PRC2 INHIBITORS FOR USE IN TREATING BLOOD DISORDERS

CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63/248,238 filed September 24, 2021, 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 blood disorders, including sickle cell disease and thalassemia.

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.

SUMMARY OF THE DISCLOSURE

[0004] In one embodiment is provided a method of treating a blood disorder in a subject, comprising administering to the subject a therapeutically effective amount of 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, CR ¹¹ , CR ⁿ OH, or C(R ⁿ )2, wherein: when X is O, is a single bond; when X is C(R ⁿ )2’ is a single bond; when X is CR ⁿ OH, is a single bond; or when X is CR ¹¹ , is a double bond;

R ¹ is aryl, heteroaryl, -L-cycloalkyl, or -L-heterocyclyl, wherein the aryl, and the heteroaryl and cyclyl portions of the -L-cycloalkyl and -L-heterocyclyl are optionally substituted with one or more R ⁴ ;

R ² is -C(R ^5a R ^5b )R ⁷ or heteroaryl;

R ³ is C1-C3 alkyl or halogen; each R ⁴ is independently cyano, halogen, alkoxy, hydroxyl, hydroxyalkyl, -P(O)(OCi-C3 alkyl)2, - COOR ¹¹ , aralkyl, heteroalkyl, haloalkyl, -Y ² -haloalkyl; -YLCi-Ce alkyl, -Y ² -Ci-Ce alkyl, -L- cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -YLheterocyclyl, -L-N(R ⁿ )2, -O-L-N(R ⁿ )2, - C(CF3)N(R ⁿ )2, -Y ¹ -N(R ¹¹ )2 or -Y ² -N(R ⁿ )2 wherein the ring of the -L-cycloalkyl, -L-heteroaryl, -L- heterocyclyl and -YLheterocyclyl is optionally substituted with one or more R ⁹ ;

L is a bond or C1-C4 alkylene;

Y ¹ is a bond, -C(O)-, or -NHC(O)-;

Y ² is a bond, -S-, -SO-, -SO2-, or -NR ⁵ SO2-;

R ^5a and R ^5b are each independently hydrogen, C1-C3 alkyl, haloalkyl, cycloalkyl or aryl, wherein at least one of R ^5a or R ^5b is hydrogen;

R ⁶ is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl;

R ⁷ is -NR ^8a R ^8b wherein R ^8a and R ^8b together with the nitrogen atom to which each is attached form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing 1, 2 or 3 heteroatoms selected from -O-, -N-, or -S- and optionally substituted with one or more R ¹⁰ ; or

R ⁷ is -OR ^8a or -N(R ^8a )2 wherein each R ^8a is independently hydrogen, C1-C3 alkyl, cycloalkyl, aralkyl or halosulfonylalkyl; each R ⁹ is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R ⁿ )2, Ci-Ce alkyl or -YLheterocyclyl, wherein the -Y ¹ -heterocyclyl is optionally substituted with one or more R ¹⁰ ; each R ¹⁰ is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R ¹¹ is independently hydrogen or C1-C3 alkyl; and n is 1 or 2.

[0005] In another embodiment is provided a method of treating a blood disorder in a subject by administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein the blood disorder is selected from Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia, APL), Amyloidosis, Anemia, Aplastic anemia, Bone marrow failure syndromes, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Deep vein thrombosis (DVT), Diamond-Blackfan anemia, Dyskeratosis congenita (DKC), Eosinophilic disorder, Essential thrombocythemia, Fanconi anemia, Gaucher disease, Hemochromatosis, Hemolytic anemia, Hemophilia, Hereditary spherocytosis, Hodgkin's lymphoma, Idiopathic thrombocytopenic purpura (ITP), Inherited bone marrow failure syndromes, Iron-deficiency anemia, Langerhans cell histiocytosis, Large granular lymphocytic (LGL) leukemia, Leukemia, Leukopenia, Mastocytosis, Monoclonal gammopathy, Multiple myeloma, Myelodysplastic syndromes (MDS), Myelofibrosis, Myeloproliferative neoplasms (MPN), Non-Hodgkin's lymphoma, Paroxysmal nocturnal hemoglobinuria (PNH), Pernicious anemia (Bl 2 deficiency), Polycythemia vera, Porphyria, Post-transplant lymphoproliferative disorder (PTLD), Pulmonary embolism (PE), Shwachman-Diamond syndrome (SDS), sickle cell disease (SCD), Thalassemia (e.g., .beta.-thalassemia), Thrombocytopenia, Thrombotic thrombocytopenic purpura (TTP), Venous thromboembolism, Von Willebrand disease, and Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma).

[0006] In another embodiment is provided a method of treating a blood disorder in a subject by administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein the blood disorder is sickle cell disease.

[0007] In another embodiment is provided a method of treating a blood disorder in a subject by administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein the blood disorder is thalassemia. In one embodiment, the thalassemia is alpha thalassemia. In another embodiment, the thalassemia is beta thalassemia.

[0008] Also provided herein is a use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of PRC2.

[0009] Also provided herein is the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a blood disorder.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0010] 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.

[0011] 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). [0012] 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.

[0013] As used herein, “EED” refers to the embryonic ectoderm development protein subunit of the PRC2 complex.

[0014] As used herein, “EZH2” or “EZH2 enzyme” refers to a mammalian histone methyltransferase, which is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), and functions to silence target genes by tri -methylating lysine 27 of histone H3 (H3K27me3).

[0015] As used herein, a “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 PRC2 enzymatic activity by binding to EED to prevent assembly of the PRC2 complex on histone H3 tails thereby inhibiting its activity.

[0016] A “PRC2-associated disease or disorder” as used herein refers to diseases or disorders associated with or mediated by or having an activating EZH2 mutation and/or aberrant expression of PRC2. A non-limiting example of an PRC2 -associated disease or disorder is a PRC2-associated blood disorder.

[0017] The term “amino” refers to -NH2.

[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, C9, 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, C9, 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, C9, 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, C9, 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 NR ^X , wherein R ^x is hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxy ethyl and methoxypropyl.

[0027] An “aryl” group is a Ce-Cw aromatic moiety comprising one to three aromatic rings. As such, “aryl” includes Ce, C10, 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-C6)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, NR ⁵ , 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-C3 - 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 1471 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 non-aromatic, 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] As used herein, “amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition” refers to any lessening, whether permanent or temporary, lasting, or transient, that can be attributed to or associated with administration of the composition.

COMPOUNDS

[0043] In one embodiment is provided a method of treating a blood disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof: wherein: represents a single or a double bond;

Z is O or S;

X is O, CR ¹¹ , CR ⁿ OH, or C(R ⁿ )2, wherein: when X is O, is a single bond; when X is C(R ⁿ )2, is a single bond; when X is CR ⁿ OH, is a single bond; or when X is CR ¹¹ , is a double bond;

R ¹ is aryl, heteroaryl, -L-cycloalkyl, or -L-heterocyclyl, wherein the aryl, and the heteroaryl and cyclyl portions of the -L-cycloalkyl and -L-heterocyclyl are optionally substituted with one or more R ⁴ ;

R ² is -C(R ^5a R ^5b )R ⁷ or heteroaryl;

R ³ is alkyl or halogen; each R ⁴ is independently cyano, halogen, alkoxy, hydroxyl, hydroxyalkyl, -P(O)(OCi -C3 alkyl)2, -

COOR ¹¹ , aralkyl, heteroalkyl, haloalkyl, -Y ² -haloalkyl; -YLCi-Ce alkyl, -Y ² -Ci-Ce alkyl, -L- cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Y'-hctcrocyclyl. -L-N(R ⁿ )2, -O-L-N(R ⁿ )2, - C(CF3)N(R ⁿ )2, -Y ¹ -N(R ¹¹ )2 or -Y ² -N(R ⁿ )2 wherein the ring of the -L-cycloalkyl, -L-heteroaryl, -L- heterocyclyl and -Y'-hctcrocyclyl is optionally substituted with one or more R ⁹ ;

L is a bond or C1-C4 alkylene;

Y ¹ is a bond, -C(O)-, or -NHC(O)-;

Y ² is a bond, -S-, -SO-, -SO2-, or -NR ⁵ SO2-;

R ^5a and R ^5b are each independently hydrogen, C1-C3 alkyl, haloalkyl, cycloalkyl or aryl, wherein at least one of R ^5a or R ^5b is hydrogen;

R ⁶ is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl;

R ⁷ is -NR ^8a R ^8b wherein R ^8a and R ^8b together with the nitrogen atom to which each is attached form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing 1, 2 or 3 heteroatoms selected from -O-, -N-, or -S- and optionally substituted with one or more R ¹⁰ ; or

R ⁷ is -OR ^8a or -N(R ^8a )2 wherein each R ^8a is independently hydrogen, C1-C3 alkyl, cycloalkyl, aralkyl or halosulfonylalkyl; each R ⁹ is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R ⁿ )2, Ci-Ce alkyl or -Y'-hctcrocyclyl. wherein the -Y'-hctcrocyclyl is optionally substituted with one or more R ¹⁰ ; each R ¹⁰ is independently oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R ¹¹ is independently hydrogen or C1-C3 alkyl; and n is 1 or 2.

[0044] In one embodiment, Z is O.

[0045] In one embodiment, X is C(R ⁿ )2 and is a single bond.

[0046] In one embodiment, Z is O or S. In one embodiment, X is O, CR ¹¹ , CR ⁿ OH or C(R ⁿ )2, wherein when X is O, is a single bond; when X is C(R ⁿ )2, is a single bond; when X is CR ⁿ OH, is a single bond; or when X is CR ¹¹ , is a double bond. In one embodiment, n is one. In one embodiment, n is two.

[0047] In one embodiment, Z is O, X is O, n is one and is a single bond. In another embodiment, Z is O, X is CR11 and is a double bond. In one embodiment, Z is O, X is C(R11)2, n is one, and is a single bond. In one embodiment, Z is O, X is CR11OH, n is one, and is a single bond. In another embodiment, Z is O, X is C(R11)2, n is two, and is a single bond. In yet another embodiment, Z is S, X is C(R11)2, n is one, and is a single bond.

[0048] In one embodiment for compounds of Formula (I), R1 is aryl, which is optionally substituted with one or more R4. In certain embodiments, the aryl is phenyl, which is optionally substituted with one or more R4. In one embodiment, the one or more R4 are each independently halogen, hydroxyl, haloalkyl, -COOR11, -Y1-C1-C6 alkyl, -Y2-C1-C6 alkyl, -L-N(R11)2, -O-L-N(R11)2, -

C(CF3)N(R11)2, -Y1-N(R11)2, -Y2-N(R11)2, -Y2-haloalkyl, -L-heterocyclyl, or -Y l-heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl and -Y l-heterocyclyl is optionally substituted with one or more R9. [0049] In one embodiment, R4 is -Y1-C1-C6 alkyl and Y1 is a bond and the Cl - C6 alkyl is methyl, ethyl, isopropyl, butyl or pentyl.

[0050] In one embodiment, R4 is -L-N(R11)2 and L is methylene or ethylene and each R11 is hydrogen, each R11 is methyl or one R11 is methyl and one R11 is hydrogen.

[0051] In one embodiment for compounds of Formula (I), the aryl is substituted with a single R4 group. In one embodiment, the aryl is substituted with two R4 groups. In one embodiment, the aryl is substituted with three R4 groups. Exemplary aryl R4 groups include halogen, hydroxyl, haloalkyl, -Y1-C1-C6 alkyl, -Y2-C1-C6 alkyl, -L-N(R11)2, -Y1-N(R11)2, -Y2-N(R11)2, -Y2-haloalkyl, -L-heterocyclyl, or -Y l-heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl, or -Y l-heterocyclyl is optionally substituted with one or more R9.

[0052] In one embodiment for compounds of Formula (I), R1 is phenyl substituted with -Y2-C1-C6 alkyl. In one embodiment, Y2 is a bond and the C1-C6 alkyl is methyl, ethyl or isopropyl. In one embodiment, R1 is phenyl substituted with the -Y2-C1-C6 alkyl, wherein Y2 is -SO2- and the Cl- C6 alkyl is methyl. In one embodiment, R1 is phenyl, which is disubstituted with methyl and -Y2-C1-C6 alkyl, wherein Y2 is -SO2- and the Cl- C6 alkyl is methyl.

[0053] In one embodiment for compounds of Formula (I), R1 is phenyl substituted one R4, wherein R4 is a cyano group.

[0054] In one embodiment for compounds of Formula (I), R1 is phenyl substituted one R4, wherein R4 is -L-heteroaryl. In certain embodiments, the -L-heteroaryl is tetrazolyl. In one embodiment, R1 is phenyl substituted one R4, wherein R4 is -P(O)(OC1 -C3 alkyl)2. In one embodiment, R1 is phenyl substituted one R4, wherein R4 is -COOR11. In one embodiment, R1 is phenyl substituted one R4, wherein R4 is - O-L-N(R11)2. In one embodiment, R1 is phenyl substituted one R4, wherein R4 is aralkyl.

[0055] In one embodiment for compounds of Formula (I), R1 is phenyl substituted with at least one R4, wherein R4 is -L-N(R11)2. In one embodiment, L is a bond. In one embodiment, L is methylene. In one embodiment, each R11 is independently hydrogen. In one embodiment, each R11 is independently Cl- C3 alkyl. In one embodiment, each C1-C3 alkyl is methyl. In one embodiment, one R11 is C1-C3 alkyl and the other is hydrogen. In one embodiment, the one C1-C3 alkyl is methyl. In one embodiment, R1 is phenyl substituted with -L-N(R11)2 and further substituted with one or more halogen and/or C1-C6 alkyl.

[0056] In one embodiment for compounds of Formula (I), R1 is phenyl substituted with one R4, wherein R4 is -Y1-N(R11)2. In certain embodiments, Y1 is -C(O)- and each R11 is C1-C3 alkyl. In one embodiment, each C1-C3 alkyl is methyl. In one embodiment, Y 1 is -C(O)- and each R11 is hydrogen. In one embodiment, Y 1 is -C(O)- and one R11 is C1-C3 alkyl and the other is hydrogen. In one embodiment, the one C1-C3 alkyl is methyl. In one embodiment, R1 is phenyl substituted with -Yl- N(R11)2 and further substituted with one or more halogen and/or C1-C6 alkyl.

[0057] In one embodiment for compounds of Formula (I), R1 is phenyl substituted with -Y2-haloalkyl, wherein Y2 is -S- or -SO2- and the haloalkyl is trifluoromethyl. [0058] In one embodiment for compounds of Formula (I), R1 is phenyl substituted with at least one -L- heterocyclyl or -Yl-heterocyclyl, each heterocyclyl optionally substituted with one or more R9. In one embodiment, R1 is phenyl substituted with one R4, wherein R4 is -Yl-heterocyclyl optionally substituted with one or more R9. In one embodiment, Y 1 is -C(O)- and the heterocyclyl is piperazinyl optionally substituted with C1-C3 alkyl.

[0059] In certain embodiments for compounds of Formula (I), the R4 group is -L-heterocyclyl optionally substituted with one or more R9. In one embodiment, L is methylene and the heterocyclyl is pyrrolidinyl, piperidinyl, piperazinyl or 4-methyl -piperazinyl. In one embodiment, L is methylene and the heterocyclyl is azetinidyl, pyrrolidinyl, piperidinyl, piperazinyl, piperazinone, tetrahydropyranyl, morpholinyl, thiomorpholinyl or diazapanyl, each optionally substituted with one or more R9. Exemplary R9 groups include oxo, halogen, hydroxyalkyl and C1-C3 alkyl.

[0060] In one embodiment for compounds of Formula (I), R1 is phenyl substituted with -Yl- heterocyclyl optionally substituted with one or more 97. In certain embodiments, Y 1 is -C(O)- and the heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or 4-methyl-piperazinyl, each optionally further substituted with one or more halogen.

[0061] In one embodiment for compounds of Formula (I), R1 is phenyl substituted with -L-heteroaryl optionally substituted with one or more R9. In certain embodiments, the -L-heteroaryl is tetrazolyl.

[0062] In one embodiment for compounds of Formula (I), R1 is phenyl substituted with -P(O)(OC1-C3 alkyl)2. In another embodiment, R1 is phenyl substituted with -COOR11. In one embodiment, R1 is phenyl substituted with hydroxyalkyl, -O-L-N(R11)2 or aralkyl.

[0063] In one embodiment for compounds of Formula (I), R1 is heteroaryl, which is optionally substituted with one or more R4. In certain embodiments, R1 is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthyridinyl, 1,2,3,4-tetrahydroisoquinolinyl, or 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, each optionally substituted with one or more R4. In certain embodiments, the heteroaryl is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, or 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazolyl, each of which is optionally substituted with one or more R4.

[0064] In one embodiment for compounds of Formula (I), the heteroaryl is substituted with a single R4 group. In one embodiment, the heteroaryl is substituted with two R4 groups. In one embodiment, the heteroaryl is substituted with three R4 groups. Exemplary heteroaryl R4 groups include amino, cyano, halogen, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -Y2-haloalkyl -Y1-C1-C6 alkyl, -Y2-C1-C6 alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, -Yl-heterocyclyl, -L-N(R11)2, or -Y1-N(R11)2, wherein the ring of the -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl and -Yl-heterocyclyl is optionally substituted with one or more R9.

