is used to link two other chemical groups.

[0077] As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described as "optionally substituted" without specifying the substituents, it means that the group optionally has 1 to 4, preferably 1 to 3, more preferably 1 or 2 non - hydrogen substituents.

[0078] The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine or iodine.

[0079] 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, fluorochloromethyl, chloromethyl and fluoromethyl.

[0080] The term "hydroxyalkyl" refers to - alkylene - OH.

[0081] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of the PRMT5 enzyme.

[0082] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or in some way reduce symptoms or stop or reverse the progression of a disorder, or negatively regulate or inhibit the activity of PRMT5. Such an amount can be administered as a single dose or can be administered according to a regimen whereby it is effective.

[0083] As used herein, "treatment" refers to any manner of ameliorating or otherwise beneficially altering the symptoms or pathology of a patient's disorder, condition or disease.

[0084] As used herein, "ameliorating the symptoms of a particular disorder by administering a particular compound or pharmaceutical composition" means any alleviation, whether permanent or temporary, durable or transient, that can be attributed to or is associated with the administration of the composition.

[0085] Compounds

[0086] In one aspect of the invention, there is provided a compound represented by formula (I):

[0087]

[0088] or a pharmaceutically acceptable salt thereof:

[0089] wherein:

[0090] R 1 is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-C1-C5 alkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, -Y-arC1-C3 alkyl or -Y-heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties are each optionally substituted with one or more R 2 substituents;

[0091] each Y is a bond or -NR 4 -;

[0092] each R 2 independently is hydroxy, halogen, cyano, cyanomethyl, -(NR 4 )2, hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, -X-arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocycloalkyl, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl or -X-heteroaryl, wherein the heterocycloalkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5 substituents;

[0093] each X independently is a bond, O, S, -NR 4 - or -NR 4 C(O)-;

[0094] each Z independently is a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-;

[0095] each L independently is a bond or C1-C3 alkylene;

[0096] R 3a and R 3b are each independently hydrogen or deuterium, or R 3a and R 3bTogether it is oxo;

[0097] Each R 4 is independently hydrogen or C1-C3 alkyl;

[0098] Each R 5 is 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-C3 alkyl or oxo, or -X-aryl; and

[0099] R 6 is hydrogen, halogen, haloalkyl, C1-C3 alkyl or alkoxy.

[0100] In one embodiment of the compound of formula (I), R 1 is hydrogen.

[0101] In another embodiment of the compound of formula (I), R 1 is halogen. In certain embodiments, the halogen is bromine.

[0102] In one embodiment of the compound of formula (I), R 1 is -L-CN. In one embodiment, L is C1-C3 alkylene. In certain embodiments, C1-C3 alkylene is methylene.

[0103] In one embodiment of the compound of formula (I), R 1 is -Y-C1-C5 alkyl. In one embodiment, Y is a bond and C1-C5 alkyl is methyl. In one embodiment, Y is -NR 4 -, and C1-C5 alkyl is methyl, ethyl or propyl.

[0104] In one embodiment of the compound of formula (I), R 1 is hydroxyalkyl.

[0105] In one embodiment of the compound of formula (I), R 1 is -Y-heterocyclic group. In certain embodiments, Y is a bond and the heterocyclic group is azetidinyl, THFyl or morpholinyl.

[0106] In one embodiment of the compound of formula (I), R 1 is -Y-aryl, wherein the aryl is optionally substituted with one or more R 2 substituents.

[0107] In certain embodiments, Y is a bond and the aryl is optionally substituted with one or two R 2Substituted phenyl. In one embodiment, one or two R 2 groups are each independently a C1-C3 alkyl group, a cyano group, or a halogen.

[0108] In one embodiment of the compound of formula (I), R 1 is -Y-cycloalkyl. In one embodiment, Y is a bond and the cycloalkyl is cyclopentyl.

[0109] In one embodiment of the compound of formula (I), R 1 is -Y-heteroaryl optionally substituted with one or more R 2 substituents. In certain embodiments, the heteroaryl is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, oxidazolyl, pyridyl, pyridazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrazolopyridyl, 1H-pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridyl, tetrahydropyrazolopyrazinyl, 2H- -imidazopyrimidinyl, 2H- -imidazopyridazinyl, oxazolopyridyl, or 5,6-dihydro-8H-imidazooxazinyl, each of which is optionally substituted with one or more R 2 substituents. In one embodiment, Y is a bond.

[0110] In one embodiment, R 1 is -Y-heteroaryl, and Y is a bond and the heteroaryl is azetidinyl and R 2 is -(NR 4 )2.

[0111] In one embodiment, R 1 is heteroaryl, Y is a bond and the heteroaryl is tetrahydropyrazolopyrazinyl, which is optionally substituted with one or more R 2 substituents. In one embodiment, the tetrahydropyrazolopyrazinyl is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl optionally substituted with one or more R 2 substituents. In one embodiment, the tetrahydropyrazolopyrazinyl is substituted with one R 2 substituent. In one embodiment, R 2 is -X-C1-C5 alkyl, arC1-C3 alkyl, -Z-C1-C5 alkyl, -Z-cycloalkyl, or -X-aryl. In one embodiment, R 2 is -Z-cycloalkyl, where Z is a bond and the cycloalkyl is cyclopropyl. In one embodiment, R 2 is -Z-cycloalkyl, where Z is -C(O)- and the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[1.1.1]pentyl.

[0112] In which R1 In one embodiment of Y - heteroaryl, Y is a bond and the heteroaryl is optionally substituted with one or more R 2 substituted pyrazolopyridinyl. In one embodiment, the pyrazolopyridinyl is substituted with one R 2 wherein one R 2 is an alkoxy or -X - aryl. In one embodiment, the alkoxy is methoxy or isopropoxy. In certain embodiments, for -X - aryl, X is O and the aryl is phenyl.

[0113] In one embodiment, Y is a bond and R 1 heteroaryl is pyridinyl, which is optionally substituted with one or two R 2 substituents. In certain embodiments, the pyridinyl is substituted with one R 2 wherein R 2 is hydroxy, halogen, cyano, cyanomethyl, -(NR 4 )2, hydroxyalkyl, alkoxy, -SO2C1 - C3 alkyl, arC1 - C3 alkyl, heteroalkyl, C2 - C4 alkynyl, -X - haloalkyl, -X - C1 - C5 alkyl, -Z - C1 - C5 alkyl, heterocyclic group, -X - L - cycloalkyl, -Z - cycloalkyl, -X - aryl, -Z - aryl or -X - heteroaryl, wherein the heterocyclic group, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 5 substituents.

[0114] In one embodiment, R 1 is -Y - heteroaryl, Y is a bond and the heteroaryl is pyridinyl and R 2 is -X - C1 - C5 alkyl, X is a bond and the C1 - C5 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl.

[0115] In one embodiment, R 1 is -Y - heteroaryl, Y is a bond and the heteroaryl is pyridinyl and R 2 is -X - haloalkyl, X is a bond and the haloalkyl is difluoromethyl or trifluoromethyl. In another embodiment, R 2 is -X - haloalkyl, wherein X is O, and wherein the haloalkyl is difluoromethyl or trifluoromethyl.

[0116] In one embodiment, R 1 is -Y - heteroaryl, Y is a bond and the heteroaryl is pyridinyl and R 2 is -X - L - cycloalkyl, wherein X is a bond, L is a bond and the cycloalkyl is cyclopropyl or cyclohexyl. In another embodiment, R 2 is -X - L - cycloalkyl, wherein X is a bond, L is methylene and the cycloalkyl is cyclopropyl. In one embodiment, R 2is -X-L-cycloalkyl, where X is O, L is methylene and cycloalkyl is cyclopropyl.

[0117] In one embodiment, R 1 is -Y-heteroaryl, Y is a bond and heteroaryl is pyridyl and R 2 is C2-C4 alkynyl, where alkynyl is ethynyl or prop-2-ynyl.

[0118] In another embodiment, R 1 is -Y-heteroaryl, Y is a bond and heteroaryl is pyridyl and R 2 is -SO2C1-C3 alkyl, where C1-C3 alkyl is methyl.

[0119] In one embodiment, R 1 is -Y-heteroaryl, Y is a bond and heteroaryl is pyridyl and R 2 is heterocyclic group, where heterocyclic group is morpholinyl or tetrahydropyranyl.

[0120] In other embodiments, R 1 is -Y-heteroaryl, Y is a bond and heteroaryl is pyridyl and R 2 is -X-heteroaryl, where heteroaryl is optionally substituted by one or more R 5 substituents. In one embodiment, X is a bond, heteroaryl is pyrazolyl substituted by one R 5 substituent, where R 5 is C1-C3 alkyl. In one embodiment, X is a bond, heteroaryl is pyridyl or pyrimidinyl, each of which is optionally substituted by one R 5 substituent.

[0121] In one embodiment, R 1 is -Y-heteroaryl, Y is a bond and heteroaryl is pyridyl and R 2 is arC1-C3 alkyl, where arC1-C3 alkyl is benzyl.

[0122] In one embodiment, where R 1 is -Y-heteroaryl, Y is a bond and heteroaryl is pyridyl and R 2 is -X-heteroaryl, where X is O, and heteroaryl is quinolinyl optionally substituted by one or more R 5 substituents. In another embodiment, X is -NR 4 -, and heteroaryl is quinolinyl optionally substituted by one or more R 5 substituents.

[0123] In one embodiment, R 1 is -Y-heteroaryl, Y is a bond and heteroaryl is pyridyl and R 2is -X-aryl, where X is O and the aryl is optionally substituted with one, two or three R 5 substituted phenyl. In one embodiment, each of the one, two or three R 5 groups is independently selected from the group consisting of cyano, halogen, C1-C3 alkyl and alkoxy. In one embodiment, X is S and the aryl is optionally substituted with one R 5 substituted phenyl, where R 5 is halogen or C1-C3 alkyl. In one embodiment, X is O and the aryl is optionally substituted with two R 5 groups, where each R 5 group is independently cyano. In one embodiment, X is -NR 4 - and the aryl is optionally substituted with two R 5 groups, where each R 5 group is independently alkoxy. In certain embodiments, each alkoxy is methoxy.

[0124] In one embodiment, R 1 is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R 2 is halogen, where the halogen is chlorine or fluorine. In one embodiment, R 1 is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl and R 2 is -X-cycloalkyl, heterocyclic or -X-aryl, where the aryl is optionally substituted with one or more R 5 substituents. In one embodiment, R 2 is -X-cycloalkyl, where X and L are each a bond and the cycloalkyl is cyclohexyl. In one embodiment, R 2 is heterocyclic, where the heterocyclic is tetrahydropyranyl. In one embodiment, R 2 is -X-aryl, where the aryl is phenyl substituted with two R 5 substituents, where each R 5 is cyano.

[0125] In certain embodiments, R 1 is -Y-heteroaryl, Y is a bond and the heteroaryl is pyridyl substituted with two R 2 substituents. In one embodiment, each R 2 is independently -X-C1-C5 alkyl or one R 2 is halogen or cycloalkyl and the second R 2 is -X-C1-C5 alkyl, where X is a bond.

[0126] In one embodiment of the compound of formula (I), R 1is -Y-heteroaryl, where Y is a bond and the heteroaryl is pyrimidinyl, which is optionally substituted by one or two R 2 substituents. In one embodiment, the pyrimidinyl is substituted by one R 2 substituent, where R 2 is -X-C1-C5 alkyl or -X-haloalkyl. In one embodiment, each X is a bond.

[0127] In one embodiment of the compound of formula (I), R 1 is -Y-heteroaryl, where Y is a bond and the heteroaryl is quinolinyl, which is optionally substituted by one or two R 2 substituents. In certain embodiments, one R 2 group is cyano. In certain embodiments, one R 2 group is cyano and the second R 2 is halogen or -X-C1 C5 alkyl.

[0128] In one embodiment of the compound of formula (I), R 1 is -Y-heteroaryl, where Y is a bond and the heteroaryl is isothiazolyl, which is optionally substituted by one or two R 2 substituents. In one embodiment, R 2 is -X-aryl optionally substituted by one R 5 substituent, where the aryl is naphthyl substituted by one R 5 substituent, where R 5 is cyano.

[0129] In one embodiment of the compound of formula (I), R 1 is -Y-heteroaryl, where Y is a bond and the heteroaryl is pyrazolyl, which is optionally substituted by one, two or three R 2 groups.

[0130] In certain embodiments, the pyrazolyl is substituted by one R 2 substituent, where R 2 is cyano, -X-C1-C5 alkyl, hydroxyalkyl, arC1-C3 alkyl or -X-aryl, where the aryl is optionally substituted by one or more R 5 substituents. In one embodiment, R 2 is -X-C1-C5 alkyl, where X is a bond and the C1-C5 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl.

[0131] In other embodiments, the pyrazolyl is substituted by two R 2 groups, where the two R 2The groups 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(R 4 )2, -(5) X-C1-C5 alkyl and -X-haloalkyl, (6) -X-C1-C5 alkyl and arC1-C3 alkyl, (7) -X-C1-C5 alkyl and -X-L-cycloalkyl, -(8) -X-C1-C5 alkyl and -heterocyclic group, (9) -X-C1-C5 alkyl and -X-aryl optionally substituted with one or more R 5 , (10) -X-C1-C5 alkyl and -X-heteroaryl optionally substituted with one or more R 5 , (11) -X-C1-C5 alkyl and cyanomethyl, (12) -X-C1-C5 alkyl and cyano, (13) cyano and halogen, where the halogen is chlorine or fluorine, (14) cyano and -X-L-cycloalkyl, (15) independently halogen, (16) cyano and alkoxy, where each X is a bond, (17) cyano and -X-aryl, (18) cyano and -X-heteroaryl, (19) cyano and heterocyclic group (20) halogen and -X-arC1-C3 alkyl or X-arC1-C3 alkyl substituted with cyano and (21) halogen and -X-aryl.

[0132] In one embodiment where R 1 is pyrazolyl, the pyrazolyl is substituted with two R 2 , where one R 2 is -X-C1-C5 alkyl and the second R 2 is -X-aryl optionally substituted with one or more R 5 . In one embodiment, each X is a bond and the aryl is a phenyl substituted with two R 5 , where (1) each R 5 is independently -X-C1-C5 alkyl, where X is a bond; (2) one R 5 is cyano and one R 5 is -X-C1-C5 alkyl, where X is a bond; (3) one R 5 is cyano and one R 5 is -X-L-cycloalkyl, where X is a bond and L is a bond, methylene or ethylene; (4) one R 5 is cyano and one R 5 is halogen; (5) one R 5 is cyano and one R 5 is alkoxy; (6) each R 5 is independently cyano or (7) each R 5 is independently halogen.

[0133] In an embodiment where R 1 is a pyrazolyl group, the pyrazolyl group is substituted by two R 2 groups, where one R 2 is -X-C1-C5 alkyl, and the second R 2 is -X-aryl optionally substituted by one or more R 5 groups. In one embodiment, X is a bond, and the aryl is a naphthyl group substituted by one R 5 group, where R 5 is cyano or halogen. In one embodiment, the naphthyl group is substituted by two R 5 groups, where one R 5 is cyano, and the second R 5 is halogen, alkoxy or cyano. In one embodiment, the naphthyl group is substituted by three R 5 groups, where one R 5 is cyano, and the second R 5 is X-haloalkyl, and the third R 5 is -X-L-cycloalkyl.

[0134] In one embodiment, where R 1 is a pyrazolyl group, the pyrazolyl group is substituted by two R 2 groups, where one R 2 is -X-C1-C5 alkyl, and the second R 2 is -X-aryl optionally substituted by one or more R 5 groups. In one embodiment, X is a bond, and the aryl is a phenyl group substituted by three R 5 groups, where (1) each R 5 is independently -X-C1-C5 alkyl, where each X is a bond; (2) one R 5 is cyano, and two R 5 are -X-C1-C5 alkyl, where each X is a bond; (3) one R 5 is cyano, one R 5 is halogen, and one R 5 is -X-C1-C5 alkyl, where X is a bond; (4) one R 5 is cyano, and two R 5 are alkoxy, (5) one R 5 is cyano, and two R 5 are halogen, (6) one R 5 is cyano, one R 5 is halogen, and one R 5 is alkoxy, (7) or one R 5 is cyano, one R 5 is halogen, and one R 5is -X-L-cycloalkyl.

[0135] In one embodiment where R 1 is a pyrazolyl group, the pyrazolyl group is substituted by two R 2 groups, where one R 2 is -X-C1-C5 alkyl, and the second R 2 is -X-heteroaryl optionally substituted by one or more R 5 groups. In one embodiment, each X is a bond, and the heteroaryl is quinolinyl, pyrazolyl, chromanyl, indolizinyl, dihydrobenzofuranyl, or pyrimidinopyridinyl, each of which is optionally substituted by one or more R 5 groups.

[0136] In one embodiment, the pyrazolyl group is substituted by three R 2 groups, where each R 2 is independently -X-C1-C5 alkyl and each X is a bond.

[0137] In one embodiment where R 1 is a pyrazolyl group, the pyrazolyl group is substituted by three R 2 groups, where (1) one R 2 is cyano, and two R 2 are halogens; (2) one R 2 is cyano, one R 2 is a halogen, and one R 2 is an alkoxy group. In other embodiments, one R 2 is an alkoxy group, and two R 2 are independently halogens.

[0138] In one embodiment of the compound of formula (I), R 1 is -Y-heteroaryl, Y is a bond and the heteroaryl is imidazolyl, 1H-pyrrolopyridinyl, tetrahydropyrazolopyrazinyl, 2H- -imidazopyrimidinyl, 2H- -imidazopyridazinyl, or oxazolopyridinyl, each of which is substituted by one R 2 group, where R 2 is -X-C1-C5 alkyl, where X is a bond. In one embodiment, the heteroaryl is 1H-pyrrolopyridinyl substituted by one R 2 group, where R 2 is cyano or -X-aryl. In certain embodiments, X of -X-aryl is a bond and the aryl is phenyl. In one embodiment, the heteroaryl is imidazolyl substituted by one R 2 group, where R 2 is hydroxyalkyl or -X-aryl.

[0139] In one embodiment of the compound of formula (I), R 1 is -Y-heteroaryl, Y is a bond and the heteroaryl is imidazopyridinyl substituted by one R 2 group, where R 2 is cyano, alkoxy, halogen or -X-C1-C5 alkyl. In other embodiments, the heteroaryl is imidazopyridinyl substituted by two R 2 groups, where one R 2 is halogen and the second R 2 group is -X-C1-C5 alkyl or halogen.

[0140] In one embodiment of the compound of formula (I), R 1 is -Y-aryl, Y is -NR 4 - and the aryl is phenyl optionally substituted by one or more R 5 substituents.

[0141] In one embodiment, R 1 is -Y-arC1-C3 alkyl. In one embodiment, Y is -NR 4 - and the arC1-C3 alkyl is benzyl.

[0142] In one embodiment, R 3a and R 3b are each hydrogen. In another embodiment, R 3a and R 3b are each deuterium. In certain embodiments, one of R 3a and R 3b is hydrogen and the other is deuterium. In one embodiment, R 3a and R 3b together are oxo.

[0143] In one embodiment, each R 4 is hydrogen. In one embodiment, each R 4 is independently C1-C3 alkyl. In one embodiment, one R 4 is hydrogen, and the other R 4 is C1-C3 alkyl.

[0144] In one embodiment, the cycloalkyl, aryl or heteroaryl ring is optionally substituted by one or more R 5 substituents, where R 5 is cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, -X-L-cycloalkyl or -X-aryl.

[0145] In one embodiment, R 6is hydrogen. In one embodiment, R 6 is a halogen. In certain embodiments, the halogen is chlorine or fluorine. In one embodiment, R 6 is a C1-C3 alkyl. In certain embodiments, the C1-C3 alkyl is methyl or ethyl. In one embodiment, R 6 is an alkoxy. In certain embodiments, the alkoxy is methoxy. In one embodiment, R 6 is a haloalkyl. In certain embodiments, the haloalkyl is trifluoromethyl.

[0146] In one aspect of the present invention, there is provided a compound represented by formula (I-A):

[0147]

[0148] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , Y, X, Z, and L are as defined for formula I, respectively.

[0149] In one aspect of the present invention, there is provided a compound represented by formula (I-B):

[0150]

[0151]

[0152] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , Y, X, Z, and L are as defined for formula I, respectively.

[0153] In one aspect of the present invention, there is provided a compound represented by formula (I-C):

[0154]

[0155] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , Y, X, Z, and L are as defined for formula I, respectively.

[0156] In another aspect of the present invention, there is provided a compound represented by formula (I-D):

[0157]

[0158] or a pharmaceutically acceptable salt thereof:

[0159] wherein:

[0160] each Y is independently a bond or -NR 4 -;

[0161] each R 2 is independently hydroxy, halogen, cyano, cyanomethyl, -(NR 4 )2, hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, -X-arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclic group, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl or -X-heteroaryl, wherein the heterocyclic group, cycloalkyl, aryl and heteroaryl are optionally substituted by one or more R 5 substituents, or;

[0162] each X is independently a bond, O, S, -NR 4 - or -NR 4 C(O)-;

[0163] each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-;

[0164] each L is independently a bond or C1-C3 alkylene;

[0165] each R 4 is independently hydrogen or C1-C3 alkyl;

[0166] each R 5 is 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 by one or more C1-C3 alkyl or oxo, or -X-aryl; and

[0167] R 6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

[0168] In one embodiment, the compounds of formula (I), formula (I-A), formula (I-B) and / or formula (I-C) are:

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189] and pharmaceutically acceptable salts of the foregoing compounds.

[0190] In one embodiment, the compound of formula (I) is:

[0191]

[0192] or a pharmaceutically acceptable salt of the foregoing compound.

[0193] The compounds of formula (I), formula (I-A), formula (I-B) and formula (I-C) can be formulated into pharmaceutical compositions.

[0194] Pharmaceutical compositions

[0195] In another aspect, the present invention provides a pharmaceutical composition comprising a PRMT5 inhibitor according to the present invention and a pharmaceutically acceptable carrier, excipient or diluent. The compounds of the present invention can be formulated by any method known in the art and can be prepared for administration by any route, including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal or rectal. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In certain other embodiments, administration by the oral route may be preferably employed.

[0196] The properties of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic material that is compatible with biological systems such as cells, cell cultures, tissues or organisms and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, in addition to the inhibitor, the compositions of the present invention may also contain diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, edited by A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0197] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above compounds and exhibits minimal or no undesirable toxicological effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and 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 may also be administered as pharmaceutically acceptable quaternary ammonium salts known to those skilled in the art, which specifically include quaternary ammonium salts of the formula -NR+Z-, where R is hydrogen, alkyl or benzyl and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, tosylate, mesylate, sulfate, phosphate or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzyloate and diphenylacetate).

[0198] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to a patient without causing serious toxic effects in the patient being treated. The dosage of the active compound for all of the above-mentioned conditions ranges from about 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg / day, more usually 0.5 to about 25 mg / kg recipient body weight / day. In a suitable carrier, a typical topical dosage is 0.01 - 3% wt / wt. The effective dosage range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself exhibits activity, the weight of the derivative or the effective dosage can be estimated as above by other means known to those skilled in the art.

[0199] A pharmaceutical composition comprising a compound of the present invention can be used in the methods described herein.

[0200] Methods of use

[0201] In another aspect, the present invention provides a method for inhibiting PRMT5 activity in a cell, the method comprising contacting in vitro a cell in need of inhibiting PRMT5 activity with an effective amount of a compound of formula (I), formula (I-A), formula (I-B) or formula (I-C), a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt. In one embodiment, the cell is an MTAP-deficient cell.

[0202] The compositions and methods provided herein are particularly contemplated for use in inhibiting PRMT5 activity in cells in vivo. In one embodiment, a cell in need of inhibiting PRMT5 activity 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 regulate the activity of PRMT5. In other embodiments, a therapeutically effective amount of a pharmaceutically acceptable salt or pharmaceutical composition comprising a compound of formula (I), formula (I-A), formula (I-B) or formula (I-C) can be used. In one embodiment, the cell is an MTAP-deficient cell. In one embodiment, the negative regulation of PRMT5 activity occurs in the presence of bound MTA.

[0203] By negatively regulating the activity of PRMT5, particularly in the case of cells lacking MTAP activity, the method is designed to inhibit PRMT5 activity to block cell proliferation. Depending on the particular treatment regimen, the cells can be contacted in a single dose or multiple doses to effect the desired negative regulation of PRMT5. The extent of PRMT5 inhibition can be monitored in vitro for the enzyme, using well-known methods, including the methods described in Example B below, in the presence and absence of MTA and in the cells, to evaluate the effectiveness and dosage of the treatment.

[0204] In another aspect, a method of treating cancer is provided, the method comprising administering to a patient suffering from cancer a therapeutically effective amount of a compound of formula (I), formula (I-A), formula (I-B) or formula (I-C), a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt. In one embodiment, the cancer is an MTAP-related cancer.

[0205] The compositions and methods provided herein can be used to treat a variety of cancers, including tumors such as prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, and the like. More specifically, the cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer, as well as sarcomas. More specifically, these compounds can be used to treat: Heart: Sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: Bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchioloalveolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), Stomach (carcinoma, lymphoma, leiomyosarcoma), Pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), Small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), Large intestine (adenocarcinoma, tubular adenoma, villous 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 tumor, lipoma); Liver: Liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: Gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: Osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), Meninges (meningioma, meningiosarcoma, gliomatosis), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), Spinal cord (neurofibroma, meningioma, glioma, sarcoma);Gynecological: uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, carcinoma, not otherwise specified), granulosa-thecal cell tumor, sertoli-stromal cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematological: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).;

[0206] In one embodiment, the cancer is an MTAP-related cancer selected from hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, and head and neck cancer.

[0207] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such compounds and salts may also be co-administered with other anti-tumor compounds (e.g., chemotherapy), or used in combination with other treatments (such as radiation or surgical intervention), as an adjuvant before or after surgery.

[0208] 1. A compound of formula (I):

[0209]

[0210] or a pharmaceutically acceptable salt thereof:

[0211] Wherein:

[0212] R 1 is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-C1-C5 alkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, -Y-arC1-C3 alkyl, or -Y-heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties are each optionally substituted with one or more R 2 substituents;

[0213] Each Y is independently a bond or -NR 4 -;

[0214] Each R 2 is independently a hydroxyl group, a halogen, a cyano group, a cyanomethyl group, -(NR 4 )2, a hydroxyalkyl group, an alkoxy group, -SO2C1-C3 alkyl, -X-arC1-C3 alkyl, a heteroalkyl group, a C2-C4 alkynyl group, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, a heterocyclic group, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl or -X-heteroaryl, wherein the heterocyclic group, the cycloalkyl group, the aryl group and the heteroaryl group are optionally substituted by one or more R 5 substituents, or;

[0215] Each X is independently a bond, O, S, -NR 4 -, or -NR 4 C(O)-;

[0216] Each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-;

[0217] Each L is independently a bond or a C1-C3 alkylene group;

[0218] R 3a and R 3b are each independently hydrogen or deuterium, or R 3a and R 3b together are oxo;

[0219] Each R 4 is independently hydrogen or a C1-C3 alkyl group;

[0220] Each R 5 is independently a cyano group, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, X-arC1-C3 alkyl substituted with a cyano group, -X-L-cycloalkyl, -X-L-heteroaryl optionally substituted with one or more C1-C3 alkyl or oxo groups, or -X-aryl; and

[0221] R 6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

[0222] 2. The compound according to item 1, wherein R 1 is hydrogen.

[0223] 3. The compound according to item 1, wherein R 1 is halogen.

[0224] 4. The compound according to item 3, wherein the halogen is bromine.

[0225] 5. The compound according to item 1, wherein R 1 is -Y-C1-C5 alkyl.

[0226] 6. The compound according to item 5, wherein Y is a bond and the C1-C5 alkyl is methyl.

[0227] 7. The compound according to item 1, wherein R 1 is hydroxyalkyl.

[0228] 8. The compound according to item 1, wherein R 1 is -L-CN.

[0229] 9. The compound according to item 8, wherein L is C1-C3 alkylene.

[0230] 10. The compound according to item 1, wherein R 1 is -Y-heterocyclic group.

[0231] 11. The compound according to item 10, wherein Y is a bond and the heterocyclic group is azetidinyl, THFyl or morpholinyl.

[0232] 12. The compound according to item 1, wherein R 1 is -Y-aryl, wherein the aryl is optionally substituted by one or more R 2 substituents.

[0233] 13. The compound according to item 12, wherein Y is a bond and the aryl is phenyl optionally substituted by one or two R 2 substituents.

[0234] 14. The compound according to item 13, wherein the one or two R 2 are each independently cyano, halogen or -Y-C1-C5 alkyl, wherein Y is a bond.

[0235] 15. The compound according to item 1, wherein R 1 is -Y-cycloalkyl.

[0236] 16. The compound according to item 15, wherein Y is a bond and the cycloalkyl is cyclopentyl.

[0237] 17. The compound according to item 1, wherein R 1 is -Y-heteroaryl optionally substituted by one or more R 2 substituents.

[0238] 18. The compound according to item 17, wherein Y is a bond, and the heteroaryl is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrazolopyridyl, 1H-pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridyl, tetrahydropyrazolopyrazinyl, 2H- -imidazopyrimidinyl, 2H- -imidazopyridazinyl, oxazolopyridyl or 5,6-dihydro-8H-imidazooxazinyl, each of which is optionally substituted by one or more R 2 substituents.

[0239] 19. The compound according to item 18, wherein the heteroaryl is tetrahydropyrazolopyrazinyl, which is optionally substituted by one or more R 2 substituents.

[0240] 20. The compound according to item 19, wherein the tetrahydropyrazolopyrazinyl is substituted by one R 2 substituent, and the R 2 is selected from the group consisting of -X-C1-C5 alkyl, arC1-C3 alkyl, -Z-C1-C5 alkyl, -Z-cycloalkyl and -X-aryl.

[0241] 21. The compound according to item 20, wherein R 2 is -Z-cycloalkyl.

[0242] 22. The compound according to item 21, wherein Z is a bond and the cycloalkyl is cyclopropyl.

[0243] 23. The compound according to item 21, wherein Z is -C(O)- and the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl.

[0244] 24. The compound according to item 17, wherein the heteroaryl is pyridyl optionally substituted by one or two R 2 substituents.

[0245] 25. The compound according to item 24, wherein the pyridyl is substituted by one R 2 substituent.

[0246] 26. The compound according to item 25, wherein R 2 is hydroxy, halogen, cyano, -(NR 4)2. Hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclic group, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl or -X-heteroaryl, wherein the heterocyclic group, the cycloalkyl, the aryl and the heteroaryl are optionally substituted by one or more R 5 Substituted.

[0247] 27. The compound according to item 26, wherein R 2 is -X-C1-C5 alkyl, X is a bond, and the C1-C5 alkyl is methyl, ethyl, propyl or isopropyl.

[0248] 28. The compound according to item 26, wherein R 2 is -X-haloalkyl, X is a bond, and the haloalkyl is difluoromethyl or trifluoromethyl.

[0249] 29. The compound according to item 26, wherein R 2 is -X-haloalkyl, X is O, and the haloalkyl is difluoromethyl or trifluoromethyl.

[0250] 30. The compound according to item 26, wherein R 2 is -X-L-cycloalkyl, wherein X is a bond, L is a bond and the cycloalkyl is cyclopropyl.

[0251] 31. The compound according to item 26, wherein R 2 is -X-L-cycloalkyl, wherein X is a bond, L is methylene, and the cycloalkyl is cyclopropyl or cyclohexyl.

[0252] 32. The compound according to item 26, wherein R 2 is -X-L-cycloalkyl, wherein X is O, L is methylene, and the cycloalkyl is cyclopropyl.

[0253] 33. The compound according to item 26, wherein R 2 is C2-C4 alkynyl, wherein the C2-C4 alkynyl is ethynyl or prop-2-ynyl.

[0254] 34. The compound according to item 26, wherein R 2 is -SO2C1-C3 alkyl, wherein the C1-C3 alkyl is methyl.

[0255] 35. The compound according to item 26, wherein R 2 is a heterocyclic group, wherein the heterocyclic group is morpholinyl or tetrahydropyranyl.

[0256] 36. The compound according to item 26, wherein R 2 is -X-heteroaryl, wherein the heteroaryl is optionally substituted with one or more R 5 .

[0257] 37. The compound according to item 36, wherein X is a bond, and the heteroaryl is a pyrazolyl group substituted with one R5, wherein R 5 is C1-C3 alkyl.

[0258] 38. The compound according to item 36, wherein the X is a bond, and the heteroaryl is pyridyl or pyrimidinyl, each of which is optionally substituted with one or more R 5 .

[0259] 39. The compound according to item 36, wherein the X is a bond or O, and the heteroaryl is a quinolinyl group optionally substituted with one or more R 5 .

[0260] 40. The compound according to item 36, wherein the X is -NR 4 -, and the heteroaryl is a quinolinyl group optionally substituted with one or more R 5 .

[0261] 41. The compound according to item 36, wherein R 2 is -X-aryl, wherein the aryl is optionally substituted with one or more R 5 .

[0262] 42. The compound according to item 41, wherein X is a bond, and the aryl is a phenyl or naphthyl group substituted with one, two or three R 5 .

[0263] 43. The compound according to item 42, wherein each R 5 is selected from the group consisting of cyano, halogen, -X-cycloalkyl, -X-haloalkyl, heterocyclic group, X-heteroaryl, C1-C3 alkyl and alkoxy.

[0264] 44. The compound according to item 41, wherein X is O, and the aryl is a phenyl group substituted with one or two R 5 .

[0265] 45. The compound according to item 44, wherein each R 5 is cyano, halogen, C1-C3 alkyl or alkoxy.

