PRC2 inhibitors for use in treating sickle cell disease

Abstract

The present disclosure relates to methods of treating a subject having sickle cell disease, comprising administering to the subject a therapeutically effective amount of an inhibitor of polycomb repressive complex 2 (PRC2). In certain embodiments of the disclosed methods, prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has (a) been administered hydroxyurea; and / or (b) been administered a stable dose of one or more of voxelotor, crizanlizumab, and L-glutamine.

Description

PRC2 INHIBITORS FOR USE IN TREATING SICKLE CELL DISEASECROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 578,568 filed August 24, 2023, which is hereby incorporated by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to compounds that inhibit the Polycomb Repressive Complex 2 (PRC2). In particular, the present disclosure relates to compounds, pharmaceutical compositions comprising the compounds and methods for use therefor in treating sickle cell disease.BACKGROUND OF THE DISCLOSURE

[0003] The Polycomb Repressive Complex 2 (PRC2) is a multiprotein complex that contributes to the epigenetic silencing of target genes to regulate development and homeostasis. The PRC2 complex is comprised of three core subunits: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). EED is a critical regulator of PRC2 in the silencing of expression of genes and gene clusters involved in development including but not limited to fetal orthologues (i.e. gamma globin), Hox genes, X chromosome inactivation, etc. Thus, EED provides a pharmacologic target for the treatment of diseases or disorders to impact transcription of specific target genes in blood and other tissues, including sickle cell disease.SUMMARY OF THE DISCLOSURE

[0004] Disclosed herein are methods of treating sickle cell disease in a subject, comprising administering to the subject a therapeutically effective amount of an inhibitor of polycomb repressive complex 2 (PRC2), wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has (a) been administered hydroxyurea; and / or (b) been administered a stable dose of one or more of voxelotor, crizanlizumab, and L-glutamine. In some embodiments are provided such methods wherein the subject is not concurrently administered the inhibitor of polycomb repressive complex 2 (PRC2) and hydroxyurea, voxelotor, crizanlizumab, or L- glutamine. In another embodiment is provided such methods, wherein the inhibitor of poly comb repressive complex 2 (PRC2) is an inhibitor of embryonic ectoderm development protein (EED). In some embodiments disclosed herein, the inhibitor of embryonic ectoderm development protein (EED) is MAK683, pociredir (FTX-6058), APG-5918 (EEDi-5273), HJM-353, or BR-002. In other embodiments, the inhibitor of embryonic ectoderm development protein (EED) is a compound of Formula (I).BRIEF DESCRIPTION OF THE FIGURES

[0005] FIG. 1A depicts the percentage of F cells (cells containing fetal hemoglobin) in 14-day differentiated cells post 7-day treatment with vehicle (veh), compound Example 32, or hydroxyurea (HU) from Donor A.

[0006] FIG. IB depicts the percentage of F cells (cells containing fetal hemoglobin) in 14-day differentiated cells post 7-day treatment with vehicle (veh), compound Example 32 or hydroxyurea (HU) in Donor B.

[0007] FIG. 2A depicts HBG1 mRNA levels in 14-day differentiated cells post 7-day treatment with vehicle (veh), compound Example 32 or hydroxyurea (HU) in Donor A.

[0008] FIG. 2B depicts HBG2 mRNA levels in 14-day differentiated cells post 7-day treatment with vehicle (veh), compound Example 32 or hydroxyurea (HU) in Donor A.

[0009] FIG. 2C depicts HBG1 mRNA levels in 14-day differentiated cells post 7-day treatment with vehicle (veh), compound Example 32 or hydroxyurea (HU) in Donor B.

[0010] FIG. 2D depicts HBG2 mRNA levels in 14-day differentiated cells post 7-day treatment with vehicle (veh), compound Example 32 or hydroxyurea (HU) in Donor B.DETAILED DESCRIPTION OF THE DISCLOSURE

[0011] Unless defined otherwise, all terms and ranges used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs, unless expressly defined otherwise. All patents, patent applications, and publications referred to herein are incorporated by reference to the extent they are consistent with the present disclosure.

[0012] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety generally refers to a monovalent radical (e.g. CH3-CH2- ), in certain circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term “alkylene.” (Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).

[0013] As used herein, “Polycomb Repressive Complex 2” or “PRC2 complex” refers to a mammalian multiprotein complex comprising three core subunits: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12) and two additional non- essential subunits, AEBP2, and RbAp48.

[0014] As used herein, “EED” refers to the embryonic ectoderm development protein subunit of the PRC2 complex.

[0015] As used herein, an “PRC2 inhibitor” refers to compounds of the present disclosure that are represented by formula (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of the PRC2 complex. While not wanting to be bound by any theory, we theorize that the inhibitors of the present disclosure may inhibit PRC2enzymatic activity by binding to EED to prevent assembly of the PRC2 complex on histone H3 tails thereby inhibiting its activity.

[0016] As used herein, the term “vaso-occlusive crisis (VOC) events” means an event during which a subject suffering from sickle cell disease experiences an obstruction of microcirculation by sickled red blood cells, causing ischemic injury to the organ supplied. A subject experiencing a vaso-occlusive crisis (VOC) event may experience pain, and so such events may also be referred to by those of ordinary skill in the art as “sickle cell pain crises” or “SCD pain crises.”

[0017] The term “amino” refers to -NEE.

[0018] The term “acetyl” refers to “-C(O)CH3.

[0019] As herein employed, the term “acyl” refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.

[0020] The term “alkyl” as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, “alkyl” encompasses Ci, C2, C3, C4, C5, Ce, C7, Cs, C>, C10, Cn and C12 groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0021] The term “alkenyl” as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, “alkenyl” encompasses C2, C3, C4, C5, Ce, C7, Cs, C>, C10, Cn and C12 groups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0022] The term “alkynyl” as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms. As such, “alkynyl” encompasses C2, C3, C4, C5, Ce, C7, Cs, C>, C10, Cn and C12 groups. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0023] An “alkylene,” “alkenylene,” or “alkynylene” group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Exemplary alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Exemplary alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.

[0024] The term “alkoxy” refers to -OCi-Ce alkyl.

[0025] The term “cycloalkyl” as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons. As such, “cycloalkyl” includes C3, C4, C5, Ce, C7, Cs, C>, C10, Cn and C12 cyclic hydrocarbon groups. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0026] The term “heteroalkyl” refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are independently replaced O, S, or NRX, wherein Rxis hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl and methoxypropyl.

[0027] An “aryl” group is a Ce-Ci4 aromatic moiety comprising one to three aromatic rings. As such, “aryl” includes Ce, Cio, C13, and C14 cyclic hydrocarbon groups. An exemplary aryl group is a Ce-Cio aryl group. Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0028] An “aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkylene group wherein the moiety is linked to another group via the alkyl moiety. An exemplary aralkyl group is -(Ci-Ce)alkyl(C6-Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.

[0029] A “heterocyclyl” or “heterocyclic” group is a mono- or bicyclic (fused or spiro) ring structure having from 3 to 12 atoms, (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently -C(O)-, N, NR5, O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons. Examples of heterocyclic groups include, without limitation, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4- piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0030] As used herein, “L-heterocyclyl” refers to a heterocyclyl group covalently linked to another group via an alkylene linker L, where L is C1-C4 alkylene.

[0031] 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 71 electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S. “Heteroaryl” also includes fused multicyclic (e.g. , bicyclic) ring systems in which one or more of the fused rings is nonaromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom.

[0032] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][l,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0033] A “L-heteroaryl,” “heteroaralkyl” or “heteroarylalkyl” group comprises a heteroaryl group covalently linked to another group via an alkylene linker. Examples of heteroalkyl groups comprise a Ci- C„ alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring atoms. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0034] An “arylene,” “heteroarylene,” or “heterocyclylene” group is an bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.

[0035] As employed herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as “optionally substituted” without expressly stating the substituents it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, nonhydrogen substituents.

[0036] The term “halogen” or “halo” as employed herein refers to chlorine, bromine, fluorine, or iodine.

[0037] The term “haloalkyl” refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, flurochloromethyl, chloromethyl, and fluoromethyl.

[0038] The term “hydroxyalkyl” refers to an alkyl chain, as defined herein, wherein at least on hydrogen of the alkyl chain has been replaced by hydroxyl.

[0039] As used herein, “an effective amount” of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of PRC2 complex.

[0040] As used herein, a “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of PRC2 complex. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0041] As used herein, “treatment” means any manner in which the symptoms or pathology of a condition, disorder or disease in a subject are ameliorated or otherwise beneficially altered.

[0042] Disclosed herein are methods of treating sickle cell disease in a subject, comprising administering to the subject a therapeutically effective amount of an inhibitor of polycomb repressive complex 2 (PRC2), wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has (a) been administered hydroxyurea; and / or (b) been administered a stable dose of one or more of voxelotor, crizanlizumab, and L-glutamine. In some embodiments, prior to the administration to the subject of the inhibitor of polycomb repressive complex 2(PRC2) the subject has been administered hydroxyurea. In some embodiments, prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has been administered hydroxyurea and been administered a stable dose of one or more of voxelotor, crizanlizumab, and L-glutamine. In some embodiments, prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has been administered hydroxyurea and been administered a stable dose of voxelotor. In some embodiments, prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has been administered hydroxyurea and been administered a stable dose of crizanlizumab. In some embodiments, prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has been administered hydroxyurea and been administered a stable dose of L-glutamine.

[0043] In other embodiments are provided such methods of treating sickle cell disease in a subject, wherein, prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has further experienced (a) one or more of (i) continued vaso-occlusive crisis (VOC) events or episodes of acute chest syndrome (ACS) for at least 6 months while being administered hydroxyurea at the maximum tolerated dose; (ii) an inability to tolerate the adverse effects of the continued administration to the subject of hydroxyurea; (iii) unmanageable drug -drug interactions as a result of the continued administration to the subject of hydroxyurea; and (iv) the subject’s refusal to continue the further administration of hydroxyurea; or (b) one or more of (i) continued pain crisis events and other vaso-occlusive crisis (VOC) events while on a stable dose of voxelotor, crizanlizumab, or L- glutamine for at least 6 months; (ii) a failure to increase hemoglobin (Hb) by 1 g / dL in a subject receiving voxelotor; (iii) continued vaso-occlusive crisis (VOC) events in a subject receiving crizanlizumab or L-glutamine; (iv) an inability to tolerate the adverse effects of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; (v) unmanageable drug -drug interactions as a result of the continued administration to the subject of voxelotor, crizanlizumab, or L- glutamine; and (vi) the subject’s refusal to continue the further administration of voxelotor, crizanlizumab, or L-glutamine.

[0044] In other embodiments are provided such methods of treating sickle cell disease in a subject, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has further experienced one or more of (i) continued vaso-occlusive crisis (VOC) events or episodes of acute chest syndrome (ACS) for at least 6 months while being administered hydroxyurea at the maximum tolerated dose; (ii) an inability to tolerate the adverse effects of the continued administration to the subject of hydroxyurea; (iii) unmanageable drug -drug interactions as a result of the continued administration to the subject of hydroxyurea; and (iv) the subject’s refusal to continue the further administration of hydroxyurea. In some embodiments, the subject further experienced continued vaso-occlusive crisis (VOC) events or episodes of acute chest syndrome (ACS) for at least 6 months while being administered hydroxyurea at the maximum tolerated dose . In some embodiments, the subject further experienced an inability to tolerate the adverse effects of the continued administration to the subject of hydroxyurea. In some embodiments, the subject further experiencedunmanageable drug -drug interactions as a result of the continued administration to the subject of hydroxyurea. In some embodiments, the subject refused to continue the further administration of hydroxyurea.

[0045] In other embodiments are provided such methods of treating sickle cell disease in a subject, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has further experienced one or more of (i) continued pain crisis events and other vaso-occlusive crisis (VOC) events while on a stable dose of voxelotor, crizanlizumab, or L-glutamine for at least 6 months; (ii) a failure to increase hemoglobin (Hb) by 1 g / dL in a subject receiving voxelotor; (iii) continued vaso-occlusive crisis (VOC) events in a subject receiving crizanlizumab or L- glutamine; (iv) an inability to tolerate the adverse effects of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; (v) unmanageable drug-drug interactions as a result of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; and (vi) the subject’s refusal to continue the further administration of voxelotor, crizanlizumab, or L-glutamine. In some embodiments, the subject further experienced continued pain crisis events and other vaso-occlusive crisis (VOC) events while on a stable dose of voxelotor, crizanlizumab, or L-glutamine for at least 6 months. In some embodiments, the subject further experienced a failure to increase hemoglobin (Hb) by 1 g / dL in a subject receiving voxelotor. In some embodiments, the subject further experienced continued vaso-occlusive crisis (VOC) events in a subject receiving crizanlizumab or L-glutamine. In some embodiments, the subject further experienced an inability to tolerate the adverse effects of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine. In some embodiments, the subject further experienced unmanageable drug-drug interactions as a result of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine. In some embodiments, the subject refused to continue the further administration of voxelotor, crizanlizumab, or L-glutamine.

[0046] In another embodiment is provided such methods of treating sickle cell disease in a subject, wherein the subject has been administered hydroxyurea prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2). In some embodiments, in the 6-month period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject further experienced one or more of (a) the same or higher number of pain crises or other vaso-occlusive crisis (VOC) events compared to the prior to the 6-month period; (b) episodes of acute chest syndrome (ACS); (c) an inability to tolerate continued administration of hydroxyurea; (d) unmanageable drug -drug interactions with the continued administration of hydroxyurea; and (e) the subject’s refusal to continue the further administration of hydroxyurea. In some embodiments, in the 6-month period prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject further experienced the same or higher number of pain crises or other vaso-occlusive crisis (VOC) events compared to the prior to the 6-month period. In some embodiments, in the 6-month period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject further experienced episodes of acute chest syndrome (ACS). In some embodiments, in the 6-month period prior to the administration to the subject of the inhibitor of poly comb repressive complex 2(PRC2) the subject further experienced an inability to tolerate continued administration of hydroxyurea. In some embodiments, the inability to tolerate continued administration of hydroxyurea is characterized by one or more of the following: (a) allergic reaction to the administration of hydroxyurea; (b) hematologic toxicity; (c) inability to tolerate gastrointestinal side effects; (d) intolerable fatigue; (e) intolerable dizziness; (f) intolerable headaches; (g) intolerable fever; (h) intolerable leg ulcers; and (i) intolerable skin changes. In some embodiments, the hematologic toxicity is characterized by a decrease in one or more of red blood cells, white blood cells, and platelets. In some embodiments, the gastrointestinal side effects are selected from one or more of nausea, vomiting, diarrhea, and abdominal pain. In some embodiments, in the 6-month period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject further experienced unmanageable drugdrug interactions with the continued administration of hydroxyurea. In some embodiments, in the 6- month period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject refused to continue the further administration of hydroxyurea.

[0047] In another embodiment is provided such methods of treating sickle cell disease in a subject, wherein the subject has been administered one or more of voxelotor, crizanlizumab, and L-glutamine prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2).

[0048] In some embodiments, the subject has been administered voxelotor prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2). In some embodiments, the subject has further exhibited one or more of (a) a failure to increase hemoglobin (Hb) by at least 1 g / dL, (b) an inability tolerate continued administration of voxelotor, (c) unmanageable drug-drug interactions as a result of the continued administration to the subject of voxelotor, and (d) the subject’s refusal to continue the further administration of voxelotor.

[0049] In some embodiments, the subject has been administered crizanlizumab prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2). In some embodiments, the subject has further exhibited one or more of (a) the same or higher number of pain crises or other vaso-occlusive crisis (VOC) events compared to the prior to the 6-month period, (b) an inability tolerate continued administration of crizanlizumab, (c) unmanageable drug-drug interactions as a result of the continued administration to the subject of crizanlizumab, and (d) the subject’s refusal to continue the further administration of crizanlizumab.

[0050] In some embodiments, the subject has been administered L-glutamine prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2). In some embodiments, the subject has further exhibited one or more of (a) the same or higher number of pain crises or other vaso-occlusive crisis (VOC) events compared to the prior to the 6-month period, (b) an inability tolerate continued administration of L-glutamine, (c) unmanageable drug -drug interactions as a result of the continued administration to the subject of L-glutamine, and (d) the subject’s refusal to continue the further administration of L-glutamine.

[0051] Further provided herein are the described methods of treating sickle cell disease in a subject, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2(PRC2) the subject has further experienced one or more of (a) 4 or more vaso-occlusive crisis (VOC) events over the prior 12-month period; (b) 2 or more vaso-occlusive crisis (VOC) events over the prior 6- month period; (c) 2 or more vaso-occlusive crisis (VOC) events over the prior 12-month period and at least one of one or more acute chest syndrome (ACS) events, hepatic and splenic sequestration, and priapism; (d) 2 or more acute chest syndrome (ACS) events, hepatic and splenic sequestration, and priapism over the prior 12-month period; (e) pulmonary hypertension; and (f) chronic kidney disease. In some embodiments, the pulmonary hypertension is characterized by one or more of (a) tricuspid regurgitant jet velocity (TRV) of greater than or equal to 3.0 m / s; (b) TRV of greater than or equal to 2.5 m / s and N-terminal pro b-type natriuretic peptide (NT-proBNP) plasma level of greater than or equal to 160 pg / mL; and (c) documented ongoing pulmonary hypertension diagnosed from previous echocardiogram or right-sided heart catheterization with mean pulmonary artery pressure greater than 25 mm Hg. In some embodiments, the chronic kidney disease is characterized by measurement on two separate and consecutive occasions of one or more of (a) an estimated glomerular filtration rate (eGFR) of greater than or equal to 30 mL / min / 1.73 m2and less than 60 mL / min / 1.73 m2; and (b) proteinuria characterized by an albumin to creatinine ratio greater than 300 mg / g or protein to creatinine ratio greater than 30 mg / mmol.

[0052] Further provided herein are the described methods of treating sickle cell disease in a subject, wherein the subject is not concurrently administered the inhibitor of polycomb repressive complex 2 (PRC2) and hydroxyurea, voxelotor, crizanlizumab, or L-glutamine. In some embodiments, the subject is not concurrently administered the inhibitor of polycomb repressive complex 2 (PRC2) and hydroxyurea, the subject is not concurrently administered the inhibitor of polycomb repressive complex 2 (PRC2) and crizanlizumab. In some embodiments, the subject is not concurrently administered the inhibitor of poly comb repressive complex 2 (PRC2) and L-glutamine.

[0053] Further provided herein are the described methods of treating sickle cell disease in a subject, wherein in the 60-day period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has not been administered one or more of hydroxyurea, voxelotor, crizanlizumab, and L-glutamine. In some embodiments, in the 60-day period prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has not been administered hydroxyurea. In some embodiments, in the 60-day period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has not been administered voxelotor. In some embodiments, in the 60-day period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has not been administered crizanlizumab. In some embodiments, in the 60-day period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has not been administered L-glutamine.

[0054] Further provided herein are the described methods of treating sickle cell disease in a subject, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject (a) has not undergone major surgery, serious illness, infection, fever, significantbleeding, cerebrovascular accident, or seizure within 14 days prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2); (b) is not being administered anticoagulants or medications that induce or inhibit cytochrome P450 (CYP) 3A4, inhibit P -glycoprotein, breast cancer resistance protein, or multidrug and toxin extrusion protein 2-K, or are substrates of CYP2B6 within 14 days prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2); (c) has not received a bone marrow transplant or human stem cell transplant or gene therapy; (d) has not received a vaccination in the 7 days prior to administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2); (e) is not exhibiting alanine aminotransferase of equal to or greater than 3 times the upper limit of normal (ULN), albumin less than 2.0 mg / dL, direct (conjugated) bilirubin greater than 1.5mg / dL, or prothrombin time greater than 1.5 ULN; (f) does not have severe renal disease defined as eGFR less than 30 mL / min / 1.73 m2; (g) is not undergoing dialysis; (h) does not have a history of human immunodeficiency virus (HIV) infection, a history of hepatitis B infection, or active hepatitis C infection; (i) is not receiving regularly scheduled transfusions; (j ) has not been transfused within the prior 60-day period; (k) has not tested positive for illicit drugs of abuse other than opioids, tetrahydrocannabinol, or cannabidiol; (1) is not pregnant, a lactating female, or a female of childbearing age unable or who is unwilling to comply with birth control or abstinence during the period during which the inhibitor of poly comb repressive complex 2 (PRC2) is administered to the subject; (m) has not exhibited a heart rate corrected QT interval -Fridericia’s method (QTcF) of greater than 450 msec (male) or greater than 470 msec (female); (n) has not exhibited an active malignancy or history of cancer (except for squamous cell skin cancer, basal cell skin cancer, or stage 0 cervical carcinoma in situ, with no recurrence for the last 5 years); or (o) has not exhibited the presence of a chromosomal abnormality or genetic mutation that may put the subject at an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

[0055] Further provided herein are the described methods of treating sickle cell disease in a subject, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject is contraindicated for transfusions.

[0056] Further provided herein are the described methods of treating sickle cell disease in a subject, wherein the inhibitor of polycomb repressive complex 2 (PRC2) is an inhibitor of embryonic ectoderm development protein (EED). In some embodiments, the inhibitor of embryonic ectoderm development protein (EED) is MAK683. In some embodiments, the inhibitor of embryonic ectoderm development protein (EED) is pociredir (FTX-6058). In some embodiments, the inhibitor of embryonic ectoderm development protein (EED) is APG-5918 (EEDi-5273). In some embodiments, the inhibitor of embryonic ectoderm development protein (EED) is HJM-353. In some embodiments, the inhibitor of embryonic ectoderm development protein (EED) is BR-002.

[0057] Further provided herein are the described methods of treating sickle cell disease in a subject, wherein the inhibitor of embryonic ectoderm development protein (EED) is a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof: wherein: represents a single or a double bond;Z is O or S;X is O, CR5, CR5OH, or C(R5)2, wherein: when X is O, is a single bond; when X is C(R5)2, is a single bond; when X is CR5OH, is a single bond; or when X is CR5, is a double bond;R1is aryl, heteroaryl, L-cycloalkyl, -N(R5)heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl and the cyclyl portion of the L-cycloalkyl, -N(R5)heterocyclyl, and L-heterocyclyl may be optionally substituted with one or more R4;R2is cyano, -COOR5or-C(O)N(R5)2, ;R3is C1-C3 alkyl or halogen; each R4is independently oxo, cyano, halogen, -P(O)(OCi-C3)2, alkoxy, hydroxyl, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR5, -Y2-haloalkyl, -Y’-Ci-Ce alkyl, -Y2-Ci-Ce alkyl, -L- cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y’-heterocyclyl, -Y2-heterocyclyl, -L-N(R5)2, -O-L- N(R5)2, -N(R5)CO(R6), -O-L-OR5, -C(CF3)N(R5)2, -Y’-N(R5)2, -Y2-N(R5)2wherein the ring portion of the aralkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl and -Y’-heterocyclyl may be optionally substituted with one or more R7;L is a bond or C1-C4 alkylene;Y1is a bond, -C(O)-, or -NHC(O)-;Y2is a bond, -S-, -SO-, -SO2-, or -NR5SO2-, each R5is independently hydrogen or C1-C3 alkyl; or each R5taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R6;R6is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl;each R7is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R5)2, Ci-Ce alkyl or -Y1-heterocyclyl, wherein -Y1-heterocyclyl may be optionally substituted with one or more R6; and n is 1 or 2.

[0058] In some embodiments are such methods wherein in the compound of Formula (I) Z is O. In some embodiments Z is S. In some embodiments n is 1. In some embodiments wherein R2is cyano. In some embodiments R2is -COOR5. In some embodiments R2is -C(O)N(R5)2. In some embodiments R3is halogen, wherein in some embodiments the halogen is fluorine. In some embodiments X is C(R5)2 and is a single bond. In some embodiments X is CR5and is a double bond. In some embodiments X is O and is a single bond.

[0059] In some embodiments, in the compounds of Formula (I) R1is aryl optionally substituted with one or more R4. In some embodiments, the aryl is phenyl optionally substituted with one or more R4. In some embodiments, the phenyl is substituted with one, two or three R4. In some embodiments, the one, two or three R4are each independently halogen, hydroxyl, haloalkyl, -COOR5, -Y’-Ci-Ce alkyl, Y2-Ci- C6alkyl, -L-N(R5)2, -O-L-N(R5)2, -C(CF3)N(R5)2, -Y1-N(R5)2, -Y2-N(R5)2, Y2-haloalkyl, -L-heterocyclyl, or -Y1-heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl or -Y1-heterocyclyl may be optionally substituted with one or more R7. In some embodiments, R4is -Y’-Ci-Ce alkyl and Y1is a bond and the Ci-Ce alkyl is methyl, ethyl, isopropyl, butyl or pentyl. In some embodiments, R4is -Y2-Ci-Ce alkyl and Y2is a -SO2- and the Ci-Ce alkyl is methyl. In some embodiments, R4is -Y2-haloalkyl and Y2is -S- or -SO2- and the haloalkyl is trifluoromethyl. In some embodiments, R4is -L-N(R5)2 and L is a bond and each R5is hydrogen, each R5is methyl, or one R5is methyl and one R5is hydrogen. In some embodiments, R4is -L-N(R5)2 and L is methylene or ethylene and each R5is hydrogen, each R5is methyl, or one R5is methyl and one R5is hydrogen. In some embodiments, R4is -Y’-N(R5)2, Y1is -C(O)- and each R5independently is hydrogen, each R5is independently methyl, or one R5is methyl and one R5is hydrogen. In some embodiments, R4is -Y2-N(R5)2, Y2is -SO2- and each R5independently is hydrogen, each R5is methyl, or one R5is methyl and one R5is independently hydrogen. In some embodiments, R4is -Y1-heterocyclyl and Y1is -C(O)- and the heterocyclyl portion of the L-heterocyclyl is piperazinyl or 4-methyl-piperazinyl. In some embodiments, R4is -L-heterocyclyl and L is a bond and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or 3X2-azabicyclo[3.I.0]hexanyl, each optionally substituted with one or more R7selected from oxo, C1-C3 alkyl, alkoxy, hydroxyl and / or halogen. In some embodiments, R4is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R7selected from C1-C3 alkyl, alkoxy, hydroxyl and / or halogen. In some embodiments, R4is -Y1-heterocyclyl and Y1is -C(O)- and the heterocyclyl portion of the Y1-heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl. In some embodiments, R4is -L-heteroaryl optionally substituted with one or more R7, wherein in some embodiments, the -L-heteroaryl is tetrazolyl. In some embodiments, R4is -POs / Ci-C s alkyl)2. Insome embodiments, R4is -COOR5. In some embodiments, R4is hydroxyalkyl. In some embodiments, R4is -O-L-N(R5)2. In some embodiments, R4is aralkyl.

[0060] In some embodiments, in the compounds of Formula (I), R1is heteroaryl optionally substituted with one or more R4. In some embodiments, the heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, each optionally substituted with one or more R4. In some embodiments, the heteroaryl is substituted with one or more R4; wherein each R4is independently cyano, halogen, -Y’-Ci-Ce alkyl, -Y2-Ci-Ce alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -L-N(R5)2, -Y’-N(R5)2, -L-heteroaryl, -L- heterocyclyl, or -Y1-heterocyclyl, wherein the heteroaryl of the -L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl, or Y1-heterocyclyl may be optionally substituted with one or more R7. In some embodiments, the heteroaryl is pyrazolyl optionally substituted with one R4independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R5)2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl may be optionally substituted with one or more R7. In some embodiments, R4is -L-heteroaryl and L is methylene where the heteroaryl is pyridyl optional substituted with one or more R7. In some embodiments, R4is -L- heterocyclyl optionally substituted with one or more R7where L is a bond and the heterocyclyl portion of the L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl or 4-methylpiperazinyl. In some embodiments, R4is -L-heterocyclyl optionally substituted with one or more R7where L is methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl or 4-methylpiperazinyl. In some embodiments, R4is -L-N(R5)2 where L is methylene and each R5is independently hydrogen, each R5is independently C1-C3 alkyl, or one R5is C1-C3 alkyl and one R5is hydrogen. In some embodiments, R4is -Y’-Ci-Ce alkyl where Y1is a bond and the Ci-Ce alkyl is methyl, ethyl or isopropyl. In some embodiments, the heteroaryl is pyrazolyl optionally substituted with two R4groups each independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, and -Y’-Ci-Ce alkyl. In some embodiments, the heteroaryl is pyridyl optionally substituted with one R4independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R5)2, -Y’-N(R5)2, -L-cycloalkyl, or - L-heterocyclyl optionally substituted with one or more R7.

[0061] In some embodiments, in the compounds of Formula (I), R1is -L-cycloalkyl optionally substituted with one or more R4.

[0062] In some embodiments, in the compounds of Formula (I), R1is -L-heterocyclyl optionally substituted with one or more R4. In some embodiments, L is a bond and the heterocyclyl is piperidinyl or tetrahydropyranyl .

[0063] In some embodiments, in the compounds of Formula (I), wherein n is two.

[0064] Further provided herein are the described methods of treating sickle cell disease in a subject, wherein the inhibitor of polycomb repressive complex 2 (PRC2) is a compound selected from

[0065] Further provided herein are the described methods of treating sickle cell disease in a subject, wherein the inhibitor of polycomb repressive complex 2 (PRC2) is a compound selected from the grouppharmaceutically acceptable salt thereof.

[0066] In other embodiments are provided the methods disclosed herein, wherein the compound ofFormulapharmaceutically acceptable salt thereof.

[0067] In other embodiments are provided the methods disclosed herein, wherein the compound ofFormulapharmaceutically acceptable salt thereof.

[0068] In other embodiments are provided the methods disclosed herein, wherein the compound ofFormulapharmaceutically acceptable salt thereof.

[0069] In other embodiments are provided the methods disclosed herein, wherein the compound ofpharmaceutically acceptable salt thereof.

[0070] Also provided herein are methods of treating sickle cell disease in a subject as disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound which is(Example 32), or a pharmaceutically acceptable salt thereof, wherein Example 32 is in crystalline form. Also provided herein are such methods wherein the crystalline form of Example 32 is an anhydrous form. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 8. 1° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 9.6° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.7° ± 0.2° 2-theta, 19.7° ± 0.2° 2-theta, and 22.0° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 9.8° ± 0.2° 2-theta, 15.2° ± 0.2° 2-theta, and 17.7° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of about 172 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 205 °C to about 210 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 206 °C to about 210 °C, or from about 207 °C to about 210 °C, or from about 208 °C to about 210 °C, or from about 209 °C to about210 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a loss in mass in a thermal gravimetric analysis of less than about 1% upon heating the sample from about 25 °C to a temperature prior to melting. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a loss in mass in a thermal gravimetric analysis of less than about 1% upon heating the sample from about 25 °C to about 380 °C.

[0071] Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 7.7° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 13.7° ± 0.2° 2-theta and 19.2° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5° ± 0.2° 2-theta, 8.6° ± 0.2° 2-theta, 15.9° ± 0.2° 2-theta, 19.9° ± 0.2° 2-theta, and 24.1° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6° ± 0.2° 2-theta, 11.0° ± 0.2° 2-theta, 15.4° ± 0.2° 2-theta, 21.0° ± 0.2° 2-theta, and 26.3° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 210 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 208 °C, or from about 203 °C to about 206 °C, or from about 203 °C to about 205 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 380 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 210 °C.

[0072] Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 7.7° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further a peak in an x-ray powder diffraction (XRPD) pattern at 15.4° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further a peak in an x-ray powder diffraction (XRPD) pattern at 19.2° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 13.7° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5° ± 0.2° 2-theta, 8.6° ± 0.2° 2-theta, 15.9° ± 0.2° 2-theta, 19.9° ± 0.2° 2-theta, and 24.1° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6° ± 0.2° 2-theta, 11.0° ± 0.2° 2-theta, 21.0° ± 0.2° 2-theta, and 26.3° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 210 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 206 °C to about 210 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 208 °C, or from about 203 °C to about 206 °C, or from about 203 °C to about 205 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the samplefrom about 25 °C to about 380 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 210 °C.

[0073] Also provided herein are such methods wherein the crystalline form of Example 32 exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 7.7° ± 0.2° 2-theta and 15.4° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 19.2° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 13.7° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5° ± 0.2° 2-theta, 8.6° ± 0.2° 2-theta, 15.9° ± 0.2° 2-theta, 19.9° ± 0.2° 2-theta, and 24.1° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6° ± 0.2° 2-theta, 11.0° ± 0.2° 2-theta, 21.0° ± 0.2° 2-theta, and 26.3° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 210 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 206 °C to about 210 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 208 °C, or from about 203 °C to about 206 °C, or from about 203 °C to about 205 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 380 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a loss in mass in athermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 210 °C.

[0074] Also provided herein are such methods wherein the crystalline form of Example 32 exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 7.7° ± 0.2° 2-theta and 19.2° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 15.4° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 13.7° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 5.5° ± 0.2° 2-theta, 8.6° ± 0.2° 2-theta, 15.9° ± 0.2° 2-theta, 19.9° ± 0.2° 2-theta, and 24.1° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 10.6° ± 0.2° 2-theta, 11.0° ± 0.2° 2-theta, 21.0° ± 0.2° 2-theta, and 26.3° ± 0.2° 2-theta. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 210 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 206 °C to about 210 °C. Also provided herein aresuch methods wherein the crystalline form of Example 32 exhibits a peak in a differential scanning calorimetry pattern of from about 203 °C to about 208 °C, or from about 203 °C to about 206 °C, or from about 203 °C to about 205 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a loss in mass in a thermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 380 °C. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits a loss in mass in athermal gravimetric analysis of less than about 2% upon heating the sample from about 25 °C to about 210 °C.

[0075] Also provided herein are such methods wherein the crystalline form of Example 32 exhibits less than about 10% degradation when stored at 25 °C and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.

[0076] Also provided herein are such methods wherein the crystalline form of Example 32 (a) exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 8. 1° ± 0.2° 2-theta, and (b) exhibits less than about 10% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Example 32 (a) exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 9.6° ± 0.2° 2-theta, 5.7° ± 0.2° 2-theta, 19.7° ± 0.2° 2-theta, and 22.0° ± 0.2° 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.

[0077] Also provided herein are such methods wherein the crystalline form of Example 32 (a) exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 7.7° ± 0.2° 2-theta, and (b) exhibits less than about 10% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 7.7° ± 0.2° 2-theta, 13.7° ± 0.2° 2-theta, and 19.2° ± 0.2° 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 25 °C and 60% relative humidity for at least 7 days.

[0078] Also provided herein are such methods wherein the crystalline form of Example 32 exhibits less than about 10% degradation when the crystalline forms are stored at 40 °C and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form ofExample 32 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.

[0079] Also provided herein are such methods wherein the crystalline form of Example 32 exhibits (a) a peak in an x-ray powder diffraction (XRPD) pattern at 8. 1° ± 0.2° 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 9.6° ± 0.2° 2-theta, 5.7° ± 0.2° 2-theta, 19.7° ± 0.2° 2-theta, and 22.0° ± 0.2° 2-theta , and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.

[0080] Also provided herein are such methods wherein the crystalline form of Example 32 exhibits (a) a peak in an x-ray powder diffraction (XRPD) pattern at 7.7° ± 0.2° 2-theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits (a) peaks in an x-ray powder diffraction (XRPD) pattern at 7.7° ± 0.2° 2-theta, 13.7° ± 0.2° 2-theta, and 19.2° ± 0.2° 2- theta, and (b) less than about 10% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 40 °C and 75% relative humidity for at least 7 days.

[0081] Also provided herein are such methods wherein the crystalline form of Example 32 exhibits less than about 10% degradation when the crystalline form is stored at 60 °C for at least one week. Also provided herein are such methods wherein the crystalline form of Example 32 exhibits less than about 1%, or less than about 2%, or less than about 3%, or less than about 4%, or less than about 5%, or less than about 6%, or less than about 7%, or less than about 8%, or less than about 9% degradation when the crystalline form is stored at 60 °C for at least one week.

[0082] In other embodiments are provided the methods disclosed herein, wherein the compound ofpharmaceutically acceptable salt thereof.In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I)pharmaceutically acceptable salt thereof.In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I)pharmaceutically acceptable salt thereof.In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I)pharmaceutically acceptable salt thereof.In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I)pharmaceutically acceptable salt thereof.In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I)pharmaceutically acceptable salt thereof.In other embodiments are provided the methods disclosed herein, wherein the compound of Formula (I)pharmaceutically acceptable salt thereof.

[0083] In other embodiments are provided the methods disclosed herein, wherein the compound ofFormula (pharmaceutically acceptable salt thereof.

[0084] In another aspect, the disclosure provides pharmaceutical compositions comprising a PRC2 inhibitor as disclosed herein and a pharmaceutically acceptable carrier, excipient, or diluent for use in the treatment of sickle cell disease in a subject. Compounds of the disclosure may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. Incertain embodiments, compounds disclosed herein are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be by the oral route.

[0085] The characteristics of the carrier will depend on the route of administration. As used herein, the term “pharmaceutically acceptable” means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the disclosure may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0086] As used herein, the term “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula — NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0087] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a subject a therapeutically effective amount without causing serious toxic effects in the subject treated. A dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg / kg, preferably 0. 1 to 100 mg / kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt / wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.Embodiments

[0088] Embodiment 1: A method of treating sickle cell disease in a subject, comprising administering to the subject a therapeutically effective amount of an inhibitor of polycomb repressive complex 2 (PRC2), wherein prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has:a. been administered hydroxyurea; and / or b. been administered a stable dose of one or more of voxelotor, crizanlizumab, and L- glutamine.

[0089] Embodiment 2: The method of embodiment 1, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has further experienced: a. one or more of (i) continued vaso-occlusive crisis (VOC) events or episodes of acute chest syndrome (ACS) for at least 6 months while being administered hydroxyurea at the maximum tolerated dose; (ii) an inability to tolerate the adverse effects of the continued administration to the subject of hydroxyurea; (iii) unmanageable drug-drug interactions as a result of the continued administration to the subject of hydroxyurea; and (iv) the subject’s refusal to continue the further administration of hydroxyurea; or b. one or more of (i) continued pain crisis events and other vaso-occlusive crisis (VOC) events while on a stable dose of voxelotor, crizanlizumab, or L-glutamine for at least 6 months; (ii) a failure to increase hemoglobin (Hb) by 1 g / dL in a subject receiving voxelotor; (iii) continued vaso-occlusive crisis (VOC) events in a subject receiving crizanlizumab or L-glutamine; (iv) an inability to tolerate the adverse effects of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; (v) unmanageable drug -drug interactions as a result of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; and (vi) the subject’s refusal to continue the further administration of voxelotor, crizanlizumab, or L-glutamine.