[0065] In one embodiment for compounds of Formula (I), R9 is amino, hydroxyl, cyano, alkoxy, or halogen. In one embodiment, R7 is C1-C3 alkyl. In one embodiment, R9 is halogen, wherein the halogen is fluorine or chlorine. In one embodiment, R9 is alkoxy, wherein the alkoxy is methoxy or ethoxy. In one embodiment, R9 is cycloalkyl, wherein the cycloalkyl is cyclopropyl.

[0066] In another embodiment for compounds of Formula (I), R1 is heteroaryl and each R4 is independently hydroxyalkyl, heteroalkyl or haloalkyl. In certain embodiments, the hydroxyalkyl is hydroxymethyl, hydroxyethyl or 2-methyl, 2-hydroxypropyl. In certain embodiments, the heteroalkyl is methoxymethyl or methoxyethyl. In certain embodiments, the haloalkyl is fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl.

[0067] In certain embodiments for compounds of Formula (I), R1 is heteroaryl and R4 is -Y1-C1-C6 alkyl, wherein Y1 is a bond and the C1-C6 alkyl is methyl, ethyl or isopropyl. In one embodiment, R4 is -Y1-C1-C6 alkyl, wherein Y1 is a -C(O)- and the C1-C6 alkyl is methyl, ethyl or isopropyl. In other embodiments, Y 1 is -NHC(O)- and the C1-C6 alkyl portion is methyl.

[0068] In one embodiment for compounds of Formula (I), R1 is heteroaryl and R4 is -Y2-C1-C6 alkyl, wherein Y2 is -SO2- and the C1-C6 alkyl is methyl. In another embodiment, R4 is -Y2-C1-C6 alkyl, wherein Y2 is -S- and the C1-C6 alkyl is methyl.

[0069] In one embodiment for compounds of Formula (I), R1 is heteroaryl and R4 is -Yl-heterocyclyl, which is optionally substituted with one or more R9. In one embodiment, Y 1 is a bond. In another embodiment, Y1 is -C(O)-. In one embodiment, Y 1 is a bond and the heterocyclyl is azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl or 4-methyl-piperazinyl. In one embodiment, R9 is C1-C3 alkyl. In one embodiment, R9 is halogen.

[0070] In one embodiment for compounds of Formula (I), the heteroaryl is substituted with at least one R4 that is -L-heterocyclyl, which is optionally substituted with one or more R9. In one embodiment, L is ethylene and the heterocyclyl is pyrrolidinyl, piperidinyl, piperazinyl or 4-methyl-piperazinyl. In one embodiment, L is methylene and the heterocyclyl is azetinidyl, pyrrolidinyl, piperidinyl, piperazinyl, piperazinone, tetrahydropyranyl, morpholinyl, thiomorpholinyl or diazapanyl, each optionally substituted with one or more R9.

[0071] In one embodiment, the R9 is independently -L-N(R11)2, hydroxyl, cyano, alkoxy, or halogen. In one embodiment, R9 is C1-C3 alkyl. In one embodiment, R7 is halogen, wherein the halogen is fluorine or chlorine. In one embodiment, R9 is alkoxy, wherein the alkoxy is methoxy or ethoxy. In one embodiment, R9 is cycloalkyl, wherein the cycloalkyl is cyclopropyl. In one embodiment, R9 is -L- N(R11)2. In one embodiment, L is a bond. In one embodiment, L is methylene. In one embodiment, each Rll is independently hydrogen. In one embodiment, each Rll is independently C1-C3 alkyl. In one embodiment, each C1-C3 alkyl is methyl. In one embodiment, one R11 is C1-C3 alkyl and the other is hydrogen. In one embodiment, the one C1-C3 alkyl is methyl.

[0072] In one embodiment for compounds of Formula (I), R1 is heteroaryl and R4 is -L-N(R11)2. In one embodiment, L is a bond. In one embodiment, L is methylene, ethylene, or propylene. In one embodiment, each R11 is independently C1-C3 alkyl. In one embodiment, each C1-C3 alkyl is methyl. In one embodiment, one R11 is C1-C3 alkyl and the other is hydrogen. In one embodiment, the one Cl- C3 alkyl is methyl. In one embodiment, each R11 is independently hydrogen. [0073] In one embodiment for compounds of Formula (I), R1 is heteroaryl and R4 is -L-heteroaryl, which is optionally substituted with one or more R9. In one embodiment, L is a bond. In one embodiment, L is C1-C3 alkylene. In one embodiment, the C1-C3 alkylene is methylene. In certain embodiments, the heteroaryl of the -L-heteroaryl is pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl or pyridazinyl. In one embodiment, the heteroaryl of the -L-heteroaryl is pyridyl.

[0074] In one embodiment for compounds of Formula (I), R1 is heteroaryl which is substituted with two R4 groups independently selected from two -Y1-C1-C6 alkyl groups; -Y1-C1-C6 alkyl and alkoxy; -Yl- CI-C6 alkyl and cycloalkyl; -Y1-C1-C6 alkyl and haloalkyl; -Y1-C1-C6 alkyl and amino; two alkoxy groups; alkoxy and halogen; alkoxy and cyano; and amino and haloalkyl. In certain embodiments, R4 is - Y1-C1-C6 alkyl, wherein each Y1 is a bond and each C1-C6 alkyl is methyl, ethyl or isopropyl. In one embodiment, the cycloalkyl is cyclopropyl. In one embodiment, the alkoxy is methoxy. In one embodiment, the halogen is fluorine or chlorine. In one embodiment, the haloalkyl is trifluoromethyl or trifluoroethyl.

[0075] In one embodiment for compounds of Formula (I), R1 is -L-heterocyclyl optionally substituted with one or more R4. In one embodiment, L is a bond and the heterocyclyl is tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl. In one embodiment, L is a methylene and the heterocyclyl is azetidinyl, pyrrolidinyl or 3X2-azabicyclo[3.1.0]hexanyl. In certain embodiments, the heterocyclyl is substituted with one or more R4 selected from oxo, halogen, alkoxy, hydroxyl and -Y1-C1-C6 alkyl, wherein Y is a bond or -C(O)-.

[0076] In one embodiment for compounds of Formula (I), R2 is -C(R5aR5b)R7. In certain embodiments, R5a is hydrogen and R5b is C1-C3 alkyl, haloalkyl, cycloalkyl or aryl. In other embodiments, R5a is C1-C3 alkyl, haloalkyl, cycloalkyl or aryl and R5b is hydrogen.

[0077] In one embodiment for compounds of Formula (I), R7 is -OR8a. In one embodiment, R8a is hydrogen or C1-C3 alkyl.

[0078] In one embodiment for compounds of Formula (I), R7 is -NR8aR8b. In one embodiment, R8a and R8b are each hydrogen. In another embodiment, R8a is hydrogen and R7b is C1-C3 alkyl, halosulfonylalkyl, cycloalkyl or aralkyl.

[0079] In one embodiment for compounds of Formula (I), R7 is -NR8aR8b, wherein R8a and R8b together with the nitrogen atom to which each is attached form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing 1, 2 or 3 heteroatoms selected from -O-, -N-, or -S- and optionally substituted with one or more R10. In certain embodiments, the 4-8 membered saturated or partially saturated heterocyclyl is azetidinyl or 3-hydroxy-azetidinyl.

[0080] In one embodiment for compounds of Formula (I), R2 is heteroaryl. In certain embodiments, the heteroaryl is tetrazolyl, oxazolyl, or oxadiazolyl.

[0081] In one embodiment, n is zero. In one embodiment, n is one and R3 is halogen. In certain embodiments, the halogen is fluorine or chlorine. In one embodiment, the halogen is fluorine. [0082] In one embodiment, R6 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl. In certain embodiments, R6 is hydrogen. In other embodiments, R6 is methyl, ethyl, or propyl.

[0083] In one embodiment, the cyclyl portion of R4 group is substituted with one R9 group. In certain embodiments, R9 is oxo, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L- N(R11)2 or C1-C3 alkyl. In certain embodiments, R9 is C1-C3 alkyl, wherein the C1-C3 alkyl is methyl, ethyl or isopropyl. In certain embodiments, R9 is halogen, wherein the halogen is fluorine or chlorine. In certain embodiments, R9 is oxo.

[0084] In one embodiment, the cyclyl portion of R4 group is substituted with two R9 groups. In certain embodiments, the two R9 groups are each halogen, wherein each halogen is fluorine.

[0085] It is understood that in the compounds of Formula (I), when represents a single bond, there are two R6 present and each is independently selected from the groups set forth herein. It is further understood that in the compounds of Formula (I), when represents a single bond, there is one R6 present selected from the groups set forth herein.

[0086] In one embodiment, the compound is: PHARMACEUTICAL COMPOSITIONS

[0087] In another aspect, the disclosure provides pharmaceutical compositions comprising a PRC2 inhibitor according to the disclosure and a pharmaceutically acceptable carrier, excipient, or diluent for use in the treatment of a blood disorder 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. In certain embodiments, compounds of the disclosure are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be by the oral route.

[0088] 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.

[0089] 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).

[0090] 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.

[0091] The pharmaceutical compositions comprising compounds of the present disclosure may be used in the methods described herein.

METHODS OF USE

[0092] In one embodiment is provided a method of treating a blood disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) as disclosed herein.

[0093] In another embodiment is provided a method of treating a blood disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) as disclosed herein, wherein the blood disorder is selected from Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia, APL), Amyloidosis, Anemia, Aplastic anemia, Bone marrow failure syndromes, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Deep vein thrombosis (DVT), Diamond-Blackfan anemia, Dyskeratosis congenita (DKC), Eosinophilic disorder, Essential thrombocythemia, Fanconi anemia, Gaucher disease, Hemochromatosis, Hemolytic anemia, Hemophilia, Hereditary spherocytosis, Hodgkin's lymphoma, Idiopathic thrombocytopenic purpura (ITP), Inherited bone marrow failure syndromes, Iron-deficiency anemia, Langerhans cell histiocytosis, Large granular lymphocytic (LGL) leukemia, Leukemia, Leukopenia, Mastocytosis, Monoclonal gammopathy, Multiple myeloma, Myelodysplastic syndromes (MDS), Myelofibrosis, Myeloproliferative neoplasms (MPN), Non-Hodgkin's lymphoma, Paroxysmal nocturnal hemoglobinuria (PNH), Pernicious anemia (Bl 2 deficiency), Polycythemia vera, Porphyria, Posttransplant lymphoproliferative disorder (PTLD), Pulmonary embolism (PE), Shwachman-Diamond syndrome (SDS), sickle cell disease (SCD), Thalassemia (e.g., .beta.-thalassemia), Thrombocytopenia, Thrombotic thrombocytopenic purpura (TTP), Venous thromboembolism, Von Willebrand disease, and Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma).

[0094] In another embodiment, the blood disorder is sickle cell disease.

[0095] In another embodiment, the blood disorder is thalassemia. In one embodiment, the thalassemia is alpha thalassemia. In another embodiment, the thalassemia is beta thalassemia.

[0096] In another embodiment is provided any of the methods disclosed herein, wherein the method results in induction of fetal hemoglobin expression in erythroid cells.

[0097] In another embodiment is provided any of the methods disclosed herein, wherein the method results in upregulation of mRNA levels of fetal hemoglobin protein.

[0098] 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.

[0099] The concentration and route of administration to the subject will vary depending on the blood disorder to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti- neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively. 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

[0100] The compounds disclosed herein may be prepared using methods described in United States Patent No. 11,091,495 and/or PCT Application Publication No. WO 2020/247475, 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.

[0101] For instance, intermediates for compounds and compounds of formula (I) of the present disclosure may be prepared according to General Reaction Schemes I - IV:

General Reaction Scheme I

[0102] In General Reaction Scheme I, R ² -ester substituted imidazo[l,2-c]pyrimidine A is coupled to R ³ optionally substituted intermediate amine B by nucleophilic substitution to yield Intermediate C. A boronic acid derivative (Y)-R ¹ D is coupled via a Suzuki reaction with halogen substituted Intermediate C in the presence of a suitable base, e.g., sodium carbonate, and the R ² ester is converted to the alcohol via a reducing agent such as lithium aluminum hydride to generate intermediate alcohol E. The alcohol E is converted to the corresponding aldehyde F via oxidation using a suitable oxidant, e.g., Dess-Martin periodinane, which is then converted to the secondary alcohol by treatment with an organometallic reagent such as a Grignard reagent to form title compound alcohol G. General Reaction Scheme II

[0103] In General Reaction Scheme II, R ² -cyano substituted imidazo[l,2-c]pyrimidine H is coupled to R ³ optionally substituted intermediate amine B by nucleophilic substitution to yield Intermediate I. A boronic acid derivative (Y)-R ¹ D is coupled via a Suzuki reaction with halogen substituted Intermediate I in the presence of a suitable base, e.g., sodium carbonate, and the R ² cyano is converted to the amine via a metal-mediated hydrogenation using hydrogen gas and a suitable metal such as Raney nickel to form title compound amine J.

General Reaction Scheme III

[0104] In General Reaction Scheme III, Intermediate F can undergo a reductive amination reaction with an R ^8a R ^8b optionally substituted Intermediate amine K using an appropriate reducing agent such as sodium triacetoxyborohydride, to form the title compound L.

General Reaction Scheme IV

[0105] In General Reaction Scheme IV, an organometallic reagent, such as an alkyl magnesium halide undergoes nucleophilic addition to R ² -cyano imidazo[l,2-c]pyrimidine I to give the R ¹¹ substituted amine intermediate M. The resultant amine M is protected with an appropriate protecting group, e.g. tert-butyloxycarbonyl to give Intermediate N. The Intermediate N can then be coupled with a boronic acid derivative (Y)-R ¹ D via a Suzuki reaction in the presence of a suitable base, such as sodium carbonate, and the protecting group removed from the resultant product via treatment with a strong acid, e.g. TFA to give the desired title compound O.

[0106] The following Intermediates are intended to illustrate various intermediates that may be used to prepare compounds of the present disclosure and are not intended to limit the scope of the disclosure.

INTERMEDIATE A-l

[0107] 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 mb, 1.52 equiv) in DMF (20.0 mb) 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 fdtration The fdtrate 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.

[0108] ’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).

[0109] 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 uh, 2.50 equiv) in POCh (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 yellow solid.

[0110] ^X 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

[0111] 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[ l,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 filtered 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.

[0112] To a solution of 8-bromo-5-oxo-6H-imidazo[ l,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 m , 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 m ). The precipitate was washed with water 50 mb, filtered and the filtrate was concentrated in vacuo to afford 8-bromo-5-oxo-6H-imidazo[ l,2-c]pyrimidine-2 -carboxamide (1.78 g, 6.92 mmol, 68.7% yield) as a light-yellow solid. EC-MS [M+l]: 257.0.

[0113] To a solution of 8-bromo-5-oxo-6H-imidazo[ l,2-c]pyrimidine-2 -carboxamide (1.70 g, 6.61 mmol, 1.00 equiv) in POCh (20.0 mb) was added DIPEA (4.27 g, 33.1 mmol, 5.76 mb, 5.00 equiv) dropwise at 0 °C. The mixture was stirred at 120 °C for 12 h. The reaction mixture was filtered and concentrated at reduced pressure to provide the crude material. The crude residue was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 10/1 to 4/1) to afford 8-bromo-5-chloro- imidazo[l,2-c]pyrimidine-2 -carbonitrile (950 mg, 3.69 mmol, 55.8% yield) as a light-yellow solid. EC- MS [M+l]: 258.9.

[0114] Alternatively, Intermediate A-2 may be prepared on a large scale as follows:

[0115] To a solution of cytosine (300 g, 2.70 mol, 1.00 equiv) in DMF (1.5 E) 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 ^J H NMR spectrum indicated that the reaction was complete. The reaction mixture was filtered and the filter 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.

[0116] Tf NMR (400MHz, DMSO-d ₆ ) 5 10.80 (br s, 1H), 11.36 - 10.16 (m, 1H), 7.74 (s, 1H), 6.83 (br s, 2H).

[0117] 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 mb, 2.50 equiv) in AcOH (1.5 L) was stirred at 120 °C for 2 h. The crude ¹ 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 filtered. The filter cake was washed with water (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.

[0118] ’H NMR (400MHz, DMSO-d ₆ ) 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).

[0119] To a solution of ethyl 8-bromo-5-oxo-5,6-dihydroimidazo[l,2-c]pyrimidine-2-carboxyl ate (150 g, 524 mmol, 1.00 equiv) in MeOH (1.5 L) was added NaOH (2 M, 786 mb, 3.00 equiv). The mixture was stirred at 65 °C for 2 h at which time the ECMS 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 mb x 4). The solid was collected and dried under vacuum to afford 8-bromo-5-oxo-5,6-dihydroimidazo[l,2-c]pyrimidine-2-carboxyl ic acid (140 g, 543 mmol, 51.7% yield) as a brown solid. LCMS (M+l): 257.9.

[0120] ’H NMR (400MHz, DMSO-d ₆ ) 5 12.86 - 11.28 (m, 1H), 8.27 (s, 1H), 7.73 (s, 1H).

[0121] 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 SOCh (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 fdter 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.

[0122] ’H NMR (400MHz, DMSO-d ₆ ) 5 8.05 (s, 1H), 7.66 (s, 1H), 7.56 (br s, 1H), 7.41 (br s, 1H).

[0123] 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.

[0124] Tf NMR (400MHz, DMSO-d ₆ ) 5 9.19 (s, 1H), 8.36 (s, 1H).

INTERMEDIATE B-l

[0125] 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(R ⁿ )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 was diluted 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.