[0266] 46. The compound according to item 41, wherein X is S, the aryl is a phenyl group substituted with one R 5 , wherein R 5is a halogen or a C1-C3 alkyl group.

[0267] 47. The compound according to item 41, wherein the X is -NR 4 -, and the aryl group is optionally substituted by one or more R 5 substituted phenyl.

[0268] 48. The compound according to item 26, wherein R 2 is a halogen, and the halogen is chlorine or fluorine.

[0269] 49. The compound according to item 18, wherein the heteroaryl group is optionally substituted by one or more R 2 substituted pyrazolopyridinyl.

[0270] 50. The compound according to item 49, wherein the pyrazolopyridinyl is substituted by one R 2 substituted, wherein the one R 2 is an alkoxy group or -X-aryl.

[0271] 51. The compound according to item 45, wherein the alkoxy group is methoxy or isopropoxy.

[0272] 52. The compound according to item 45, wherein for the -X-aryl, X is O and the aryl is phenyl.

[0273] 53. The compound according to item 1, wherein R 1 is -Y-aryl, where Y is -NR 4 - and the aryl is optionally substituted by one or more R 5 substituted phenyl.

[0274] 54. The compound according to item 1, wherein R 1 is -Y-C1-C5 alkyl, where Y is -NR 4 - and the C1-C5 alkyl is methyl, ethyl or propyl.

[0275] 55. The compound according to item 1, wherein R 1 is -Y-arC1-C3 alkyl, where Y is -NR 4 - and the arC1-C3 alkyl is benzyl.

[0276] 56. The compound according to item 24, wherein the pyridinyl is substituted by two R 2 substituted.

[0277] 57. The compound according to item 56, wherein each R 2 is -X-C1-C5 alkyl, or one R 2is a halogen or -X-L-cycloalkyl, and the second R 2 is -X-C1-C5 alkyl, where each X is a bond.

[0278] 58. The compound according to item 18, wherein the heteroaryl is pyrimidinyl, which is optionally substituted by one or more R 2 substituents.

[0279] 59. The compound according to item 58, wherein the pyrimidinyl is substituted by one R 2 substituent.

[0280] 60. The compound according to item 59, wherein R 2 is -X-C1-C5 alkyl or -X-haloalkyl.

[0281] 61. The compound according to item 18, wherein the heteroaryl is pyrazolyl, which is optionally substituted by one, two or three R 2 substituents.

[0282] 62. The compound according to item 61, wherein the pyrazolyl is substituted by one R 2 substituent.

[0283] 63. The compound according to item 62, wherein R 2 is -X-C1-C5 alkyl, hydroxyalkyl, arC1-C3 alkyl or -X-aryl optionally substituted by one or more R 5 substituents.

[0284] 64. The compound according to item 63, wherein R 2 is -X-C1-C5 alkyl, where X is a bond and the C1-C5 alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl.

[0285] 65. The compound according to item 61, wherein the pyrazolyl is substituted by two independently selected R 2 substituents.

[0286] 66. The compound according to item 65, wherein the two R 2 groups are independently (1) -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(R 4 )2, -(5) X-C1-C5 alkyl and -X-haloalkyl, (6) -X-C1-C5 alkyl and arC1-C3 alkyl, (7) -X-C1-C5 alkyl and -X-L-cycloalkyl, -(8) -X-C1-C5 alkyl and -heterocyclic group, (9) -X-C1-C5 alkyl and optionally substituted by one or more R5 Substituted -X-aryl, (10)-X-C1-C5 alkyl and optionally one or more R 5 Substituted -X-heteroaryl, (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 heterocyclic group (20) halogen and -X-arC1-C3 alkyl or X-arC1-C3 alkyl substituted with cyano and (21) halogen and -X-aryl.

[0287] 67. The compound according to item 66, wherein the pyrazolyl is substituted with -X-C1-C5 alkyl and optionally one or more R 5 Substituted -X-aryl, wherein X is a bond and the aryl is phenyl substituted with two R 5 Each R 5 Independently is -X-C1-C5 alkyl, wherein each X is a bond; one R 5 Is cyano and one R 5 Is -X-C1-C5 alkyl, wherein each X is a bond; one R 5 Is cyano and one R 5 Is -X-L-cycloalkyl, wherein X is a bond and L is a bond, methylene or ethylene; one R 5 Is cyano and one R 5 Is halogen; one R 5 Is cyano and one R 5 Is alkoxy; or each R 5 Independently is halogen.

[0288] 68. The compound according to item 66, wherein the pyrazolyl is substituted with -X-C1-C5 alkyl and optionally one or more R 5 Substituted -X-aryl, wherein X is a bond and the aryl is phenyl substituted with three R 5 Each R 5 Is -X-C1-C5 alkyl, wherein each X is a bond; one R 5 Is cyano and two R 5 Is -X-C1-C5 alkyl, wherein each X is a bond; one R 5 Is cyano, one R 5 Is halogen, and one R 5 Is -X-C1-C5 alkyl, wherein X is a bond; one R5 is cyano and two R 5 Is alkoxy, one R5 is cyano and two Rs 5 are halogen, and one R 2 is cyano and two Rs 2 are halogen; and one R 2 is cyano, and one R 2 is halogen, and one R 2 is alkoxy, or one R 2 is alkoxy, and two Rs 2 are independently halogen.

[0289] 69. The compound according to item 18, wherein the heteroaryl is imidazolyl, 1H-pyrrolopyridinyl, tetrahydropyrazolopyrazinyl, 2H- -imidazopyrimidinyl, 2H- -imidazopyridazinyl or oxazolopyridinyl, each of which is substituted by one R 2 group, wherein each R 2 is -X-C1-C5 alkyl, wherein X is a bond.

[0290] 70. The compound according to item 18, wherein the heteroaryl is imidazopyridinyl substituted by one R 2 group, wherein R 2 is cyano, alkoxy, halogen or -X-C1-C5 alkyl, and X is a bond.

[0291] 71. The compound according to item 18, wherein the heteroaryl is imidazopyridinyl substituted by two R 2 groups, wherein one R 2 group is halogen and the second R 2 group is -X-C1-C5 alkyl, wherein X is a bond or halogen.

[0292] 72. The compound according to any one of items 2 to 71, wherein R 3a and R 3b are each hydrogen.

[0293] 73. The compound according to any one of items 2 to 71, wherein R 3a and R 3b are each deuterium.

[0294] 74. The compound according to any one of items 2 to 71, wherein one of R 3a and R 3b is hydrogen and the other is deuterium.

[0295] 75. The compound according to any one of items 2 to 71, wherein R 3a and R 3b together are oxo.

[0296] 76. The compound according to any one of items 2 to 75, wherein R 4 is hydrogen.

[0297] 77. The compound according to any one of items 2 to 75, wherein R 4 is methyl.

[0298] 78. The compound according to any one of items 2 to 77, wherein R 6 is hydrogen.

[0299] 79. The compound according to any one of items 2 to 77, wherein R 6 is a halogen.

[0300] 80. The compound according to item 79, wherein the halogen is chlorine or fluorine.

[0301] 81. The compound according to any one of items 2 to 77, wherein R 6 is a C1-C3 alkyl group.

[0302] 82. The compound according to item 81, wherein the C1-C3 alkyl group is methyl or ethyl.

[0303] 83. The compound according to any one of items 2 to 77, wherein R 6 is an alkoxy group.

[0304] 84. The compound according to item 83, wherein the alkoxy group is methoxy.

[0305] 85. The compound according to any one of items 2 to 77, wherein R 6 is a haloalkyl group.

[0306] 86. The compound according to item 85, wherein the haloalkyl group is trifluoromethyl.

[0307] 87. A compound of formula (I-D):

[0308]

[0309] or a pharmaceutically acceptable salt thereof:

[0310] Wherein:

[0311] Each Y is independently a bond or -NR 4 -;

[0312] Each R 2 is independently hydroxy, halogen, cyano, cyanomethyl, -(NR 4)2. Hydroxyalkyl, alkoxy, -SO2C1-C3 alkyl, -X-arC1-C3 alkyl, heteroalkyl, C2-C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclic group, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl or -X-heteroaryl, wherein the heterocyclic group, the cycloalkyl group, the aryl group and the heteroaryl group are optionally substituted by one or more R 5 substituted, or;

[0313] Each X is independently a bond, O, S, -NR 4 -, or -NR 4 C(O)-;

[0314] Each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-;

[0315] Each L is independently a bond or C1-C3 alkylene;

[0316] Each R 4 is independently hydrogen or C1-C3 alkyl;

[0317] Each R 5 is independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, X-arC1-C3 alkyl substituted by cyano, -X-L-cycloalkyl, -X-L-heteroaryl optionally substituted by one or more C1-C3 alkyl or oxo, or -X-aryl; and

[0318] R 6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.

[0319] 88. The compound according to item 1, wherein the compound is:

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341] or a pharmaceutically acceptable salt thereof.

[0342] 89. The compound according to item 1, wherein the compound is:

[0343]

[0344] or a pharmaceutically acceptable salt thereof.

[0345] 90. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of items 1 to 89 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0346] 91. A method for inhibiting PRMT5 activity in a cell, the method comprising contacting a cell in need of inhibiting PRMT5 activity with an effective amount of a compound of formula (I) according to any one of items 1 to 89 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to item 90.

[0347] 92. A method for treating cancer, the method comprising administering, alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent, a therapeutically effective amount of a compound of formula (I) according to any one of items 1 to 89, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate of a compound of formula (I) to a patient suffering from cancer.

[0348] 93. The method according to item 92, wherein the therapeutically effective amount of the compound is about 0.01 to 300 mg / kg / day.

[0349] 94. The method according to item 92, wherein the therapeutically effective amount of the compound is about 0.1 to 100 g / kg / day.

[0350] 95. The method according to any one of items 91 to 94, wherein the cancer is selected from the group consisting of: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous 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, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord (neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), (serous cystadenocarcinoma, mucinous cystadenocarcinoma, carcinoma, not otherwise specified), granulosa - theca cell tumor, Sertoli - Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematological: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non - Hodgkin lymphoma (malignant lymphoma);Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

[0351] 96. The method according to any one of items 91 to 95, wherein the cancer is an MTAP-related cancer.

[0352] 97. The method according to item 95, wherein the cancer is hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer or head and neck cancer.

[0353] General reaction schemes, intermediates and examples

[0354] General reaction scheme

[0355] The compounds of the present invention can be prepared using commercially available reagents and intermediates in the synthesis methods and reaction schemes described herein, or can be prepared using other reagents and conventional methods well known to those skilled in the art.

[0356] For example, the intermediates and compounds for preparing the compounds of formula (I), formula (I-A), formula (I-B) or formula (I-C) of the present invention can be prepared according to general reaction schemes I-XVI:

[0357] General reaction scheme I

[0358]

[0359] wherein R 1 Compounds of formula (I) wherein R is aryl or heteroaryl can be prepared according to general reaction scheme I. Compounds 7a and 7b are both examples of formula (I), wherein R 1 is aryl or heteroaryl, and R 3a and R 3bIt is H. The haloaryl cyclic anhydride 1 is treated with a bis(nucleophile) such as hydrazine hydrate in acetic acid at high temperature to form phthalohydrazide 2, which is treated with a halogenating agent such as POCl3 to obtain trihalophthalazine 3. The trihalophthalazine 3 is treated with an alcohol such as benzyl alcohol and NaH in THF at 0 °C to obtain the dihaloalkoxyphthalazines 4a and 4b as a mixture of regioisomers. The mixture of 4a and 4b is subjected to palladium-catalyzed cross-coupling conditions such as Stille coupling or Suzuki coupling with an aryl / heteroaryl metal reactant, such as with the corresponding aryl / heteroaryl-tributyltin or aryl / heteroaryl boronic acid / ester, to provide the substituted haloalkoxyphthalazines 5a and 5b as a mixture of regioisomers. The mixture of substituted haloalkoxyphthalazines 5a and 5b is subjected to metal-mediated cyanation conditions with, for example, Pd2(dba)3, dppf, Zn, and ZnCN2 in DMF at high temperature, and the resulting cyanoalkoxyphthalazine mixture 6a and 6b is subjected to hydrogenation conditions with, for example, Pd / C, HCl, and H2 in methanol to obtain the phthalazinone methylamine mixture 7a and 7b. The regioisomeric mixture of 7a and 7b is separated by chromatography such as supercritical fluid chromatography (SFC) to provide the desired compounds 7a and 7b of formula (I).

[0360] General Reaction Scheme II

[0361]

[0362] wherein R 1 The compounds of formula (I) wherein R is aryl or heteroaryl can be prepared according to General Reaction Scheme II. Compounds 7a and 7b are both examples of formula (I), wherein R 1 is aryl or heteroaryl, and R 3a and R 3b are H. The mixture of regioisomers 4a and 4b is separated by chromatography such as supercritical fluid chromatography (SFC) to obtain isomerically pure dihaloalkoxyphthalazinones 4a and 4b. Then, 4a or 4b is subjected to metal-mediated cross-coupling conditions with an aryl / heteroaryl boronic acid / ester, such as Suzuki conditions, to provide the substituted haloalkoxyphthalazines 5a or 5b. The substituted haloalkoxyphthalazines 5a or 5b are subjected to metal-mediated cyanation conditions with, for example, Pd2(dba)3, dppf, Zn, and ZnCN2 in DMF at high temperature to provide the cyanoalkoxyphthalazines 6a or 6b. The cyanoalkoxyphthalazines 6a or 6b are subjected to hydrogenation conditions with, for example, Pd / C, HCl, and H2 in methanol to obtain the phthalazinone 7a or 7b, to provide the desired compounds of formula (I).

[0363] General Reaction Scheme III-A

[0364]

[0365] wherein R 1 Compounds of formula (I) wherein R is aryl, heteroaryl, heterocyclic or alkyl can be prepared according to general reaction scheme III-A. Compound 7a is an example of formula (I) wherein R 1 is aryl, heteroaryl, heterocyclic or alkyl, and R 3a and R 3b are H. Treatment of 1-(5-halo-2-methylphenyl)ethenone 8a with an oxidizing agent, such as KMnO4 in water at 50 °C, provides 2-(carboxycarbonyl)-4-halobenzoic acid 9a. 9a is condensed, for example, with hydrazine hydrate in ethanol at elevated temperature to produce 7-halo-4-oxo-3,4-dihydrophthalazine-1-carboxylic acid 10a, which is then esterified with an acid and an alcohol, such as sulfuric acid and methanol. Methyl 7-halo-4-oxo-3,4-dihydrophthalazine-1-carboxylate 11a is reduced by hydride, such as with sodium borohydride and CaCl2 in methanol, to give 6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12a, which is then treated with a halogenating agent, such as thionyl chloride, for 12 hours to provide 6-halo-4-(halomethyl)phthalazin-1(2H)-one 13a. Nucleophilic S N 2 displacement of 13a with a nitrogen nucleophile, such as potassium phthalimide, in DMF at elevated temperature gives 14a, which is subjected to metal-mediated cross-coupling conditions, such as Suzuki conditions, with an aryl / heteroaryl / heterocyclic / alkyl boronic acid / ester to provide a phthalazinone coupling product 15a. The phthalimide protecting group of 15a is removed under solvolysis conditions, such as with hydrazine hydrate in ethanol, to provide the desired compound 7a of formula (I).

[0366] General reaction scheme III-B

[0367]

[0368] wherein R 1 Compounds of formula (I) wherein R is aryl, heteroaryl, heterocyclic or alkyl can be prepared according to general reaction scheme III-B. Compound 7b is an example of formula (I) wherein R 1 is aryl, heteroaryl, heterocyclic or alkyl, and R 3a and R 3bIt is H. 1-(5-Halo-2-methylphenyl)ethenone 8b is treated with an oxidizing agent, such as KMnO4 in water at 50 °C, to afford 2-(carboxycarbonyl)-4-halobenzoic acid 9b. 9b is condensed, for example, with hydrazine hydrate in ethanol at elevated temperature to yield 7-halo-4-oxo-3,4-dihydrophthalazine-1-carboxylic acid 10b, which is then esterified with an acid and an alcohol, such as sulfuric acid and methanol. Methyl 7-halo-4-oxo-3,4-dihydrophthalazine-1-carboxylate 11b is reduced by a hydride, such as sodium borohydride and CaCl2 in methanol, to give 6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12b, which is then treated with a halogenating agent, such as thionyl chloride, for 12 h to afford 6-halo-4-(halomethyl)phthalazin-1(2H)-one 13b. 13b is subjected to nucleophilic S N substitution with a nitrogen nucleophile, such as potassium phthalimide, in DMF at elevated temperature to give 14b, which is subjected to metal-mediated cross-coupling conditions with an aryl / heteroaryl / heterocyclic / alkyl boronic acid / ester, such as Suzuki conditions, to afford a phthalazinone coupling product 15b. The phthalimide protecting group of 15b is removed under solvolysis conditions, such as with hydrazine hydrate in ethanol, to provide the desired compound 7b of formula (I).

[0369] General reaction scheme IV-A

[0370]

[0371] wherein R 1 is pyridyl and R 2 is -O-aryl or -O-heteroaryl can be prepared according to general reaction scheme IV-A. Compound 29 is an example of formula (I) wherein R 1 is pyridyl, R 2 is -O-aryl or -O-heteroaryl, and R 3a and R 3b are H. 5-Bromopyridin-3-ol 25 is heated with a suitably substituted aryl / heteroaryl halide 26, such as in a mixture of DMF and NaH, to afford 3-halo-5-R 2 -oxypyridine 27. 3-Halo-5-R 2 -pyridine 27 is coupled with a boronic acid intermediate AN under palladium-catalyzed cross-coupling conditions, such as Suzuki coupling, to generate an R 2 -pyridyl coupling product 28. The R 2 -pyridyl coupling product 28 is subjected to solvolysis conditions, such as with hydrazine hydrate in ethanol, to provide the free amine 29 of formula (I).

[0372] General reaction scheme IV-B

[0373]

[0374] wherein R 1 is pyridyl and R 2 is -O-aryl or -O-heteroaryl can be prepared according to General Reaction Scheme IV-B. Compound 29 is an example of formula (I) wherein R 1 is pyridyl, R 2 is -O-aryl or -O-heteroaryl, and R 3a and R 3b are H. 5-Bromopyridin-3-ol 25 is heated with an aryl / heteroaryl halide 26, for example in a mixture of DMF and NaH, to afford 3-halo-5-R 2 -pyridine 27. 3-Halo-5-R 2 -pyridine 27 is coupled with a boronic acid intermediate J under palladium-catalyzed cross-coupling conditions, such as Suzuki coupling, to generate the coupling product 28-Boc. The coupling product 28-Boc is subjected to acidic conditions, such as with TFA, to afford the desired compound 29 of formula (I).

[0375] General Reaction Scheme IV-C

[0376]

[0377] wherein R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl and R 2 is -C1-C5 alkyl, heterocyclic group, -L-cycloalkyl, -CH2-aryl and -CH2-heteroaryl (wherein L is a bond or C1-C3 alkylene) can be prepared according to General Reaction Scheme IV-C. Compound 34 is an example of formula (I) wherein R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, R 2 is -C1-C5 alkyl, heterocyclic group, -L-cycloalkyl, -CH2-aryl and -CH2-heteroaryl (wherein L is a bond or C1-C3 alkylene), and R 3a and R 3b are H. 3-Bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 30 is reacted with an aldehyde or ketone 31 under reductive amination conditions, such as with sodium borohydride in methanol, to form the R 2 -substituted product 32. The amination product 32 is coupled with a boronic acid ester intermediate AN under palladium-catalyzed cross-coupling, such as Suzuki conditions, to afford the coupling product 33. The coupling product 33 is then exposed to solvolysis conditions, such as with hydrazine hydrate, to give the free amine 34 of formula (I).

[0378] General reaction scheme IV-D

[0379]

[0380] wherein R 1 Compounds of formula (I) wherein R is aryl or heteroaryl can be prepared according to general reaction scheme IV-D. Compound 94 is an example of formula (I) wherein R 1 is a suitably substituted aryl or heteroaryl, and R 3a and R 3b are H. The N-Boc boronate intermediate J is coupled with the aryl / heteroaryl-substituted halide 92 under palladium-catalyzed cross-coupling conditions, such as Suzuki coupling conditions, to produce the N-Boc-R 1 -substituted coupling product 90. The N-Boc-R 1 -substituted coupling product 90 is subjected to acidic conditions to remove the Boc group, such as TFA, to afford the R 1 -substituted amine 94 of formula (I).

[0381] General reaction scheme IV-E

[0382]

[0383] wherein R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl and R 2 is -C1-C5 alkyl, heterocyclic group, -L-cycloalkyl, -CH2-aryl and -CH2-heteroaryl (wherein L is a bond or C1-C3 alkylene) of formula (I) can be prepared according to general reaction scheme IV-E. Compound 34 is an example of formula (I) wherein R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, R 2 is -C1-C5 alkyl, heterocyclic group, -L-cycloalkyl, -CH2-aryl and -CH2-heteroaryl (wherein L is a bond or C1-C3 alkylene), and R 3a and R 3b are H. 3-Bromo-5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine 32 is borated, for example under Miyaura conditions, to afford the boronate 32a-Bpin. Under palladium-catalyzed cross-coupling conditions, such as Suzuki conditions, the borylated product 32a-Bpin is coupled with the intermediate F to give the coupling product 33a. Under acidic conditions such as TFA, the coupling product 33a is deprotected to afford the amine 34a of formula (I).

[0384] General Reaction Scheme IV-F

[0385]

[0386] Wherein R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl and R 2 is aryl or heteroaryl can be prepared according to General Reaction Scheme IV-F. Compound 34 is an example of formula (I) wherein R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, R 2 is aryl or heteroaryl, and R 3a and R 3b are H. 3-Bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 30 reacts with aryl / heteroaryl halide 26 under copper-catalyzed Ullman coupling conditions, for example, reacts with Cu(I)I, Cs2CO3, L-proline in DMF at high temperature to form amination product 32. R 2 -substituted amination product 32 couples with intermediate AN under palladium-catalyzed cross-coupling conditions, for example, under Suzuki conditions, to provide coupling product 33. Coupling product 33 is subjected to solvolysis conditions, such as hydrazine hydrate, to produce amine 34 of formula (I).

[0387] General Reaction Scheme IV-G

[0388]

[0389] Wherein R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl and R 2 is -C(O)-aryl or -C(O)-heteroaryl can be prepared according to General Reaction Scheme IV-G. Compound 40 is an example of formula (I) wherein R 1 is 5-R 2 -6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl, R 2 is -C(O)-aryl or -C(O)-heteroaryl, and R 3a and R 3bis H. 3-Bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 30 is coupled to carboxylic acid 37 in DMF using a coupling agent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and a base such as triethylamine to form amide 38. Under palladium-catalyzed cross-coupling conditions, such as Suzuki coupling, amide 38 is coupled to boronate intermediate AN to afford coupled product 39. R 2 - The coupled product 39 is subjected to solvolysis conditions, such as with hydrazine monohydrate, to remove the phthalimide moiety and provide the amine compound 40 of formula (I).

[0390] General reaction scheme IV-H

[0391]

[0392] wherein R 1 is 1-methyl-5-R 2 -1H-pyrazol-4-yl and R 2 is alkyl, aryl or heteroaryl can be prepared according to general reaction scheme IV-H. Compound 45 is an example of formula (I) wherein R 1 is 1-methyl-5-R 2 -1H-pyrazol-4-yl, R 2 is alkyl, aryl or heteroaryl, and R 3a and R 3b are H. 4-Bromo-1-methyl-1H-pyrazole 41 is coupled in NMP at elevated temperature with an alkyl / aryl / heteroaryl-substituted halide 42, such as with palladium acetate, DavePhos, tetrabutylammonium acetate, pivalic acid, to afford R 2 -substituted bromopyrazole 43. R 2 -substituted bromopyrazole 43 is coupled with intermediate AN under palladium-mediated cross-coupling conditions, such as under Suzuki conditions, to afford R 2 -substituted coupled product 44. The coupled product 44 is subjected to solvolysis conditions, such as with hydrazine hydrate, to provide amine 45 of formula (I).

[0393] General reaction scheme IV-I

[0394]

[0395] wherein R 1 is pyridinyl, R 2 is -S-aryl or -S-heteroaryl can be prepared according to general reaction scheme IV-I. Compound 57 is an example of formula (I) wherein R 1 is pyridinyl, R 2is -S-aryl or -S-heteroaryl, and R 3a and R 3b is H. 3-Bromo-5-fluoropyridine 53a is subjected to S N Ar substitution conditions, such as aryl / heteroaryl thiolate 54, NaH, in DMF at elevated temperature to afford 3-bromo-5-(aryl / heteroarylthio)pyridine 55. 3-Bromo-5-(aryl / heteroarylthio)pyridine 55 is coupled with borate intermediate AN under palladium cross-coupling conditions, such as under Suzuki conditions, to afford R 2 -pyridyl cross-coupling product 56. R 2 -pyridyl cross-coupling product 56 is subjected to solvolysis conditions, such as with hydrazine hydrate, to produce amine 57 of formula (I).

[0396] General reaction scheme IV-J

[0397]

[0398] wherein R 1 is pyridyl, R 2 is -S(O)-aryl or -S(O)-heteroaryl of formula (I) can be prepared according to general reaction scheme IV-J. Compound 94 is an example of formula (I) wherein R 1 is pyridyl, R 2 is -S(O)-aryl or -S(O)-heteroaryl, and R 3a and R 3b are H. 3-Bromo-5-(R 2 -thio)pyridine 55 is subjected to oxidation conditions, such as mCPBA in dichloromethane at ambient temperature, to afford 3-bromo-5-(R 2 -sulfinyl)pyridine 92. 3-Bromo-5-(R 2 -sulfinyl)pyridine 92 is coupled with borate intermediate AN under palladium-catalyzed cross-coupling conditions, such as Suzuki conditions, to afford R 2 -substituted sulfinylpyridyl product 93. R 2 -substituted sulfinylpyridyl product 93 is subjected to solvolysis conditions, such as with hydrazine hydrate, to afford R 2 -substituted sulfinylpyridylamine 94 of formula (I).

[0399] General reaction scheme IV-K

[0400]

[0401] wherein R 1 is 1-methyl-5-R 2 -1H-pyrazol-4-yl and R 2Compounds of formula (I) that are alkyl, aryl or heteroaryl can be prepared according to general reaction scheme IV-K. Compound 111 is an example of formula (I), where R 1 is 1-methyl-5-R 2 -1H-pyrazol-4-yl, R 2 is alkyl, aryl or heteroaryl, and R 3a and R 3b are H. Under palladium-catalyzed conditions, such as in the presence of an acid such as p-toluenesulfonic acid, in a solvent such as dichloroethane, at a high temperature such as 70 °C, H-R 2 107 is halogenated with a halogenating agent such as N-bromosuccinimide or N-chlorosuccinimide to obtain halide 108. 4-Bromo-1-methyl-1H-pyrazole 41 is coupled with an alkyl / aryl / heteroaryl-substituted halide 108 at a high temperature, for example, using palladium acetate, DavePhos, tetrabutylammonium acetate, pivalic acid in NMP, to provide R 2 -substituted-bromopyrazole 109. Under palladium-mediated cross-coupling conditions, such as under Suzuki conditions, the R 2 -substituted-bromopyrazole 109 is coupled to intermediate J to provide N-Boc-R 2 -substituted coupling product 110. The coupling product 110 is subjected to acidic conditions to remove the Boc group, such as TFA, to obtain the R 2 -substituted amine 111 of formula (I).

[0402] General reaction scheme V

[0403]

[0404] where R 1 is cycloalkyl or heterocyclic group of formula (I) can be prepared according to general reaction scheme V. Compound 7a is an example of formula (I), where R 1 is cycloalkyl or heterocyclic group, and R 3a and R 3b are H. 2-((7-Bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione intermediate F is coupled with a 4-6 membered cycloalkene boronic acid 17 under palladium-catalyzed coupling conditions, such as under Suzuki coupling conditions, to provide a suitable olefin coupling product 18. The olefin coupling product 18 is then subjected to hydrogenation conditions, such as Pd / C and H2, to provide a suitable hydrogenation product 19. The hydrogenation product is then subjected to hydrazine solvolysis conditions, such as with hydrazine hydrate, to provide the primary amine compound 7a of formula (I).

[0405] General reaction scheme VI-A

[0406]

[0407] wherein R 1 Compounds of formula (I) wherein R is an N-linked heteroaryl or N-linked heterocyclic group can be prepared according to general reaction scheme VI-A. Compound 22 is an example of formula (I) wherein R 1 is an N-linked heteroaryl or N-linked heterocyclic group, and R 3a and R 3b are H. The boronate intermediate AN and the nitrogen-containing heterocyclic or heteroaryl group 20 are subjected to metal-catalyzed cross-coupling conditions, such as Ullmann, Buchwald-Hartwig or Chan-Lam conditions, to provide the appropriate N-coupled product 21. This N-coupled product 21 is subjected to solvolysis conditions, such as with hydrazine hydrate, to remove phthalimide to provide the desired primary amine 22 of formula (I).

[0408] General reaction scheme VI-B

[0409]

[0410] wherein R 1 Compounds of formula (I) wherein R is an N-linked heteroaryl or N-linked heterocyclic group can be prepared according to general reaction scheme VI-B. Compound 23 is an example of formula (I) wherein R 1 is an N-linked heteroaryl or N-linked heterocyclic group, and R 3a and R 3b are H. The 2-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione intermediate F and the nitrogen-containing heterocyclic or heteroaryl group 20 are subjected to metal-catalyzed cross-coupling conditions, such as Ullmann, Buchwald-Hartwig or Chan-Lam conditions, to provide the appropriate N-coupled product 21a. This N-coupled product 21a is then subjected to solvolysis conditions, such as with hydrazine hydrate, to provide the desired primary amine 91a of formula (I).

[0411] General reaction scheme VI-C

[0412]

[0413] wherein R 1 Compounds of formula (I) wherein R is an N-linked heteroalkyl, N-linked arylheteroalkyl or N-linked aralkyl can be prepared according to general reaction scheme VI-C. Compound 24 is an example of formula I wherein R 1 is an N-linked heteroalkyl, N-linked arylheteroalkyl or N-linked aralkyl, and R 3a and R 3bIs H. The intermediate F, 2-((6-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione, is subjected to metal-catalyzed cross-coupling conditions with a heteroalkyl / aryl heteroalkyl / aralkylamine 20, such as Ullmann, Buchwald-Hartwig or Chan-Lam conditions, to provide a suitable N-coupled product 21b. The N-coupled product 21b is then subjected to solvolysis conditions, such as with hydrazine hydrate, to provide the desired product 91b of formula (I) substituted with R 1 Substituted product 91b.

[0414] General reaction scheme VII

[0415]

[0416] Wherein R 1 Is pyridyl and R 2 Is O-aryl or O-heteroaryl, and compounds of formula (I) can be prepared according to general reaction scheme VII. Compound 29 is an example of formula (I), wherein R 1 Is pyridyl, and R 2 Is O-aryl or O-heteroaryl, and R 3a And R 3b Is H. 3-Bromo-5-hydroxypyridine 25 is coupled with borate intermediate AN under palladium-catalyzed cross-coupling conditions such as Suzuki coupling conditions Pd(dppf)Cl2, NaHCO3, dioxane / water at 80 °C to generate the coupled product 28-OH. The coupled product 28-OH is subjected to S 2 Ar reaction conditions, such as K2CO3 in DMF, with an R N Substituted aryl / heteroaryl halide 26 at 110 °C to obtain an R 2 Substituted aryl / heteroaryl pyridyl ether 28. The R 2 Substituted aryl / heteroaryl pyridyl ether 28 is subjected to solvolysis conditions, such as hydrazine hydrate, to provide the free amine 29 of formula (I).

[0417] General reaction scheme VIII-A

[0418]

[0419] Wherein R 1 Is pyridyl and R 2 Is aryl or heteroaryl, and compounds of formula (I) can be prepared according to general reaction scheme VIII-A. Compound 85 is an example of formula (I), wherein R 1 Is pyridyl, R 2 Is aryl or heteroaryl, and R 3a And R 3bIs H. Intermediate CB is borated under Miyaura conditions, for example, borated with bis(pinacolato)diboron, Pd(dppf)Cl2, KOAc in dioxane at elevated temperature to afford boronic acid 86. Boronic acid 86 is coupled with R 2 halide 26 under palladium-catalyzed cross-coupling conditions such as Suzuki conditions to afford R 2 -pyridyl coupling product 84. R 2 -pyridyl coupling product 84 is subjected to solvolysis conditions, such as with hydrazine hydrate, to afford primary amine 85 of formula (I).

[0420] General reaction scheme VIII-B

[0421]

[0422] Wherein R 1 is pyridyl and R 2 is aryl or heteroaryl can be prepared according to general reaction scheme VIII-B. Compound 85 is an example of formula (I) wherein R 1 is pyridyl, R 2 is aryl or heteroaryl, and R 3a and R 3b is H. Under palladium-catalyzed cross-coupling conditions such as Suzuki conditions, intermediate AN is coupled with 3-bromo-5-iodopyridine 53b to afford 3-bromo-pyridyl coupling product intermediate CB. Then under palladium-catalyzed cross-coupling conditions such as Suzuki coupling conditions, intermediate CB is coupled with an aryl / heteroaryl-substituted boronic ester to afford R 2 -substituted pyridyl coupling product 84. Coupling product 84 is subjected to solvolysis, such as with hydrazine hydrate, to afford primary amine 85 of formula (I).