[0090] Embodiment 3 : The method of embodiment 2, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has further experienced one or more of (i) continued vaso-occlusive crisis (VOC) events or episodes of acute chest syndrome (ACS) for at least 6 months while being administered hydroxyurea at the maximum tolerated dose; (ii) an inability to tolerate the adverse effects of the continued administration to the subject of hydroxyurea; (iii) unmanageable drug -drug interactions as a result of the continued administration to the subject of hydroxyurea; and (iv) the subject’s refusal to continue the further administration of hydroxyurea.

[0091] Embodiment 4: The method of embodiment 2, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has further experienced one or more of (i) continued pain crisis events and other vaso-occlusive crisis (VOC) events while on a stable dose of voxelotor, crizanlizumab, or L-glutamine for at least 6 months; (ii) a failure to increase hemoglobin (Hb) by 1 g / dL in a subject receiving voxelotor; (iii) continued vaso-occlusive crisis (VOC) events in a subject receiving crizanlizumab or L-glutamine; (iv) an inability to tolerate the adverse effects of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; (v) unmanageable drug -drug interactions as a result of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; and (vi) the subject’s refusal to continue the further administration of voxelotor, crizanlizumab, or L-glutamine.

[0092] Embodiment 5: The method of embodiment 1, wherein the subject has been administered hydroxyurea prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2).

[0093] Embodiment 6: The method of embodiment 5, wherein in the 6-month period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has further experienced one or more of (a) the same or higher number of pain crises or other vaso-occlusive crisis (VOC) events compared to the prior to the 6-month period; (b) episodes of acute chest syndrome (ACS); (c) an inability to tolerate continued administration of hydroxyurea; (d) unmanageable drug -drug interactions with the continued administration of hydroxyurea; and (e) the subject’s refusal to continue the further administration of hydroxyurea.

[0094] Embodiment 7 : The method of embodiment 6, wherein the inability to tolerate continued administration of hydroxyurea is characterized by one or more of the following: (a) allergic reaction to the administration of hydroxyurea; (b) hematologic toxicity; (c) inability to tolerate gastrointestinal side effects; (d) intolerable fatigue; (e) intolerable dizziness; (f) intolerable headaches; (g) intolerable fever; (h) intolerable leg ulcers; and (i) intolerable skin changes.

[0095] Embodiment 8: The method of embodiment 7, wherein the hematologic toxicity is characterized by a decrease in one or more of red blood cells, white blood cells, and platelets.

[0096] Embodiment 9: The method of embodiment 7, wherein the gastrointestinal side effects are selected from one or more of nausea, vomiting, diarrhea, and abdominal pain.

[0097] Embodiment 10: The method of embodiment 1, wherein the subject has been administered one or more of voxelotor, crizanlizumab, and L-glutamine prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2).

[0098] Embodiment 11: The method of embodiment 10, wherein the subject has been administered voxelotor prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2).