[0126] ’H NMR (400MHz, CDCI3) 5 = 7.17 - 7.07 (m, 3H), 6.88 - 6.84 (m, 1H), 4.82 (t, J=5.2 Hz, 1H), 3.99 (d. .7=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, J=12 Hz, 6H). [0127] 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.

[0128] ’H NMR (400MHz, CDC1 ₃ ) 5 = 7.70 (s, 1H), 7.67 (d, .7=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, J=1.6, 8.4 Hz, 1H), 7.21 - 7.15 (m, 1H), 6.85 - 6.80 (m, 1H), 6.78 - 6.73 (m, 1H).

[0129] 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(PPh ₃ )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, fdtered, and concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to afford benzofuran-4-carbonitrile (1.60 g, 10.1 mmol, 76.2% yield, 90.0% purity) as a light-yellow oil.

[0130] 1H 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).

[0131] 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 fdtered 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 7V-(2,3- dihydrobenzofuran-4-ylmethyl) carbamate (140 mg, 562 pmol, 11.9% yield) as a colorless oil.

[0132] ’H NMR (400MHz, CDC1 ₃ ) 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).

[0133] 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.

[0134] 1H NMR (400MHz, CDC13) 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 [0135] 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 CR ¹¹ , is a double bond and one R ³ is fluorine. To a mixture of 5-fhiorobenzofuran-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 filtered 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.

[0136] ¹ 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

[0137] 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(R ⁿ )2, is a single bond and one R ³ is 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 filtered and the filtrate 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.

[0138] ’H NMR (400MHz, DMSO-d ₆ ) 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, J=8.8 Hz, 2H), 3.45 (br t, J=8.8 Hz, 2H).

[0139] 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 filtered 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. [0140] 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 mL, 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.

[0141] ³ H NMR (400MHz, DMSO-d ₆ ) 5 =7.87 (br s, 1H), 7.63 (br s, IH), 7.17 (d, J=8.4 Hz, 1H), 6.79 (d, .7=8,4 Hz, 1H), 4.58 (t, J=8.8 Hz, 2H), 3. 18 (t, J=8.8 Hz, 2H). [0142] 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 BH ₃ -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

[0143] 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(R ⁿ )2, is a single bond and one R ³ is 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)-l -fluoro-benzene (171 g, 501 mmol, 95.7% yield, 90.0% purity) as a light-yellow oil. [0144] ³ H NMR (400MHz, CDC1 ₃ ) 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, .7=7,2 Hz. 6H).

[0145] 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(PPh ₃ )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 x 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 -fluorobenzofuran (78 g, crude) as a white solid.

[0146] To a solution of 4-bromo-5-fluoro-benzofuran (87.3 g, 203 mmol, 1.00 equiv) in DMAC (600 mL) was added zinc cyanide (94.6 g, 805 mmol, 3.97 equiv) and Pd(PPh ₃ )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 mL 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.

[0147] ¹ H NMR (400MHz, CDCfi) 5 = 7.84 (d, J=2.0 Hz, 1H), 7.73 - 7.67 (m, 1H), 7.14 (t, J=9.2 Hz, 1H), 7.02 - 6.96 (m, 1H).

[0148] 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-/crt-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.

[0149] ’H NMR (400MHz, CDCI3) 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, .7=8,8 Hz, 2H), 4.30 (br d, .7=6,0 Hz, 2H), 3.30 (br t, J=8.8 Hz, 2H), 1.44 (s, 9H).

[0150] 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.

[0151] ’H NMR (400MHz, CDCI3) 5 = 6.85 - 6.76 (m, 1H), 6.60 (dd, J=4.0, 8.8 Hz, 1H), 4.61 (t, .7=8,8 Hz, 2H), 3.82 (s, 2H), 3.24 (t, J=8.8 Hz, 2H).

[0152] Alternatively, Intermediate B-4 may be prepared on a large scale as follows:

[0153] 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.

[0154] 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 (6.00 L) 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 Na2SC>4, filtered 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 -fluorobenzofuran and 6-bromo-5 -fluorobenzofuran (800 g, 3.72 mol, 71.4% yield) as a brown oil.

[0155] 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(PPh3)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.

[0156] 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(PPh3)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.

[0157] ’H NMR (400MHz, CD ₃ OD) 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).

[0158] 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.

[0159] ’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). [0160] 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 fdter cake was washed by MTBE (100 mL x 2). The fdter 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 -dihydrobenzo furan-4-yl)methanamine (50.0 g, 299 mmol, 79.9% yield) as a brown oil.

[0161] ’H NMR (400MHz, DMSO-d ₆ ) 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

[0162] 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(R ⁿ )2, is a single bond and one R ³ is fluorine. A mixture of 3-bromo-4-fluoro-benzenethiol (4.50 g, 21.7 mmol, 1.00 equiv), 2-bromo- 1,1 -diethoxyethane (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 DMF (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.

[0163] ’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).

[0164] 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.

[0165] ‘H NMR (400 MHz, CDCI3) 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, lH), 7.17 (t, J= 8.8 Hz, 1H).

[0166] 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.

[0167] ‘H NMR (400 MHz, CDCh) 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).

[0168] To a mixture of 5-fluorobenzothiophene-4-carbonitrile (300 mg, 1.69 mmol, 1.00 equiv) in THF (2.00 mL) 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- yljmethanamine (150 mg, 828 pmol, 48.9% yield) as a yellow solid.

INTERMEDIATE B-6

[0169] 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(R ⁿ )2, is a single bond and one R ³ is fluorine.

[0170] 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 (SiCL, Petroleum ether/Ethyl acetate = 10/1 to 4/1) to afford ethyl (£)-3-(2-bromo-6- hydroxy-phenyl)prop-2 -enoate (380 mg, 1.37 mmol, 92.0% yield, 98.0% purity) as a white solid.

[0171] ³ H NMR (400MHz, CD ₃ OD) 5 = 8.02 (d, J=I6.0 Hz, 1H), 7.15 (dd, J=1.2, 8.0 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 6.97 (d, J=I6.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 4.56 (s, 1H), 4.25 (q, J=12 Hz, 2H), 1.33 (t, .7=7,2 Hz. 3H).

[0172] To a solution of ethyl (£)-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, fdtered, and concentrated in vacuo. The crude residue was purified by column chromatography (SiCf. 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. [0173] ’H NMR (400MHz, CDC1 ₃ ) 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=1.2 Hz, 2H), 3.50 (s, 1H), 3.10 - 3.03 (m, 2H), 2.87 - 2.79 (m, 2H), 1.28 - 1.24 (m, 3H).

[0174] 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, fdtered, 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.

[0175] Tf NMR (400MHz, CDCL) 8 = 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).

[0176] 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 PPh ₃ (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, filtered, 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.

[0177] 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 K2CO ₃ (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.

[0178] A mixture of 5-bromochromane (0. 10 g, 469 pmol, 1.00 eq.), Zn(CN) ₃ (110 mg, 939 pmol, 2.00 eq.), Pd(PPh ₃ )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 (SiCL, PE: EA = 10: 1) to afford chromane-5 -carbonitrile (60.0 mg, 377 pmol, 80.3% yield) as a light-yellow oil.

[0179] ^X H NMR (400MHz, CDC1 ₃ ) 8 = 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, J=6A Hz, 2H), 2.16 - 2.02 (m, 2H).

[0180] 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

[0181] A seventh exemplary Intermediate B, Intermediate B-7, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R ⁿ ) ₂ , is a single bond, one R ³ is fluorine and two methylene hydrogens are replaced with deuteriums.

[0182] To a solution of 5-fhiorobenzofuran-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 mb, 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 fdtered and concentrated under vacuum to give 5-fhiorobenzofuran-4-carboxamide (1.80 g, 10.1 mmol, 81.0% yield) as a white solid.

[0183] ¹ H NMR (400 MHz, DMSO-t/e) 5 = 8.11 (d, J=2.0 Hz, 1H), 7.81 (br s, IH), 7.73 (dd, J=4.0, 8.8 Hz, 2H), 7.23 (dd, J=9.2, 10.4 Hz, 1H), 7.10 (d, J=1.2 Hz, 1H).

[0184] 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 fdtered 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.

[0185] ¹ 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, .7=4.0, 8.8 Hz, 1H), 4.54 (t, J=8.8 Hz, 2H), 3.25 (t, J=8.8 Hz, 2H).

[0186] 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 fdtered 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.

[0187] ’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, .7=8,8 Hz, 2H), 3.23 (t, J=8.8 Hz, 2H).

INTERMEDIATE B-8 [0188] An eighth exemplary Intermediate B, Intermediate B-8, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is C(R ⁿ )2, is a single bond, one R ³ is fluorine, two methylene hydrogens and two hydrogens on the benzofuran ring are replaced with deuteriums.

[0189] To a solution of 5-fluorobenzofuran-4-carbonitrile (100 mg, 620 pmol, 1.00 equiv) in methanol-tA (1.00 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)carba mate (45.0 mg, 166 pmol, 26.7% yield) as a white solid.

[0190] ’H NMR (400MHz, CDC1 ₃ ) 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, .7=10.0 Hz, 1H), 3.27 (br d, J=6.8 Hz, 1H), 1.46 - 1.41 (s, 9H).

[0191] To a solution of tert-butyl ((5-fhioro-2,3-dihydrobenzofuran-4-yl-2,3-d2)methyl-d2)carba mate (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

[0192] A ninth exemplary Intermediate B, Intermediate B-9, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is O, is a single bond, and one R ³ is fluorine.

[0193] To a solution of 5 -fluoro- 1,3 -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.

[0194] ³ H NMR (400 MHz, DMSO-t/e) 5 = 10.07 (s, 1H), 7.12 (dd, J=4.4, 8.4 Hz, 1H), 6.72 (dd, .7=8.8, 11.6 Hz, 1H), 6.17 (s, 2H).

[0195] 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.

[0196] ¹ H NMR (400 MHz, DMSO-t/ ₆ ) 5 = 11.68 (s, 1H), 8.08 (s, 1H), 6.91 (br dd. .7=4,0. 8.4 Hz, 1H), 6.77 - 6.65 (m, 1H), 6.12 (s, 2H).

[0197] 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 fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si O2- 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.

[0198] 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 for 0.5 h. The reaction mixture was neutralized with saturated aq potassium carbonate (5.00 mL) and stirred for 30 min. The aqueous phase was extracted with DCM (5.00 mL x 2). The combined organic phase was washed with brine (5.00 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (5-fluorobenzo[d][l,3]dioxol-4-yl)methanamine (45.0 mg, 266 pmol. 84.3% yield) as a yellow oil.

[0199] Tf NMR (400 MHz, CDC1 ₃ ) 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

[0200] 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(R ⁿ )2, is a single bond and one R ³ is 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-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (250.34 mg, 1.50 mmol, 1.20 equiv), DIEA (322 mg, 2.50 mmol, 434 uL, 2.00 equiv) in DMF (3.00 mL) was purged with nitrogen and was stirred at 85 °C for 0.5 h. To this mixture was added water (10.0 mL) and ethyl acetate (8.00 mL). The biphasic mixture was filtered to remove a solid impurity and the organic layer was concentrated in vacuo to provide ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amin o)imidazo[l,2- c] pyrimidine -2 -carboxylate (443 mg, 1.02 mmol, 81.5% yield) as a white solid. [0201] ‘H NMR (400 MHz, DMSO-t/ ₆ ) 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

[0202] 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 CR ¹¹ , is a double bond and one R ³ is fluorine. A mixture of 8-bromo-5-chloro-imidazo[l,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 uL, 2.00 equiv) in DMF (2.00 mL) 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[l,2-c]pyri midine-2-carboxylate (180 mg, 78.2% yield) as abrown solid. LCMS [M+l]: 433.1.

[0203] 1H NMR (400MHz, CD3OD) 5 = 8.63 (s, 1H), 7.92 (s, 1H), 7.80 (d, .7=2,0 Hz, 1H), 7.45 (dd, .7=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, .7=6,8 Hz, 2H), 1.38 (t, .7=7,2 Hz. 3H).

INTERMEDIATE C-3

[0204] 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[l,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 mL) was added DIEA (42.4 mg, 328 pmol, 57.2 uL, 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 mL 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+l] 421.2.

[0205] ’H NMR (400MHz, DMSO-d ₆ ) 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, .7=4,8 Hz, 2H), 4.36 - 4.3 l(m, 2H), 1.33 (t, J=12 Hz, 3H). INTERMEDIATE C-4

[0206] 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(R ⁿ )2, is a single bond and one R ³ is 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 mL) 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

[0207] 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(R ⁿ )2, and is a single bond. To a solution of ethyl 8-bromo-5- chloro-imidazo[ 1, 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 filtered. 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+I] 433.3.

INTERMEDIATE C-4B

[0208] 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(R ⁿ )2, is a single bond and one R ³ is fluorine. To a solution of (5-fluorobenzothiophen-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 mb) was added DIEA (60.2 mg, 466 pmol, 81.2 ph, 3.00 eq.). The reaction mixture was stirred at 85 °C for 1 h. The mixture was diluted with ethyl acetate (10.0 mb), washed with brine (10.0 mb x 2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the crude residue. The crude material was purified by prep-TEC(petroleum ether/ethyl acetate = 1/1) to give 8-bromo-5-((5- fluorobenzo[b]thiophen-4-yl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (35.0 mg, 87.0 pmol, 56.0% yield) as a brown solid. ECMS [M+l]: 404.0.

INTERMEDIATE C-5

[0209] 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(R ⁿ )2, is a single bond and one R ³ is fluorine. A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofiiran-4-yl)methyl)ami no)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-fluoro-2,3-dihydrobenzofiiran-4-yl)methyl)ami no)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.

[0210] A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofiiran-4-yl)methyl)ami no)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 uL, 8 equiv) in DMF (1.00 m ) 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 m ) and the resultant solid was collected by fdtration. 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.

[0211] To a mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofiiran-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 uh, 19.4 equiv) in THF (2.00 mb) was added TFAA (302 mg, 1.44 mmol, 200 uL, 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. LC-MS: [M+l] 387.8.

[0212] Alternatively, Intermediate C-5 may be prepared as follows:

[0213] 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

[0214] 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(R ⁿ )2, is a single bond and one R ³ is fluorine.

[0215] 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 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-TEC (SiO2, petroleum ether/ethyl acetate, 3/1) to afford ethyl 8-bromo-5-((tert-butoxycarbonyl)((5-fluoro-2,3-dihydrobenzof uran-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. EC-MS [M+l]: 537.2. [0216] ’H NMR (400MHz, CDC1 ₃ ) 5 = 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=7.2 Hz, 2H), 3.32 (br t, J=8.8 Hz, 2H), 1.43 (t, .7=7,2 Hz. 3H), 1.36 (s, 9H).

INTERMEDIATE C-7

[0217] 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(R ⁿ )2, is a single bond, one R ³ is fluorine and two methylene hydrogens are replaced with deuteriums.

[0218] To a solution of (5-fluoro-2,3-dihydrobenzofuran-4-yl)methan-<72-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 mb) was added DIEA (110 mg, 851 pmol, 148 pL, 3.00 equiv). The mixture was stirred at 85 °C for 1 h. The reaction mixture was diluted with water (1.00 mb) and extracted with ethyl acetate (1.00 mb x 3). The combined organic layer was washed with brine (3.00 mb x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 8-bromo-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl-d2)amino)imidazo[l,2-c]pyrimid ine-2-carbonitrile (20.0 mg, crude) as a white solid. LCMS [M+l]: 390.0.

INTERMEDIATE C-8

[0219] 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(R ⁿ )2, is a single bond, one R ³ is fluorine, two methylene hydrogens and two hydrogens on the benzofuran ring are replaced with deuteriums.

[0220] 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 mb) was added DIEA (108 uL, 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, filtered and concentrated under reduced pressure to afford 8- bromo-5-(((5-fhioro-2.3-dihydrobcnzofuran-4-yl-2.3-t )mcthyl-£ )amino)imidazo| l .2-c|pyrimidinc-2- carbonitrile (25.0 mg, 63.7 pmol, 41.0% yield) as a white solid.

[0221] ‘H NMR (400MHz, CDC1 ₃ ) 5 = 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, J=I0.0 Hz, 1H), 3.33 (br d, J=8.4 Hz, 1H).

INTERMEDIATE C-9

[0222] A ninth exemplary Intermediate C, Intermediate C-9, may be used to synthesize compounds of formula I wherein Z is O, n is one, X is O, is a single bond, and one R ³ is fluorine.

[0223] To a solution of 8-bromo-5-chloroimidazo[I,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 mL) was added DIEA (54. 1 pL, 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 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (3.00 mL x 2). The combined organic phase was washed with brine (3.00 mL x 2), dried with anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to afford 8-bromo-5-(((5-fluorobenzo[d][I,3]dioxol-4- yl)methyl)amino)imidazo[I,2-c]pyrimidine-2 -carbonitrile (50.0 mg, 128 pmol, 82.5% yield) as a yellow solid.

[0224] ’H NMR (400 MHz, DMSO-t/ ₆ ) 5 = 8.92 (s, 1H), 8.567 (br s, 1H), 7.95 (s, 1H), 6.88 (dd, .7=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

[0225] An exemplary Intermediate D, Intermediate D-l, may be used to synthesize compounds of formula I wherein R ¹ is a disubstituted heteroaryl.