[0423] General reaction scheme IX-A

[0424]

[0425] Wherein R 1 is aryl or heteroaryl, R 3a is alkyl and R 3b is H of formula (I) can be prepared according to general reaction scheme IX-A. Compound 100 is an example of formula (I) wherein R 1 is aryl or heteroaryl, R 3a is alkyl and R 3bIt is H. Using hydride reduction conditions, for example, sodium borohydride in methanol, CaCl2 to reduce methyl 7-halo-4-oxo-3,4-dihydrophthalazine-1-carboxylate 11a at 0 °C to obtain the primary alcohol 6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12a. React 6-halo-4-(hydroxymethyl)phthalazin-1(2H)-one 12a with an oxidizing agent such as MnO2 in dichloroethane to provide 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 tert-butylsulfonamide in THF, titanium tetraisopropoxide and heating to 60 °C for 12 hours. Tert-butylsulfonamide 96 then reacts with alkylmagnesium halide in THF at -78 °C to form methylsulfonamide 97. Under palladium-catalyzed cross-coupling conditions such as Suzuki conditions, couple methylsulfonamide 97 to a suitable R 1 substituted boronic acid ester to obtain an R 1 substituted coupling product 99. The R 1 substituted coupling product 99 is desulfonylated under acidic conditions (e.g., HCl / dioxane) to obtain the R 1 substituted primary amine 100 of formula (I).

[0426] General reaction scheme IX-B

[0427]

[0428] Wherein R 1 is aryl or heteroaryl, R 3a is alkyl and R 3b is H, the compound of formula (I) can be prepared according to General reaction scheme IX-B. Compounds 9-5a and 9-5b are examples of the compound of formula (I) wherein R 1 is aryl or heteroaryl, R 3a is alkyl and R 3b is H. The tert-butylsulfinamide intermediate 97 is borated under Miyaura conditions, for example, with bis(pinacolato)diboron in dioxane, Pd(dppf)Cl2, KOAc at high temperature to provide the boronic acid ester 9-2, which is then coupled with a suitable R 1 substituted halide under palladium-catalyzed cross-coupling conditions such as Suzuki conditions to provide an R 1 substituted coupling product 9-3. The R 1 substituted coupling product 9-3 is desulfonylated under acidic conditions, e.g., in HCl / dioxane, to obtain the R 1Substituted primary amine 9-4. The racemic mixture of 9-4 is then separated into the corresponding pure enantiomers by chiral preparative HPLC and / or chiral SFC to afford chiral amines 9-5a and 9-5b which are examples of compounds of formula (I).

[0429] General Reaction Scheme X

[0430]

[0431] Where R 1 Compounds of formula (I) that are aryl, heteroaryl, heterocyclyl or alkyl can be prepared according to general reaction scheme X. Compound 10-10 is an example of formula (I) wherein R 1 is aryl, heteroaryl, heterocyclic or alkyl, R 3a and R 3b is H, and R 6 is hydrogen, halogen, C1-C3 alkyl or alkoxy. 1-(5-bromo-2-methyl-3-substituted phenyl)ethanone 10-1 is treated with an oxidizing agent, such as KMnO4 in water at 50°C to give 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 an acid and an alcohol, such as sulfuric acid and methanol, to give the ester 10 -4. 7-Bromo-4-oxo-3,4-dihydrophthalazine-5-substituted-1-carboxylic acid methyl ester 10-4 is reduced by hydride reduction, such as sodium borohydride and CaCl2 in methanol, to give 6-bromo-4-(hydroxymethyl)-8-substituted-phthalazin-1(2H)-one 10-5, which is then treated with a halogenating agent such as thionyl chloride for 12 hours to provide 6-halo-4-(chloromethyl)-8-substituted-phthalazin-1(2H)-one 10-6. Nucleophilization of 10-6 with a nitrogen nucleophile such as potassium phthalimide in DMF at elevated temperature is performed. N 2 displacement to give 10-7, which is borylated, for example, using Miyaura conditions, to give the boronate ester 10-8. Palladium-mediated cross-coupling conditions, such as Suzuki conditions, with the boronate ester 10-8 and aryl / heteroaryl / heterocyclyl / alkyl halide provide the phthalazinone coupling product 10-9. The phthalimide protecting group of 10-9 is removed under solvolysis conditions, such as using hydrazine hydrate in ethanol, to give the desired compound 10-10 of formula (I).

[0432] General Reaction Scheme XI

[0433]

[0434] Where R 1Compounds of formula (I) that are aryl, heteroaryl, heterocyclic or alkyl can be prepared according to general reaction scheme XI. Compound 11-7 is an example of formula (I), where R 1 is aryl, heteroaryl, heterocyclic or alkyl, R 3a and R 3b are D, and R 6 is hydrogen, halogen, C1-C3 alkyl or alkoxy. Methyl 7-bromo-4-oxo-3,4-dihydrophtalazine-5-substituted-1-carboxylate 10-4 is reduced by deuterium, for example with sodium borodeuteride and CaCl2 in methanol-d4, to give 6-bromo-4-((hydroxy-d)methyl-d2)-8-substituted-phtalazin-1(2H)-one 11-2, which is then treated with a halogenating agent such as thionyl chloride for 12 hours to afford 6-bromo-4-(chloromethyl-d2)-8-substituted-phtalazin-1(2H)-one 11-3. At high temperature, nucleophilic S N 2 displacement of 11-3 with a nitrogen nucleophile such as potassium phthalimide in DMF gives 11-4, which is borated, for example under Miyaura conditions, to give boronic ester 11-5. Palladium-mediated cross-coupling conditions, such as Suzuki conditions, with boronic ester 11-5 and aryl / heteroaryl / heterocyclic / alkyl halide provide the phtalazinone coupling product 11-6. Under solvolysis conditions, for example with hydrazine hydrate in ethanol, the phthalimide protecting group of 11-6 is removed to give the desired compound of formula (I) 11-7.

[0435] General reaction scheme XII

[0436]

[0437] where R 2 is aryl or heteroaryl, can be prepared according to general reaction scheme XII. Compound 12-3 is an example of formula (I), where R 2 is aryl or heteroaryl, R 3a and R 3b are H, R 6 is hydrogen, halogen, C1-C3 alkyl or alkoxy, and the substituent is alkyl, aryl or heteroaryl. Bromo- or chloro-compound 12-1 undergoes palladium-mediated cross-coupling conditions, such as Suzuki conditions, with alkyl / aryl / heteroaryl boronic acid / ester to give the substituent coupling product 12-2. Then the BOC group is removed under acidification conditions such as TFA to give the R 2 -substituted amine 12-3 of formula (I).

[0438] General reaction scheme XIII

[0439]

[0440] Wherein R 1 Compounds of formula (I) wherein R is alkyl cyano can be prepared according to general reaction scheme XIII. Compound 13-3 is an example of formula (I) wherein R 1 is CH2CN. The bromo- or chloro-compound 13-1 and the isoxazole boronic acid / ester are subjected to palladium-mediated cross-coupling conditions such as Suzuki conditions to obtain the substituent-coupled product 13-2. Then the isoxazole is subjected to hydrazine hydrate in an alcoholic solvent such as ethanol at a high temperature, followed by acid treatment, for example, treatment with HCl at pH 1, to obtain the nitrile product 13-3 of formula (I).

[0441] General reaction scheme XIV

[0442]

[0443] Wherein R 2 is aryl or heteroaryl and R 6 is alkoxy, compounds of formula (I) can be prepared according to general reaction scheme XIV. Compound 14-3 is an example of formula (I) wherein R 2 is aryl or heteroaryl, and R 6 is alkoxy. The fluoro-compound 14-1 having an amine appropriately protected with, for example, a BOC group or a phthalimide group is subjected to aromatic S N 2 conditions, where -F is the leaving group and the corresponding oxyanion is the nucleophile. For example, heating with sodium alkyl oxide in a polar solvent to obtain the substituent-substituted product 14-2. Then the protecting group is removed under appropriate conditions. For example, BOC is removed under acidic conditions such as HCl or TFA in dioxane, or the phthalimide group is removed by heating under basic nucleophilic conditions such as hydrazine hydrate in ethanol, to obtain the R 6 -substituted amine 14-3 of formula (I).

[0444] General reaction scheme XV

[0445]

[0446] Wherein R 2 is aryl or heteroaryl and R 6 is C1-C3 alkyl, compounds of formula (I) can be prepared according to general reaction scheme XV. Compound 15-3 is an example of formula (I) wherein R 2 is aryl or heteroaryl, and R 6is a C1-C3 alkyl group. Under palladium-catalyzed cross-coupling conditions such as Suzuki-Miyaura coupling conditions, a chlorinated compound 15-1 having an amine appropriately protected with, for example, a BOC group or a phthalimide group is coupled with a suitable C1-C3 trialkylborane to obtain the corresponding R 6 substituted coupling product 15-2. The protecting group is then removed under appropriate conditions. For example, BOC is removed under acidic conditions such as HCl in dioxane or TFA in dioxane, and the phthalimide group is removed by heating under basic nucleophilic conditions such as hydrazine hydrate in ethanol to obtain the R 6 substituted amine 15-3 of formula (I).

[0447] General reaction scheme XVI

[0448]

[0449] wherein R 1 is 1-methyl-5-R 2 -1H-pyrazol-4-yl and R 2 is alkyl, aryl or heteroaryl can be prepared according to General reaction scheme XVI. Compound 16-6 is an example of formula (I), wherein R 1 is 1-methyl-5-R 2 -1H-pyrazol-4-yl, R 2 is alkyl, aryl or heteroaryl, and R 3a and R 3b are H. H-R 2 16-1 is halogenated, for example, with a halogenating agent such as 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, at a high temperature such as 70 °C to obtain the halide 16-2. The bromo- or iodo-compound 16-2 is subjected to palladium-mediated cross-coupling conditions, such as Suzuki conditions, with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain the coupling product 16-3. 1-methyl-5-R 2 -1H-pyrazole 16-3 is halogenated, for example, with a halogenating agent such as N-bromosuccinimide or N-iodosuccinimide in a polar solvent such as acetonitrile to obtain a 4-halo-1-methyl-5-R 2 -1H-pyrazole compound 16-4. 4-bromo-1-methyl-5-R 2 -1H-pyrazole 16-4 is coupled with intermediate J under palladium-mediated cross-coupling conditions such as Suzuki conditions to provide N-Boc-R 2Substituted coupling product 16-5. The coupling product 16-5 is subjected to acidic conditions to remove the Boc group, such as TFA, to give R of formula (I). 2 Substituted amine 16-6.

[0450] Intermediates C, D, and E

[0451]

[0452] Step 1: 5-Bromoisobenzofuran-1,3-dione 1a (55.0 g, 242 mmol, 1.00 equivalent) and acetic acid (165 mL) were stirred at 125 °C for 1 h. After this time, the mixture was cooled to 10 °C and hydrazine hydrate (12.7 g, 254 mmol, 12.4 mL, 1.05 equivalent) was added dropwise, resulting in the formation of a thick white precipitate. Additional acetic acid (55 mL) was added and the mixture was stirred at 125 °C for an additional 30 min. After this 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 5% (w / w) sodium hydroxide solution (800 mL). The solution was acidified with acetic acid (200 mL) to give a viscous white precipitate, which was filtered. The filter cake was washed with water (50 mL × 3), then with methanol, and then dried in vacuo to give 6-bromo-2,3-dihydrophtalazine-1,4-dione 2a (45.6 g, crude) as a white solid. This solid was then used in the next step without further purification. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.17 (d, J = 2.0 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.95 - 7.89 (m, 1H).

[0453] Step 2: A solution of 6-bromo-2,3-dihydrophtalazine-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 h. After this time, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (150 mL) and added dropwise to ice water. The mixture was then extracted with dichloromethane (300 mL × 3), and the combined organic layers were washed with aqueous sodium bicarbonate (200 mL × 5), brine (200 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-bromo-1,4-dichloro-phtalazine 3a (14.5 g, crude) as a yellow solid. This solid was then used in the next step without further purification. 1 1H NMR (400 MHz, CDCl3) δ = 8.49 (d, J = 1.2 Hz, 1H), 8.23 - 8.15 (m, 2H).

[0454] Step 3: A solution of benzyl alcohol (4.59 g, 42.4 mmol, 4.41 mL) and sodium hydride (3.77 g, 94.3 mmol, 60% dispersion in mineral oil) in THF (30 mL) was stirred at 0 °C for 0.5 h. Then the mixture was added dropwise at 0 °C to a solution of 6-bromo-1,4-dichloro-phthalazine 3a (13.1 g, crude) in THF (80 mL). The reaction mixture was heated to 10 °C and stirred at 10 °C for 1 h. After this 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 a 1:1 mixture of intermediate C, 4-benzyloxy-7-bromo-1-chloro-phthalazine 4c and 4-benzyloxy-6-bromo-1-chloro-phthalazine 4d as a yellow solid (9.79 g, 28.0 mmol, 66% yield). 1 1H NMR (400 MHz, CDCl3) δ = 8.39 (d, J = 1.2 Hz, 1H), 8.35 (d, J = 1.6 Hz, 1H), 8.17 - 8.10 (m, 1H), 8.08 - 8.05 (m, 1H), 8.04 (d, J = 2.0 Hz, 1H), 8.00 (dt, J = 1.6, 8.4 Hz, 1H), 7.59 - 7.53 (m, 4H), 7.47 - 7.36 (m, 6H), 5.70 (s, 4H).

[0455] Step 4: The regioisomers of the 1:1 mixture of intermediate C, 4c and 4d (9.79 g, 28.0 mmol) were separated by SFC (column: DAICEL CHIRALPAK AD (250×30 mm, 10 μm); mobile phase: [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: 1 1H NMR (400 MHz, CDCl3) δ = 8.36 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.99 (dd, J = 2.0, 8.8 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.46 - 7.36 (m, 3H), 5.70 (s, 2H). LCMS [M+1] +351.0. Intermediate E: 4 - Benzyloxy - 6 - bromo - 1 - chloro - phthalazine: 1 H NMR(400MHz,CDCl3)δ=8.39(d,J=1.6Hz,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.

[0456] Intermediate F - Route 1

[0457]

[0458] Step 1: To a solution of 1 - (5 - bromo - 2 - methyl - phenyl) ethenone 8c (100 g, 445 mmol, 1.00 equiv) in water (1.00 L) was added potassium carbonate (92.4 g, 668 mmol, 1.50 equiv) and potassium permanganate (493 g, 3.12 mol, 7.00 equiv). The mixture was stirred at 50 °C for 3 h, then ethanol (1.00 L) was added and the resulting mixture was stirred at 50 °C for an additional 30 min. After this time, the solid was filtered off and the filtrate was adjusted to pH 2 with concentrated hydrochloric acid (500 mL). The mixture was then extracted with ethyl acetate (1.00 L), the organic layer was separated and then concentrated in vacuo to give 4 - bromo - 2 - oxalyl - 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.

[0459] Step 2: To a solution of 4 - bromo - 2 - oxalyl - benzoic acid 9c (382 g, 1.27 mol) in ethanol (3.00 L) was added hydrazine hydrate (71.2 g, 1.39 mol, 69.1 mL). The mixture was stirred at 75 °C for 4 h and the precipitate formed was filtered off, washed with ethanol (500 mL) and dried to give 7 - bromo - 4 - oxo - 3H - phthalazine - 1 - carboxylic acid 10c (280 g, 1.03 mol, 81% yield) as a white solid, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO - d6)δ=8.72 - 8.81(m,1H),8.11 - 8.21(m,1H),7.95 - 8.09(m,1H).

[0460] Step 3: To a solution of 7-bromo-4-oxo-3H-phthalazine-1-carboxylic acid 10c (200 g, 675 mmol) in methanol (2.00 L) was added sulfuric acid (131 g, 1.31 mol, 71.0 mL), and the reaction mixture was stirred at 65 °C for 24 h. After this time, the cooled reaction mixture was filtered and the cake was dried under reduced pressure to afford methyl 7-bromo-4-oxo-3H-phthalazine-1-carboxylate 11b (216 g, crude) as a white solid, which was used in the next step without further purification. LCMS [M+1] + = 283.0; 1 H NMR (400 MHz, DMSO-d6) δ = 13.31 (s, 1H), 8.72 (s, 1H), 8.16 - 8.18 (d, J = 8.4 Hz, 1H), 8.03 - 8.05 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H).

[0461] Step 4: At 0 °C, a stirred solution of methyl 7-bromo-4-oxo-3H-phthalazine-1-carboxylate 11c (159 g, 494 mmol) in ethanol (1.50 L) was treated portionwise with sodium borohydride (48.6 g, 1.29 mol, 2.60 equiv). A solution of calcium chloride (65.8 g, 593 mmol, 1.20 equiv) was added to the mixture. The mixture was then stirred at 0 °C for 2 h and at 20 °C for an additional 1 h. After this 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 1 N hydrochloric acid (300 mL), and the precipitate was filtered, washed with water (300 mL × 3) and dried to afford 6-bromo-4-(hydroxymethyl)-2H-phthalazin-1-one 12c (162 g, crude) as a yellow solid. LCMS [M+1] + = 255.0; 1 H NMR (400 MHz, DMSO-d6) δ = 12.66 (s, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 8.4, 2.0 Hz, 1H), 5.58 (t, J = 5.6 Hz, 1H), 4.67 (d, J = 6.0 Hz, 2H).

[0462] Step 5: Dissolve 6-bromo-4-(hydroxymethyl)-2H-phthalazin-1-one 12c (162 g, crude) in thionyl chloride (1.00 L), and stir the mixture at 70 °C for 2 hours, then concentrate under reduced pressure (35 °C). Dissolve the concentrated residue in dichloromethane (1.00 L) and concentrate to dryness to obtain 6-bromo-4-(chloromethyl)-2H-phthalazin-1-one 13c (154 g, crude) as a white solid, which was used in the next step without further purification. LCMS [M+1] + = 274.8; 1 1H NMR (400 MHz, DMSO-d6) δ = 12.92 (s, 1H), 8.30 (s, 1H), 8.18 - 8.20 (d, J = 7.6 Hz, 1H), 8.06 - 8.08 (t, J = 8.8 Hz, 1H), 5.07 (s, 2H).

[0463] Step 6: Add potassium (1,3-dioxoisoindolin-2-yl) (121 g, 653 mmol) to a solution of 6-bromo-4-(chloromethyl)-2H-phthalazin-1-one 13c (148 g, crude) in DMF (1.5 L). Stir the reaction mixture at 90 °C for 2 hours, then cool to 25 °C. Filter the formed precipitate, wash with DMF (200 mL x 2), and grind the filter cake with water (1.00 L), filter and dry to obtain intermediate F, 2-[(7-bromo-4-oxo-3H-phthalazin-1-yl)methyl]isoindoline-1,3-dione (162 g, 413 mmol, 76% yield) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 12.59 (s, 1H), 8.43 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.07 (dd, J = 1.6, 8.4 Hz, 1H), 7.97 - 7.93 (m, 2H), 7.92 - 7.86 (m, 2H), 5.19 (s, 2H). LCMS [M+1]: 383.9.

[0464] Intermediate F - Route 2

[0465]

[0466] Step 1: A mixture of 5-bromo-1(3H)-isobenzofuranone (50.0 g, 235 mmol, 1.00 equiv), DMF-DMA (180 g, 1.51 mol, 201 mL, 6.44 equiv) and t-BuOK (2.63 g, 23.5 mmol, 0.10 equiv) was degassed and purged with N2 three times, then stirred at 110 °C for 20 h under a N2 atmosphere. After this time, the reaction mixture was concentrated under reduced pressure to remove DMF-DMA, and the resulting residue was stirred in petroleum ether (100 mL) at 25 °C for 30 min. The formed solid was filtered, and the filter cake was stirred in ethyl acetate (200 mL) at 80 °C for 12 h, filtered, and the filter cake was dried under reduced pressure to afford (Z)-5-bromo-3-((dimethylamino)methylene)-1(3H)-isobenzofuranone as a red solid (39.0 g, 120 mmol, 51% yield, 82% purity). LCMS [M+1] + = 270.1; 1 H NMR (400 MHz, DMSO-d6) δ = 7.97 (d, J = 1.2 Hz, 1H), 7.61 - 7.59 (d, J = 8.0, 1H), 7.30 - 7.27 (dd, J = 8.0 & 1.2 Hz, 1H), 3.10 (s, 6H).

[0467] Step 2: To a mixture of (Z)-5-bromo-3-((dimethylamino)methylene)-1(3H)-isobenzofuranone (39.0 g, 119 mmol, 82.0% purity, 1.00 equiv) in EtOH (650 mL) at 25 °C was added NH2NH2·H2O (12.5 g, 245 mmol, 12.1 mL, 2.05 equiv). The mixture was degassed with N2, then stirred at 25 °C for 0.5 h, then stirred at 70 °C for 12 h. After this time, the reaction mixture was filtered, and the solid was dried to afford 6-bromo-4-((dimethylamino)methyl)phthalazin-1(2H)-one as a yellow solid (30.0 g, 105 mmol, 88% yield, 99% purity). LCMS [M+1] + = 282.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.6 (s, 1H), 8.33 (s, 1H), 8.14 - 8.12 (d, J = 8.4 Hz, 1H), 8.00 - 7.98 (m, 1H), 3.61 (s, 1H), 2.18 (s, 1H).

[0468] Step 3: A mixture of 6-bromo-4-((dimethylamino)methyl)phthalazin-1(2H)-one (15.0 g, 53.2 mmol, 1.00 eq) in THF (187 mL) was degassed with N2 three times and then cooled to 0 °C. Then isobutyl carbonochloridate (8.71 g, 63.80 mmol, 8.38 mL, 1.20 eq) was added dropwise, and the mixture was stirred at 25 °C under N2 for 6 h. After this time, the mixture was cooled to 0 °C, then HCl (0.5 M, 250 mL) was added while maintaining the temperature between 0 °C and 10 °C. After the addition was complete, the solid was filtered, washed with THF (30 mL x 3) and dried to give 6-bromo-4-(chloromethyl)phthalazin-1(2H)-one (11.0 g, 37.56 mmol, 71% yield, 93% purity) as a yellow solid. LCMS [M+1] + = 256.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.19 - 8.17 (d, J = 8.0 Hz, 1H), 8.06 - 80.4 (dd, J = 8.0 Hz & 1.6 Hz, 1H), 5.06 (s, 2H).

[0469] 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 potassium (1,3-dioxoisoindolin-2-yl) (5.61 g, 30.3 mmol, 1.10 eq), and the mixture was stirred at 25 °C for 1 h. After this time, the mixture was washed with HCl (0.5 M, 100 mL), filtered, and the solid was washed with saturated NaHCO3 (30 mL x 2), pure water (30 mL x 2), and then triturated with EtOH (15 mL) at 70 °C for 1 h. Then the solid was filtered and dried to give Intermediate F (8.30 g, 17.9 mmol, 65.0% yield, 83% purity) as a yellow solid. LCMS [M+1] + = 384.1 / 386.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.6 (s, 1H), 8.43 (s, 1H), 8.18 - 8.16 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.95 - 7.89 (m, 4H), 5.18 (s, 2H).

[0470] Intermediate G

[0471]

[0472] Step 1: To a solution of 1-(4-bromo-2-methyl-phenyl)ethenone 8d (10.0 g, 46.9 mmol, 1.00 equiv) in water was added potassium carbonate (9.73 g, 70.40 mmol, 1.50 equiv) and potassium permanganate (51.9 g, 329 mmol, 7.00 equiv). The mixture was stirred at 50 °C for 3 h, then ethanol (50 mL) was added, and the resulting mixture was stirred at 50 °C for an additional 30 min. After this time, the solid was filtered off, and the pH of the filtrate was adjusted to pH 2 with concentrated hydrochloric acid (5 mL). The mixture was then extracted with ethyl acetate (50 mL), the organic layer was separated and concentrated in vacuo to afford 5-bromo-2-oxalyl-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.

[0473] Step 2: To a solution of 5-bromo-2-oxalyl-benzoic acid 9d (10.0 g, crude) in ethanol (120 mL) was added hydrazine hydrate (1.87 g, 36.6 mmol, 1.82 mL), and the mixture was stirred at 75 °C for 4 h. After this time, the formed precipitate was filtered off, washed with ethanol (5 mL) and dried to afford 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.

[0474] Step 3: To a solution of 6-bromo-4-oxo-3H-phthalazine-1-carboxylic acid 10d (7.50 g, 27.9 mmol, 1.00 equiv) in methanol (40 mL) was added sulfuric acid (16.7 g, 167 mmol, 9.10 mL, 6.00 equiv), and the reaction mixture was stirred at 65 °C for 12 h. After this time, the reaction mixture was allowed to cool, and the formed precipitate was filtered off and dried to afford 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.

[0475] Step 4: At 0 °C, a stirred solution of sodium borohydride (2.43 g, 64.29 mmol, 2.60 eq) in ethanol (250 mL) was treated portionwise with methyl 6-bromo-4-oxo-3H-phthalazine-1-carboxylate 11d (7.00 g, 24.7 mmol, 1.00 eq). A solution of calcium chloride (3.29 g, 29.7 mmol, 1.20 eq) in ethanol (250 mL) was added dropwise to the mixture. The mixture was then stirred at 0 °C for 3 h and an additional 1 h at 20 °C. After this time, the mixture was concentrated under reduced pressure and the concentrated residue was suspended in water (30 mL) and the pH was adjusted to pH 5 with 1 N hydrochloric acid (5 mL). The precipitate formed was filtered, washed with water (5 mL × 3), triturated with ethanol (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.

[0476] Step 5: At 0 °C, 7-bromo-4-(hydroxymethyl)-2H-phthalazin-1-one 12d (6.00 g, 23.5 mmol) was dissolved in thionyl chloride (50 mL). The reaction mixture was stirred at 20 °C for 12 h 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.

[0477] 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 potassium (1,3-dioxoisoindolin-2-yl)ide (5.59 g, 30.2 mmol). The reaction mixture was stirred at 90 °C for 2 h, then cooled to 25 °C and the precipitate formed was filtered and triturated with ethanol (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. 11H NMR (400 MHz, DMSO-d6) δ = 12.66 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.22 - 8.18 (m, 1H), 8.14 - 8.10 (m, 1H), 7.97 - 7.93 (m, 2H), 7.91 - 7.87 (m, 2H), 5.18 (s, 2H). LCMS [M+1]: 386.1。

[0478] Intermediate I

[0479]

[0480] Step 1: A solution of intermediate F (3.00 g, 7.81 mmol, 1.00 equiv) and hydrazine hydrate (1.60 g, 31.2 mmol, 1.55 mL, 4.00 equiv) was stirred at 80 °C for 2 h, cooled and concentrated under reduced pressure. The concentrated residue was then washed with water and triturated with ethanol at 25 °C to afford 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。

[0481] Step 2: Di-tert-butyl dicarbonate (3.26 g, 15.0 mmol, 3.44 mL, 2.00 equiv) was added to a solution of 4-(aminomethyl)-6-bromo-2H-phthalazin-1-one 106 (1.90 g, 7.48 mmol, 1.00 equiv) and triethylamine (2.27 g, 22.4 mmol, 3.12 mL, 3.00 equiv) in dichloromethane (40.0 mL). The mixture was stirred at 25 °C for 2 h, filtered and concentrated under reduced pressure to give a residue. The concentrated residue was triturated with dichloromethane (40 mL), then filtered and dried to afford tert-butyl N-[(7-bromo-4-oxo-3H-phthalazin-1-yl)methyl]carbamate, intermediate I (1.97 g, 5.56 mmol, 74% yield). LCMS [M+1] +＝ 356.1。 1 1H NMR (400 MHz, DMSO-d6) δ = 12.71 (s, 1H), 8.26 (br s, 1H), 8.16 (br d, J = 8.0 Hz, 1H), 8.02 (br d, J = 8.0 Hz, 1H), 7.46 (br s, 1H), 4.41 (br d, J = 4.4 Hz, 2H), 1.40 (br s, 9H).

[0482] Intermediate J

[0483]

[0484] A mixture of Intermediate I (130.0, 275 mmol, 1.00 equiv) in dioxane (2.60 L), bis(pinacolato)diboron (BPD) (104.9 g, 412.9 mmol, 1.50 equiv), Pd(dppf)Cl2 (20.1 g, 27.5 mmol, 0.10 equiv), and KOAc (81.0 g, 825 mmol, 3.00 equiv) was degassed and purged with N2. The mixture was then stirred at 100 °C for 2 h. After this time, the mixture was filtered, concentrated, and the residue was triturated with petroleum ether / ethyl acetate 10 / 1 (400 mL) at 25 °C for 1 h. The solid was then filtered and dried to afford Intermediate J (68.0 g, 162 mmol, 59% yield) as a brown solid. LCMS [M+1] + = 402.3; 1 H NMR (400 MHz, CDCl3) δ = 12.62 (s, 1H), 8.25 (s, 2H), 8.01 - 8.13 (m, 1H), 7.21 - 7.45 (m, 1H), 4.34 - 4.63 (m, 2H), 1.42 (s, 9H), 1.32 (s, 12H).

[0485] Intermediate K

[0486]

[0487] A solution of 4-bromo-1-methyl-pyrazole (500 mg, 3.11 mmol, 1.00 equiv) and 1-bromo-3-fluorobenzene (543 mg, 3.11 mmol, 346 μL, 1.00 equiv) in N-methylpyrrolidone (10 mL) was degassed with nitrogen. Then, palladium acetate (7.0 mg, 31.1 μmol, 0.10 equiv) and 2-(2-dicyclohexylphosphinophenyl)-N,N-dimethylaniline (DavePhos) (24.0 mg, 62.1 μmol, 0.02 equiv) were added. To the resulting dark brown solution was added tetrabutylammonium acetate (1.87 g, 6.21 mmol, 2 mL, 2.00 equiv) and pivalic acid (317 mg, 3.11 mmol, 357 μL, 1.00 equiv), and the resulting solution was stirred at 100 °C for 15 h. After completion of the reaction, the mixture was cooled. Ethyl acetate (100 mL) was added, and the resulting mixture was washed with brine (3 × 100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated 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. 1 H NMR (400 MHz, CDCl3) δ = 7.56 (s, 1H), 7.50 (dt, J = 6.0, 8.0 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.18 - 7.13 (m, 1H), 3.85 (s, 3H).

[0488] Intermediates A-1 to A-32 shown in Table I-I were prepared according to the teachings of the general reaction scheme and the method for preparing Intermediate K.

[0489]

[0490]

[0491]

[0492]

[0493]

[0494] Intermediate AA

[0495]

[0496] To a solution of 3-bromo-5-fluoropyridine (2.20 g, 12.5 mmol, 1.00 equiv) in dimethylformamide (50 mL) was added sodium phenylsulfonamide (1.98 g, 15.0 mmol, 1.20 equiv), and the mixture was then stirred at 110 °C for 12 h. After this 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 afford 3-bromo-5-phenylsulfonamidopyridine, Intermediate AA (1.31 g, 4.48 mmol, 35% yield) as a yellow oil. LCMS [M+1] + = 268.0; 1 H NMR (400 MHz, MeOD) δ = 8.44 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.45 - 7.41 (m, 3H).

[0497] Intermediate AB

[0498]

[0499] To a solution of 2-chlorobenzenethiol (296 mg, 2.05 mmol, 233 μL, 1.20 equiv) in DMF (2 mL) was added sodium hydride (82 mg, 2.05 mmol, 60% purity, 1.20 equiv) and 3-bromo-5-fluoropyridine (300 mg, 1.70 mmol, 1.00 equiv), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of water (10 mL), and then extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 20%) to afford 3-bromo-5-(2-chlorophenyl)sulfonamidopyridine, Intermediate AB (280 mg, 931 μmol, 54% yield) as a white solid. LCMS [M+1] + = 302.0; 1 H NMR (400 MHz, CDCl3-d) δ = 8.56 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 7.73 (t, J = 2.0 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.33 - 7.28 (m, 2H), 7.26 - 7.22 (m, 1H).

[0500] Intermediates AC to AG shown in Table I-IIa were prepared according to the teachings of the general reaction scheme and the method for preparing intermediate AB.

[0501]

[0502] Intermediate AH

[0503]

[0504] Step 1: Potassium carbonate (1.68 g, 12.2 mmol, 1.00 equiv) and 2-chloroacetonitrile (920 mg, 12.2 mmol, 773 μL, 1.00 equiv) were added to a solution of 2-methyl-1H-imidazole (1.00 g, 12.2 mmol, 1.00 equiv) in DMF (10 mL), and the mixture was stirred at 50 °C for 5 h. After this time, the reaction mixture was diluted with water (20 mL), 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. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 10 - 100%) to afford 2-(2-methylimidazol-1-yl)acetonitrile as a yellow oil (460 mg, 3.80 mmol, 31% yield). 1 1H NMR (400 MHz, CDCl3) δ = 6.98 (d, J = 1.2 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H), 4.79 (s, 2H), 2.47 (s, 3H).

[0505] Step 2: A solution of N-bromosuccinimide (542 mg, 3.05 mmol, 0.90 equiv) in acetonitrile (10 mL) was added dropwise to a solution of 2-(2-methylimidazol-1-yl) (410 mg, 3.38 mmol, 1.00 equiv) in acetonitrile (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and after this 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%) and then by a second column of SiO2, petroleum ether:ethyl acetate:methanol 1:1:0.4) to afford 2-(5-bromo-2-methyl-imidazol-1-yl)acetonitrile, intermediate AH, as a brown solid (460 mg, 2.30 mmol, 67% yield). 1 1H NMR (400 MHz, CDCl3) δ = 6.97 (s, 1H), 4.82 (s, 2H), 2.53 (s, 3H).