[0099] Embodiment 12: The method of embodiment 11, wherein the subject has further exhibited one or more of (a) a failure to increase hemoglobin (Hb) by at least 1 g / dL, (b) an inability tolerate continued administration of voxelotor, (c) unmanageable drug-drug interactions as a result of the continued administration to the subject of voxelotor, and (d) the subject’s refusal to continue the further administration of voxelotor.[000100] Embodiment 13: The method of embodiment 10, wherein the subject has been administered crizanlizumab prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2).[000101] Embodiment 14: The method of embodiment 13, wherein the subject has further exhibited one or more of (a) the same or higher number of pain crises or other vaso-occlusive crisis (VOC) events compared to the prior to the 6-month period, (b) an inability tolerate continued administration of crizanlizumab, (c) unmanageable drug-drug interactions as a result of the continued administration to thesubject of crizanlizumab, and (d) the subject’s refusal to continue the further administration of crizanlizumab.[000102] Embodiment 15: The method of embodiment 10, wherein the subject has been administered L- glutamine prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2).[000103] Embodiment 16: The method of embodiment 15, wherein the subject has further exhibited one or more of (a) the same or higher number of pain crises or other vaso-occlusive crisis (VOC) events compared to the prior to the 6-month period, (b) an inability tolerate continued administration of L- glutamine, (c) unmanageable drug-drug interactions as a result of the continued administration to the subject of L-glutamine, and (d) the subject’s refusal to continue the further administration of L- glutamine.[000104] Embodiment 17: The method of any one of embodiments 1 to 16, wherein prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has further experienced one or more of: a. 4 or more vaso-occlusive crisis (VOC) events over the prior 12-month period; b. 2 or more vaso-occlusive crisis (VOC) events over the prior 6-month period; c. 2 or more vaso-occlusive crisis (VOC) events over the prior 12-month period and at least one of one or more acute chest syndrome (ACS) events, hepatic and splenic sequestration, and priapism; d. 2 or more acute chest syndrome (ACS) events, hepatic and splenic sequestration, and priapism over the prior 12-month period; e. pulmonary hypertension; and f. chronic kidney disease.[000105] Embodiment 18: The method of embodiment 17, wherein the pulmonary hypertension is characterized by one or more of (a) tricuspid regurgitant jet velocity (TRV) of greater than or equal to 3.0 m / s; (b) TRV of greater than or equal to 2.5 m / s and N-terminal pro b-type natriuretic peptide (NT- proBNP) plasma level of greater than or equal to 160 pg / mL; and (c) documented ongoing pulmonary hypertension diagnosed from previous echocardiogram or right-sided heart catheterization with mean pulmonary artery pressure greater than 25 mm Hg.[000106] Embodiment 19: The method of embodiment 17, wherein the chronic kidney disease is characterized by measurement on two separate and consecutive occasions of one or more of (a) an estimated glomerular fdtration rate (eGFR) of greater than or equal to 30 mL / min / 1.73 m2and less than 60 mL / min / 1.73 m2; and (b) proteinuria characterized by an albumin to creatinine ratio greater than 300 mg / g or protein to creatinine ratio greater than 30 mg / mmol.[000107] Embodiment 20: The method of any one of embodiments 1 to 19, wherein the subject is not concurrently administered the inhibitor of polycomb repressive complex 2 (PRC2) and hydroxyurea, voxelotor, crizanlizumab, or L-glutamine.[000108] Embodiment 21 : The method of any one of embodiments 1 to 20, wherein in the 60-day period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has not been administered one or more of hydroxyurea, voxelotor, crizanlizumab, and L- glutamine.[000109] Embodiment 22: The method of any one of embodiments 1 to 21, wherein prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject: a. has not undergone major surgery, serious illness, infection, fever, significant bleeding, cerebrovascular accident, or seizure within 14 days prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2); b. is not being administered anticoagulants or medications that induce or inhibit cytochrome P450 (CYP) 3A4, inhibit P-glycoprotein, breast cancer resistance protein, or multidrug and toxin extrusion protein 2-K, or are substrates of CYP2B6 within 14 days prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2); c. has not received a bone marrow transplant or human stem cell transplant or gene therapy; d. has not received a vaccination in the 7 days prior to administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2); e. is not exhibiting alanine aminotransferase of equal to or greater than 3 times the upper limit of normal (ULN), albumin less than 2.0 mg / dL, direct (conjugated) bilirubin greater than 1.5mg / dL, or prothrombin time greater than 1.5 ULN; f. does not have severe renal disease defined as eGFR less than 30 mL / min / 1.73 m2; g. is not undergoing dialysis; h. does not have a history of human immunodeficiency virus (HIV) infection, a history of hepatitis B infection, or active hepatitis C infection; i. is not receiving regularly scheduled transfusions; j . has not been transfused within the prior 60-day period; k. has not tested positive for illicit drugs of abuse other than opioids, tetrahydrocannabinol, or cannabidiol; l. is not pregnant, a lactating female, or a female of childbearing age unable or who is unwilling to comply with birth control or abstinence during the period during which the inhibitor of poly comb repressive complex 2 (PRC2) is administered to the subject; m. has not exhibited a heart rate corrected QT interval -Fridericia’s method (QTcF) of greater than 450 msec (male) or greater than 470 msec (female); n. has not exhibited an active malignancy or history of cancer (except for squamous cell skin cancer, basal cell skin cancer, or stage 0 cervical carcinoma in situ, with no recurrence for the last 5 years); oro. has not exhibited the presence of a chromosomal abnormality or genetic mutation that may put the subject at an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).[000110] Embodiment 23 : The method of any one of embodiments 1 to 22, wherein prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject is contraindicated for transfusions.[000111] Embodiment 24: The method of any one of embodiments 1 to 23, wherein the inhibitor of polycomb repressive complex 2 (PRC2) is an inhibitor of embryonic ectoderm development protein (EED).[000112] Embodiment 25 : The method of embodiment 24, wherein the inhibitor of embryonic ectoderm development protein (EED) is MAK683, pociredir (FTX-6058), APG-5918 (EEDi-5273), HJM-353, or BR-002.[000113] Embodiment 26: The method of embodiment 24, wherein the inhibitor of embryonic ectoderm development protein (EED) is a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof: wherein: represents a single or a double bond;Z is O or S;X is O, CR5, CR5OH, or C(R5)2, wherein: when X is O, is a single bond; when X is C(R5)2, is a single bond; when X is CR5OH, is a single bond; or when X is CR5, is a double bond;R1is aryl, heteroaryl, L-cycloalkyl, -N(R5)heterocyclyl, or L-heterocyclyl, wherein the aryl, the heteroaryl and the cyclyl portion of the L-cycloalkyl, -N(R5)heterocyclyl, and L-heterocyclyl may be optionally substituted with one or more R4;R2is cyano, -COOR5or-C(O)N(R5)2, ;R3is C1-C3 alkyl or halogen;each R4is independently oxo, cyano, halogen, -P(O)(OCi-C3)2, alkoxy, hydroxyl, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, -COOR5, -Y2-haloalkyl, -Y’-Ci-Ce alkyl, -Y2-Ci-Ce alkyl, -L- cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y’-heterocyclyl, -Y2-heterocyclyl, -L-N(R5)2, -O-L- N(R5)2, -N(R5)CO(R6), -O-L-OR5, -C(CF3)N(R5)2, -Y’-N(R5)2, -Y2-N(R5)2wherein the ring portion of the aralkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl and -Y’-heterocyclyl may be optionally substituted with one or more R7;L is a bond or C1-C4 alkylene;Y1is a bond, -C(O)-, or -NHC(O)-;Y2is a bond, -S-, -SO-, -SO2-, or -NR5SO2-, each R5is independently hydrogen or C1-C3 alkyl; or each R5taken together with the nitrogen atom to which they are attached form a 5 - 8 membered heterocyclic ring optionally substituted with one or more R6;R6is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R7is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R5)2, Ci-Ce alkyl or -Y’-heterocyclyl, wherein -Y’-heterocyclyl may be optionally substituted with one or more R6; and n is 1 or 2.[000114] Embodiment 27: The method of embodiment 26, wherein Z is O.[000115] Embodiment 28: The method of embodiment 26, wherein Z is S.[000116] Embodiment 29: The method according to any of embodiments 26 to 28, wherein n is 1.[000117] Embodiment 30: The method according to any of embodiments 26 to 29, wherein R2is cyano.[000118] Embodiment 31 : The method according to any of embodiments 26 to 29, wherein R2is -COOR5.[000119] Embodiment 32: The method according to any of embodiments 26 to 29, wherein R2is - C(O)N(R5)2.[000120] Embodiment 33: The method according to any of embodiments 26 to 32, wherein R3is halogen.[000121] Embodiment 34: The method of embodiment 33, wherein the halogen is fluorine.[000122] Embodiment 35: The method according to any of embodiments 26 to 33, wherein X is C(R5)2 and is a single bond.[000123] Embodiment 36: The method according to any of embodiments 26 to 33, wherein X is CR5and is a double bond.[000124] Embodiment 37: The method according to any of embodiments 26 to 33, wherein X is O and is a single bond.[000125] Embodiment 38: The method according to any of embodiments 26 to 37, wherein R1is aryl optionally substituted with one or more R4.[000126] Embodiment 39: The method of embodiment 38, wherein the aryl is phenyl optionally substituted with one or more R4.[000127] Embodiment 40: The method of embodiment 39, wherein the phenyl is substituted with one, two or three R4.[000128] Embodiment 41 : The method of embodiment 40, wherein the one, two or three R4are each independently halogen, hydroxyl, haloalkyl, -COOR5, -Y’-Ci-Ce alkyl, Y2-Ci-Ce alkyl, -L-N(R5)2, -O-L- N(R5)2, -C(CF3)N(R5)2, -Y’-N(R5)2, -Y2-N(R5)2,Y2-haloalkyl, -L-heterocyclyl, or -Y1-heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl or -Y1-heterocyclyl may be optionally substituted with one or more R7.[000129] Embodiment 42: The method of embodiment 41, wherein R4is -Y'-Ci-Ce alkyl and Y1is a bond and the Ci-Ce alkyl is methyl, ethyl, isopropyl, butyl or pentyl.[000130] Embodiment 43: The method of embodiment 41, wherein R4is -Y2-Ci-Ce alkyl and Y2is a - SO2- and the Ci-Ce alkyl is methyl.[000131] Embodiment 44: The method of embodiment 41, wherein R4is -Y2-haloalkyl and Y2is -S- or - SO2- and the haloalkyl is trifluoromethyl.[000132] Embodiment 45: The method of embodiment 41, wherein R4is -L-N(R5)2 and L is a bond and each R5is hydrogen, each R5is methyl, or one R5is methyl and one R5is hydrogen.[000133] Embodiment 46: The method of embodiment 41, wherein R4is -L-N(R5)2 and L is methylene or ethylene and each R5is hydrogen, each R5is methyl, or one R5is methyl and one R5is hydrogen. [000134] Embodiment 47: The method of embodiment 41, wherein R4is -Y'-N(R5)2, Y1is -C(O)- and each R5independently is hydrogen, each R5is independently methyl, or one R5is methyl and one R5is hydrogen.[000135] Embodiment 48: The method of embodiment 41, wherein R4is -Y2-N(R5)2, Y2is -SO2- and each R5independently is hydrogen, each R5is methyl, or one R5is methyl and one R5is independently hydrogen.[000136] Embodiment 49: The method of embodiment 41, , wherein R4is -Y1-heterocyclyl and Y1is - C(O)- and the heterocyclyl portion of the L-heterocyclyl is piperazinyl or 4-methyl-piperazinyl.[000137] Embodiment 50: The method of embodiment 41, wherein R4is -L-heterocyclyl and L is a bond and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or 3X2-azabicyclo[3.1.0]hexanyl, each optionally substituted with one or more R7selected from oxo, C1-C3 alkyl, alkoxy, hydroxyl and / or halogen.[000138] Embodiment 51: The method of embodiment 41, wherein R4is -L-heterocyclyl, wherein L is a methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl piperidinyl, each optionally substituted with one or more R7selected from C1-C3 alkyl, alkoxy, hydroxyl and / or halogen.[000139] Embodiment 52: The method of embodiment 41, wherein R4is -Y1-heterocyclyl and Y1is - C(O)- and the heterocyclyl portion of the Y1-heterocyclyl is morpholinyl optionally substituted with one or more C1-C3 alkyl.[000140] Embodiment 53: The method of embodiment 41, wherein R4is -L-heteroaryl optionally substituted with one or more R7.[000141] Embodiment 54: The method of embodiment 53, wherein the -L-heteroaryl is tetrazolyl. [000142] Embodiment 55: The method of embodiment 26, wherein R4is -POsCCi-Cs alkyl)2.[000143] Embodiment 56: The method of embodiment 41, wherein R4is -COOR5.[000144] Embodiment 57: The method of embodiment 26, wherein R4is hydroxyalkyl.[000145] Embodiment 58: The method of embodiment 41, wherein R4is -O-L-N(R5)2.[000146] Embodiment 59: The method of embodiment 26, wherein R4is aralkyl.[000147] Embodiment 60: The method according to any of embodiments 26 to 37, wherein R1is heteroaryl optionally substituted with one or more R4.[000148] Embodiment 61 : The method of embodiment 60, wherein the heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H- pyrrolo[l,2-b]pyrazolyl, each optionally substituted with one or more R4.[000149] Embodiment 62: The method of embodiment 61, wherein the heteroaryl is substituted with one or more R4; wherein each R4is independently cyano, halogen, -Y’-Ci-Ce alkyl, -Y2-Ci-Ce alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -L-N(R5)2, -Y’-N(R5)2, -L-heteroaryl, -L- heterocyclyl, or -Y1-heterocyclyl, wherein the heteroaryl of the -L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl, or Y1-heterocyclyl may be optionally substituted with one or more R7.[000150] Embodiment 63 : The method of embodiment 62, wherein the heteroaryl is pyrazolyl optionally substituted with one R4independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R5)2, L-heterocyclyl or L-heteroaryl, wherein the heteroaryl of the L-heteroaryl or the heterocyclyl portion of the L-heterocyclyl may be optionally substituted with one or more R7.[000151] Embodiment 64: The method of embodiment 63, wherein R4is -L-heteroaryl and L is methylene where the heteroaryl is pyridyl optional substituted with one or more R7.[000152] Embodiment 65: The method of embodiment 63, wherein R4is -L-heterocyclyl optionally substituted with one or more R7where L is a bond and the heterocyclyl portion of the L-heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl or 4-methylpiperazinyl.[000153] Embodiment 66: The method of embodiment 63, wherein R4is -L-heterocyclyl optionally substituted with one or more R7where L is methylene and the heterocyclyl portion of the L-heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinone, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl or 4-methylpiperazinyl.[000154] Embodiment 67: The method of embodiment 63, wherein R4is -L-N(R5)2 where L is methylene and each R5is independently hydrogen, each R5is independently C1-C3 alkyl, or one R5is Ci- C3 alkyl and one R5is hydrogen.[000155] Embodiment 68: The method of embodiment 63, wherein R4is -Y'-Ci-Ce alkyl where Y1is a bond and the Ci-Ce alkyl is methyl, ethyl or isopropyl.[000156] Embodiment 69: The method of embodiment 63, wherein the heteroaryl is pyrazolyl optionally substituted with two R4groups each independently selected from hydroxyalkyl, heteroalkyl, haloalkyl, and -Y’-Ci-Ce alkyl.[000157] Embodiment 70: The method of embodiment 63, wherein the heteroaryl is pyridyl optionally substituted with one R4independently selected from cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y’-Ci-Ce alkyl, -L-N(R5)2, -Y’-N(R5)2, -L-cycloalkyl, or -L-heterocyclyl optionally substituted with one or more R7.[000158] Embodiment 71: The method according to any of embodiments 26 to 37, wherein R1is -L- cycloalkyl optionally substituted with one or more R4.[000159] Embodiment 72: The method according to any of embodiments 26 to 37, wherein R1is -L- heterocyclyl optionally substituted with one or more R4.[000160] Embodiment 73: The method of embodiment 72, wherein L is a bond and the heterocyclyl is piperidinyl or tetrahydropyranyl.[000161] Embodiment 74: The method according to any of embodiments 26 to 28, wherein n is two. [000162] Embodiment 75: The method of any one of embodiments 1 to 24, wherein the inhibitor of polycomb repressive complex 2 (PRC2) is a compound selected from a compound disclosed herein. [000163] Embodiment 76: The method according to any one of embodiments 1 to 75, wherein the method results in induction of fetal hemoglobin expression in erythroid cells.[000164] Embodiment 77: The method according to any one of embodiments 1 to 75, wherein the method results in upregulation of mRNA levels of fetal hemoglobin protein in the subject.[000165] Embodiment 78: The method according to any one of embodiments 1 to 75, wherein the method results in increased levels of fetal hemoglobin protein in the subject.METHODS OF USE[000166] In one embodiment is provided a method of treating sickle cell disease in a subject, comprising administering to the subject a therapeutically effective amount of an inhibitor of polycomb repressive complex 2 (PRC2) as disclosed herein.[000167] In another embodiment is provided any of the methods disclosed herein, wherein the method results in induction of fetal hemoglobin expression in erythroid cells.[000168] In another embodiment is provided any of the methods disclosed herein, wherein the method results in upregulation of mRNA levels of fetal hemoglobin protein.[000169] In another embodiment is provided any of the methods disclosed herein, wherein the method results in increased levels of fetal hemoglobin protein in the subject.[000170] The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. The degree of mono- and dimethylation of histone H3K27 may be monitored in the subject using well known methods, including those described in Example A below, to access the effectiveness of treatment, along with other prognostic or biological factors, and dosages may be adjusted accordingly by the attending medical practitioner.GENERAL REACTION SCHEME, INTERMEDIATES AND EXAMPLES GENERAL REACTION SCHEMES[000171] Inhibitors of polycomb repressive complex 2 (PRC2) are known to those of ordinary skill in the art or may be prepared by methods known to those having ordinary skill in the art.[000172] The compounds of Formula (I) disclosed herein may be prepared using methods described in United States Patent No. 11,091,495, the contents of which are incorporated by reference herein for that purpose. The compounds disclosed herein may also be prepared using methods known to those having ordinary skill in the art and commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or may be prepared using other reagents and conventional methods well known to those skilled in the art.[000173] For instance, intermediates for compounds and compounds of Formula (I) of the present disclosure may be prepared according to General Reaction Schemes I or II:General Reaction Scheme I[000174] In General Reaction Scheme I, R2-ester substituted imidazo[l,2-c]pyrimidine A is coupled to R3optionally substituted intermediate amine B by nucleophilic substitution to yield Intermediate C. A boronic acid derivative (Y)-R1D is coupled via a Suzuki reaction with halogen substituted Intermediate C in the presence of a suitable base, e.g., sodium carbonate, and the R2ester is converted to the acid by saponification with NaOH to generate intermediate acid E. The acid is converted to the corresponding amide, which is dehydrated to form title compound nitrile G.General Reaction Scheme II[000175] Halogenated Intermediate C containing a suitable R2reactant, e.g., an ester, in the presence of a suitable base is converted to acid intermediate by saponification, then treated with NH4CI in the presence of HATU to form the amide which is subsequently dehydrated to form nitrile Intermediate H. R1is coupled to Intermediate H via a Suzuki reaction using boronic acid derivative (Y) in the presence of base. The nitrile group of R1 -containing Intermediate G is hydrolyzed in the presence of acid and water to afford title compound amide F.INTERMEDIATE A-l[000176] An exemplary Intermediate A, Intermediate A-l, may be used to synthesize compounds of formula (I). A mixture of 6-amino-5 -bromo- lH-pyrimidin-2 -one (2.00 g, 10.5 mmol, 1.00 equiv) and ethyl 3-bromo-2-oxo-propanoate (3.12 g, 16.0 mmol, 2.00 m , 1.52 equiv) in DMF (20.0 m ) was stirred at 80 °C for 3 h. The mixture was concentrated in vacuo to give a residue. To the residue was added water (50.0 mb), the mixture was extracted with ethyl acetate (80.0 mb x 3) and the organic layer was concentrated in vacuo. The crude material was heated in methanol (5.00 mb) and the solid was removed by filtration The filtrate was concentrated under reduced pressure to provide ethyl 8-bromo-5- oxo-6H-imidazo[ l,2-c]pyrimidine-2 -carboxylate (1.00 g, 3.50 mmol, 33.2% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-t / 6) 5 = 12.09 (br s, 1H), 8.32 (s, 1H), 7.73 (s, 1H), 4.30 (q, J= 7.2 Hz, 2H), 1.31 (t, J= 7.2 Hz, 3H).[000177] A mixture of ethyl 8-bromo-5-oxo-6H-imidazo[ l,2-c]pyrimidine-2 -carboxylate (500 mg, 1.75 mmol, 1 equiv) and DIEA (564 mg, 4.37 mmol, 760 pL, 2.50 equiv) in POCI3 (8.00 mb) was stirred for 15 h at 120 °C. The mixture was concentrated in vacuo to afford the crude residue. The crude material was purified by column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 1 / 1) to provide ethyl 8- bromo-5-chloro-imidazo[l,2-c]pyrimidine-2-carboxylate (380 mg, 1.25 mmol, 71.4% yield) as a yellowsolid. 'H NMR (400 MHz, CD3OD) 5 = 8.61 (s, 1H), 8.20 (s, 1H), 4.46 (q, J= 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).INTERMEDIATE A-2[000178] A second exemplary Intermediate A, Intermediate A-2, also may be used to synthesize compounds of formula (I). To a solution of ethyl 8-bromo-5-oxo-6H-imidazo[ 1 ,2-c]pyrimidine-2- carboxylate (3.00 g, 10.2 mmol, 1.00 equiv) in MeOH (60.0 mb) was added NaOH (1 M, 30.5 mb, 3.00 equiv). The resultant mixture was stirred at 60 °C for 1 h. Subsequently, the reaction mixture was concentrated and the pH was adjusted to 4 with IM aq HC1 at which time a precipitate formed. The solid was fdtered and dried under vacuum to provide 8-bromo-5-oxo-6H-imidazo[ 1 ,2-c]pyrimidine-2- carboxylic acid (2.60 g, 10.1 mmol, 99. 1% yield) as a brown solid.[000179] To a solution of 8-bromo-5-oxo-6H-imidazo[ 1, 2-c]pyrimidine-2 -carboxylic acid (2.60 g, 10.1 mmol, 1.00 equiv) in DMF (60.0 mb) was added NH4CI (1.62 g, 30.2 mmol, 3.00 equiv), DIPEA (11.7 g, 90.7 mmol, 15.8 mb, 9.00 equiv) and HATU (5.75 g, 15.1 mmol, 1.50 equiv). The mixture was stirred at 15 °C for 12 h and was subsequently concentrated in vacuo. The resultant residue was triturated with MeOH (30 mb). The precipitate was washed with water 50 mb, fdtered and the fdtrate was concentrated in vacuo to afford 8-bromo-5-oxo-6H-imidazo[ 1, 2-c]pyrimidine-2 -carboxamide (1.78 g, 6.92 mmol, 68.7% yield) as a light-yellow solid. LC-MS [M+l]: 257.0.[000180] To a solution of 8-bromo-5-oxo-6H-imidazo[I,2-c]pyrimidine-2-carboxamide (1.70 g, 6.61 mmol, 1.00 equiv) in POCI3 (20.0 mb) was added DIPEA (4.27 g, 33.1 mmol, 5.76 mL, 5.00 equiv) dropwise at 0 °C. The mixture was stirred at 120 °C for 12 h. The reaction mixture was fdtered and concentrated at reduced pressure to provide the crude material. The crude residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate = 10 / 1 to 4 / 1) to afford 8-bromo-5-chloro- imidazo[I,2-c]pyrimidine-2-carbonitrile (950 mg, 3.69 mmol, 55.8% yield) as a light-yellow solid. LC- MS [M+l]: 258.9.[000181] Alternatively, Intermediate A-2 may be prepared on a large scale as follows:[000182] To a solution of cytosine (300 g, 2.70 mol, 1.00 equiv) in DMF (1.5 L) was added NBS (480 g, 2.70 mol, 1.00 equiv). The mixture was stirred at 25 °C for 10 h at which time the crude 'H NMR spectrum indicated that the reaction was complete. The reaction mixture was fdtered and the fdter cake was washed with water (1 L x 4). The solid was collected and dried under reduced pressure to afford 5- bromocytosine (480 g, 2.53 mol, 93.6% yield) as a white solid. 'H NMR (400MHz, DMSO-de) 5 10.80 (br s, 1H), 11.36 - 10.16 (m, 1H), 7.74 (s, 1H), 6.83 (br s, 2H).[000183] A mixture of compound 5 -bromocytosine (150 g, 789 mmol, 1.00 equiv) and ethyl 3-bromo-2- oxo-propanoate (385 g, 1.97 mol, 247 mL, 2.50 equiv) in AcOH (1.5 L) was stirred at 120 °C for 2 h.The crude ’H NMR spectrum indicated that the reaction was complete. Three batches were concentrated to provide a residue that was triturated with MTBE (3 L) and fdtered. The fdter cake was washed withwater (1 L x 4) and dried to afford ethyl 8-bromo-5-oxo-5,6-dihydroimidazo[l,2-c]pyrimidine-2- carboxylate (300 g, 1.05 mol, 44.3% yield) as a brown solid. ’H NMR (400MHz, DMSO-de) 5 12.47 - 11.64 (m, 1H), 8.33 (s, 1H), 8.06 (s, 2H), 7.73 (s, 1H), 4.31 (q, J= 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). [000184] To a solution of ethyl 8-bromo-5-oxo-5,6-dihydroimidazo[l,2-c]pyrimidine-2-carboxylate (150 g, 524 mmol, 1.00 equiv) in MeOH (1.5 L) was added NaOH (2 M, 786 mL, 3.00 equiv). The mixture was stirred at 65 °C for 2 h at which time the LCMS indicated that the reaction was complete. The reaction mixture was concentrated to give a residue that was acidified with HC1 (2 M) to pH = 2~3. The solid was filtered and the filter cake was washed with water (800 mL x 4). The solid was collected and dried under vacuum to afford 8-bromo-5-oxo-5,6-dihydroimidazo[l,2-c]pyrimidine-2 -carboxylic acid (140 g, 543 mmol, 51.7% yield) as a brown solid. LCMS (M+l): 257.9. 'H NMR (400MHz, DMSO-d6) 5 12.86 - 11.28 (m, 1H), 8.27 (s, 1H), 7.73 (s, 1H).[000185] To a suspension of 8-bromo-5-oxo-5,6-dihydroimidazo[l,2-c]pyrimidine-2 -carboxylic acid (120 g, 465 mmol, 1.00 equiv) in SOCk (787 g, 6.62 mol, 480 mL, 14.2 equiv) was added DMF (340 mg, 4.65 mmol, 358 pL, 0.01 equiv) and the mixture was stirred at 80 °C for 2 h. The solution was concentrated to give a residue that was dissolved in DCM (200 mL). The resulting mixture was added dropwise to cone, ammonium hydroxide (1.09 kg, 9.35 mol, 1.20 L, 20.1 equiv) at 0 °C and the mixture was subsequently stirred at 25°C for 1 h. LCMS indicated that the reaction was complete. The mixture was fdtered, the filter cake was washed with MeOH (200 mL), and the solid was dried under vacuum to afford 8-bromo-5-oxo-5,6-dihydroimidazo[l,2-c]pyrimidine-2 -carboxamide (120 g, crude) as a brown solid. LCMS (M+l): 257.0 / 259.0. ' H NMR (400MHz, DMSO-d6) 5 8.05 (s, 1H), 7.66 (s, 1H), 7.56 (br s, 1H), 7.41 (br s, 1H).[000186] To a solution of 8-bromo-5-oxo-5,6-dihydroimidazo[l,2-c]pyrimidine-2 -carboxamide (20.0 g, 77.8 mmol, 1.00 equiv) in POCI3 (388 g, 2.53 mol, 235 mL, 32.5 equiv) was added DIEA (50.3 g, 389 mmol, 67.8 mL, 5.00 equiv) dropwise at 0 °C. The mixture was stirred at 120 °C for 12 h. The reaction mixture (4 identical batches combined) was cooled to room temperature and was concentrated to afford a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1 to 5: 1) to provide 8-bromo-5-chloroimidazo[l,2-c]pyrimidine-2-carbonitrile (19.9 g, 76.1 mmol, 24.5% yield, 98.6% purity) as an off-white solid. LCMS (M+l): 388.0 / 390.0. 'H NMR (400MHz, DMSO-d6) 5 9.19 (s, 1H), 8.36 (s, 1H).INTERMEDIATE B-l[000187] An exemplary Intermediate B, Intermediate B-l, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R5)2, and is a single bond. A mixture of 3- bromophenol (10.0 g, 57.8 mmol, 1.00 equiv) and 2-bromo- 1,1 -diethoxy-ethane (13.7 g, 69.4 mmol, 10.4 mL, 1.20 equiv) in DMF (100 mL) was added potassium carbonate (24.0 g, 173 mmol, 3.00 equiv). The resultant mixture was stirred at 110 °C for 12 h under a nitrogen atmosphere. The reaction mixture wasdiluted with petroleum ether (100 mL) and washed with brine (50.0 mL x 4). dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether) to afford l-bromo-3-(2,2- diethoxyethoxy)benzene (17.0 g, 48.2 mmol, 83.4% yield, 82.0% purity) as a light yellow oil. 'H NMR (400MHz, CDCh) 5 = 7.17 - 7.07 (m, 3H), 6.88 - 6.84 (m, 1H), 4.82 (t, J=5.2 Hz, 1H), 3.99 (d, J=5.2 Hz, 2H), 3.80 - 3.74 (m, 1H), 3.80 - 3.73 (m, 2H), 3.68 - 3.61 (m, 2H), 1.25 (t, .7=7,2 Hz. 6H).[000188] To a solution of polyphosphoric acid (21.5 g, 63.6 mmol, 1.50 equiv) in toluene (80.0 mL) was added l-bromo-3-(2,2-diethoxyethoxy)benzene (15.0 g, 42.5 mmol, 1.00 equiv) at 90 °C. The mixture was stirred at 90 °C for 2 h and then concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether) to afford 4 -bromobenzofuran (5.20 g, 13.2 mmol, 31.0% yield, 50.0% purity) as a yellow oil. 'HNMR (400MHz, CDC13) 5 = 7.70 (s, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.61 (d, .7=2,4 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.0 Hz, 1H), 7.37 (dd, .7=1.6, 8.4 Hz, 1H), 7.21 - 7.15 (m, 1H), 6.85 - 6.80 (m, 1H), 6.78 - 6.73 (m, 1H).[000189] To a solution of 4-bromobenzofuran (5.20 g, 13.2 mmol, 1.00 equiv) in DMAC (50.0 mL) was added zinc cyanide (6.85 g, 58.3 mmol, 4.42 equiv) and Pd(PPhs)4 (1.52 g, 1.32 mmol, 0.100 equiv). The mixture was stirred at 140 °C for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (80.0 mL), washed with brine (50.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether / ethyl acetate = 50 / I to O / l) to afford benzofuran -4- carbonitrile (1.60 g, 10.1 mmol, 76.2% yield, 90.0% purity) as a light-yellow oil. 'H NMR (400MHz, CDC13) 5 = 7.80 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.4 Hz, 1H), 7.03 - 7.00 (m, 1H).[000190] To a solution of benzofuran-4-carbonitrile (750 mg, 4.72 mmol, 1.00 equiv) in methyl alcohol (10.0 mL) was added BOC2O (3.09 g, 14.2mmol, 3.00 equiv) and Pd / C (4.72 mmol, 10.0 w. %, 1.00 equiv). The mixture was stirred at 30 °C for 24 h under hydrogen (50.0 psi). The reaction mixture was filtered and concentrated under reduced pressure to give the crude material, which was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 50 / 1) to afford tert-butyl N-(2,3- dihydrobenzofuran-4-ylmethyl) carbamate (140 mg, 562 pmol, 11.9% yield) as a colorless oil. 'H NMR (400MHz, CDCh) 5 = 7.10 (t, J=8.0 Hz, 1H), 6.74 (dd, J=8.0, 14.0 Hz, 2H), 4.75 (br s, 1H), 4.59 (t, .7=8,8 Hz, 2H), 4.28 (br d, J=5.6 Hz, 2H), 3.20 (t, J=8.8 Hz, 2H), 1.47 (s, 9H).[000191] To a solution of tert-butyl N-(2,3-dihydrobenzofuran-4-ylmethyl) carbamate (140 mg, 562 pmol, 1.00 equiv) in DCM (2.00 mL) was added TFA (640 mg, 5.62 mmol, 416 pL, 10.0 equiv). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with DCM (10.0 mL) and was added to a saturated potassium carbonate aqueous solution (10.0 mL). The biphasic mixture was stirred at 25 °C for 0.5 h. The organic phase was separated, dried over sodium sulfate, concentrated in vacuo to afford 2,3-dihydrobenzofuran-4-ylmethanamine (80.0 mg, 483 pmol, 85.9% yield, 90.0% purity) as a yellow solid. 'HNMR (400MHz, CDCH) 5 = 7.13 (t, J=8.0 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 4.60 (t, .7=8,8 Hz, 2H), 3.82 (s, 2H), 3.20 (t, J=8.8 Hz, 2H).INTERMEDIATE B-2[000192] A second exemplary Intermediate B, Intermediate B-2, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is CR5, is a double bond and one R3is fluorine. To a mixture of 5-fhrorobenzofuran-4-carbonitrile (250 mg, 1.47 mmol, 1.00 equiv) and Raney-Ni (126 mg, 1.47 mmol, 1.00 equiv) in methyl alcohol (6.60 mb) was added ammonium hydroxide (1.60 mb). The mixture was purged with nitrogen and stirred at 25 °C for 12 h under a hydrogen atmosphere. The reaction mixture was fdtered and concentrated under reduced pressure to afford (5-fluorobenzofuran-4- yl) methanamine (220 mg, 1.20 mmol, 81.3% yield, 90.0% purity) as a brown oil. 'H NMR (400MHz, CDCh) 5 = 7.67 (s, 1H), 7.33 (br d, J=5.6 Hz, 1H), 7.04 (br t, J=9.6 Hz, 1H), 6.90 (s, 1H), 4.54 - 3.78 (m, 2H).INTERMEDIATE B-3[000193] A third exemplary Intermediate B, Intermediate B-3, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R5)2, is a single bond and one R3is chlorine. To a solution of benzofuran -4-carboxylic acid (900 mg, 5.55 mmol, 1 equiv) in MeOH (9.00 mb) was added palladium on activated carbon (20.0 mg, 555 pmol, 10.0 wt %, 0.10 equiv) under nitrogen. The vessel was evacuated and purged with hydrogen several times. The mixture was stirred at 25 °C for 12 h under hydrogen (50.0 psi). The reaction mixture was fdtered and the fdtrate was concentrated in vacuo to afford 2,3-dihydrobenzofuran-4-carboxylic acid (750 mg, 3.66 mmol, 65.9% yield, 80.0% purity) as a white solid. 'H NMR (400MHz, DMSO-d6) 5 = 7.38 (d, J=8.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 4.54 (t, .7=8,8 Hz, 2H), 3.45 (br t, J=8.8 Hz, 2H).[000194] To a solution of 2,3-dihydrobenzofuran-4-carboxylic acid (750 mg, 3.66 mmol, 1.00 equiv) in DMF (1.00 mb) was added Pd(OAc)2 (82.1 mg, 366 pmol, 0.10 equiv) and NCS (586 mg, 4.39 mmol, 1.20 equiv). The reaction was stirred at 110 °C for 12 h under an atmosphere of nitrogen. The reaction mixture was fdtered and concentrated in vacuo and the resultant residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1 to dichloromethane / methanol = 10 / 1) to afford 5- chloro-2,3-dihydrobenzofuran-4-carboxylic acid (600 mg, crude) as a yellow oil. LC-MS: [M+l] 198.9. [000195] To a solution of 5-chloro-2,3-dihydrobenzofuran-4-carboxylic acid (600 mg, 3.02 mmol, 1.00 equiv) in DMF (5.00 mb) was added ammonium chloride (242 mg, 4.53 mmol, 1.50 equiv), HATU (2.30 g, 6.04 mmol, 2.00 equiv), DIEA (1.17 g, 9.06 mmol, 1.58 mb, 3.00 equiv). The reaction mixture was stirred at 25 °C for 12 h and concentrated in vacuo to give the crude material, which was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to afford 5-chloro-2,3- dihydrobenzofuran-4-carboxamide (700 mg, 2.83 mmol, 93.8% yield, 80.0% purity) as a white solid. ’HNMR (400MHz, DMSO-d6) 5 =7.87 (br s, 1H), 7.63 (br s, 1H), 7.17 (d, .7=8,4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 4.58 (t, .7=8,8 Hz, 2H), 3.18 (t, J=8.8 Hz, 2H).[000196] To a solution of 5-chloro-2,3-dihydrobenzofuran-4-carboxamide (300 mg, 1.21 mmol, 1.00 equiv) in THF (5.00 mL) was added dropwise BH3-DMS (10.0 M, 607 pL, 5.00 equiv). The reaction was stirred at 70 °C for 2.5 h, quenched with MeOH (5.00 mL) and concentrated in vacuo to provide a residue. To the residue was added water (20.0 mL) and the mixture was extracted with DCM (20.0 mLx3). The combined organic phase was washed with brine (20.0 mLx2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford (5-chloro-2,3-dihydrobenzofuran-4-yl)methanamine (240 mg, crude) as a brown oil. LC-MS: [M-16] 167.1.INTERMEDIATE B-4[000197] A fourth exemplary Intermediate B, Intermediate B-4, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R5)2, is a single bond and one R3is fluorine. To a solution of 3-bromo-4-fluoro-phenol (100 g, 524 mmol, 1.00 equiv) and 2 -bromo- 1, 1 -diethoxy-ethane (124 g, 628 mmol, 94.5 mb, 1.20 equiv) in DMF (600 mL) was added potassium carbonate (217 g, 1.57 mol, 3.00 equiv). The mixture was stirred at 110 °C for 12 h under an atmosphere of nitrogen. The reaction mixture was diluted with ethyl acetate (500 mL), washed with brine (500 ml 5), and concentrated at reduced pressure to provide a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to afford 2-bromo-4-(2,2- diethoxyethoxy)- 1 -fluoro-benzene (171 g, 501 mmol, 95.7% yield, 90.0% purity) as a light-yellow oil. 'HNMR (400MHz, CDC13) 5 = 7.12 (dd, J=2.8, 5.6 Hz, 1H), 7.06 - 6.98 (m, 1H), 6.84 (td, J=3.2, 9.2 Hz, 1H), 4.81 (t, J=5.2 Hz, 1H), 3.96 (d, J=5.2 Hz, 2H), 3.81 - 3.72 (m, 2H), 3.68 - 3.59 (m, 2H), 1.25 (t, J=7.2 Hz, 6H).[000198] To a solution of PPA (254 g, 752 mmol, 1.50 equiv) in toluene (1.30 L) was added 2-bromo-4- (2,2-diethoxyethoxy)-l -fluoro-benzene (171 g, 501 mmol, 1.00 equiv) at 90 °C. The mixture was stirred at 95 °C for 2 h and concentrated at reduced pressure to provide a residue. The residue was purified by column chromatography (petroleum ether) to give 4-bromo-5-fluoro-benzofuran (87.3 g, 203 mmol, 40.5% yield, 50.0% purity) as a yellow oil. To a mixture of 4-bromo-5-fluoro-benzofuran (85.5 g, 398 mmol, 1.00 equiv) and 6-bromo-5-fluoro-benzofuran (85.5 g, 398 mmol, 1.00 equiv) in DMAC (1.50 L) was added zinc cyanide (31.1 g, 264 mmol, 0.67 equiv) and Pd(PPhs)4 (23.0 g, 19.9 mmol, 0.05 equiv). The mixture was stirred at 90 °C for 12 h under an atmosphere of nitrogen. The reaction mixture was diluted with ethyl acetate (1.00 L) and filtered. The filtrate was washed with brine (1.00 L * 3) and the organic layer was concentrated at reduced pressure to provide a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 50 / 1) to afford 4-bromo-5-fluoro- benzofuran (78 g, crude) as a white solid.[000199] To a solution of 4-bromo-5-fluoro-benzofuran (87.3 g, 203 mmol, 1.00 equiv) in DMAC (600 mb) was added zinc cyanide (94.6 g, 805 mmol, 3.97 equiv) and Pd(PPh3)4(23.5 g, 20.3 mmol, 0.10 equiv). The mixture was stirred at 110 °C for 12 h under an atmosphere of nitrogen. The reaction mixture was diluted with ethyl acetate (500 mL), washed with brine (400 mb x 5). dried over anhydrous sodium sulfate, fdtered, and concentrated at reduced pressure to provide a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 50 / 1) to afford 5-fluorobenzofuran-4- carbonitrile (20.0 g, 118 mmol, 58.1% yield, 95.0% purity) as a white solid. 'H NMR (400MHz, CDCh) 5 = 7.84 (d, .7=2,0 Hz, 1H), 7.73 - 7.67 (m, 1H), 7. 14 (t, J=9.2 Hz, 1H), 7.02 - 6.96 (m, 1H).[000200] To a solution of 5-fluorobenzofuran-4-carbonitrile (19.6 g, 116 mmol, 1.00 equiv) in methyl alcohol (1.00 L) was added di-tert-butyl dicarbonate (75.7 g, 347 mmol, 3.00 equiv) and Pd / C 10 w. % (1.16 g). The mixture was stirred at 35 °C for 24 h under an atmosphere of hydrogen gas (50.0 psi). The reaction mixture was filtered and concentrated at reduced pressure to provide a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to afford tert-butyl N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]carbamate (22.0 g, 78.2 mmol, 67.7% yield, 95.0% purity) as a white solid.1H NMR (400MHz, CDCh) 5 = 6.82 - 6.76 (m, 1H), 6.62 (dd, J=4.0, 8.8 Hz, 1H), 4.88 (br s, 1H), 4.60 (t, J=8.8 Hz, 2H), 4.30 (br d, J=6.0 Hz, 2H), 3.30 (br t, J=8.8 Hz, 2H), 1.44 (s, 9H).[000201] To a solution of tert-butyl / V-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl] carbamate (22.0 g, 78.2 mmol, 1.00 equiv) in DCM (200 mL) was added TFA (89.2 g, 782 mmol, 57.9 mL, 10.0 equiv). The mixture was stirred at 25 °C for 0.5 h and subsequently quenched with satd aq potassium carbonate (200 mL). The mixture was allowed to stir at 25 °C for 0.5 hour. The organic phase was separated and dried over sodium sulfate, concentrated in vacuo to afford (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (13.0 g, 73.9 mmol, 94.5% yield, 95.0% purity) as a light yellow oil. 'H NMR (400MHz, CDCh) 5 = 6.85 - 6.76 (m, 1H), 6.60 (dd, J=4.0, 8.8 Hz, 1H), 4.61 (t, J=8.8 Hz, 2H), 3.82 (s, 2H), 3.24 (t, J=8.8 Hz, 2H).[000202] Alternatively, Intermediate A-2 may be prepared on a large scale as follows:[000203] To a solution of 3-bromo-4-fluorophenol (1.00 kg, 5.24 mol, 1.00 equiv) and CS2CO3 (3.41 kg, 10.5 mol, 2.00 equiv) in DMF (5.00 L) was added compound 2-bromo- 1,1 -diethoxyethane (1.24 kg, 6.28 mol, 1.20 equiv) in one portion. The suspension was stirred at 110°C for 12 h. TLC (petroleum ether / ethyl acetate = 10 / 1, Rf = 0.50) indicated that the reaction was complete. The reaction mixture was filtered, diluted with water (15.0 L), and extracted with MTBE (5.00 L x 2). The combined organic layers were washed with brine (3.00 L), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give compound 2-bromo-4-(2,2-diethoxyethoxy)-l -fluorobenzene (1.61 kg, crude) as a yellow oil.[000204] Two reactions were conducted in parallel on the same scale and combined during the workup. To a mixture of polyphosphoric acid (1.30 kg) in toluene (2.40 L) was added 2-bromo-4-(2,2- diethoxyethoxy)-l -fluorobenzene (800 g, 2.60 mol, 1.00 equiv) in one portion at 90 °C. The mixture was stirred at 90 °C for 3 h. TLC (petroleum ether / EtOAc = 10 / 1, Rf = 0.6) indicated that the reaction was complete. The two reactions were combined prior to work up. The mixture was poured into water (6.00L) and extracted with MTBE (6.00 L x 2). The combined organic layer was washed with brine (5.00 L x 2), dried over anhydrous ISfeSCh, fdtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 1 / 0 to 100 / 1) to give a ~1: 1 mixture of 4-bromo-5- fhiorobenzofuran and 6-bromo-5-fluorobenzofuran (800 g, 3.72 mol, 71.4% yield) as a brown oil. [000205] Two reactions were conducted in parallel on the same scale and combined during the workup. To a mixture of 4-bromo-5 -fluorobenzofuran (150 g, 698 mmol, 1.00 equiv) and 6-bromo-5- fluorobenzofuran (150 g, 698 mmol, 1.00 equiv) in DMA (2.40 L) was added Zn(CN)2 (49.2 g, 419 mmol, 0.60 equiv) and Pd(PPhs)4 (40.3 g, 34.9 mmol, 0.05 equiv) in one portion at 25 °C under N2. The mixture was stirred at 90 °C for 12 h. TLC (petroleum ether / EtOAc = 10 / 1) indicated the consumption of the undesired isomer (6-bromo-5-fluorobenzofuran). The two reactions were combined prior to work up. The mixture was diluted with EtOAc (5.00 L) and filtered. The filtrate was poured into water (8.00 L) and the mixture was extracted with EtOAc (3.00 L x 2). The combined organic phase was washed with brine (4.00 L x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 1 / 0 to 5 / 1) to give compound 4-bromo-5 -fluorobenzofuran (340 g) as a yellow oil.[000206] Two reactions were conducted in parallel on the same scale and combined during the workup. To a mixture of compound 4-bromo-5 -fluorobenzofuran (170 g, 791 mmol, 1.00 equiv) in DMA (1.30 L) was added Zn(CN)2 (92.8 g, 791 mmol, 1.00 eq.) and Pd(PPhs)4 (91.4 g, 79.1 mmol, 0.10 equiv) in one portion at 25 °C under N2. The resultant mixture was stirred at 120 °C for 12 h. TLC (petroleum ether / EtOAc = 10 / 1) indicated that the reaction was complete. The two reactions were combined prior to work up and the mixture was poured into water (3.00 L) and EtOAc (4.00 L), filtered, and the filtrate was extracted with EtOAc (2.00 L x 2). The combined organic layer was washed with brine (3.00 L x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 1 / 0 to 50 / 1) to afford compound 5-fluorobenzofuran-4- carbonitrile (120 g, 745 mmol, 47. 1% yield) as a yellow oil. 'H NMR (400MHz, CD3OD) 5 8.06 (d, J = 2.0 Hz, 1H), 7.82-7.86 (m, 1H), 7.23-7.28 (m, 1H), 7.02 (d, J= 2.0 Hz, 1H).[000207] Two reactions were conducted in parallel on the same scale and combined during the workup. To a solution of compound 5-fluorobenzofuran-4-carbonitrile (60.0 g, 372 mmol, 1.00 equiv) in MeOH (1.50 L) was added BOC2O (122 g, 559 mmol, 1.50 equiv) and Pd / C (12.0 g, 10 wt %) under N2. The suspension was evacuated and purged with H2 several times and the mixture was stirred under H2 (50 psi) at 50 °C for 12 h. TLC (petroleum ether / EtOAc = 10 / 1) indicated that the reaction was complete. The two reactions were combined prior to work up and filtered. The filtrate was concentrated to afford a residue that was triturated with petroleum ether (500 mb), filtered, and dried at 45 °C under vacuum to provide tert-butyl ((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (100 g, 374 mmol, 50.2% yield) as a white solid. 'H NMR (400MHz, CDCI3) 5 6.76-6.81 (m, 1H), 6.60-6.63 (m, 1H), 4.60 (t, J= 8.8 Hz, 2H), 4.29-4.31 (m, 2H), 3.30 (t, J= 8.8 Hz, 2H), 1.44 (s, 9H).[000208] Two reactions were conducted in parallel on the same scale and combined during the workup. To a mixture of tert-butyl ((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (50.0 g, 187 mmol,1.00 equiv) in EtOAc (400 mL) was added HCl / EtOAc (300 mL, 4M) in one portion at 25 °C under N2 The resultant mixture was stirred for 4 h at which time TLC (petroleum ether / EtOAc = 5 / 1) indicated that the reaction was complete. The two reactions were combined prior to work up, fdtered, and the filter cake was washed by MTBE (100 mL x 2). The filter cake was dissolved in water (200 mL) and the pH was adjusted to 9 with sat.aq. K2CO3 at 0 °C prior to extraction with DCM (200 mL x 4). The combined organic phase was washed with brine (200 mL x 2), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to afford (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (50.0 g, 299 mmol, 79.9% yield) as a brown oil. 'H NMR (400MHz, DMSO-d6) 5 8.57 (br. s., 3H), 6.97 (m, 1H), 6.77-6.80 (m, 1H), 4.55-4.59 (m, 2H), 3.94 (s, 2H), 3.37-3.42 (m, 2H).INTERMEDIATE B-5[000209] A fifth exemplary Intermediate B, Intermediate B-5, may be used to synthesize compounds of formula I wherein Z is S, n is one, X is C(R5)2, is a single bond and one R3is fluorine. A mixture of 3-bromo-4-fluoro-benzenethiol (4.50 g, 21.7 mmol, 1.00 equiv), 2-bromo- 1,1 -diethoxy-ethane (4.71 g, 23.9 mmol, 3.60 mL, 1.10 equiv), and potassium carbonate (3.60 g, 26.1 mmol, 1.20 equiv) in DME (50.0 mL) was purged with nitrogen. The mixture was stirred at 80 °C for 0.5 h under an atmosphere of nitrogen. The mixture was concentrated in vacuo to provide a residue, which was purified by column chromatography (petroleum ether / ethyl acetate, 20 / 1 to 5 / 1) to afford 2-bromo-4-(2,2- diethoxyethylsulfanyl)-l -fluoro-benzene (6.2 g, 19.2 mmol, 88.3 % yield) as a colorless liquid. ’H NMR (400 MHz, CDCI3) 5 = 7.63 (dd, J= 2.4, 6.4 Hz, 1H), 7.32 (ddd, J= 2.4, 4.4, 8.8 Hz, 1H), 7.03 (t, J= 8.4 Hz, 1H), 4.63 (t, J= 5.6 Hz, 1H), 3.72 - 3.65 (m, 2H), 3.57 - 3.51 (m, 2H), 3.08 (d, J= 5.6 Hz, 2H), 1.20 (t, J= 7.2 Hz, 6H).