[0226] 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 uL, 3.00 equiv) and cesium carbonate (2.32 g, 7.11 mmol, 4.00 equiv) in acetonitrile (7.00 mL) was purged with nitrogen and subsequently stirred at 90 °C for 4 h. The reaction mixture was filtered 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-1,3,2- dioxaborolan-2-yl)pyrazole (170 mg, 34.4% yield, 90.0% purity) and I -isopropyl-5 -methyl -4-(4, 4,5,5- tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyrazole (170 mg, 34.4% yield, 90.0% purity) as a light yellow oil.

ECMS [M+l]: 251.4.

[0227] ‘H NMR (400MHz, CDCI3) 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

[0228] A second exemplary Intermediate D, Intermediate D-2, may be used to synthesize compounds of formula I, wherein R ¹ is heteroaryl substituted with two R ⁴ substituents. 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 mb) was purged with nitrogen and stirred at 90 °C for 3 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 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.

[0229] ’H NMR (400MHz, CDC1 ₃ ) 5 = 8.47 (s, 1H), 6.51 (s, 1H), 3.93 (s, 3H), 2.45 (s, 3H), 1.33 (s,

12H).

INTERMEDIATE D-3

[0230] A third exemplary Intermediate D, Intermediate D-3, may be used to synthesize compounds of formula I or formula II wherein R ¹ is heteroaryl substituted with two R ⁴ substituents. 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 mb, 1.00 equv), sodium ethoxide (8.09 g, 119 mmol, 2.00 equiv) in ethanol (500 mb) was purged with nitrogen and subsequently stirred at 25 °C for 12 h. The residue was dissolved in water (25.0 mb) 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. EC-MS [M+l]: 151.3.

[0231] ’H NMR (400MHz, DMSO-d ₆ ) 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). [0232] 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 filtered 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.

[0233] 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 uL, 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.

[0234] A mixture of 5-bromo-4-chloro-2-cyclopropyl-6-methyl-pyrimidine (2.31 g, 9.33 mmol, 1.00 equiv), 4-methylbenzenesulfonohydrazide (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 /V-(5-bromo-2-cyclopropyl-6-methyl- 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.

[0235] Tf NMR (400MHz, DMSO-d ₆ ) 5 =10.08 (br s, 1 H), 7.64 (d, J=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).

[0236] A mixture of A'-(5-bromo-2-cyclopropyl-6-methyl-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.

[0237] ^X H NMR (400MHz, CDCL) 5 = 8.49 (s, 1H), 2.56 (s, 3H), 2.25 - 2.08 (m, 1H), 1.19 - 0.99 (m, 4H).

[0238] 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-diox aborolan-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.

[0239] ^X H NMR (400MHz, CDC1 ₃ ) 5 = 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

[0240] A fourth exemplary Intermediate D, Intermediate D-4, may be used to synthesize compounds of formula I, wherein R ¹ is heteroaryl substituted with two R ⁴ substituents. 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 mb). The aqueous phase was extracted with ethyl acetate (10.0 mb x 3) and the combined organic phase was washed with brine (10.0 mb x 3). dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to 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.

[0241] 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-dioxaborola n-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 mb) 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.

[0242] ⁴ H NMR (400MHz, MeOD) 5 = 8.69 (s, 1H), 4.03 (s, 3H), 2.65 (s, 3H), 1.38 (s, 12H).

INTERMEDIATE D-5

[0243] A fifth exemplary Intermediate D, Intermediate D-5, may be used to synthesize compounds of formula I, wherein R ¹ is heteroaryl substituted with two R ⁴ substituents. To a solution of isopropanol (869 mg, 14.5 mmol, 1.11 mb, 3.00 equiv) in THF (10.0 mb) 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 Na2SO4, fdtered and concentrated to provide 5-bromo-2- isopropoxy-4-methyl- pyrimidine (600 mg, 2.60 mmol, 53.9 % yield) as a yellow oil.

[0244] 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-dioxaborola n-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- 1,3, 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

[0245] A sixth exemplary Intermediate D, Intermediate D-6, may be used to synthesize compounds of formula I, wherein R ¹ is aryl substituted with two R ⁴ substituents. To a solution of l-bromo-4-fluoro-2- methyl-benzene (1.00 g, 5.29 mmol, 1.00 equiv) in DMF (10.0 mL) 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 mL x 3), dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to afford l-bromo-2 - methyl-4- methylsulfanyl -benzene (900 mg, crude) as a light yellow oil.

[0246] ’H NMR (400MHz, MeOD) 5 = 7.42 (d, J=8.4 Hz, 1H), 7.17 (d, .7=2,0 Hz, 1H), 6.97 (dd, .7=2.0, 8.4 Hz, 1H), 2.45 (s, 3H), 2.35 (s, 3H).

[0247] 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 l-bromo-2 -methyl -4- methylsulfonyl-benzene (370 mg, 1.41 mmol, 34.0% yield, 95.0% purity) as a white solid.

[0248] ‘H NMR (400MHz, MeOD) 5 = 7.87 (d, J=L6 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.66 (dd, .7=2.0, 8.4 Hz, 1H), 3.12 (s, 3H), 2.50 (s, 3H).

[0249] 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) and 4.4.5.5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborola n-2-yl) -1,3,2- dioxaborolane (247 mg, 972 pmol, 1.50 equiv) in dioxane (3.00 mb) was purged with nitrogen. The resultant reaction mixture was stirred at 105 °C for 1 h. The mixture was fdtered and concentrated under reduced pressure to give a residue. The crude material was purified by prep-TLC (petroleum ether / ethyl acetate, 5 / 1) to afford

4.4.5.5-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

[0250] A seventh exemplary Intermediate D, Intermediate D-7, may be used to synthesize compounds of formula I, wherein R ¹ is aryl substituted with an R ⁴ substituent. 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 mb, 5.00 equiv) in methanol (16.0 mb) was added NaBPhCN (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 mb) and the aqueous phase was extracted with ethyl acetate (5.00 mb). The combined organic phase was washed with brine (2.00 mb), dried over anhydrous Na2SC>4, filtered and concentrated to afford l-[l-(4-bromophenyl)ethyl]pyrrolidine (1.00 g, 3.93 mmol, 78.3% yield) as a yellow oil.

[0251] 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-dioxabor olan-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]et hyl]pyrrolidine (110 mg) as a red oil.

INTERMEDIATE D-8

[0252] An eighth exemplary Intermediate D, Intermediate D-8, may be used to synthesize compounds of formula I, wherein R ¹ is heteroaryl substituted with two R ⁴ substituents. To a solution of n- butyllithium (2.50 M, 1.80 mb, 1.00 equiv) was added dropwise over one min to z-PrMgCl (2.00 M, 1.12 mb, 0.500 equiv) in THE (12 mb) 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 uL, 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)pyrid ine (1.00 g, 3.71 mmol, 82.5% yield) as a gray solid, which used for the next step without further purification.

[0253] ¹ H NMR (400 MHz, CDCh) 5 = 8.47 (s, 1H), 6.77 (s, 1H), 3.97 (s, 3H), 1.38 (s, 12H).

INTERMEDIATE D-9

[0254] A ninth exemplary Intermediate D, Intermediate D-9 may be used to synthesize compounds of formula I, wherein R ¹ is heteroaryl substituted with three R ⁴ substituents. 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 uL, 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

[0255] A tenth exemplary Intermediate D, Intermediate D-10, may be used to synthesize compounds of formula I, wherein R ¹ is heteroaryl substituted with two R ⁴ substituents. A mixture of 3-bromo-6- fluoro-2-methyl -pyridine (1.00 g, 5.26 mmol, 1.00 equiv) and A-methylpiperazine (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 Na2SC>4, filtered and concentrated to provide l-(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.

[0256] 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-dioxaborola n-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)pyridi n-2-yl)piperazine (210 mg, 662 pmol, 44.7% yield) as a brown oil. LCMS [M+l]: 318.3.

INTERMEDIATE D-l 1

[0257] An eleventh exemplary Intermediate D, Intermediate D-l 1, may be used to synthesize compounds of formula I, wherein R ¹ is heteroaryl substituted with three R ⁴ substituents. 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), (2.S')-2-mcthyloxiranc (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- l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]propan-2-ol (56.0 mg, 44.4% yield) as a yellow oil. LCMS [M + 1]: 281.3.

INTERMEDIATE D-12

[0258] A twelfth exemplary Intermediate D, Intermediate D-12, may be used to synthesize compounds of formula I, wherein R ¹ is aryl substituted with two R ⁴ substituents. 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 '. '-dimcthylaminc (2.00 M in THF, 1.27 mL, 2.00 equiv) in DMF (3.00 mL) 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 mL). The mixture was extracted with dichloromethane (20.0 mL x3). The combined organic layer was washed with water (30.0 mL) and concentrated to provide the crude mixture. The resultant residue was purified by column chromatography (SiCE, petroleum ether/ethyl acetate = 5/1 to 2/1) to afford 4-bromo-3-chloro- '. '- dimethyl-benzamide (430 mg, 983 pmol, 77.0% yield, 60.0% purity) as a white solid. LCMS [M + 1]: 264.0.

[0259] ’H NMR (400MHz, CDCh) 5 = 7.67 (d, .7=8,2 Hz, 1H), 7.53 (d, J=1.6 Hz, 1H), 7.18 (dd, .7=2.0, 8.4 Hz, 1H), 3.11 (s, 3H), 2.99 (s, 3H). [0260] 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-dioxaborola n-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-TLC (SiC>2, petroleum ether/ethyl acetate = 2/1) afforded [2-chloro-4- (dimethylcarbamoyl)phenyl]boronic acid (200 mg) as a yellow solid. LCMS [M + 1]: 228.0.

INTERMEDIATE D-13

[0261] A thirteenth exemplary Intermediate D, Intermediate D-13, may be used to synthesize compounds of formula I, wherein R ¹ is aryl substituted with two R ⁴ substituents. A mixture of 4-bromo- 3 -methyl -benzaldehyde (500 mg, 2.51 mmol, 1.00 equiv) and '. '-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 another 3 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)- 'A'-dimcthyl- methanamine (570 mg) as a brown oil.

[0262] ’H NMR (400MHz, CD ₃ OD) 5 = 7.61 (d, J=8.0 Hz, 1H), 7.38 (d, J=1.6 Hz, 1H), 7.16 (dd, .7=1.6, 8.0 Hz, 1H), 3.96 (s, 2H), 2.63 (s, 6H), 2.42 (s, 3H).

[0263] A mixture of l-(4-bromo-3-methyl-phenyl)-/V,/V-dimethyl-methanamine (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 '.A-dimcthyl- l-|3-mcthyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methanam ine (70.0 mg, 185 pmol, 8.99% yield, 72.8% purity) as a brown oil. LCMS [M+l]: 275.6.

INTERMEDIATE D-14

[0264] A fourteenth exemplary Intermediate D, Intermediate D-14, may be used to synthesize compounds of formula I, wherein R ¹ is aryl substituted with one R ⁴ substituent. To a solution of 4- bromobenzenesulfonyl chloride (200 mg, 783 pmol, 1.00 equiv) in THF (2.00 mb) 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 mL). The aqueous phase was extracted with ethyl acetate (10.0 mL x 3) and the combined organic phase was washed with brine (3.00 mL 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.

[0265] ’H NMR (400MHz, DMSO-t/ ₆ ) 5 = 7.82 - 7.72 (m, 4H), 7.46 (s, 2H).

[0266] 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 mL) 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 mL) and the aqueous phase was extracted with ethyl acetate (10.0 mL x 3). The combined organic phase was washed with brine (5.00 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated to afford 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzenesulfon amide (95.0 mg, 336 pmol, 79.2% yield) as a red solid.

[0267] ¹ H NMR (400MHz, CDC1 ₃ ) 5 = 7.96 - 7.88 (m, 4H), 7.26 (s, 2H), 1.35 (s, 12H).

INTERMEDIATE D-15

[0268] A fifteenth exemplary Intermediate D, Intermediate D-15, may be used to synthesize compounds of formula I, wherein R ¹ is a monosubstitued heteroaryl. To a solution of 2-methoxyethanol (236 mg, 3.10 mmol, 245 pL, 1.50 equiv) in tetrahydrofiiran (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 filtered 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.

[0269] ‘H NMR (400MHz, CD ₃ OD) 5 = 8.54 (s, 2H), 4.42 - 4.37 (m, 2H), 3.68 - 3.62 (m, 2H), 3.30 (s, 3H).

[0270] 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-dioxaborola n-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 fdtered 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.

[0271] ’H NMR (400MHz, CDC1 ₃ ) 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

[0272] A sixteenth exemplary Intermediate D, Intermediate D-16, may be used to synthesize compounds of formula I, wherein R ¹ is a disubstitued heteroaryl. 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 (SiCL, 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.

[0273] ’H NMR (400MHz, CDC1 ₃ ) 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).

[0274] 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+I]: 292.15.

INTERMEDIATE D-17

[0275] A seventeenth exemplary Intermediate D, Intermediate D-17, may be used to synthesize compounds of formula I, wherein R ¹ is a monosubstitued bicyclic heteroaryl. 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-l, 2,3,4- tetrahydroisoquinoline (350 mg, 1.65 mmol, 1.00 equiv) followed by NaCNBH; (114 mg, 1.82 mmol, 1.1 equiv). The mixture was stirred at 40°C for 1 h and was subsequently filtered 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.

[0276] ’H NMR (400MHz, CD ₃ OD) 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).

[0277] A mixture of 6-bromo-2-methyl-3,4-dihydro-177-isoquinoline (220 mg, 973 pmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborola n-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-l,3,2- dioxaborolan-2-yl)-3,4-dihydro-177-isoquinoline (150 mg, crude) as a white solid.

INTERMEDIATE D-18

[0278] An eighteenth exemplary Intermediate D, Intermediate D-18, may be used to synthesize compounds of formula I, wherein R ¹ is a N-protected bicyclic heteroaryl. To a solution of 6-bromo- 1,2,3,4-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- IH-isoqiiinolinc-2 -carboxylate (150 mg, 480 pmol, 25.5% yield) as a white solid.

[0279] ’H NMR (400MHz, CD ₃ OD) 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, J=6.0 Hz, 2H), 1.51 (s, 9H).

[0280] 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-dioxaborola n-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 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 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.

[0281] ‘H NMR (400MHz, CD ₃ OD) 5 = 7.58 - 7.54 (m, 2H), 7.13 (d, J=8.0 Hz, 1H), 4.58 (br s, 2H), 3.65 (br t, .7=6,0 Hz, 2H), 2.84 (t, .7=6,0 Hz, 2H), 1.35 (s, 12H), 1.19 (br s, 1H), 1.22 (s, 9H).

INTERMEDIATE D-19

[0282] A nineteenth exemplary Intermediate D, Intermediate D-19, may be used to synthesize compounds of formula I, wherein R ¹ is a monosubstitued aryl. A mixture of paraformaldehyde (133 mg, 4.42 mmol, 122 pL, 10.0 equiv) and methyl alcohol (1.00 mb) 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 fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCE, 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+I]: 240.1.

[0283] ^X H NMR (400MHz, CDC1 ₃ ) 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).

[0284] 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 fdtered and concentrated under reduced pressure to provide a residue. The residue was purified by prep-TLC (SiCE, petroleum ether/ethyl acetate = 3/1) to afford l-methyl-2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)p henyl]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

[0285] A twentieth exemplary Intermediate D, Intermediate D-20, may be used to synthesize compounds of formula I, wherein R ¹ is a monosubstituted aryl. 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 mL) 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-l -carboxylate (55.0 mg, 163 pmol, 73.6% yield, 96.5% purity) as a yellow oil. LC-MS [M-55]: 272.1.

[0286] 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 filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiCL, petroleum ether/ethyl acetate = 5/1) to afford tert-butyl 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.

[0287] ’H NMR (400MHz, CDC1 ₃ ) 5 = 7.75 (br d, .7=7,6 Hz, 2H), 7.17 (br d, .7=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

[0288] A twenty first exemplary Intermediate D, Intermediate D-21, may be used to synthesize compounds of formula I, wherein R ¹ is a monosubstitued heteroaryl. 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 NaBH ₄ (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.

[0289] ’H NMR (400MHz, CDC1 ₃ ) 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).

[0290] 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 was quenched with water and extracted with ether (2 x 20.0 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 2-(4- bromophenyl)tetrahydrofuran (420 mg, 1.85 mmol, 97.5% yield) as a white solid. [0291] ‘H NMR (400MHz, CDC1 ₃₎ 5 = 7.49 - 7.42 (m, 2H), 7.24 - 7.18 (m, 2H), 4.85 (t, J=7.2 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).

[0292] 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-dioxaborola n-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 mb) 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.

[0293] ’H NMR (400MHz, CDC1 ₃ ) 5 = 7.78 (d, .7=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

[0294] A twenty second exemplary Intermediate D, Intermediate D-22, may be used to synthesize compounds of formula I, wherein R ¹ is a monosubstitued aryl. 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)-A'A'-dimcthyl-cthanaminc (200 mg, 877 pmol, 87.7% yield) as a colorless oil.

[0295] 1H NMR (400MHz, CDC1 ₃ ) 5 = 7.40 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 2.73 (d, .7=8,4 Hz, 2H), 2.56 - 2.48 (m, 2H), 2.29 (s, 6H).

[0296] A mixture of 2-(4-bromophcnyl)-A'A'-dimcthyl-cthanaminc (160 mg, 701 pmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborola n-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 (SiCL, dichloromethane/methanol = 10/1) to afford N, A-dimethyl-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

[0297] A twenty third exemplary Intermediate D, Intermediate D-23, may be used to synthesize compounds of formula I, wherein R ¹ is a monosubstitued aryl. 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 mb) 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 (SiCE, 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.