[0506] Intermediate AI

[0507]

[0508] At 0 °C, a solution of sodium nitrite (86 mg, 1.25 mmol, 1.10 eq) in water (1.8 mL) was slowly added 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). After stirring for 10 minutes, the mixture was added portionwise to a solution of copper(I) 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 h. After this time, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with aqueous sodium bicarbonate solution (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether: ethyl acetate 25%) to afford 4-bromo-5-chloro-1-methyl-pyrazole, Intermediate AI (92 mg, 363 μmol, 31% yield) as a white solid. LCMS [M+1] + = 197.0; 1 H NMR (400 MHz, CDCl3-d) δ = 7.48 (s, 1H), 3.88 (s, 3H).

[0509] Intermediate AJ

[0510]

[0511] Sodium borohydride (22 mg, 572 μmol, 1.50 eq) was slowly added to a solution of (5-bromopyridin-3-yl)(phenyl)methanone (100 mg, 381 μmol, 1.00 eq) in ethanol (5 mL). After stirring at 25 °C for 2 h, the reaction was quenched with water (2 mL) and concentrated in vacuo. The residue was diluted with ethyl acetate (10 mL), washed with brine (10 × 3 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford (5-bromopyridin-3-yl)(phenyl)methanol, Intermediate AJ (97 mg, 367 μmol, 96% yield) as a colorless oil. LCMS [M+1] + = 263.9. 11H NMR (400 MHz, CDCl3) δ = 8.53 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 7.89 (t, J = 2.0 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.38 - 7.31 (m, 4H), 5.85 (s, 1H), 2.85 (s, 1H).

[0512] Intermediate AK

[0513]

[0514] To a solution of 3-bromo-5-(phenylthio)pyridine, Intermediate AA (200 mg, 751 μmol, 1.00 equiv) in dichloromethane (4 mL) was added 3-chloroperoxybenzoic acid (153 mg, 751 μmol, 85.0% purity, 1.00 equiv). The resulting mixture was stirred under nitrogen at 25 °C for 1 hour. After this time, aqueous sodium hydroxide solution (4 N, 40 mL) was added and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic layers were washed with brine (5 mL × 2), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 5 - 20%) to afford 3-bromo-5-(phenylsulfinyl)pyridine, Intermediate AK (150 mg, 532 μmol, 70% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 8.72 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.16 (t, J = 2.0 Hz, 1H), 7.72 - 7.68 (m, 2H), 7.55 - 7.27 (m, 3H).

[0515] Intermediate AL

[0516]

[0517] At 0 °C, a solution of oxone (2.10 g, 3.42 mmol, 2.00 equiv) in water (10 mL) was added to a solution of 3-bromo-5-phenylsulfanyl-pyridine Intermediate AA (500 mg, 1.71 mmol, 1.00 equiv) in THF (10 mL) and methanol (10 mL). The resulting mixture was stirred at 35 °C for 12 hours and after this time was filtered and the filtrate concentrated in vacuo. The residue formed was purified by reverse phase HPLC (0.1% FA conditions) to afford 3-(phenylsulfonyl)-5-bromo-pyridine, Intermediate AL (300 mg, 1.01 mmol, 59% yield) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ = 9.13 (d, J = 2.0 Hz, 1H), 9.01 (d, J = 2.0 Hz, 1H), 8.66 (t, J = 2.0 Hz, 1H), 8.12 - 8.08 (m, 2H), 7.77 - 7.72 (m, 1H), 7.69 - 7.64 (m, 2H).

[0518] Intermediate AM

[0519]

[0520] Step 1: At 0 °C, phosphorus oxychloride (4.71 g, 30.7 mmol, 2.9 mL, 1.23 equiv) was added dropwise to DMF (6 mL), and then the mixture was stirred at 0 °C for 10 minutes. After this time, a solution of 1-acetophenone (3.00 g, 25.0 mmol, 2.91 mL, 1.00 equiv) in DMF (25 mL) was added dropwise with stirring. Then the reaction mixture was heated at 60 °C for 3 hours. After this time, the solution was cooled to room temperature and slowly poured into an aqueous sodium acetate solution (10%, 100 mL). The pH was adjusted to 4 with additional sodium acetate solution (10 mL), and the mixture was 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 as a yellow oil (2.50 g, 14.1 mmol, 56% yield). LCMS [M+1] + = 167.1. 1 1H NMR (400 MHz, CDCl3) δ = 10.24 (d, J = 6.8 Hz, 1H), 7.49 (m, 5H), 6.69 (d, J = 6.8 Hz, 1H).

[0521] Step 2: Hydrogen cyanide (HCN) is produced as a by-product in this reaction. Appropriate safety precautions and procedures. (Z)-3-chloro-3-phenyl-prop-2-enal (1.76 g, 10.6 mmol, 1.00 equiv) and ammonium thiocyanate (1.61 g, 21.1 mmol, 1.61 mL, 2.00 equiv) in acetone (25 mL) were degassed, purged with nitrogen, and stirred at 80 °C for 1 h. After this time, the cooled mixture was poured into saturated aqueous sodium bicarbonate (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 residue formed was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 0 - 50%) to afford 5-phenylisothiazole as a yellow oil (1.00 g, 6.20 mmol, 58% yield). LCMS [M+1] + = 162.2. 1 1H NMR (400 MHz, CDCl3) δ = 8.49 (d, J = 2.0 Hz, 1H), 7.64 - 7.60 (m, 2H), 7.48 - 7.43 (m, 3H), 7.42 (d, J = 2.0 Hz, 1H).

[0522] Step 3: Bromine (952 mg, 5.95 mmol, 307 μL, 3.20 equiv) was added dropwise over a 30 min period to a stirred mixture of 5-phenylisothiazole (300 mg, 1.86 mmol, 1.00 equiv), potassium acetate (365 mg, 3.72 mmol, 2.00 equiv), and acetic acid (12 mL). The reaction mixture was stirred at 25 °C for 5 h and, after this time, treated with aqueous sodium bisulfite (33%, 10 mL). The solution was made basic with aqueous sodium hydroxide (20%, 10 mL) and extracted with dichloromethane (3 × 80 mL). The combined organic extracts were dried (anhydrous sodium sulfate), filtered, and concentrated to afford 4-bromo-5-phenyl-isothiazole, Intermediate AM, as a colorless oil (300 mg, 1.25 mmol, 67% yield). LCMS [M+1] + = 240.9 1 1H NMR (400 MHz, CDCl3) δ = 8.39 (s, 1H), 7.69 - 7.65 (m, 2H), 7.52 - 7.47 (m, 3H). 13 13C NMR (400 MHz, CDCl3) δ = 161.0, 159.5, 129.9, 129.3, 129.0, 128.5, 106.0.

[0523] Intermediate AN

[0524]

[0525] A mixture of Intermediate I (160 g, 416 mmol, 1.00 equiv) in dioxane (2.0 L), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (BPD) (158 g, 624 mmol, 1.50 equiv), Pd(dppf)Cl2 (30.4 g, 41.6 mmol, 0.10 equiv), and potassium acetate (122 g, 1.25 mol, 3.00 equiv) was purged with nitrogen and stirred at 100 °C for 3 h. After this 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 afford 2-((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophtalazin-1-yl)methyl)isoindoline-1,3-dione, Intermediate AN (93.0 g, 209 mmol, 50% yield) as a gray solid. LCMS [M+1] + = 432.4. 1 H NMR: (400 MHz DMSO-d6) δ: 12.54 (s, 1H), 8.24 - 8.37 (m, 2H), 8.13 (d, J = 7.6 Hz, 1H), 7.93 - 7.99 (m, 2H), 7.87 - 7.93 (m, 2H), 5.22 (s, 2H), 1.36 (s, 12H).

[0526] Intermediate AO

[0527]

[0528] To a solution of 3,5-dibromopyridine (1.00 g, 4.22 mmol, 1.00 equiv) in DMF (10 mL) at 0 °C was added sodium hydride (270 mg, 6.75 mmol, 60% purity, 1.60 equiv) over 10 min, followed by N-methylaniline (452 mg, 4.22 mmol, 458 μL, 1.00 equiv). The resulting mixture was stirred at 100 °C for 2 h. After this 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 chromatography (400 g SiO2, water / acetonitrile, 0 - 100% 70 mL / min) to afford 5-bromo-N-methyl-N-phenylpyridin-3-amine, Intermediate AO (50.0 mg, 190 μmol, 5% yield) as a yellow solid. LCMS [M+1] +262.9. 1 1H NMR (400 MHz, CDCl3-d) δ = 8.12 (br d, J = 6.4 Hz, 2H), 7.44 - 7.35 (m, 2H), 7.26 - 7.24 (m, 1H), 7.23 - 7.19 (m, 1H), 7.19 - 7.17 (m, 1H), 7.17 - 7.14 (m, 1H), 3.33 (s, 3H).

[0529] Intermediate AP

[0530]

[0531] A mixture of (5-bromo-3-pyridyl)boronic acid (325 mg, 1.61 mmol, 1.50 equiv), 1H-pyrazole-5-carbonitrile (100 mg, 1.07 mmol, 1.00 equiv), pyridine (255 mg, 3.22 mmol, 260 μL, 3.00 equiv), molecular sieve (20.0 mg, 1.07 mmol) and copper(II) acetate (585 mg, 3.22 mmol, 3.00 equiv) in dichloromethane (5 mL) was degassed with nitrogen and stirred at 20 °C under an oxygen atmosphere (15 psi) for 12 h. After this 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 afford 2-(5-bromo-3-pyridyl)pyrazole-3-carbonitrile, Intermediate AP (150 mg, 602 μmol, 56% yield) as a white solid. LCMS [M+1] + 249.0. 1 1H NMR (400 MHz, DMSO-d6) δ = 9.15 (d, J = 2.4 Hz, 1H), 8.91 (d, J = 2.4 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.63 (t, J = 2.0 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H).

[0532] Intermediate AS

[0533]

[0534] Step 1: At 0 °C, sodium hydride (310 mg, 7.74 mmol, 60.0% purity, 1.10 equiv) was added to a solution of cyclopropanol (450 mg, 7.74 mmol, 1.10 equiv) in THF (10 mL), then 5-fluoro-2-nitropyridine (1.00 g, 7.04 mmol, 1.00 equiv) was added and the mixture was heated to 20 °C and stirred for 2 h. After completion, the mixture was filtered and concentrated in vacuo, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 20 - 80%) to give 5-(cyclopropoxy)-2-nitropyridine (1.10 g, 6.11 mmol, 86% yield) as a white solid. LCMS [M+1] + = 181.1.

[0535] Step 2: Palladium on activated carbon (100 mg, 1.11 mmol, 10% purity, 1.00 equiv) was added to a solution of 5-(cyclopropoxy)-2-nitropyridine (200 mg, 1.11 mmol, 1.00 equiv) in methanol (4 mL) and the mixture was stirred at 30 °C for 4 h under a 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 was used in the next step without further purification. LCMS [M+1] + = 151.1.

[0536] Step 3: 2-Chloroacetaldehyde (313 mg, 1.60 mmol, 257 μL, 2.00 equiv) and sodium bicarbonate (70.5 mg, 839 μmol, 1.05 equiv) were added to a solution of 5-(cyclopropoxy)pyridin-2-amine (120 mg, 799 μmol, 1.00 equiv) in methanol (2 mL) and water (1.0 mL). The mixture was stirred at 70 °C for 2 h. After this 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 was used in the next step without further purification. LCMS [M+1] + = 175.2.

[0537] Step 4: To a solution of 6-(cyclopropoxy)imidazo[1,2-a]pyridine (220 mg, crude) in acetonitrile (2 mL) was added N-iodosuccinimide (313 mg, 1.39 mmol). The mixture was stirred at 20 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 20 - 80%) to afford 6-(cyclopropoxy)-3-iodo-imidazo[1,2-a]pyridine, Intermediate AS (220 mg, 733 μmol, 58% yield) as a white solid. LCMS [M+1] + = 300.9. 1 H NMR (400 MHz, DMSO-d6) δ = 8.03 (d, J = 2.0 Hz, 1H), 7.76 (s, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.17 (dd, J = 2.4, 9.6 Hz, 1H), 4.08 - 4.05 (m, 1H), 0.88 - 0.82 (m, 2H), 0.80 - 0.72 (m, 2H).

[0538] Intermediate AT

[0539]

[0540] Step 1: To a solution of 5-(trifluoromethoxy)pyridin-2-amine (250 mg, 1.40 mmol, 1.00 equiv) in methanol (5 mL) and water (2.5 mL) was added 2-chloroacetaldehyde (289 mg, 1.47 mmol, 237 μL, 1.05 equiv) and sodium bicarbonate (118 mg, 1.41 mmol, 54.8 μL, 1.00 equiv). The mixture was stirred at 70 °C for 2 h. Then the reaction mixture was concentrated under reduced pressure and the residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were concentrated to afford 6-(trifluoromethoxy)imidazo[1,2-a]pyridine (250 mg, crude) as a colorless oil, which was used in the next step without further purification.

[0541] Step 2: At 0 °C, a solution of N-iodosuccinimide (291 mg, 1.30 mmol) in acetonitrile (5 mL) was added to a solution of 6-(trifluoromethoxy)imidazo[1,2-a]pyridine (238 mg, crude) in acetonitrile (10 mL), 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 a yellow solid. LCMS [M+1] + = 329.0. 1 HNMR (400 MHz, CDCl3) δ = 8.23 - 8.19 (s, 1H), 7.80 (s, 1H), 7.71 (d, J = 9.6 Hz, 1H), 7.27 (m, 1H).

[0542] Intermediate AU

[0543]

[0544] Step 1: A mixture of 6-iodoimidazo[1,2-a]pyridine (500 mg, 2.05 mmol, 1.00 equiv), phenylboronic acid (275 mg, 2.25 mmol, 1.10 equiv), Pd(dppf)Cl2 (150 mg, 205 μmol, 0.10 equiv), sodium bicarbonate (344 mg, 4.10 mmol, 159 μL, 2.00 equiv) in dioxane (5 mL) and water (1.00 mL) was degassed with nitrogen and stirred at 80 °C for 1 hour. After this time, the reaction mixture was concentrated under reduced pressure and the residue was diluted with ethanol (5 mL), then the solution was concentrated. The residue was purified by preparative TLC (dichloromethane: methanol, 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.

[0545] Step 2: To a solution of 6-phenylimidazo[1,2-a]pyridine (100 mg, 515 μmol, 1.00 equiv) in acetonitrile (2 mL) was added N-iodosuccinimide (127 mg, 566 μmol, 1.10 equiv) and the mixture was stirred at 0 °C for 1 h. After this time, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethanol (2 mL), and the supernatant was removed and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate 10%) to afford 3-iodo-6-phenyl-imidazo[1,2-a]pyridine, Intermediate AU (120 mg, 375 μmol, 72% yield) as a yellow solid. LCMS [M+1] + = 321.0. 1 H NMR (400 MHz, DMSO-d6) δ = 8.40 (br s, 1H), 7.77 (m, 3H), 7.73 - 7.62 (m, 2H), 7.58 - 7.49 (m, 2H), 7.45 (m, 1H).

[0546] Intermediate AV

[0547]

[0548] To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.00 g, 10.2 mmol, 1.00 equiv) in methanol (10 mL) was added formaldehyde (610 mg, 20.3 mmol, 559 μL, 2.00 equiv) and sodium hydroxide (812 mg, 20.3 mmol, 2.00 equiv) and the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5 - 20%) and then by preparative TLC (petroleum ether: ethyl acetate 20%) to afford 5-bromo-3-(methoxymethyl)-1H-pyrrolo[2,3-b]pyridine, Intermediate AV (120 mg, 498 μmol, 5% yield) as a white solid. LCMS [M+1] + = 243.0. 1 H NMR (400 MHz, DMSO-d6) δ = 11.83 (br s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 4.53 (s, 2H), 3.25 (s, 3H).

[0549] Intermediate AX

[0550]

[0551] To a solution of 5-bromopyridin-3-ol (500 mg, 2.87 mmol, 1.00 equiv) in DMF (10 mL) was added cesium carbonate (1.87 g, 5.75 mmol, 2.00 equiv), 2-iodopyridine (707 mg, 3.45 mmol, 366 μL, 1.20 equiv), 2,2,6,6-tetramethylheptane-3,5-dione (212 mg, 1.15 mmol, 237 μL, 0.40 equiv), and copper(I) iodide (109 mg, 575 μmol, 0.20 equiv). The mixture was stirred at 100 °C for 0.5 h. Then the reaction mixture was 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 the 3-bromo-5-(2-pyridyloxy)pyridine intermediate AX (600 mg, 1.45 mmol, 50% yield) as a yellow oil. LCMS [M+1] + = 250.8. 1 H NMR (400 MHz, DMSO-d6) δ = 8.57 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.16 (ddd, J = 0.8, 2.0, 4.8 Hz, 1H), 8.02 (s, 1H), 7.91 (ddd, J = 2.0, 7.2, 8.0 Hz, 1H), 7.21 - 7.15 (m, 2H).

[0552] Intermediate AY

[0553]

[0554] To a solution of 2-chloropyrimidine (300 mg, 2.62 mmol, 1.00 equiv) in DMF (2 mL) was added potassium carbonate (724 mg, 5.24 mmol, 2.00 equiv) and 5-bromopyridin-3-ol (479 mg, 2.75 mmol, 1.05 equiv). The mixture was stirred at 110 °C for 5 h. 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), which was used directly in the next step without further purification. LCMS [M+1] + = 252.0; 11H NMR (400 MHz, DMSO-d6) δ = 8.70 (s, 1H), 8.69 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.17 (t, J = 2.0 Hz, 1H), 7.34 (t, J = 4.8 Hz, 1H).

[0555] Intermediate AY-1

[0556]

[0557] Step 1: Potassium carbonate (1.06 g, 7.65 mmol, 1.50 equiv) was added to a solution of 2-methylpyrazol-3-ol (500 mg, 5.10 mmol, 1.00 equiv) and (bromomethyl)benzene (1.05 g, 6.12 mmol, 726 μL, 1.20 equiv) in DMF (6.00 mL). The mixture was stirred at 120 °C for 4 h. Then the reaction mixture was 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 afford 5-benzyloxy-1-methyl-pyrazole (450 mg, 2.39 mmol, 47% yield) as a colorless oil. LCMS [M+1] + = 189.2; 1 1H NMR (400 MHz, CDCl3) δ = 7.43 - 7.41 (m, 3H), 7.40 - 7.35 (m, 2H), 7.31 (d, J = 2.0 Hz, 1H), 7.24 - 7.21 (d, J = 2.0 Hz, 1H), 5.08 (s, 2H), 3.67 (s, 3H).

[0558] Step 2: NBS (416 mg, 2.34 mmol, 1.10 equiv) was added to a solution of 5-benzyloxy-1-methyl-pyrazole (400 mg, 2.13 mmol, 1.00 equiv) in acetonitrile (6 mL). The mixture was stirred at 0 °C for 0.5 h. Then the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to afford 5-benzyloxy-4-bromo-1-methyl-pyrazole (320 mg, 1.20 mmol, 56% yield) as a yellow oil. LCMS [M+1] + = 266.9; 11H NMR (400 MHz, CDCl3) δ = 7.39 (s, 5H), 7.32 (s, 1H), 5.28 (s, 2H), 3.45 (s, 3H).

[0559] The intermediate AY-2 shown in Table I-IIb was prepared according to the teachings of the general reaction scheme and the method for preparing intermediate AY-1.

[0560]

[0561] General procedure for intermediates B-1 to B-15

[0562]

[0563] At 0 °C under nitrogen, sodium hydride (4.28 mmol, 60% purity, 1.10 equivalents) was added to the corresponding aryl / heteroaryl phenol (3.89 mmol, 1.00 equivalent) in DMF (10 mL). After the addition, the mixture was stirred at 25 °C for 0.5 h, then 3-bromo-5-fluoropyridine (3.89 mmol, 1.00 equivalent) was added and the mixture was stirred for an additional 12 h at 100 °C. After this time, the reaction mixture was quenched by the addition of water (10 mL), 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.

[0564] According to the teachings of the general reaction scheme and the general procedure for intermediates B-1 to B-15, the intermediates in Table I-III were prepared.

[0565]

[0566]

[0567] Intermediate BN

[0568]

[0569] To a solution of 3-bromo-5-fluoropyridine (210 mg, 1.19 mmol, 0.95 equiv) in DMF (10 mL) was added potassium carbonate (347 mg, 2.51 mmol, 2.00 equiv) and 3-chloro-2,4-dimethylphenol (197 mg, 1.26 mmol, 1.00 equiv). The mixture was stirred at 110 °C for 12 h. After this 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 afford 3-bromo-5-(3-chloro-2,4-dimethylphenoxy)pyridine, Intermediate BN (178 mg, 569 μmol, 45% yield) as a colorless oil. LCMS [M+1] + = 314.0. 1 H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.57 (t, J = 2.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 2.34 (s, 3H), 2.22 (s, 3H).

[0570] Intermediate BP

[0571]

[0572] To a solution of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (300 mg, 949 μmol, 1.00 equiv, TFA) and benzaldehyde (131 mg, 1.23 mmol, 125 μL, 1.30 equiv) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (402 mg, 1.90 mmol, 2.00 equiv) and acetic acid (114 mg, 1.90 mmol, 109 μL, 2.00 equiv). The mixture was then stirred at 25 °C for 4 h. After this 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 preparative TLC (SiO2, petroleum ether: ethyl acetate 25%) to afford 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. 11H NMR (400 MHz, CD3OD) δ = 7.45 (s, 1H), 7.41 - 7.32 (m, 5H), 4.12 (t, J = 5.6 Hz, 2H), 3.77 (s, 2H), 3.57 (s, 2H), 2.96 (t, J = 5.6 Hz, 2H).

[0573] Intermediate BQ

[0574]

[0575] A mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (400 mg, 1.27 mmol, 1.00 equiv), acetaldehyde (5.0 M, 508 μL, 2.01 equiv), sodium cyanoborohydride (160 mg, 2.54 mmol, 2.01 equiv), and zinc chloride (1.0 M, 2.53 mL, 2.00 equiv) in methanol (8 mL) was stirred at 25 °C for 2 h. After this time, the solvent was evaporated and the residue was purified by column chromatography (SiO2, dichloromethane:methanol 0 - 10%). The product was further purified by preparative HPLC (Waters Xbridge C18 150×50 mm×10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 16% - 46%, 11.5 min) to afford 3-bromo-5-ethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine, Intermediate BQ (100 mg, 434 μmol, 34% yield) as a colorless oil. 1 1H NMR (400 MHz, CD3OD) δ = 7.47 (s, 1H), 4.21 - 4.11 (t, J = 6.0 Hz, 2H), 3.61 (s, 2H), 3.03 - 2.94 (t, J = 6.0 Hz, 2H), 2.69 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H).

[0576] Intermediate BR

[0577]

[0578] Step 1: Sodium triacetoxyborohydride (420 mg, 1.98 mmol, 2.00 eq) was added 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). After stirring the mixture at 25 °C for 14 h, the mixture was extracted with dichloromethane (5 mL × 3), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane: methanol 10%) to afford 3-bromo-5-isopropyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine as a yellow oil (150 mg, 531 μmol, 54% yield). LCMS [M+1] + = 244.0. 1 H NMR (400 MHz, CDCl3) δ = 7.35 (s, 1H), 4.12 - 4.06 (t, J = 5.2 Hz, 2H), 3.59 (s, 2H), 2.96 - 2.90 (m, 1H), 2.89 - 2.86 (t, J = 5.2 Hz, 2H), 1.09 (s, 3H), 1.07 (s, 3H).

[0579] 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'-bis(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 and then stirred at 90 °C for 20 h. Then the mixture was concentrated under reduced pressure to afford 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, as a black solid (700 mg, 303 umol, 92% yield). LCMS [M+1] + = 292.2。

[0580] Intermediate BS

[0581]

[0582] Charge a pressure tube with 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (260 mg, 1.29 mmol, 1.00 equiv) in THF (5 mL) and ethanol (5 mL), (1-ethoxycyclopropoxy)trimethylsilane (673 mg, 3.86 mmol, 776 μL, 3.00 equiv), sodium cyanoborohydride (243 mg, 3.86 mmol, 3.00 equiv) and acetic acid (773 mg, 12.9 mmol, 736 μL, 10.0 equiv). Stir the resulting solution at 60 °C for 2 h, then concentrate the reaction mixture to give a residue. Purify the residue by preparative TLC (SiO2, petroleum ether:ethyl acetate 20%) to give 3-bromo-5-cyclopropyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine, Intermediate BS (150 mg, 620 μmol, 48% yield) as a yellow solid. 1 1H NMR (400 MHz, CD3OD) δ = 7.45 (s, 1H), 4.14 - 4.09 (m, 2H), 3.75 (s, 2H), 3.20 - 3.10 (m, 2H), 2.02 - 1.96 (m, 1H), 0.65 - 0.57 (m, 2H), 0.56 - 0.44 (m, 2H).

[0583] Intermediate BT

[0584]

[0585] Degas a mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (500 mg, 1.58 mmol, 1.00 equiv), iodobenzene (1.29 g, 6.33 mmol, 705 μL, 4.00 equiv), copper(I) iodide (60.3 mg, 316 μmol, 0.20 equiv), (2S)-pyrrolidine-2-carboxylic acid (72.9 mg, 633 μmol, 0.40 equiv) and cesium carbonate (1.03 g, 3.16 mmol, 2.00 equiv) in DMF (10 mL), purge with nitrogen, then stir at 100 °C for 1.5 h. After this time, cool the mixture, extract with ethyl acetate (5 mL × 3), wash with brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the resulting residue 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 a yellow solid. LCMS [M+1] + = 278.2.

[0586] Intermediate BU

[0587]

[0588] A mixture of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (200 mg, 633 μmol, 1.00 equiv), acetoacetic ester (96.9 mg, 949 μmol, 88.9 μL, 1.50 equiv), and DMAP (7.73 mg, 63.3 μmol, 0.10 equiv) in dichloromethane (10 mL) was degassed and purged with nitrogen, and then stirred at 40 °C for 3 h. After completion, the reaction mixture was concentrated under reduced pressure to afford 1-(3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)ethenone, Intermediate BU (100 mg, crude) as a white solid. LCMS [M+1] + = 244.2.

[0589] Intermediate BV

[0590]

[0591] To a solution of 3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (250 mg, 791 μmol, 1.00 equiv) in dimethylformamide (2 mL) was added triethylamine (240 mg, 2.37 mmol, 330 μL, 3.00 equiv), HATU (601 mg, 1.58 mmol, 2.00 equiv), and cyclopropanecarboxylic acid (102 mg, 1.19 mmol, 93.7 μL, 1.50 equiv). The mixture was stirred at 35 °C for 1 h. After this 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 residue formed was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 0-50%) to afford (3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-cyclopropyl-methanone, Intermediate BV (139 mg, 515 μmol, 65% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3) δ = 7.48 (s, 1H), 4.89 - 4.68 (m, 2H), 4.33 - 4.05 (m, 4H), 1.87 - 1.79 (m, 1H), 1.09 - 1.04 (m, 2H), 0.93 - 0.84 (m, 2H).

[0592] Intermediates C-1 to C-5 were prepared according to the teachings of the general reaction scheme and the procedure for Intermediate BV, as shown in Tables I-IV:

[0593]

[0594]

[0595] Intermediate CB

[0596]

[0597] A mixture of 3-bromo-5-iodopyridine (3.00 g, 10.6 mmol, 1.00 equiv), Intermediate AN (2.28 g, 5.28 mmol, 0.50 equiv), sodium bicarbonate (1.78 g, 21.1 mmol, 822 μL, 2.00 equiv), and Pd(dppf)Cl2 (773 mg, 1.06 mmol, 0.10 equiv) in dioxane (50 mL) and water (10 mL) was degassed with nitrogen 3 and then stirred at 80 °C for 1 hour. The cooled reaction mixture was then concentrated under reduced pressure, diluted with water (200 mL), filtered, and the filter cake was triturated with dichloromethane:methanol (10%, 150 mL). The solid was filtered and dried, and the solid was triturated a second time in methanol (100 mL), then filtered and dried to give 2-[[7-(5-bromo-3-pyridinyl)-4-oxo-3H-phthalazin-1-yl]methyl]isoindoline-1,3-dione, Intermediate CB (775 mg, crude) as a gray solid. 1 H NMR (400 MHz, DMSO-d6) δ = 12.54 (s, 1H), 9.16 (d, J = 1.2 Hz, 1H), 8.82 (d, J = 1.6 Hz, 1H), 8.73 (s, 1H), 8.52 (s, 1H), 8.38 - 8.28 (m, 2H), 7.98 - 7.95 (m, 2H), 7.90 (m, 2H), 5.38 (s, 2H).

[0598] Intermediate CC

[0599]

[0600] Step 1: To a solution of pyrazolo[1,5-a]pyridin-5-ol (250 mg, 1.86 mmol, 1.00 equiv) in DMF (2 mL) was added potassium carbonate (773 mg, 5.59 mmol, 3.00 equiv) and the mixture was stirred at 30 °C for 0.5 h. Iodoethane (872 mg, 5.59 mmol, 447 μL, 3.00 equiv) was added and the resulting mixture was stirred at 30 °C for 12 h. After this 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 preparative TLC (SiO2, petroleum ether / ethyl acetate 20%) to afford 5-ethoxypyrazolo[1,5-a]pyridine as a white solid (272 mg, 1.68 mmol, 90% yield). LCMS [M+1] + = 163.2; 1 H NMR (400 MHz, DMSO-d6) δ = 8.50 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 6.52 (dd, J = 2.8, 7.6 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H), 4.06 (q, J = 6.8 Hz, 2H), 1.35 (t, J = 6.8 Hz, 3H).

[0601] Step 2: To a solution of 5-ethoxypyrazolo[1,5-a]pyridine (260 mg, 1.60 mmol, 1.00 equiv) in acetonitrile (1.0 mL) was added NIS (397 mg, 1.76 mmol, 1.10 equiv). The mixture was stirred at 25 °C for 1 h, then the mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate 20%) to afford 5-ethoxy-3-iodopyrazolo[1,5-a]pyridine as a pink solid (369 mg, 1.28 mmol, 80% yield). LCMS [M+1] + = 289.1; 1 H NMR (400 MHz, DMSO-d6) δ = 8.57 (d, J = 7.6 Hz, 1H), 7.96 (s, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.59 (dd, J = 2.4, 7.6 Hz, 1H), 4.14 (q, J = 6.8 Hz, 2H), 1.37 (t, J = 6.8 Hz, 3H).

[0602] Intermediate CD

[0603]

[0604] Following the same procedure used for the preparation of Intermediate CC, using 2-iodopropane, Intermediate CD, 3-iodo-5-isopropoxypyrazolo[1,5-a]pyridine was prepared as a yellow solid (299 mg, 0.99 mmol, 87% yield over 2 steps). LCMS [M+1] + = 303.0; 1 H NMR (400 MHz, DMSO-d6) δ = 8.56 (d, J = 7.6 Hz, 1H), 7.96 (s, 1H), 6.67 (d, J = 2.8 Hz, 1H), 6.57 (dd, J = 2.8, 7.6 Hz, 1H), 4.77 (td, J = 6.0, 12.0 Hz, 1H), 1.32 (s, 3H), 1.30 (s, 3H).

[0605] Intermediate CE

[0606]

[0607] Step 1: A mixture of pyrazolo[1,5-a]pyridin-5-ol (300 mg, 2.24 mmol, 1.00 equiv) in dichloromethane (10 mL), phenylboronic acid (545 mg, 4.47 mmol, 2.00 equiv), MS (30 mg), copper(II) acetate (812 mg, 4.47 mmol, 2.00 equiv) and triethylamine (1.13 g, 11.2 mmol, 1.56 mL, 5.00 equiv) was degassed with oxygen and stirred at 25 °C under an oxygen (15 psi) atmosphere for 10 h. After this time, the reaction mixture was filtered, concentrated and the residue formed was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 0 - 20%) to afford 5-phenoxypyrazolo[1,5-a]pyridine as a yellow oil (200 mg, 0.95 mmol, 43% yield). LCMS [M+1] + = 211.2.

[0608] Step 2: To a solution of 5-phenoxypyrazolo[1,5-a]pyridine (180 mg, 0.86 mmol, 1.00 equiv) in acetonitrile (2 mL) was added NIS (212 mg, 0.94 mmol, 1.10 equiv). The mixture was stirred at 0 °C for 1 h. Then the reaction mixture was concentrated and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 0 - 5%) to afford 3-iodo-5-phenoxy-pyrazolo[1,5-a]pyridine (170 mg, 0.51 mmol, 59% yield) as a yellow oil. LCMS [M+1] + = 336.9.

[0609] Intermediate CF

[0610]

[0611] Step 1: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.50 g, 7.21 mmol, 1.00 equiv), [(E)-2-bromovinyl]benzene (2.90 g, 15.8 mmol, 2.03 mL, 2.20 equiv), Pd(PPh3)2Cl2 (506 mg, 721 μmol, 0.10 equiv), potassium carbonate (1.30 g, 9.41 mmol, 1.30 equiv) in ethanol (3.8 mL) and DMF (7.5 mL) was degassed with nitrogen and then stirred at 75 °C for 2 h. After this 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 afford 1-methyl-5-[(E)-styryl]pyrazole (990 mg, 5.37 mmol, 74% yield) as a yellow solid. LCMS [M+1] + = 185.2; 1 1H NMR (400 MHz, DMSO-d6) δ = 7.65 (d, J = 7.2 Hz, 2H), 7.42 - 7.36 (m, 3H), 7.32 - 7.25 (m, 2H), 7.12 (d, J = 16.0 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H).