[000210] To a solution of polyphosphoric acid (39 g, 710 pL, 1.00 equiv) in chlorobenzene (70.0 mL) was added 2-bromo-4-(2,2-diethoxyethylsulfanyl)-l -fluoro-benzene (5.9 g, 18.3 mmol, 1.00 equiv) and the resultant mixture was stirred at 130 °C for 12 h. The mixture was concentrated in vacuo to provide a residue. The residue was purified by column chromatography (petroleum ether) to afford 4-bromo-5- fluoro -benzothiophene (2.50 g, 10.8 mmol, 29.8% yield, 50% purity) as a colorless liquid. ’H NMR (400 MHz, CDC13) 5 = 7.75 (dd, J= 4.4, 8.8 Hz, 1H), 7.61 (d, J= 5.6 Hz, 1H), 7.49 (d, J= 5.6 Hz, 1H), 7.17 (t, J= 8.8 Hz, 1H).[000211] To a solution of 4-bromo-5 -fluoro-benzothiophene (1.25 g, 5.41 mmol, 1.00 equiv) in DMAC (12.0 mL) was added zinc cyanide (953 mg, 8.11 mmol, 515 pL, 1.50 equiv) and Pd(PPh3)4 (938 mg, 811 pmol, 0.150 equiv). The mixture was stirred at 100 °C for 12 h under an atmosphere of nitrogen. Water (50.0 mL) was added and the mixture was extracted with ethyl acetate (80.0 mL x 3). The combined organic layer was concentrated in vacuo to provide a residue. The residue was purified by column chromatography (petroleum ether) to afford 5-fluorobenzothiophene-4-carbonitrile (530 mg, 2.99 mmol,27.7% yield) as a white solid. ’H NMR (400 MHz, CDC13) 5 = 8.05 (dd, J= 4.4, 8.8 Hz, 1H), 7.80 (d, J = 5.6 Hz, 1H), 7.57 (d, J= 5.6 Hz, 1H), 7.23 (t, J= 8.8 Hz, 1H).[000212] To a mixture of 5-fluorobenzothiophene-4-carbonitrile (300 mg, 1.69 mmol, 1.00 equiv) in THF (2.00 mb) was added BH3-Me2S (10 M, 677 pL. 4.00 equiv) at 0 °C and the mixture was stirred for 6 h at 75 °C. The mixture was cooled to room temperature and was quenched with ethanol (10.0 mL) and the pH was adjusted to 3 with aq HC1 (2 M). The mixture was concentrated in vacuo to provide a residue to which water (20 .0 mL) was added. The aqueous mixture was extracted with ethyl acetate (40.0 mL x 4) and the combined organic layer was concentrated to afford (5 -fluorobenzothiophen -4-yl)methanamine (150 mg, 828 pmol, 48.9% yield) as a yellow solid.INTERMEDIATE B-6[000213] A sixth exemplary Intermediate B, Intermediate B-6, may be used to synthesize compounds of formula I wherein Z is O, n is two, X is C(R5)2, is a single bond and one R3is fluorine.[000214] To a solution of 2-bromo-6-hydroxy-benzaldehyde (0.30 g, 1.49 mmol, 1.00 eq.) and ethyl 2- diethoxyphosphorylacetate (669 mg, 2.98 mmol, 592 pL, 2.00 eq.) in DMF (3.00 mL) was added NaH (119 mg, 2.98 mmol, 60% purity, 2.00 eq.) at rt under a nitrogen atmosphere. The resultant mixture was stirred at 40 °C for 12 h. The reaction mixture was diluted with ethyl acetate (50.0 mL) and quenched with water (10.0 mL). The combined organic phase was washed with brine (30.0 mL x 3), dried over sodium sulfate, fdtered, and concentrated in vacuo. The crude residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 10 / 1 to 4 / 1) to afford ethyl (A')-3-(2-bromo-6- hydroxy-phenyl)prop-2 -enoate (380 mg, 1.37 mmol, 92.0% yield, 98.0% purity) as a white solid. ’H NMR (400MHz, CD3OD) 5 = 8.02 (d, J=16.0 Hz, 1H), 7.15 (dd, J=1.2, 8.0 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 6.97 (d, J=16.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 4.56 (s, 1H), 4.25 (q, J=12 Hz, 2H), 1.33 (t, J=12 Hz, 3H).[000215] To a solution of ethyl (E)-3-(2-bromo-6-hydroxy-phenyl)prop-2 -enoate (380 mg, 1.37 mmol, 1.00 eq.) in THF (5.00 mL) and water (5.00 mL) was added NaOAc (225 mg, 2.75 mmol, 2.00 eq.) and 4-methylbenzenesulfonohydrazide (512 mg, 2.75 mmol, 2.00 eq.). The mixture was stirred at 70 °C for 12 h. The mixture was cooled to rt and extracted with ethyl acetate (20.0 mL x 2). The combined organic phase was washed with brine (30.0 mL x 3), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to afford ethyl 3-(2-bromo-6-hydroxy-phenyl)propanoate (380 mg, 1.32 mmol, 96.2% yield, 95.0% purity) as a light-yellow oil. 'H NMR (400MHz, CDC13) 5 = 8.27 (s, 1H), 7.14 (dd, J=1.2, 8.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.93 - 6.88 (m, 1H), 4.17 (q, J=12 Hz, 2H), 3.50 (s, 1H), 3.10 - 3.03 (m, 2H), 2.87 - 2.79 (m, 2H), 1.28 - 1.24 (m, 3H).[000216] To a solution of ethyl 3-(2-bromo-6-hydroxy-phenyl)propanoate (0.10 g, 348 pmol, 1.00 eq.) in THF (2.00 mL) was added LAH (39.6 mg, 1.04 mmol, 3.00 eq.) at 0 °C. The mixture was stirred at rt for 2 h. The reaction mixture was quenched with water (0.50 mL) and was diluted with DCM (30.0 mL). The mixture was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by prep-TLC (SiCL, PE: EA = 2: 1) to afford 3-bromo-2-(3-hydroxypropyl)phenol (70.0 mg, 297 pmol, 85.4% yield, 98.0% purity) as a yellow oil. ’H NMR (400MHz, CDCL) 5 = 7.66 (br s, 1H), 7.14 (dd, J=1.2, 8.0 Hz, 1H), 6.97 (t, J=8.0 Hz, 1H), 6.84 (dd, J=1.2, 8.0 Hz, 1H), 3.64 (t, J=5.6 Hz, 2H), 3.03 - 2.94 (m, 2H), 2.01 - 1.90 (m, 2H).[000217] Iodine (3.30 g, 13.0 mmol, 2.62 mL, 1.65 eq.) was added to a solution of imidazole (2.42 g, 35.5 mmol, 4.50 eq.) and PPhs (3.72 g, 14.2 mmol, 1.80 eq.) in DCM (40.0 mL) at 0 °C. The reaction mixture was stirred for 15 min followed by the dropwise addition of a solution of 3-bromo-2-(3- hydroxypropyl)phenol (1.85 g, 7.89 mmol, 1.00 eq.) in DCM (10.0 mL). The reaction mixture was protected from light and stirred for 12 h at rt. The mixture was diluted with DCM (50.0 mL) and washed with brine (40.0 mL x 2). The combined organic phase was dried over sodium sulfate, fdtered, and concentrated in vacuo. The crude material was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to afford 3-bromo-2-(3-iodopropyl)phenol (2.10 g, 6.16 mmol, 78.1% yield) as a white solid.[000218] To a solution of 3-bromo-2-(3-iodopropyl)phenol (2.10 g, 6.16 mmol, 1.00 eq.) in acetone (50.0 mL) was added K2CO3 (1.70 g, 12.3 mmol, 2.00 eq.). The mixture was stirred at 50 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiCL, petroleum ether) to afford 5-bromochromane (1.20 g, 5.63 mmol, 91.5% yield, 100% purity) as a light-yellow oil.[000219] A mixture of 5-bromochromane (0. 10 g, 469 pmol, 1.00 eq.), Zn(CN)2 (110 mg, 939 pmol, 2.00 eq.), Pd(PPhs)4 (81.4 mg, 70.4 pmol, 0.15 eq.) in DMAC (1.00 mL) was purged with nitrogen. The mixture was stirred at 100 °C for 8 h. The reaction mixture was diluted with ethyl acetate (20.0 mL) and washed with brine (15.0 mL x 3). The combined organic phase was dried over sodium sulfate, fdtered, and concentrated in vacuo. The crude material was purified by prep-TLC (SiCK PE: EA = 10: 1) to afford chromane-5 -carbonitrile (60.0 mg, 377 pmol, 80.3% yield) as a light-yellow oil. 'HNMR (400MHz, CDCh) 5 = 7.22 - 7.18 (m, 1H), 7.18 - 7.13 (m, 1H), 7.02 (dd, J=1.2, 8.0 Hz, 1H), 4.28 - 4.19 (m, 2H), 2.97 (t, .7=6,4 Hz, 2H), 2.16 - 2.02 (m, 2H).[000220] To a solution of chromane-5 -carbonitrile (60.0 mg, 377 pmol, 1.00 eq.) in THF (3.00 mL) was added LAH (57.2 mg, 1.51 mmol, 4.00 eq.) at 0 °C. The mixture was stirred at rt for 2 h. The reaction mixture was quenched with water (1.00 mL) and diluted with DCM (30 mL). The mixture was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford chroman-5- ylmethanamine (70.0 mg, crude) as a light-yellow oil.INTERMEDIATE B-7[000221] To a solution of 5-fluorobenzofuran-4-carbonitrile (2.00 g, 12.4 mmol, 1.00 equiv) in dimethyl sulfoxide (20.0 mL) was added hydrogen peroxide (7.04 g, 62.1 mmol, 5.96 mL, 30% purity, 5.00 equiv) and potassium carbonate (1.72 g, 12.4 mmol, 1.00 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 h. The residue was poured into ice-water (5.00 mL) and stirred for 10 min. The mixture was filtered and concentrated under vacuum to give 5-fluorobenzofuran-4-carboxamide (1.80 g, 10.1 mmol, 81.0% yield) as a white solid. 'H NMR (400 MHz, DMSO-t / 6) 5 = 8.11 (d, J=2.0 Hz, 1H), 7.81 (br s, 1H), 7.73 (dd, .7=4.0, 8.8 Hz, 2H), 7.23 (dd, J=9.2, 10.4 Hz, 1H), 7.10 (d, J=1.2 Hz, 1H).[000222] A solution of 5-fluorobenzofuran-4-carboxamide (1.80 g, 10.1 mmol, 1.00 equiv) in methyl alcohol (4.00 mL) was charged with hydrogen (50 psi) and Pd / C (500 mg, 50% purity). The mixture was stirred at 35 °C for 12 h. The mixture was filtered and concentrated under vacuum to give 5-fluoro-2,3- dihydrobenzofuran-4-carboxamide (1.60 g, 8.83 mmol, 87.9% yield) as a white solid. LCMS [M+l]: 182.2. 'H NMR (400 MHz, DMSO-t / 6) 5 = 7.82 - 7.55 (m, 2H), 6.96 (t, J=8.8 Hz, 1H), 6.79 (dd, J=4.0, 8.8 Hz, 1H), 4.54 (t, J=8.8 Hz, 2H), 3.25 (t, J=8.8 Hz, 2H).[000223] To a solution of 5-fluoro-2,3-dihydrobenzofuran-4-carboxamide (1.60 g, 8.83 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL) was added lithium aluminumdeuteride (670 mg, 17.7 mmol, 911 pL, 2.00 equiv) at 0 °C. The mixture was stirred at 60 °C for 12 h. The mixture was quenched with water (1.60 mL) (stirred for 15 min), followed by sodium hydroxide (1.50 mL, 15% aq.) (15 min) and water (4.80 mL) (30 min). The suspension was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (basic conditions) to afford (5-fluoro-2,3-dihydrobenzofuran-4-yl)methan- d2 -amine (0.80 g, 4.56 mmol, 51.6% yield, 96.4% purity) as a red oil. 'H NMR (400 MHz, CHLOROFORM- ) 5 = 6.82 - 6.76 (m, 1H), 6.59 (dd, J=4.0, 8.8 Hz, 1H), 4.59 (t, J=8.8 Hz, 2H), 3.23 (t, .7=8,8 Hz, 2H).INTERMEDIATE B-8[000224] To a solution of 5-fluorobenzofuran-4-carbonitrile (100 mg, 620 pmol. 1.00 equiv) in methanol-rL (LOO mL) was added di-tert-butyl dicarbonate (135 mg, 620 pmol, 143 pL, 1.00 equiv) and palladium on carbon (100 mg, 10.0 w%, 0.09 equiv). The mixture was stirred at 35 °C for 12 h under a deuterium gas atmosphere (15 psi). The reaction was filtered and concentrated at reduced pressure to give tert-butyl ((5-fluoro-2,3-dihydrobenzofuran-4-yl-2,3-d2)methyl-d2)carbamate (45.0 mg, 166 pmol, 26.7% yield) as a white solid.1H NMR (400MHz, CDC13) 5 = 6.82 - 6.76 (m, 1H), 6.62 (dd, J=3.6, 8.4 Hz, 1H), 4.86 (br s, 1H), 4.57 (br d, J=10.0 Hz, 1H), 3.27 (br d, J=6.8 Hz, 1H), 1.46 - 1.41 (s, 9H).[000225] To a solution of tert-butyl ((5-fluoro-2,3-dihydrobenzofuran-4-yl-2,3-d2)methyl-d2)carbamate (40.0 mg, 147 pmol, 1.00 equiv) in dichloromethane (2.00 mL) was added trifluoroacetic acid (109 pL, 1.47 mmol, 10.0 equiv). The mixture was stirred at 25 °C for 1 h. and subsequently was concentrated at reduced pressure to give a residue. The residue was added to saturated sodium bicarbonate (2.00 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (2.00 mL x 3). The combined organic phase was washed with brine (2.00 mL x 3). dried with anhydrous sodium sulfate, fdtered, and concentrated at reduced pressure to afford dideuterio-(2,3-dideuterio-5-fluoro-2,3-dihydrobenzofuran -4- yl)methanamine (25.0 mg, crude) as a white solid, which was used without further purification.INTERMEDIATE B-9[000226] To a solution of 5-fluoro-l,3-benzodioxole (500 mg, 3.57 mmol, 1.00 equiv) in THF (5.00 mL) was added w-BuLi (2.50 M, 1.57 mL, 1.10 equiv) dropwise at -78 °C. The mixture was stirred at -78 °C for 15 min followed by the dropwise addition of DMF (235 mg, 3.21 mmol, 247 pL, 0.90 equiv) and continued stirring at -78 °C for 0.5 h. The mixture was poured into saturated ammonium chloride aqueous solution (5.00 mL) and stirred for 15 min. The aqueous phase was extracted with ethyl acetate (6.00 mL x 2). The combined organic phase was washed with brine (6.00 mL x 3). dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-fluoro-l,3-benzodioxole-4- carbaldehyde (370 mg, 2.20 mmol, 61.7% yield) as a white solid. ’H NMR (400 MHz, DMSO- e) 5 = 10.07 (s, 1H), 7.12 (dd, J=4.4, 8.4 Hz, 1H), 6.72 (dd, J=8.8, 11.6 Hz, 1H), 6.17 (s, 2H).[000227] To a solution of 5-fluoro-l,3-benzodioxole-4-carbaldehyde (200 mg, 1.19 mmol, 1.00 equiv) in ethyl alcohol (6.00 mL) was added hydroxylamine -hydrochloride (248 mg, 3.57 mmol, 3.00 equiv) and triethylamine (827 pL, 5.95 mmol, 5.00 equiv). The mixture was stirred at 15 °C for 0.5 h and the mixture was concentrated under reduced pressure to give a residue. The residue was triturated with water (3.00 mL x 2) and filtered, the filter cake was collected and dried under reduced pressure to give 5- fluoro-l,3-benzodioxole-4-carbaldehyde oxime (200 mg, 1.09 mmol, 91.8% yield) as a white solid. ’H NMR (400 MHz, DMSO-6) 5 = 11.68 (s, 1H), 8.08 (s, 1H), 6.91 (br dd, J=4.0, 8.4 Hz, 1H), 6.77 - 6.65 (m, 1H), 6.12 (s, 2H).[000228] To a solution of 5-fluoro-l,3-benzodioxole-4-carbaldehyde oxime (280 mg, 2.07 mmol, 1.00 equiv) in methyl alcohol (3.00 mL) was added Pd / C (2.07 mmol, 10% purity, 1.00 equiv) and di-tert- butyl dicarbonate (906 mg, 4.15 mmol, 953 pL, 2.00 equiv). The mixture was stirred at 25 °C for 12 h under a hydrogen atmosphere (15 psi). The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to afford tert-butyl / V-[(5-fluoro-l,3-benzodioxol-4-yl)methyl]carbamate (350 mg, 1.71 mmol, 82.3% yield) as a white solid. LCMS [M-55]: 214.1.[000229] To a solution of tert-butyl ((5-fluorobenzo[d][l,3]dioxol-4-yl)methyl)carbamate (85.0 mg, 316 pmol, 1.00 equiv) in DCM (1.00 mL) was added TFA (0.30 mL). The mixture was stirred at 25 °C for0.5 h. The reaction mixture was neutralized with saturated aq potassium carbonate (5.00 mb) and stirred for 30 min. The aqueous phase was extracted with DCM (5.00 mb x 2). The combined organic phase was washed with brine (5.00 mb x 2), dried with anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to give (5-fluorobenzo[d][I,3]dioxol-4-yl)methanamine (45.0 mg, 266 pmol, 84.3% yield) as a yellow oil. 'HNMR (400 MHz, CDC13) 5 = 6.63 (dd, J=4.4, 8.4 Hz, 1H), 6.52 (dd, J=8.4, 10.4 Hz, 1H), 6.00 (s, 2H), 3.89 (s, 2H).INTERMEDIATE C-l[000230] An exemplary Intermediate C, Intermediate C-l, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R5)2, is a single bond and one R3is fluorine. A mixture of ethyl 8-bromo-5-chloro-imidazo[l,2-c]pyrimidine-2 -carboxylate (380 mg, 1.25 mmol, 1.00 equiv), (5-fhioro-2,3-dihydrobenzofuran-4-yl)methanamine (250.34 mg, 1.50 mmol, 1.20 equiv), DIEA (322 mg, 2.50 mmol, 434 pL, 2.00 equiv) in DMF (3.00 m ) was purged with nitrogen and was stirred at 85 °C for 0.5 h. To this mixture was added water (10.0 m ) and ethyl acetate (8.00 mb). The biphasic mixture was fdtered to remove a solid impurity and the organic layer was concentrated in vacuo to provide ethyl 8-bromo-5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[I,2- c]pyrimidine-2 -carboxylate (443 mg, 1.02 mmol, 81.5% yield) as a white solid. 'H NMR (400 MHz, DMSO-t / ,) 5 = 8.87 (s, 1H), 8.50 (t, J= 4.8 Hz, 1H), 7.90 (s, 1H), 6.93 (t, J= 9.6 Hz, 1H), 6.69 (dd, J = 4.0, 8.8 Hz, 1H), 4.65 (d, J= 4.8 Hz, 2H), 4.52 (t, J= 8.8 Hz, 2H), 4.32 (q, J= 7.2 Hz, 2H), 3.25 (t, J = 8.8 Hz, 2H), 1.32 (t, J= 7.2 Hz, 3H).INTERMEDIATE C-2[000231] A second exemplary Intermediate C, Intermediate C-2, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is CR5, is a double bond and one R3is fluorine. A mixture of 8-bromo-5-chloro-imidazo[I,2-c]pyrimidine-2-carboxylate (160 mg, 525 pmol. 1.00 equiv), (5-fluorobenzofuran-4-yl)methanamine (116 mg, 630 pmol, 1.20 equiv) and DIEA (136 mg, 1.05 mmol, 183 ph, 2.00 equiv) in DMF (2.00 mb) was stirred at 85 °C for 0.5 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether / ethyl acetate, 0 / 1 to 2 / 1) to afford ethyl 8-bromo-5- (((5-fhiorobenzofuran-4-yl)methyl)amino)imidazo[I,2-c]pyrimidine-2-carboxylate (180 mg, 78.2%yield) as a brown solid. LCMS [M+I]: 433.1. 'H NMR (400MHz, CD3OD) 5 = 8.63 (s, 1H), 7.92 (s, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.45 (dd, J=3.6, 8.8 Hz, 1H), 7.13 - 7.07 (m, 1H), 7.06 (d, J=1.2 Hz, 1H), 5.04 (s, 2H), 4.38 (q, J=6.8 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H).INTERMEDIATE C-3[000232] A third exemplary Intermediate C, Intermediate C-3, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is O, and is a single bond. To a solution of ethyl 8-bromo- 5-chloro-imidazo[I,2-c] pyrimidine -2 -carboxylate (103 mg, 328 pmol, 1.00 equiv), l,3-benzodioxol-4- ylmethanamine (54.6 mg, 361 pmol, 1.10 equiv) in DMF (2.00 mb) was added DIEA (42.4 mg, 328 pmol, 57.2 pL, 1.00 equiv). The resultant mixture was stirred at 85 °C for 1 h and was subsequently concentrated to afford the crude material. The residue was washed with water (3.00 m x 2) to provide ethyl 5-((benzo[d][l,3]dioxol-4-ylmethyl)amino)-8-bromoimidazo[l,2-c]pyrimidine-2 -carboxylate (120 mg, 286.24 pmol, 87.2% yield) as a brown solid. LCMS: [M+I] 421.2. 'H NMR (400MHz, DMSO-d6) 5 = 8.87 (s, 1H), 8.65 (br s, 1H), 7.88 (s, 1H), 6.90 - 6.77 (m, 3H), 6.03 (s, 2H), 4.66 (d, J=4.8 Hz, 2H), 4.36 - 4.3 l(m, 2H), 1.33 (t, J=7.2 Hz, 3H).INTERMEDIATE C-4[000233] A fourth exemplary Intermediate C, Intermediate C-4, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R5)2, is a single bond and one R3is chlorine. To a solution of ethyl 8-bromo-5-chloro-imidazo[l,2-c]pyrimidine-2 -carboxylate (230 mg, 755 pmol, 1.00 equiv), (5-chloro-2,3-dihydrobenzofuran-4-yl)methanamine (118 mg, 642 pmol, 0.850 equiv) in DMF (2.00 m ) was added DIEA (195 mg, 1.51 mmol, 263 pL, 2.00 equiv) and the reaction mixture was stirred at 85 °C for 1 h. The solution was concentrated in vacuo to give the crude material, which was purified by prep-TLC (petroleum ether / ethyl acetate = 1 / 1) to afford ethyl 8-bromo-5-(((5-chloro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[ 1, 2-c]pyrimidine-2 -carboxylate (320 mg) as a brown solid. LCMS: [M+3] 453.1.INTERMEDIATE C-4A[000234] Another Intermediate C, Intermediate C-4A, may be used to synthesize compounds of formula I wherein Z is O, n is two, X is C(R5)2, and is a single bond. To a solution of ethyl 8-bromo-5- chloro-imidazo[I,2-c]pyrimidine-2-carboxylate (250 mg, 802 pmol, 1.00 eq.) in DMF (3.00 mL) was added DIPEA (207 mg, 1.60 mmol, 279 pL, 2.00 eq.) and chroman-5-ylmethanamine (170 mg, 1.04 mmol, 1.30 eq.). The mixture was stirred at 85 °C for 30 min. The reaction mixture was diluted with water (40 mL) and fdtered. The solid was dried under vacuum to afford ethyl 8-bromo-5-((chroman-5- ylmethyl)amino)imidazo[I,2-c]pyrimidine-2 -carboxylate (320 mg, 742 pmol, 92.5% yield) as a yellow solid. LC-MS: [M+l] 433.3.INTERMEDIATE C-4B[000235] Yet another exemplary Intermediate C, Intermediate C-4B, may be used to synthesize compounds of formula I wherein Z is S, n is one, X is C(R5)2, is a single bond and one R3is fluorine. To a solution of (5-fhiorobenzothiophen-4-yl)methanamine (39.4 mg, 218 pmol, 1.40 eq.) and 8-bromo-5-chloro-imidazo[l,2-c]pyrimidine-2 -carbonitrile (40.0 mg, 155 pmol, 1.00 eq.) in DMF (2.00 mL) was added DIEA (60.2 mg, 466 pmol, 81.2 pL, 3.00 eq.). The reaction mixture was stirred at 85 °C for 1 h. The mixture was diluted with ethyl acetate (10.0 mL), washed with brine (10.0 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the crude residue. The crude material was purified by prep-TLC(petroleum ether / ethyl acetate = 1 / 1) to give 8-bromo-5-((5- fhiorobenzo[b]thiophen-4-yl)amino)imidazo[I,2-c]pyrimidine-2-carbonitrile (35.0 mg, 87.0 pmol, 56.0% yield) as a brown solid. LCMS [M+l]: 404.0.INTERMEDIATE C-5[000236] A fifth exemplary Intermediate C, Intermediate C-5, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R5)2, is a single bond and one R3is fluorine. Amixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2-carboxylate (160 mg, 367 pmol, 1 equiv) and sodium hydroxide (1 M, 1.10 mb, 3 equiv) in methanol (3.30 mb) was stirred at 55 °C for 0.5 h under an atmosphere of nitrogen. The mixture was concentrated in vacuo and the residue was diluted with water (1.00 mb). The pH was adjusted to pH = 2 with HC1 (I M) and the solid was collected by filtration. The resultant solid was dried under reduced pressure to afford 8-bromo-5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carboxylic acid (124 mg, 304 pmol, 82.8% yield) as a white solid. EC-MS: [M+l] 408.8. [000237] A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carboxylic acid (124 mg, 304. pmol, 1.00 equiv), ammonium chloride (48.8 mg, 913 pmol, 3.00 equiv), HATU (173 mg, 1.50 equiv), DIEA (314 mg, 2.44 mmol, 424 ph, 8 equiv) in DMF (1.00 mb) was stirred at 30 °C for 1 h under an atmosphere of nitrogen. Subsequently, the mixture was concentrated in vacuo. To the crude material was added water (1.00 mb) and the resultant solid was collected by filtration. The solid was dried under reduced pressure to provide 8-bromo-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxamide (100 mg) as a white solid, which was used without further purification.[000238] To a mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxamide (100 mg, 246. pmol, 1.00 equiv), TEA (484 mg, 4.79 mmol, 666 ph, 19.4 equiv) in THF (2.00 mb) was added TFAA (302 mg, 1.44 mmol, 200 ph, 5.84 equiv) at 0 °C. Subsequently, the mixture was stirred at 0-30 °C for 40 min under an atmosphere of nitrogen. The mixture was concentrated to provide the crude residue, which was purified by column chromatography (petroleum ether / ethyl acetate, 5 / 1 to 0 / 1) to afford 8-bromo-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (100 mg, 245 pmol, 99.7% yield) as a yellow solid. EC-MS: [M+l] 387.8.[000239] Alternatively, Intermediate C-5 may be prepared as follows:[000240] To a solution of 8-bromo-5-chloro-imidazo[l,2-c]pyrimidine-2- carbonitrile (3.00 g, 11.7 mmol, 1.00 equiv) and (5-fluoro-2,3-dihydrobenzofuran-4-yl) methanamine (2.14 g, 12.8 mmol, 1.10 equiv) in DMF (30.0 mb) was added DIEA (3.01 g, 23.3 mmol, 4.06 m , 2.00 equiv). The resultant mixture was stirred at 85 °C for 1 h, cooled to rt, and poured into water (100 m ). The mixture was extracted with ethyl acetate (50.0 mb x 3). The combined organic phase was washed with brine (50.0 mb x 2), dried with anhydrous sodium sulfate, fdtered, and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to afford 8-bromo-5- (((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (4.00 g, 10.3 mmol, 88.4% yield) as a yellow solid. ECMS [M+l]: 390.1.INTERMEDIATE C-6[000241] A sixth exemplary Intermediate C, Intermediate C-6, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R5)2, is a single bond and one R3is fluorine. A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2-carboxylate (204 mg, 460 pmol, 1.00 equiv), di-tert-butyl dicarbonate (201 mg, 919 pmol, 2.00 equiv), 4-(dimethylamino)pyridine (561 ug, 4.60 pmol, 0.01 equiv) in tetrahydrofuran (2.00 mb) was purged with nitrogen and subsequently allowed to stir at 25 °C for 2 h under an atmosphere of nitrogen. The mixture was diluted with water (3.00 mL) and extracted with ethyl acetate (2.00 mb x 3). The combined organic layers were washed with brine (2.00 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The crude material was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate, 3 / 1) to afford ethyl 8 -bromo-5 -((tertbutoxy carbonyl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2- carboxylate (160 mg, 198 pmol, 43.0% yield, 66. 2% purity) as a white solid. LC-MS [M+l]: 537.2. ’H NMR (400MHz, CDC13) 8 = 8.11 (s, 1H), 7.93 (s, 1H), 6.67 - 6.61 (m, 1H), 6.59 - 6.54 (m, 1H), 5.08 (s, 2H), 4.58 (t, J=8.8 Hz, 2H), 4.47 (q, J=12 Hz, 2H), 3.32 (brt, J=8.8 Hz, 2H), 1.43 (t, J=12 Hz, 3H), 1.36 (s, 9H).INTERMEDIATE C-7[000242] A seventh exemplary Intermediate C, Intermediate C-7, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R5)2, is a single bond, one R3is fluorine and R1is heteroaryl which may then be further substituted with one or more R4. To a solution of tert-butyl (8- bromo-2-cyanoimidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (500 mg, 1.01 mmol, 1.00 eq.), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (295 mg, 1.52 mmol, 1.50 eq.) and sodium bicarbonate (170 mg, 2.03 mmol, 2.00 eq.) in a mixture of dioxane (4.00 m ) and water (0.80 m ) was added Pd(dppf)C12 (80.0 mg, 109 pmol, 0.01 eq). The mixture was purged with nitrogen and stirred at 105 °C for 2 h. The reaction mixture was cooled to rt and fdtered through a pad of Celite. The filtrate was concentrated to give a residue. The residue was purified by prep- TLC (SiC>2, dichloromethane / methanol = 10 / 1) to afford tert-butyl (2-cyano-8-(lH-pyrazol-3-yl)imidazo [ 1 ,2-c]pyrimidin-5 -y 1) (( 5 -fluoro-2,3 -dihydrobenzofuran-4-yl)methyl)carbamate (120 mg, 230 pmol, 22.7% yield, 91% purity) as a yellow solid.INTERMEDIATE C-8[000243] An eighth exemplary Intermediate C, Intermediate C-8, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R5)2, is a single bond, one R3is fluorine and R1is heteroaryl which is substituted two R4groups, one of which serves as an intermediate to generate various R4groups, e.g., L-N(R5)2. To a solution of 5-bromo-6-methyl-pyridine-2-carbaldehyde (300 mg, 1.50 mmol, 1.00 eq.) in toluene (10.0 m ) was added TsOH’ILO (28.5 mg, 150 pmol, 0.10 eq.) and ethylene glycol (186 mg, 3.00 mmol, 168 pL, 2.00 eq.). The mixture was stirred at 120 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (SiC>2, petroleum ether / ethyl acetate = 1 / 1) to give compound 3 -bromo-6-(l, 3 -dioxolan-2-yl)-2 -methyl -pyridine (260 mg, 1.07 mmol, 71.0% yield) as a yellow oil.[000244] To a solution of 3-bromo-6-(l,3-dioxolan-2-yl)-2-methyl-pyridine (0.30 g, 1.23 mmol, 1.00 eq.) in Et2O (15.0 m ) was added w-BuLi (2.50 M, 737 pL, 1.50 eq.) dropwise at -78 °C. The mixture was stirred at -78 °C for 30 min prior to the addition of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (457 mg, 2.46 mmol, 501 pL, 2.00 eq.). The mixture was stirred at -78 °C for an additional hour. The reaction mixture was quenched with water (2.00 mb) and the resulting mixture was extracted with ethyl acetate (30.0 mb x 2). The combined organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (SiCK petroleum ether / ethyl acetate = 1 / 1) to give [6-(l,3-dioxolan-2-yl)-2-methyl-3-pyridyl]boronic acid (160 mg, 766 pmol, 62.3% yield) as yellow oil. LC-MS [M+l]: 209.9.[000245] A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2-carbonitrile (0.20 g, 515 pmol, 1.00 eq.), [6-(l,3-dioxolan-2-yl)-2-methyl-3- pyridyl]boronic acid (162 mg, 773 pmol, 1.50 eq.), sodium bicarbonate (130 mg, 1.55 mmol, 3.00 eq.) and Pd(dppf)C12 (56.6 mg, 77.3 pmol, 0.15 eq.) in water (0.60 mb) and dioxane (1.80 mb) was purged with nitrogen and the resultant mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiCL, dichloromethane: methanol = 20: 1) to give 8-(6-(l,3-dioxolan-2-yl)-2-methylpyridin-3-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile (150 mg, 317 pmol, 61.6% yield) as a yellow oil. LC-MS [M+l]: 473.3.[000246] To a solution of 8-(6-(l,3-dioxolan-2-yl)-2-methylpyridin-3-yl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (120 mg, 254 pmol, 1.00 eq.) in DMSO (3.00 mL) and water (0.30 mL) was added lithium chloride (53.8 mg, 1.27 mmol, 5.00 eq.) and the mixture was stirred at 130 °C for 3 h. The mixture was cooled to rt and diluted with water (15.0 mL). The mixture was extracted with ethyl acetate (20.0 mLx3) and the combined organic phase was washed with brine (20.0 mLx2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(6-formyl-2-methylpyridin-3- yl)imidazo[l,2-c]pyrimidine-2 -carbonitrile (100 mg, 233 pmol, 91.9% yield) as a brown solid. LC-MS [M+l]: 429.1.INTERMEDIATE C-9[000247] To a solution of 2-(l,3-dioxolan-2-yl)-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (45.0 mg, 155 pmol, 1.00 equiv), 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (60.0 mg, 155 pmol, 1.00 equiv) in dioxane (1.00 mb) and water (0.30 mL) was added Pd(dppf)C12 (11.3 mg, 15.5 pmol, 0.10 equiv) and sodium bicarbonate (26.0 mg, 309 pmol, 2.00 equiv) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 1 h. The mixture was concentrated in vacuo to provide the crude residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 0 / 1) to afford 5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)-8-(6-formyl-4-methylpyridin-3-yl)imidazo[l,2-c]pyrimidine-2- carbonitrile (32.0 mg, 67.7 pmol, 43.8% yield) as a yellow solid. LCMS [M+l]: 473.2.INTERMEDIATE C-10[000248] A mixture of (4-formyl-2-methyl-phenyl)boronic acid (80.0 mg, 488 pmol, 1.50 eq), 8-bromo- 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (126 mg, 325 pmol, 1.00 eq.), sodium bicarbonate (54.7 mg, 651 pmol, 2.00 eq.) and Pd(dppf)C12 (23.8 mg, 32.5 pmol, 0.10 eq.) in dioxane (1.00 mL) and water (0.30 mL) was purged with nitrogen 3 times and subsequently stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction mixture was dilutedwith water (10.0 mb) and extracted with ethyl acetate (10.0 mb x 3). The combined organic layer was washed with brine (20.0 mb), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by prep-TEC (dichloromethane / methanol = 10 / 1) to afford 5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(4-formyl-2- methylphenyl)imidazo[l,2-c]pyrimidine-2 -carbonitrile (74 mg, crude) as a yellow solid. ’H NMR (400MHz, DMSO-t / 6) 5 10.04 (s, 1H), 8.93 (s, 1H), 8.55 (t, J=4.8 Hz, 1H), 7.85 (s, 1H), 7.82 - 7.77 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.01 - 6.90 (m, 1H), 6.71 (dd, J=4.0, 8.8 Hz, 1H), 4.73 (d, .7=4,4 Hz, 2H), 4.55 (t, .7=8,8 Hz, 2H), 3.38 - 3.32 (m, 2H), 2.27 (s, 3H).INTERMEDIATE C-ll[000249] To a solution of (5-fluoro-2,3-dihydrobenzofuran-4-yl)methan-t / 2-amine (50.0 mg, 284 pmol, 1.00 equiv), 8-bromo-5-chloroimidazo[l,2-c]pyrimidine-2-carbonitrile (73.1 mg, 284 pmol, 1.00 equiv) in DMF (1.00 m ) was added DIEA (110 mg, 851 pmol, 148 ph, 3.00 equiv). The mixture was stirred at 85 °C for 1 h. The reaction mixture was diluted with water (1.00 m ) and extracted with ethyl acetate (1.00 m x 3). The combined organic layer was washed with brine (3.00 mb x 2), dried over sodium sulfate, fdtered, and concentrated under reduced pressure to afford 8-bromo-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl-d2)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile (20.0 mg, crude) as a white solid. ECMS [M+l]: 390.0.INTERMEDIATE C-12[000250] A mixture of (3-fhroro-4-formyl-phenyl)boronic acid (80.0 mg, 476 pmol, 1.50 equiv), 8- bromo-5 -(((5 -fluoro-2, 3 -dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (123 mg, 318 pmol, 1.00 equiv), sodium bicarbonate (53.4 mg, 635 pmol, 2.00 equiv) and Pd(dppf)C12 (23.2 mg, 31.8 pmol, 0.10 equiv) in dioxane (1.00 mb) and water (0.30 mb) was purged with nitrogen and subsequently allowed to stir at 100 °C for 2 h under a nitrogen atmosphere. The reaction mixture was diluted with water (10.0 mb) and extracted with ethyl acetate (10.0 mb x 3). The combined organic layer was washed with brine (20.0 mb), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue that was purified by prep-TEC (dichloromethane / methanol = 10 / 1)to afford 5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl) methylamino]-8-(3-fluoro-4-formyl- phenyl)imidazo[l,2-c]pyrimidine-2 -carbonitrile (87.0 mg, crude) as a yellow solid. ’H NMR (400MHz, DMSO-t / ,.) 5 = 10.24 (s, 1H), 8.97 (s, 1H), 8.81 (t, . =5.2 Hz. 1H), 8.44 (s, 1H), 8.22 - 8.16 (m, 2H), 7.95- 7.91 (m, 1H), 6.99 - 6.93 (m, 1H), 6.72 (dd, J=4.0, 8.8 Hz, 1H), 4.77 (d, .7=4.8 Hz, 2H), 4.56 (t, J=8.8 Hz, 2H), 3.36 - 3.33 (m, 2H).INTERMEDIATE C-13[000251] A mixture of 5-formyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 -yl)benzonitrile (100 mg, 388 pmol, 1.00 equiv), 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2-carbonitrile (31.7 mg, 81.7 pmol, 0.21 equiv), Pd(dppf)C12 (28.5 mg, 38.9 pmol, 0.10 equiv) and sodium bicarbonate (98.0 mg, 1.17 mmol, 3.00 equiv) in dioxane (1.50 m ) and water (0.30 m ) was purged with nitrogen and subsequently stirred at 95 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 1 / 1) to afford 2-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-5-formylbenzamide (70 mg, 31.5% yield, 80% purity) as a yellow solid. LCMS [M+l]: 457.2. 'H NMR (400MHz, DMSO-d6) 5 = 10.09 (s, 1H), 8.92 (s, 1H), 8.60 (br s, 1H), 8.06 (s, 1H), 8.03 (br d, J=8.4 Hz, 1H), 7.93 (br s, 1H), 7.88 - 7.77 (m, 2H), 7.38 (br s, 1H), 6.95 (br t, J=9.2 Hz, 1H), 6.71 (dd, J=3.6, 8.4 Hz, 1H), 4.72 (br s, 2H), 4.55 (br t, J=8.8 Hz, 2H), 3.53 - 3.48 (m, 2H).[000252] To a solution of 2-(2-cyano-5-(((5-fhroro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-5-formylbenzamide (70.0 mg, 123 pmol, 1.00 equiv) in THF (1.00 mb) was added TEA (248mg, 2.45 mmol, 341 pL, 20.0 equiv) followed by TFAA (258 mg, 1.23 mmol, 171 pL, 10 equiv) dropwise at 0 °C. The mixture was stirred at 25 °C for 2 h and was subsequently concentrated under reduced pressure. The resultant residue was diluted with dichloromethane (6 mb) and the combined organic layer was washed with brine (3 mb x 2), dried over sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (ethyl acetate) to afford 8-(2-cyano-4-formylphenyl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (30.0 mg, 50.2% yield, 90.0% purity) as a yellow solid.1H NMR (400MHz, DMSO-d6) 5 = 10.09 (s, 1H), 8.99 (s, 1H), 8.86 (br s, 1H), 8.50 (d, .7=1.2 Hz, 1H), 8.26 (dd, J=1.6, 8.0 Hz, 1H), 8.14 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 6.96 (t, J=9.6 Hz, 1H), 6.72 (dd, J=4.0, 8.8 Hz, 1H), 4.77 (br s, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.39 - 3.35 (m, 2H).INTERMEDIATE C-14[000253] To a solution of l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenyl] ethanone (41.2 mg, 167 pmol, 1.30 equiv) and 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (50.0 mg, 129 pmol, 1.00 equiv) in dioxane (1.00 mL) and water (0.20 mL) was added Pd(dppf)C12 (9.42 mg, 12.9 pmol, 0.10 equiv) and sodium bicarbonate (21.6 mg, 258 pmol, 2.00 equiv). The mixture was purged with nitrogen and subsequently stirred at 100 °C for 1 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 1 / 1) to afford 8-(4-acetylphenyl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (30.0 mg, 54.5% yield) as a yellow solid. LCMS [M+l]: 428.0. ’H NMR (400MHz, DMSO-t / 6) 5 = 8.96 (s, 1H), 8.24 (s, 1H), 8.19 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H), 6.93 (t, J=9.2 Hz, 1H), 6.68 (dd, J=3.6, 8.4 Hz, 1H), 4.74 (s, 2H), 4.53 (t, J=8.4 Hz, 2H), 3.31 - 3.28 (m, 2H), 2.60 (s, 3H).INTERMEDIATE C-15[000254] A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carbonitrile (50.0 mg, 129 pmol, 1.00 equiv), (4-formyl-3-methyl-phenyl)boronic acid (31.7 mg, 193 pmol, 1.50 equiv), sodium bicarbonate (21.6 mg, 258 pmol, 2.00 eq) and Pd(dppf)C12.CH2C12 (10.5 mg, 12.9 pmol, 0.10 equiv) and in dioxane (1 mL) and water (0.30 mL) was purged with nitrogen and then stirred at 95 °C for 2 h. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The combined organic layer was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 1 / 1) to afford 5- (((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(4-formyl-3-methylphenyl)imidazo[l,2- c]pyrimidine-2 -carbonitrile (25.0 mg, 58.5 pmol, 45.4% yield) as a yellow solid. 'H NMR (400MHz,DMSO-t / ,) 5 = 10.25 (s, 1H), 8.96 (s, 1H), 8.69 (br t, J=4.8 Hz, 1H), 8.29 (s, 1H), 8.12 (dd, J=1.2, 8.4 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 6.96 (t, J=9.2 Hz, 1H), 6.71 (dd, J=4.0, 8.4 Hz, 1H), 4.76 (br d, .7=4.8 Hz, 2H), 4.56 (t, J=8.8 Hz, 2H), 3.31 - 3.29 (m, 2H), 2.70 (s, 3H).INTERMEDIATE C-16[000255] A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylate (3.00 g, 6.89 mmol, 1.00 equiv), 2-[4-(l,3- dioxolan-2-yl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.60 g, 8.96 mmol, 1.3 equiv), NaHCOs (1.74 g, 20.7 mmol, 3.00 equiv), Pd(dppf)C12.CH2C12 (338 mg, 414 pmol, 0.06 equiv) in dioxane (35.0 m ) and H2O (7.00 m ) was purged with N2 and then stirred at 100 °C for 4 h. The reaction mixture was fdtered and concentrated in vacuo. The residue was purified column chromatography (SiC>2, dichloromethane / methyl alcohol = 100 / 1 to 30 / 1) to afford ethyl 8-(4-( 1 ,3- dioxolan-2-yl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2-carboxylate (1.70 g, 3.28 mmol, 47.6% yield) as a yellow solid. LCMS [M+l]: 519.2. [000256] To a solution of ethyl 8-(4-(l,3-dioxolan-2-yl)-2-methylphenyl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxylate (1.60 g, 3.09 mmol, 1.00 equiv) in methanol (16.0 mb) was added NaOH (1 M in water, 9.28 mb, 3.01 equiv) until the solution was adjusted to pH >12. The mixture was stirred at 50 °C for 2 h and was subsequently acidified to pH = 6 with IM HC1. The formed precipitate was filtered and dried under vacuum to give the crude product 8- (4-(l,3-dioxolan-2-yl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylic acid (1.55 g). LCMS [M+l]: 491.0.[000257] To a solution of 8-(4-(l,3-dioxolan-2-yl)-2-methylphenyl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxylic acid (1.53 g, 3.12 mmol, 1.00 equiv) and ammonium chloride (536 mg, 10.0 mmol, 3.21 equiv) in DMF (15 mb) was added HATU (1.77 g, 4.67 mmol, 1.50 equiv) and DIEA (1.21 g, 9.35 mmol, 1.63 mb, 3.00 equiv). The mixture was stirred at 25 °C for 1 h and was subsequently diluted with water (20.0 mb). The suspension was filtered and the solid was dried under reduced pressure to give the crude product. The crude product diluted with water (60.0 mL) and extracted with ethyl acetate (60.0 mb* 2). The combined organic layer was washed with brine (80.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 8-(4-(l,3-dioxolan-2-yl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxamide (1.1 g, crude) as a yellow solid. LCMS [M+l]: 490.3.[000258] To a solution of 8-(4-(l,3-dioxolan-2-yl)-2-methylphenyl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxamide (500 mg, 1.02 mmol, 1.00 equiv) and triethylamine (2.07 g, 20.4 mmol, 2.84 mb, 20.0 equiv) in THF (2.00 mb) was added dropwise TFAA (1.82 g, 8.68 mmol, 1.21 mb, 8.50 equiv) at 0 °C. The mixture was warmed to room temperature and stirred for 2 h and was subsequently concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=5 / l to 1 / 1) to provide the crude product. The crude product was triturated with methanol (5.00 mb) and the solid was collected by filtration to afford 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(4- formyl -2 -methylphenyl)imidazo[l,2-c]pyrimidine-2 -carbonitrile (740 mg, 1.73 mmol, 84.8% yield) as a light yellow solid. 'H NMR (400 MHz, DMSO-76) 5 = 10.04 (s, 1H), 8.93 (s, 1H), 8.55 (t, 7=4.8 Hz, 1H), 7.86 (s, 1H), 7.86 (s, 1H), 7.55 (d, 7=7.6 Hz, 1H), 7.03 - 6.88 (m, 1H), 6.72 (dd, 7=4.0, 8.8 Hz, 1H), 4.73 (d, 7=4.8 Hz, 2H), 4.56 (t, 7=8.8 Hz, 2H), 3.30 - 3.28 (m, 2H), 2.27 (s, 3H).INTERMEDIATE C-17[000259] To a solution of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (300 mg, 773 pmol, 1.00 equiv) and tributyl(l- ethoxyvinyl)stannane (279 mg, 773 pmol, 261 pL, 1.00 equiv) in dioxane (5.00 mb) was added Pd(PPh3)2Cl2(54.2 mg, 113 pmol, 0. 10 equiv). The reaction was stirred at 100 °C for 2 h under nitrogen. The reaction was quenched with saturated aqueous potassium fluoride (20.0 mb) and extracted with ethyl acetate (20.0 mLx2). The combined organic phase was washed with brine (20.0 mLx2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to afford 8-(l- ethoxyvinyl)-5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2- carbonitrile (100 mg, 264 pmol, 34.1% yield) as a brown solid. ’H NMR (400 MHz, CDCh) 5 = 8.21 (s, 1H), 7.88 (s, 1H), 6.87 - 6.80 (m, 1H), 6.66 (dd, 7=4.0, 8.4 Hz, 1H), 5.80 (d, 7=2.4 Hz, 1H), 5.55 (br t, 7=5.6 Hz, 1H), 4.81 (d, 7=5.6 Hz, 2H), 4.63 (t, 7=8.8 Hz, 2H), 4.59 (d, 7=2.4 Hz, 1H), 4.03 - 3.95 (m, 2H), 3.41 (t, 7=8.8 Hz, 2H), 1.44 (t, 7=6.8 Hz, 3H).[000260] To a solution of 8-(l-ethoxyvinyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile (100 mg, 264 pmol, 1.00 equiv) in DCM (1.00 mb) was added TFA (1.00 mb). The reaction was stirred at 25 °C for 1 h. The reaction was concentrated under vacuum to give 8-acetyl-5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carbonitrile (90.0 mg, 256 pmol, 97.2% yield) as a brown solid. 'H NMR (400 MHz,DMSO-t / e) 8 = 9.16 (br s, 1H), 8.95 (s, 1H), 8.44 (s, 2H), 6.98 - 6.91 (m, 1H), 6.71 (dd, 7=4.4, 8.8 Hz, 1H), 4.78 (s, 2H), 4.54 (t, 7=8.8 Hz, 2H), 3.28 (t, 7=8.8 Hz, 2H), 2.72 (s, 3H).[000261] To a solution of 8-acetyl-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carbonitrile (50.0 mg, 142 pmol, 1.00 equiv) in THF (2.00 mb) was added di-tert-butyl dicarbonate (62.1 mg, 285 pmol, 2.00 equiv) and DMAP (1.74 mg, 14.2 pmol, 0.10 equiv). The reaction was stirred at 80 °C for 1 h. The reaction was concentrated under vacuum to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 3 / 1) to afford tert-butyl (8-acetyl-2- cyanoimidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (40.0 mg, 88.6 pmol, 62.3% yield) as a white solid. 'H NMR (400 MHz, DMSO-76) 8 = 8.87 (s, 1H), 8.60 (s, 1H), 6.83 - 6.77 (m, 1H), 6.64 (dd, 7=3.6, 8.4 Hz, 1H), 5.09 (s, 2H), 4.54 (t, 7=8.8 Hz, 2H), 3.30 - 3.25 (m, 2H), 2.86 (s, 3H), 1.33 (s, 9H).[000262] A solution of tert-butyl (8-acetyl-2-cyanoimidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)carbamate (30.0 mg, 66.5 pmol, 1.00 equiv) in DMF-DMA (209 mg, 1.76 mmol, 233 pL, 26.5 equiv) was stirred at 100 °C for 1 h. The reaction was concentrated under vacuum to give a residue. The residue was purified by prep-TLC(petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (E)-(2-cyano-8-(3-(dimethylamino)acryloyl)imidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)carbamate (20.0 mg, 39.5 pmol, 59.4% yield) as a yellow solid. ’H NMR (400 MHz, CDCh) 8 = 8.71 (s, 1H), 8.01 (br d, 7=12.8 Hz, 1H), 7.81 (s, 1H), 6.76 (br d, 7=12.0 Hz, 1H), 6.70 - 6.63 (m, 1H), 6.56 (dd, 7=4.0, 8.8 Hz, 1H), 5.12 (s, 2H), 4.56 (t, 7=8.8 Hz, 3H), 3.28 (t, 7=8.4 Hz, 2H), 3.23 (s, 3H), 3.06 (s, 3H), 1.38 (s, 9H).INTERMEDIATE C-18[000263] To a solution of dideuterio-(2,3-dideuterio-5-fluoro-2,3-dihydrobenzofuran -4-yl)methanamine (31.9 mg, 186 pmol, 1.20 equiv) and 8-bromo-5-chloroimidazo[l,2-c]pyrimidine-2 -carbonitrile (40.0 mg, 155 pmol, 1.00 equiv) in DMF (1.00 m ) was added DIEA (108 pL, 621 pmol, 4.00 equiv) and the mixture was stirred at 85 °C for 0.5 h. The mixture was concentrated at reduced pressure to give a residue, which was poured into water (3.00 mb) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (3.00 mb x 3). The combined organic phase was washed with brine (3.00 mb x 2), dried with anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to afford 8- bromo-5 -(((5 -fluoro-2,3 -dihydrobenzofuran-4-yl-2,3 - 7 cth I - 7am i no)i m idazo [ 1 ,2-c]pyrimidine-2- carbonitrile (25.0 mg, 63.7 pmol, 41.0% yield) as a white solid. 'H NMR (400MHz, CDCE) 8 = 8.30 (s, 1H), 7.94 (s, 1H), 7.93 (s, 1H), 6.83 - 6.76 (m, 1H), 6.64 (dd, 7=4.0, 8.8 Hz, 1H), 4.59 (br d, 7=10.0 Hz, 1H), 3.33 (br d, 7=8.4 Hz, 1H).INTERMEDIATE C-19[000264] To a solution of 8-bromo-5-chloroimidazo[l,2-c]pyrimidine-2 -carbonitrile (40.0 mg, 155 pmol, 1.00 equiv) and (5-fluorobenzo[d][l,3]dioxol-4-yl)methanamine (31.5 mg, 186 pmol, 1.20 equiv) in DMF (0.50 m ) was added DIEA (54.1 ph, 310 pmol, 2.00 equiv). The mixture was stirred at 85 °C for 0.5 h under a nitrogen atmosphere. The mixture was poured into water (3.00 m ) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (3.00 m x 2). The combined organic phase was washed with brine (3.00 mb x 2), dried with anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to afford 8-bromo-5-(((5-fluorobenzo[d][l,3]dioxol-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (50.0 mg, 128 pmol, 82.5% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-t / 6) 5 = 8.92 (s, 1H), 8.567 (br s, 1H), 7.95 (s, 1H), 6.88 (dd, J=4.4, 8.4 Hz, 1H), 6.69 (dd, J=8.8, 10.4 Hz, 1H), 6.04 (s, 2H), 4.67 (br d, .7=2,0 Hz, 2H).INTERMEDIATE D-l[000265] An exemplary Intermediate D, Intermediate D-l, may be used to synthesize compounds of formula I wherein R1is a disubstituted heteroaryl. A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (370 mg, 1.78 mmol, 1.00 equiv), 2-iodopropane (907 mg, 5.33 mmol, 533 ph, 3.00 equiv) and cesium carbonate (2.32 g, 7.11 mmol, 4.00 equiv) in acetonitrile (7.00 mb) was purged with nitrogen and subsequently stirred at 90 °C for 4 h. The reaction mixture was fdtered and concentrated under reduced pressure to provide a residue. The crude material was purified by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 3 / 1) to afford a mixture of l-isopropyl-3- methyl-4- (4, 4, 5, 5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (170 mg, 34.4% yield, 90.0% purity) and l-isopropyl-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (170 mg, 34.4% yield, 90.0% purity) as a light yellow oil. ECMS [M+l]: 251.4. 'H NMR (400MHz, CDC13) 5 = 7.73 (s, 0.6H), 7.65 (s, 1H), 4.50 - 4.36 (m, 2H), 2.45 (s, 2H), 2.40 (s, 3H), 1.50-1.44 (m, 12H), 1.31 (s, 22H).INTERMEDIATE D-2[000266] A second exemplary Intermediate D, Intermediate D-2, may be used to synthesize compounds of formula I, wherein R1is heteroaryl substituted with two R4substituents. A mixture of 5-bromo-2- methoxy-4-methyl-pyridine (350 mg, 1.73 mmol, 1.00 equiv), bis(pinacolato)diboron (2.20 g, 8.66 mmol, 5.00 equiv), potassium acetate (527 mg, 5.37 mmol, 3.10 equiv), Pd(dppf)C12 (127 mg, 173 pmol, 0.10 equiv) in dioxane (5.00 mL) was purged with nitrogen and stirred at 90 °C for 3 h. The residue was diluted with ethyl acetate (3.00 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layers were washed with brine (2.00 mL x 3), dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether / ethyl acetate, 100 / 1 to 20 / 1) to afford 2-methoxy-4-methyl-5- (4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (150 mg, 546 pmol, 31.5% yield, 90.6% purity) as a white solid. 'H NMR (400MHz, CDC13) 5 = 8.47 (s, 1H), 6.51 (s, 1H), 3.93 (s, 3H), 2.45 (s, 3H), 1.33 (s, 12H).INTERMEDIATE D-3[000267] A third exemplary Intermediate D, Intermediate D-3, may be used to synthesize compounds of formula I or formula II wherein R1is heteroaryl substituted with two R4substituents. A mixture of cyclopropanecarboxamidine-HCl (5.00 g, 59.4 mmol, 1.00 equiv), ethyl 3-oxobutanoate (7.74 g, 59.4 mmol, 7.51 mL, 1.00 equiv), sodium ethoxide (8.09 g, 119 mmol, 2.00 equiv) in ethanol (500 mL) was purged with nitrogen and subsequently stirred at 25 °C for 12 h. The residue was dissolved in water (25.0 mL) and the pH was adjusted to ~4 with HC1 (I M). After cooling to 5 °C, the solid was collected and dried under reduced pressure to give 2-cyclopropyl-6-methyl-pyrimidin-4-ol (4.00 g, 26.6 mmol, 44.8% yield, 100% purity) as a white solid. LC-MS [M+I]: 151.3. ’H NMR (400MHz, DMSO-d6) 5 = 12.45 (s, 1H), 5.93(s, 1H), 2.07 (s, 3H), 1.90 - 1.85 (m, 1H), 1.00 - 0.97 (m, 4H).