[0298] ’H NMR (400MHz, CDC1 ₃ ) 5 = 7.73 - 7.57 (m, 4H), 4.22 - 3.99 (m, 4H), 1.32 (t, J=7.2 Hz, 6H).

[0299] 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-dioxaborola n-2-yl) -1,3,2-dioxaborolane (104 mg, 409 pmol, 1.20 equiv) in dioxane (2.00 mb) was added Pd(dppf)Ch (24.9 mg, 34.1 pmol, 0.10 equiv) and potassium acetate (67.0 mg, 682 umol, 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 (SiCE, 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.

[0300] ’H NMR (400MHz, CDC1 ₃ ) 5 = 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, .7=7,2 Hz. 6H).

INTERMEDIATE D-24

[0301] A twenty fourth exemplary Intermediate D, Intermediate D-24, may be used to synthesize compounds of formula I, wherein R ¹ is a disubstitued aryl. To a solution of 2-(4-bromo-3 -methyl - phenyl)pyrrolidine (500 mg, 2.08 mmol, 1.00 equiv) in dichloromethane (5.00 mb) 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 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si O2- petroleum ether/ethyl acetate=30/l to 20/1) to afford tert-butyl 2-(4-bromo-3-methyl-phenyl)pyrrolidine-l- carboxylate (600 mg, 84.7% yield) as a yellow oil.

[0302] ¹ H NMR (400MHz, CD3OD) 5 = 7.46 (br d, J=8.4 Hz, 1H), 7.10 (d, J=1.6 Hz, 1H), 6.92 (dd, .7=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).

[0303] A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborola n-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 (SiCL, 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. [0304] Tf NMR (400MHz, CDCh) 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

[0305] A twenty fifth exemplary Intermediate D, Intermediate D-25, may be used to synthesize compounds of formula I, wherein R ¹ is a disubstitued aryl. To a solution of 4-bromo-3 -methylbenzaldehyde (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.

[0306] ^X H NMR (400 MHz, CDCh) 5 =7.54 (d, J=8.4 Hz, IH), 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).

[0307] A mixture of 2-(4-bromo-3-methyl-phenyl)-l,3-dioxolane (2.50 g, 10.3 mmol, 1.00 equiv), PimEE (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 umol, 0.05 equiv) in dioxane (30.0 mL) was purged with N2 and then stirred at 100 °C for 6 h. The mixture was filtered 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-( 1 ,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.

[0308] ^X 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

[0309] A twenty sixth exemplary Intermediate D, Intermediate D-26, may be used to synthesize compounds of formula I, wherein R ¹ is a monosubstitued heteroaryl. A mixture of tert-butyl A-[(5- bromopyrimidin-2-yl)methyl]carbamate (100 mg, 347 pmol, 1.00 equiv), PimEE (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 mb) was purged with N2 and then stirred at 100 °C for 2 h. The reaction mixture was filtered and concentrated in vacuo to afford [2-[(tert-butoxycarbonylamino)methyl]pyrimidin-5- yl]boronic acid (100 mg, crude) as a red oil. LCMS [M-55]: 198.1.

INTERMEDIATE D-27

[0310] A twenty seventh exemplary Intermediate D, Intermediate D-27, may be used to synthesize compounds of formula I, wherein R ¹ a monosubstitued bicyclic heteroaryl. A mixture of 6-bromo-3,4- dihydro-2H-isoquinolin-l-one (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 filtered through a pad of Celite and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiCE, 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.

[0311] ’H NMR (400MHz, CDCI3) 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, J=6.4 Hz, 2H), 1.37 (s, 12H).

INTERMEDIATE D-28

[0312] A twenty eighth exemplary Intermediate D, Intermediate D-28, may be used to synthesize compounds of formula I, wherein R ¹ is a disubstitued bicyclic heteroaryl. To a suspension of NaH (79. 1 mg, 60%, 1.98 mmol, 2.00 equiv) in DMF (3.00 mL) 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 was quenched 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 -1- one (300 mg, crude) as a black oil. LCMS [M+l]: 288.1.

[0313] ’H NMR (400MHz, CHCL-d) 5 = 8.07 (d, .7=7,6 Hz, 1H), 7.77 (d, .7=7,6 Hz, 1H), 7.63 (s, 1H), 3.56 (t, J=6.8 Hz, 2H), 3.16 (s, 3H), 3.01 (t, J=6.8 Hz, 2H), 1.36 (s, 12H).

INTERMEDIATE D-29

[0314] A twenty ninth exemplary Intermediate D, Intermediate D-29, may be used to synthesize compounds of formula I, wherein R ¹ is a disubstitued aryl. 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 mL, 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, filtered, 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.

[0315] ’H NMR (400MHz, CDCI3) 5 = 7.77 (d, .7=2,0 Hz, 1H), 7.69 (dd, J=2.0, 8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 3.59 (s, 2H), 1.59 (br s, 6H).

[0316] 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

[0317] A thirtieth exemplary Intermediate D, Intermediate D-30, may be used to synthesize compounds of formula I, wherein R ¹ is a disubstitued heteroaryl. To a solution of Ir(COD)2(OMe)2 (5.00 mg, 7.54 pmol, 0.02 equiv) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (68.5 mg, 535 pmol, 77.7 pL, 1.50 equiv) in w-pcntanc (0.50 mL) was added 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (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-pcntanc (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). The organic 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.

[0318] ’H NMR (400MHz, CDC1 ₃ ) 5 = 7.28 (s, 1H), 4.15 (s, 3H), 3.93 (s, 3H), 1.35 (s, 12H).

INTERMEDIATE D-31

[0319] A thirty first exemplary Intermediate D, Intermediate D-31, may be used to synthesize compounds of formula I, wherein R ¹ is a disubstitued aryl, in which one substituent has two hydrogens replaced with deuteriums. To a solution of 4-bromo-A'A'.3-trimcthyl-bcnzamidc (500 mg, 2.07 mmol, 1.00 equiv) in THF (5.00 mL) 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 mL). The reaction was quenched upon the dropwise addition of deuterium oxide (0.24 mL), 15% NaOD solution in deuterium oxide (0.24 mL) at 0 °C, and finally deuterium oxide (0.72 mL). 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 (SiCf. 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

[0320] A thirty second exemplary Intermediate D, Intermediate D-32, may be used to synthesize compounds of formula I, wherein R ¹ is a disubstitued aryl. To a solution of 4-bromo-3 -methyl -aniline (4.00 g, 21.5 mmol, 1.00 equiv) in concentrated sulfuric acid (40.0 mL) and water (40.0 mL) 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 mL, 1.35 equiv) in water (16.0 mL) 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 (SiCL, petroleum ether) to afford (4-bromo-3 -methyl -phenyl) thiocyanate (2.00 g, 8.77 mmol, 40.8% yield) as a yellow oil.

[0321] ‘H NMR (400MHz, CDC1 ₃ ) 5 = 7.52 (d, J=8.4 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.14 (dd, .7=2.4, 8.4 Hz, 1H), 2.36 (s, 3H).

[0322] 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 mL) was stirred at room temperature for 4 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether) to afford l-bromo-2-methyl-4- (trifluoromethylsulfanyl)benzene (450 mg, 1.66 mmol, 75.7% yield) as a colorless oil.

[0323] ’H NMR (400MHz, CDC1 ₃ ) 5 = 7.59 (d, J=8.0 Hz, 1H), 7.52 (d, .7=2,0 Hz, 1H), 7.34 (dd, .7=2.4, 8.0 Hz, 1H), 2.44 (s, 3H).

[0324] 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 mL) 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 1- bromo-2-methyl-4- (trifluoromethylsulfonyl) benzene (400 mg, 1.32 mmol, 79.5% yield) as a white solid.

[0325] ‘H NMR (400MHz, CDC1 ₃ ) 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).

[0326] 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 fdtered and concentrated under reduced pressure to afford 4,4,5,5-tetramethyl-2-[2-methyl-4- (trifluoromethylsulfonyl)phenyl]-l,3,2- dioxaborolane (200 mg, crude) as a black solid that was used into the next step without further purification.

INTERMEDIATE D-33

[0327] A thirty third exemplary Intermediate D, Intermediate D-33, may be used to synthesize compounds of formula I, wherein R ¹ is a monosubstitued heteroaryl. 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 uL, 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 uL, 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.

[0328] ¹ H NMR (400 MHz, CDC1 ₃ ) 5 = 7.51 (d, J=1.6 Hz, 1H), 6.32 (d, J=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

[0329] A thirty fourth exemplary Intermediate D, Intermediate D-44, may be used to synthesize compounds of formula I, wherein R ¹ is a disubstitued heteroaryl. 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 filtered and concentrated in vacuo to provide a residue. The residue was purified by prep-TLC (SiCE, 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.

[0330] ’H NMR (400MHz, DMSO-t/ ₆ ) 5 = 7.87 (d, .7=4,4 Hz, 1H), 7.78 (d, .7=4,4 Hz, 1H), 3.72 (s, 3H).

[0331] 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(PPh ₃ )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 (SiCh, 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.

[0332] Tf NMR (400MHz, CD ₃ OD) 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

[0333] A thirty fifth exemplary Intermediate D, Intermediate D-35, may be used to synthesize compounds of formula I, wherein R ¹ is a tri substituted heteroaryl. To a solution of 2,5-dibromo-3- fluoro-pyridine (0.50 g, 1.96 mmol, 1.00 equiv) in THF (10.0 mb) was added w-BuLi (2.50 M, 1.18 mb, 1.50 equiv) dropwise at -65 °C. The mixture was stirred at -65 °C for 0.5 h followed by the addition of A-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 NH4CI (10.0 mb) and the resulting mixture was extracted with ethyl acetate (20.0 mb x 3). The combined organic phase was washed with brine (30.0 mb x 2), dried over anh sodium sulfate, filtered, and concentrated under reduced pressure to give the crude residue. The residue was purified by prep-HPEC (acidic conditions) to afford 2,5-dibromo-3-fluoro-4-methyl- pyridine (300 mg, 1.12 mmol, 56.9% yield) as a yellow solid. ECMS [M+l]: 269.7.

[0334] 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 mb) was added w-Bubi (2.5 M, 1.19 mb, 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 ph, 1.50 equiv). After an additional 30 min of stirring at -65 °C the reaction mixture was quenched with satd aq NH4CI (5.00 mb) and the resulting mixture was extracted with ethyl acetate (30.0 mb x 2). The combined organic phase was washed with brine (30.0 mb 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 (SiCh, 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.

[0335] ’H NMR (400MHz, CDC1 ₃ ) 5 = 10.20 (d, .7=0,8 Hz, 1H), 8.69 (s, 1H), 2.48 (d, .7=2,4 Hz, 3H). [0336] 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 TSOH-H2O (26.2 mg, 138 pmol, 0.10 equiv) and ethylene glycol (171 mg, 2.75 mmol, 14 ph, 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 (SiCh, 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. [0337] 'H NMR (400MHz, CDC1 ₃ ) 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).

[0338] 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 (SiCL, 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+I]: 228.0.

INTERMEDIATE D-36

[0339] A thirty sixth exemplary Intermediate D, Intermediate D-36, may be used to synthesize compounds of formula I, wherein R ¹ is a monosubstitued aryl. 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.

[0340] 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 phcnyl- ' -iodanediyl bis(2,2,2-trifluoroacetate) (1.04 g, 2.42 mmol, 1.10 equiv) and iodine (559 mg, 2.20 mmol, 444 uL, 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 (SiCL, 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.

[0341] ’H NMR (400MHz, DMSO-t/ ₆ ) 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=I2.0 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). [0342] 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-dioxaborola n -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 mL) 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 (SiCE, 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 umol, 38.5% yield) as white oil.

[0343] ’H NMR (400MHz, DMSO-t/ ₆ ) 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-44

Characterization of Intermediates D37 - D44

[0344] 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-dihyd robenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)methanol

[0345] 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)pyra zole (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 mb) 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 fdtered and concentrated in vacuo. The crude material was purified by prep-TLC (SiCL, PE: EA = 2:3) to afford ethyl 8-( 1 ,3 -dimethyl- 1 H-py razol -5 -y 1) -5 -(((5 -fluoro-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. LCMS [M+l]: 450.9.

[0346] To a solution of ethyl 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobe nzofuran- 4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylate (50.0 mg, 107 pmol, 1.00 eq.) in THF (2.00 mL) was added lithium aluminum hydride (8.09 mg, 213 pmol, 2.00 eq.) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with DCM (5.00 mL) and cooled to 0 °C, then quenched by addition water dropwise (0.30 mL) and 10% sodium hydroxide aqueous solution (0.30 mL), followed by water (0.90 mL). The suspension was dried with anhydrous Mg2SC>4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge 150*50 lOp; mobile phase: [phase A: water (0.05% ammonia hydroxide v/v), phase B: ACN] and lyophilization to give ( 8-( 1.3 -dimethyl - 1 //-pyrazol -5 -yl )-5 -(((5 - fluoro-2,3 -dihydrobenzofuran-4-yl)methyl)amino)imidazo [ 1 ,2-c]pyrimidin-2-yl)methanol (9.37 mg, 21.2 % yield, 98.3 % purity) as a white solid. LCMS [M+l]: 409.4.

[0347] ’H NMR (400 MHz, DMSO-t/ ₆ ) 5 =8.32 (t, J = 4.8 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 6.86(t, J = 8.8, 1H), 6.69 (dd, J =8.4, 4.4 Hz, 1H), 6.19 (s, 1H), 5.31 (t, J = 5.6 Hz, 1H), 4.72 (d, J = 4.8 Hz, 2H), 4.58 - 4.51 (m, 4 H), 3.68 (s, 3H), 3.32 - 3.27 (m, 2H), 2.17 (s, 3H). EXAMPLE 2

(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8 -(2-methyl-4-

(methylsulfonyl)phenyl)imidazo[ 1 ,2-c]pyrimidin-2-yl)methanol

[0348] A mixture of ethyl 8-bromo-5-[(5-fluoro-2,3-dihydrobenzofuran -4- yl)methylamino]imidazo[l,2-c]pyrimidine-2-carboxylate (120 mg, 275 pmol, 1.00 eq.), 4, 4,5,5- tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-l,3,2-diox aborolane (100 mg, 332 pmol, 1.21 eq.), Pd(dppf)C12 (20.2 mg, 27.6 pmol, 0.10 eq.) and sodium bicarbonate (69.5 mg, 827 pmol, 32.2 pL, 3.00 eq.) in dioxane (2.00 mL), water (0.20 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 95 °C for Ihour under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was triturated with methanol (3.00 mL), the suspension was filtered, the filter cake was collected and dried in vacuum to give ethyl 5- (((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-me thyl-4- (methylsulfonyl)phenyl)imidazo[l,2-c]pyrimidine-2 -carboxylate (100 mg, , 68.4% yield, 99.0% purity) as a white solid. LCMS [M+l]: 525.0.

[0349] To a solution of ethyl 5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2- methyl-4- (methylsulfonyl)phenyl)imidazo[l,2-c]pyrimidine-2 -carboxylate (50.0 mg, 94.4 pmol, 1.00 eq.) in THF (2.00 mL) was added lithium aluminum hydride (7.16 mg, 188 pmol, 2.00 eq.) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched by addition water (0.01 mL) and 10 % sodium hydroxide solution (0.01 mL) at 0 °C, followed by water (0.03 mL), the mixture stirred at 25 °C for 10 min, then filtered and concentrated under reduced pressure to give a residue. The residue was triturated with methanol (2.00 mL), the suspension was filtered, the filter cake was collected and dried in vacuum to give (5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2 -methyl-4- (methylsulfonyl)phenyl)imidazo[l,2-c]pyrimidin-2-yl)methanol (14.1 mg, 29.3% yield, 94.5% purity) as a white solid. LCMS [M+l]: 483.4.

[0350] ‘H NMR (400 MHz, DMSO-t/ ₆ ) 5 = 8.25 (br s, 1H), 8.01 (br s, 1H), 7.86 (s, 1H), 7.78 (br d, J = 8.0 Hz, 1H), 7.61 - 7.55 (m, 2H), 6.94 (br t, J =9.2 Hz, 1H), 6.70 (dd, J = 3.6, 8.4 Hz, 1H), 5.28 (br s, 1H), 4.73 (s, 2H), 4.58 - 4.50 (m, 4H), 3.30 - 3.29 (m, 2H), 3.26 (s, 3H), 2.29 (s, 3H).

[0351] Following the teachings of the General Reaction Schemes, Examples 1 & 2, and the intermediates disclosed herein, Examples 3 - 6 were prepared as shown in Table 1.

Table 1

Characterization of EXAMPLES 3 - 6

EXAMPLE 7 l-(8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydr obenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)ethan-l-ol

[0352] To a solution of (8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrob enzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)methanol (120 mg, 276 pmol, 1.00 eq.) in DCM (3.00 mL) was added Dess-Martin periodinane (175 mg, 413 pmol, 127 pL, 1.50 eq.) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was triturated with methanol (3.00 mL), the suspension was fdtered, the fdter cake was collected and dried in vacuum to give 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5- (((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[ l,2-c]pyrimidine-2-carbaldehyde (100 mg, 83.7 % yield, 93.7 % purity) as a white solid. LCMS [M+l]: 407.0.