[0612] Step 2: Under nitrogen, Pd / C (10.0 mg, 10% Pd) was added to a solution of 1-methyl-5-[(E)-styryl]pyrazole (400 mg, 2.17 mmol, 1.00 equiv) in ethanol (3 mL). The suspension was degassed under vacuum and purged with hydrogen several times, and then the mixture was stirred under hydrogen (15.0 psi) at 25 °C for 12 h. After this time, the reaction mixture was filtered and concentrated under reduced pressure to give 1-methyl-5-(2-phenylethyl)pyrazole as a yellow oil (385 mg, 1.93 mmol, 89% yield), which was used in the next step without further purification. LCMS [M+1] + = 187.2.

[0613] Step 3: N-Bromosuccinimide (343 mg, 1.93 mmol, 1.00 equiv) was added to a solution of 1-methyl-5-(2-phenylethyl)pyrazole (385 mg, 1.93 mmol, 1.00 equiv) in acetonitrile (10 mL). The mixture was then stirred at 0 °C for 0.5 h. After this time, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (SiO2, 20% petroleum ether / ethyl acetate) to give 4-bromo-1-methyl-5-(2-phenylethyl)pyrazole as a yellow oil (430 mg, 1.62 mmol, 84% yield). 1 1H NMR (400 MHz, DMSO-d6) δ = 7.43 (s, 1H), 7.31 - 7.24 (m, 2H), 7.23 - 7.18 (m, 1H), 7.17 - 7.11 (m, 2H), 3.58 (s, 3H), 2.97 - 2.89 (t, J = 7.2 Hz, 2H), 2.84 - 2.77 (t, J = 7.2 Hz, 2H).

[0614] Intermediate CG

[0615]

[0616] Step 1: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.00 g, 4.81 mmol, 1.00 equiv), 2-bromopyridine (911 mg, 5.77 mmol, 0.55 mL, 1.20 equiv), cesium carbonate (3.13 g, 9.61 mmol, 2.00 equiv) and Pd(dppf)Cl2 (352 mg, 0.48 mmol, 0.10 equiv) 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 h. After this 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 was used directly in the next step without further purification. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.69 - 8.66 (m, 1H), 7.89 (dt, J = 1.6, 7.6 Hz, 1H), 7.78 (td, J = 1.2, 8.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.37 (ddd, J = 1.2, 4.8, 7.6 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H), 4.14 (s, 3H).

[0617] Step 2: N-Bromosuccinimide (850 mg, 4.77 mmol) was added to a solution of 2-(2-methylpyrazol-3-yl)pyridine (760 mg, crude) in acetonitrile (10 mL). The mixture was stirred at 0 °C for 0.5 h. Then the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative 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. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.77 (td, J = 0.8, 4.0 Hz, 1H), 8.01 (dt, J = 2.0, 7.6 Hz, 1H), 7.76–

[0618] 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 h. Then the reaction mixture was quenched with additional 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 was purified by preparative TLC (SiO2, 50% petroleum ether / ethyl acetate) to afford 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)pyridine 1-oxide (185 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LCMS [M+1] + = 254.1; 1 H NMR (400 MHz, DMSO-d6) δ = 8.46 (d, J = 6.4 Hz, 1H), 7.70 (s, 1H), 7.5 (dt, J = 1.2, 7.6 Hz, 2H), 7.52 - 7.47 (m, 1H), 3.74 (s, 3H).

[0619] Intermediate CH

[0620]

[0621] Step 1: A mixture of quinolin-8-ol (454 mg, 3.13 mmol, 0.54 mL, 1.10 eq), 3-bromo-5-fluoropyridine (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 and then stirred at 110 °C for 3 h. After this 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 afford 8-[(5-bromo-3-pyridinyl)oxy]quinoline (0.30 g, 0.75 mmol, 26% yield) as a yellow oil. LCMS [M+1] + = 301.0; 11H NMR (400 MHz, CDCl3) δ = 8.95 (dd, J = 2.0, 4.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.25 (dd, J = 2.0, 8.4 Hz, 1H), 7.73 (dd, J = 1.6, 8.4 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.50 (dd, J = 4.0, 8.4 Hz, 1H), 7.47 - 7.43 (m, 2H).

[0622] Intermediate CI

[0623]

[0624] Step 1: A mixture of 3,5-dibromopyridine (1.48 g, 6.25 mmol, 1.00 equiv), quinolin-8-amine (901 mg, 6.25 mmol, 1.00 equiv), sodium tert-butoxide (901 mg, 9.37 mmol, 1.50 equiv), Pd2(dba)3 (57.2 mg, 62.5 μmol, 0.01 equiv), and Xantphos (72.3 mg, 125 μmol, 0.02 equiv) in dioxane (10 mL) was degassed with nitrogen and then stirred at 100 °C for 2 h. After this 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 was purified by reverse-phase HPLC (0.1% formic acid (FA) conditions) to afford N-(5-bromo-3-pyridyl)quinolin-8-amine (160 mg, 486 μmol, 7% yield) as a yellow solid. LCMS [M+1] + = 300.0; 1 1H NMR (400 MHz, CDCl3) δ = 8.82 (dd, J = 1.6, 4.0 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.40 (br s, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.17 (dd, J = 1.6, 8.4 Hz, 1H), 7.92 (t, J = 2.0 Hz, 1H), 7.51 - 7.46 (m, 3H), 7.37 (dd, J = 1.6, 8.0 Hz, 1H).

[0625] Step 2: Dissolve N-(5-bromo-3-pyridyl)quinolin-8-amine (130 mg, 394 μmol, 1.00 equiv) in DMF (2 mL), then add sodium hydride (32 mg, 790 μmol, 60.0% purity, 2.00 equiv) at 0 °C, and stir the mixture at 0 °C for 10 minutes. After this time, add iodomethane (224 mg, 1.58 mmol, 98 μL, 4.00 equiv) and stir the resulting mixture at 20 °C for 1 hour. Then quench the reaction mixture with water (10 mL), extract with ethyl acetate (20 mL × 3), and wash the combined organic phases with brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain N-(5-bromo-3-pyridyl)-N-methyl-quinolin-8-amine as a yellow oil (150 mg, 334 μmol, 85% yield). LCMS [M+1] + = 314.1; 1 H NMR (400 MHz, CDCl3) δ = 8.90 (dd, J = 1.6, 4.4 Hz, 1H), 8.24 (dd, J = 1.6, 8.4 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.82 (dd, J = 1.6, 8.0 Hz, 1H), 7.65 - 7.62 (m, 1H), 7.61 - 7.57 (m, 1H), 7.46 (dd, J = 4.4, 8.4 Hz, 1H), 7.10 (t, J = 2.4 Hz, 1H), 3.49 (s, 3H).

[0626] Intermediate CJ

[0627]

[0628] Step 1: Degas a mixture of 2-ethylbenzonitrile (500 mg, 3.81 mmol, 0.51 mL, 1.00 equiv), p-toluenesulfonic acid (363 mg, 1.91 mmol, 0.50 equiv), N-bromosuccinimide (746 mg, 4.19 mmol, 1.10 equiv), and palladium acetate (85.6 mg, 0.38 mol, 0.10 equiv) in 1,2-dichloroethane (10 mL) with nitrogen, then stir at 70 °C for 12 hours. After this time, concentrate the reaction mixture under reduced pressure, and purify the residue by column chromatography (SiO2, petroleum ether / ethyl acetate 0 - 5%) to obtain 2-bromo-6-ethyl-benzonitrile as a yellow oil (446 mg, 1.15 mmol, 30% yield). 11H NMR (400 MHz, DMSO-d6) δ = 7.76 (dd, J = 0.8, 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.60 - 7.54 (m, 1H), 2.81 (m, 2H), 1.22 (m, 3H).

[0629] Step 2: A mixture of 2-bromo-6-ethyl-benzonitrile (446 mg, 1.15 mmol, 1.00 equiv), 4-bromo-1-methyl-pyrazole (203 mg, 1.26 mmol, 1.10 equiv), palladium(II) acetate (2.57 mg, 0.12 mmol, 0.01 equiv), DavePhos (9.0 mg, 0.23 mmol, 0.02 equiv), 2-methylpropanoic acid (30.3 mg, 0.34 mmol, 31.9 uL, 0.30 equiv) and tetrabutylammonium acetate (691 mg, 2.29 mmol, 0.70 mL, 2.00 equiv) in N-methylpyrrolidone (10 mL) was degassed with nitrogen and then stirred at 100 °C for 12 h. After this 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 afford 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-ethyl-benzonitrile (310 mg, 0.44 mmol, 39% yield) as a yellow solid. LCMS [M+1] + = 290.1; 1 1H NMR (400 Hz, DMSO-d6) δ = 7.83 - 7.78 (m, 1H), 7.73 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.50 - 7.47 (m, 1H), 3.71 (s, 3H), 2.90 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H).

[0630] Intermediates D-1 to D-20 shown in Tables I-V were prepared according to the teachings of the general reaction scheme and the method for preparing intermediate CJ.

[0631]

[0632]

[0633]

[0634] Intermediate DA

[0635]

[0636] Step 1: A mixture of 3-bromophenol (1.00 g, 5.78 mmol, 1.00 equiv), bromocyclobutane (1.17 g, 8.65 mmol, 0.82 mL, 1.50 equiv) and potassium carbonate (3.20 g, 23.1 mmol, 4.00 equiv) in DMF (10 mL) was stirred at 120 °C for 6 h. The reaction mixture was diluted with water (80 mL) and extracted with (petroleum ether / ethyl acetate 20%) (50 mL×3). The combined extracts were washed with aqueous sodium hydroxide solution (1.00 M, 50 mL), brine (50 mL), dried over sodium sulfate and concentrated to give 1-bromo-3-(cyclobutoxy)benzene (1.20 g, 5.27 mmol, 91% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3) δ = 7.04 - 6.93 (m, 2H), 6.86 (t, J = 2.4 Hz, 1H), 6.64 (ddd, J = 1.2, 2.4, 8.0 Hz, 1H), 4.60 - 4.44 (m, 1H), 2.34 (tddd, J = 2.8, 6.8, 8.0, 9.6 Hz, 2H), 2.14 - 1.98 (m, 2H), 1.83 - 1.71 (m, 1H), 1.66 - 1.50 (m, 1H).

[0637] Step 2: 1-Bromo-3-(cyclobutoxy)benzene (300 mg, 1.32 mmol, 1.00 equiv), 4-bromo-1-methyl-pyrazole (213 mg, 1.32 mmol, 1.00 equiv), palladium(II) acetate (2.97 mg, 13.2 mmol, 0.01 equiv), tetrabutylammonium acetate (224 mg, 2.91 mmol, 2.20 equiv), 2-methylpropanoic acid (34.9 mg, 396 μmol, 36.8 μL, 0.30 equiv) and DavePhos (10.4 mg, 26.4 μmol, 0.02 equiv) in NMP (5 mL) were degassed with nitrogen and heated at 100 °C for 12 h. Then the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (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. 11H NMR (400 MHz, CDCl3) δ = 7.54 (s, 1H), 7.45 (s, 1H), 6.98 - 6.90 (m, 2H), 6.86 - 6.83 (m, 1H), 4.68 (t, J = 7.2 Hz, 1H), 3.83 (s, 3H), 2.54 - 2.40 (m, 2H), 2.27 - 2.14 (m, 2H), 1.95 - 1.66 (m, 2H).

[0638] The intermediates E-1 and E-2 shown in Tables I-VI were prepared according to the teachings of the general reaction scheme and the method for preparing intermediate DA.

[0639]

[0640] Intermediate DB

[0641]

[0642] Step 1: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.50 g, 7.21 mmol, 1.00 equiv), 1-bromo-2-chlorobenzene (1.38 g, 7.21 mmol, 0.84 mL, 1.00 equiv), sodium carbonate (2.29 g, 21.6 mmol, 3.00 equiv), Pd(dppf)Cl2 (528 mg, 0.72 mmol, 0.10 equiv) in water (2.4 mL) and dioxane (12 mL) was degassed with nitrogen and then stirred at 80 °C for 2 h. After this time, the mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10 - 20%) to afford 5-(2-chlorophenyl)-1-methyl-pyrazole (0.56 g, 2.88 mmol, 40% yield) as a yellow solid. LCMS [M+1] + = 193.1; 1 1H NMR (400 MHz, CDCl3) δ = 7.56 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 1.2, 7.6 Hz, 1H), 7.43 - 7.33 (m, 3H), 6.30 (d, J = 2.0 Hz, 1H), 3.74 (s, 3H).

[0643] Step 2: A mixture of 5-(2-chlorophenyl)-1-methyl-pyrazole (200 mg, 1.04 mmol, 1.00 eq) and N-bromosuccinimide (203 mg, 1.14 mmol, 1.10 eq) in acetonitrile (2 mL) was degassed with nitrogen and then stirred at 0 °C for 2 h. After this time, the mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (petroleum ether / ethyl acetate 20%) to afford 4-bromo-5-(2-chlorophenyl)-1-methyl-pyrazole (220 mg, 0.77 mmol, 74% yield) as a yellow solid. LCMS [M+1] + = 273.1; 1 H NMR (400 MHz, CDCl3) δ = 7.59 - 7.55 (m, 2H), 7.50 - 7.40 (m, 2H), 7.36 - 7.33 (m, 1H), 3.74 (s, 3H).

[0644] Intermediates F-1 to F-22 shown in Tables I - VII were prepared according to the teachings of the general reaction scheme and the method for preparing intermediate DB.

[0645]

[0646]

[0647]

[0648]

[0649] Intermediate DC

[0650]

[0651] Step 1: To a solution of 2-bromonaphthalene-1-carbaldehyde (220 mg, 0.94 mmol, 1.00 eq) in water (5 mL) was added ammonium hydrogensulfate (212 mg, 1.87 mmol, 2.00 eq). The mixture was stirred at 50 °C for 12 h. Then the suspension was filtered and the cake was dried under reduced pressure to afford (1E)-2-bromonaphthalene-1-carbaldehyde oxime (220 mg, 0.88 mmol, 94% yield) as a white solid, which was used without further purification. 11H NMR (400 MHz, DMSO-d6) δ = 11.79 (s, 1H), 8.58 (s, 1H), 8.55 (dd, J = 1.6, 8.0 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.67 - 7.57 (m, 2H). Triethylamine (890 mg, 8.80 mmol, 1.22 mL) and trifluoroacetic anhydride (924 mg, 4.40 mmol, 0.61 mL) were added to a solution of (1E)-2-bromonaphthalene-1-carbaldehyde oxime (220 mg, crude) in THF (5 mL), and the mixture was stirred at 20 °C for 1 hour. After this time, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO2, 10% petroleum ether / ethyl acetate) to give 2-bromonaphthalene-1-carbonitrile (190 mg, 0.82 mmol, 93% yield) as a white solid. GCMS [M+1] + = 230.9; 1 1H NMR (400 MHz, DMSO-d6) δ = 8.26 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.85 (dt, J = 1.2, 8.4 Hz, 1H), 7.79 - 7.71 (m, 1H).

[0652] Step 2: A mixture of 2-bromonaphthalene-1-carbonitrile (190 mg, 0.82 mmol, 1.00 equiv), 4-bromo-1-methyl-pyrazole (132 mg, 0.82 mmol, 1.00 equiv), tetrabutylammonium acetate (494 mg, 1.64 mmol, 0.50 mL, 2.00 equiv), DavePhos (6.4 mg, 16 μmol, 0.02 equiv), 2-methylpropanoic acid (22 mg, 246 μmol, 23 μL, 0.30 equiv) and palladium(II) acetate (1.8 mg, 8.2 μmol, 0.01 equiv) in N-methylpyrrolidone (NMP) (6 mL) was degassed with nitrogen, and then the mixture was stirred at 100 °C for 12 hours. After this 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 reverse-phase HPLC (0.1% formic acid conditions) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)naphthalene-1-carbonitrile (190 mg, 0.61 mmol, 74% yield) as a yellow oil. LCMS [M+1] + = 314.1;1 1H NMR (400 MHz, DMSO-d6) δ = 8.49 (d, J = 8.4 Hz, 1H), 8.24 (t, J = 8.4 Hz, 2H), 7.92 (dt, J = 1.2, 8.4 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.81 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H).

[0653] Intermediate DD

[0654]

[0655] Step 1: Sodium hydride (180 mg, 4.50 mmol, 60.0% purity, 3.00 equiv) was added to a solution of ethanol (207 mg, 4.50 mmol, 0.26 mL, 3.00 equiv) in THF (3 mL), and then a solution of 2-bromo-6-fluoro-benzonitrile (300 mg, 1.50 mmol, 1.00 equiv) in THF (1 mL) was added dropwise. After the addition was complete, the mixture was stirred at 25 °C for 3 h. After this time, the reaction was quenched with water (0.2 mL) and concentrated in vacuo, and the residue was purified by column chromatography (SiO2, 10% petroleum ether / ethyl acetate) to give 2-bromo-6-ethoxy-benzonitrile (200 mg, 0.89 mmol, 59% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 7.38 - 7.32 (t, J = 8.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H).

[0656] Step 2: A mixture of 2-bromo-6-ethoxy-benzonitrile (200 mg, 0.89 mmol, 1.00 equiv), 4-bromo-1-methyl-pyrazole (185 mg, 1.15 mmol, 1.30 equiv), palladium(II) acetate (2.0 mg, 8.9 μmol, 0.01 equiv), DavePhos (7.0 mg, 17.7 μmol, 0.02 equiv), isobutyric acid (23.4 mg, 265 μmol, 25 μL, 0.30 equiv) and tetrabutylammonium acetate (533 mg, 1.77 mmol, 2.00 equiv) was degassed with nitrogen, and then the mixture was stirred at 100 °C for 15 h. After this 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 vacuo. The residue was then purified by preparative TLC (SiO2, 20% petroleum ether / ethyl acetate) to afford 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; 1 H NMR (400 MHz, CDCl3) δ = 7.56 (dd, J = 7.6, 8.4 Hz, 1H), 7.49 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.73 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H).

[0657] Intermediate DE

[0658]

[0659] A mixture of 4-bromo-2-methyl-pyrazol-3-ol (300 mg, 1.69 mmol, 1.00 equiv), 1-(bromomethyl)-2-chlorobenzene (348 mg, 1.69 mmol, 0.22 mL, 1.00 equiv) and potassium carbonate (469 mg, 3.39 mmol, 2.00 equiv) in DMF (8 mL) was stirred at 18 °C for 2 h. After this 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 was purified by reverse phase HPLC (0.1% FA conditions) to afford 4-bromo-5-[(2-chlorophenyl)methoxy]-1-methyl-pyrazole (220 mg, 0.72 mmol, 42% yield) as a yellow solid. LCMS [M+1] + = 303.0;1 1H NMR (400 MHz, CDCl3) δ = 7.48 - 7.43 (m, 2H), 7.37 - 7.27 (m, 3H), 5.40 (s, 2H), 3.55 (s, 3H).

[0660] The G-1 to G-4 intermediates shown in Tables I - VIII were prepared according to the teachings of the general reaction scheme and the method for preparing intermediate DE.

[0661]

[0662]

[0663] Intermediate H-1

[0664]

[0665] Step 1: A mixture of 2-bromo-6-fluoro-benzonitrile (600 mg, 3.00 mmol, 1.00 equiv), propan-2-ol (225 mg, 3.75 mmol, 0.29 mL, 1.25 equiv), and cesium carbonate (1.47 g, 4.50 mmol, 1.50 equiv) in DMF (6 mL) was stirred at 75 °C for 1 hour. After this 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 reverse-phase HPLC (0.1% formic acid conditions) to afford 2-bromo-6-isopropoxy-benzonitrile (540 mg, 2.25 mmol, 75% yield) as a white solid. LCMS [M+1] + = 241.9; 1 1H NMR (400 MHz, DMSO-d6) δ = 7.56 (t, J = 8.4 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.90 - 4.75 (m, 1H), 1.32 (d, J = 6.0 Hz, 6H).

[0666] Step 2: A mixture of 2-bromo-6-isopropoxy-benzonitrile (500 mg, 2.08 mmol, 1.00 equiv), 4-bromo-1-methyl-pyrazole (335 mg, 2.08 mmol, 1.00 equiv), diacetoxypalladium (4.7 mg, 0.021 mmol, 0.01 equiv), DavePhos (16 mg, 0.042 mmol, 0.02 equiv), tetrabutylammonium acetate (1.26 g, 4.16 mmol, 2.00 equiv) and isobutyric acid (55 mg, 0.63 mmol, 0.06 mL, 0.30 equiv) in 1-methyl-2-pyrrolidone (7 mL) was degassed with nitrogen and then stirred at 100 °C for 12 h. After this 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 reverse-phase HPLC (0.1% formic acid conditions) to afford 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-isopropoxy-benzonitrile (160 mg, 0.50 mmol, 24% yield) as a white solid. LCMS [M+1] + = 319.9; 1 H NMR (400 MHz, DMSO-d6) δ = 7.81 - 7.76 (m, 1H), 7.72 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 4.88 (td, J = 6.0, 12.0 Hz, 1H), 3.71 (s, 3H), 1.36 (d, J = 6.0 Hz, 6H).

[0667] Intermediates H-2 to H-8 shown in Tables I-IX were prepared according to the teachings of the general reaction scheme and the method for preparing Intermediate H-1.

[0668]

[0669]

[0670] Intermediate I-1

[0671]

[0672] Step 1: At 0 °C, a solution of trifluoromethanesulfonic anhydride (0.86 mmol, 0.141 mL, 1.00 equiv) in dichloromethane (1 mL) was added dropwise to a solution of 6 - hydroxychroman - 5 - carbonitrile (150 mg, 0.86 mmol, 1.00 equiv) and triethylamine (2.57 mmol, 0.36 mL, 3.00 equiv) in dichloromethane (2 mL). The mixture was then stirred at 0 °C for 0.5 h. After this time, the mixture was diluted with ethyl acetate (50 mL), washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate 10%) to give (5 - cyanochroman - 6 - yl) trifluoromethanesulfonate as a colorless liquid (80 mg, 0.26 mmol, 30% yield). 1 1H NMR (400 MHz, CDCl3) δ = 7.21 - 7.15 (m, 1H), 7.09 - 7.04 (m, 1H), 4.31 - 4.20 (m, 2H), 3.00 (t, J = 6.4 Hz, 2H), 2.18 - 2.02 (m, 2H).

[0673] Step 2: A mixture of (5 - cyanochroman - 6 - yl) trifluoromethanesulfonate (70 mg, 0.23 mmol, 1.00 equiv), 1 - methyl - 5 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl) pyrazole (71 mg, 0.34 mmol, 1.50 equiv), Pd(dtbpf)Cl2 (15 mg, 0.23 mmol, 0.10 equiv), and sodium bicarbonate (38 mg, 0.46 mmol, 2.00 equiv) in DMF (2 mL) was degassed with nitrogen. The mixture was then stirred at 80 °C for 1 h, cooled to 25 °C, diluted with ethyl acetate (30 mL), washed with brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate 30%) to give 6 - (2 - methylpyrazol - 3 - yl) chroman - 5 - carbonitrile as a white solid (40 mg, 0.17 mmol, 73% yield). LCMS [M + 1] + = 240.0; 1 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).

[0674] Step 3: To a solution of 6-(2-methylpyrazol-3-yl)chroman-5-carbonitrile (30 mg, 0.125 mmol, 1.00 equiv) in acetonitrile (1.5 mL) was added NBS (34 mg, 0.19 mmol, 1.50 equiv). The mixture was stirred at 25 °C for 1 h and then concentrated. The residue was purified by preparative TLC (SiO2, 30% petroleum ether / ethyl acetate) to afford 6-(4-bromo-2-methyl-pyrazol-3-yl)chroman-5-carbonitrile (25 mg, 0.79 mmol, 63% yield) as a yellow solid. LCMS [M+1] + = 320.1; 1 H NMR (400 MHz, CDCl3) δ = 7.57 (s, 1H), 7.18 - 7.11 (m, 2H), 4.29 (dd, J = 4.4, 6.0 Hz, 2H), 3.79 (s, 3H), 3.05 (dt, J = 2.0, 6.4 Hz, 2H), 2.15 (dq, J = 4.4, 6.4 Hz, 2H).

[0675] Intermediates I-2 to I-4 shown in Tables I-X were prepared according to the teachings of the general reaction scheme and the method for preparing Intermediate I-1.

[0676]

[0677]

[0678] Intermediate DF

[0679]

[0680] A mixture of tert-butyl 5-bromo-3-iodo-pyrrolo[2,3-b]pyridine-1-carboxylate (120 mg, 0.28 mmol, 1 equiv), (2-cyanophenyl)boronic acid (83 mg, 0.57 mmol, 2 equiv), Pd(dppf)Cl2 (21 mg, 0.03 mmol, 0.1 equiv), NaHCO3 (71 mg, 0.85 mmol) in DMF (2 mL) was degassed with nitrogen and then stirred at 80 °C for 3 h. After this time, the mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL × 3). The organic phase was concentrated and the residue was purified by preparative TLC (SiO2, 15% petroleum ether / ethyl acetate) to afford 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; 11H NMR (400 MHz, CDCl3) δ = 8.62 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 8.03 (s, 1H), 7.84 (dd, J = 1.2, 8.0 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.52 (dt, J = 1.2, 7.6 Hz, 1H), 1.70 (s, 9H).

[0681] Intermediate DG

[0682]

[0683] Step 1: A mixture of 6-bromo-7-methoxy-quinoline (100 mg, 0.420 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (105 mg, 0.504 mmol, 1.20 equiv), Pd(dtbpf)Cl2 (27 mg, 0.042 mmol, 0.10 equiv) and sodium carbonate (89 mg, 0.840 mmol, 2.00 equiv) in dioxane (1.0 mL) and water (0.2 mL) was degassed with nitrogen. The mixture was then stirred at 80 °C for 2 h, concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO2, ethyl acetate) to afford 7-methoxy-6-(2-methylpyrazol-3-yl)quinoline (80 mg, 0.334 mmol, 80% yield) as a yellow solid. LCMS [M+1] + = 240.2; 1 1H NMR (400 MHz, CDCl3) δ = 8.82 (dd, J = 1.6, 4.4 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.48 (s, 1H), 7.27 (dd, J = 4.4, 8.0 Hz, 1H), 6.28 (d, J = 1.6 Hz, 1H), 3.91 (s, 3H), 3.70 (s, 3H).

[0684] Step 2: A mixture of 7-methoxy-6-(2-methylpyrazol-3-yl)quinoline (500 mg, 2.09 mmol, 1.00 equiv) and pyridine hydrochloride (2.41 g, 20.9 mmol, 10.0 equiv) was stirred at 160 °C for 0.5 h. After this time, the residue was purified by reverse preparative HPLC (0.1% formic acid) to afford 6-(2-methylpyrazol-3-yl)quinolin-7-ol (260 mg, 1.07 mmol, 51% yield, 92% purity) as a yellow solid. LCMS [M+1]+ = 226.1。

[0685] Step 3: At 0 °C, trifluoromethanesulfonic anhydride (0.29 mL, 1.73 mmol, 1.50 equiv) was added dropwise to a solution of 6-(2-methylpyrazol-3-yl)quinolin-7-ol (260 mg, 1.15 mmol, 1.00 equiv) and triethylamine (0.32 mL, 2.31 mmol, 2.00 equiv) in dichloromethane (5 mL). The mixture was stirred at 20 °C for 1 h, 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 was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10 - 100%) to afford [6-(2-methylpyrazol-3-yl)-7-quinolinyl] trifluoromethanesulfonate (0.97 g, 0.706 mmol, 61%) as a yellow oil. LCMS [M+1] + = 358.1。

[0686] Step 4: A mixture of [6-(2-methylpyrazol-3-yl)-7-quinolinyl] trifluoromethanesulfonate (970 mg, 0.668 mmol, 1.00 equiv), zinc cyanide (157 mg, 1.34 mmol, 2.00 equiv), Pd2(dba)3 (61 mg, 0.67 mmol, 0.1 equiv), DPPF (74 mg, 0.134 mmol, 0.20 equiv), and zinc powder (4.3 mg, 0.67 mmol, 0.10 equiv) in DMF (10 mL) was degassed with nitrogen and then stirred at 100 °C for 2 h. After this 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 was purified by HPLC (0.1% formic acid conditions) to afford 6-(2-methylpyrazol-3-yl)quinoline-7-carbonitrile (100 mg, 0.249 mmol, 37% yield) as a brown solid. LCMS [M+1] + = 235.2。

[0687] Step 5: To a solution of 6-(2-methylpyrazol-3-yl)quinoline-7-carbonitrile (90 mg, 0.384 mmol, 1.00 equiv) in acetonitrile (5 mL) was added N-bromosuccinimide (103 mg, 0.576 mmol, 1.50 equiv). The mixture was stirred at 20 °C for 0.5 h, then concentrated under reduced pressure, and the residue was purified by preparative TLC (dichloromethane / methanol 10%) to afford 6-(4-bromo-2-methyl-pyrazol-3-yl)quinoline-7-carbonitrile (50 mg, 0.160 mmol, 41% yield) as a yellow solid. LCMS [M+1] + = 315.1; 1 H NMR (400 MHz, CDCl3) δ = 9.14 (dd, J = 1.6, 4.4 Hz, 1H), 8.68 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.69 - 7.65 (m, 1H), 7.65 (s, 1H), 3.86 (s, 3H).

[0688] Intermediate DH

[0689]

[0690] Step 1: A mixture of 6-bromo-7-methoxy-quinoline (100 mg, 0.420 mmol, 1.00 equiv), zinc cyanide (98 mg, 0.840 mmol, 2.00 equiv), Pd2(dba)3 (38 mg, 0.042 mmol, 0.10 equiv), DPPF (47 mg, 0.084 mmol, 0.20 equiv) and zinc powder (2.8 mg, 0.042 mmol, 0.10 equiv) in DMF (2 mL) was degassed and purged with nitrogen. Then the mixture was stirred at 100 °C for 2 h, then diluted with water (2 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic extracts were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by HPLC (0.1% formic acid) to afford 7-methoxyquinoline-6-carbonitrile (56 mg, 0.304 mmol, 72% yield) as a white solid. LCMS [M+1] + = 185.2; 1 H NMR (400 MHz, CDCl3) δ = 8.97 (dd, J = 1.6, 4.0 Hz, 1H), 8.17 (s, 1H), 8.15 (dd, J = 1.2, 8.4 Hz, 1H), 7.53 (s, 1H), 7.40 (dd, J = 4.0, 8.4 Hz, 1H), 4.09 (s, 3H).

[0691] Step 2: Aluminum trichloride (3.04 g, 22.8 mmol, 1.25 mL, 3.00 eq) was added to a solution of 7-methoxyquinoline-6-carbonitrile (1.40 g, 7.60 mmol, 1.00 eq) in toluene (20 mL). The mixture was stirred at 100 °C for 1 h, then the reaction mixture was diluted with water (3 mL) and the pH was adjusted to 4 - 5 with sodium hydroxide (2N, 0.1 mL). The solid formed was filtered and dried under reduced pressure to give 7-hydroxyquinoline-6-carbonitrile (1.20 g, crude) as a black solid, which was used directly in the next step without further purification. LCMS [M+1] + = 171.1.

[0692] Step 3: At 0 °C, trifluoromethanesulfonic anhydride (0.73 mL, 4.41 mmol, 1.50 eq) was added dropwise 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). The mixture was stirred at 20 °C for 1 h and after this 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-quinolinyl) trifluoromethanesulfonate (250 mg, 0.570 mmol, 19% yield) as a yellow oil. LCMS [M+1] + = 303.0; 1 1H NMR (400 MHz, CDCl3) δ = 9.15 (dd, J = 1.6, 4.0 Hz, 1H), 8.37 (s, 1H), 8.32 - 8.30 (d, J = 8.4 Hz 1H), 8.23 (s, 1H), 7.65 (dd, J = 4.0, 8.4 Hz, 1H).

[0693] Step 4: A mixture of (6-cyano-7-quinolyl) trifluoromethanesulfonate (237 mg, 0.541 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (135 mg, 0.649 mmol, 1.20 equiv), sodium bicarbonate (91 mg, 1.08 mmol, 2.00 equiv) and Pd(dtbpf)Cl2 (35 mg, 0.054 mmol, 0.10 equiv) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and stirred at 80 °C for 1 h. After this time, the mixture was concentrated and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10 - 100%) to afford 7-(2-methylpyrazol-3-yl)quinoline-6-carbonitrile (120 mg, 0.498 mmol, 92% yield) as a yellow solid. LCMS [M+1] + = 235.2.

[0694] Step 5: A mixture of 7-(2-methylpyrazol-3-yl)quinoline-6-carbonitrile (120 mg, 0.512 mmol, 1.00 equiv) and N-bromosuccinimide (164 mg, 0.922 mmol, 1.80 equiv) in acetonitrile (4 mL) was degassed with nitrogen and stirred at 20 °C for 2 h. After this time, the mixture was concentrated and the residue was purified by preparative TLC (SiO2, dichloromethane / methanol 10%) to afford 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; 1 1H NMR (400 MHz, CDCl3) δ = 9.15 (dd, J = 2.0, 4.4 Hz, 1H), 8.43 (s, 1H), 8.33 (dd, J = 0.8, 8.4 Hz, 1H), 8.23 (s, 1H), 7.68 - 7.63 (m, 2H), 3.87 (s, 3H).

[0695] Intermediate DI

[0696]

[0697] To a solution of N-(4-bromo-2-methyl-pyrazol-3-yl)benzamide (500 mg, 1.78 mmol, 1.00 equiv) in DMF (5 mL) at 0 °C was added sodium hydride (143 mg, 3.57 mmol, 60.0% purity, 2.00 equiv) and the mixture was stirred at 0 °C for 30 minutes. After this time, iodomethane (0.133 mL, 2.14 mmol, 1.20 equiv) in DMF (1 mL) was added and the mixture was stirred at 0 °C for an additional 10 minutes. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 3), and the combined organic extracts were washed with brine (70 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 0 - 30%) to afford N-(4-bromo-2-methyl-pyrazol-3-yl)-N-methyl-benzamide (400 mg, 1.36 mmol, 76% yield) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 7.44 (s, 1H), 7.36 - 7.41 (m, 1H), 7.26 - 7.33 (m, 4H), 3.72 (s, 3H), 3.23 (s, 3H).