[000268] A mixture of 2-cyclopropyl-6-methyl-pyrimidin-4-ol (4.00 g, 26.6 mmol, 1.00 equiv), bromine (4.34 g, 27.2 mmol, 1.40 mL, 1.00 equiv), potassium hydroxide (1.49 g, 26.6 mmol, 1.00 equiv) in water (32.6 mL) was stirred at 25 °C for 2 h under a nitrogen atmosphere. The solid was fdtered to give 5- bromo-2-cyclopropyl-6-methyl-pyrimidin-4-ol (2.76 g, 9.31 mmol, 35.0% yield, 77.3% purity) as a white solid. LC-MS [M+3]: 231.0.[000269] A mixture of 5-bromo-2-cyclopropyl-6-methyl-pyrimidin-4-ol (2.50 g, 8.44 mmol, 1.00 equiv) and dimethyl formamide (1.54 g, 21.1 mmol, 1.62 mL, 2.50 equiv) in toluene (36.9 mL) was added dropwise a solution of phosphorus oxychloride (1.57 g, 10.2 mmol, 951 pL, 1.21 equiv) in toluene (9.20 mL) at 0 °C. The mixture was subsequently stirred at 25 °C for 3 h under a nitrogen atmosphere. The mixture was poured into sodium carbonate (1.00 M, 55.2 mL) and extracted with ethyl acetate (10.0 mL x 3). The combined organic phase was concentrated to afford compound 5-bromo-4-chloro-2- cyclopropyl-6-methyl-pyrimidine (2.31 g, 4.51 mmol, 53.5% yield, 48.4% purity) as a yellow oil. LC- MS [M+3]: 249.1.[000270] A mixture of 5-bromo-4-chloro-2-cyclopropyl-6-methyl-pyrimidine (2.31 g, 9.33 mmol, 1.00 equiv), 4 -methylbenzene sulfonohydrazide (5.91 g, 31.7 mmol, 3.40 equiv) in chloroform (4.30 mL) was stirred at 90 °C for 16 h under a nitrogen atmosphere. The solid was fdtered and rinsed with dichloromethane (20.0 mL) to afford A'-(5-bromo-2-cyclopropyl-6-mcthyl- pyrimidin-4-yl)-4-methyl- benzenesulfonohydrazide (1.60 g, 4.02 mmol, 43.1% yield, 99.8% purity) as a white solid. LC-MS [M+3]: 399.2. 'HNMR (400MHz, DMSO-d6) 5 =10.08 (br s, 1 H), 7.64 (d, .7=8,4 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 2.44 (br s, 3H), 2.37 (s, 3H), 2.05 - 1.83 (m, 1 H), 1.05 - 0.90 (m, 2H), 0.87-0.75 (m, 2H).[000271] A mixture of A'-(5-bromo-2-cyclopropyl-6-mcthyl-pyrimidin-4-yl) -4-methyl- benzenesulfonohydrazide (1.60 g, 4.02 mmol, 1.00 equiv) and aqueous sodium carbonate (0.57 M, 90.6 mL, 12.8 equiv) was stirred at 90 °C for 1 h under a nitrogen atmosphere. The mixture was diluted with ethyl acetate (50.0 mL) and the organic phase was separated and concentrated to afford 5-bromo-2- cyclopropyl-4-methyl-pyrimidine (620 mg, 2.59 mmol, 64.6% yield, 89.2% purity) as a brown oil. LC- MS [M+l]: 213.2. ’H NMR (400MHz, CDC13) 8 = 8.49 (s, 1H), 2.56 (s, 3H), 2.25 - 2.08 (m, 1H), 1.19 - 0.99 (m, 4H).[000272] A mixture of 5-bromo-2-cyclopropyl-4-methyl-pyrimidine (580 mg, 2.43 mmol, 1.00 equiv),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) -1,3,2 - dioxaborolane (863 mg, 3.40 mmol, 1.40 equiv), potassium acetate (715 mg, 7.28 mmol, 3.00 equiv), and Pd(dppf)C12 (88.8 mg, 121 pmol, 0.05 equiv) in dioxane (5.00 mL) was purged with nitrogen and was subsequently stirred at 90 °C for 4 h under a nitrogen atmosphere. The residue was diluted with water (3.00 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layers were washed with brine (2.00 mL x 3), dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether / ethyl acetate, 100 / 1 to 10 / 1) to afford 2-cyclopropyl-4-methyl -5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (1.00 g, 1.92 mmol, 79.2% yield, 50.0% purity) as a yellow oil. ’H NMR (400MHz, CDCh) 8 = 8.73 (s, 1H), 2.62 (s, 3H), 2.27 - 2.14 (m, 1H), 1.34 (s, 12H), 1.18 - 1.13 (m, 2H), 1.07 - 1.01 (m, 2H).INTERMEDIATE D-4[000273] A fourth exemplary Intermediate D, Intermediate D-4, may be used to synthesize compounds of formula I, wherein R1is heteroaryl substituted with two R4substituents. A mixture of sodium (111 mg, 4.82 mmol, 1.00 equiv) in methanol (772 mg, 24.1 mmol, 975. pL, 5.00 equiv) was stirred at 25 °C for 0.5 h. To this solution was added 5-bromo-2-chloro-4-methyl-pyrimidine (1.00 g, 4.82 mmol, 1.00 equiv) and the mixture was stirred at 25 °C for 2 h. The reaction was quenched upon the addition of water (5 mL). The aqueous phase was extracted with ethyl acetate (10.0 mL x 3) and the combined organic phase was washed with brine (10.0 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated in vacuoto afford 5-bromo-2-methoxy-4-methyl-pyrimidine (500 mg, 2.46 mmol, 51.1% yield) as a red oil. LCMS: [M+l] 203.1.[000274] To a solution of 5-bromo-2-methoxy-4-methyl-pyrimidine (500 mg, 2.46 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (813 mg, 3.20 mmol, 1.30 equiv) and potassium acetate (483 mg, 4.93 mmol, 2.00 equiv) in dioxane (5.00 mL) was added Pd(dppf)C12 (180 mg, 246 pmol, 0.10 equiv) under nitrogen. The resultant mixture was stirred at 105 °C for 2 h. The mixture was concentrated in vacuo to give the crude material, which was purified by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 1: 1) to afford 2-methoxy-4-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (150 mg, 539 pmol, 21.9% yield, 90.0% purity) as a red oil. 'HNMR (400MHz, MeOD) 5 = 8.69 (s, 1H), 4.03 (s, 3H), 2.65 (s, 3H), 1.38 (s, 12H).INTERMEDIATE D-5[000275] A fifth exemplary Intermediate D, Intermediate D-5, may be used to synthesize compounds of formula I, wherein R1is heteroaryl substituted with two R4substituents. To a solution of isopropanol (869 mg, 14.5 mmol, 1.11 mL, 3.00 equiv) in THF (10.0 mL) was added portionwise NaH (578 mg, 14.5 mmol, 60.0 % purity, 3.00 equiv) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Subsequent to the addition of 5-bromo-2-chloro-4-methyl-pyrimidine (1.00 g, 4.82 mmol, 1.00 equiv) the mixture was allowed to stir at 25 °C for 3 h. The mixture was poured into water (20.00 mL) and the aqueous phase was extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was washed with brine (20.0 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated to provide 5-bromo-2- isopropoxy-4-methyl- pyrimidine (600 mg, 2.60 mmol, 53.9 % yield) as a yellow oil.[000276] To a solution of 5-bromo-2-isopropoxy-4-methyl-pyrimidine (300 mg, 1.30 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) -1,3,2- dioxaborolane (429 mg, 1.69 mmol, 1.30 equiv) and potassium acetate (255 mg, 2.60 mmol, 2.00 equiv) in dioxane (5.00 mL) was added Pd(dppf)C12 (95.0 mg, 130 pmol, 0.10 equiv). The mixture was stirred at 105 °C for 2 h under an atmosphere of nitrogen. The mixture was concentrated in vacuo to provide the crude material, which was purified by column chromatography (petroleum ether / ethyl acetate, 1 / 1 to dichloromethane: methanol, 10 / 1) to afford 2-isopropoxy-4-methyl-5- (4, 4, 5, 5 -tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (60.0 mg, 216 pmol, 16.6% yield) as a white oil. LCMS: [M+l] 279.3.INTERMEDIATE D-6[000277] A sixth exemplary Intermediate D, Intermediate D-6, may be used to synthesize compounds of formula I, wherein R1is aryl substituted with two R4substituents. To a solution of l-bromo-4-fluoro-2- methyl-benzene (1.00 g, 5.29 mmol, 1.00 equiv) in DMF (10.0 mb) was added NaSMe (869 mg, 5.29 mmol, 1.00 equiv). The mixture was stirred at 50 °C for 12 h. The reaction mixture was diluted with ethyl acetate (50.0 mL) and the organic layer was washed with brine (40.0 mb x 3). dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to afford 1 -bromo-2 -methyl -4- methylsulfanyl-benzene (900 mg, crude) as a light yellow oil. 'H NMR (400MHz, MeOD) 5 = 7.42 (d, J=8.4 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 6.97 (dd, J=2.0, 8.4 Hz, 1H), 2.45 (s, 3H), 2.35 (s, 3H).[000278] To a solution of l-bromo-2-methyl-4-methylsulfanyl-benzene (900 mg, 4.15 mmol, 1.00 equiv) in DCM (9.00 mL) was added m-CPBA (1.43 g, 8.29 mmol, 2.00 equiv) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with DCM (20.0 mL), washed with satd aq potassium carbonate (20.0 mL x 3), brine (20.0 mL x 2), and the organic phase was concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 3 / 1) to afford 1 -bromo-2 -methyl -4- methylsulfonyl-benzene (370 mg, 1.41 mmol, 34.0% yield, 95.0% purity) as a white solid. 'HNMR (400MHz, MeOD) 5 = 7.87 (d, J=L6 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.66 (dd, J=2.0, 8.4 Hz, 1H), 3.12 (s, 3H), 2.50 (s, 3H).[000279] A mixture of l-bromo-2-methyl-4-methylsulfonyl-benzene (170 mg, 648 pmol, 1.00 equiv), potassium acetate (127 mg, 1.30 mmol, 2.00 equiv), Pd(dppf)C12 (47.4 mg, 64.8 pmol, 0.100 equiv) and4.4.5.5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) -1,3,2- dioxaborolane (247 mg, 972 pmol, 1.50 equiv) in dioxane (3.00 mL) was purged with nitrogen. The resultant reaction mixture was stirred at 105 °C for 1 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The crude material was purified by prep-TLC (petroleum ether / ethyl acetate, 5 / 1) to afford4.4.5.5-tetramethyl-2-(2-methyl-4-methylsulfonyl-phenyl)-l,3,2-dioxaborolane (110 mg, 338 pmol, 52.1% yield, 90.9% purity) as a colorless oil. LCMS [M+l]: 296.9.INTERMEDIATE D-7[000280] A seventh exemplary Intermediate D, Intermediate D-7, may be used to synthesize compounds of formula I, wherein R1is aryl substituted with an R4substituent. To a solution of l-(4- bromophenyl)ethanone (1.00 g, 5.02 mmol, 1.00 equiv) , pyrrolidine (1.79 g, 25.1 mmol, 2.10 mL, 5.00 equiv) in methanol (16.0 mL) was added NaBHsCN (347 mg, 5.53 mmol, 1.10 equiv). The mixture was stirred at 20 °C for 24 h. To the mixture was added water (4.00 mL) and the aqueous phase was extracted with ethyl acetate (5.00 mL). The combined organic phase was washed with brine (2.00 mL), dried over anhydrous Na2SC>4, fdtered and concentrated to afford l-[l-(4-bromophenyl)ethyl]pyrrolidine (1.00 g, 3.93 mmol, 78.3% yield) as a yellow oil.[000281] To a solution of l-[l-(4-bromophenyl)ethyl]pyrrolidine (400 mg, 1.57 mmol, 1.00 equiv) , 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (799 mg, 3.15 mmol, 2.00 equiv) and potassium acetate (308 mg, 3.15 mmol, 2.00 equiv) in dioxane (2.00 mb) was added Pd(dppf)C12 (115 mg, 157 pmol, 0. 100 equiv). The reaction mixture was stirred at 105 °C for 2 h under an atmosphere of nitrogen. The mixture was concentrated in vacuo to give a residue. The crude material was purified by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 1 / 1) to afford 1- [l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]ethyl]pyrrolidine (110 mg) as a red oil.INTERMEDIATE D-8[000282] An eighth exemplary Intermediate D, Intermediate D-8, may be used to synthesize compounds of formula I, wherein R1is heteroaryl substituted with two R4substituents. To a solution of n- butyllithium (2.50 M, 1.80 m , 1.00 equiv) was added dropwise over one min to z-PrMgCl (2.00 M, 1.12 mb, 0.500 equiv) in THF (12 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 5 min followed by the addition of 5-bromo-4-chloro-2 -methoxy-pyridine (1.00 g, 4.50 mmol, 1.00 equiv) after which the mixture was stirred at 0 °C for 45 min. To this solution was added 2-isopropoxy- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (836 mg, 4.50 mmol, 917 pL, 1.00 equiv) and the mixture stirred for an additional 15 min prior to stirring at 20 °C for 3 h. The reaction mixture was quenched by the addition of satd aq ammonium chloride (20.0 mL) at 20 °C and was extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-chloro-2-methoxy-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.00 g, 3.71 mmol, 82.5% yield) as a gray solid, which used for the next step without further purification. ’H NMR (400 MHz, CDCL) 5 = 8.47 (s, 1H), 6.77 (s, 1H), 3.97 (s, 3H), 1.38 (s, 12H).INTERMEDIATE D-9[000283] A ninth exemplary Intermediate D, Intermediate D-9 may be used to synthesize compounds of formula I, wherein R1is heteroaryl substituted with three R4substituents. A mixture of 3,5-dimethyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (100 mg, 450 pmol, 1.00 equiv), isopropyl iodide (306 mg, 1.80 mmol, 180 pL, 4.00 equiv) and cesium carbonate (587 mg, 1.80 mmol, 4.00 equiv) in acetonitrile (3.00 mL) was purged with nitrogen and subsequently stirred at 65 °C for 4 h. The mixture was filtered and the solvent was removed in vacuo to afford l-isopropyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (100 mg, 368 pmol, 81 .8% yield, 97.3% purity) as a green oil. LC-MS [M+l]: 265.INTERMEDIATE D-10[000284] A tenth exemplary Intermediate D, Intermediate D-10, may be used to synthesize compounds of formula I, wherein R1is heteroaryl substituted with two R4substituents. A mixture of 3-bromo-6- fIuoro-2-methyl-pyridine (1.00 g, 5.26 mmol, 1.00 equiv) and A-mcthylpipcrazinc (685 mg, 6.84 mmol, 759 pL, 1.30 equiv) was stirred at 110 °C for 12 h. The mixture was diluted with ethyl acetate (50.0 mL), washed with brine (20.0 mL x 3). dried over anhydrous ISfeSCL, filtered and concentrated to provide 1- (5-bromo-6-methyl-2-pyridyl)-4-methyl-piperazine (1.10 g, 4.07 mmol, 77.4% yield) as a yellow solid. LCMS [M+l]: 272.1.[000285] To a solution of l-(5-bromo-6-methyl-2-pyridyl)-4-methyl-piperazine (400 mg, 1.48 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (752 mg, 2.96 mmol, 2.00 equiv) and potassium acetate (291 mg, 2.96 mmol, 2.00 equiv) in dioxane (2.00 mL) was added Pd(dppf)C12 (108 mg, 148 pmol, 0.100 equiv). The reaction was stirred at 105 °C for 2 h under an atmosphere of nitrogen. The mixture was concentrated in vacuo to give a residue. The crude material was purified by prep-TLC (DCM / MeOH = 10 / 1) to afford compound 1 -methyl -4-(6- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (210 mg, 662 pmol. 44.7% yield) as a brown oil. LCMS [M+l]: 318.3.INTERMEDIATE D-ll[000286] An eleventh exemplary Intermediate D, Intermediate D-l l, may be used to synthesize compounds of formula I, wherein R1is heteroaryl substituted with three R4substituents. To a solution of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (100 mg, 450 pmol, 1.00 equiv), (2S)-2 -methyloxirane (392 mg, 6.75 mmol, 473 pL, 15.0 equiv) was added cesium carbonate (29.3 mg, 90.1 pmol, 0.20 equiv). The reaction mixture was stirred at 50 °C for 16 h and was subsequently concentrated under vacuum to give a residue. The crude residue was purified by prep-TLC (SiC>2, petroleum ether: ethyl acetate = 1: 1) to afford (2.8)- 1 - [3,5- dimethyl -4- (4, 4, 5, 5 -tetramethyl- I,3,2-dioxaborolan-2-yl)pyrazol-I-yl]propan-2-ol (56.0 mg, 44.4% yield) as a yellow oil. LCMS [M + 1]: 281.3.INTERMEDIATE D-12[000287] A twelfth exemplary Intermediate D, Intermediate D-12, may be used to synthesize compounds of formula I, wherein R1is aryl substituted with two R4substituents. To a solution of 4-bromo-3 -chlorobenzoic acid (300 mg, 1.27 mmol, 1. 00 equiv), DIEA (490 mg, 3.79 mmol, 660 pL, 3.00 equiv) and AA'-dimcthylaminc (2.00 M in THF, 1.27 m , 2.00 equiv) in DMF (3.00 m ) was added HATU (727 mg, 1.91 mmol, 1.50 equiv). The mixture was stirred at room temperature for 2 h and the reaction mixture was subsequently quenched upon the addition water (15.0 mb). The mixture was extracted with dichloromethane (20.0 mb x3). The combined organic layer was washed with water (30.0 mb) and concentrated to provide the crude mixture. The resultant residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to afford 4-bromo-3-chloro-A.A-dimcthyl-bcnzamidc (430 mg, 983 pmol, 77.0% yield, 60.0% purity) as a white solid. ECMS [M + 1]: 264.0. ’H NMR (400MHz, CDCh) 5 = 7.67 (d, J=8.2 Hz, IH), 7.53 (d, J=1.6 Hz, 1H), 7.18 (dd, J=2.0, 8.4 Hz, 1H), 3.11 (s, 3H), 2.99 (s, 3H).[000288] To a solution of 4-bromo-3-chloro-A.A-dimcthyl-bcnzamidc (150 mg, 343 pmol. 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (870 mg, 3.43 mmol, 10.0 equiv) and potassium acetate (67.0 mg, 683pmol, 2.00 equiv) in dioxane (10.0 mb) was added Pd(PPh3)2C12 (24.0 mg, 34.2 pmol, 0.10 equiv). The vessel was flushed with nitrogen and the mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to rt and filtered through a pad of Celite. Purification by prep-TEC (SiC>2, petroleum ether / ethyl acetate = 2 / 1) afforded [2-chloro-4- (dimethylcarbamoyl)phenyl]boronic acid (200 mg) as a yellow solid. ECMS [M + 1]: 228.0.INTERMEDIATE D-13[000289] A thirteenth exemplary Intermediate D, Intermediate D-13, may be used to synthesize compounds of formula I, wherein R1is aryl substituted with two R4substituents. A mixture of 4-bromo- 3 -methyl -benzaldehyde (500 mg, 2.51 mmol, 1.00 equiv) and A.A-dimcthylaminc (2 M in THF, 6.3 mb, 12.6 mmol, 5.00 equiv) in methanol (10.0 mb) was stirred at 40 °C for 30 min. Subsequently, sodium triacetoxyborohydride (1.60 g, 7.54 mmol, 3.00 equiv) was added and the mixture was stirred for another3 h. The solution was concentrated under reduced pressure to give a residue. The crude residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1 then dichloromethane / methanol = 20 / 1 to 10 / 1) to afford l-(4-bromo-3 -methyl -phcnyl)- '. '-dimcthyl- methanamine (570 mg) as a brown oil. 'H NMR (400MHz, CDsOD) 5 = 7.61 (d, J=8.0 Hz, 1H), 7.38 (d, .7=1.6 Hz, 1H), 7.16 (dd, J=1.6, 8.0 Hz, 1H), 3.96 (s, 2H), 2.63 (s, 6H), 2.42 (s, 3H).[000290] A mixture of I -(4-bromo-3-mcthyl-phcnyl)-A'.A'-dimcthyl-mcthanaminc (470 mg, 2.06 mmol, 1.00 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (785 mg, 3.09 mmol, 1.50 equiv), potassium acetate (404 mg, 4.12 mmol, 2.00 equiv) and Pd(dppf)C12 (151 mg, 206 pmol, 0.100 equiv) in dioxane (8.00 mb) was purged with nitrogen and allowed to stir at 105 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) to afford / V,7V-dimethyl-l-[3-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methanamine (70.0 mg, 185 pmol, 8.99% yield, 72.8% purity) as a brown oil. LCMS [M+l]: 275.6.INTERMEDIATE D-14[000291] A fourteenth exemplary Intermediate D, Intermediate D-14, may be used to synthesize compounds of formula I, wherein R1is aryl substituted with one R4substituent. To a solution of 4- bromobenzenesulfonyl chloride (200 mg, 783 pmol, 1.00 equiv) in THF (2.00 m ) was added ammonia (7 N in MeOH, 224 pL, 1.57 mmol, 2.00 equiv). The reaction mixture was stirred at 25 °C for 30 min. The mixture was concentrated in vacuo to provide a residue that was poured into water (10.0 m ). The aqueous phase was extracted with ethyl acetate (10.0 mb x 3) and the combined organic phase was washed with brine (3.00 mb x 3). dried with anhydrous sodium sulfate, filtered, and concentrated to give 4-bromobenzenesulfonamide (180 mg, 762 pmol, 97.4% yield) as a white solid. 'H NMR (400MHz, DMSO-d6) 5 = 7.82 - 7.72 (m, 4H), 7.46 (s, 2H).[000292] To a solution of 4-bromobenzenesulfonamide (100 mg, 424 pmol, 1.00 equiv) and 4, 4, 5, 5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (129 mg, 508 pmol, 1.20 equiv) in DMSO (2.00 mb) was added potassium acetate (83.1 mg, 847 pmol, 2.00 equiv) and Pd(dppf)C12 (31.0 mg, 42.4 pmol, 0.10 equiv) under an atmosphere of nitrogen. The mixture was stirred at 80 °C for 3 h and was subsequently concentrated under vacuum to give a residue. The residue was poured into water (10.0 mb) and the aqueous phase was extracted with ethyl acetate (10.0 mb x 3). The combined organic phase was washed with brine (5.00 mb x 3). dried with anhydrous sodium sulfate, filtered, and concentrated to afford 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzenesulfonamide (95.0 mg, 336 pmol, 79.2% yield) as a red solid. 'H NMR (400MHz, CDC13) 5 = 7.96 - 7.88 (m, 4H), 7.26 (s, 2H), 1.35 (s, 12H).INTERMEDIATE D-15[000293] To a solution of 2-methoxyethanol (236 mg, 3.10 mmol, 245 pL, 1.50 equiv) in tetrahydrofuran (2.00 mL) was added portionwise sodium hydride (99.3 mg, 60.0%, 2.48 mmol, 1.20 equiv) at 0 °C. The mixture was stirred at this temperature for 45 min followed by the dropwise addition of 5-bromo-2 -chloro -pyrimidine (400 mg, 2.07 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for an additional 4 h. The mixture was fdtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 10 / 1) to afford 5-bromo- 2-(2-methoxyethoxy)pyrimidine (150 mg, 644 pmol, 31.1% yield) as a white solid. 'H NMR (400MHz, CD3OD) 5 = 8.54 (s, 2H), 4.42 - 4.37 (m, 2H), 3.68 - 3.62 (m, 2H), 3.30 (s, 3H).[000294] A mixture of 5-bromo-2-(2-methoxyethoxy)pyrimidine (150 mg, 644 pmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2 -dioxaborolane (327 mg, 1.29 mmol, 2.00 equiv), potassium acetate (126 mg, 1.29 mmol, 2.00 equiv), Pd(dppf)C12 (47.1 mg, 64.4 pmol, 0.10 equiv) in dioxane (1.00 mL) was purged with nitrogen stirred at 100 °C for 2 h. The reaction was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 1 / 1) to afford 2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidine (130 mg, 464 pmol, 72.1% yield) as a yellow oil. 'H NMR (400MHz, CDCh) 5 = 8.83 - 8.79 (m, 2H), 4.61 - 4.54 (m, 2H), 3.82 - 3.76 (m, 2H), 3.44 (s, 3H), 1.36 (s, 12H).INTERMEDIATE D-16[000295] To a solution of ethylene glycol (310 mg, 5.00 mmol, 280 pL, 2.00 equiv), 5-bromo-4-methyl- pyridine-2-carbaldehyde (500 mg, 2.50 mmol, 1.00 equiv) in toluene (20.0 mL) was added p- toluenesulfonic acid (47.6 mg, 250 pmol, 0. 10 equiv). The mixture was stirred at 110 °C for 12 h and was subsequently concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 1 / 0 to 5: 1) to afford 5-bromo-2-(l,3-dioxolan-2- yl)-4-methylpyridine (320 mg, 1.24 mmol, 49.6% yield) as a colorless oil. 'H NMR (400MHz, CDCI3) 5 = 8.64 (s, 1H), 7.42 (s, 1H), 5.80 (s, 1H), 4.19 - 4.14 (m, 2H), 4.10 - 4.05 (m, 2H), 2.42 (s, 3H).[000296] To a solution of 5-bromo-2-(l,3-dioxolan-2-yl)-4-methylpyridine (300 mg, 1.23 mmol, 1.00 equiv) in diethyl ether (20.0 mL) was added w-butyllithium (2.5 M, 737 pL, 1.50 equiv) at -78 °C under a nitrogen atmosphere. The mixture was stirred at -78 °C for 0.5 h followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (457 mg, 2.46 mmol, 501 pL, 2.00 equiv). The mixture was warmed to 0 °C and stirred for an additional 1.5 h. The mixture was quenched with water (15.0 mL) and the resulting mixture was extracted with ethyl acetate (20.0 mL x 2). The combined organic phase was dried over sodium sulfate, fdtered, and concentrated under reduced pressure to afford 2-(l,3-dioxolan-2-yl)-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (150 mg, crude) as a yellow oil. LCMS [M+l]: 292.15.INTERMEDIATE D-17[000297] A mixture of paraformaldehyde (350 mg, 3.63 mmol, 2.20 equiv) in methanol (1.00 mL) was stirred at 60 °C for 1 h and then cooled to 40 °C. To the mixture was added AcOH (1 drop) and 6-bromo-1.2.3.4-tetrahydroisoquinoline (350 mg, 1.65 mmol, 1.00 equiv) followed by NaCNBtL (114 mg, 1.82 mmol, 1.1 equiv). The mixture was stirred at 40°C for 1 h and was subsequently fdtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 2 / 1) to afford 6-bromo-2-methyl-3,4-dihydro -IH-isoquinoline (360 mg, 1.59 mmol, 96.5% yield) as a yellow oil. 'HNMR (400MHz, CD3OD) 5 = 7.32 (s, 1H), 7.28 (dd, J=2.0, 8.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.57 (s, 2H), 2.94 (t, .7=6,0 Hz, 2H), 2.75 - 2.72 (m, 2H), 2.46 (s, 3H).[000298] A mixture of 6-bromo-2-methyl-3,4-dihydro-lH-isoquinoline (220 mg, 973 pmol. 1.00 equiv),4.4.5.5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (494 mg, 1.95 mmol, 2.00 equiv), potassium acetate (191 mg, 1.95 mmol, 2.00 equiv), Pd(dppf)C12 (71.2 mg, 97.3 pmol, 0.10 equiv) in dioxane (3.00 mL) was purged with nitrogen and subsequently stirred at 100 °C for 2 h. The mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 2 / 1) to afford 2-methyl-6-(4, 4, 5, 5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,4-dihydro-lH-isoquinoline (150 mg, crude) as a white solid.INTERMEDIATE D-18[000299] To a solution of 6-bromo-l,2,3,4-tetrahydroisoquinoline (400 mg, 1.89 mmol, 1.00 equiv) in tetrahydrofuran (2.00 mL) was added BOC2O (617 mg, 2.83 mmol, 1.50 equiv) and dimethylaminopyridine (46.1 mg, 377 pmol, 0.20 equiv). The mixture was stirred at 25 °C for 3 h and was subsequently filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 20 / 1 to 3 / 1) to afford tert-butyl 6-bromo-3, 4-dihydro-lH-isoquinoline-2 -carboxylate (150 mg, 480 pmol, 25.5% yield) as a white solid. ’H NMR (400MHz, CD3OD) 5 = 7.38 - 7.32 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 4.52 (br s, 2H), 3.64 (br t, .7=6,0 Hz, 2H), 2.84 (t, .7=6,0 Hz, 2H), 1.51 (s, 9H).[000300] A mixture of tert-butyl 6-bromo-3,4-dihydro-177-isoquinoline-2 -carboxylate (140 mg, 448 pmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (228 mg, 897 pmol, 2.00 equiv), Pd(dppf)C12 (32.8 mg, 44.8 pmol, 0.10 equiv), potassium acetate (88.0 mg, 897 pmol, 2.00 equiv) in dioxane (1.00 mb) was purged with nitrogen and subsequently stirred at 100 °C for 2 h. The mixture was fdtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 2 / 1) to afford tert-butyl 6-(4,4,5,5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-3,4-dihydro-lH-isoquinoline-2 -carboxylate (100 mg, 278 pmol, 62.1% yield) as a yellow oil.1H NMR (400MHz, CD3OD) 5 = 7.58 - 7.54 (m, 2H), 7.13 (d, J=8.0 Hz, 1H), 4.58 (br s, 2H), 3.65 (br t, J=6.0 Hz, 2H), 2.84 (t, J=6.0 Hz, 2H), 1.35 (s, 12H), 1.19 (br s, 1H), 1.22 (s, 9H).INTERMEDIATE D-19[000301] A mixture of paraformaldehyde (133 mg, 4.42 mmol, 122 pL, 10.0 equiv) and methyl alcohol (1.00 m ) was stirred at 60 °C for 1 h and then cooled to 0 °C. To the mixture was added acetic acid (52.5 mg, 874 pmol, 0.05 mb, 1.98 equiv) and 2-(4-bromophenyl)pyrrolidine (100 mg, 442 pmol, 1.00 equiv). The mixture was allowed to stir for 1 h at room temperature prior to the addition of sodium cyanoborohydride (83.4 mg, 1.33 mmol, 3.00 equiv) and an additional hour of stirring. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, petroleum ether / ethyl acetate = 3 / 1) to afford 2-(4-bromophenyl)-l -methyl -pyrrolidine (100 mg, 413 pmol, 93.3% yield, 99.1% purity) as a white solid. LC-MS [M+l]: 240.1. 'H NMR (400MHz, CDCh) 5 = 7.48 - 7.41 (m, 2H), 7.26 - 7.21 (m, 2H), 3.33 - 3.14 (m, 1H), 3.02 (t, .7=8,4 Hz, 1H), 2.29 (q, J=9.2 Hz, 1H), 2.16 (s, 3H), 2.06 - 1.89 (m, 1H), 1.86 - 1.77 (m, 1H), 1.76 - 1.69 (m, 2H).[000302] A mixture of 2-(4-bromophenyl)-l -methyl -pyrrolidine (48.0 mg, 200 pmol, 1.00 equiv), bis(pinacolato)diboron (76.1 mg, 300 pmol, 1.50 equiv), potassium acetate (58.9 mg, 600 pmol, 3.00 equiv), Pd(dppf)C12 (14.6 mg, 20.0 pmol, 0.10 equiv) in dioxane (1.00 mb) was purged with nitrogen and then stirred at 90 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by prep-TLC (SiCL, petroleum ether / ethyl acetate = 3 / 1) to afford 1- methyl-2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine (23.0 mg, 73.3 pmol, 36.7% yield, 91.5% purity) as a white solid. LC-MS [M+l]: 288.0.INTERMEDIATE D-20[000303] A mixture of 2-(4-bromophenyl)pyrrolidine (50.0 mg, 221 pmol, 1.00 equiv), di-tert-butyl dicarbonate (57.9 mg, 265 pmol, 1.20 equiv) and dimethylaminopyridine (2.70 mg, 22.1 pmol, 0.10 equiv) in tetrahydrofuran (1.00 mb) was purged with nitrogen and then was stirred at 25 °C for 2 h. The mixture was fdtered and concentrated under reduced pressure. The resultant residue was purified by prep-TLC (SiCL, petroleum ether / ethyl acetate = 10 / 1) to afford tert-butyl 2-(4-bromophenyl)pyrrolidine- 1-carboxylate (55.0 mg, 163 pmol, 73.6% yield, 96.5% purity) as a yellow oil. LC-MS [M-55]: 272.1. [000304] A mixture of tert-butyl 2-(4-bromophenyl)pyrrolidine-l -carboxylate (46.6 mg, 138 pmol, 1.00 equiv), bis(pinacolato)diboron (52.5 mg, 207 pmol, 1.50 equiv), potassium acetate (40.6 mg, 414 pmol, 3.00 equiv) and Pd(dppf)C12 (10.1 mg, 13.8 pmol, 0.10 equiv) in dioxane (1.00 mL) was purged with nitrogen and then stirred at 90 °C for 2 h. The mixture was fdtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiCK petroleum ether / ethyl acetate = 5 / 1) to afford tertbutyl 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)phenyl]pyrrolidine-l -carboxylate (45.0 mg, 102 pmol, 74.3% yield, 85.0% purity) as a yellow solid. LC-MS [M-55]: 318.2. 'H NMR (400MHz, CDC13) 5 = 7.75 (br d, J=7.6 Hz, 2H), 7.17 (br d, J=7.6 Hz, 2H), 4.80 (br s, 1H), 3.63 (br s, 2H), 2.32 (br s, 1H), 1.98 - 1.75 (m, 3H), 1.58 (s, 9H), 1.35 (br s, 12H).INTERMEDIATE D-21[000305] To a solution of a l-(4-bromophenyl)-4-chloro-butan-l-one (1.00 g, 3.82 mmol, 1.00 equiv) in methanol (13.0 mL) was added portionwise NaBLL (300 mg, 7.93 mmol, 2.07 equiv) at room temperature. The mixture was allowed to stir at room temperature for 2 h and was subsequently quenched by the addition of water (10.0 mL). The mixture was diluted with dichloromethane (20 mL) and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product l-(4-bromophenyl)-4-chloro-butan-l-ol (1.00 g, 3.79 mmol, 99.2% yield) as a light yellow oil.1H NMR (400MHz, CDC13) 5 = 7.49 (d, .7=8,4 Hz, 2H), 7.24 (d, .7=8,4 Hz, 2H), 4.71 (br t, .7=6,0 Hz, 1H), 3.54 (s, 2H), 2.01 - 1.72 (m, 4H).[000306] A solution of l-(4-bromophenyl)-4-chloro-butan-l-ol (500 mg, 1.90 mmol, 1.00 equiv) and t- BuOK (1.0 M in THF, 1.90 mL, 1.00 equiv) was stirred for 2 h at room temperature. The reaction wasquenched with water and extracted with ether (2 x 20.0 ml). The combined organic phase was dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to provide 2-(4- bromophenyl)tetrahydrofuran (420 mg, 1.85 mmol, 97.5% yield) as a white solid. 'H NMR (400MHz, CDCh) 5 = 7.49 - 7.42 (m, 2H), 7.24 - 7.18 (m, 2H), 4.85 (t, J=12 Hz, 1H), 4.13 - 4.05 (m, 1H), 3.97 - 3.90 (m, 1H), 2.38 - 2.27 (m, 1H), 2.06 - 1.95 (m, 2H), 1.80 - 1.70 (m, 1H).[000307] To a mixture of 2-(4-bromophenyl)tetrahydrofuran (150 mg, 661 pmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2 -dioxaborolane (252 mg, 992 pmol, 1.50 equiv), potassium acetate (195 mg, 1.99 mmol, 3.01 equiv) in dioxane (5.00 mL) was added Pd(dppf)C12 (48.3 mg, 66.0 pmol, 0.10 equiv). The mixture was stirred at 105 °C for 1 h, cooled to room temperature and fdtered through a pad of Celite. The fdtrate was concentrated to give a residue that was purified by prep-TLC (SiCL, petroleum ether / ethyl acetate = 2 / 1) to afford 4,4,5,5-tetramethyl-2-(4- tetrahydrofuran-2-ylphenyl)-l,3,2-dioxaborolane (240 mg, 639 pmol, 96.8% yield, 73% purity) as a colorless oil. LCMS [M+l]: 275.1. 'H NMR (400MHz, CDC13) 8 = 7.78 (d, J=8.4 Hz, 2H), 7.34 (d, .7=7,6 Hz, 2H), 4.92 (t, J=12 Hz, 1H), 4.17 - 4.06 (m, 1H), 4.00 - 3.90 (m, 1H), 2.41 - 2.27 (m, 1H), 2.09 - 1.91 (m, 2H), 1.85 - 1.73 (m, 1H), 1.35 (s, 12H).INTERMEDIATE D-22[000308] To a cooled solution of 2-(4-bromophenyl)ethanamine (200 mg, 1.0 mmol, 155 pL, 1.00 equiv) in formalin (300 mg, 9.99 mmol, 275 pL, 10.0 equiv) was added HCOOH (5.00 mL) and the solution was stirred at 110 °C for 16 h under nitrogen. The reaction mixture was concentrated to give a residue. To the residue was added HC1 (3 N, 1.00 mL) and the mixture was washed with ethyl acetate (310 mL). The aqueous phase was basified to pH = 14 with NaOH (10 N, 1.00 mL) and then extracted with ethyl acetate (3 x 15.0 mL). The combined organic phase was washed with brine (2 x 15.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 2-(4-bromophcnyl)-N.N-dimcthyl- ethanamine (200 mg, 877 pmol, 87.7% yield) as a colorless oil. 'HNMR (400MHz, CDCh) 8 = 7.40 (d, J=8.4 Hz, 2H), 7.09 (d, .7=8,4 Hz, 2H), 2.73 (d, J=8.4 Hz, 2H), 2.56 - 2.48 (m, 2H), 2.29 (s, 6H).[000309] A mixture of 2-(4-bromophenyl)-7V,7V-dimethyl-ethanamine (160 mg, 701 pmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2 -dioxaborolane (268mg, 1.06 mmol, 1.50 equiv), Pd(dppf)C12 (51.2 mg, 70.0 pmol, 0.10 equiv), potassium acetate (206 mg, 2.10 mmol, 3.00 equiv) in dioxane (8.00 mL) was purged with nitrogen and was stirred at 100 °C for 1 h. The mixture was concentrated to give a residue that was purified by prep-TLC (SiCK dichloromethane / methanol = 10 / 1) to afford N.N-dimcthyl-2 -[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl] ethanamine (350 mg, crude) as a black oil. LCMS [M+l]: 276.2.INTERMEDIATE D-23[000310] To a solution of l-bromo-4-iodo-benzene (200 mg, 707 pmol, 1.00 equiv), diethyl phosphite (97.6 mg, 707 pmol, 91.2 pL, 1.00 equiv) in tetrahydrofuran (2.00 mL) was added Pd(OAc)2 (4.76 mg, 21.2 pmol, 0.03 equiv), potassium acetate (9.02 mg, 91.9 pmol, 0.13 equiv), DPPF (23.5 mg, 42.4 pmol, 0.06 equiv) and triethylamine (107 mg, 1.06 mmol, 147 pL, 1.50 equiv). The vessel was flushed with nitrogen and stirred at 68 °C for 1 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiC>2, petroleum ether / ethyl acetate = 1 / 1) to afford l-bromo-4- diethoxyphosphoryl -benzene (110 mg, 341 pmol, 48.2% yield, 90.8% purity) as a red solid. LCMS [M+3]: 294.9. ' H NMR (400MHz, CDC13) 8 = 7.73 - 7.57 (m, 4H), 4.22 - 3.99 (m, 4H), 1.32 (t, J=7.2 Hz, 6H).[000311] To a solution of l-bromo-4-diethoxyphosphoryl -benzene (100 mg, 341 pmol, 1.00 equiv),4.4.5.5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (104 mg, 409 pmol, 1.20 equiv) in dioxane (2.00 mL) was added Pd(dppf)C12 (24.9 mg, 34.1 pmol, 0.10 equiv) and potassium acetate (67.0 mg, 682 pmol, 2.00 equiv) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 2 h and was subsequently concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiC>2, petroleum ether / ethyl acetate = 1 / 1) to afford 2-(4-diethoxyphosphorylphenyl)-4.4.5.5- tetramethyl-l,3,2-dioxaborolane (55.0 mg, 162 pmol, 47.4% yield) as a red oil. ’H NMR (400MHz, CDCh) 8 = 7.93 - 7.87 (m, 2H), 7.85 - 7.76 (m, 2H), 4.21 - 4.01 (m, 4H), 1.36 (s, 12H), 1.32 (t, J=7.2 Hz, 6H).INTERMEDIATE D-24[000312] To a solution of 2-(4-bromo-3 -methyl -phenyl)pyrrolidine (500 mg, 2.08 mmol, 1.00 equiv) in dichloromethane (5.00 mL) was added BOC2O (1.05 g, 4.79 mmol, 1.10 mL, 2.30 equiv) and dimethylaminopyridine (25.4 mg, 208 pmol, 0.10 equiv). The mixture was stirred at 25 °C for 1 h and was subsequently fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=30 / l to 20 / 1) to afford tertbutyl 2-(4-bromo-3 -methyl -phenyl)pyrrolidine-l- carboxylate (600 mg, 84.7% yield) as a yellow oil. ’H NMR (400MHz, CD3OD) 8 = 7.46 (br d, .7=8,4 Hz, 1H), 7.10 (d, J=1.6 Hz, 1H), 6.92 (dd, J=1.6, 8.0 Hz,1H), 4.73 (br s, 1H), 3.65 - 3.51 (m, 2H), 2.37 (s, 3H), 2.34 - 2.27 (m, 1H), 1.93 - 1.82 (m, 2H), 1.82 - 1.73 (m, 1H), 1.45 (br s, 3H), 1.24 - 1.13 (m, 6H).[000313] A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3,2- dioxaborolane (268 mg, 1.06 mmol, 1.20 equiv), tert-butyl 2-(4-bromo-3 -methyl -phenyl) pyrrolidine- 1- carboxylate (300 mg, 882 pmol, 1.00 equiv), Pd(dppf)C12 (64.1 mg, 88.2 pmol, 0.10 equiv) and potassium acetate (173 mg, 1.76 mmol, 2.00 equiv) in dioxane (3.00 mL) was purged with nitrogen and then the mixture was stirred at 100 °C for 1.5 h. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=20 / l to 10 / 1) to afford tert-butyl 2-[3-methyl-4 -(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]pyrrolidine-l -carboxylate (260 mg, 76.1% yield) as a white solid. ’H NMR (400MHz, CDC13) 5 = 7.68 (br d, .7=7,6 Hz, 1H), 7.0 - 6.94 (m, 2H), 4.98 - 4.66 (m, 1H), 3.61 (br s, 2H), 2.52 (s, 3H), 2.36 (br s, 1H), 1.93 - 1.76 (m, 3H), 1.35 (br s, 12H), 1.29 - 1.25 (m 3H), 1.21 (br s, 6H).INTERMEDIATE D-25[000314] To a solution of 4-bromo-3 -methyl -benzaldehyde (2.00 g, 10.1 mmol, 1.00 equiv) in toluene (100 mL) was added TsOHTLO (191 mg, 1.00 mmol, 0.10 equiv) and ethylene glycol (1.25 g, 20.1 mmol, 1.12 mL, 2.00 equiv). The mixture was stirred at 130 °C for 12 h prior to cooling to room temperature. The pH was adjusted to 9 with DMAP and then concentrated in vacuo. The residue was purified by column chromatography (neutral AI2O3, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to afford 2-(4-bromo-3-methyl-phenyl)-l,3-dioxolane (2.30 g, 9.46 mmol, 94.2% yield) as a yellow oil. [000315] 'H NMR (400 MHz, CDCI3) 5 =7.54 (d, .7=8,4 Hz, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.17 (dd, .7=2.4, 8.0 Hz, 1H), 5.76 (s, 1H), 4.15 - 4.08 (m, 2H), 4.08 - 4.00 (m, 2H), 2.42 (s, 3H).[000316] A mixture of 2-(4-bromo-3-methyl-phenyl)-l,3-dioxolane (2.50 g, 10.3 mmol, 1.00 equiv), PimEh (3.39 g, 13.4 mmol, 1.30 equiv), KOAc (2.02 g, 20.6 mmol, 2.00 equiv) and Pd(dppf)C12 (376 mg, 514 pmol, 0.05 equiv) in dioxane (30.0 mL) was purged with N2 and then stirred at 100 °C for 6 h. The mixture was fdtered and concentrated in vacuo. The residue was purified by column chromatography (neutral AI2O3, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1) to afford 2-[4-(l,3-dioxolan-2-yl)-2-methyl- phenyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (2.60 g, 8.96 mmol, 87. 1% yield) as a green oil. ’H NMR (400 MHz, CDCI3) 5 = 7.78 (d, J=7.6 Hz, 1H), 7.29 - 7.25 (m, 2H), 5.81 (s, 1H), 4.15 - 4.08 (m, 2H), 4.07 - 4.01 (m, 2H), 2.56 (s, 3H), 1.35 (s, 12H).INTERMEDIATE D-26[000317] A mixture of tert-butyl / V-[(5-bromopyrimidin-2-yl)methyl]carbamate (100 mg, 347 pmol, 1.00 equiv), PimEL (176 mg, 694 pmol, 2.00 equiv), KO Ac (68.1 mg, 694 pmol, 2.00 equiv) and Pd(dppf)C12 (25.4 mg, 34.7 pmol, 0.10 equiv) in dioxane (2.00 m ) was purged with N2 and then stirred at 100 °C for 2 h. The reaction mixture was fdtered and concentrated in vacuo to afford [2-[(tertbutoxycarbonylamino)methyl]pyrimidin-5-yl]boronic acid (100 mg, crude) as a red oil. LCMS [M-55]: 198.1.INTERMEDIATE D-27[000318] A mixture of 6-bromo-3.4-dihydro-2H-isoquinolin- l -onc (150 mg, 664 pmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2 -dioxaborolane (253 mg, 996 pmol, 1.50 equiv), Pd(dppf)C12 (48.55 mg, 66.35 pmol, 0.10 equiv), potassium acetate (195 mg, 1.99 mmol, 3.00 equiv) in dioxane (5.00 mb) was purged with nitrogen and then stirred at 95 °C for 2 h. The reaction mixture was cooled and fdtered through a pad of Celite and the fdtrate was concentrated to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to afford 6-(4,4,5,5-tetramethyl-l,3,2 -dioxaborolan-2-yl)-3,4-dihydro-2H-isoquinolin-l-one (180 mg, 659 pmol, 99.32% yield) as an off-white solid. LCMS [M+l]: 274.1. H NMR (400MHz, CDCh) 5 = 8.07 (d, J=8.0 Hz, 1H), 7.80 (d, .7=7,6 Hz, 1H), 7.67 (s, 1H), 6.04 (s, 1H), 3.57 (dt, J=2.8, 6.4 Hz, 2H), 3.02 (t, .7=6,4 Hz, 2H), 1.37 (s, 12H).INTERMEDIATE D-28[000319] To a suspension ofNaH (79.1 mg, 60%, 1.98 mmol, 2.00 equiv) in DMF (3.00 m ) at 0 °C was added dropwise a solution of 6-(4,4,5,5-tetramethyl-l,3,2 -dioxaborolan-2-yl)-3,4-dihydro-2H- isoquinolin-l-one (270 mg, 989 pmol, 1.00 equiv) in DMF. The mixture was stirred at this temperature for an additional 30 min prior to the dropwise addition of CH3I (1.40 g, 9.89 mmol, 615 pL, 10.0 equiv) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction wasquenched upon the addition of 20.0 mL of water followed by extraction with diethyl ether (3x30.0 mL). The combined organic layer was washed with water (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3,4-dihydroisoquinolin -l-one (300 mg, crude) as a black oil. LCMS [M+l]: 288.1. 'H NMR (400MHz, CHCL-d) 5 = 8.07 (d, .7=7.6 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.63 (s, 1H), 3.56 (t, .7=6.8 Hz, 2H), 3.16 (s, 3H), 3.01 (t, .7=6.8 Hz, 2H), 1.36 (s, 12H).INTERMEDIATE D-29[000320] A mixture of 5-bromo-2-(bromomethyl)benzonitrile (100 mg, 364 pmol, 1.00 equiv), diisopropylethylamine (141 mg, 1.09 mmol, 190 pL, 3.00 equiv) and dimethylamine (2.00 M, 1.82 mb, 10.0 equiv) in dimethyl formamide (2.00 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with water 5.00 mL and extracted with ethyl acetate (5.00 mL x 3). The combined organic layer was washed with brine (3.00 mL x 3). dried over sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 3 / 1) to afford 5-bromo-2-[(dimethylamino)methyl]benzonitrile (50.0 mg, 209 pmol. 57.5% yield) as a yellow oil. LC-MS [M+l]: 239.2. 'H NMR (400MHz, CDCh) 5 = 7.77 (d, .7=2,0 Hz, 1H), 7.69 (dd, .7=2.0, 8.4 Hz, 1H), 7.46 (d, .7=8,4 Hz, 1H), 3.59 (s, 2H), 1.59 (br s, 6H).[000321] A mixture of 5-bromo-2-[(dimethylamino)methyl]benzonitrile (30.0 mg, 125 pmol, 1.00 equiv), bis(pinacolato)diboron (63.7 mg, 251 pmol, 2.00 equiv), potassium acetate (36.9 mg, 376 pmol, 3.00 equiv) and Pd(dppf)C12.CH2C12 (3.07 mg, 3.76 pmol, 0.03 equiv) in dioxane (1.00 mL) was purged with nitrogen and then stirred at 90 °C for 4 h. The mixture was filtered and concentrated under reduced pressure to give the crude product 2-[(dimethylamino)methyl]-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)benzonitrile (40.0 mg) as a black oil which was used in the next step without further purification.INTERMEDIATE D-30[000322] To a solution of Ir(COD)2(OMe)2 (5.00 mg, 7.54 pmol, 0.02 equiv) and 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (68.5 mg, 535 pmol, 77.7 pL, 1.50 equiv) in w-pentane (0.50 mL) was added 4-tert- butyl-2-(4- / -biityl-2-pyridyl)pyridinc (5.00 mg, 18.6 pmol, 0.05 equiv) and the mixture was stirred at 25 °C for 20 minutes. To this mixture was added a solution of methyl 1 -methylpyrazole-3 -carboxylate (50.0 mg, 357 pmol, 1.00 equiv) in w-pentane (0.50 mL) and THF (0.50 mL) and the mixture was stirred at 25 °C for 24 h. The mixture was partitioned between ethyl acetate (10.0 mL) and water (10.0 mL). Theorganic phase was dried over anhydrous sodium sulfate and concentrated to afford the crude product methyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylate (50.0 mg, 113 pmol, 31.6% yield, 60.0% purity) as a black oil.1H NMR (400MHz, CDC13) 5 = 7.28 (s, 1H), 4.15 (s, 3H), 3.93 (s, 3H), 1.35 (s, 12H).INTERMEDIATE D-31[000323] To a solution of 4-bromo- / V, / V,3-trimethyl-benzamide (500 mg, 2.07 mmol, 1.00 equiv) in THF (5.00 m ) was added lithium tetradeuterioalumanide (235 mg, 6.20 mmol, 3.00 equiv). The mixture was stirred at 0 °C for 1.5 h and subsequently was warmed to room temperature and allowed to stir for another hour. The reaction mixture was cooled to 0 °C and diluted with THF (10.0 m ). The reaction was quenched upon the dropwise addition of deuterium oxide (0.24 mb), 15% NaOD solution in deuterium oxide (0.24 mb) at 0 °C, and finally deuterium oxide (0.72 mb). The mixture was stirred at room temperature for 10 min, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, dichloromethane / methanol = 50 / 1 to 20 / 1) to afford l-(4-bromo-3-methyl-phenyl)-l,l-dideuterio- / V,N-dimethyl-methanamine (220 mg, crude) as a brown oil. LCMS [M+l]: 232.1.INTERMEDIATE D-32[000324] To a solution of 4-bromo-3 -methyl -aniline (4.00 g, 21.5 mmol, 1.00 equiv) in concentrated sulfuric acid (40.0 mb) and water (40.0 mb) was added sodium nitrite (1.62 g, 23.4 mmol, 1.09 equiv) at 0 °C and the mixture was stirred for 90 min. Subsequently, potassium thiocyanate (2.82 g, 29.0 mmol, 2.82 mb, 1.35 equiv) in water (16.0 mb) and thiocyanatocopper (6.80 g, 55.9 mmol, 2.60 equiv) was then added to the suspension at 5 °C. After stirring at 5 °C for 2 h, the mixture was allowed to stir at room temperature for 10 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether) to afford (4-bromo-3- methyl-phenyl) thiocyanate (2.00 g, 8.77 mmol, 40.8% yield) as a yellow oil. 'H NMR (400MHz, CDCh) 5 = 7.52 (d, J=8.4 Hz, 1H), 7.33 (d, .7=2,4 Hz, 1H), 7.14 (dd, J=2.4, 8.4 Hz, 1H), 2.36 (s, 3H). [000325] A mixture of (4-bromo-3 -methyl -phenyl) thiocyanate (500 mg, 2.19 mmol, 1.00 equiv), trimethyl(trifluoromethyl)silane (1.00 g, 7.04 mmol, 3.21 equiv) and tetrabutylammonium fluoride (1.00 M, 701 pL, 0.32 equiv) in tetrahydrofuran (1.00 mb) was stirred at room temperature for 4 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, petroleum ether) to afford 1 -bromo-2 -methyl -4-(trifluoromethylsulfanyl)benzene(450 mg, 1.66 mmol, 75.7% yield) as a colorless oil. 'H NMR (400MHz, CDC13) 5 = 7.59 (d, J=8.0 Hz, 1H), 7.52 (d, .7=2.0 Hz, 1H), 7.34 (dd, J=2.4, 8.0 Hz, 1H), 2.44 (s, 3H).[000326] A mixture of l-bromo-2-methyl-4-(trifluoromethylsulfanyl)benzene (450 mg, 1.66 mmol, 1.00 equiv) and m-chloropcrbcnzoic acid (2.02 g, 85.0%, 9.96 mmol, 6.00 equiv) in chloroform (10.0 mb) was stirred at room temperature for 2 h. The mixture was heated to 60 °C and allowed to stir for an additional 10 h. The mixture was diluted with saturated sodium bicarbonate (15.0 mL) and extracted with dichloromethane (5.00 mL x3). The combined organic phase was washed with sodium sulfite (5.00 mL), brine (5.00 mL), dried over sodium sulfate, filtered, and concentrated under pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether) to afford l-bromo-2- methyl-4- (trifluoromethylsulfonyl) benzene (400 mg, 1.32 mmol, 79.5% yield) as a white solid. 'H NMR (400MHz, CDC13) 5 = 7.88 (d, .7=2.0 Hz, 1H), 7.86 (d, J=8.4 Hz 1H), 7.71 (dd, J=2.4, 8.4 Hz, 1H), 2.55 (s, 3H).[000327] A mixture of l-bromo-2 -methyl -4-(trifluoromethylsulfonyl)benzene (100 mg, 330 pmol, 1.00 equiv), bis(pinacolato)diboron (168 mg, 660 pmol, 2.00 equiv), potassium acetate (97.1 mg, 990 pmol, 3.00 equiv) and Pd(dppf)C12 (24.1 mg, 33.0 pmol, 0.10 equiv) in dioxane (2.00 mL) was purged with nitrogen and then stirred at 90 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to afford 4,4,5,5-tetramethyl-2-[2-methyl-4- (trifluoromethylsulfonyl)phenyl]- 1,3,2- dioxaborolane (200 mg, crude) as a black solid that was used into the next step without further purification.INTERMEDIATE D-33[000328] To a solution of diisopropylamine (243 mg, 2.40 mmol, 339 pL, 1.30 equiv) in THF (4.00 mL) was added dropwise w-BuLi (2.50 M, 961 pL, 1.30 equiv) at -78 °C and then the reaction was stirred at - 78 °C for 30 mins. 1 -cyclopropylpyrazole (200 mg, 1.85 mmol, 1.00 equiv) was added and the reaction was stirred at -78°C for 1 h. Tributyl(chloro)stannane (602 mg, 1.85 mmol, 498 pL, 1.00 equiv) was added drop-wise and the reaction was stirred at -78 °C for another 30 min. The reaction mixture was partitioned between ethyl acetate (5.00 mL) and saturated ammonium chloride (5.00 mL). The organic phase was separated, washed with brine (5.00 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tributyl-(2-cyclopropylpyrazol-3-yl)stannane (1.00 g, crude) as a colorless oil which used for the next step without further purification. ’H NMR (400 MHz, CDCL) 5 = 7.51 (d, .7=1.6 Hz, 1H), 6.32 (d, .7=1.6 Hz, 1H), 3.54 - 3.49 (m, 1H), 1.61 - 1.50 (m, 6H), 1.37 - 1.31 (m, 6H), 1.21 - 1.13 (m, 6H), 0.97 - 0.89 (m, 13H).INTERMEDIATE D-34[000329] To a solution of 4-chloropyridazin-3-ol (300 mg, 2.30 mmol, 1.00 equiv) and methyl iodide (3.26 g, 23.0 mmol, 1.43 mL, 10.0 equiv) in dioxane (6.00 mL) was added silver oxide (533 mg, 2.30 mmol, 1.00 equiv). The mixture was stirred at 60 °C for 5 h. The mixture was fdtered and concentrated in vacuo to provide a residue. The residue was purified by prep-TLC (SiCL, petroleum ether / ethyl acetate = 1 / 1) to afford 4-chloro-2-methyl-pyridazin-3-one (110 mg, 761 pmol, 33.1% yield) as a yellow solid. 