[0353] To a solution of 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobe nzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbaldehyde (30.0 mg, 69.2 pmol, 1.00 eq.) in THF (0.50 mL) was added magnesium methyl bromide (3.00 M, 73.8 pL, 3.20 eq.) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by addition saturated ammonium chloride aqueous solution (5.00 mL), extracted with ethyl acetate (5.00 mL x 3). The combined organic layers were washed with brine (10.0 mL x 2), dried over sodium sulfate, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25* 10pm; mobile phase: [phase A: water(0.1%TFA), phase B: ACN]) and lyophilization to give I -(8-( 1 ,3-dimcthyl- l//-pyrazol-5-yl)-5-(((5-fhioro-2.3-dihydrobcnzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)ethan-l-ol (8.76 mg, 29.1 % yield, 97.2 % purity) as yellow oil. LCMS [M+l]: 423.4.

[0354] Tf NMR (400 MHz, DMSO-t/ ₆ ) 5 = 8.61 (br s, 1H), 8.13 (br s, 1H), 7.87 (br s, 1H), 6.94 (t, J = 9.2 Hz, 1H), 6.71 (dd, J = 8.4, 3.6 Hz, 1H), 6.22 (s, 1H), 4.84 (d, J = 6.4 Hz, 1H), 4.73 (d, J = 4.4 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 3.67 (s, 3H), 3.32 (t, J = 8.8 Hz, 2H), 2.20 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H).

(8-( 1 ,3 -dimethyl- 1 H-pyrazol-5 -y 1) -5 -(((5 -fluoro-2,3 -dihydrobenzofuran-4- yl)methyl)amino)imidazo[ 1 ,2-c]pyrimidin-2-yl)(phenyl)methanol

[0355] Step A: To a solution of 1 -phenylpropane- 1,2-dione (1.00 g, 6.75 mmol, 909 pL, 1.00 eq.) in CHCI , (10.0 mL) was added Br2 (1.19 g, 7.42 mmol, 383 pL, 1.10 eq. dropwise at 75 °C, the mixture was stirred at 75 °C for 4 hr. The reaction mixture was diluted with DCM 50 mL and washed with brine (30 mL x 2), the separated organic phase was dried over sodium sulfate, fdtered, and concentrated in vacuo. The residue was purified by column chromatography (SiCL, Petroleum ether/Ethyl acetate=l/O to 100/1) to give compound 3 -bromo- 1 -phenylpropane- 1,2-dione (1.40 g, 4.62 mmol, 68.5% yield, 75.0% purity) as a yellow oil.

[0356] Tf NMR (400MHz, CDC1 ₃ ) 5 = 8.06 - 8.01 (m, 2H), 7.72 - 7.65 (m, 1H), 7.56 - 7.52 (m, 2H), 4.41 (s, 2H), 2.54 (s, 1H).

[0357] Step B: To a solution of 6-amino-5-bromopyrimidin-2(17/)-one (0.64 g, 3.30 mmol, 1.00 eq.) in AcOH (6.00 mL) was added 3 -bromo- 1 -phenylpropane- 1,2-dione (1.40 g, 4.62 mmol, 1.40 eq.), the mixture was stirred at 120 °C for 1 hr. The reaction mixture was concentrated in vacuo to remove AcOH, the residue was triturated with MTBE 50 mL and then water (60 mL x 3) mL, the precipitate was filtered and evaporated to provide 2-benzoyl-8-bromoimidazo[l,2-c]pyrimidin-5(677)-one (180 mg, 388 pmol, 11.7% yield, 68.5% purity) as a brown solid. LCMS [M+l]: 318.2.

[0358] Step C: To a solution of 2-benzoyl-8-bromoimidazo[l,2-c]pyrimidin-5(677)-one (0.18 g, 388 pmol, 1.00 eq.) in POCL (5.00 mL) was added DIPEA (150 mg, 1.16 mmol, 203 pL, 3.00 eq.) dropwise at 0 °C, and the mixture was stirred at 120 °C for 12 hr. The reaction mixture was concentrated in vacuo, and the residue was purified by prep-TLC (SiCL, PE: EA = 3: 1) to give compound (8-bromo-5- chloroimidazo[l,2-c]pyrimidin-2-yl)(phenyl)methanone (45.0 mg, 133 pmol, 34.2% yield, 99.2% purity) as a red solid. LCMS [M+l]: 338.0.

[0359] Step D: To a solution of (8-bromo-5-chloroimidazo[l,2-c]pyrimidin-2-yl)(phenyl)methan one (45.0 mg, 133 pmol, 1.00 eq.) in DMF (3.00 mL) was added DIPEA (34.3 mg, 265 pmol, 46.2 pL, 2.00 eq.) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (28.01 mg, 159.16 pmol, 1.2 eq ). The mixture was stirred at 85 °C for 30 minutes, then diluted with water 20 mL and filtered. The precipitate was dried in vacuo to give compound (8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)(phenyl)methano ne (55.0 mg, 118 pmol, 88.7% yield) as a yellow solid. LCMS [M+l]: 467.1.

[0360] Step E: A mixture of (8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)(phenyl)methano ne (60.0 mg, 128 pmol, 1.00 eq ), 1,3- dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (42.8 mg, 193 pmol, 1.5.0 eq.), NaHCCF (32.4 mg, 385 pmol, 15.0 pL, 3.00 eq.), Pd(dppf)C12 (14.1 mg, 19.3 pmol, 0.15 eq.) in dioxane (1.50 m ) and H2O (0.50 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 °C for 1 hr under N2 atmosphere. The reaction mixture was fdtered and concentrated in vacuum. The residue was purified by prep-TLC (SiCL, DCM: MeOH = 20:1) to give compound (8-(l,3- dimethyl- 1 H-pyrazol-5-yl)-5-(((5-fl uoro-2,3-dihydrobenzofuran -4-yl )methyl )amino)imidazo[ 1,2- c]pyrimidin-2-yl)(phenyl)methanone (33.3 mg, 65.9 pmol, 51.3% yield, 95.3% purity) as ayellow solid. LCMS [M+l]: 483.2.

[0361] ¹ H NMR (400MHz, DMSO-de) 5 = 8.91 (s, 1H), 8.65 (br s, 1H), 8.19 (d, J = 7.2 Hz, 2H), 7.81 (s, 1H), 7.71 - 7.65 (m, 1H), 7.61 - 7.55 (m, 2H), 6.95 (t, J = 9.6 Hz, 1H), 6.71 (dd, J = 4.0, 8.8 Hz, 1H), 6.25 (s, 1H), 4.73 (br d, J = 2.8 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.76 (s, 3H), 2.18 (s, 3H).

[0362] Step F: 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]pyrimidin- 2-yl)(phenyl)methanone (19.0 mg, 37.5 pmol, 1.00 eq.) in THF (2.00 mL) was added NaBlL (1.70 mg, 45.0 pmol, 1.20 eq.) at 0 °C, the mixture was stirred at 10 °C for 1 hr. The reaction mixture was quenched with water (0.1 mL) and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25* 10pm; mobile phase: [phase A: water(0.1%TFA), phase B: ACN]) to give compound (8-(l,3-dimethyl-lH- pyrazol-5 -y 1) -5 -(((5 -fluoro-2,3 -dihydrobenzofuran-4-yl)methyl)amino)imidazo [ 1 ,2-c]pyrimidin-2- yl)(phenyl)methanol (7.00 mg, 14.3 pmol, 38.2% yield, 99.1% purity) as a white solid. LCMS [M+l]: 485.3.

[0363] ’H NMR (400MHz, DMSO-d ₆ ) 5 = 8.52 (br s, 1H), 8.07 (s, 1H), 7.78 (br s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.29 - 7.22 (m, 1H), 6.98 - 6.90 (m, 1H), 6.70 (dd, J = 4.0, 8.8 Hz, 1H), 6.18 (s, 1H), 5.79 (s, 1H), 4.70 (br d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.60 (s, 3H), 3.31 (brt, J = 8.8 Hz, 2H), 2.18 (s, 3H).

EXAMPLE 9

8-(l,3-dimethyl-lH-pyrazol-5-yl)-A-((5-fluoro-2,3-dihydro benzofuran-4-yl)methyl)-2- (methoxymethy l)imidazo [1,2 -c]pyrimidin-5 -amine

[0364] Step A: 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]pyrimidin- 2-yl)methanol (1.50 g, 3.67 mmol, 1.00 eq.) in THF (15.0 mb) was added di-tert-butyl dicarbonate (2.00 g, 9.18 mmol, 2.11 mb, 2.50 eq.) and DMAP (44.9 mg, 367 pmol, 0.10 eq ), the reaction mixture was stirred at 80 °C for 1 hour. The reaction was concentrated in vacuo to give a residue, the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5/1 to dichloromethane/methanol = 20/1) to give tert-butyl (2-(((tert- butoxycarbonyl)oxy)methyl)-8-(l,3-dimethyl-lH-pyrazol-5-yl)i midazo[l,2-c]pyrimidin-5-yl)((5-fluoro- 2,3-dihydrobenzofuran-4-yl)methyl)carbamate (2.10 g, 3.45 mmol, 93.9% yield) as brown oil. LCMS [M+l]: 609.1.

[0365] Step B: To a solution of (2-(((tert-butoxycarbonyl)oxy)methyl)-8-(l,3-dimethyl-lH-pyr azol-5- yl)imidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzof uran-4-yl)methyl)carbamate (400 mg, 657 pmol, 1.00 eq.) in methanol (6.00 mb) was added potassium carbonate (182 mg, 1.31 mmol, 2.00 eq.), the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (dichloromethane/methanol: 10/1) to give tert-butyl (8-( 1,3 -dimethyl- lH-pyrazol-5 -yl)-2- (hydroxymethyl)imidazo [ 1 ,2-c]pyrimidin-5 -yl)((5 -fluoro-2,3 -dihydrobenzofuran-4-yl)methyl)carbamate (200 mg, 393 pmol, 59.8% yield) as a white solid. LCMS [M+l]: 509.3.

[0366] Step C: To a solution of tert-butyl (8-(l,3-dimethyl-lH-pyrazol-5-yl)-2- (hydroxymethyl)imidazo [ 1 ,2-c]pyrimidin-5 -yl)((5 -fluoro-2,3 -dihydrobenzofuran-4-yl)methyl)carbamate (80.0 mg, 157 pmol, 1.00 eq.) in THF (4.00 mb) was added sodium hydride (12.6 mg, 315 pmol, 60.0% purity, 2.00 eq.) at 0 °C, the reaction mixture was stirred at 0 °C for 30 minutes, then methyl iodide (44.7 mg, 315 pmol, 19.6 pL, 2.00 eq.) was added dropwise. The reaction mixture was then warmed to 25 °C and stirred for 30 minutes. The reaction was quenched with water (10.0 mb), and the aqueous phase was extracted with ethyl acetate (10.0 mLx3). The combined organic phase was washed with brine (10.0 mLx2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue, the residue was purified by prep-TLC (dichloromethane/methanol=10/l) to give tert-butyl (8- ( l,3-dimethyl-lH-pyrazol-5-yl)-2-(methoxymethyl)imidazo[ l,2-c]pyrimidin-5-yl)((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)carbamate (71.0 mg, 128 pmol, 81.5% yield, 94.4% purity) as brown oil. LCMS [M+l]: 523.3.

[0367] Step D: A solution of tert-butyl (8-( l.3-dimcthyl-IH-pyrazol-5-yl)-2- (methoxymethyl)imidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3-d ihydrobenzofuran-4- yl)methyl)carbamate (71.0 mg, 128 pmol, 1.00 eq.) in TFA (0.30 mb) and DCM (1.00 mb) was stirred at 25 °C for 12 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution. (10.0 mb), extracted with DCM (5.00 mLx3). The combined organic phases were washed with brine (5.00 mLx2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was triturated with petroleum ether/ethyl acetate = 1/1 (5.00 mb), filtered, the filter cake was collected and dried in vacuo to 8-( 1,3 -dimethyl- lH-pyrazol-5-yl)-A-((5-fluoro-2, 3- dihydrobenzofuran-4-yl)methyl)-2-(methoxymethyl)imidazo[l,2- c]pyrimidin-5-amine (15.9 mg, 35.1 pmol, 27.4% yield, 93.4% purity) as an off-white solid. LCMS [M+l]: 423.3.

[0368] ‘H NMR (400 MHz, CD ₃ OD) 5 = 7.91 (s, 1H), 7.71 (s, 1H), 6.84 (t, J= 9.2 Hz, 1H), 6.62 (dd, J= 3.6, 8.4 Hz, 1H), 6.22 (s, 1H), 4.81 (s, 2H), 4.59 - 4.54 (m, 2H), 4.54 (s, 2H), 3.70 (s, 3H), 3.42 (s, 3H), 3.35 (t, J= 8.8 Hz, 2H), 2.27 (s, 3H).

2-(aminomethyl)-8-( 1,3 -dimethyl- lH-pyrazol-5-yl)-A-((5-fluoro-2, 3 -dihydrobenzofuran-4- yl)methyl)imidazo [ 1 ,2-c]pyrimidin-5 -amine

[0369] Step A: A mixture 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 eq.), sodium hydroxide (1 M, 1.10 mL, 3 eq.) in methanol (3.30 mL) was stirred at 55 °C for 30 minutes under N2 atmosphere. The mixture was concentrated in vacuo to give a residue, water (1.00 mL) was added and HC1 (1 M) was added until pH = 2, the solid was collected through filtration, dried in vacuo to give compound 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. LCMS: [M+l] 408.8.

[0370] Step B: 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 eq.), ammonium chloride (48.8 mg, 913 pmol, 31.9 pL, 3.00 eq.), HATU (173 mg, 456 pmol, 1.50 eq.), DIEA (314 mg, 2.44 mmol, 424 pL, 8 eq.) in DMF (1.00 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 30 °C for 1 hr under a N2 atmosphere. The mixture was concentrated in vacuo to give a residue. Water (1.00 mL) was added to the residue and the solid was collected through filtration, then dried in vacuo to give compound 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-

4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carboxamide (100 mg, crude) as a white solid which was used into the next step without further purification.

[0371] Step C: 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 eq.), TEA (484 mg, 4.79 mmol, 666 pL, 19.4 eq.) in THF (2.00 mL) was added TFAA (302 mg, 1.44 mmol, 200 pL, 5.84 eq.) at 0 °C, and then the mixture was stirred at 0-30 °C for 40 mins, under aN2 atmosphere. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate 5/1 to 0/1) to give compound 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, 95.3 % purity) as a yellow solid. LCMS: [M+l] 387.8.

[0372] Step D: 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 eq.), 1,3-dimethyl-

5-(4.4.5.5-tctramcthyl- l .3.2-dioxaborolan-2-yl)- l7/-pyrazolc (103 mg, 463 pmol, 2.00 eq.), Pd(dppf)C12 (16.9 mg, 23.1 pmol, 0.100 eq.), sodium bicarbonate (58.4 mg, 695 pmol, 27.0 pL, 3 eq.) in dioxane (6.00 mL) and water (3.00 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 100 °C for 2 hrs under a N2 atmosphere. Water (8.00mL) was added and the mixture was extracted with ethyl acetate (8.00 mL x 3). The organic layers were concentrated in vacuo to give a residue. The residue was purified by reversed phased prep-HPLC (column: Phenomenex Synergi Cl 8 150*25* lOpmpnobile phase: [water(0.1%TFA)-ACN]; B%: 33%-63%,13min) to give compound 8-

( 1, 3 -dimethyl- l7/-pyrazol-5-yl)-5-(((5-fluoro-2.3-dihydrobcnzofuran -4-yl )methyl )amino)imidazo[ 1,2- c]pyrimidine-2-carbonitrile (51.0 mg, 120 pmol, 52.0 % yield, 95.4 % purity) as a white solid. LCMS: [M+l] 404.

[0373] ¹ H 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). [0374] Step E: To a solution of 8-( 1 ,3-dimethyl- lH-pyrazol-5-yl)-5 -(((5 -fluoro-2,3 - dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine -2-carbonitrile (80.0 mg, 193 pmol, 1.00 eq.) in THF (2.00 m ) and NFk’FEO (14.0 M, 0.80 m , 58.0 eq.) was added Raney nickel (16.53 mg, 192.95 pmol, 1.00 eq.) under nitrogen. The suspension was degassed under vacuum and purged with nitrogen several times and stirred under an H2 atmosphere (15 psi) at 25 °C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was triturated with methanol (3.00 mbx2), the suspension was filtered and the filter cake was collected, and dried in vacuo to give 2-(aminomethyl)-8-( 1 ,3-dimethyl- lH-pyrazol-5-yl)-A-((5-fluoro-2, 3- dihydrobenzofuran-4-yl)methyl)imidazo[l,2-c]pyrimidin-5 -amine (34.8 mg, 41.5 % yield, 94.0 % purity) as a yellow solid. ECMS: [M+l] 408.1.

[0375] ’H NMR (400 MHz, DMSO-t/ ₆ ) 5 = 8.62 (br.s, 1H), 8.21 (s, 1H), 7.97 (br.s, 2H), 7.74 (s, 1H), 6.94 (t, J = 8.4 Hz, 1H), 6.74 - 6.66 (m, 1H), 6.21 (s, 1H), 4.72 (s, 2H), 4.55 (t, J = 8.0 Hz, 2H), 4.12 (s, 2H), 3.69 (s, 3H), 3.31 - 3.27 (m, 2H), 2.18 (s, 3H).