[0698] Intermediate DJ

[0699]

[0700] Step 1: To a stirred solution of methyl 7-bromo-4-oxo-3H-phthalazine-1-carboxylate (1.00 g, 3.53 mmol, 1.00 equiv) and sodium borohydride (347 mg, 9.18 mmol, 2.60 equiv) in methanol-d4 (30 mL) at 0 °C was added calcium chloride (470 mg, 4.24 mmol, 1.20 equiv). The mixture was then stirred at 0 °C for 3 hours and then at 20 °C for 1 hour. After this time, the reaction mixture was concentrated. The residue was diluted with water (30 mL), the pH was adjusted to 5 with hydrochloric acid (1 N, 5 mL) and the mixture was filtered, and the filter cake was washed with water (5 mL × 3) and then triturated with ethanol (20 mL) to afford 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; 11H NMR (400 MHz, DMSO-d6) δ = 12.66 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.02 (dd, J = 2.0, 8.4 Hz, 1H), 5.53 (s, 1H).

[0701] Step 2: A mixture of 6-bromo-4-((hydroxy-d)methyl-d2)phthalazin-1(2H)-one (463 mg, 1.61 mmol, 1.00 equiv) and thionyl chloride (10 mL) was stirred at 30 °C for 12 h. After this time, the mixture was concentrated and the residue was dissolved in dichloromethane and concentrated 3 times (2 mL × 3) to afford 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.

[0702] Step 3: To a solution of 6-bromo-4-(chloromethyl-d2)phthalazin-1(2H)-one (450 mg, 1.63 mmol, 1.00 equiv) in DMF (3 mL) was added potassium (1,3-dioxoisoindolin-2-yl) (454 mg, 2.45 mmol, 1.50 equiv) and the mixture was stirred at 90 °C for 2 h. After this time, the cooled reaction mixture was filtered and the collected solid was triturated with ethanol (5 mL), filtered and dried to afford 2-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl-d2)isoindoline-1,3-dione (300 mg, crude) as a white solid. LCMS [M+1] + = 386.0; 1 1H NMR (400 MHz, DMSO-d6) δ = 12.60 (s, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.09 - 8.05 (m, 1H), 7.97 - 7.92 (m, 2H), 7.92 - 7.87 (m, 2H).

[0703] 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 h and after this time the mixture was concentrated and the residue was triturated with methanol (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; 1 1H NMR (400 MHz, DMSO-d6) δ = 12.70 - 12.28 (m, 1H), 8.35 - 8.25 (m, 2H), 8.13 (br s, 1H), 7.93 (brd, J = 17.0 Hz, 4H), 1.34 (br s, 12H).

[0704] Intermediate DK

[0705]

[0706] Step 1: To a solution of K2CO3 (44.7 g, 323 mmol) in water (500 mL) was added 1-(5-bromo-3-chloro-2-methylphenyl)ethan-1-one (40.0 g, 162 mmol) and the mixture was heated to 50 °C. Then KMnO4 was carefully added in 10 portions (165 g, 1.04 mol) while maintaining the temperature below 80 °C to avoid uncontrolled exotherm. After the addition was complete, the mixture was stirred at 60 °C for 6 h. After this time, the mixture was cooled to 0 °C and quenched by dropwise addition of saturated sodium sulfite solution (200 mL) while maintaining the temperature below 10 °C. Then, the mixture was stirred at 0 °C for 30 min. After this time, the clear colorless mixture was filtered through diatomaceous earth and the filter cake was washed with water (100 mL) and the aqueous phase was washed with MTBE (200 mL). The aqueous phase was then acidified to pH 2 by addition of 3M HCl and then extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 4-bromo-2-(carboxycarbonyl)-6-chlorobenzoic acid as a white solid (20.0 g, 65.0 mmol, 36% yield). LCMS [M-1] - = 306.8; 1 H NMR (400 MHz, DMSO-d6) δ 12.7 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H).

[0707] Step 2: Under N2, to a solution of 4-bromo-2-(carboxycarbonyl)-6-chlorobenzoic acid (20.0 g, 65.0 mmol) in EtOH (200 mL) was added a portion of NH2NH2·H2O (4.30 g, 85.9 mmol). The mixture was then stirred at 70 °C for 1 h. After this time, the cooled reaction mixture was filtered, washed and the solid was dried in vacuo to afford 7-bromo-5-chloro-4-oxo-3,4-dihydrophtalazine-1-carboxylic acid as a white solid (14.0 g, 46.1 mmol, 71% yield). LCMS [M+1] + = 305.2; 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H).

[0708] Step 3: Under nitrogen, a portion of concentrated H2SO4 (9.23 g, 92.2 mmol) was added 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). The mixture was then heated to 70 °C for 16 hours, then allowed to cool to ambient temperature, filtered, and dried to afford methyl 7-bromo-5-chloro-4-oxo-3,4-dihydrophthalazine-1-carboxylate (7.50 g, 23.6 mmol, 51% yield) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 13.2 (s, 1H), 6.68 (d, J = 1.6 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H).

[0709] Step 4: At 0 °C, NaBH4 (2.32 g, 61.4 mmol) was added to a solution of methyl 7-bromo-5-chloro-4-oxo-3,4-dihydrophthalazine-1-carboxylate (7.50 g, 23.6 mmol) in EtOH (70 mL), and then CaCl2 (3.15 g, 28.3 mmol) was carefully added dropwise over 2 hours at 0 °C. The mixture was then allowed to warm to 15 °C and stirred for an additional 2 hours. After this time, the reaction was poured onto saturated NH4Cl (100 mL), and the solid was filtered, washed with water (10 mL), then with EtOH (10 mL), and dried to afford 6-bromo-8-chloro-4-(hydroxymethyl)phthalazin-1(2H)-one (4.00 g, 13.8 mmol, 54% yield) as a white solid. LCMS [M+1] + = 291.0; 1 1H NMR (400 MHz, DMSO-d6) δ 12.6 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 5.61 - 5.58 (t, J = 2 Hz, 1H), 4.65 - 4.63 (d, J = 8 Hz, 2H).

[0710] 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 hour. After this time, the mixture was concentrated, and the crude residue was triturated with MTBE (30 mL) at 25 °C for 30 minutes. The solid was then filtered and dried to afford 6-bromo-8-chloro-4-(chloromethyl)phthalazin-1(2H)-one (3.50 g, 11.4 mmol, 82% yield) as a pale yellow solid. LCMS [M+1] + = 309.1;1 1H NMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 5.06 (s, 1H).

[0711] Step 6: At 0 °C, a solution of 6-bromo-8-chloro-4-(chloromethyl)phthalazin-1(2H)-one (3.50 g, 11.3 mmol) in DMF (35 mL) was added to a mixture of potassium phthalimide (2.53 g, 13.6 mmol) in DMF (5 mL), and the mixture was stirred at 0 °C for 2 h. After this time, the mixture was poured onto ice water (200 mL), stirred for 30 min, filtered, and 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 a pale yellow solid. LCMS [M+1] + = 420.0; 1 1H NMR (400 MHz, DMSO-d6) δ 12.5 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7.97 - 7.94 (m, 2H), 7.92 - 7.89 (m, 2H), 5.14 (s, 2H).

[0712] 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 was stirred at 70 °C for 2.5 h. After this time, the mixture was cooled to room temperature, filtered, and the concentrated residue was triturated with MeOH (30.0 mL) at 15 °C for 30 min. The solid was then filtered, washed with MTB and dried to give 2-((5-chloro-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (910 mg, 1.95 mmol, 63% yield) as a pale yellow solid. LCMS [M+1] + = 383.9; 1HNMR(400MHz, DMSO-d6) δ 12.5(s, 1H), 8.20(s, 1H), 7.79(s, 1H), 7.96 - 7.94(m, 2H), 7.91 - 7.89(m, 2H), 5.17(s, 2H), 1.35(s, 12H).

[0713] Intermediate DL

[0714]

[0715] Following the same procedure used 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-dihydrophtalazin-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; 1 H NMR(400MHz, DMSO-d6) δ = 12..51(s, 1H), 8.09(s, 1H), 7.96–7.89(m, 4H), 7.40(d, 1H), 5.17(s, 2H), 1.36(s, 12H).

[0716] Intermediate DM

[0717]

[0718] Step 1: At 20 °C, 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), and then N,O-dimethylhydroxylamine (55.9 g, 573 mmol, HCl). The resulting solution was stirred at 20 °C for 2 h, and after this 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 phases were washed with brine (1.0 L), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness under reduced pressure to afford 5-bromo-N-methoxy-N,2-dimethyl-3-pivalamidobenzamide as a brown oil (135 g, 378 mmol, 99% yield). 1HNMR: 400 MHz, DMSO-d6 δ 9.06 (s, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 3.43 (s, 3H), 3.27 (s, 3H), 2.01 (s, 3H), 1.23 (s, 9H).

[0719] Step 2: At 0 °C, MeMgBr (3.0 M, 315 mL) was added to a solution of 5-bromo-N-methoxy-N,2-dimethyl-3-pivalamidobenzamide (135 g, 378 mmol) in THF (1.5 L). The resulting solution was allowed to warm to 20 °C and stirred for 12 h. After this time, an additional portion of MeMgBr (3 M, 63.0 mL) was added and the mixture was stirred for an additional 4 h. 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 over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford N-(3-acetyl-5-bromo-2-methylphenyl)pivalamide (115 g, 368 mmol, 98% yield) as a yellow solid. 1 H NMR 400 MHz, DMSO-d6 δ 9.10 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 2.55 (s, 3H), 2.10 (s, 3H), 1.23 (s, 9H).

[0720] Step 3: At 50 °C, K2CO3 (50.9 g, 368 mmol) and KMnO4 (204 g, 1.29 mol) were added to a solution of N-(3-acetyl-5-bromo-2-methylphenyl)pivalamide (57.5 g, 184 mmol) in H2O (600 mL). The resulting solution was stirred at 50 °C for 17 h. After this time, the reaction mixture was quenched with saturated sodium thiosulfate solution and filtered through diatomaceous earth. The pH was adjusted to 2 with 2N HCl and the mixture was extracted with 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 afford 4-bromo-2-(carboxycarbonyl)-6-pivalamidobenzoic acid (58.0 g, crude) as a pale yellow oil. 1 H NMR 400 MHz, DMSO-d6 δ 9.87 (s, 1H), 8.63 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 1.27 (s, 9H).

[0721] Step 4: To a solution of 4-bromo-2-(carboxycarbonyl)-6-pivalamidobenzoic acid (110 g, 296 mmol) in EtOH (1.10 L) was added NH2NH 2· H2O (18.1 g, 355 mmol, 17.6 mL), and the solution was stirred at 75 °C for 3 h. After this time, the reaction mixture was filtered and the cake was dried to afford 7-bromo-4-oxo-5-pivalamido-3,4-dihydrophtalazine-1-carboxylic acid (30.0 g, 81.5 mmol, 28% yield) as a white solid. 1 1H NMR 400 MHz, DMSO-d6 δ 13.0 (s, 1H), 9.06 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 1.27 (s, 9H).

[0722] Step 5: To a solution of 7-bromo-4-oxo-5-pivalamido-3,4-dihydrophtalazine-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 heated to 70 °C and stirred for 36 h to form a yellow solid. The reaction was concentrated, diluted with water (100 mL), and the pH was adjusted to pH 8 with 1 N NaOH, stirred for 0.5 h, then filtered. The cake was washed with water (50 mL) then with EtOH (100 mL) and dried to afford the crude product methyl 5-amino-7-bromo-4-oxo-3,4-dihydrophtalazine-1-carboxylate (20.0 g, crude) as a yellow solid.

[0723] Step 6: At 0 °C under N2, to a solution of methyl 5-amino-7-bromo-4-oxo-3,4-dihydrophtalazine-1-carboxylate (15.0 g, 50.3 mmol) in MeCN (500 mL) was added TosOH (34.6 g, 200 mmol). 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 min, then a solution of KI (25.0 g, 150 mmol) in H2O (20.0 mL) was added dropwise. The mixture was stirred at 20 °C for 1 h and the reaction was quenched with Na2S2O3. The mixture was concentrated to remove MeCN, then diluted with water (200 mL) and filtered. The cake was washed with water (50 mL) then with EtOH (100 mL) and dried to afford methyl 7-bromo-5-iodo-4-oxo-3,4-dihydrophtalazine-1-carboxylate (15.0 g, crude) as a yellow solid.

[0724] Step 7: In 8 batches, a solution of methyl 7-bromo-5-iodo-4-oxo-3,4-dihydrophtalazine-1-carboxylate (4.00 g, 9.78 mmol) in EtOH (60 mL) was added portionwise to NaBH4 (740 mg, 19.6 mmol) at 0 °C, and then CaCl2 (1.30 g, 11.7 mmol) was added portionwise at 0 °C. The reaction was stirred at 20 °C for 1 hour. Then the 8 batches were combined and quenched with NH4Cl (200 mL). The mixture was concentrated to remove EtOH, diluted with water (200 mL), then filtered, and the filter cake was washed with water (100 mL) and dried. The residue was triturated in MeOH (200 mL) for 10 hours, filtered and dried to afford 6-bromo-4-(hydroxymethyl)-8-iodophthalazin-1(2H)-one (19.0 g, 38.9 mmol, 50% yield) as a yellow solid. 1 1H NMR 400 MHz, DMSO-d6 δ 12.64 (s, 1H), 8.56 (d, J = 1.88 Hz, 1H), 8.29 (d, J = 1.88 Hz, 1H), 5.62 - 5.54 (m, 1H), 4.62 (d, J = 5.70 Hz, 2H).

[0725] Step 8: In three batches, a solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, Cs2CO3 (4.28 g, 13.1 mmol) and Pd(dppf)Cl2 (384 mg, 524 mmol) in THF (3.67 mL, 13.1 mmol, 50% purity) was added to a mixture of 6-bromo-4-(hydroxymethyl)-8-iodophthalazin-1(2H)-one (2.00 g, 5.25 mmol) in dioxane (40 mL). The reaction was stirred at 100 °C for 10 hours. The three batches were combined and filtered through Celite. The filtrate was concentrated and the residue was purified by preparative HPLC (Phenomenex luna C18 250x150 mm x 15 μm; mobile phase: [water (0.1% TFA)-MeOH]; B%: 30% - 60%, 20 minutes) to afford 6-bromo-4-(hydroxymethyl)-8-methylphthalazin-1(2H)-one (1.1 g, 4.06 mmol, 26% yield) as a pale yellow solid. LCMS [M+1] + = 271; 1 1H NMR 400 MHz, DMSO-d6 δ 12.44 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 4.63 (s, 3H), 2.81 (s, 3H).

[0726] Step 9: At 70 °C, a solution of 6-bromo-4-(hydroxymethyl)-8-methylphthalazin-1(2H)-one (1.20 g, 4.46 mmol) in SOCl2 (13 mL) was stirred for 2 h. After this time, the mixture was concentrated and the residue was triturated in petroleum ether for 0.5 h, filtered and dried to afford 6-bromo-4-(chloromethyl)-8-methylphthalazin-1(2H)-one (1.20 g, 4.17 mmol, 94% yield) as a pale yellow solid. LCMS [M+1] + = 289; 1 H NMR 400 MHz, DMSO-d6 δ 12.70 (s, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 5.03 (s, 2H), 2.81 (s, 3H).

[0727] Step 10: Under N2 at 0 °C, a portion of potassium phthalimide (850 mg, 4.59 mmol) was added to a mixture of the obtained 6-bromo-4-(chloromethyl)-8-methylphthalazin-1(2H)-one (1.10 g, 3.83 mmol) in DMF (30 mL). The mixture was stirred at 25 °C for 1 h and after this time, the mixture was slowly poured into ice water (100 mL) and the formed white solid was filtered, washed with water and dried to afford the crude product 2-((7-bromo-5-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)isoindoline-1,3-dione (1.10 g, 2.32 mmol, 61% yield) as a white solid. LCMS [M+1] + = 400; 1 H NMR 400 MHz, DMSO-d6 δ 12.37 (s, 1H), 8.20 (d, J = 1.32 Hz, 1H), 7.97 - 7.87 (m, 5H), 5.12 (s, 2H), 2.81 (s, 3H).

[0728] Step 11: 2-((7-Bromo-5-methyl-4-oxo-3,4-dihydrophtalazin-1-yl)methyl)isoindoline-1,3-dione (1.10 g, 2.76 mmol), Pd(dppf)Cl2 (202 mg, 276 μmol), KOAc (542 mg, 5.52 mmol) and bis(pinacolato)diboron (1.05 g, 4.14 mmol) in dioxane were degassed with nitrogen and then heated at 80 °C for 10 h. After this time, the reaction was filtered through Celite and the filter cake was washed with MeOH (10 mL), and the filtrate was concentrated. The residue was triturated with MeOH (10 mL) for 1 h, filtered and the filter cake was washed with MeOH and dried to give 2-((5-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophtalazin-1-yl)methyl)isoindoline-1,3-dione, Intermediate DM (510 mg, 1.15 mmol, 42% yield) as a grey solid. LCMS: Boric acid [M+1] + = 364; Boronate ester [M+1] + = 446). 1 H NMR 400 MHz, DMSO-d6 δ 12.27 (s, 1H), 8.06 (s, 1H), 7.92 - 7.82 (m, 5H), 5.11 (s, 2H), 2.80 (s, 3H), 1.31 (s, 12H).

[0729] Intermediate DN

[0730]

[0731] Step 1: To a solution of 5-(chloromethyl)-1-methyl-pyrazole (584 mg, 3.50 mmol, 1.00 equiv) and 2-phenylacetonitrile (819 mg, 6.99 mmol, 2.00 equiv) in DMF (10 mL) was added potassium carbonate (966 mg, 6.99 mmol, 2.00 equiv). The mixture was stirred at 120 °C for 4 h and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10 - 50%) to 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; 1HNMR(400MHz,CDCl3)δ=7.35 - 7.22(m,4H),7.18 - 7.10(m,2H),6.11(d,J=1.6Hz,1H),3.98(t,J=6.8Hz,1H),3.41(s,3H),3.26 - 3.18(m,1H),3.16 - 3.05(m,1H).

[0732] Step 2: To a mixture of 3-(2-methylpyrazol-3-yl)-2-phenyl-propanenitrile (160 mg, 0.76 mmol, 1.00 equiv) in dry acetonitrile (2.0 mL) was added portions of NBS (121 mg, 0.68 mmol, 0.90 equiv). The mixture was stirred at 15 °C for 2 h. After this time, ethyl acetate (40 mL) and water (40 mL) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2) and the combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to afford 3-(4-bromo-2-methyl-pyrazol-3-yl)-2-phenyl-propanenitrile (90.0 mg, 0.31 mmol, 41% yield) as a yellow oil. LCMS [M+1] + = 289.8; 1 H NMR(400MHz,CDCl3)δ=7.37(s,1H),7.35 - 7.26(m,3H),7.20 - 7.14(m,2H),4.04(t,J=7.6Hz,1H),3.40(s,3H),3.30(dd,J=7.2,14.8Hz,1H),3.07(dd,J=8.0,14.8Hz,1H).

[0733] Intermediate DO

[0734]

[0735] Step 1: n-Butyllithium (2.5 M in hexanes, 959 μL, 1.50 equiv) was added dropwise over 5 min to a solution of 2,2,6,6-tetramethylpiperidine (2.40 mmol, 407 μL, 1.50 equiv) in THF (3 mL) maintained at 0 °C. After 30 min, the reaction mixture was cooled to -78 °C and a solution of 5-chloronaphthalene-1-carbonitrile (300 mg, 1.60 mmol, 1.00 equiv) in THF (1.00 mL) was added dropwise over 10 min. The resulting dark solution was maintained at -78 °C for 2 h. Then a solution of iodine (609 mg, 2.40 mmol, 1.50 equiv) in THF (3 mL) was added dropwise over 10 min. The reaction mixture was maintained at -78 °C for 2 h and then allowed to warm to 20 °C for 3 h. The reaction mixture was quenched with water (1 mL) and the resulting mixture was diluted with ethyl acetate (150 mL). The mixture was washed successively with saturated aqueous sodium thiosulfate (3 × 150 mL), 1 M HCl (2 × 150 mL), and brine (1 × 150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 5%) to afford 5-chloro-2-iodo-1-naphthonitrile (180 mg, 574 μmol, 36% yield) as a yellow solid. GCMS [M+H] + = 312.9; 1 1H NMR (400 MHz, CDCl3) δ = 8.55 (d, J = 8.8 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.73 - 7.69 (m, 1H), 7.67 - 7.64 (m, 1H), 7.63 - 7.58 (m, 1H).

[0736] Step 2: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (104 mg, 498 μmol, 1.30 equiv), 5-chloro-2-iodo-1-naphthonitrile (120 mg, 383 μmol, 1.00 equiv), Pd(dtbpf)Cl2 (25 mg, 38 μmol, 0.10 equiv), and sodium carbonate (81 mg, 766 μmol, 2.00 equiv) in dioxane (3 mL) and water (0.6 mL) was degassed with nitrogen and then stirred at 80 °C for 1 h. The mixture was then concentrated and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 30%) to afford 5-chloro-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (90 mg, 336 μmol, 87% yield) as a yellow solid. LCMS [M+1] + = 268.2; 11H NMR (400 MHz, CDCl3) δ = 8.62 (d, J = 8.8 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.73 - 7.67 (m, 1H), 7.67 - 7.63 (m, 2H), 6.61 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H).

[0737] Step 3: To a solution of 5-chloro-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (170 mg, 635 μmol, 1.00 equiv) in acetonitrile (3 mL) was added NBS (124 mg, 699 μmol, 1.10 equiv). The mixture was stirred at 35 °C for 2 h and then concentrated to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate 30%) to afford 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-1-naphthonitrile, Intermediate DO (130 mg, 375 μmol, 59% yield). LCMS [M+1] + = 347.8; 1 1H NMR (400 MHz, CDCl3) δ = 8.67 (dd, J = 0.8, 8.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 1.2, 7.6 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.66 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H).

[0738] Intermediate DP

[0739]

[0740] Step 1: At -10 °C under a nitrogen atmosphere, n-butyllithium (2.50 M, 1.57 mL, 1.20 equiv) was added to a solution of 2,2,6,6-tetramethylpiperidine (553 mg, 3.92 mmol, 0.67 mL, 1.20 equiv) in THF (7 mL). The mixture was stirred for 10 minutes, cooled to -65 °C, and triisopropyl borate (859 mg, 4.57 mmol, 1.05 mL, 1.40 equiv) was added. After 5 minutes, a solution of 1-naphthonitrile (500 mg, 3.26 mmol, 1.00 equiv) in THF (3 mL) was added dropwise, and then the reaction was allowed to warm slowly to 25 °C and then stirred for 16 hours. After this time, acetic acid (392 mg, 6.53 mmol, 0.37 mL, 2.00 equiv) was added, then propane-1,3-diol (994 mg, 13.1 mmol, 0.95 mL, 4.00 equiv) was added, and then the mixture was stirred at 25 °C for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride solution (20 mL), 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-dioxaborolan-2-yl)-1-naphthonitrile (600 mg, 2.53 mmol, 78% yield) as a pale yellow solid. 1 HNMR (400 MHz, CDCl3) δ = 8.40 (d, J = 8.0 Hz, 1H), 8.04 - 8.00 (m, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.71 - 7.60 (m, 2H), 4.30 (t, J = 5.6 Hz, 4H), 2.17 (quin, J = 5.6 Hz, 2H).

[0741] Step 2: At 20 °C under a nitrogen atmosphere, an aqueous solution of potassium carbonate (2.00 M, 0.915 mL, 2.00 equiv) and Pd(PPh3)4 (106 mg, 0.091 mmol, 0.10 equiv) were added to a solution of 5-bromoisothiazole (150 mg, 0.915 mmol, 1.00 equiv) and 2-(1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (217 mg, 0.915 mmol, 1.00 equiv) in toluene (8 mL) and ethanol (0.8 mL). 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 pale yellow solid. 11H NMR (400 MHz, CDCl3) δ = 8.62 (d, J = 1.6 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.79 (dt, J = 1.2, 7.6 Hz, 1H), 7.74 - 7.66 (m, 2H).

[0742] Step 3: At 20 °C, N-bromosuccinimide (753 mg, 4.23 mmol, 10.0 equiv) was added to a solution of 2-(isothiazol-5-yl)-1-naphthonitrile (100 mg, 0.42 mmol, 1.00 equiv) in acetonitrile (2 mL), and the mixture was stirred in a sealed tube at 100 °C for 48 h. The mixture was then concentrated under reduced pressure, and the residue was 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 preparative HPLC (Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 45% - 75%, 8 min) to afford 2-(4-bromoisothiazol-5-yl)-1-naphthonitrile (50 mg, 0.16 mmol, 38% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 8.51 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.81 (dt, J = 1.2, 7.6 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H).

[0743] Intermediate DQ

[0744]

[0745] Step 1: At -78 °C, a solution of 4-chloro-2-naphthonitrile (200 mg, 1.07 mmol, 1.00 equiv) in THF (5 mL) was added dropwise to a solution of LDA (2.00 M, 0.587 mL, 1.10 equiv) in THF (10 mL). The mixture was then stirred at -78 °C for 1 h. After this time, a solution of iodine (285 mg, 1.12 mmol, 1.05 equiv) in THF (2 mL) was added dropwise at -78 °C. The mixture was then allowed to warm to room temperature and stirred at 20 °C for 2 h. After this time, the reaction mixture was quenched by the addition of saturated ammonium chloride solution (15 mL) and saturated sodium dithionite solution (10 mL × 3). The mixture was then extracted with ethyl acetate (20 mL × 2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by flash chromatography (SiO2, petroleum ether: ethyl acetate 0 - 5%) to afford 4-chloro-3-iodo-2-naphthonitrile (200 mg, 0.606 mmol, 30% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 8.35 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 7.93 - 7.87 (m, 1H), 7.77 (ddd, J = 1.2, 7.2, 8.4 Hz, 1H), 7.72 - 7.65 (m, 1H).

[0746] Step 2: At 25 °C, potassium carbonate (283 mg, 2.04 mmol, 2.00 equiv) and Pd(dppf)Cl2 (75 mg, 0.102 mmol, 0.10 equiv) were added to a solution of 4-chloro-3-iodo-2-naphthonitrile (320 mg, 1.02 mmol, 1.00 equiv) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (319 mg, 1.53 mmol, 1.50 equiv) in dioxane (30 mL) and water (6 mL). The mixture was degassed with nitrogen and then stirred at 100 °C for 16 h. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (30 mL × 4). The combined organic layers were washed with brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by flash chromatography (SiO2, petroleum ether: ethyl acetate 0 - 5%) to afford 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; 11H NMR (400 MHz, CDCl3) δ = 8.48 - 8.39 (m, 1H), 8.34 - 8.27 (m, 1H), 8.04 - 7.95 (m, 1H), 7.90 - 7.81 (m, 1H), 7.78 (br t, J = 7.6 Hz, 1H), 7.70 - 7.63 (m, 1H), 6.52 - 6.43 (m, 1H), 3.80 - 3.72 (m, 3H).

[0747] Step 3: At 25 °C, N-iodosuccinimide (504 mg, 2.24 mmol, 6.00 equiv) was added to a solution of 4-chloro-3-(1-methyl-1H-pyrazol-5-yl)-2-naphthonitrile (100 mg, 0.374 mmol, 1.00 equiv) in acetonitrile (10 mL), and the mixture was stirred at 80 °C for 16 h. After this 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 residue formed was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate 30%) to afford 4-chloro-3-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2-naphthonitrile (50 mg, 0.121 mmol, 32% yield) as a white solid. LCMS [M+1] + = 393.9 / 395.9; 1 1H NMR (400 MHz, CDCl3) δ = 8.46 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.92 - 7.86 (m, 1H), 7.84 - 7.79 (m, 1H), 7.71 (s, 1H), 3.81 (s, 3H).

[0748] Intermediate DR

[0749]

[0750] Step 1: A mixture of 4-chloro-2,5-difluorobenzonitrile (2.00 g, 11.5 mmol, 1.00 eq), N-bromosuccinimide (4.10 g, 23.1 mmol, 2.00 eq), palladium(II) acetate (259 mg, 1.15 mmol, 0.10 eq) and p-toluenesulfonic acid (992 mg, 5.76 mmol, 0.50 eq) in dichloroethane (50 mL) was degassed with nitrogen and then stirred at 75 °C for 12 h. After this 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 was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 0 - 3%) to give 2-bromo-4-chloro-3,6-difluorobenzonitrile (1.10 g, 4.36 mmol, 38% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 7.38 - 7.31 (m, 1H).

[0751] Step 2: A mixture of 2-bromo-4-chloro-3,6-difluorobenzonitrile (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 and then stirred at 75 °C for 2 h. After this time, the mixture was concentrated and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 7%) to give 2-bromo-4-chloro-6-(cyclopropoxy)-3-fluorobenzonitrile (600 mg, 2.07 mmol, 47% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 7.36 (d, J = 5.6 Hz, 1H), 3.88 - 3.79 (m, 1H), 0.91 (d, J = 4.8 Hz, 4H).

[0752] 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 solution (694 mg, 8.26 mmol, 0.321 mL, 4.00 eq), di-tert-butyl(cyclopentyl)phosphine; 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 h. After this time, the mixture was concentrated and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 5 - 20%) to afford 4-chloro-6-(cyclopropoxy)-3-fluoro-2-(2-methylpyrazol-3-yl)benzonitrile (180 mg, 0.524 mmol, 25% yield) as a yellow solid. LCMS [M+1] + = 292.1; 1 H NMR (400 MHz, CDCl3) δ = 7.62 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 6.0 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 3.92 - 3.85 (m, 1H), 3.81 (d, J = 1.2 Hz, 3H), 0.96 - 0.92 (m, 4H).

[0753] 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 under a nitrogen atmosphere for 2 h. After this time, the mixture was concentrated and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 20%) to afford 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; 1 H NMR (400 MHz, CDCl3) δ = 7.61 (s, 1H), 7.55 (d, J = 6.0 Hz, 1H), 3.93 - 3.85 (m, 1H), 3.80 (s, 4H), 0.97 - 0.94 (m, 4H).

[0754] Intermediate DS

[0755]

[0756] 2-(4-Bromo-2-methyl-pyrazol-3-yl)naphthalene-1-carbonitrile (150 mg, 0.48 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (134 mg, 0.528 mmol, 1.10 equiv), potassium acetate (141 mg, 1.44 mmol, 3.00 equiv) and di-tert-butyl(cyclopentyl)phosphine; dichloropalladium-iron (31.3 mg, 0.048 mmol, 0.10 equiv) in dioxane (3 mL) were degassed with nitrogen and then stirred at 80 °C for 2 h. After this time, the reaction mixture was concentrated under reduced pressure to afford 2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]naphthalene-1-carbonitrile (160 mg, crude) as a brown liquid, which was used in the next step without further purification. LCMS [M+1] + = 360.2.

[0757] Intermediate DT

[0758]

[0759] Step 1: At 0 °C, a solution of sodium hydroxide (466 mg, 11.6 mmol, 2.20 equiv) in water (1 mL) was added dropwise to 4-bromo-2-methyl-pyrazole-3-carbaldehyde (1.00 g, 5.29 mmol, 1.00 equiv) and nitromethane (420 mg, 6.88 mmol, 0.37 mL, 1.30 equiv) in methanol (10 mL). The reaction mixture was then stirred at 0 °C for 0.5 h. After this time, the reaction mixture was quenched by the addition of HCl (1.00 M, 5 mL), filtered, and the filtrate was concentrated under reduced pressure to afford 4-bromo-1-methyl-5-[(E)-2-nitrovinyl]pyrazole (627 mg, crude) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ = 8.10 (d, J = 13.6 Hz, 1H), 7.93 (d, J = 13.6 Hz, 1H), 7.57 (s, 1H), 4.03 (s, 3H).

[0760] Step 2: 2-Pyridin-1-ium-1-ylacetonitrile chloride (627 mg) and A suspension of MS (1.00 g, 0.215 mmol) was cooled to 0 °C, and then 2,6-dimethylpyridine (1.45 g, 13.5 mmol, 1.57 mL, 5.00 equiv) was added. After stirring for 15 minutes, 4-bromo-1-methyl-5-[(E)-2-nitrovinyl]pyrazole (627 mg, 2.70 mmol, 1.00 equiv) was added, and then copper(II) acetate (736 mg, 4.05 mmol, 1.50 equiv) was added. The mixture was then stirred at 0 °C for 15 minutes, then heated to 25 °C and stirred at 25 °C for 5 h. After this 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 afford 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; 1 H NMR (400 MHz, CDCl3) δ = 8.34 (d, J = 6.0 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.18 - 7.11 (m, 1H), 6.96 (dt, J = 1.2, 6.8 Hz, 1H), 6.62 (s, 1H), 3.91 (s, 3H).

[0761] Intermediate DU

[0762]

[0763] Step 1: A mixture of 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)quinoline-5-carbonitrile, Intermediate A-25 (120 mg, 0.38 mmol, 1.00 equiv), and N-iodosuccinimide (517 mg, 2.30 mmol, 6.00 equiv) in acetic acid (5 mL) was stirred at 80 °C under a nitrogen atmosphere for 48 h. The mixture was then concentrated, and saturated sodium sulfite solution (10 mL) was added to the residue. The mixture was then extracted with ethyl acetate (5 mL), and the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 50%) to afford 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; 11H NMR (400 MHz, CDCl3) δ = 9.26 (d, J = 2.0 Hz, 1H), 9.03 (dd, J = 0.8, 2.0 Hz, 1H), 8.43 (dd, J = 0.8, 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 3.87 (s, 3H).