'HNMR (400MHz, DMSO-t / ,.) 5 = 7.87 (d, .7=4,4 Hz, 1H), 7.78 (d, .7=4,4 Hz, 1H), 3.72 (s, 3H).[000330] To a solution of 4-chloro-2-methyl-pyridazin-3-one (110 mg, 761 pmol, 1.00 equiv) and hexamethylditin (998 mg, 3.04 mmol, 631 pL, 4.00 equiv) in dioxane (2.00 mL) was added Pd(PPh3)4 (87.93 mg, 76.09 pmol, 0.10 equiv) under nitrogen. The mixture was stirred at 110 °C for 2 h and was subsequently filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiCK petroleum ether / ethyl acetate = 1 / 1) to afford 2-methyl-4-trimethylstannyl-pyridazin-3-one (130 mg, 476 pmol, 62.6% yield) as a white solid.1H NMR (400MHz, CD3OD) 5 = 7.79 (d, J=3.6 Hz, 1H), 7.51 (d, J=3.6 Hz, 1H), 3.73 (s, 3H), 0.32 (s, 9H).INTERMEDIATE D-35[000331] To a solution of 2,5 -dibromo-3 -fluoro-pyridine (0.50 g, 1.96 mmol, 1.00 equiv) in THF (10.0 mL) was added w-BuLi (2.50 M, 1.18 mL, 1.50 equiv) dropwise at -65 °C. The mixture was stirred at - 65 °C for 0.5 h followed by the addition of / V-isopropylpropan-2 -amine (397 mg, 3.92 mmol, 554 pL, 2.00 equiv) one portion and stirring at this temperature for an additional 30 min. To this mixture was added methyl iodide (334 mg, 2.35 mmol, 147 pL, 1.20 equiv) and the mixture was allowed to stir at - 65 °C for 1 h. The reaction mixture was quenched by the addition of satd aq NLLCl (10.0 mL) and the resulting mixture was extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was washed with brine (30.0 mL x 2), dried over anh sodium sulfate, fdtered, and concentrated under reduced pressure to give the crude residue. The residue was purified by prep-HPLC (acidic conditions) to afford 2,5-dibromo-3-fhioro-4-methyl-pyridine (300 mg, 1.12 mmol, 56.9% yield) as a yellow solid. LCMS [M+l]: 269.7.[000332] To a solution of 2,5 -dibromo-3 -fluoro-4-methyl -pyridine (0.80 g, 2.97 mmol, 1.00 equiv) in THF (10.0 mL) was added w-BuLi (2.5 M, 1.19 mL, 1.00 equiv) at -65 °C and the resultant mixture was stirred for 0.5 h followed by the dropwise addition of DMF (326 mg, 4.46 mmol, 343 pL, 1.50 equiv). After an additional 30 min of stirring at -65 °C the reaction mixture was quenched with satd aq NFLC1 (5.00 mL) and the resulting mixture was extracted with ethyl acetate (30.0 mL x 2). The combined organic phase was washed with brine (30.0 mL x 2), dried over anh sodium sulfate, filtered, and concentrated under reduced pressure to give the crude residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to afford 5-bromo-3-fluoro-4- methyl-pyridine-2-carbaldehyde (300 mg, 1.38 mmol, 46.3% yield) as a yellow solid.[000333] 'H NMR (400MHz, CDC13) 5 = 10.20 (d, J=0.8 Hz, 1H), 8.69 (s, 1H), 2.48 (d, .7=2,4 Hz, 3H). [000334] To a solution of 5-bromo-3-fluoro-4-methyl-pyridine-2-carbaldehyde (300 mg, 1.38 mmol, 1.00 equiv) in Tol. (10.0 mb) was added TsOHTLO (26.2 mg, 138 pmol, 0.10 equiv) and ethylene glycol (171 mg, 2.75 mmol, 14 pL, 2.00 equiv). The mixture was stirred at 120 °C for 2 h. The reaction mixture was concentrated under reduced pressure to provide a crude residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to afford 5-bromo-2-(l,3- dioxolan-2-yl)-3-fluoro-4-methyl-pyridine (250 mg, 954 pmol, 69.3% yield) as a colorless oil. 'H NMR (400MHz, CDCh) 5 = 8.49 (s, 1H), 6.13 (s, 1H), 4.32 - 4.20 (m, 2H), 4. 14 - 4.04 (m, 2H), 2.39 (d, .7=2,4 Hz, 3H).[000335] To a solution of 5-bromo-2-(l,3-dioxolan-2-yl)-3-fluoro-4-methyl-pyridine (450 mg, 1.72 mmol, 1.00 equiv) in Et2O (10.0 mL) was added dropwise w-BuLi (2.5 M, 756 pL, 1.10 equiv) at -70 °C. The mixture was stirred for 0.5 h at -70 °C f and subsequently 2-isopropoxy-4, 4, 5, 5 -tetramethyl- 1,3,2- dioxaborolane (639 mg, 3.43 mmol, 701 pL, 2.00 equiv) was added. The mixture was stirred at -70 °C for 1 h and was quenched with satd aq NH4CI (10 mL). The mixture was extracted with DCM (30 mL x 3) and the combined organic phase was washed with brine (50.0 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude solid. The crude material was purified by prep-TLC (SiC>2, petroleum ether / ethyl acetate = 1 / 1) to afford [6-(l,3-dioxolan-2-yl)-5-fluoro-4- methyl-3-pyridyl]boronic acid (220 mg, 940 pmol, 54.8% yield, 97.0% purity) as a light yellow oil. LCMS [M+l]: 228.0.INTERMEDIATE D-36[000336] To a solution of 3 -phenylmorpholine (500 mg, 3.06 mmol, 1.00 equiv) in tetrahydrofuran (5.00 mL) was added triethylamine (512 pL, 3.68 mmol, 1.20 equiv) and di-tert-butyl dicarbonate (669 mg, 3.06 mmol, 704 pL, 1.00 eq.). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue (1.30 g, crude) that was used in the next step directly.[000337] To a solution of tert-butyl 3-phenylmorpholine-4-carboxylate (580 mg, 2.20 mmol, 1.00 equiv) in dichloromethane (6.00 mL) was added phenyl-X3-iodanediyl bis(2,2,2-trifluoroacetate) (1.04 g, 2.42 mmol, 1.10 equiv) and iodine (559 mg, 2.20 mmol, 444 pL, 1.00 equiv). The reaction mixture was stirred at 20 °C for 2 h. The mixture was diluted with sodium bicarbonate solution (20.0 mL) and extracted with dichloromethane (10.0 mL x 3). The combined organic layer was washed with saturated sodium thiosulfate solution (20.0 mL), brine (20 mL), dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=l / 0 to 10 / 1) to afford tert-butyl 3-(4- iodophenyl)morpholine-4-carboxylate (260 mg, 668 pmol, 30.3% yield) as a white oil. 'H NMR(400MHz, DMSO-d6) 5 = 7.73 (br d, J=8.4 Hz, 2H), 7.16 (br d, J=8.0 Hz, 2H), 4.92 (br s, 1H), 4.20 (br d, J=12.0 Hz, 1H), 3.84 - 3.78 (m, 1H), 3.76 - 3.65 (m, 2H), 3.50 - 3.40 (m, 1H), 3.04 - 2.93 (m, 1H), 1.39 (s, 9H).[000338] A mixture of tert-butyl 3-(4-iodophenyl)morpholine-4-carboxylate (260 mg, 668 pmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)-l,3,2-dioxaborolane (254 mg, 1.00 mmol, 1.50 equiv), potassium acetate (131 mg, 1.34 mmol, 2.00 equiv) and Pd(dppf)C12 (48.9 mg, 66.8 pmol, 0.10 equiv) in dioxane (2.00 mb) was purged with and subsequently stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was fdtered and concentrated at reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=l / O to 10 / 1) to afford tert-butyl 3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)phenyl]morpholine-4- carboxylate (100 mg, 257 pmol, 38.5% yield) as white oil. 'H NMR (400MHz, DMSO-tL) 5 = 7.67 (d, J=8.0 Hz, 2H), 7.37 (d, .7=7,6 Hz. 2H), 4.98 (br s, 1H), 4.29 - 4.23 (m, 1H), 3.86 - 3.66 (m, 3H), 3.51 - 3.42 (m, 1H), 3.07 - 2.96 (m, 1H), 1.41 - 1.38 (m, 9H), 1.30 (s, 12H).INTERMEDIATES D-37 - D-38Characterization of Intermediates D36 - D38[000339] The following Examples are intended to illustrate further certain embodiments of the disclosure and are not intended to limit the scope of the disclosure.EXAMPLE 1 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylic acid[000340] A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxylate (0.100 g, 230 pmol, 1.00 equiv), 1,3-dimethyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (81.6 mg, 368 pmol, 1.60 equiv), sodium bicarbonate (77.2 mg, 919 pmol, 4.00 equiv), Pd(dppf)C12 (16.8 mg, 23.0 pmol, 0.100 equiv) in dioxane (2.10 mL) and water (0.700 mL) was purged with nitrogen three times. Subsequently, the mixture was stirred at 105 °C for 1 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated in vacuo. The crude material was purified by prep-TLC (SiC>2, PE: EA = 2:3) to afford ethyl 8-( 1 ,3- dimethyl-lH-pyrazol-5-yl)-5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carboxylate (60.0 mg, 47.9 % yield, 82.6 % purity) as an orange solid. LC-MS: [M+l] 450.9.[000341] To a solution of ethyl 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxylate (55.0 mg, 101 pmol, 1.00 equiv) in methanol (2.00 mL) was added aq sodium hydroxide (1.00 M, 303 pL, 3.00 equiv). The resultant mixture was stirred at 60 °C for 0.5 h. The mixture was fdtered and the majority of the methanol was removed in vacuo. The residue was adjusted to pH 4 with 2.00 M aq hydrochloric acid and the precipitate was filtered and dried under vacuum. The crude product was rinsed with methanol (2.00 mL) and dried under vacuum to afford 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylic acid (19.7 mg, 44.2% yield, 95.5% purity) as a yellow solid. LC-MS: [M+l] 423.0. 'HNMR (400MHz, MeOD) 5 = 8.63 (s, 1H), 7.80 (s, 1H), 6.92 - 6.82 (m, 1H), 6.65 (dd, J=4.0, 8.8 Hz, 1H), 6.27 (s, 1H), 4.83 (s, 2H), 4.59 (t, J=8.8 Hz, 2H), 3.75 (s, 3H), 3.39 (t, .7=8.8 Hz, 2H), 2.28 (s, 3H).EXAMPLE 2 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l,2- c]pyrimidine-2-carboxylic acid[000342] To a solution of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxylate (50.0 mg, 115 pmol, 1.00 equiv), 2-methyl-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (37.8 mg, 172 pmol, 1.50 equiv) in dioxane (3.00 mL) was added water (1.00 mL) followed by Pd(dppf)C12 (8.41 mg, 11.5 pmol, 0.100 equiv) and sodium bicarbonate (29.0 mg, 345 pmol, 3.00 equiv). The reaction mixture was stirred at 105 °C for 1 h under nitrogen. The mixture was cooled to 25 °C and filtered. The filtrate was concentrated in vacuo to provide a residue. The crude material was purified by prep-TLC (dichloromethane / methanol = 10 / 1) to afford ethyl 5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l,2- c]pyrimidine-2 -carboxylate (40.0 mg, 75.0% yield, 96.4% purity) as a brown solid.[000343] To a solution of ethyl 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2- methylpyridin-3-yl)imidazo[l,2-c]pyrimidine-2-carboxylate (40.0 mg, 86.2 pmol, 1.00 equiv) in methanol (4.00 mL) and water (1.00 mL) was added sodium hydroxide (10.3 mg, 258 pmol, 3.00 equiv). The reaction mixture was stirred at 55 °C for 20 min. The mixture was concentrated in vacuo to remove the majority of the methanol and the pH was adjusted to ~6 with aq hydrochloric acid (1.00 M, 0.500 mL). The resultant suspension was filtered and the filter cake was dried under vacuum to afford 5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l,2-c]pyrimidine-2- carboxylic acid (18.1 mg, 48.0% yield, 95.7% purity) as a white solid. LCMS: [M+l] 420.2. ’HNMR (400MHz, CD3OD) 5 = 8.74 (dd, J=1.2, 6.0 Hz, 1H), 8.68 (s, 1H), 8.50 (dd, J=1.2, 7.6 Hz, 1H), 7.93 (dd, .7=6.4, 8.0 Hz, 1H), 7.88 (s, 1H), 6.91 - 6.83 (m, 1H), 6.66 (dd, J=4.0, 8.8 Hz, 1H), 4.86 (s, 2H), 4.60 (t, .7=8,8 Hz, 2H), 3.43 (t, J=8.8 Hz, 2H), 2.68 (s, 3H).EXAMPLE 3 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l,2-c]pyrimidine-2-[000344] A mixture of ethyl 8-bromo-5-(((5-fluorobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2-carboxylate (120 mg, 274 pmol. 1.00 equiv), 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (120 mg, 548 pmol, 2.00 equiv), sodium bicarbonate (69.0 mg, 822 pmol, 32.0 pL, 3.00 equiv) and Pd(dppf)C12 (22.4 mg, 27.4 pmol, 0.100 equiv) in dioxane (3.00 mL) and water (0.600 mL) was purged with nitrogen and stirred at 105 °C for 1 h under a nitrogen atmosphere. The mixture was concentrated at reduced pressure to give a residue. The crude material was purified by prep- TLC (DCM / Methyl alcohol = 20 / 1) to afford ethyl 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2- methylpyridin-3-yl)imidazo[l,2-c]pyrimidine-2-carboxylate (100 mg, 78.9% yield, 96.3% purity) as a brown solid. LCMS [M+l]: 446.2.[000345] To a solution of ethyl 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3- yl)imidazo[l,2-c]pyrimidine-2-carboxylate (100 mg, 216 pmol, 1.00 equiv) in methyl alcohol (4.00 mL) and water (1.00 mL) was added sodium hydroxide (17.3 mg, 432 pmol, 2.00 equiv). The resultant mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated at reduced pressure, water (2 ml) was added, and the pH was adjusted to 5 with aq hydrochloric acid (1.00 M). The precipitate was filtered to provide the crude material (80 mg) as a brown solid. The crude material was purified by prep- HPLC(column: Phenomenex Synergi C18 150x25x 10 pm; mobile phase:[water (0.1 %TFA) - ACN]; B%: 12% - 42%, 10 min) to afford 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3- yl)imidazo[l,2-c]pyrimidine-2 -carboxylic acid (10.0 mg, 99.7 % purity) as a gray solid. LCMS [M+l]: 418.1. 'H NMR (400MHz, CD3OD) 5 = 8.74 (dd, J=1.6, 5.6 Hz, 1H), 8.64 (s, 1H), 8.56 (dd, J=1.6, 8.0 Hz, 1H), 7.97 (dd, J=6.0, 7.6 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J=2.4 Hz, 1H), 7.47 (dd, J=3.6, 8.8 Hz, 1H), 7.15 - 7.08 (m, 2H), 5.13 (s, 2H), 2.67 (s, 3H).EXAMPLE 45-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(4-methyl-lH-imidazol-l- yl)imidazo[l,2-c]pyrimidine-2-carboxylic acid[000346] A mixture of 4-methyl-lH-imidazole (102 mg, 1.24 mmol, 4.40 equiv), ethyl 8-bromo-5-[tert- butoxycarbonyl-[(5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl]amino]imidazo[l,2-c]pyrimidine-2- carboxylate (160 mg, 282 pmol, 1.00 equiv), Pd2(dba)s (25.9 mg, 28.2 pmol, 0.10 equiv), ditert-butyl- [2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane (27.2 mg, 56.5 pmol, 0.20 equiv) and potassium phosphate (155 mg, 734 pmol, 2.60 equiv) in dioxane (5.00 mL) was purged with nitrogen. The resultant mixture was stirred at 120 °C for 2 h under a nitrogen atmosphere. The mixture was diluted with ethyl acetate (3 mL) and extracted with ethyl acetate (2.00 mL x 3). The combined organic layers were washed with brine (2.00 mL x 3 ). dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure to afford ethyl 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(4- methyl-lH-imidazol-l-yl)imidazo[l,2-c]pyrimidine-2-carboxylate (120 mg, crude) as a yellow oil. [000347] A mixture of ethyl 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(4-methyl-lH- imidazol-l-yl)imidazo[l,2-c]pyrimidine-2 -carboxylate (120 mg, 275 pmol, 1.00 equiv), sodium hydroxide (33.0 mg, 825 pmol, 3.00 equiv) in methyl alcohol (3.00 mb) and water (1.00 mb) was purged with nitrogen. The mixture was stirred at 60 °C for 1 h. The residue was diluted with ethyl acetate (3.00 mb) and extracted with ethyl acetate (2.00 mb x 3). The combined organic layers were washed with brine (2.00 mb x 3). dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to provide a residue. The crude material was purified by prep-HPEC (basic conditions) to give 5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(4-methyl-lH-imidazol-l-yl)imidazo[l,2- c]pyrimidine-2 -carboxylic acid (37.1 mg, 90.0 pmol, 32.7 % yield, 99.1% purity) as a bluish solid. LC- MS [M+l]: 409.3. ’H NMR (400MHz, DMSO-d6) 5 = 8.68 (s, 1H), 8.54 (br s, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.47 (s, 1H), 6.97 - 6.88 (m, 1H), 6.68 (dd, J=3.6, 8.8 Hz, 1H), 4.70 (br s, 2H), 4.53 (t, J=8.8 Hz, 2H), 3.31 (br d, .7=8,8 Hz, 2H), 2.18 (s, 3H).[000348] EXAMPEES 5 -10 were prepared following the procedure set forth in Example 4 and using the general reactions schemes and intermediates described herein.TABLE 1Characterization of EXAMPLES 5-10EXAMPLE 118-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxamide[000349] To a solution of 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxylic acid (24.9 mg, 52.7 pmol, 1.00 equiv) in DMF (1 mL) was added ammonium chloride (8.45 mg, 158 pmol, 3.00 equiv), DIPEA (47.7 mg, 369 pmol, 64.2 pL, 7.00 equiv) and HATU (40.1 mg, 105 pmol, 2.00 equiv). The resultant mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (10.0 mL) and filtered. The precipitate was washed with methanol (1.00 mL) and dried at reduced pressure to provide 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxamide (12.3 mg, 53.8% yield, 97.5% purity) as a gray solid. LC-MS: [M+l] 422.1. ’H NMR (400MHz, DMSO-d6) 5 = 8.64 (s, 1H), 8.51 (br s, 1H), 7.74 (s, 1H), 7.62 (br s, 1H), 7.45 (br s, 1H), 6.93 (t, J=9.6 Hz, 1H), 6.69 (dd, J=4.0, 8.8 Hz, 1H), 6.25 (s, 1H), 4.71 (br d. .7=4.4 Hz. 2H), 4.54 (brt, J=8.8 Hz, 2H), 3.72 (s, 3H), 3.31 - 3.27 (m, 2H), 2.18 (s, 3H).EXAMPLE 12 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l,2-c]pyrimidine-2-[000350] A mixture of 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3- yl)imidazo[l,2-c]pyrimidine-2 -carboxylic acid (80.0 mg, 192 pmol, 1.00 equiv), DIEA (74.3 mg, 575 pmol, 100 pL, 3.00 equiv) and ammonium chloride (30.8 mg, 575 pmol, 3 equiv) in DMF (3.00 mL) was cooled to 0 °C. To this mixture was added HATU (109 mg, 287 pmol, 1.50 equiv) and the mixture was stirred at 25 °C for 1 h. The solution was diluted with water (10.0 mL), filtered, the filter cake was dried to afford 5-(((5-fhiorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l,2- c]pyrimidine-2-carboxamide (61.0 mg, 74.0 % yield, 96.8 % purity) as a white solid. LCMS [M+l]: 417.2. 'H NMR (400MHz, DMSO-d6) 5 = 8.64 (s, 1H), 8.59 (t, J=5.2 Hz, 1H), 8.48 (dd, J=1.6, 4.8 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.72 (dd, J=1.6, 7.6 Hz, 1H), 7.65 (s, 1H), 7.59 (dd, J=3.6, 9.0 Hz, 1H), 7.50(br s, 1H), 7.39 (br s, 1H), 7.29 (dd, J=5.2, 7.6 Hz, 1H), 7.25-7.18(m, 2 H), 5.00 (d, J=5.2 Hz, 2H), 2.39 (s, 3H).[000351] EXAMPLES 13 -21 were prepared following the procedure set forth in Example 12 and using the general reactions schemes and intermediates described herein.TABLE 2Characterization of EXAMPLES 13-21EXAMPLE 225-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l,2-c]pyrimidine-2-[000352] To a solution of 5-(((5-fluorobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3- yl)imidazo[l,2-c]pyrimidine-2-carboxamide (45.0 mg, 108 pmol, 1.00 equiv), TEA (219 mg, 2.16 mmol, 301 pL, 20.0 equiv) in THF (1.50 mL) was added TFAA (136 mg, 648 pmol, 90.2 pL, 6.00 equiv) at 0 °C. The mixture was subsequently stirred at 25 °C for 1 h. The reaction mixture was diluted with ethyl acetate (10.0 mL) and washed with water (10.0 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure to give a residue. The crude material was purified by prep-HPLC(column: Phenomenex Synergi C18 150x25x 10 um; mobile phase: [A = water (0.1 % TFA) - B = acetonitrile]; B%: 18% - 48%, 12 min) to afford 5-(((5-fhrorobenzofuran-4- yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l,2-c]pyrimidine-2-carbonitrile (13.0 mg, 29.9% yield, 99.1% purity) as an off-white solid. LCMS [M+l]: 399.3. 'HNMR (400MHz, METHANOL-d4) 5= 8.75 (dd, J=1.6, 6.0 Hz, 1H), 8.65 (s, 1H), 8.54 (dd, J=1.6, 7.6 Hz, 1H), 8.0 - 7.95 (m, 2H), 7.83 (d, .7=2,0 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.18 - 7.11 (m, 2H), 5.15 (d, J=0.4 Hz, 2H), 2.68 (s, 3H).EXAMPLE 235-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(l-isopropyl-3-methyl-lH-pyrazol-4- yl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000353] To a solution of 5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(l-isopropyl-3- methyl-lH-pyrazol-4-yl)imidazo[l,2-c]pyrimidine-2 -carboxamide (49.0 mg, 106 pmol, 1.00 equiv) and TEA (215 mg, 2.12 mmol, 296 pL, 20.0 equiv) in THF (1.00 mL) was added TFAA (134 mg, 637 pmol, 88.7 pL, 6.00 equiv) at 0 °C. The mixture was subsequently stirred at 25 °C for 1 h. The reaction mixture was diluted with ethyl acetate (10.0 mL), the pH was adjusted to ~7 with TFA, and the organic layer was washed with brine (5.00 mL x 3). Concentration in vacuo provided the crude material. The crude residue was triturated with methyl alcohol (2.00 mL) and filtered to afford 5-(((5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)amino)-8-(l-isopropyl-3-methyl-lH-pyrazol-4-yl)imidazo[l,2-c]pyrimidine-2 -carbonitrile (43.0 mg, 92.7% yield, 98.8% purity) as a white solid. LCMS [M+l]: 432.3. 'H NMR (400MHz, DMSO-d6) 5 = 8.90 (s, 1H), 8.32 (br s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 6.94 (t, .7=9.2 Hz, 1H), 6.70 (dd, J=3.6, 8.4 Hz, 1H), 4.70 (br s, 2H), 4.58 - 4.44 (m, 3H), 3.30 - 3.24 (m, 2H), 2.30 (s, 3H), 1.43 (d, .7=6,8 Hz, 6H).[000354] EXAMPLES 24 -85 were prepared following the procedure set forth in Example 23 and using the general reactions schemes and intermediates described herein.TABLE 3Characterization of EXAMPLES 24-85IllEXAMPLE 86 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile[000355] A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carbonitrile (90.0 mg, 231 pmol, 1.00 equiv), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazole (103 mg, 463 pmol, 2.00 equiv), Pd(dppf)C12 (16.9 mg, 23.1 pmol, 0.100 equiv), sodium bicarbonate (58.4 mg, 695 pmol, 27.0 pL, 3 equiv) in dioxane (6.00 mL) and water (3.00 mL) was purged with nitrogen. The resultant mixture was stirred at 100 °C for 2 h under an atmosphere of nitrogen. Water (8.00 mL) was added and the mixture was extracted with ethyl acetate (8.00 mL x 3). The combined organic layer was concentrated in vacuo to give a residue. The crude material was purified by Prep-HPLC (column: Phenomenex Synergi C18 150*25* 10 pm; mobile phase: [water(0.1%TFA)- ACN];B%: 33%-63%,13min) to 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (51.0 mg, 120 pmol, 52.0% yield, 95.4% purity) as a white solid. LC-MS: [M+l] 404.1H NMR (400 MHz, DMSO-t / 6) 5 = 8.92 (s, 1H), 8.64 (br t, J= 4.8 Hz, 1H), 7.86 (s, 1H), 6.99 - 6.91 (m, 1H), 6.71 (dd, J= 4.0, 8.8 Hz, 1H), 6.23 (s, 1H), 4.72 (br d, J= 4.4 Hz, 2H), 4.55 (t, J= 8.8 Hz, 2H), 3.67 (s, 3H), 3.31 (t, J= 8.8 Hz, 2H), 2.18 (s, 3H).EXAMPLE 875-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000356] A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carbonitrile (90.0 mg, 231 pmol, 1.00 equiv), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazole (103 mg, 463 pmol, 2.00 equiv), Pd(dppf)C12 (16.9 mg, 23.1 pmol, 0.100 equiv), sodium bicarbonate (58.4 mg, 695 pmol, 27.0 pL, 3 equiv) in dioxane (6.00 mL) and water (3.00 mL) was purged with nitrogen. The resultant mixture was stirred at 100 °C for 2 h under an atmosphere of nitrogen. Water (8.00 mL) was added and the mixture was extracted with ethyl acetate (8.00 mL x 3).The combined organic layer was concentrated in vacuo to give a residue. The crude material was purified by Prep-HPLC (column: Phenomenex Synergi C18 150*25* 10 pm; mobile phase: [water(0.1%TFA)- ACN];B%: 33%-63%,13min) to 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (51.0 mg, 120 pmol, 52.0% yield, 95.4% purity) as a white solid. LC-MS: [M+l] 404.1H NMR (400 MHz, DMSO-t / 6) 5 = 8.92 (s, 1H), 8.64 (br t, J= 4.8 Hz, 1H), 7.86 (s, 1H), 6.99 - 6.91 (m, 1H), 6.71 (dd, J= 4.0, 8.8 Hz, 1H), 6.23 (s, 1H), 4.72 (br d, J= 4.4 Hz, 2H), 4.55 (t, J= 8.8 Hz, 2H), 3.67 (s, 3H), 3.31 (t, J= 8.8 Hz, 2H), 2.18 (s, 3H).[000357] EXAMPLES 88 -136 were prepared following the procedure set forth in Example 87 and using the general reactions schemes and intermediates described herein.TABLE 4Characterization of EXAMPLES 88-136EXAMPLE 137 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l,2- c] pyrimidine- 2-carboxamide[000358] A mixture of 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3- yl)imidazo[l,2-c]pyrimidine-2 -carbonitrile (38.0 mg, 92.5 pmol, 1.00 equiv) in cone, hydrochloric acid (1.00 mL) was stirred at 26 °C for 4 h. The reaction mixture was adjusted to pH 7 with satd aq sodium bicarbonate aqueous solution at which time a precipitate formed. The precipitate was filtered and dried at reduced pressure. The crude product was washed with methanol (2.00 mL) and filtered to afford 5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methylpyridin-3-yl)imidazo[l,2-c]pyrimidine-2- carboxamide (24.0 mg, 60.4 % yield, 97.4 % purity) as an off-white solid. LC-MS: [M+l] 419.1. ’H NMR (400MHz, DMSO-d6) 5 = 8.65 (s, 1H), 8.48 (m, 1H), 8.42 (br t, 7=4.8 Hz, 1H), 7.72 (m, 1H), 7.65 (s, 1H), 7.50 (br s, 1H), 7.40 (br s, 1H), 7.30 (dd, 7=4.8, 7.6 Hz, 1H), 6.94 (t, 7=9.6 Hz, 1H), 6.70 (dd, 7=4.0, 8.8 Hz, 1H), 4.72 (br d, 7=4.4 Hz, 2H), 4.55 (t, 7=8.8 Hz, 2H), 3.33 - 3.29 (m, 2H), 2.40 (s, 3H).EXAMPLE 1385-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-6-(4-methylpiperazin-l- yl)pyridin-3-yl)imidazo[l,2-c]pyrimidine-2-carboxamide[000359] 5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-6-(4-methylpiperazin-l- yl)pyridin-3-yl)imidazo[l,2-c]pyrimidine-2-carbonitrile (25.0 mg, 49.8 pmol, 1.00 equiv) in HC1 (0.500 mL) was stirred at 25 °C for 0.5 h. The pH was adjusted to 8 with saturated aqueous NaHCOs and filtered. The precipitate was triturated with MeOH (2.00 mL) to afford 5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-6-(4-methylpiperazin-l-yl)pyridin-3- yl)imidazo[l,2-c]pyrimidine-2 -carboxamide (6.00 mg, 11.2 pmol, 22.4% yield, 96.0% purity) as a brown solid. LCMS [M+l]: 517.5. 'H NMR (400MHz, DMSO-d6) 5 = 8.62 (s, 1H), 8.30 (br s, 1H), 7.56 (s,1H), 7.51 - 7.45 (m, 2H), 7.39 (br s, 1H), 6.94 (brt, J=9.2 Hz, 1H), 6.75 - 6.67 (m, 2H), 4.71 (br d, J=4.4 Hz, 2H), 4.55 (brt, J=8.4 Hz, 2H), 3.53 (br s, 4H), 3.32 - 3.25 (m, 6H), 2.25 (s, 6H).EXAMPLE 1395-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(4-methyl-lH-imidazol-l- yl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000360] A mixture of tert-butyl (8-bromo-2-cyanoimidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)carbamate (70.0 mg, 139 pmol, 1.00 equiv), 4-methyl-177-imidazole (50.2 mg, 612 pmol, 4.40 equiv) , Pd2(dba)s (12.7 mg, 13.9 pmol, 0.100 equiv), ditert-butyl-[2, 3,4,5- tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl] phosphane (13.4 mg, 27.8 pmol, 0.20 eq.) and potassium phosphate (76.7 mg, 362 pmol, 2.60 equiv) in dioxane (0.50 mL) was purged with nitrogen. The mixture was stirred at 120 °C for 12 h under an atmosphere of nitrogen. The mixture was filtered and concentrated in vacuo to provide the crude residue. The residue was triturated with methanol (2.00 mL) and filtered to afford 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(4-methyl-lH-imidazol- l-yl)imidazo[l,2-c]pyrimidine-2 -carbonitrile (9.89 mg, 24.8 pmol, 17.8% yield, 97.6% purity) as a yellow solid. LC-MS [M+l]: 390.4. 'HNMR (400MHz, DMSO-d6) 5 = 8.97 (s, 1H), 8.63 (brt, .7=4,8 Hz, 1H), 8.13 - 8.06 (m, 2H), 7.42 (s, 1H), 6.95 (t, J=9.2 Hz, 1H), 6.71 (dd, J=4.0, 8.8 Hz, 1H), 4.71 (br d, .7=4.8 Hz, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.31 - 3.23 (m, 2H), 2.18 (s, 3H).EXAMPLE 140[000361] A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxylate (0.20 g, 460 pmol, 1.00 equiv), tert-butyl4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-277-pyridine-l-carboxylate(227 mg, 735 pmol, 1.60 equiv), NaHCOs (116 mg, 1.38 mmol, 3.00 equiv), Pd(dppf)C12 (33.6 mg, 46.0 pmol, 0.100 equiv) in dioxane (2.10 mL) and water (0.700 mL) was purged with nitrogen. The mixture was stirred at 105 °C for 1 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiCL, DCM / MeOH, 20 / 1) to provide ethyl 8 -(l-(tert-butoxy carbonyl) -l,2,3,6-tetrahydropyridin-4-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carboxylate (230 mg, 89.8% yield, 96.4% purity) as a yellow oil. LC-MS [M+l]: 538.3. [000362] A mixture of ethyl 8-(l-(tert-butoxycarbonyl)-l,2,3,6-tetrahydropyridin-4-yl)-5-(((5-fluoro- 2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylate (220 mg, 395 pmol, 1.00 equiv) and Pd / C 10 w. % (100 mg) in methanol (5.00 mb) was stirred at 25 °C for 12 h under an atmosphere of hydrogen gas (15.0 psi). The reaction mixture was fdtered and concentrated in vacuo to provide ethyl 8-(l-(tert-butoxycarbonyl)piperidin-4-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxylate (230 mg) as a yellow oil. LC-MS[M+1]: 540.2.[000363] To a solution of ethyl 8-(l-(tert-butoxycarbonyl)piperidin-4-yl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxylate (260 mg, 476 pmol, 1.00 equiv) in methanol (5.00 mL) was added aq sodium hydroxide (1.00 M, 1.43 mL, 3.00 equiv). The mixture was stirred at 25 °C for 3 h and subsequently concentrated in vacuo. The mixture was adjusted to pH=6 with acetic acid and the resultant precipitate was fdtered. The solid was dried at reduced pressure to provide 8-(l-(tert-butoxycarbonyl)piperidin-4-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxylic acid (230 mg, 450 pmol, 94.5% yield) as a light yellow solid. LC-MS [M+l]: 512.3.[000364] To a solution of 8-(l-(tert-butoxycarbonyl)piperidin-4-yl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxylic acid (0.220 g, 430 pmol, 1.00 equiv) in DMF (3.00 mL) was added ammonium chloride (184 mg, 3.44 mmol, 8.00 equiv), DIEA (1.00 g, 7.74 mmol, 1.35 mL, 18.0 equiv) and HATU (327 mg, 860 pmol, 2.00 equiv). The mixture was stirred at 25 °C for 1 h and subsequently diluted with water 10.0 mL. The formed precipitate was fdtered and dried at reduced pressure to provide tert-butyl 4-(2-carbamoyl-5-(((5-fluoro-2,3-dihydrobenzofuran- 4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)piperidine-l-carboxylate (210 mg, 95.6% yield) as a white solid. LC-MS: [M+l] 511.2.[000365] To a solution of tert-butyl 4-(2-carbamoyl-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)piperidine-l-carboxylate (150 mg, 294 pmol, 1.00 equiv) in THF (3.00 mL) was added triethylamine (595 mg, 5.88 mmol, 818 pL, 20.0 equiv) followed by TFAA (370 mg, 1.76 mmol, 245 pL, 6.00 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 h and subsequently diluted with DCM 30 mL. The organic layer was washed with brine (20 mL x 2) and the organic phase was dried over sodium sulfate, fdtered, and concentrated in vacuo. The resultant residue was purified by prep-TLC (SiCL, PE / EA, 1 / 1) to afford tert-butyl 4-(2-cyano-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo [ 1 ,2-c]pyrimidin-8-yl)piperidine- 1 -carboxylate (130 mg, 263 pmol, 89.4% yield, 99.5% purity) as a yellow solid. LC-MS: [M+Na+] 515.3.[000366] To a solution of tert-butyl 4-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)piperidine-l-carboxylate (100 mg, 202 pmol, 1.00 equiv) in DCM (3.00 mL) was added 2,6-lutidine (173 mg, 1.62 mmol, 188 pL, 8.00 equiv) followed by TMSOTf (112 mg, 505 pmol, 91.3 pL, 2.50 equiv) at 0 °C. The mixture was stirred at 25 °C for 48 h andsubsequently diluted with DCM (10 mL) and water (10 mL). The resultant mixture was filtered and the precipitate was dried at reduced pressure. The crude material was triturated with hot methanol (2 mL) and fdtered. The solid was dried at reduced pressure to afford 5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)-8-(piperidin-4-yl)imidazo[l,2-c]pyrimidine-2 -carbonitrile (44.4 mg, 111 pmol, 55.1% yield, 98.5% purity) as an off-white solid. LC-MS: [M+l] 393.3. 'HNMR (400MHz, DMSO-d6) 5 = 8.94 (s, 1H), 8.44 (br s, 1H), 7.60 (br s, 1H), 6.93 (br t, J=9.6 Hz, 1H), 6.69 (br d, .7=4,8 Hz, 1H), 4.65 (br s, 2H), 4.54 (br t, J=8.0 Hz, 2H), 3.21 - 3.06 (m, 4H), 2.99 (br s, 3H), 2.01 (br s, 4H).EXAMPLE 141[000367] To a solution of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylate (100 mg, 230 pmol, 1.00 equiv), 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (48.3 mg, 230 pmol, 1.00 equiv) and cesium carbonate (150 mg, 460 pmol, 2.00 equiv) in dioxane (1.00 mL) and water (0.300 mL) was added Pd(dppf)C12 (16.8 mg, 23.0 pmol, 0.100 equiv). The vessel was purged with nitrogen, stirred at 105 °C for 1 h and subsequently concentrated in vacuo to provide a residue. The residue was purified by Prep- TLC (SiC>2, petroleum ether / ethyl acetate, 1 / 1) to afford ethyl 8-(3,6-dihydro-2H-pyran-4-yl)-5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[ l,2-c]pyrimidine-2 -carboxylate (81.0 mg, 77.7% yield, 96.6% purity) as a white solid. LCMS [M+l]: 439.2.[000368] To a solution of ethyl 8-(3,6-dihydro-2H-pyran-4-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylate (70.0 mg, 160 pmol, 1.00 equiv) in methanol (5.00 mL) and THF (5.00 mL) was added palladium on carbon 10 w. % (172 mg, 0. 1 equiv) at 25 °C. The mixture was purged with hydrogen and allowed to stir for 1 h at 25 °C under an atmosphere of hydrogen gas (15.0 psi). The mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was rinsed with 5 mL petroleum ether / ethyl acetate (2 / 1) to afford ethyl 5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(tetrahydro-2H-pyran-4-yl)imidazo[l,2- c]pyrimidine-2 -carboxylate (50.0 mg, 64.6 yield, 90.9% purity) as a white solid.[000369] To a solution of ethyl 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(tetrahydro- 2H-pyran-4-yl)imidazo[l,2-c]pyrimidine-2 -carboxylate (50.0 mg, 103 pmol, 1.00 equiv) in THF (6.0 mL) and water (3.0 mL) was added sodium hydroxide (4.13 mg, 103 pmol, 1.00 equiv). The mixture was stirred at 25 °C for 1 h and subsequently concentrated in vacuo to remove the majority of the THF. The aqueous solution was adjusted to pH = 6 with aq hydrochloric acid (1.0 M, 0.5 mL) and the resultant precipitate was filtered. The solid was triturated with 3 mL petroleum ether / ethyl acetate (2: 1) and dried at reduced pressure to afford 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(tetrahydro-2H-pyran-4-yl)imidazo[l,2-c]pyrimidine-2-carboxylic acid (41.0 mg, 95.0% yield, 98.6% purity) as a white solid. LCMS [M+l]: 413.2. 'H NMR (400MHz, CD30D) 5 = 8.08 (s, 1H), 7.50 (s, 1H), 6.85 (t, J=9.2 Hz, 1H), 6.64 (dd, J=4.0, 8.8 Hz, 1H), 4.76 (s, 2H), 4.56 (t, J=8.8 Hz, 2H), 4.06 (dd, J=3.2, 11.2 Hz, 2H), 3.73 - 3.64 (m, 2H), 3.44 - 3.37 (m, 1H), 3.32 - 3.28 (m, 2H), 2.00 (dd, J=2.0, 12.8 Hz, 2H), 1.91 - 1.77 (m, 2H).[000370] A mixture of 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(tetrahydro-2H- pyran-4-yl)imidazo[l,2-c]pyrimidine-2 -carboxylic acid (34.0 mg, 81.3 pmol, 1.00 equiv), HATU (46.4 mg, 122 pmol, 1.50 equiv), DIEA (84.1 mg, 650 pmol, 113 pL, 8.00 equiv) and ammonium chloride (13.0 mg, 244 pmol, 3.00 equiv) in DMF (2.00 m ) was purged with nitrogen. The mixture was stirred at 30 °C for 1 h and was subsequently concentrated in vacuo to provide the crude solid. The solid was rinsed with water (1.00 m ), fdtered and dried at reduced pressure. The solid was triturated with 2 mb petroleum ether / ethyl acetate (2: 1) to afford 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8- (tetrahydro-2H-pyran-4-yl)imidazo[l,2-c]pyrimidine-2-carboxamide (20.0 mg, 46.6 pmol, 57.3% yield, 95.8% purity) as a white solid. ECMS [M+l]: 412.17. ’H NMR (400MHz, DMSO-d6) 5 = 8.54 (s, 1H), 8.11 (br t, .7=4,8 Hz, 1H), 7.57 (br s, 1H), 7.52 (s, 1H), 7.47 (br s, 1H), 6.92 (t, J=9.2 Hz, 1H), 6.68 (dd, J=3.6, 8.8 Hz, 1H), 4.65 (br d, .7=4,8 Hz, 2H), 4.53 (t, J=8.8 Hz, 2H), 3.97 (br d, J=10.8 Hz, 2H), 3.53 - 3.40 (m, 3H), 3.30 - 3.24 (m, 2H), 3.18 - 3.10 (m, 1H), 1.93 - 1.82 (m, 4H).[000371] To a mixture of 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(tetrahydro-2H- pyran-4-yl)imidazo[l,2-c]pyrimidine-2 -carboxamide (28.0 mg, 68.1 pmol, 1 equiv), triethylamine (138 mg, 1.36 mmol, 189 ph, 20.0 equiv) in THF (4.00 mb) was added TFAA (42.9 mg, 204 pmol, 28.4 ph, 3.00 equiv) at 0 °C. The resultant mixture was stirred at 0 - 30 °C for 1 h and was subsequently fdtered and concentrated to provide the crude residue. The residue was purified by prep-HPEC (column: Gemini 150x25 5 u; mobile phase: [water (0.04 %NHsH2O) - ACN]; B %: 35.0 % - 65.0 %, 10 min) to afford 5- (((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(tetrahydro-2H-pyran-4-yl)imidazo[l,2- c]pyrimidine-2 -carbonitrile (26.0 mg, 63.1 pmol, 92.7% yield, 95.5% purity) as a yellow solid. ’H NMR (400MHz, DMSO-d6) 5 = 8.84 (s, 1H), 8.24 (br s, 1H), 7.63 (s, 1H), 6.93 (t, J=9.6 Hz, 1H), 6.69 (dd, J=3.6, 8.4 Hz, 1H), 4.65 (br d, J=3.2 Hz, 2H), 4.54 (br t, J=8.8 Hz, 2H), 4.01 - 3.90 (m, 2H), 3.53 - 3.42 (m, 1H), 3.29 - 3.27 (m, 3H), 3.16 - 3.05 (m, 1H), 1.94 - 1.74 (m, 4H). ECMS: [M+l] 394.1.EXAMPLE 142 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(pyridazin-3-yl)imidazo[l,2- c] pyrimidine- 2-carbonitrile[000372] A mixture of tributyl(pyridazin-3-yl)stannane (90.7 mg, 246 pmol, 1.20 eq.), 8-bromo-5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[ l,2-c]pyrimidine-2 -carbonitrile (80.0 mg, 205 pmol, 1.00 eq.) and Pd(PPhs)4 (23.7 mg, 20.5 pmol, 0.10 eq.) in toluene (1.00 mL) was purged with nitrogen and was subsequently stirred at 110 °C for 2 h. The reaction mixture was cooled to rt and quenched with sat aq potassium fluoride (2.00 mL). The mixture was extracted with ethyl acetate (2.00 mL x 3) and the combined organic layer was washed with brine (2.00 mL x 2), dried over sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC and lyophilized to provide title compound 5-[(5-fluoro-2,3-dihydrobenzofuran -4- yl)methylamino]-8-pyridazin-3-yl-imidazo[l,2-c]pyrimidine-2 -carbonitrile (6.84 mg, 8.51% yield, 98.6% purity) as a yellow solid. LCMS [M+l]: 388.3. 'HNMR (400MHz, DMSO-d6) 5 = 9.95 (dd, J=0.8, 2.0 Hz, 1H), 9.26 (dd, J=0.8, 5.6 Hz, 1H), 8.99 (s, 1H), 8.95 (br t, J=5.2 Hz, 1H), 8.62 (s, 1H), 8.46 (dd, .7=2.4, 5.6 Hz, 1H), 7.01 - 6.91 (m, 1H), 6.72 (dd, J=4.0, 8.8 Hz, 1H), 4.78 (d, J=5.2 Hz, 2H), 4.55 (t, .7=8,8 Hz, 2H), 3.32 - 3.28 (m, 2H).[000373] EXAMPLES 143 -146 were prepared following the procedure set forth in Example 142 and using the general reactions schemes and intermediates described herein.TABLE 5Characterization of EXAMPLES 143-146EXAMPLE 1475-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(6-(hydroxymethyl)pyridin-3- yl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000374] A solution of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2-carbonitrile (100 mg, 252 pmol, 1.00 eq.), tert-butyl-dimethyl-[[5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-2-pyridyl]methoxy]silane (200 mg, 458 pmol, 1.82 eq.), sodium bicarbonate (65.0 mg, 774 pmol, 3.10 eq.) and Pd(dppf)C12 (19 mg, 26 pmol, 0.1 eq.) in dioxane (1.70 mL) and water (0.30 mL) was flushed with nitrogen. The mixture was stirred at 95 °C for 1 h. The mixture was cooled to rt, filtered, and concentrated to provide the crude material. The residue was purified by prep-TLC (SiC>2, dichloromethane / MeOH = 20 / 1) to afford 8-[6-[ | / c' / 7-biityl(dimcthyl)silyl ]-oxymethyl ]-3- pyridyl] -5-[(5- fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[l,2-c]pyrimidine-2-carbonitrile (140 mg, 224 pmol, 89.1% yield, 85.0% purity) as a yellow oil. LCMS [M + l]: 531.2. ’H NMR (400MHz, DMSO- d6) 5 = 9.05 (d, .7=2,0 Hz, 1H), 8.95 (s, 1H), 8.59 (t, J=5.2 Hz, 1H), 8.41 (dd, J=2.0, 8.0 Hz, 1H), 8.20 (s,1H), 7.53 (d, J=8.4 Hz, 1H), 7.01 - 6.89 (m, 1H), 6.71 (dd, J=4.0, 8.4 Hz, 1H), 4.80 (s, 2H), 4.74 (br d, .7=4,4 Hz, 2H), 4.54 (t, J=8.8 Hz, 2H), 3.34 - 3.29 (m, 2H), 0.94 (s, 9H), 0.13 (s, 6H).[000375] A solution of 8-[6-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-pyridyl]-5-[(5-fluoro-2,3- dihydrobenzofuran-4-yl)methylamino]imidazo[l,2-c]pyrimidine-2 -carbonitrile (90.0 mg, 144 pmol, 1.00 eq.) in dichloromethane (1.00 mb) and TFA (2.00 mL) was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, dichloromethane / methanol = 10 / 1) to provide the crude product. The solid was triturated with methanol (7.00 mL) and collected by filtration to afford title compound 5-[(5-fluoro-2,3-dihydrobenzofuran-4- yl)methylamino]-8-[6-(hydroxymethyl)-3- pyridyl] imidazo[l,2-c]pyrimidine-2 -carbonitrile (45.0 mg, 106 pmol, 73.5% yield, 98.0% purity) as an off-white solid. LCMS [M + 1]: 417.0. 'H NMR (400MHz, DMSO-d6) 5 = 9.04 (s, 1H), 8.94 (s, 1H), 8.59 (t, J=4.8 Hz, 1H), 8.37 (dd, J=2.0, 8.0 Hz, 1H), 8.18 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 6.95 (t, J=9.2 Hz, 1H), 6.71 (dd, J=4.0, 8.8 Hz, 1H), 5.44 (t, J=6.0 Hz, 1H), 4.74 (br d, .7=4,8 Hz, 2H), 4.61 (d, J=5.6 Hz, 2H), 4.55 (t, J=8.8 Hz, 2H), , 3.29 - 3.33 (m, 2H).EXAMPLE 148 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-(hydroxymethyl)pyridin-3- yl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000376] A solution of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2-carbonitrile (30.0 mg, 75.0 pmol, 1.00 eq.), [2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3- pyridyl]boronic acid (20.0 mg, 74.9 pmol, 0.10 eq.), sodium bicarbonate (18.9 mg, 225 pmol, 3.00 eq.) and Pd(dppf)C12 (5.50 mg, 7.50 pmol, 0.10 eq.) in dioxane (1.00 mL) and water (0.20 mL) was purged with nitrogen and stirred at 95 °C for 1 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford 8-(2-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile (30.0 mg, 41.8 pmol, 55.8% yield, 74.0% purity) as a white solid.[000377] A mixture of 8-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (15.0 mg, 20.9 pmol, 1.00 eq.) and trifluoroacetic acid (1.11 mL, 15.0 mmol, 717 eq.) in dichloromethane (1.00 mL) was stirred at rt for 1 h. The mixture was filtered and concentrated under reduced pressure to provide the crude residue. The residue was purified by prep-HPLC to afford title compound 5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)-8-(2-(hydroxymethyl)pyridin-3-yl)imidazo[l,2-c]pyrimidine-2-carbonitrile (3.05 mg, 7.05 pmol, 33.7% yield, 96.3% purity) as a yellow oil. LC-MS [M+l]: 417.3. ’H NMR (400MHz, DMSO-t / 6) 5 = 8.95 (s, 1H), 8.65 (d, J=4.0 Hz, 1H), 8.61 (br s, 1H), 8.00 (br d, J=7.6 Hz, 1H), 7.89 (s, 1H), 7.60 - 7.54 (m, 1H), 7.00 - 6.92 (m, 1H), 6.72 (dd, J=4.0, 8.8 Hz, 1H), 4.74 (d, .7=4,4 Hz, 2H), 4.59 - 4.52 (m, 4H), 3.34 - 3.32 (m, 2H).EXAMPLE 1498-(4-((dimethylamino)methyl)-3,5-difluorophenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile[000378] To a solution of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (50.0 mg, 129 pmol, 1.00 eq.), (3,5-difluoro-4- formyl-phenyl)boronic acid (28.7 mg, 155 pmol, 1.20 eq.) in dioxane (1.00 mL) and water (0.20 mL) was added Pd(dppf)C12 (9.42 mg, 12.9 pmol, 0.10 eq.) and sodium bicarbonate (21.6 mg, 257 pmol, 2.00 eq.) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 1 h and subsequently concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiCE, petroleum ether / ethyl acetate = 1 / 1) to give 8-(3,5-difhroro-4-formylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (30.0 mg, 66.8 pmol, 51.8% yield) as a white solid.[000379] To a solution of 8-(3,5-difhioro-4-formylphenyl)-5-(((5-fhioro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (30.0 mg, 66.8 pmol, 1.00 eq.), N- methyhnethanamine (2M in THF, 67.6 pL, 133 pmol, 2.00 eq.) in methanol (2.00 mL) was added sodium triacetoxyborohydride (28.3 mg, 134 pmol, 2.00 eq.). The mixture was stirred at 40 °C for 30 min. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (TFA condition) to give 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2- (hydroxymethyl)pyridin-3-yl)imidazo[l,2-c]pyrimidine-2 -carbonitrile (11.0 mg, 17.8 pmol, 26.7% yield, 96.0% purity, TFA salt) as a white solid. LCMS [M+l]: 479.4. 'H NMR (400MHz, DMSO-d6) 5 = 9.96 (br s, 1H), 8.99 (s, 1H), 8.85 (t, .7=4,8 Hz, 1H), 8.44 (s, 1H), 8.08 (d, J=9.6 Hz, 2H), 7.00 - 6.92 (m, 1H), 6.72 (dd, J=4.0, 8.8 Hz, 1H), 4.76 (d, .7=4,8 Hz, 2H), 4.56 (t, .7=8,4 Hz, 2H), 4.40 (br s, 2H), 3.33 - 3.29 (m, 2H), 2.84 (s, 6H).[000380] EXAMPLES 150 -152 were prepared following the procedure set forth in Example 149 and using the general reactions schemes and intermediates described herein.TABLE 6Characterization of EXAMPLES 150-152EXAMPLE 1535-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(l-((tetrahydrofuran-2-yl)methyl)-lH- pyrazol-3-yl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000381] To a solution of tert-butyl (2-cyano-8-(lH-pyrazol-3-yl)imidazo[l,2-c]pyrimidin-5-yl)((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (30.0 mg, 57.4 pmol, 1.00 eq.) in DMF (1.00 mL) was added sodium hydride (4.59 mg, 115 pmol, 60.0% purity, 2.00 eq.) at 0 °C. The mixture was stirred at 0 °C for 30 min prior to the dropwise addition of 2-(bromomethyl)tetrahydrofuran (11.5 mg, 69.7 pmol, 1.21 eq.). The mixture was allowed to stir for 3 h and was quenched with water (10.0 mL) and extracted with ethyl acetate (20.0 mLx 2). The combined organic layer was washed with water (20.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give title compound 5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)-8-(l-((tetrahydrofuran-2-yl)methyl)-lH-pyrazol-3-yl)imidazo[l,2-c]pyrimidine-2- carbonitrile (12.2 mg, 26.5 pmol, 46.2% yield, 99.8% purity) as a white solid. LCMS [M + 1]: 460.3. ’H NMR (400MHz, DMSO-d6) 5 =8.92 (s, 1H), 8.48 (t, J=5.2 Hz, 1H), 8.30 (s, 1H), 7.77 (d, .7=2,4 Hz, 1H), 7.06 (d, .7=2.4 Hz, 1H), 6.99 - 6.91 (m, 1H), 6.71 (dd, J=3.6, 8.4 Hz, 1H), 4.73 (d, J=4.8 Hz, 2H), 4.55 (t, .7=8,8 Hz, 2H), 4.24 - 4.18 (m, 3H), 3.80 - 3.72 (m, 1H), 3.68 - 3.60 (m, 1H), 3.30 (t, .7=8,4 Hz. 2H), 2.01- 1.88 (m, 1H), 1.84 - 1.70 (m, 2H), 1.69 - 1.57 (m, 1H).[000382] EXAMPLE 154 was prepared following the procedure set forth in Example 153 and using the general reactions schemes and intermediates described herein.TABLE 7Characterization of EXAMPLE 154EXAMPLE 155 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile[000383] To a solution of tert-butyl (8-bromo-2-cyanoimidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)carbamate (200 mg, 410 pmol, 1.00 eq.) in acetonitrile (4.50 mL) was added periodic acid (345 mg, 1.52 mmol, 345 pL, 3.70 eq.) and chromium trioxide (90.1 mg, 901 pmol, 2.20 eq.). The mixture was stirred at 15 °C for 3 h. The reaction mixture was filtered through a plug of Celite. The filtrate was diluted with water (3.00 mL) and extracted with ethyl acetate (5.00 mL x 3). The combined organic phase was washed with aqueous sodium sulfite solution (2.00 mL), brine (2.00 mL), dried over anh sod sulfate, filtered, and concentrated to provide the crude material. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 10 / 1 to 5: 1) to give tert-butyl (8-bromo-2-cyanoimidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-3-oxo-2,3-dihydrobenzofuran-4- yl)methyl)carbamate (114 mg, 227 pmol, 18.5% yield) as a colorless oil. LCMS [M+l]: 503.8.[000384] 'H NMR (400MHz, CDCl3-d) 5 = 8.09 (s, 1H), 7.70 (s, 1H), 7.24 (t, .7=9,4 Hz, 1H), 6.99 (dd, .7=3.6, 9.2 Hz, 1H), 5.34 (s, 2H), 4.47 (s, 2H), 1.34 (s, 9H).