EXAMPEES 11 & 12

2-( 1 -aminoethyl)-8-( 1 ,3 -dimethyl- 17/-py razol -5 -yl)-A-((5 -fluoro-2,3 -dihydrobenzofuran-4- yl)methyl)imidazo [ 1 ,2-c]pyrimidin-5 -amine

[0376] Step A: To a solution of 8-bromo-5 -(((5 -fluoro-2,3 -dihydrobenzofuran -4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile (3.50 g, 9.02 mmol, 1.00 eq.) in THF (10.0 mb) was added methyl magnesium bromide (3.00 M, 18.0 mb, 6.00 eq) dropwise at 0 °C. The mixture was stirred at 0 °C for 2 hours, then the reaction was added methanol (5.00 mb), after 15 min the mixture was added sodium borohydride (1.36 g, 36.1 mmol, 4.00 eq.) and stirred at 0 - 25 °C for 7 hours. The reaction was poured into ice-water (15.0 mL) and stirred for 15 mins, the aqueous phase was extracted with ethyl acetate (30.0 mL x 3). The combined organic phases were washed with brine (30.0 mL x 3). dried with anhydrous sodium sulfate, fdtered, and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 100/1 to 1/1) to give 2-(l-aminoethyl)-8-bromo-/V-((5-fhioro-2,3-dihydrobenzofuran -4-yl)methyl)imidazo[l,2- c]pyrimidin-5 -amine (3.00 g, crude) as a yellow solid.

[0377] ’H NMR (400 MHz, DMSO-t/ ₆ ) 5 = 8.28 (t, J = 5.2 Hz, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 6.95 - 6.88 (m, 1H), 6.68 (dd, J = 4.0, 8.8 Hz, 1H), 5.62 (br s, 1H), 5.43 - 5.33 (m, 1H), 4.65 (d, J = 4.8 Hz, 2H), 4.53 (t, J = 8.8 Hz, 2H), 3.88 - 3.75 (m, 1H), 3.25 (t, J = 8.8 Hz, 2H), 1.50 (d, J = 6.8 Hz, 3H). [0378] Step B: To a solution of 2-(l-aminoethyl)-8-bromo-/V-((5-fluoro-2,3-dihydrobenzofiira n-4- yl)methyl)imidazo[l,2-c]pyrimidin-5-amine (3.00 g, 7.38 mmol, 1.00 eq.) and di-Z rt-but l dicarbonate (3.22 g, 14.8 mmol, 3.39 mL, 2.00 eq.) in THF (15.0 mL) was added TEA (2.24 g, 22.15 mmol, 3.08 mL, 3.00 eq.) and DMAP (90.2 mg, 738 pmol, 0.10 eq.). The mixture was stirred at 40 °C for 1 hour. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate=100/l to 2/1) to give tert-butyl (l-(8-bromo-5- (((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[ l,2-c]pyrimidin-2-yl)ethyl)carbamate (1.30 g, 2.57 mmol, 34.8% yield) as a yellow solid.

[0379] Tf NMR (400 MHz, DMSO-t/ ₆ ) 5 = 8.28 (br t, J = 4.8 Hz, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.25 (br d, J = 8.0 Hz, 1H), 6.96 - 6.86 (m, 1H), 6.68 (dd, J = 4.0, 8.8 Hz, 1H), 4.78 - 4.69 (m, 1H), 4.65 (t, J = 4.0 Hz, 2H), 4.53 (t, J = 8.8 Hz, 2H), 3.25 (t, J = 8.4 Hz, 2H), 1.43 - 4.35 (m, 12H).

[0380] Step C: To a solution of tert-butyl (l-(8-bromo-5-(((5-fhioro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)ethyl)carbamate (600 mg, 1.18 mmol, 1.00 eq.) and 1,3- dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (395 mg, 1.78 mmol, 1.50 eq.) in dioxane (1.00 mL) and water (0.20 mL) was added sodium bicarbonate (199 mg, 2.37 mmol, 92.2 pL, 2.00 eq.) and Pd(dppf)C12 (86.7 mg, 118 pmol, 0.10 eq.) under nitrogen atmosphere. The mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate=100/l to 1/1) to give tert-butyl ( l-(8-( 1,3 -dimethyl- lH-pyrazol-5-yl)-5 -(((5 -fluoro-2, 3- dihydrobenzofiiran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin -2-yl)ethyl)carbamate (500 mg, 767 pmol, 64.7% yield, 80.0% purity) as a red solid. LCMS [M-99]: 422.3.

[0381] Step D: To a solution of tert-butyl ( l-(8-( l.3-dimcthyl-l7/-pyrazol-5-yl)-5-(((5-fluoro-2.3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin- 2-yl)ethyl)carbamate (500 mg, 767 pmol, 1.00 eq.) in dichloromethane (6.00 mL) was added TFA (2.00 mL). The mixture was stirred at 25 °C for 30 minutes. The mixture was adjusted to pH=8 with ammonium hydroxide and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: waters xbridge C18 150 x 50mm x 10pm;mobile phase: [water (10 mM NFUHCCLj-ACN]; B%: 22%-52%,11.5min) to give 2-(l- aminoethyl)-8-(l,3-dimethyl-lH-pyrazol-5-yl)-N-((5-fluoro-2, 3-dihydrobenzofiiran-4- yl)methyl)imidazo[l,2-c]pyrimidin-5-amine (280 mg, 661 pmol, 86.2% yield, 99.5% purity) as a white solid. LCMS [M+l]: 422.3.

[0382] ¹ H NMR (400 MHz, DMSO-t/ ₆ ) 5 = 8.23 (brt, J = 4.8 Hz, 1H), 7.94 (s, 1H), 7.63 (s, 1H), 6.96

- 6.88 (m, 1H), 6.68 (dd, J = 3.6, 8.4 Hz, 1H), 6.17 (s, 1H), 4.69 (br d, J = 4.0 Hz, 2H), 4.53 (t, J = 8.8 Hz, 2H), 4.04 - 3.99 (m, 1H), 3.68 (s, 3H), 3.29 - 3.26 (m, 2H), 2.16 (s, 3H), 1.99 (br s, 2H), 1.32 (d, J = 6.4 Hz, 3H).

[0383] Enantiomers of 2-( 1 -aminoethyl)-8-( 1 ,3-dimethyl- l7/-pyrazol-5-yl)-A'-((5-fluoro-2.3- dihydrobenzofuran-4-yl)methyl)imidazo[l,2-c]pyrimidin-5 -amine were separated by chiral SFC to provide enantiomerically pure compounds, Example 11 and Example 12.

[0384] Example 11: Column: Chiralcel OD-3 50x4.6mm I.D., 3um; Mobile phase: Phase A for CO2, and Phase B for IPA(0.05%DEA); Gradient elution: IPA (0.05% DEA) in CO2 from 5% to 40%. Flow rate: 3mL/min; Wavelength: 220nm. Column Temp: 35 °C; Back Pressure: lOOBar. t _r = 1.742 min. LCMS [M+l]: 422.1.

[0385] Tf NMR (400 MHz, CD ₃ OD) 5 = 8.23 (s, 1H), 8.07 (s, 1H), 6.90 - 6.79 (m, 1H), 6.72 (s, 1H), 6.64 (dd, J = 3.9, 8.7 Hz, 1H), 4.88 - 4.86 (m, 2H), 4.69 (q, J = 6.8 Hz, 1H), 4.59 (t, J = 8.7 Hz, 2H), 3.98 (s, 3H), 3.41 (t, J = 8.6 Hz, 2H), 2.47 (s, 3H), 1.73 (d, J = 6.8 Hz, 3H).

[0386] Example 12: Column: Chiralcel OD-3 50x4.6mm I.D., 3um; Mobile phase: Phase A for CO2, and Phase B for IPA(0.05%DEA); Gradient elution: IPA (0.05% DEA) in CO2 from 5% to 40%. Flow rate: 3mL/min; Wavelength: 220nm. Column Temp: 35 °C; Back Pressure: lOOBar. t _r = 1.796 min. LCMS [M+l]: 422.3.

[0387] ^X H NMR (400 MHz, CD3OD) 5 = 8.27 - 8.16 (m, 1H), 8.10 - 7.99 (m, 1H), 6.94 - 6.81 (m, 1H), 6.74 - 6.60 (m, 2H), 4.94 - 4.89 (m, 2H), 4.69 (br t, J = 6.8 Hz, 1H), 4.60 (/, J= 8.8 Hz, 2H), 3.96 (m, 3H), 3.42 (t, J = 8.8 Hz, 2H), 2.46 (br d, J = 10.0 Hz, 3H), 1.80 - 1.71 (m, 3H).

EXAMPLE 13

2-(aminomethyl)-A-((5-fluoro-2,3-dihydrobenzofuran-4-yl)m ethyl)-8-(2-methyl-4- (methylsulfonyl)phenyl)imidazo [ 1 ,2-c] pyrimidin-5 -amine yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (121 mg, 302. pmol, 1.00 eq) and 4, 4,5,5- tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-l,3,2-diox aborolane (150 mg, 456 pmol, 1.50 eq), sodium bicarbonate (76.0 mg, 905 pmol, 35.2 pL, 3.00 eq) in a mixture solvent of dioxane (1.70 mb) and water (0.30 mb) was added Pd(dppf)C12.CH2C12 (25.0 mg, 30.6 pmol, 0.10 eq). The mixture was stirred at 95 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was evaporated to give a residue, the residue was purified by prep-TLC (SiCE, dichloromethane: methanol = 20: 1) to give 5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-methyl- 4-(methylsulfonyl)phenyl)imidazo[l,2- c]pyrimidine-2 -carbonitrile (80.0 mg, 49.4% yield, 89.0% purity) as a light yellow solid. LCMS [M+l]:

478.1.

[0389] Tf NMR (400MHz, DMSO-d6) 5 = 8.93 (s, 1H), 8.58 (t, J = 5.2 Hz, 1H), 7.89 (d, J = 1.2 Hz, 1H), 7.83 - 7.78 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.04 - 6.89 (m, 1H), 6.72 (dd, J =3.6, 8.4 Hz, 1H), 4.73 (d, 7=4.8 Hz, 2H), 4.56 (t, 7=8.8 Hz, 2H), 3.37 - 3.29 (m, 2H), 3.26 (s, 3H), 2.28 (s, 3H).

[0390] Step B: A mixture of 5-(((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2- methyl-4- (methylsulfonyl)phenyl)imidazo[l,2-c]pyrimidine-2 -carbonitrile (80.0 mg, 149 pmol, 1.00 eq) and Raney nickel (15.0 mg) in methanol (1.50 mb) and ammonium hydroxide (0.50 mb) was degassed and purged with H2 3 times, and then the mixture was stirred under H2 (15 psi) at 25 °C for 12 hours. The reaction mixture was filtered and the filtrate was evaporated to give a residue, the residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25* 10pm; mobile phase: [water(0.05%HCl)- ACN];B%: 20%-40%,10min) to give 2-(aminomethyl)-N-((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)-8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[l,2- c]pyrimidin-5-amine (29.1 mg, 37.5% yield, 99.4% purity, HC1 salt) as a white solid. LCMS [M+l]: 482.2.

[0391] ’H NMR (400MHz, DMSO-d6) 5 = 8.82 (s, 1H), 8.43 ( s, 3H), 8.35 (s, 1H), 7.90 (s, 1H), 7.80 (d, 7= 7.6 Hz, 1H), 7.75 (s, 1H), 7.59 (d, 7= 8.0 Hz, 1H), 6.94 (t, 7= 9.2 Hz, 1H), 6.70 (dd, 7= 3.6, 8.4 Hz, 1H), 4.74 (br d, 7= 4.8 Hz, 2H), 4.55 (t, 7= 8.8 Hz, 2H), 4.10 (br d, 7= 5.6 Hz, 2H), 3.34 (t, 7= 8.8 Hz, 2H), 3.27 (s, 3H), 2.30 (s, 3H).

[0392] Following the teachings of the General Reaction Schemes, Examples 10 - 13, and the intermediates disclosed herein, Examples 14 - 24 were prepared as shown in Table 2. Table 2

Characterization of EXAMPLES 14-24

EXAMPLE 25

8-(l,3-dimethyl-lH-pyrazol-5-yl)-A-((5-fluoro-2,3-dihydro benzofuran-4-yl)methyl)-2- ((methylamino)methyl)imidazo [ 1 ,2-c]pyrimidin-5 -amine

[0393] To a solution of 8-( 1 ,3-dimethyl- lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbaldehyde (30.0 mg, 69.2 pmol, 1.00 eq.), methylamine (2.00 M in THF, 69.1 pL, 2.00 eq.) in methanol (2.00 mb) was added acetic acid (2.08 mg, 34.7 pmol, 1.98 pL, 0.50 eq.). The reaction mixture was stirred at 40 °C for 2 hours, then the mixture was added sodium triacetoxyborohydride (44.0 mg, 207 pmol, 3.00 eq.) in one portion and stirred at 40 °C for 2 hours. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was triturated with methanol (3.00 mL), the suspension was filtered, the filter cake was washed with water (2.00 mL), collected and dried in vacuo to 8-(l,3-dimethyl-lH-pyrazol-5-yl)-JV- ((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-2-((methylamin o)methyl)imidazo[l,2-c]pyrimidin-5- amine (8.07 mg, 27.1% yield, 97.7% purity) as a white solid. LCMS [M+l]: 422.4.

[0394] ¹ H NMR (400 MHz, DMSO-t/ ₆ ) 5 = 8.40 (br s, 1H), 8.10 (s, 1H), 7.71 (s, 1H), 6.94 (brt, J= 9.6 Hz, 1H), 6.77 - 6.63 (m, 1H), 6.20 (s, 1H), 4.72 (br d, J= 4.4 Hz, 2H), 4.55 (br t, J= 8.8 Hz, 2H), 3.98 (s, 2H), 3.69 (s, 3H), 3.30 - 3.28 (m, 2H), 2.46 (br s, 3H), 2.18 (s, 3H).

EXAMPLE 26

8-( 1 ,3-dimcthyl- 1 //-pyrazol-5-yl)-2-((dimcthylamino)mcthyl)-A'-((5-fluoro-2.3 -dihydrobcnzofii ran -4- yl)methyl)imidazo [ 1 ,2-c]pyrimidin-5 -amine [0395] To a solution of 2-(aminomethyl)-8-( 1 ,3-dimethyl- l//-pyrazol-5-yl)-A-((5-fluoro-2.3- dihydrobenzofuran-4-yl)methyl)imidazo[l,2-c]pyrimidin-5 -amine (19.9 mg, 45.8 pmol. 1.00 eq.) in methanol (1.00 mL) and DCE (1.00 mL) was added formaldehyde (7.44 mg, 91.6 pmol, 6.82 pL, 37.0% purity, 2.00 eq.), formic acid (220 pg, 4.58 pmol, 0.10 eq.) and sodium triacetoxyborohydride (19.4 mg, 91.6 pmol, 2.00 eq.), the reaction mixture was stirred at 25 °C for 12 hours. The reaction was fdtered and concentrated in vacuo to give a residue, the residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150><25xl0pm; mobile phase: [water(0.1%TFA)-ACN]; B%: 20%- 50%,9min) and lyophilization to give 2-[(dimethylamino)methyl]-8-(2,5-dimethylpyrazol-3-yl)-A-[(5 - fluoro -2,3-dihydrobenzofuran-4-yl)methyl]imidazo[l,2-c]pyrimidin-5 -amine (7.82 mg, 14.1 pmol, 30.7% yield, 98.9% purity, trifluoroacetic acid salt) as a white solid. LCMS [M+l]: 436.2.

[0396] ¹ H NMR (400 MHz, CD ₃ OD) 5 = 8.16 (S, 1H), 7.84 (S, 1H), 6.89 - 6.83 (m, 1H), 6.65 (dd, J = 4.0, 8.8 Hz, 1H), 6.30 (s, 1H), 4.84 (s, 3H), 4.59 (t, J= 8.8 Hz, 2H), 4.46 (s, 2H), 3.77 (s, 3H), 3.41 (t, J = 8.4 Hz, 2H), 2.92 (s, 6H), 2.30 (s, 3H).

2-(((8-( 1 ,3 -dimethyl- 1 H-py razol -5 -y 1) -5 -(((5 -fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)methyl)amino)et hane-l-sulfonyl fluoride

[0397] To a solution of 2-(aminomethyl)-8-(2,5-dimethylpyrazol-3-yl)-A- [(5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl]imidazo[l,2-c]pyrimidin-5-amin e (20.0 mg, 49.1 pmol, 1.00 eq.) in dichloromethane (0.50 mL) was added ethenesulfonyl fluoride (2.70 mg, 24.5 pmol, 0.50 eq). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Luna C18 150 x 25 5u; mobile phase: [water (0.075% TFA)-ACN]; B%: 18%-48%, 9min) to give 22-(((8-( l.3-dimcthyl-l//-pyrazol-5-yl)-5-(((5-fluoro-2.3- dihydrobenzofuran-4-yl)methyl)amino)imidazo [ 1 ,2-c]pyrimidin-2-yl)methyl)amino)ethane- 1 -sulfonyl fluoride (8.00 mg, 11.2 pmol, 22.9% yield, 88.6% purity) as ayellow solid. LCMS [M+l]: 518.2. [0398] ‘H NMR (400 MHz, DMSO-t/ ₆ ) 5 = 9.53 - 8.86 (m, 1H), 8.57 (br t, J= 5.2 Hz, 1H), 8.23 (s, 1H), 7.76 (s, 1H), 6.97 - 6.89 (m, 1H), 6.70 (dd, J= 4.0, 8.8 Hz, 1H), 6.21 (s, 1H), 4.72 (br d, J= 4.8 Hz, 2H), 4.54 (t, J= 8.8 Hz, 2H), 4.38 (s, 2H), 4.36 - 4.29 (m, 2H), 3.68 (s, 3H), 3.61 - 3.57 (m, 2H), 3.31 (brt, J= 8.8 Hz, 2H), 2.17 (s, 3H).