[0764] Step 2: A mixture of 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-iodoquinoline-5-carbonitrile (35 mg, 0.080 mmol, 1.00 equiv), sodium methoxide (13 mg, 0.24 mmol, 3.00 equiv), and copper(I) iodide (1.5 mg, 0.008 mmol, 0.10 equiv) in methanol (1 mL) was degassed with nitrogen and then stirred at 105 °C for 16 h. After this time, the mixture was filtered and the filtrate was concentrated, and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 50%) to afford 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-methoxyquinoline-5-carbonitrile (12 mg, 0.035 mmol, 44% yield) as a white solid. LCMS [M+1] + = 345.1; 1 1H NMR (400 MHz, CDCl3) δ = 8.86 (d, J = 2.8 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 2.8 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 4.07 (s, 3H), 3.87 (s, 3H).

[0765] Intermediate DV

[0766]

[0767] A mixture of 6-(4-bromo-2-methyl-pyrazol-3-yl)-3-chloro-2-methyl-benzonitrile, Intermediate D-18 (400 mg, 1.29 mmol, 1.00 equiv) in THF (5 mL) was added to lithium diisopropylamide (2.00 M, 1.29 mL, 2.00 equiv) and stirred at -78 °C for 30 minutes. Then methyl iodide (5.15 mmol, 0.32 mL, 4.00 equiv) was added at -78 °C and the mixture was stirred for 2 hours. Then the reaction mixture was 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 preparative TLC (SiO2, petroleum ether: ethyl acetate 20%) to give 6-(4-bromo-2-methyl-pyrazol-3-yl)-3-chloro-2-ethyl-benzonitrile as a yellow oil (280 mg, 0.86 mmol, 67% yield). LCMS [M+1] + = 326.0; 1 H NMR (400 MHz, CDCl3) δ = 7.71 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.14 - 3.11 (m, 2H), 1.35 - 1.32 (m, 3H).

[0768] Intermediate DW

[0769]

[0770] Using Intermediate D-19 instead of Intermediate D-18, 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-ethylbenzonitrile was prepared as a white solid (30 mg, 0.074 mmol, 23%) using the same method as used for the preparation of Intermediate DV. LCMS [M+1] + = 419.2; 1 H NMR (400 MHz, DMSO-d6) δ = 12.88 (s, 1H), 8.38 (br s, 3H), 8.28 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.42 (dd, J = 1.6, 8.4 Hz, 1H), 4.39 - 4.22 (m, 2H), 3.75 (s, 3H), 2.83 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H).

[0771] Intermediate DX

[0772]

[0773] At 20 °C under a nitrogen atmosphere, a portion of sodium methoxide (449 mg, 8.32 mmol, 10.0 equiv) was added to a mixture of 2-(4-bromo-2-methyl-pyrazol-3-yl)-4-chloro-6-ethyl-benzonitrile, intermediate DW (270 mg, 0.83 mmol, 1.00 equiv) in methanol (2 mL). The mixture was stirred at 100 °C in a sealed tube for 2 h and a pale yellow solution was formed. The mixture was then concentrated and the residue was dissolved in ethyl acetate (10 mL) and water (5 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (5 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate 25%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)-6-ethyl-4-methoxy-benzonitrile (220 mg, about 70% purity) as a white solid. LCMS [M+1] + = 321.9; 1 H NMR (400 MHz, CDCl3) δ = 7.58 (s, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 2.97 - 2.92 (m, 2H), 1.37 - 1.34 (t, J = 6.8 Hz 3H).

[0774] Intermediate DY

[0775]

[0776] Step 1: A mixture of 2-bromo-5-methoxynaphthalen-1-ol (2.60 g, 10.3 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.21 g, 15.4 mmol, 1.50 equiv), di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (670 mg, 1.03 mmol, 0.10 equiv) and sodium carbonate (2.18 g, 20.6 mmol, 2.00 equiv) in dioxane (30 mL) and water (6 mL) was degassed with nitrogen and then stirred at 100 °C for 0.5 h. After this 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 afford 5-methoxy-2-(2-methylpyrazol-3-yl)naphthalen-1-ol (720 mg, 2.83 mmol, 28% yield) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 9.57 (s, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.33 (d, J = 1.6 Hz, 1H), 3.97 (s, 3H), 3.69 (s, 3H).

[0777] Step 2: Under nitrogen at -40 °C, trifluoromethanesulfonic anhydride (Tf2O) (3.83 mmol, 0.63 mL, 1.50 equiv) was added dropwise to a solution of 5-methoxy-2-(2-methylpyrazol-3-yl)naphthalen-1-ol (650 mg, 2.56 mmol, 1.00 equiv), molecular sieves (1.00 g) and triethylamine (7.67 mmol, 1.07 mL, 3.00 equiv) in dichloromethane (20 mL). The reaction mixture was stirred at -40 °C for 0.5 h, then concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 0 - 15%) to afford [5-methoxy-2-(2-methylpyrazol-3-yl)-1-naphthyl] trifluoromethanesulfonate (341 mg, 0.79 mmol, 30% yield) as a yellow oil. LCMS [M+1] + = 387.1; 11H NMR (400 MHz, CDCl3) δ = 8.40 (dd, J = 0.8, 8.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.45 (d, J = 2.0 Hz, 1H), 4.07 (s, 3H), 3.82 (s, 3H).

[0778] Step 3: A mixture of [5-methoxy-2-(2-methylpyrazol-3-yl)-1-naphthyl] trifluoromethanesulfonate (290 mg, 0.67 mmol, 1.00 equiv), zinc cyanide (0.81 mmol, 51.1 μL, 1.20 equiv), Pd2(dba)3 (612 mg, 0.067 mmol, 0.10 equiv), DPPF (74 mg, 0.134 mmol, 0.20 equiv) and zinc powder (4.4 mg, 0.067 mmol, 0.10 equiv) in DMF (10 mL) was degassed with nitrogen and then stirred at 120 °C for 1 h. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (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; 1 1H NMR (400 MHz, CDCl3) δ = 8.59 (dd, J = 0.8, 8.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.68 (t, J = 8.4 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 2.0 Hz, 1H), 4.07 (s, 3H), 3.89 (s, 3H).

[0779] Step 4: To a solution of 5-methoxy-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (180 mg, 0.68 mmol, 1.00 equiv) in acetonitrile (2 mL) was added N-bromosuccinimide (146 mg, 0.82 mmol, 1.20 equiv). The mixture was stirred at 35 °C for 0.5 h, then concentrated under reduced pressure, and the residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate 30%) to afford 2-(4-bromo-2-methyl-pyrazol-3-yl)-5-methoxy-naphthalene-1-carbonitrile (174 mg, 0.51 mmol, 74% yield) as an off-white solid. LCMS [M+1] + = 342.0; 1 H NMR (400 MHz, CDCl3) δ = 8.64 (dd, J = 0.8, 8.8 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 4.08 (s, 3H), 3.84 (s, 3H).

[0780] Intermediate DZ

[0781]

[0782] Intermediate DZ, 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-chloro-1-naphthonitrile was prepared as a yellow solid (25 mg, 0.072 mmol, 2% yield over 4 steps) starting from 2-bromo-4-chloro-naphthalen-1-ol according to the method described for the preparation of Intermediate DX. LCMS [M+1] + = 347.8; 1 H NMR (400 MHz, CDCl3-d) δ = 8.48 - 8.43 (m, 1H), 8.42 - 8.38 (m, 1H), 7.91 - 7.82 (m, 2H), 7.65 (d, J = 4.4 Hz, 2H), 3.88 (s, 3H).

[0783] Intermediate EA

[0784]

[0785] Step 1: A mixture of [4-chloro-2-(2-methylpyrazol-3-yl)-1-naphthyl] trifluoromethanesulfonate (38 mg, 0.097 mmol, 1.00 equiv), zinc cyanide (22 mg, 190 μmol, 12.4 μL, 2.00 equiv), DPPF (5.4 mg, 9.7 μmol, 0.10 equiv), zinc powder (640 μg, 9.7 μmol, 0.10 equiv), and Pd2(dba)3 (4.5 mg, 4.86 μmol, 0.05 equiv) in DMF (1.0 mL) was degassed with nitrogen and then stirred at 100 °C for 4 h. The mixture was then concentrated and the residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate 20%) to afford 2-(2-methylpyrazol-3-yl)naphthalene-1,4-dicarbonitrile (30 mg, 93.4 μmol, 96% yield) as a yellow solid. LCMS [M+1] + = 259.0; 1 H NMR (400 MHz, CDCl3) δ = 8.48 - 8.44 (m, 1H), 8.44 - 8.39 (m, 1H), 7.96 (s, 1H), 7.96 - 7.94 (m, 1H), 7.94 - 7.92 (m, 1H), 7.67 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 3.92 (s, 3H).

[0786] Step 2: A mixture of 2-(2-methylpyrazol-3-yl)naphthalene-1,4-dicarbonitrile (30 mg, 0.093 mmol, 1.00 equiv) and N-bromosuccinimide (41 mg, 0.23 mmol, 2.00 equiv) in acetonitrile (2.0 mL) was degassed with nitrogen and then stirred at 35 °C for 2 h. The mixture was then concentrated and the residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate 25%) to afford 2-(4-bromo-2-methyl-pyrazol-3-yl)naphthalene-1,4-dicarbonitrile (25 mg, 0.067 mmol, 58% yield) as a yellow solid. LCMS [M+1] + = 339.0; 1 H NMR (400 MHz, CDCl3-d) δ = 8.52 - 8.41 (m, 2H), 8.01 - 7.96 (m, 2H), 7.95 (s, 1H), 7.68 (s, 1H), 3.88 (s, 3H).

[0787] Intermediate EB

[0788]

[0789] Step 1: At 0 °C, a solution of n-butyllithium (2.50 M, 1.87 mL, 1.00 equiv) 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 equiv) in THF (10 mL). The mixture was then cooled to -78 °C and a solution of 4-fluoronaphthalene-1-carbonitrile (0.80 g, 4.67 mmol, 1.00 equiv) in THF (3 mL) was added over 15 min. The mixture was then stirred at -78 °C for 2 h. After this time, a solution of iodine (1.19 g, 4.67 mmol, 1.00 equiv) in THF (3 mL) was added over 30 min and the reaction mixture was stirred at -78 °C for 2 h, then allowed to warm to 25 °C and stirred for an additional 12 h. The reaction mixture was then quenched with water (50 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated sodium thiosulfate (30 mL × 3), 1 M hydrochloric acid (30 mL × 3) and brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash silica chromatography (ethyl acetate:petroleum ether 0 - 5%) to afford 4-fluoro-3-iodo-naphthalene-1-carbonitrile (1.00 g, 3.37 mmol, 72% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 8.15 (d, J = 8.4 Hz, 1H), 8.13 - 8.07 (m, 2H), 7.72 (dt, J = 1.2, 7.7 Hz, 1H), 7.68 - 7.61 (m, 1H).

[0790] Step 2: To a solution of 4-fluoro-3-iodo-naphthalene-1-carbonitrile (900 mg, 3.03 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.58 g, 7.57 mmol, 2.50 equiv) and potassium phosphate (1.29 g, 6.06 mmol, 2.00 equiv) in dioxane (10 mL) and water (2 mL) was added di-tert-butyl(cyclopentyl)phosphine; dichloropalladium - ferrocene (197 mg, 0.30 mmol, 0.10 equiv). The reaction was stirred at 80 °C for 18 h under a nitrogen atmosphere. The reaction mixture was then partitioned between water (20 mL) and ethyl acetate (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was then purified by flash silica chromatography (0 - 25% ethyl acetate:petroleum ether gradient) to afford 4-fluoro-3-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (0.80 g, 2.87 mmol, 95% yield) as a white solid. 11H NMR (400 MHz, CDCl3) δ = 8.33 - 8.25 (m, 2H), 7.91 (s, 1H), 7.88 - 7.82 (m, 1H), 7.82 - 7.75 (m, 1H), 7.63 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 3.89 (d, J = 1.6 Hz, 3H).

[0791] Step 3: To a solution of 4-fluoro-3-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (200 mg, 0.80 mmol, 1.00 equiv) in acetonitrile (5 mL) was added 1-bromopyrrolidine-2,5-dione (212 mg, 1.19 mmol, 1.50 equiv) and the reaction was stirred at 25 °C for 12 h. The reaction was then concentrated and the residue was purified by flash silica chromatography (0 - 15% ethyl acetate:petroleum ether) to afford 3-(4-bromo-2-methyl-pyrazol-3-yl)-4-fluoro-naphthalene-1-carbonitrile (0.20 g, 0.61 mmol, 76% yield) as a grey solid. LCMS [M+1] + = 332.1 / 300.1; 1 1H NMR (400 MHz, CDCl3) δ = 8.32 (dd, J = 8.4, 13.1 Hz, 2H), 7.95 - 7.86 (m, 2H), 7.84 - 7.76 (m, 1H), 7.64 (s, 1H), 3.85 (d, J = 1.2 Hz, 3H).

[0792] Intermediate EC

[0793]

[0794] Step 1: At 20 °C under a nitrogen atmosphere, potassium carbonate (1.49 g, 10.8 mmol, 2.00 equivalents) and Pd(dppf)Cl2 (393 mg, 0.538 mmol, 0.10 equivalent) were added to a solution of 6-bromopyridinecarboxaldehyde (1.00 g, 5.38 mmol, 1.00 equivalent) 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 equivalent) in dioxane (15 mL) and water (3 mL). The mixture was then stirred at 80 °C for 6 h. After this 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 afford 6-(1-methyl-1H-pyrazol-5-yl)pyridinecarboxaldehyde (800 mg, 4.27 mmol, 80% yield) as a yellow solid. 1 1H NMR (400 MHz, CDCl3) δ = 10.13 (d, J = 0.8 Hz, 1H), 7.99 - 7.89 (m, 2H), 7.83 (dd, J = 1.6, 7.2 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 4.35 (s, 3H).

[0795] Step 2: At 20 °C, N-bromosuccinimide (1.14 g, 6.41 mmol, 1.50 equivalents) was added to a solution of 6-(1-methyl-1H-pyrazol-5-yl)pyridinecarboxaldehyde (800 mg, 4.27 mmol, 1.00 equivalent) in acetonitrile (12 mL), and the mixture was stirred for 16 h. After this time, the mixture was concentrated, and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 25%) to afford 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)pyridinecarboxaldehyde (750 mg, 2.82 mmol, 66% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 10.13 (s, 1H), 8.08 - 7.98 (m, 3H), 7.58 (s, 1H), 4.15 (s, 3H).

[0796] Step 3: At 20 °C, to a solution of 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)picolinaldehyde (250 mg, 0.94 mmol, 1.00 equiv) in DMF (3 mL) was added glycine (78 mg, 1.03 mmol, 1.10 equiv), iodine (238 mg, 0.940 mmol, 0.19 mL, 1.00 equiv), and sodium bicarbonate (158 mg, 1.88 mmol, 2.00 equiv). The mixture was then stirred at 60 °C for 6 h, 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 was purified by preparative TLC (SiO2, ethyl acetate) to afford 5-(4-bromo-1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]pyridine as a yellow solid (35 mg, 0.126 mmol, 13% yield). 1 1H NMR (400 MHz, CDCl3) δ = 7.77 (s, 1H), 7.68 (s, 1H), 7.64 - 7.59 (m, 2H), 6.87 (dd, J = 6.4, 9.2 Hz, 1H), 6.66 (d, J = 6.4 Hz, 1H), 3.79 (s, 3H).

[0797] Intermediate ED

[0798]

[0799] Step 1: To a solution of 4-bromo-5-chloro-1H-pyrazole (1.00 g, 5.51 mmol, 1.00 equiv) and 2-(bromomethyl)benzonitrile (1.08 g, 5.51 mmol, 1.00 equiv) in acetonitrile (20 mL) was added potassium carbonate (914 mg, 6.61 mmol, 1.20 equiv), and the mixture was stirred under a nitrogen atmosphere at 80 °C for 10 h. After this time, the reaction was quenched with water (200 mL), 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 residue formed was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1) to afford 2-((4-bromo-3-chloro-1H-pyrazol-1-yl)methyl)benzonitrile as a white solid (1.00 g, 3.37 mmol, 61% yield). LCMS [M+1] + = 297.9; 11H NMR (400 MHz, DMSO-d6) δ = 8.27 (s, 1H), 7.89 (dd, J = 0.8, 7.6 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.61 - 7.49 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 5.52 (s, 2H).

[0800] Step 2: Under a nitrogen atmosphere, Pd(dppf)Cl2 (99 mg, 0.135 mmol, 0.10 equivalent) was added to a solution of 2-((4-bromo-3-chloro-1H-pyrazol-1-yl)methyl)benzonitrile (400 mg, 1.35 mmol, 1.00 equivalent), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (561 mg, 2.70 mmol, 2.00 equivalents), and sodium bicarbonate (227 mg, 2.70 mmol, 2.00 equivalents) in dioxane (10 mL) and water (1 mL). The mixture was stirred at 110 °C for 10 h, then the reaction was quenched by adding water (200 mL), and 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; 1 1H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.79 - 7.70 (m, 1H), 7.62 - 7.52 (m, 1H), 7.50 - 7.42 (m, 2H), 6.42 (d, J = 2.0 Hz, 1H), 5.58 (s, 2H), 3.81 (s, 3H).

[0801] Step 3: To a solution of 2-((3'-chloro-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)methyl)benzonitrile (200 mg, 0.672 mmol, 1.00 equiv) in acetonitrile (10 mL) was added N-bromosuccinimide (132 mg, 0.739 mmol, 1.10 equiv) and the mixture was stirred at 25 °C for 10 h under a nitrogen atmosphere. After this time, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (40 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 5%) to afford 2-((4-bromo-3'-chloro-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)methyl)benzonitrile (130 mg, 0.345 mmol, 51% yield) as a yellow solid. LCMS [M+1] + = 377.9; 1 H NMR (400 MHz, DMSO-d6) δ = 8.37 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.83 - 7.71 (m, 1H), 7.67 (s, 1H), 7.62 - 7.55 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 5.61 (s, 2H), 3.73 (s, 3H).

[0802] Step 4: Under a nitrogen atmosphere, Pd(dtbpf)Cl2 (21 mg, 32 μmol, 0.10 equivalent) was added to a solution of tert-butyl ((4-oxo-7-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrophtalazin-1-yl)methyl)carbamate (256 mg, 0.637 mmol, 2.00 equivalents), 2-((4-bromo-3'-chloro-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)methyl)benzonitrile (120 mg, 0.319 mmol, 1.00 equivalent), and sodium bicarbonate (54 mg, 0.637 mmol, 25 mL, 2.00 equivalents) in water (0.5 mL) and dioxane (5.0 mL). Then the mixture was stirred at 110 °C for 10 h. The reaction was 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 afford tert-butyl ((7-(3'-chloro-1'-(2-cyanobenzyl)-2-methyl-1'H,2H-[3,4'-bipyrazol]-4-yl)-4-oxo-3,4-dihydrophtalazin-1-yl)methyl)carbamate (115 mg, 0.201 mmol, 63% yield) as a dark brown oil. LCMS [M+1] + = 571.1; 1 H NMR (400 MHz, DMSO-d6) δ = 12.48 (s, 1H), 11.94 (s, 1H), 8.42 (s, 1H), 8.13 - 8.05 (m, 2H), 7.92 (d, J = 7.6 Hz, 1H), 7.80 - 7.72 (m, 1H), 7.62 - 7.55 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 - 7.31 (m, 1H), 5.64 (s, 2H), 4.36 (br d, J = 5.6 Hz, 2H), 3.74 (s, 3H), 1.38 (s, 9H).

[0803] Intermediate EE

[0804]

[0805] Step 1: To a solution of phenylboronic acid (1.92 g, 15.8 mmol, 2.00 equiv) and 3-chloro-4-iodo-1H-pyrazole (1.80 g, 7.88 mmol, 1.00 equiv) in dichloromethane (30 mL) was added a portion of pyridine (1.86 g, 23.5 mmol, 1.90 mL, 2.99 equiv) and copper(II) acetate (1.72 g, 9.46 mmol, 1.20 equiv). The mixture was stirred at 20 °C for 16 h, then filtered and concentrated, and the residue was purified by flash silica gel chromatography (0 - 5% ethyl acetate:petroleum ether) to afford 3-chloro-4-iodo-1-phenyl-pyrazole as a yellow liquid (1.50 g, 4.93 mmol, 63% yield). LCMS [M+1] + = 305.0; 1 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.63 - 7.59 (m, 2H), 7.49 - 7.43 (m, 2H), 7.36 - 7.30 (m, 1H).

[0806] Step 2: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.23 g, 5.91 mmol, 1.50 equiv), 3-chloro-4-iodo-1-phenyl-pyrazole (1.20 g, 3.94 mmol, 1.00 equiv), potassium phosphate (1.67 g, 7.88 mmol, 2.00 equiv) and di-tert-butyl(cyclopentyl)phosphine; dichloropalladium - ferrous (256 mg, 0.39 mmol, 0.10 equiv) in dioxane (20 mL) and water (4 mL) was degassed and then heated to 80 °C under a nitrogen atmosphere for 16 h. The reaction mixture was then concentrated, the residue was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3), dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 10 - 15%) to afford 3-chloro-4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole, Intermediate EE-1, as a yellow oil (0.80 g, 3.09 mmol, 79% yield). LCMS [M+1] + = 258.9; 1 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.71 - 7.67 (m, 2H), 7.55 (d, J = 2.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 2H), 7.39 - 7.34 (m, 1H), 6.43 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H).

[0807] Step 3: A mixture of 3-chloro-4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole (210 mg, 0.811 mmol, 1.00 equiv), potassium tetra-hexacyanoferrate(4-) trihydrate (1.03 g, 2.44 mmol, 3.00 equiv), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium-dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphine (73.6 mg, 0.081 mmol, 0.10 equiv) in dimethylacetamide (6 mL) and water (3 mL) was heated to 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10 - 15%) to afford 4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole-3-carbonitrile (200 mg, 0.80 mmol, 99% yield) as a yellow solid. LCMS [M+1] + = 249.9; 1 1H NMR (400 MHz, CDCl3) δ = 8.09 (s, 1H), 7.76 - 7.72 (m, 2H), 7.56 (d, J = 2.0 Hz, 1H), 7.51 - 7.56 (m, 2H), 7.43 - 7.48 (m, 1H), 6.59 (d, J = 2.0 Hz, 1H), 3.98 (s, 3H).

[0808] Step 4: To a mixture of 4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole-3-carbonitrile (180 mg, 0.722 mmol, 1.00 equiv) in acetonitrile (5 mL) was added N-bromosuccinimide (192 mg, 1.08 mmol, 1.50 equiv). The mixture was stirred at 20 °C for 16 h. The reaction mixture was then quenched with saturated sodium sulfite (15 mL), extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10 - 20%) to afford 4-(4-bromo-2-methyl-pyrazol-3-yl)-1-phenyl-pyrazole-3-carbonitrile (220 mg, 0.67 mmol, 93% yield) as a yellow solid. LCMS [M+1] + = 327.9; 1 1H NMR (500 MHz, CDCl3) δ = 8.17 (s, 1H), 7.78 - 7.74 (m, 2H), 7.59 (s, 1H), 7.58 - 7.54 (m, 2H), 7.49 - 7.45 (m, 1H), 3.95 (s, 3H).

[0809] Intermediate EF

[0810]

[0811] At 20 °C, a portion of 1-bromopyrrolidine-2,5-dione (165 mg, 0.927 mmol, 1.20 equiv) was added to a mixture of 3-chloro-4-(2-methylpyrazol-3-yl)-1-phenyl-pyrazole, Intermediate EE-1 (200 mg, 0.773 mmol, 1.00 equiv) in acetonitrile (1 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was then concentrated and the residue was purified by flash silica gel chromatography (0 - 17% ethyl acetate:petroleum ether) to afford 4-bromo-5-(3-chloro-1-phenyl-pyrazol-4-yl)-1-methyl-pyrazole as a yellow oil (200 mg, 0.592 mmol, 77% yield). 1 HNMR (500 MHz, CDCl3) δ = 8.07 - 8.04 (m, 1H), 7.72 (dd, J = 1.2, 8.4 Hz, 2H), 7.58 (s, 1H), 7.54 - 7.49 (m, 2H), 7.42 - 7.35 (m, 1H), 3.88 (s, 3H).

[0812] Intermediate EG

[0813]

[0814] Steps 1 - 6: 2-((7-Bromo-4-oxo-5-(trifluoromethyl)-3,4-dihydrophtalazin-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 according to the same procedure as described for the first 6 steps of Intermediate DK. LCMS [M+1] + = 454.0; 1 H NMR (400 MHz, DMSO-d6) δ = 12.75 (s, 1H), 8.74 (d, J = 1.6 Hz, 1H), 8.41 (s, 1H), 7.97 - 7.92 (m, 2H), 7.91 - 7.86 (m, 2H), 5.22 (s, 2H).

[0815] Step 7: A mixture of 2-((7-bromo-4-oxo-5-(trifluoromethyl)-3,4-dihydrophtalazin-1-yl)methyl)isoindoline-1,3-dione (50 mg, 0.111 mmol, 1.00 equiv), bis(pinacolato)diboron (34 mg, 0.133 mmol, 1.20 equiv), Pd(dppf)Cl2 (8 mg, 0.011 mmol, 0.10 equiv) and potassium acetate (22 mg, 0.221 mmol, 2.00 equiv) in dioxane (2 mL) was degassed with nitrogen and stirred at 100 °C for 1 h. The reaction mixture was then concentrated under reduced pressure to afford [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.

[0816] Intermediate EH

[0817]

[0818] Using the same 4-step procedure as used for the preparation of Intermediate DY, but starting from 7-bromochroman-8-ol, 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). LCMS [M + 1] + = 413.2; 1 1H NMR (400 MHz, DMSO-d6) δ = 12.40 (br s, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 1.6, 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 4.35 (br t, J = 4.8 Hz, 2H), 3.72 (s, 3H), 3.68 (d, J = 2.0 Hz, 2H), 2.89 (br t, J = 6.0 Hz, 2H), 2.05 - 2.00 (m, 2H).

[0819] Intermediate EI

[0820]

[0821] Following the same procedure as described for the preparation of intermediate DC, starting from 2-bromo-6-fluoro-1-naphthaldehyde, 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). LCMS [M+1] + = 329.8 / 331.8; 1 H NMR (400 MHz, CDCl3-d) δ = 8.39 (dd, J = 5.2, 9.2 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.62 - 7.56 (m, 1H), 7.54 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H).

[0822] Intermediate EJ

[0823]

[0824] Following the same procedure as described for the preparation of intermediate DC, starting from 3-bromo-1-chloro-2-naphthaldehyde, 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-1-chloro-2-naphthonitrile, intermediate EJ was prepared as a pale yellow solid (35 mg, 0.101 mmol, 18% yield over 2 steps). 1 H NMR (400 MHz, CDCl3-d) δ = 10.60 (s, 1H), 8.47 - 8.41 (m, 1H), 8.11 (s, 1H), 7.89 - 7.77 (m, 1H), 7.74 - 7.66 (m, 2H).

[0825] Intermediate EK

[0826]

[0827] Step 1: To a solution of 6-bromoquinoline-5-carbonitrile (1.00 g, 4.29 mmol, 1.00 equiv) in acetic acid (20 mL) was added N-chlorosuccinimide (5.73 g, 42.9 mmol, 10.0 equiv). The mixture was stirred at 135 °C for 24 h. Then the pH of the reaction mixture was adjusted to 7 with 2 N aqueous sodium hydroxide (5 mL), diluted with water (50 mL), and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 10 - 15%) to afford 6-bromo-3-chloroquinoline-5-carbonitrile as an off-white solid (512 mg, 1.91 mmol, 45% yield). LCMS [M+1] += 269.0; 1 1H NMR (400 MHz, CDCl3) δ = 8.94 (s, 1H), 8.49 (dd, J = 0.8, 2.4 Hz, 1H), 8.18 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H).

[0828] Step 2: A mixture of 6-bromo-3-chloro-quinoline-5-carbonitrile (512 mg, 1.91 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (398 mg, 1.91 mmol, 1.00 equiv), di-tert-butyl(cyclopentyl)phosphine; dichloropalladium-iron (125 mg, 0.19 mmol, 0.10 equiv), and sodium bicarbonate (322 mg, 3.83 mmol, 0.15 mL, 2.00 equiv) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and stirred at 80 °C for 0.5 h. After this time, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate 30%) to afford 3-chloro-6-(2-methylpyrazol-3-yl)quinoline-5-carbonitrile (250 mg, 0.930 mmol, 49% yield) as a yellow solid. LCMS [M+1] + = 269.1; 1 1H NMR (400 MHz, CDCl3) δ = 9.00 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 6.63 (d, J = 1.6 Hz, 1H), 3.92 (s, 3H).

[0829] Step 3: To a solution of 3-chloro-6-(2-methylpyrazol-3-yl)quinoline-5-carbonitrile (249 mg, 0.927 mmol, 1.00 equiv) in acetonitrile (5 mL) was added N-bromosuccinimide (214 mg, 1.20 mmol, 1.30 equiv). The mixture was stirred at 35 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10 - 15%) to afford 6-(4-bromo-2-methyl-pyrazol-3-yl)-3-chloro-quinoline-5-carbonitrile (289 mg, 0.831 mmol, 90% yield) as a yellow solid. LCMS [M+1] + = 349.0; 11H NMR (400 MHz, CDCl3) δ = 9.04 (d, J = 2.4 Hz, 1H), 8.64 (dd, J = 0.8, 2.4 Hz, 1H), 8.49 - 8.46 (m, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 3.87 (s, 3H).

[0830] Intermediates EL-A and EL-B

[0831]

[0832] Step 1: At -30 °C under nitrogen, n-butyllithium (2.50 M in THF, 88.9 mL, 1.05 equivalents) was added dropwise to a solution of 1,3-dibromo-2-chloro-5-fluorobenzene (61.0 g, 212 mmol, 1.00 equivalent) and 1-methylpyrrole (34.3 g, 423 mmol, 37.7 mL, 2.00 equivalents) in toluene (1500 mL). The mixture was then stirred at -30 °C for 0.5 h, then allowed to warm to 25 °C and stirred for 12 h. After this 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 as a brown liquid (30.0 g, 118 mmol, 56% yield). 1 1H NMR (400 MHz, CDCl3) δ = 7.10 - 6.65 (m, 4H), 4.83 - 4.44 (m, 2H), 2.31 - 2.09 (m, 3H).

[0833] Step 2: m-CPBA (98.2 g, 484 mmol, 85% purity, 2.00 equiv) was carefully added portionwise to a solution of 3-bromo-5-fluoro-11-methyl-11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5,9-tetraene (61.5 g, 242 mmol, 1.00 equiv) in chloroform (1300 mL), keeping the internal temperature below 40 °C. After 2 h, the brown solution turned yellow and the mixture was stirred at 25 °C for an additional 24 h. After this time, the mixture was diluted with dichloromethane (1000 mL), washed with saturated sodium sulfite (1500 mL × 2), then with 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 afford 1-bromo-3-fluoronaphthalene (37.8 g, 168 mmol, 70% yield) as a colorless liquid. 1 1H NMR (400 MHz, CDCl3) δ = 8.25 - 8.18 (m, 1H), 7.75 (br d, J = 3.2 Hz, 1H), 7.63 (dd, J = 2.4, 8.0 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.47 - 7.40 (m, 1H).

[0834] Step 3: A mixture of 1-bromo-3-fluoronaphthalene (34.8 g, 155 mmol, 1.00 equiv), Pd2(dba)3 (14.2 g, 15.5 mmol, 0.10 equiv), zinc cyanide (45.4 g, 387 mmol, 24.5 mL, 2.50 equiv), DPPF (17.1 g, 30.9 mmol, 0.20 equiv) and Zn powder (1.01 g, 15.5 mmol, 0.10 equiv) in DMF (400 mL) was degassed with nitrogen, then the mixture was stirred at 115 °C for 4 h. After this 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 afford 3-fluoronaphthalene-1-carbonitrile (21.5 g, 126 mmol, 81% yield) as a yellow solid. 1 1H NMR (400 MHz, CDCl3) δ = 8.26 - 8.21 (m, 1H), 7.92 - 7.85 (m, 1H), 7.76 - 7.65 (m, 4H).

[0835] Step 4: At -70 °C, n-butyllithium (2.50 M in hexanes, 2.83 mL, 1.10 equiv) was added to a solution of N-isopropylpropan-2-amine (845 mg, 8.35 mmol, 1.18 mL, 1.30 equiv) in THF (15 mL), and the reaction mixture was stirred at -70 °C for 15 minutes. Then, at -70 °C, 3-fluoronaphthalene-1-carbonitrile (1.10 g, 6.43 mmol, 1.00 equiv) in THF (2 mL) was added to the mixture, and the reaction mixture was stirred at -70 °C for 30 minutes. Then, at -70 °C, a solution of iodine (2.12 g, 8.35 mmol, 1.30 equiv) in THF (2.00 mL) was added to the reaction mixture, and the solution was stirred at -70 °C for an additional 30 minutes. Then the mixture was heated to 25 °C and stirred at 25 °C for 10 hours. After this time, the reaction was quenched with 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 residue formed was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 0 - 15%) to afford 3-fluoro-2-iodonaphthalene-1-carbonitrile (1.70 g, 5.72 mmol, 89% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 8.36 - 8.24 (m, 1H), 7.83 - 7.71 (m, 1H), 7.59 - 7.48 (m, 3H).