[0100] A mixture of tert-butyl (8-bromo-2-cyanoimidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-3-oxo-2,3- dihydrobenzofuran-4-yl)methyl)carbamate (114 mg, 227 pmol, 1.00 eq.), 1, 3-dimethyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (101 mg, 454 pmol, 2.00 eq.), Pd(dppf)C12 (16.6 mg, 22.7 pmol, 0.10 eq.) and sodium bicarbonate (38.1 mg, 454 pmol, 2.00 eq.) in dioxane (1.50 mL) and water (0.30 mL) was purged with nitrogen and subsequently stirred at 95 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 3: 1) to afford tert-butyl (2-cyano-8-(l,3-dimethyl-lH-pyrazol-5-yl)imidazo[l,2- c]pyrimidin-5-yl)((5-fluoro-3-oxo-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (40.0 mg, 77.3 pmol, 34.1% yield) as a yellow oil. LCMS [M+l]: 518.4.[000385] To a solution of tert-butyl (2-cyano-8-(l,3-dimethyl-lH-pyrazol-5-yl)imidazo[l,2-c]pyrimidin- 5-yl)((5-fluoro-3-oxo-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (40.0 mg, 77.3 pmol, 1.00 eq.) in dichloromethane (0.30 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol, 0.10 mL, 17.5 eq.). The mixture was stirred at 15 °C for 30 min and was subsequently concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2.00 mL) and washed with sat sodium bicarbonate (1.00 mL) and brine (1.00 mL). The organic phase was dried, filtered and concentrated to give 8-(l,3-dimethyl-lH-pyrazol-5 -y 1) -5 -(((5 -fluoro-3 -oxo-2,3 -dihydrobenzofuran-4-yl)methyl)amino)imidazo [ 1 ,2-c]pyrimidine- 2-carbonitrile (30.0 mg, 71.9 pmol, 93.0% yield) as a brown solid. LCMS [M+l]: 418.1.[000386] To a solution of 8-(2,5-dimethylpyrazol-3-yl)-5-[(5-fluoro-3-oxo-benzofuran-4- yl)methylamino]imidazo[l,2-c]pyrimidine-2-carbonitrile (30.0 mg, 71.9 pmol, 1.00 eq.) in methanol (0.50 mb) was added sodium borohydride (5.44 mg, 144 pmol, 2.00 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 h prior to being quenched with water (0.10 mL). The mixture was purified by prep-HPLC to give title compound 8 -( 1 ,3 -dimethyl- lH-pyrazol-5 -y 1) -5 -(((5 -fluoro-3 -hydroxy-2,3 -dihydrobenzofuran- 4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (6.52 mg, 15.5 pmol, 21.6% yield, 99.7% purity) as an off-white solid. LCMS [M+l]: 420.2.[000387] 'HNMR (400MHz, MeOD-d4) 5 = 8.59 (br s, 1H), 7.80 (s, 1H), 7.12 - 6.97 (m, 1H), 6.78 (dd, .7=3.6, 8.8 Hz, 1H), 6.25 (s, 1H), 5.68 (br d, J=6.0 Hz, 1H), 5.05 (br d, .7=14.6 Hz, 1H), 4.56 (br dd, .7=6.0, 10.4 Hz, 2H), 4.44 (br d, .7=10.4 Hz, 1H), 3.71 (s, 3H), 2.27 (s, 3H).EXAMPLE 1565-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(l-methyl-2-oxo-l,2-dihydropyridin-3- yl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000388] To a solution of tert-butyl (2-cyano-8-(2-oxo-l,2-dihydropyridin-3-yl)imidazo[l,2- c]pyrimidin-5 -yl)((5 -fluoro-2, 3 -dihydrobenzofuran -4-yl)methyl)carbamate (45.0 mg, 89.6 pmol, 1.00 eq.) in DMF (0.50 mL) was added potassium carbonate (24.8 mg, 179 pmol, 2.00 eq.) at 0 °C. The mixture was stirred at 0 °C for 30 min prior to the dropwise addition of methyl iodide (15.3 mg, 107 pmol, 6.69 pL, 1.20 eq.). The mixture was stirred at 0 °C for 1 hour followed by being quenched with saturated ammonium chloride (1.50 mL). The mixture was extracted with ethyl acetate (2.00 mL x3) and the combined organic phase was washed with brine (2.00 mLx2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl (2-cyano-8-(l-methyl-2-oxo-l,2-dihydropyridin-3- yl)imidazo [ 1 ,2-c]pyrimidin-5 -y 1) (( 5 -fluoro-2, 3 -dihydrobenzofuran-4-yl)methyl)carbamate (30.0 mg, 62.2% yield, 96.0% purity) as a yellow solid. LCMS [M+l]: 517.4.[000389] To a solution of tert-butyl (2-cyano-8-(l-methyl-2-oxo-l,2-dihydropyridin-3-yl)imidazo[l,2- c]pyrimidin-5-yl)((5 -fluoro-2, 3 -dihydrobenzofuran -4-yl)methyl)carbamate (30.0 mg, 55.8 pmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (380 mg, 3.33 mmol, 247 pL, 59.8 eq.). The mixture was stirred at 25 °C for 1 h prior to being filtered and concentrated under reduced pressure to provide the crude residue. The crude material was purified by prep-HPLC to give title compound 5- (((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(l-methyl-2 -oxo-1, 2-dihydropyridin-3- yl)imidazo[l,2-c]pyrimidine-2-carbonitrile (16.8 mg, 71.3% yield, 98.5% purity) as a white solid.LCMS [M+l]: 417.3. 'H NMR (400MHz, DMSO-t / 6) 5 = 8.90 (s, 1H), 8.58 (s, 1H), 8.49 (t,J=5.2 Hz, 1H), 8.31 (dd, J=2.0, 7.2 Hz, 1H), 7.75 (dd, J=2.0, 6.4 Hz, 1H), 6.99 - 6.91 (m, 1H), 6.71 (dd, J=4.0, 8.8 Hz, 1H), 6.40 (t, .7=6.8 Hz, 1H), 4.73 (d, J=5.2 Hz, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.53 (s, 3H), 3.33 - 3.28 (m, 2H).EXAMPLES 157 - 184[000390] EXAMPLES 157 -184 were prepared following the procedure set forth in EXAMPLE 87 and using the general reactions schemes and intermediates described herein.TABLE 8Characterization of EXAMPLES 157 - 184EXAMPLES 193 and 194[000391] EXAMPLES 193 and 194 were prepared following the procedure set forth in EXAMPLE 142 and using the general reactions schemes and intermediates described herein.TABLE 9Characterization of EXAMPLES 193 and 194EXAMPLES 195 -202[000392] EXAMPLES 195 -202 were prepared following the procedure set forth in EXAMPLE 149 and using the general reactions schemes and intermediates described herein.TABLE 10Characterization of EXAMPLES 195 - 202EXAMPLE 203 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(l,2,3,4-tetrahydroisoquinolin-6- yl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000393] A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carbonitrile (70.0 mg, 180 pmol, 1.00 equiv), tert-butyl 6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,4-dihydro-lH-isoquinoline-2 -carboxylate (97.2 mg, 270 pmol, 1.50 equiv), sodium bicarbonate (30.3 mg, 361 pmol, 14.0 pL, 2.00 equiv), Pd(dppf)C12 (13.2 mg, 18.0 pmol, 0.10 equiv) in dioxane (1.00 mL) and water (0.30 mL) was purged with nitrogen and then stirred at 100 °C for 2 h. The reaction was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 2 / 1) to afford tert-butyl 6-(2-cyano-5-(((5-fhioro-2,3-dihydrobenzofuran- 4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate (67.0 mg, 124 pmol, 68.7% yield) as a yellow solid.[000394] 'H NMR (400MHz, CD3OD) 5 = 8.61 (s, 1H), 7.98 (s, 1H), 7.69 (s, 1H), 7.67 (br d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.87 (t, J=9.2 Hz, 1H), 6.66 (dd, J=4.0, 8.8 Hz, 1H), 4.83 (br s, 2H), 4.63 - 4.58 (m, 4H), 3.70 (brt, J=6.0 Hz, 2H), 3.38 (brt, J=8.8 Hz, 2H), 2.94 (br t, J=6.0 Hz, 2H), 1.53 (s, 9H). [000395] To a solution of tert-butyl 6-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate (50.0 mg, 92.5 pmol, 1.00 equiv) in dichloromethane (1.00 mL) was added trifluoroacetic acid (10.6 mg, 92.5 pmol, 6.85 pL, 1.00 equiv), the mixture was stirred at room temperature for 0.5 h. The mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (hydrochloric acid conditions) to afford 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8- (l,2,3,4-tetrahydroisoquinolin-6-yl)imidazo[l,2-c]pyrimidine-2-carbonitrile hydrochloride salt (12.4 mg, 25.7 pmol, 27.8% yield, 98.6% purity) as a yellow solid. LC-MS [M+l]: 441.1. 'H NMR (400MHz, DMSO-t / 6) 5 = 9.43 (br s, 2H), 9.08 (s, 1H), 8.77 (br s, 1H), 8.10 (s, 1H), 7.86 (br d, J=8.4 Hz, 1H), 7.84 (br s, 1H), 7.31 (br d, J=7.6 Hz, 1H), 6.94 (br t, J=9.6 Hz, 1H), 6.70 (br dd, J=3.6, 8.4 Hz, 1H), 4.73 (br d, J=4.4 Hz, 2H), 4.54 (brt, J=8.8 Hz, 2H), 4.30 (br s, 2H), 3.30 - 3.27 (m, 2H), 3.26 - 3.19 (m, 2H), 3.09 (br d, .7=5.2 Hz, 2H).[000396] EXAMPLE 204 was prepared following the procedure set forth in EXAMPLE 193 and using the general reactions schemes and intermediates described herein.TABLE 11Characterization of EXAMPLE 194EXAMPLE 2065-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(4-(2-methoxyethoxy)-2- methylphenyl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000397] To a solution of (4-hydroxy-2-methyl-phenyl)boronic acid (30.5 mg, 201 pmol, 1.40 equiv), tert-butyl (8 -bromo-2-cyanoimidazo [ 1 ,2-c]pyrimidin-5 -y 1) (( 5 -fluoro-2,3 -dihydrobenzofuran-4- yl)methyl)carbamate (70.0 mg, 143 pmol, 1.00 equiv) in dioxane (1.00 mL) and water (0.20 mL) were added Pd(dppf)C12 (10.5 mg, 14.3 pmol, 0.10 equiv) and sodium bicarbonate (24.1 mg, 286 pmol, 2.00 equiv) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 2 h and subsequently wasconcentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiCL, petroleum ether / ethyl acetate = 1 / 1) to afford tert-butyl (2-cyano-8-(4-hydroxy-2-methylphenyl)imidazo[l,2- c]pyrimidin-5 -yl)((5 -fluoro-2, 3 -dihydrobenzofuran -4-yl)methyl)carbamate (70.0 mg, 136 pmol, 94.7% yield) as a yellow solid. LCMS [M+l]: 516.1. 'HNMR (400MHz, DMSO-r / 6) 5 = 9.64 (s, 1H), 8.71 (s, 1H), 7.99 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.82 - 6.74 (m, 2H), 6.72 (dd, J=2.4, 8.4 Hz, 1H), 6.62 (dd, .7=4.0, 8.8 Hz, 1H), 5.04 (s, 2H), 4.54 (t, J=8.8 Hz, 2H), 3.30 - 3.26 (m, 2H), 2.02 (s, 3H), 1.34 (s, 9H). [000398] To a solution tert-butyl (2-cyano-8-(4-hydroxy-2-methylphenyl)imidazo[l,2-c]pyrimidin-5- yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (70.0 mg, 135 pmol, 1.00 equiv), 1-chloro- 2-methoxy-ethane (51.4 mg, 543 pmol, 49.4 pL, 4.00 equiv) in acetonitrile (1.00 mL) was added potassium carbonate (37.5 mg, 272 pmol, 2.00 equiv). The mixture was stirred at 85 °C for 12 h. The mixture was concentrated in vacuo to afford tert-butyl (2-cyano-8-(4-(2-methoxyethoxy)-2- methylphenyl)imidazo [ 1 ,2-c]pyrimidin-5 -yl)((5 -fluoro-2, 3 -dihydrobenzofuran-4-yl)methyl)carbamate (30.0 mg, crude) as a gray solid. LCMS [M+l]: 574.6.[000399] To a solution of tert-butyl (2-cyano-8-(4-(2-methoxyethoxy)-2-methylphenyl)imidazo[l,2- c]pyrimidin-5-yl)((5 -fluoro-2, 3 -dihydrobenzofuran -4-yl)methyl)carbamate (25.0 mg, 43.6 pmol, 1.00 equiv) in dichloromethane (1.00 mL) was added trifluoroacetic acid (0.30 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (neutral conditions) to afford 5-[(5-fluoro-2,3 -dihydrobenzofuran-4- yl)methylamino]-8-[4-(2-methoxyethoxy)-2-methyl-phenyl]imidazo[l,2-c]pyrimidine-2 -carbonitrile (6.50 mg, 13.7 pmol, 31.5% yield, 99.9% purity) as a gray solid. LCMS [M+l]: 474.4. ’H NMR (400MHz, DMSO-t / 6) 5 = 8.89 (s, 1H), 8.39 (br s, 1H), 7.65 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.99 - 6.92 (m, 1H), 6.90 (d, .7=2.4 Hz, 1H), 6.83 (dd, .7=2.8, 8.4 Hz, 1H), 6.71 (dd, .7=4.0, 8.8 Hz, 1H), 4.71 (br d, J=3.6 Hz, 2H), 4.55 (t, J=8.8 Hz, 2H), 4.18 - 4.10 (m, 2H), 3.70 -3.66 (m, 2H), 2.12 (s, 3H).EXAMPLE 2078-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile[000400] A mixture of tert-butyl (2-cyano-8-(4-((dimethylamino)methyl)-2-methylphenyl)imidazo[l,2- c]pyrimidin-5-yl)((5 -fluoro-2, 3 -dihydrobenzofuran -4-yl)methyl)carbamate (200 mg, 359 pmol, 1.00 equiv), chromium trioxide (53.9 mg, 539 pmol, 20.0 pL, 1.50 equiv) and periodic acid (221 mg, 970 pmol, 221 pL, 2.70 equiv) in acetonitrile (1.00 mL ) was stirred at room temperature for 2 h. The mixturewas filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (trifluoroacetic acid conditions) to afford tert-butyl (2-cyano-8-(4-((dimethylamino)methyl)-2- methylphenyl)imidazo [ 1 ,2-c]pyrimidin-5 -y 1) ( (5 -fluoro-3 -oxo-2,3 -dihydrobenzofuran-4- yl)methyl)carbamate (30.0 mg, 48.9 pmol, 13.6% yield, 93.0% purity) as a white solid. LCMS [M+l]: 571.3.[000401] A mixture of tert-butyl (2-cyano-8-(4-((dimethylamino)methyl)-2-methylphenyl)imidazo[l,2- c]pyrimidin-5-yl)((5-fluoro-3-oxo-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (30.0 mg, 52.6 pmol, 1.00 equiv) and trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 257 equiv) in dichloromethane (3.00 mL) was stirred at room temperature for 1 h. The mixture was fdtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (trifluoroacetic acid conditions) to afford 8-(4- ((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-3-oxo-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (20.0 mg, 31.0 pmol, 59.0 % yield, 90.6% purity, trifluoroacetic acid salt) as a purple solid. LC-MS [M+l] : 471.1. ’H NMR (400MHz, DMSO-r / 6) 5 = 9.64 (br s, 1H), 8.85 (s, 1H), 8.33 (t, .7=4.4 Hz, 1H), 7.72 (s, 1H), 7.65 (t, J=9.2 Hz, 1H), 7.48 - 7.38 (m, 3H), 7.34 (dd, J=3.2, 8.8 Hz, 1H), 5.05 (d, J=4.4 Hz, 2H), 4.91 (s, 2H), 4.30 (br s, 2H), 2.79 (br s, 6H), 2.21 (s, 3H).[000402] A mixture of 8-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-3-oxo-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (10.0 mg, 21.3 pmol, 1.00 equiv) and sodium borohydride (1.61 mg, 42.5 pmol, 2.00 equiv) in methyl alcohol (1.00 mL) was stirred at 0 °C for 2.5 h. The mixture was concentrated under reduced pressure to give a residue. The mixture was purified by prep-HPLC (neutral conditions) to afford 8-(4-((dimethylamino)methyl)-2- methylphenyl)-5-(((5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carbonitrile (3.69 mg, 7.80 pmol, 36.7% yield, 99.9% purity) as an off-white solid. LC- MS [M+l]:473.4.EXAMPLE 208 5-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)- N,l-dimethyl-lH-pyrazole-3-carboxamide[000403] To a solution of 5-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-l-methyl-lH-pyrazole-3-carboxylic acid (150 mg, 346 pmol, 1.00 equiv), DIEA (135 mg, 1.04 mmol, 182 pL, 3.02 equiv) and methylamine (2 M in THF, 519.16 pL, 3.00 equiv) in DMF (1.50 mL) was added HATU (200 mg, 526 pmol, 1.52 equiv). Themixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (5.00 mL) and filtered to afford the crude product. The crude product was triturated with methanol (5.00 mL) and collected by filtration to provide 5-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-N,l-dimethyl-lH-pyrazole-3-carboxamide (130 mg, 256 pmol, 74.0% yield, 88.0% purity) as a yellow solid. A portion (40 mg) of the material was purified by prep-HPLC (neutral conditions) to give 5-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-N, l-dimethyl-lH-pyrazole-3-carboxamide (8.4 mg, 17.5 pmol, 22.2% yield, 93.0% purity) as a white solid. LCMS [M+l]: 447.2.1H NMR (400MHz, DMSO-t / 6) 5 = 8.92 (s, 1H), 8.12 (d, .7=4.8 Hz, 1H), 7.94 (s, 1H), 6.95 (t, J=9.6 Hz, 1H), 6.81 (s, 1H), 6.71 (dd, .7=4.0, 8.8 Hz, 1H), 4.73 (s, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.83 (s, 3H), 3.30 - 3.32 (m, 2H), 2.76 (d, J=4.8 Hz, 3H).EXAMPLE 2095-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(l-methyl-3-(morpholine-4-carbonyl)- lH-pyrazol-5-yl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000404] To a solution of 5-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-l-methyl-lH-pyrazole-3-carboxylic acid (50.0 mg, 115 pmol, 1.00 equiv) and morpholine (20.00 mg, 229 pmol, 20.2 pL, 1.99 equiv) in DMF (1.00 mL) was added HATU (83.0 mg, 173 pmol, 1.50 equiv) and DIEA (45.0 mg, 348 pmol, 60.7 pL, 3.02 equiv). The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (15.0 mL) and extracted with dichloromethane (10.0 mL x3). The combined organic layer was washed with water (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral conditions) to afford 5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)-8-(l-methyl-3-(morpholine-4-carbonyl)-lH-pyrazol-5- yl)imidazo[l,2-c]pyrimidine-2-carbonitrile (6.10 mg, 11.6 pmol, 10.0% yield, 95.3% purity) as a white solid. LCMS [M+l]: 503.2. 'H NMR (400MHz, DMSO-t / 6) 5 = 8.92 (s, 1H), 7.94 (s, 1H), 6.95 (t, J=9.6 Hz, 1H), 6.77 (s, 1H), 6.71 (dd, J=4.0, 8.8 Hz, 1H), 4.73 (s, 2H), 4.55 (t, J= 8.8 Hz, 2H), 4.02 (s, 2H), 3.81 (s, 3H), 3.63 (s, 6H), 3.32 - 3.30 (m, 2H).EXAMPLE 210 8-(3-((dimethylamino)methyl)-l-methyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile[000405] To a solution of 5 -(2-cyano-5 -(((5 -fluoro-2,3 -dihydrobenzofuran-4- yl)methyl)amino)imidazo[ 1 ,2-c ] py rim idin-8-y 1 )-N, N, 1 -trimethyl- lH-pyrazole-3-carboxamide (100 mg, 217 pmol, 1.00 equiv) in THF (1.00 mL) was added di-tert-butyl dicarbonate (56.9 mg, 261 pmol, 59.9 pL, 1.20 equiv) and DMAP (2.65 mg, 21.7 pmol, 0.10 equiv). The mixture was stirred at 60 °C for 4 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to afford tert-butyl (2-cyano-8- (3 -(dimethylcarbamoyl)- 1 -methyl- lH-pyrazol-5 -yl)imidazo [ 1 ,2-c]pyrimidin-5 -y 1) ( (5 -fluoro-2,3 - dihydrobenzofuran-4-yl)methyl)carbamate (80.0 mg, 143 pmol, 65.7% yield) as an off-white solid. LCMS [M+l]: 561.6. ' H NMR (400MHz, CDC13) 5 = 8.07 (s, 1H), 7.84 (s, 1H), 7.00 (s, 1H), 6.74 - 6.65 (m, 1H), 6.64 - 6.56 (m, 1H), 5.14 (s, 2H), 4.60 (t, J=8.8 Hz, 2H), 3.95 (s, 3H), 3.42 (s, 3H), 3.34 (brt, .7=8.8 Hz, 2H), 3.14 (s, 3H), 1.43 (s, 9H).[000406] To a flame dried RBF charged with tert-butyl (2-cyano-8-(3-(dimethylcarbamoyl)-l-methyl- lH-pyrazol-5-yl)imidazo[l,2-c]pyrimidin-5-yl)((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (30.0 mg, 53.5 pmol, 1.00 equiv) was added dichloromethane (1.00 mL) followed by trifluoromethanesulfonic anhydride (30.2 mg, 107 pmol, 17.7 pL, 2.00 equiv). The resultant solution was stirred at room temperature under an atmosphere of nitrogen for 30 min followed by the addition diethyl 2,6-dimethyl-l,4-dihydropyridine -3, 5 -dicarboxylate (54.2 mg, 214 pmol, 4.00 equiv). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to give a residue. The residue was purified by prep-TLC (SiC>2, dichloromethane / methanol = 10 / 1) to afford tert-butyl (2- cyano-8-(3-((dimethylamino)methyl)-l-methyl-lH-pyrazol-5-yl)imidazo[l,2-c]pyrimidin-5-yl)((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)carbamate (30.0 mg) as a light yellow solid. LCMS [M+l]: 547.3.[000407] A mixture of tert-butyl (2-cyano-8-(3-((dimethylamino)methyl)-l-methyl-lH-pyrazol-5- yl)imidazo [ 1 ,2-c]pyrimidin-5 -y 1) (( 5 -fluoro-2,3 -dihydrobenzofuran-4-yl)methyl)carbamate (30.0 mg, 54.9 pmol, 1.00 equiv) in trifluoroacetic acid (0.30 mL) and dichloromethane (1.00 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (neutral conditions) to afford 8-(3-((dimethylamino)methyl)-l-methyl-lH-pyrazol-5-yl)-5- (((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (2.50 mg,5.46 pmol, 9.96% yield, 97.6% purity) as a yellow solid. LCMS [M+l]: 447.2. 'H NMR (400MHz, CD3OD) 5 = 8.63 (s, 1H), 7.91 (s, 1H), 6.94 - 6.83 (m, 1H), 6.67 (dd, J=4.0, 8.8 Hz, 1H), 6.48 (s, 1H), 4.60 (t, .7=8,8 Hz, 2H), 3.80 (s, 3H), 3.56 (s, 2H), 3.40 (br t, J=8.8 Hz, 2H), 2.33 (s, 6H).EXAMPLE 2115-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(l-methyl-3-((methylamino)methyl)-lH- pyrazol-5-yl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000408] To a solution of 5-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo [ 1 ,2 -c] pyrimidin-8 -yl)- V, 1 -dimethyl- 1 H-pyrazole -3 -carboxamide (80.0 mg, 157 pmol, 1.00 equiv) in THF (1.50 mL) was added di-tert-butyl dicarbonate (41.3 mg, 189 pmol, 1.20 equiv) and DMAP (2.06 mg, 16.9 pmol, 0.10 equiv). The mixture was stirred at 60 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=3 / l to 1 / 1) to afford tert-butyl (2-cyano-8- ( 1 -methyl-3 -(methylcarbamoyl)- lH-pyrazol-5 -yl)imidazo [ 1 ,2-c]pyrimidin-5 -y 1) ( (5 -fluoro-2,3 - dihydrobenzofuran-4-yl)methyl)carbamate (50.0 mg, 91.5 pmol, 58.0% yield) as a yellow solid. LCMS [M+l]: 547.2.[000409] To a flame-dried 10 mL round-bottom flask was added tert-butyl (2-cyano-8-(l-methyl-3- (methylcarbamoyl)-lH-pyrazol-5-yl)imidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)carbamate (25.0 mg, 45.7 pmol, 1.00 equiv) followed by dichloromethane (1.80 mL) and 2- fluoropyridine (9.80 mg, 101 pmol, 8.67 pL, 2.21 equiv). The solution was then cooled to -78 °C and stirred for 10 min. To this solution was added dropwise Tf2O (27.1 mg, 96.1 pmol, 15.9 pL, 2.10 equiv) and the reaction was stirred for an additional 10 min. The solution was warmed at 0 °C and the reaction was stirred for 10 min. To this solution was added dropwise EtsSiH (11.7 mg, 101 pmol, 16.07 pL, 2.20 equiv) and the reaction was stirred for 10 min. The solution was allowed to warm to room temperature and was stirred for 5 h. To the mixture was added diethyl l,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate (34.8 mg, 137.2 pmol, 3.00 equiv) and the yellow suspension was stirred for 12 h at room temperature. The reaction mixture was concentrated to give a residue. The residue was purified by prep-TLC (SiC>2, dichloromethane / methanol = 10 / 1) to give partially pure material. This material was purified by prep-HPLC (HC1 conditions) to afford 5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)-8-(l-methyl-3-((methylamino)methyl)-lH-pyrazol-5-yl)imidazo[l,2-c]pyrimidine-2- carbonitrile hydrochloride salt (2.50 mg, 5.75 pmol, 12.6% yield, 99.4% purity) as an off-white solid. LCMS [M+l]: 433.2. ' H NMR (400MHz, CD3OD) 5 = 8.65 (s, 1H), 7.90 (s, 1H), 6.91 - 6.81 (m, 1H),6.65 (dd, .7=4.0, 8.8 Hz, 1H), 6.58 (s, 1H), 4.63 - 4.54 (m, 2H), 4.26 - 4.19 (m, 2H), 3.82 (s, 3H), 3.42 - 3.35 (m, 2H), 3.32 (s, 2H), 2.77 (s, 3H).EXAMPLE 2128-(3-cyano-l-methyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile[000410] To a solution of 5-[2-cyano-5-[(5-fluoro-2,3-dihydrobenzofuran -4- yl)methylamino]imidazo[l,2-c]pyrimidin-8-yl]-l-methyl-pyrazole-3-carboxylic acid (100 mg, 185 pmol, 1.00 equiv) and ammonium chloride (30.0 mg, 561 pmol, 3.04 equiv) in DMF (2.00 mL) was added HATU (105 mg, 276 pmol, 1.50 equiv) and DIEA (72.0 mg, 557 pmol, 97.0 pL, 3.02 equiv). The mixture was stirred at room temperature for 3 h. The mixture was diluted with water (20.0 mL) at which time a precipitate formed. The solid was fdtered and dried under reduced pressure to give the crude product. The crude product was triturated with methanol (10.0 mL) and fdtered to afford 5-(2-cyano-5- (((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-l-methyl-lH- pyrazole -3 -carboxamide (44 mg) as a yellow solid that was used into the next step without further purification. LC-MS [M+l]: 433.1.[000411] To a mixture of 5-(2-cyano-5-(((5-fhroro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-l-methyl-lH-pyrazole-3-carboxamide (44.0 mg, 102 pmol, 1.00 equiv), TEA (206 mg, 2.04 mmol, 283 pL, 20.0 equiv) in anhydrous THF (0.50 mL) was added TFAA (192 mg, 916 pmol, 127 pL, 9.00 equiv) at 0 °C with stirring. The resulting mixture was warmed to room temperature and stirred for 12 h. The reaction mixture was concentrated to give a residue. The residue was purified by prep-TLC (SiCL, petroleum ether / ethyl acetate = 1 / 1). The obtained material was purified again by prep-HPLC (hydrochloric acid conditions) to give 8-(3-cyano-l-methyl- lH-pyrazol-5-yl)-5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2- carbonitrile (6.10 mg, 14.6 pmol, 14.4% yield, 99.3% purity) as a white solid. LC-MS [M+l]: 415.2. ’H NMR (400MHz, CD3OD) 5 = 8.63 (s, 1H), 7.93 (s, 1H), 7.34 (s, 1H), 6.97 (s, 1H), 6.85 (t, J=9.6 Hz, 1H), 6.65 (dd, J=3.6, 8.8 Hz, 1H), 4.76 ( s, 2H), 4.58 (t, J=8.8 Hz, 2H), 3.89 (s, 3H), 3.39 (brt, J=8.8 Hz, 2H).EXAMPLES 213 and 214 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl-4-(pyrrolidin-2- yl)phenyl)imidazo[l,2-c]pyrimidine-2-carbonitrile[000412] A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carbonitrile (255 mg, 657 pmol, 1.00 equiv), tert-butyl 2-[3-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine -1 -carboxylate (280 mg, 723 pmol, 1.10 equiv), Pd(dppf)C12 (48.1 mg, 65.7 pmol, 0.10 equiv) and sodium bicarbonate (166 mg, 1.97 mmol, 76.7 pL, 3.00 equiv) in dioxane (3.00 mL) and water (0.60 mL) was purged with nitrogen and then stirred at 95 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, petroleum ether / ethyl acetate = 1 / 1) to afford tert-butyl 2-(4-(2- cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-3- methylphenyl)pyrrolidine-l -carboxylate (160 mg, 38.7% yield, 90.4% purity) as a yellow solid. ’HNMR (400MHz, CD3OD) 5 = 8.61 (s, 1H), 7.69 (s, 1H), 7.26 (br d, J=7.6 Hz, 1H), 7.15 (s, 1H), 7.10 (br d, .7=7,6 Hz, 1H), 6.92 - 6.84 (m, 1H), 6.70 - 6.62 (m, 1H), 4.82 - 4.75 (m, 1H), 4.62 - 4.56 (m, 4H), 3.65 - 3.60 (m, 2H), 3.39 (t, J=8.8 Hz, 2H), 2.40 (br s, 1H), 2.20 (s, 3H), 2.0 - 1.80 (m, 3H), 1.49 (br s, 3H), 1.31 - 1.23 (m, 6H).[000413] Chiral SFC separation of tert-butyl 2-(4-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)-3-methylphenyl)pyrrolidine-l-carboxylate provided enantiomerically pure intermediates A and B.[000414] To a solution of A or B (60.0 mg, 105 pmol, 1.00 equiv) was added TFA (2.31 g, 20.3 mmol, 1.50 mL, 192 equiv). The mixture was stirred at room temperature for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, dichloromethane / methanol = 10 / 1) to afford 5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)-8-(2-methyl-4-(pyrrolidin-2-yl)phenyl)imidazo[l,2-c]pyrimidine-2 -carbonitrile. [000415] EXAMPLE 213: (18.06 mg, 34.6 % yield, 94.6 % purity), LCMS [M+l]: 469.1, (Amycoat 50x4.6mm I.D., 3 pm; 30% MeOH (0.05% DEA) in CO2; 3 mL / min; tr= 1.32 min).[000416] 'HNMR (400MHz, CD3OD) 5 = 8.60 (s, 1H), 7.68 (s, 1H), 7.35 (s, 1H), 7.28 (s, 2H), 6.85 (t, J=9.2 Hz, 1H), 6.64 (dd, J=4.0, 8.8 Hz, 1H), 4.81 (s, 2H), 4.57 (t, J=8.8 Hz, 2H), 4.20 (dd, J=7.2, 8.8 Hz, 1H), 3.40 - 3.35 (m, 2H), 3.29 - 3.24 (m, 1H), 3.11 - 3.03 (m, 1H), 2.37 - 2.26 (m, 1H), 2.19 (s, 3H), 2.09 - 1.95 (m, 2H), 1.94 - 1.82 (m, 1H).[000417] EXAMPLE 214: (18.1 mg, 35.7 pmol, 33.8% yield, 92.4% purity), LCMS [M+l]: 469.1, (Amycoat 50x4.6mm I.D., 3 pm; 30% MeOH (0.05% DEA) in CO2; 3 mL / min; tr= 3.22 min).[000418] 'HNMR (400MHz, CD3OD) 5 = 8.61 (s, 1H), 7.69 (s, 1H), 7.38 (s, 1H), 7.32 (d, J=0.8 Hz, 2H), 6.89 - 6.82 (m, 1H), 6.64 (dd, J=4.0, 8.8 Hz, 1H), 4.81 (s, 2H), 4.58 (t, 7=8.8 Hz, 2H), 4.42 - 4.36 (m, 1H), 3.40 - 3.35 (m, 2H), 3.27 - 3.20 (m, 1H), 2.45 - 2.35 (m, 1H), 2.21 (s, 3H), 2.19 - 2.12 (m, 1H), 2.11 - 1.98 (m, 2H).EXAMPLE 215 5-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-8- yl)picolinic acid[000419] A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carbonitrile (39.0 mg, 100 pmol, 1.00 equiv), tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-2 -carboxylate (73.6 mg, 121 pmol, 1.20 equiv), sodium bicarbonate (25.3 mg, 301 pmol, 3.00 equiv) and Pd(dppf)C12 (7.35 mg, 10.1 pmol, 0.10 equiv) in dioxane (1.00 mL) and water (0.20 mL) was purged with nitrogen and stirred at 95 °C for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiC dichloromethane / methyl alcohol = 10 / 1) to afford tert-butyl 5-(2-cyano-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)picolinate (50.0 mg, 60.0 pmol, 59.8% yield, 58.4% purity) as a yellow solid. LC-MS [M+l]: 487.4. 'H NMR (400MHz, DMSO-t / 6) 5 = 9.30 (d, 7=1.6 Elz, 1H), 8.97 (s, 1H), 8.77 (t, J=5.2 Hz, 1H), 8.63 (dd,J=2.4, 8.0 Hz, 1H), 8.68 - 8.59 (m, 1H), 8.36 (s, 1H), 8.09 (d, 7=8.0 Hz, 1H), 6.99 - 6.92 (m, 1H), 6.71 (dd, 7=4.0, 8.8 Hz, 1H), 4.77 (br d, 7=4.4 Hz, 2H), 4.55 (brt, 7=8.8 Hz, 2H), 3.31 - 3.29 (m, 2H), 1.59 (s, 9H).[000420] A mixture of tert-butyl 5-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)picolinate (50.0 mg, 103 pmol, 1.00 equiv) and trifluoroacetic acid (3.85 g, 33.8 mmol, 2.50 mL, 329 equiv) in dichloromethane (0.50 mL) was stirred at 25 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (basic conditions) to afford 5-(2-cyano-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)picolinic acid (6.73 mg, 15.4 pmol, 15.0% yield, 98.4% purity) as a yellow solid. LC-MS [M+l]: 431.3. 'H NMR (400MHz, DMSO-76) 5 = 9.25 (br s, 1H), 8.98 (s, 1H), 8.48 (br d, J=9.6 Hz, 1H), 8.27 (br s, 1H), 8.05 (br d, 7=8.4 Hz, 1H), 7.01 - 6.92 (m, 1H), 6.71 (dd, 7=4.0, 8.8 Hz, 1H), 4.77 (s, 2H), 4.55 (t, 7=8.8 Hz, 2H), 3.26 - 3.24 (m, 2H).EXAMPLE 2168-(2-((dimethylamino)methyl)pyrimidin-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile[000421] To a solution of tert-butyl ((5-(2-cyano-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-8-yl)pyrimidin-2-yl)methyl)carbamate (90.0 mg, 156 pmol, 1.00 equiv) in DCM (2.00 mL) was added TFA (890 mg, 7.81 mmol, 578 pL, 50.0 equiv). The mixture was stirred at room temperature for 1 h prior to concentration under reduced pressure. The residue was diluted with saturated sodium bicarbonate aqueous solution and subsequently filtered to provide 8-[2- (aminomethyl)pyrimidin-5 -yl] -5 -[(5 -fluoro-2, 3 -dihydrobenzofuran -4-yl)methylamino]imidazo [1,2- c]pyrimidine-2 -carbonitrile (75.0 mg, 147 pmol, 93.9% yield, 81.4% purity) as a purple solid. LCMS [M+l]: 417.0.[000422] To a solution of 8-[2-(aminomethyl)pyrimidin-5-yl] -5-[(5-fluoro-2,3-dihydrobenzofuran-4- yl)methylamino]imidazo[l,2-c]pyrimidine-2-carbonitrile (65.0 mg, 127 pmol, 1 equiv) in MeOH (0.60 mL) was added paraformaldehyde (11.5 mg, 381 pmol, 10.5 pL, 3.00 equiv) and CH3COOH (1 drop). The mixture was stirred at 60 °C for 1 h and then cooled to room temperature. To the resultant mixture was added NaBHsCN (24.0 mg, 381 pmol, 3.00 equiv). After 1 h, the mixture was filtered and concentrated in vacuo to provide a residue. The residue was purified by prep-HPLC (basic conditions) to afford 8-(2-((dimethylamino)methyl)pyrimidin-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile (2.16 mg, 4.19 pmol, 3.3% yield, 86.3% purity) as a yellow gum. LCMS [M+l]: 445.1. 'H NMR (400MHz, DMSO-6) 5 = 9.36 (s, 2H), 8.97 (s, 1H), 8.75 (br s, 1H), 8.32 (s, 1H), 6.96 (t, 7=8.8 Hz, 1H), 6.71 (dd, 7=4.0, 8.8 Hz, 1H), 4.76 (br s, 2H), 4.55 (t, 7=8.8 Hz, 2H), 3.70 (s, 2H), 3.31 - 3.28 (m, 2H), 2.28 (s, 6H).EXAMPLE 217 8-(3-(2-(dimethylamino)ethyl)phenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile[000423] A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2- c]pyrimidine-2 -carbonitrile (50.0 mg, 129 pmol, 1.00 equiv), [3-(2-hydroxyethyl)phenyl]boronic acid (32.1 mg, 193 pmol, 1.50 equiv), sodium bicarbonate (32.5 mg, 386 pmol, 3.00 equiv) and Pd(dppf)C12 (9.42 mg, 12.9 pmol, 0.10 equiv) in dioxane (2.00 mL) and water (0.40 mL) was purged with nitrogen and subsequently allowed to stir at 100 °C for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane / methanol=10 / l) to afford 5- (((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(3-(2-hydroxyethyl)phenyl)imidazo[l,2- c]pyrimidine-2 -carbonitrile (38.0 mg, 87.6 pmol, 68.0% yield, 99.0% purity) as a yellow solid. LC-MS [M+l]: 430.2. 'HNMR (400MHz, CDC13) 5 = 7.97 (s, 1H), 7.90 (s, 1H), 7.74 (br s, 2H), 7.44 (t, 7=8.0 Hz, 1H), 7.30 - 7.28 (m, 1H), 6.87 (t, J=9.6 Hz, 1H), 6.69 (dd, J=4.0, 8.4 Hz, 1H), 5.43 (s, 1H), 4.84 (d, J=5.6 Hz, 2H), 4.65 (t, 7=8.8 Hz, 2H), 3.94 (t, 7=6.4 Hz, 2H), 3.44 (t, 7=8.8 Hz, 2H...