[0836] Step 5: A mixture of 3-fluoro-2-iodonaphthalene-1-carbonitrile (800 mg, 2.69 mmol, 1.00 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.23 g, 5.92 mmol, 2.20 equiv), Pd(dtbpf)Cl2 (176 mg, 0.269 mmol, 0.10 equiv), sodium bicarbonate (679 mg, 8.08 mmol, 3.00 equiv) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and stirred at 80 °C for 12 hours. After this time, the mixture was concentrated and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 5 - 50%) to afford 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; 11H NMR (400 MHz, CDCl3) δ = 8.35 - 8.27 (m, 1H), 8.00 - 7.92 (m, 1H), 7.87 (d, J = 9.6 Hz, 1H), 7.79 - 7.70 (m, 2H), 7.68 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 3.85 (d, J = 1.2 Hz, 3H).

[0837] Step 6: To a solution of 3-fluoro-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (500 mg, 1.99 mmol, 1.00 equiv) in acetonitrile (8 mL) was added N-bromosuccinimide (638 mg, 3.58 mmol, 1.80 equiv). The mixture was stirred at 25 °C for 3 h. After this time, the mixture was concentrated and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 10 - 50%) to afford 2-(4-bromo-2-methyl-pyrazol-3-yl)-3-fluoro-naphthalene-1-carbonitrile (550 mg, 1.56 mmol, 78% yield) as a yellow solid. LCMS [M+1] + = 331.9; 1 1H NMR (400 MHz, CDCl3) δ = 8.40 - 8.31 (m, 1H), 8.01 - 7.95 (m, 1H), 7.91 (d, J = 9.6 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.68 (s, 1H), 3.84 (s, 3H).

[0838] Step 7: To a solution of 3-fluoro-2-(2-methylpyrazol-3-yl)naphthalene-1-carbonitrile (20.0 g, 79.6 mmol, 1.00 equiv) in acetonitrile (300 mL) was added N-iodosuccinimide (89.5 g, 398 mmol, 5.00 equiv). The mixture was stirred at 80 °C for 12 h. After this time, the mixture was concentrated and the residue was triturated with methanol (100 mL) at 25 °C for 30 min and the mixture was filtered and dried to afford 3-fluoro-2-(4-iodo-2-methyl-pyrazol-3-yl)naphthalene-1-carbonitrile (25.2 g, 66.8 mmol, 84% yield) as a yellow solid. LCMS [M+1] + = 378.0; 1 1H NMR (400 MHz, CDCl3) δ = 8.35 (br d, J = 8.4 Hz, 1H), 7.98 (br d, J = 8.4 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.74 - 7.67 (m, 1H), 3.92 - 3.82 (m, 3H).

[0839] Intermediate EM

[0840]

[0841] A mixture of 2-(2-hydroxyphenyl)acetonitrile (182 mg, 1.36 mmol, 1.20 equiv), 3-bromo-5-fluoropyridine (200 mg, 1.14 mmol, 1.00 equiv), and potassium carbonate (393 mg, 2.84 mmol, 2.50 equiv) in DMF (10 mL) was stirred under a nitrogen atmosphere at 75 °C for 3 h. The mixture was concentrated, and the residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate 15%) to afford 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.

[0842] Intermediate EN

[0843]

[0844] Step 1: At 25 °C, to a solution of 6-bromo-3-cyclopropoxypyridinecarbonitrile (800 mg, 3.35 mmol, 1.00 equiv) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (732 mg, 3.51 mmol, 1.05 equiv) in dioxane (20 mL) and water (0.4 mL) was added di-tert-butyl(cyclopentyl)phosphine-dichloropalladium-iron (218 mg, 0.335 mmol, 0.10 equiv) and sodium carbonate (709 mg, 6.69 mmol, 2.00 equiv). The mixture was degassed and purged with nitrogen 3 times, then stirred at 80 °C for 2 h. After this time, the reaction mixture was quenched with water (20 mL), 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 chromatography (SiO2, petroleum ether: ethyl acetate 0-10%) to afford 3-cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)pyridinecarbonitrile (750 mg, 2.97 mmol, 89% yield) as a white solid. 1 1H NMR (400 MHz, CD3OD) δ = 7.77 (s, 2H), 7.51 (d, J = 2.0 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 4.22 (s, 3H), 3.96 - 3.91 (m, 1H), 0.98 - 0.92 (m, 4H).

[0845] Step 2: At 0 °C, N-bromosuccinimide (723 mg, 4.06 mmol, 1.50 equiv) was added to a solution of 3-cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)pyridinecarbonitrile (650 mg, 2.71 mmol, 1.00 equiv) in acetonitrile (20 mL), and the mixture was stirred at 25 °C for 16 h. 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 was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to afford 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypyridinecarbonitrile (1.1 g, crude) as a yellow solid. LCMS [M+1] = 318.9 / 320.9; 1 H NMR (400 MHz, CDCl3) δ = 8.00 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.52 (s, 1H), 4.05 (s, 3H), 3.99 - 3.92 (m, 1H), 0.99 - 0.92 (m, 4H).

[0846] Step 3: At 25 °C, DIBAL-H (1.00 M, 5.64 mL, 6.00 equiv) was added to a solution of 6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypyridinecarbonitrile (300 mg, 0.94 mmol, 1.00 equiv) in THF (20 mL), and the mixture was stirred at 25 °C for 3 h. After this time, the reaction was quenched by the addition of a 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 preparative TLC (SiO2, petroleum ether:ethyl acetate 1:1) to afford (6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypyridin-2-yl)methanamine (160 mg, 0.495 mmol) as a yellow solid. A solution of (6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypyridin-2-yl)methanamine (160 mg, 0.495 mmol, 1.00 equiv) in ethyl formate (3 mL) was stirred at 25 °C for 2 h, then water (2 mL) was added. 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 preparative TLC (SiO2, petroleum ether:ethyl acetate 0 - 10%) to afford N-((6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypyridin-2-yl)methyl)formamide (140 mg, 0.359 mmol, 73% yield). LCMS [M+1] + = 351.0 / 353.0; 1 H NMR (400 MHz, CDCl3) δ = 8.36 (s, 1H), 7.68 - 7.61 (m, 2H), 7.55 - 7.52 (m, 1H), 7.03 (br s, 1H), 4.62 (d, J = 4.4 Hz, 2H), 3.99 (s, 3H), 3.85 (tt, J = 3.2, 5.6 Hz, 1H), 0.92 - 0.85 (m, 4H).

[0847] Step 4: At -40 °C, trifluoromethanesulfonic anhydride (Tf2O) (225 mg, 0.078 mmol, 0.13 mL, 2.00 equiv) was added to a solution of N-((6-(4-bromo-1-methyl-1H-pyrazol-5-yl)-3-cyclopropoxypyridin-2-yl)methyl)formamide (140 mg, 0.359 mmol, 1.00 equiv) and diisopropylethylamine (104 mg, 0.80 mmol, 0.14 mL, 2.00 equiv) in dichloromethane (8 mL). Then, the mixture was allowed to warm to ambient temperature and stirred at 25 °C for 6 h. After this time, water (2 mL) was added and the mixture was extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 0 - 10%) to afford 5-(4-bromo-1-methyl-1H-pyrazol-5-yl)-8-cyclopropoxyimidazo[1,5-a]pyridine (110 mg, 0.314 mmol, 79% yield) as a yellow solid. LCMS [M+1] + = 332.9 / 334.9; 1 1H NMR (400 MHz, CDCl3) δ = 7.72 - 7.60 (m, 3H), 6.61 (d, J = 7.6 Hz, 1H), 6.49 (d, J = 7.4 Hz, 1H), 3.98 - 3.92 (m, 1H), 3.77 (s, 3H), 0.98 - 0.87 (m, 4H).

[0848] Intermediate EO

[0849]

[0850] Step 1: 1-Bromopyrrolidine-2,5-dione (1.43 g, 8.06 mmol, 2.50 equiv) was added to a solution of 1-(2-methylpyrazol-3-yl)ethanone (400 mg, 3.22 mmol, 1.00 equiv) in THF (6 mL) and the mixture was stirred at 25 °C for 12 h. After this time, the reaction mixture was concentrated and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 20%) to afford 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; 1 1H NMR (400 MHz, CDCl3) δ = 7.54 (s, 1H), 4.62 (s, 2H), 4.16 (s, 3H).

[0851] 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 h, then triethylamine (431 mg, 4.26 mmol, 0.59 mL, 3.00 eq) was added and stirring was continued at 70 °C for an additional 1 h. The reaction mixture was then concentrated and the residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate 30%) to afford 2-(4-bromo-2-methyl-pyrazol-3-yl)indolizine-1-carbonitrile (100 mg, 0.332 mmol, 23% yield) as a yellow solid. LCMS [M+1] + = 301.0; 1 1H NMR (400 MHz, CDCl3) δ = 8.10 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.59 (s, 1H), 7.44 (s, 1H), 7.22 - 7.15 (m, 1H), 6.89 (t, J = 6.4 Hz, 1H), 3.96 (s, 3H).

[0852] Intermediate EP

[0853]

[0854] 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 h. The reaction mixture was then diluted with ethyl acetate (30 mL), washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate 20%) to afford 4-chloro-2-(cyclopropoxy)-6-(4-iodo-2-methyl-pyrazol-3-yl)benzonitrile (135 mg, 0.33 mmol, 61% yield) as a yellow solid. LCMS [M+H] + = 399.9; 1 1H NMR (400 MHz, CDCl3) δ = 7.53 (s, 1H), 7.41 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 3.90 - 3.79 (m, 1H), 3.75 (s, 3H), 0.99 - 0.76 (m, 4H).

[0855] Intermediate EQ

[0856]

[0857] 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 triphenylphosphine (141 mg, 0.54 mmol, 0.10 eq) in DMF (10 mL) and water (2 mL) was degassed and purged with nitrogen three times. Then palladium(II) acetate (60 mg, 0.27 mmol, 0.05 eq) was added to the mixture, and the mixture was stirred at 80 °C for 16 h. After this reagent, 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; 1 1H NMR (400 MHz, CDCl3) δ = 10.14 - 10.06 (m, 1H), 8.93 (dd, J = 1.6, 4.8 Hz, 1H), 7.79 (dd, J = 1.2, 7.6 Hz, 1H), 7.64 - 7.58 (m, 2H), 6.30 (d, J = 2.0 Hz, 1H), 3.67 (s, 3H).

[0858] 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 h. The reaction was diluted with ethyl acetate (35 mL), washed with saturated sodium thiosulfate (5 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 20 - 100%) to 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; 11H NMR (400 MHz, CDCl3) δ = 10.07 (s, 1H), 8.97 (dd, J = 1.6, 4.8 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.68 (dd, J = 4.8, 7.6 Hz, 1H), 7.63 (s, 1H), 3.69 (s, 3H).

[0859] Step 3: To either of 3-(4-iodo-2-methyl-pyrazol-3-yl)pyridine-2-carbaldehyde (290 mg, 0.93 mmol, 1.00 equiv) in DMF (5 mL) was added glycine (77 mg, 1.02 mmol, 1.10 equiv), iodine (235 mg, 0.93 mmol, 0.18 mL, 1.00 equiv) and sodium bicarbonate (155 mg, 1.85 mmol, 2.00 equiv). The mixture was then stirred at 60 °C for 6 h. 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 afford 8-(4-iodo-2-methyl-pyrazol-3-yl)imidazo[1,5-a]pyridine as a yellow gum (100 mg, 0.31 mmol, 33% yield). LCMS [M-1]- = 324.9; 1 1H NMR (400 MHz, CDCl3) δ = 8.24 (s, 1H), 8.05 (d, J = 6.4 Hz, 1H), 7.65 (s, 1H), 7.19 (s, 1H), 6.78 - 6.69 (m, 2H), 3.82 (s, 3H).

[0860] Intermediate ER

[0861]

[0862] Step 1: A mixture of 4-chloro-6-(cyclopropoxy)-3-fluoro-2-(2-methylpyrazol-3-yl)benzonitrile (200 mg, 0.69 mmol, 1.00 equiv), methylboronic acid (205 mg, 3.43 mmol, 5.00 equiv), di-tert-butyl(cyclopentyl)phosphine-dichloropalladium-iron (45 mg, 0.069 mmol, 0.10 equiv), and potassium carbonate (284 mg, 2.06 mmol, 3.00 equiv) in dioxane (2 mL) was degassed, purged with nitrogen three times, and stirred at 100 °C for 2 h. The mixture was then concentrated and purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 25%) to afford 6-(cyclopropoxy)-3-fluoro-4-methyl-2-(2-methylpyrazol-3-yl)benzonitrile (35 mg, 0.10 mmol, 15% yield) as a yellow oil. LCMS [M+1] + = 274.3; 1 H NMR (400 MHz, CDCl3) δ = 7.60 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 6.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 3.86 (td, J = 2.8, 5.6 Hz, 1H), 3.80 (s, 3H), 2.43 (d, J = 2.0 Hz, 3H), 0.93 - 0.88 (m, 4H).

[0863] Step 2: A mixture of 6-(cyclopropoxy)-3-fluoro-4-methyl-2-(2-methylpyrazol-3-yl)benzonitrile (35 mg, 0.13 mmol, 1.00 equiv) and N-bromosuccinimide (46 mg, 0.26 mmol, 2.00 equiv) in acetonitrile (3 mL) was stirred at 40 °C for 2 h under a nitrogen atmosphere. The mixture was then concentrated, and the residue was purified by preparative 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; 1 H NMR (400 MHz, CDCl3) δ = 7.59 (d, J = 2.8 Hz, 1H), 7.31 (br d, J = 2.8 Hz, 1H), 3.90 - 3.83 (m, 1H), 3.78 (d, J = 2.8 Hz, 3H), 2.44 (br s, 3H), 0.92 (br dd, J = 3.2, 6.4 Hz, 4H).

[0864] Intermediate ES

[0865]

[0866] Step 1: To a mixture of 2-iodobenzothiophene-3-carbonitrile (280 mg, 0.98 mmol, 1.00 equiv), sodium carbonate (312 mg, 2.95 mmol, 3.00 equiv), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (409 mg, 1.96 mmol, 2.00 equiv) in dioxane (4 mL) and water (1 mL) was added di-tert-butyl(cyclopentyl)phosphine-dichloropalladium-iron (64 mg, 0.098 mmol, 0.10 equiv) and sodium carbonate (312 mg, 2.95 mmol, 3.00 equiv), and the mixture was stirred at 80 °C for 2 h. After this time, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate 10%) to afford 2-(2-methylpyrazol-3-yl)benzothiophene-3-carbonitrile (150 mg, 64% yield) as a yellow solid. 1 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.06 - 8.01 (m, 1H), 7.94 - 7.89 (m, 1H), 7.64 - 7.61 (m, 1H), 7.61 - 7.51 (m, 2H), 6.79 (d, J = 1.6 Hz, 1H), 4.09 (s, 3H).

[0867] Step 2: To a mixture of 2-(2-methylpyrazol-3-yl)benzothiophene-3-carbonitrile (150 mg, 0.63 mmol, 1.00 equiv) in acetonitrile (2 mL) was added N-bromosuccinimide (112 mg, 0.63 mmol, 1.00 equiv), and the mixture was stirred at 25 °C for 12 h. After this time, the reaction mixture was added to saturated sodium bicarbonate solution (5 mL), and the mixture was 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 afford 2-(4-bromo-2-methyl-pyrazol-3-yl)benzothiophene-3-carbonitrile (160 mg, 75% yield) as a yellow solid. LCMS [M+1] + = 319.9; 11H NMR (400 MHz, CDCl3) δ (ppm) = 8.10 - 8.05 (m, 1H), 7.98 - 7.93 (m, 1H), 7.65 (s, 1H), 7.63 - 7.56 (m, 2H), 3.98 (s, 3H).

[0868] Intermediate ET

[0869]

[0870] 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) according to the procedure described for Intermediate ER from thieno[2,3-b]pyridine-3-carbonitrile. LCMS [M+1] + = 320.9; 1 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.78 (dd, J = 1.6, 4.4 Hz, 1H), 8.34 (dd, J = 1.6, 8.0 Hz, 1H), 7.66 (s, 1H), 7.58 (dd, J = 4.4, 8.0 Hz, 1H), 3.99 (s, 3H).

[0871] Intermediate EU

[0872]

[0873] Step 1: At 0 °C, sodium hydride (183 mg, 4.58 mmol, 60.0% purity, 1.20 eq) was added to a solution of 2-methylsulfonylethanol (569 mg, 4.58 mmol, 1.20 eq) in DMF (30 mL). After stirring for 0.5 h, 4-chloro-2-fluoro-6-(2-methylpyrazol-3-yl)benzonitrile (900 mg, 3.82 mmol, 1.00 eq) in DMF (5 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. After this time, the mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), the aqueous phase was adjusted to pH 1 with HCl (10 mL) and further extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 4-chloro-2-hydroxy-6-(2-methylpyrazol-3-yl)benzonitrile (455 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS [M] + = 234.1; 11H NMR (400 MHz, DMSO-d6) δ = 11.96 (br s, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 3.76 (s, 3H).

[0874] Step 2: To a solution of 4-chloro-2-hydroxy-6-(2-methylpyrazol-3-yl)benzonitrile (150 mg, 0.642 mmol, 1.00 equiv) and sodium 2-chloro-2,2-difluoroacetate (392 mg, 2.57 mmol, 4.00 equiv) in DMF (2 mL) and water (0.2 mL) was added cesium carbonate (314 mg, 0.96 mmol, 1.50 equiv). The mixture was stirred at 100 °C for 1 h. Then the reaction mixture was quenched by adding 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 preparative TLC (SiO2, petroleum ether: ethyl acetate 25%) to afford 4-chloro-2-(difluoromethoxy)-6-(2-methylpyrazol-3-yl)benzonitrile (85 mg, 0.30 mmol, 47% yield) as a yellow solid. LCMS [M] + = 284.0; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.76 (s, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.72 - 7.71 (m, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 6.60 (d, J = 2.0 Hz, 1H), 3.80 (s, 3H).

[0875] Step 3: To a solution of 4-chloro-2-(difluoromethoxy)-6-(2-methylpyrazol-3-yl)benzonitrile (85 mg, 0.30 mmol, 1.00 equiv) in acetic acid (2 mL) was added N-iodosuccinimide (135 mg, 0.60 mmol, 2.00 equiv). The mixture was stirred at 25 °C for 1 h, then the reaction mixture was quenched by adding 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 preparative TLC (SiO2, petroleum ether: ethyl acetate 20%) to afford 4-chloro-2-(difluoromethoxy)-6-(4-iodo-2-methyl-pyrazol-3-yl)benzonitrile (90 mg, 0.22 mmol, 73% yield) as a yellow solid. LCMS [M+H]+ = 409.9; 1 1H NMR (400 MHz, CD3OD-d4) δ (ppm) = 7.72 - 7.68 (m, 1H), 7.67 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.42 - 7.02 (m, 1H), 3.83 (s, 3H).

[0876] Intermediate EV

[0877]

[0878] Step 1: A mixture of 7-bromo-1,3-benzothiazol-6-amine (2.00 g, 8.73 mmol, 1.00 equiv), zinc cyanide (1.54 g, 13.1 mmol, 1.50 equiv), Pd2(dba)3 (80 mg, 0.87 mmol, 0.01 equiv), DPPF (97 mg, 0.175 mmol, 0.02 equiv) and zinc powder (5.7 mg, 0.087 mmol, 0.01 equiv) in DMF (20 mL) was degassed and purged with nitrogen three times, then stirred at 140 °C for 16 h. After this 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 residue formed was purified by column chromatography (SiO2, petroleum ether: ethyl acetate 10 - 25%) to give 6-amino-1,3-benzothiazole-7-carbonitrile (1.05 g, 4.66 mmol, 53% yield) as a yellow solid. LCMS [M+1] + = 176.1; 1 1H NMR (400 MHz, CDCl3-d) δ = 8.79 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.69 (br s, 2H).

[0879] Step 2: A mixture of 6-amino-1,3-benzothiazole-7-carbonitrile (500 mg, 2.85 mmol, 1.00 equiv), p-toluenesulfonic acid (590 mg, 3.42 mmol, 1.20 equiv), tert-butyl nitrite (353 mg, 3.42 mmol, 407 μL, 1.20 equiv), tetrabutylammonium bromide (1.84 g, 5.71 mmol, 2.00 equiv) and copper(II) bromide (64 mg, 0.286 mmol, 0.10 equiv) in acetonitrile (15 mL) was degassed with nitrogen and stirred at 25 °C for 6 h. The mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 10 - 25%) to afford 6-bromo-1,3-benzothiazole-7-carbonitrile (300 mg, 1.25 mmol, 44% yield) as a yellow solid. LCMS [M+1] + = 240.9; 1 H NMR (400 MHz, CDCl3) δ = 9.11 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H).

[0880] Step 3: A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (261 mg, 1.25 mmol, 1.00 equiv), 6-bromo-1,3-benzothiazole-7-carbonitrile (300 mg, 1.25 mmol, 1.00 equiv), di-tert-butyl(cyclopentyl)phosphine; palladium dichloride ferrocene (82 mg, 0.125 mmol, 0.10 equiv) and sodium hydrogen carbonate (316 mg, 3.76 mmol, 3.00 equiv) in dioxane (10 mL) and water (2 mL) was degassed with nitrogen and then stirred at 80 °C for 3 h under a nitrogen atmosphere. The mixture was then concentrated and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate 5 - 25%) to afford 6-(2-methylpyrazol-3-yl)-1,3-benzothiazole-7-carbonitrile (280 mg, 0.89 mmol, 71% yield) as a yellow solid. LCMS [M+1] + = 241.0; 1 H NMR (400 MHz, CDCl3-d) δ = 9.21 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.66 - 7.58 (m, 2H), 6.58 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H).

[0881] Step 4: A mixture of 6-(2-methylpyrazol-3-yl)-1,3-benzothiazole-7-carbonitrile (140 mg, 0.58 mmol, 1.00 equiv) and N-bromosuccinimide (207 mg, 1.17 mmol, 2.00 equiv) in acetonitrile (3 mL) was stirred at 40 °C under a nitrogen atmosphere for 2 h. The mixture was then concentrated and the residue was purified by column chromatography (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; 1 1H NMR (400 MHz, CDCl3-d) δ = 9.25 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H).

[0882] Intermediate EW

[0883]

[0884] Step 1: Thionyl chloride (667 mg, 5.61 mmol, 407 uL, 1.20 equiv) was added to a solution of 3-(hydroxymethyl)-1-methylpyridin-2(1H)-one (650 mg, 4.67 mmol, 1.00 equiv) in dichloromethane (15 mL), and the mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to give 3-(chloromethyl)-1-methyl-pyridin-2-one (650 mg, crude) as a white solid.

[0885] Step 2: Potassium carbonate (683 mg, 4.94 mmol, 1.20 equiv) was added to a solution of 3-(chloromethyl)-1-methyl-pyridin-2-one (650 mg, 4.12 mmol, 1.00 equiv) and 4-bromo-5-chloro-1H-pyrazole (747 mg, 4.12 mmol, 1.00 equiv) in acetonitrile (20 mL), and the mixture was stirred at 80 °C for 12 h. 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.

[0886] Step 3: To a solution of 3-[(4-bromo-5-chloro-pyrazol-1-yl)methyl]-1-methyl-pyridin-2-one (270 mg, 0.89 mmol, 1.00 equiv) and 4-bromo-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (512 mg, 1.78 mmol, 2.00 equiv) in dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl2 (65 mg, 0.089 mmol, 0.10 equiv) and sodium bicarbonate (150 mg, 1.78 mmol, 69 μL, 2.00 equiv). The mixture was stirred at 110 °C for 10 h. The reaction mixture was then quenched by the addition of water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini-NX 80 mm × 40 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 5%-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; 1 H NMR (400 MHz, DMSO-d6) δ = 8.24 (s, 1H), 7.73 (d, J = 2.0, 6.8 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 5.2 Hz, 1H), 6.39 (d, J = 2.0 Hz, 1H), 6.25 (t, J = 6.8 Hz, 1H), 5.14 (s, 2H), 3.79 (s, 3H), 3.45 (s, 3H)

[0887] Step 4: To a solution of 3-((5'-chloro-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)methyl)-1-methylpyridin-2(1H)-one (47.0 mg, 0.155 mmol, 1.00 equiv) in acetonitrile (1 mL) was added N-bromosuccinimide (26 mg, 0.147 mmol, 0.95 equiv). The mixture was stirred at 25 °C for 10 h. 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 preparative TLC (SiO2, dichloromethane:methanol 10%) to afford 3-((4-bromo-5'-chloro-2-methyl-1'H,2H-[3,4'-bipyrazol]-1'-yl)methyl)-1-methylpyridin-2(1H)-one (45 mg, 0.118 mmol, 76% yield) as a white solid. LCMS [M+1] + = 383.9; 1 H NMR (400 MHz, DMSO-d6) δ = 7.89 (s, 1H), 7.71 (d, J = 6.8, 1.2 Hz, 1H), 7.67 (s, 1H), 6.93 - 6.96 (m, 1H), 6.23 (t, J = 6.8 Hz, 1H), 5.22 (s, 2H), 3.74 (s, 3H), 3.47 (s, 3H).

[0888] Intermediate EX

[0889]

[0890] Steps 1 - 6: Following the same procedure as described in the first 6 steps of Intermediate DK, starting from 1-(5-bromo-2-methyl-3-(methoxy)phenyl)ethan-1-one, 2-((7-bromo-4-oxo-5-(methoxy)-3,4-dihydrophtalazin-1-yl)methyl)isoindoline-1,3-dione was prepared as a white solid (4.22 g, 10.2 mmol, 8% yield over 6 steps). LCMS [M+1] + = 414.0.

[0891] Step 7: A mixture of 2-((7-bromo-4-oxo-5-(methoxy)-3,4-dihydrophtalazin-1-yl)methyl)isoindoline-1,3-dione (4.22 g, 10.2 mmol, 1.0 equiv), bis(pinacolato)diboron (3.88 g, 15.3 mmol, 1.5 equiv), Pd(dppf)Cl2·CH2Cl2 (745 mg, 1.02 mmol, 0.1 equiv) and potassium acetate (3.00 g, 30.6 mmol, 3.0 equiv) in dioxane (60 mL) was degassed and purged with nitrogen three times and stirred at 100 °C for 1 hour. The mixture was then concentrated and the residue was triturated with methanol, filtered and dried to give the intermediate EX as a grey solid (2.01 g, 43% yield). LCMS [M+1] + = 380.1 (boronic acid loss from terpineol).

[0892] Intermediate EY

[0893]

[0894] Following the procedure described for the preparation of intermediate DQ, 6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile was prepared as a white solid (120 mg, 0.30 mmol, 20% over 3 steps). LCMS [M+1] + = 383.8; 1 1H NMR (400 MHz, CDCl3) δ = 7.65 (s, 1H), 7.51 - 7.40 (m, 2H), 3.93 - 3.87 (m, 1H), 3.83 (s, 3H), 1.00 - 0.89 (m, 4H).

[0895] Intermediate EZ

[0896]

[0897] Following the procedure described for the preparation of intermediate DQ, 6-cyclopropoxy-3-chloro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile was prepared as a yellow solid (160 mg, 0.40 mmol, 22% over 3 steps). LCMS [M+1] + = 399.9; 1 1H NMR (400 MHz, CDCl3) δ = 7.70 (d, J = 9.2 Hz, 1H), 7.64 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H), 3.92 (td, J = 2.8, 5.6 Hz, 1H), 3.78 (s, 3H), 0.99 - 0.90 (m, 4H).

[0898] Intermediate FA

[0899]

[0900] Step 1: To a solution of 4-chloro-2-cyclopropoxy-6-(1-methyl-1H-pyrazol-5-yl)benzonitrile (177 mg, 0.65 mmol, 1.00 equiv) in dioxane (10 mL) was added potassium carbonate (268 mg, 1.94 mmol, 3.00 equiv), di-tert-butyl(cyclopentyl)phosphine; dichloropalladium-iron (42 mg, 0.064 mmol, 0.10 equiv) and methylboronic acid (194 mg, 3.23 mmol, 5.00 equiv). The mixture was stirred at 100 °C for 2 h, 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 preparative 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; 1 1H NMR (400 MHz, CDCl3) δ = 7.98 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 0.8 Hz, 1H), 7.27 (s, 1H), 6.85 (d, J = 2.0 Hz, 1H), 4.35 - 4.29 (m, 1H), 4.27 (s, 3H), 2.91 (s, 3H), 1.36 - 1.31 (m, 4H).

[0901] Step 2: To a solution of 2-(cyclopropoxy)-4-methyl-6-(2-methylpyrazol-3-yl)benzonitrile (100 mg, 0.40 mmol, 1.00 equiv) in acetic acid (2 mL) was added N-iodosuccinimide (178 mg, 0.79 mmol, 2.00 equiv). The mixture was stirred at 25 °C for 1 h, 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 was purified by preparative 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; 11H NMR (400 MHz, CDCl3) δ = 7.66 - 7.55 (m, 1H), 7.27 (s, 1H), 6.80 (s, 1H), 3.89 (tt, J = 3.2, 6.0 Hz, 1H), 3.85 - 3.79 (m, 3H), 2.50 (s, 3H), 1.04 - 0.80 (m, 4H).

[0902] Intermediate FB

[0903]

[0904] Step 1: To a solution of 2-fluoronaphthalen-1-ol (0.50 g, 3.08 mmol, 1.00 equiv) in dichloromethane (8 mL) was added NBS (521 mg, 2.93 mmol, 0.95 equiv) and the mixture was stirred at -50 °C for 0.25 h. Then water (10 mL) was added and the separated organic phase was dried, concentrated, and the residue was purified by column chromatography (SiO2, 1% petroleum ether / ethyl acetate) to give 4-bromo-2-fluoronaphthalen-1-ol (500 mg, 2.07 mmol, 67% yield) as a pale yellow solid. 1 1H NMR (400 MHz, CDCl3) δ = 8.27 - 8.21 (m, 1H), 8.19 - 8.11 (m, 1H), 7.63 (d, J = 10.2 Hz, 1H), 7.61 - 7.54 (m, 2H), 5.68 (br d, J = 4.0 Hz, 1H).

[0905] Step 2: To a solution of 4-bromo-2-fluoronaphthalen-1-ol (2.30 g, 9.54 mmol, 1.00 equiv), DIEA (21.0 mmol, 3.66 mL, 2.20 equiv) and DMAP (58 mg, 0.48 mmol, 0.05 equiv) in dichloromethane (40 mL) at 0 °C was added acetyl chloride (19.1 mmol, 1.36 mL, 2.00 equiv) dropwise. The mixture was stirred at 28 °C for 1 h, then the mixture was concentrated and the residue formed was purified by column chromatography (SiO2, 1% petroleum ether / ethyl acetate) to give (4-bromo-2-fluoronaphthalen-1-yl) acetate (2.50 g, 8.83 mmol, 93% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 8.26 - 8.18 (m, 1H), 7.94 - 7.86 (m, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.66 - 7.56 (m, 2H), 2.51 (s, 3H).

[0906] Step 3: A mixture of (4-bromo-2-fluoro-1-naphthyl) acetate (2.50 g, 8.83 mmol, 1.00 equiv) in DMA (40 mL), Pd2(dba)3 (809 mg, 0.88 mmol, 0.10 equiv), Zn(CN)2 (9.71 mmol, 0.62 mL, 1.10 equiv), zinc (29 mg, 0.442 mmol, 0.05 equiv) and DPPF (979 mg, 1.77 mmol, 0.20 equiv) was degassed with nitrogen three times and then stirred at 120 °C for 3 h. The reaction mixture was then diluted with ethyl acetate (100 mL), filtered, and the fil...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof: Wherein: R 1 is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-C1-C5 alkyl, -Y-cycloalkyl, -Y-heterocycloalkyl, -Y-aryl, -Y-arC1-C3 alkyl or -Y-heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties are each optionally substituted with one or more R 2 substituents; Each Y is independently a bond or -NR 4 -; Each R 2 is independently a hydroxyl group, a halogen, a cyano group, a cyanomethyl group, -(NR 4 )2, a hydroxyalkyl group, an alkoxy group, -SO2C1-C3 alkyl, -X-arC1-C3 alkyl, a heteroalkyl group, a C2-C4 alkynyl group, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, a heterocyclic group, -X-L-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl or -X-heteroaryl, wherein the heterocyclic group, the cycloalkyl group, the aryl group and the heteroaryl group are optionally substituted by one or more R 5 substituents, or; Each X is independently a key, O, S, -NR 4 - or -NR 4 C(O)-; Each Z is independently a bond, -SO-, -SO2-, -CH(OH)- or -C(O)-; Each L is independently a bond or a C1-C3 alkylene; R 3a and R 3b each independently is hydrogen or deuterium, or R 3a and R 3b together are oxo; Each R 4 is independently hydrogen or a C1-C3 alkyl group; Each R 5 is 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-C3 alkyl or oxo, or -X-aryl; and R 6 is hydrogen, a halogen, a C1-C3 alkyl group, a haloalkyl group or an alkoxy group.

2. The compound according to claim 1, wherein R 1 is hydrogen.

3. The compound according to claim 1, wherein R 1 is a halogen.

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

5. The compound according to claim 1, wherein R 1 is -Y-C1-C5 alkyl.

6. The compound according to claim 5, wherein Y is a bond and the C1-C5 alkyl is methyl.

7. The compound according to claim 1, wherein R 1 is a hydroxyalkyl group.

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

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

10. The compound according to claim 1, wherein R 1 is -Y-heterocyclic group.

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