Claims

CLAIMSWE CLAIM:

1. A method of treating sickle cell disease in a subject, comprising administering to the subject a therapeutically effective amount of an inhibitor of polycomb repressive complex 2 (PRC2), wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has: a. been administered hydroxyurea; and / or b. been administered a stable dose of one or more of voxelotor, crizanlizumab, and L- glutamine; and wherein the inhibitor of polycomb repressive complex 2 (PRC2) is a compound selected from the group consisting of:

2. The method of claim 1, wherein the inhibitor of poly comb repressive complex 2 (PRC2) is aThe method of claim 1, wherein the inhibitor of poly comb repressive complex 2 (PRC2) is thepharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has further experienced: a. one or more of (i) continued vaso-occlusive crisis (VOC) events or episodes of acute chest syndrome (ACS) for at least 6 months while being administered hydroxyurea at the maximum tolerated dose; (ii) an inability to tolerate the adverse effects of the continued administration to the subject of hydroxyurea; (iii) unmanageable drug -drug interactions as a result of the continued administration to the subject of hydroxyurea; and (iv) the subject’s refusal to continue the further administration of hydroxyurea; or b. one or more of (i) continued pain crisis events and other vaso-occlusive crisis (VOC) events while on a stable dose of voxelotor, crizanlizumab, or L-glutamine for at least 6 months; (ii) a failure to increase hemoglobin (Hb) by 1 g / dL in a subject receiving voxelotor; (iii) continued vaso-occlusive crisis (VOC) events in a subject receiving crizanlizumab or L-glutamine; (iv) an inability to tolerate the adverse effects of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; (v) unmanageable drug -drug interactions as a result of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; and (vi) the subject’s refusal to continue the further administration of voxelotor, crizanlizumab, or L-glutamine.

5. The method of claim 4, wherein prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has further experienced one or more of (i) continued vaso-occlusive crisis (VOC) events or episodes of acute chest syndrome (ACS) for at least 6 months while being administered hydroxyurea at the maximum tolerated dose; (ii) an inability to tolerate the adverse effects of the continued administration to the subject of hydroxyurea; (iii) unmanageable drug-drug interactions as a result of the continued administration to the subject of hydroxyurea; and (iv) the subject’s refusal to continue the further administration of hydroxyurea.

6. The method of claim 4, wherein prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has further experienced one or more of (i) continued pain crisis events and other vaso-occlusive crisis (VOC) events while on a stable dose of voxelotor, crizanlizumab, or L-glutamine for at least 6 months; (ii) a failure to increase hemoglobin (Hb) by 1 g / dL in a subject receiving voxelotor; (iii) continued vaso-occlusive crisis (VOC) events in a subject receiving crizanlizumab or L-glutamine; (iv) an inability to tolerate the adverse effects of the continued administration to the subject of voxelotor, crizanlizumab, or L- glutamine; (v) unmanageable drug-drug interactions as a result of the continued administration to the subject of voxelotor, crizanlizumab, or L-glutamine; and (vi) the subject’s refusal to continue the further administration of voxelotor, crizanlizumab, or L-glutamine.

7. The method of claim 1, wherein the subject has been administered hydroxyurea prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2).

8. The method of claim 7, wherein in the 6-month period prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has further experienced one or more of (a) the same or higher number of pain crises or other vaso-occlusive crisis (VOC) events compared to the prior to the 6-month period; (b) episodes of acute chest syndrome (ACS); (c) an inability to tolerate continued administration of hydroxyurea; (d) unmanageable drug-drug interactions with the continued administration of hydroxyurea; and (e) the subject’s refusal to continue the further administration of hydroxyurea.

9. The method of claim 1, wherein the subject has been administered one or more of voxelotor, crizanlizumab, and L-glutamine prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2).

10. The method of claim 9, wherein the subject has been administered voxelotor prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2).

11. The method of claim 9, wherein the subject has been administered crizanlizumab prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2).

12. The method of claim 9, wherein the subject has been administered L-glutamine prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2).

13. The method claim 1, wherein prior to the administration to the subject of the inhibitor of poly comb repressive complex 2 (PRC2) the subject has further experienced one or more of: a. 4 or more vaso-occlusive crisis (VOC) events over the prior 12-month period; b. 2 or more vaso-occlusive crisis (VOC) events over the prior 6-month period; c. 2 or more vaso-occlusive crisis (VOC) events over the prior 12-month period and at least one of one or more acute chest syndrome (ACS) events, hepatic and splenic sequestration, and priapism; d. 2 or more acute chest syndrome (ACS) events, hepatic and splenic sequestration, and priapism over the prior 12-month period; e. pulmonary hypertension; and f. chronic kidney disease.

14. The method of claim 1, wherein the subject is not concurrently administered the inhibitor of polycomb repressive complex 2 (PRC2) and hydroxyurea, voxelotor, crizanlizumab, or L- glutamine.

15. The method of claim 1, wherein in the 60-day period prior to the administration to the subject of the inhibitor of polycomb repressive complex 2 (PRC2) the subject has not been administered one or more of hydroxyurea, voxelotor, crizanlizumab, and L-glutamine.

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