EXAMPLE 28

[0399] To a solution of 2-(aminomethyl)-8-( 1 ,3-dimethyl- l//-pyrazol-5-yl)-A'-((5-fluoro-2.3- dihydrobenzofuran-4-yl)methyl)imidazo[l,2-c]pyrimidin-5 -amine (30.0 mg, 73.6 pmol, 1 eq.) in dichloromethane (0.50 mb) was added ethenesulfonyl fluoride (7.30 mg, 66.3 pmol, 0.90 eq.). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Luna C18 150 x 25 5p; mobile phase: [water(0.075%TFA)-ACN]; B%: 30%-60%, 9 min) to give 2,2'-(((8-(l,3-dimethyl-lH-pyrazol-5-yl)-5- (((5-fhioro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[ l,2-c]pyrimidin-2- yl)methyl)azanediyl)bis(ethane-l -sulfonyl fluoride) (30.0 mg, 40.2 pmol, 54.6% yield, 99.3% purity, trifluoroacetic acid salt) as white oil. LCMS [M+l]: 628.4.

[0400] Tf NMR (400 MHz, DMSO-t/ ₆ ) 5 = 8.64 (br s, 1H), 8.13 (s, 1H), 7.86 (br s, 1H), 6.99 - 6.91 (m, 1H), 6.70 (dd, J = 4.0, 8.8 Hz, 1H), 6.23 (s, 1H), 4.74 (d, J = 4.8 Hz, 2H), 4.54 (t, J = 8.8 Hz, 2H), 4.19 - 4.12 (m, 4H), 3.91 (s, 2H), 3.68 (s, 3H), 3.31 (t, J = 8.8 Hz, 2H), 3.13 (t, J = 6.8 Hz, 4H), 2.19 (s, 3H).

EXAMPLE 29

2-(azetidin-l-yhnethyl)-A-((5-fhioro-2,3-dihydrobenzofura n-4-yl)methyl)-8-( 1 -methyl- lH-pyrazol-5- yl)imidazo[ 1 ,2-c]pyrimidin-5 -amine

[0401] To a solution of 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobe nzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbaldehyde (70.0 mg, 141 pmol, 1.00 eq.), azetidine hydrochloride (40.3 mg, 430 pmol, 3.05 eq.), Ti(Oi-Pr)4 (119 mg, 419 pmol, 124 pL, 2.96 eq.) and acetic acid (1.05 mg, 17.5pmol, 1.00 pL, 0.12 eq.) in DCE (2.50 mL) was added sodium cyanoborohydride (17.5 mg, 278 pmol, 1.97 eq.), the reaction was stirred at 25 °C for 1.5 hours. The reaction mixture diluted with ammonium chloride solution (20.0 mL) and the suspension was filtered, the filtrate was extracted with ethyl acetate (30.0 mL x 2). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25* 10pm; mobile phase: [water(0.05%HCl)-ACN]; B%: 20%-40%) to give 2-(azetidin-l- ylmethyl)-A-((5 -fluoro-2,3 -dihydrobenzo furan-4-yl)methyl)-8-( 1 -methyl- lH-pyrazol-5 -yl)imidazo [ 1 ,2- c]pyrimidin-5 -amine (25.6 mg, 48.4 pmol, 34.3% yield, 91.5% purity, hydrochloride) as a white solid. LCMS [M+l]: 448.2.

[0402] Tf NMR (400MHz, CD ₃ OD) 5 = 8.43 (s, 1H), 8.21 (s, 1H), 6.91 - 6.83 (m, 1H), 6.81 (s, 1H), 6.67 (dd, J = 4.0, 8.8 Hz, 1H), 4.91 (br s, 2H), 4.66 (s, 2H), 4.61 (t, J = 8.8 Hz, 2H), 4.40 - 4.17 (m, 4H), 4.02 (s, 3H), 3.44 (t, J = 8.8 Hz, 2H), 2.68 - 2.41 (m, 5H).

EXAMPLE 30

2-((cyclobutylamino)mcthyl)-8-( l.3-dimcthyl-I H-pyrazol-5-yl)-N-((5-fluoro-2.3-dihydrobcnzofiiran-4-

[0403] To a solution of 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobe nzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbaldehyde (30.0 mg, 73.8 pmol, 1.00 eq.) and cyclobutylamine (15.8 mg, 221 pmol, 19.0 pL, 3.00 eq.) in methanol (2.00 mb) was added acetic acid (39.4 mg, 656 pmol, 37.5 pL, 8.88 eq.). The mixture was stirred at 50 °C for 2 hours then sodium cyanoborohydride (9.28 mg, 148 pmol, 2.00 eq.) was added to the reaction mixture at 20 °C. The reaction mixture was stirred at 20 °C for 30 minutes. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25* lOum; mobile phase: [water(0.05%HCl)-ACN]; B%: 20%-40%) to give 2-[(cyclobutylamino)methyl]-8-(2,5-dimethylpyrazol-3-yl)-JV- [(5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl]imidazo[l,2-c]pyrimidin-5-amine (17.1 mg, 36.0 pmol, 48.8% yield, 96.9% purity) as a white solid. LCMS [M+l]: 462.5.

[0404] ’H NMR (400 MHz, DMSO-t/6) 5 = 10.00 (br s, 1H), 9.48 (br s, 1H), 8.65 (s, 1H), 7.97 (s, 1H), 6.96 - 6.87 (m, 1H), 6.68 (dd, J= 4.0, 8.8 Hz, 1H), 6.41 (s, 1H), 4.73 (br s, 2H), 4.53(t, J= 8.4 Hz, 2H), 4.15 (br s, 2H), 4.09 - 3.97 (m, 1H), 3.77 (s, 3H), 3.73 - 3.60 (m, 1H), 3.35 (brt, J= 8.8 Hz, 2H), 2.30 - 2.18 (m, 5H), 2.17 - 2.08 (m, 2H), 1.81 - 1.66 (m, 2H).

[0405] Following the teachings of the General Reaction Schemes, Examples 29 - 30, and the intermediates disclosed herein, Examples 31 - 33 were prepared as shown in Table 3. Table 3

Characterization of EXAMPLES 31-33 EXAMPLE 34

2-(l-aminoethyl)-A-((5-fluoro-2,3-dihydrobenzofuran-4-yl) methyl)-8-(2-methyl-4-

(methylsulfonyl)phenyl)imidazo [ 1 ,2-c] pyrimidin-5 -amine

[0406] Step A: A mixture of tert-butyl (l-(8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)ethyl)carbamate (70.0 mg, 138 pmol, 1.00 eq.), 4, 4,5,5- tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-l,3,2-diox aborolane (81.9 mg, 276 pmol, 2.00 eq.), Pd(dppf)C12 (10.1 mg, 13.8 pmol, 0.10 eq.) and sodium bicarbonate (34.8 mg, 415 pmol, 16.1 pL, 3.00 eq.) in a mixture solvent of water (0.40 mL) and dioxane (2.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 30 minutes under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was evaporated to give a residue. The residue was purified by prep-TLC (SiCE, petroleum ether/ethyl acetate= 1/1) to give tert-butyl (l-(5- (((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-8-(2-me thyl-4- (methylsulfonyl)phenyl)imidazo[l,2-c]pyrimidin-2-yl)ethyl)ca rbamate (80.0 mg, crude) as yellow oil. LCMS [M+l]: 596.1.

[0407] Step B: A solution of tert-butyl (l-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 8-(2-methyl-4-(methylsulfonyl)phenyl)imidazo[l,2-c]pyrimidin -2-yl)ethyl)carbamate (80.0 mg, 134 pmol, 1.00 eq.) in a mixture solvent of dichloromethane (3.00 mL) and trifluoroacetic acid (1.00 mL), the reaction mixture was stirred at 25 °C for 30 minutes. After completion of the reaction, the reaction mixture was evaporated to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mm><5um;mobile phase: [water(10mM NH4HCO ₃ )-ACN];B%: 22%-52%,10min) to give 2-(l-aminoethyl)-/V-((5-fluoro-2,3-dihydrobenzofiiran-4-yl)m ethyl)-8-(2-methyl-4- (methylsulfonyl)phenyl)imidazo[l,2-c]pyrimidin-5 -amine (25.9 mg, 50.0 pmol, 37.2% yield, 95.6% purity) as a white solid. LCMS [M+l]: 496.3.

[0408] Tf NMR (400M Hz, CD ₃ OD) 5 = 7.91 (s, 1H), 7.85 (dd, J = 1.6, 8.0 Hz, 1H), 7.80 (s, 1H), 7.62 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 6.92 - 6.78 (m, 1H), 6.64 (dd, J = 4.0, 8.8 Hz, 1H), 4.82 (s, 2H), 4.57 (t, J = 8.8 Hz, 2H), 4.35 - 4.18 (m, 1H), 3.41 - 3.34 (m, 2H), 3.16 (s, 3H), 2.31 (s, 3H), 1.46 (d, J = 6.8 Hz, 3H).

[0409] Following the teachings of the General Reaction Schemes, Example 34, and the intermediates disclosed herein, Examples 35 - 39 were prepared as shown in Table 4.

Table 4

Characterization of EXAMPLES 35 - 39

EXAMPLE 40 -(2-( 1 -aminoethyl)-5 -(((5 -fluoro-2,3 -dihydrobenzofuran-4-yl)methyl)amino)imidazo [ 1 ,2-c]pyrimidin- 8-yl)- 1 -methyl- lH-pyrazole-3-carbonitrile

[0410] Step A: A mixture of methyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole -3 -carboxylate (263 mg, 988 pmol, 2.00 eq.), tert-butyl (l-(8-bromo-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin- 2-yl)ethyl)carbamate (250 mg, 494 pmol, 1.00 eq.), bis(tri-tert-butylphosphine) palladium (0) (50.5 mg, 98.7 pmol, 0.20 eq.) and potassium carbonate (341 mg, 2.47 mmol, 5.00 eq.) in amixture solvent of dioxane (5.00 mL) and water (1.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was evaporated to give a residue. The residue was purified by column chromatography (SiCL, dichloromethane/methanol=l/0 to 10/1) to give methyl 5-(2- ( 1 -((tert-butoxycarbonyl)amino)ethyl)-5 -(((5 -fluoro-2,3 -dihydrobenzofuran-4- yl)methyl)amino)imidazo[ l,2-c]pyrimidin-8-yl)-l-methyl-lH-pyrazole-3-carboxylate (270 mg, 434 pmol, 88.0% yield, 91.0% purity) as an off-white solid. LCMS [M+l]: 566.6.

[0411] Tf NMR (400 MHz, CD ₃ OD) 5 = 7.81 (s, 1H), 7.78 (s, 1H), 6.95 (s, 1H), 6.85 (t, J = 9.6 Hz, 1H), 6.64 (dd, J = 4.0, 8.8 Hz, 1H), 4.83 (s, 2H), 4.58 (t, J = 8.8 Hz, 2H), 4.15 - 4.10 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.41 - 3.35 (m, 2H), 1.44 (s, 12H), 1.41 (s, 3H).

[0412] Step B: A mixture of methyl 5-(2-(l-((/ert-butoxycarbonyl)amino)ethyl)-5-(((5-fluoro-2,3 - dihydrobenzofuran-4-yl)methyl)amino)imidazo [ 1 ,2-c]pyrimidin-8-yl)- 1 -methyl- 1 H-py razolc-3 - carboxylate (250 mg, 402 pmol, 1.00 eq.) and sodium hydroxide (1.00 M in water, 1.21 mL, 3.00 eq.) in methanol (10.0 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 50 °C for 1 hour under a nitrogen atmosphere. After completion of the reaction, the mixture was acidified to pH=7 with hydrochloric acid aqueous solution (1.00 M). During this period, white precipitate was formed, the suspension was filtered, the filter cake was collected and dried in vacuo to give 5-(2-(l-((tert-butoxycarbonyl)amino)ethyl)-5-(((5-fluoro-2,3 -dihydrobenzofuran-4- yl)methyl)amino)imidazo[ l,2-c]pyrimidin-8-yl)-l-methyl-lH-pyrazole-3-carboxylic acid (250 mg, crude) as a white solid which was used directly.

[0413] ¹ H NMR (400 MHz, DMSO- ₆ ) 5 = 8.41 (S, 1H), 7.96 (S, 1H), 7.68 (S, 1H), 7.22 (br d, J = 7.6 Hz, 1H), 6.96 - 6.87 (m, 1H), 6.69 (dd, J = 4.0, 8.8 Hz, 1H), 6.50 (s, 1H), 4.77 - 4.66 (m, 3H), 4.54 (t, J = 8.8 Hz, 2H), 3.77 (s, 3H), 3.31 - 3.28 (m, 2H), 1.40 (s, 3H), 1.38 (s, 9H).

[0414] Step C: To a solution of 5-(2-(l-((tert-butoxycarbonyl)amino)ethyl)-5-(((5-fluoro-2,3 - dihydrobenzofuran-4-yl)methyl)amino)imidazo [ 1 ,2-c]pyrimidin-8-yl)- 1 -methyl- I H-py razolc-3 - carboxylic acid (230 mg, 417 pmol, 1.00 eq.) and ammonium chloride (66.9 mg, 1.25 mmol, 3.00 eq.) in DMF (3.00 mb) was added diisopropylethylamine (162 mg, 1.25 mmol, 218 pL, 3.00 eq.) and HATU (238 mg, 625 pmol, 1.50 eq.). The mixture was stirred at 25 °C for 30 minutes. After completion of the reaction, the reaction mixture was triturated with water (20.0 mb), the suspension was filtered and the cake was collected and dried under reduced pressure to give the crude tert-butyl (l-(8-(3-carbamoyl-l- methyl- 1 H-pyrazol-5-yl)-5 -(((5 -fluoro-2, 3 -dihydrobenzofuran -4-yl )methyl )amino)imidazo[ 1,2- c]pyrimidin-2-yl)ethyl)carbamate (140 mg, 254 pmol, 61.0% yield) as a white solid which was used into the next step directly.

[0415] ^X H NMR (400 MHz, DMSO-t/e) 5 = 8.42 (t, J = 4.4, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.48 (s, 1H), 7.26 - 7.19 (m, 1H), 6.99 - 6.91 (m, 1H), 6.79 (s, 1H), 6.70 (dd, J = 4.0, 8.8 Hz, 1H), 4.82 - 4.65 (m, 3H), 4.55 (t, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.30 - 3.29 (m, 2H), 1.41 (s, 3H), 1.39 (s, 9H).

[0416] Step D: To a mixture of tert-butyl ( l-(8-(3-carbamoyl-l-mcthyl-IH-pyrazol-5-yl)-5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c ]pyrimidin-2-yl)ethyl)carbamate (120 mg, 218 pmol, 1.00 eq.) and triethylamine (441 mg, 4.36 mmol, 607 pL, 20.0 eq.) in anhydrous tetrahydrofuran (2.00 mb) was added trifluoroacetic anhydride (458 mg, 2.18 mmol, 303 pL, 10.0 eq.) at 0 °C, The resulting mixture was warmed to 25 °C and stirred for 30 minutes. The reaction mixture diluted with ammonium chloride aqueous solution (20.0 mL) and the suspension was filtered, and the filtrate was extracted with ethyl acetate (30.0 mb* 2). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl ( l-(8-(3-cyano-l-mcthyl-IH-pyrazol-5-yl)-5-(((5-fluoro-2.3-di hydrobcnzofiiran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)ethyl)carbamate (120 mg, crude) as a yellow oil which used directly. LCMS [M+l]: 533.3.

[0417] Step E: A solution of tert-butyl ( l-(8-(3-cyano-l-mcthyl-IH-pyrazol-5-yl)-5-(((5-fluoro-2.3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidin- 2-yl)ethyl)carbamate (120 mg, 225 pmol, 1.00 eq.) in a mixture solvent of dichloromethane (1.50 mL) and trifluoroacetic acid (0.50 mL) was stirred at 25°C for 30 minutes. The reaction mixture was evaporated to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx5pm;mobile phase: [water(10mM NHJTCC^-ACN]; B%: 22%-52%,10min) to give 5-(2-(l-aminoethyl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo [ 1 ,2-c]pyrimidin-8-yl)- 1 -methyl- 1 H-py razolc-3 - carbonitrile (4.70 mg, 10.6 pmol, 4.72% yield, 97.8% purity) as a white solid. LCMS [M+l]: 433.3. [0418] ¹ H NMR (400 MHz, CD ₃ OD) 5 = 7.82 (s, 1H), 7.79 (s, 1H), 6.95 (s, 1H), 6.87 - 6.80 (m, 1H), 6.63 (dd, J = 4.0, 8.8 Hz, 1H), 4.82 (s, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.18 - 4.13 (m, 1H), 3.87 (s, 3H), 3.37 (t, J = 8.4 Hz, 2H), 1.49 (d, J = 6.4 Hz, 3H).

EXAMPLE 41

2-(amino(cyclopropyl)methyl)-8-(l,3-dimethyl-lH-pyrazol-5 -yl)-A-((5-fluoro-2,3-dihydrobenzofuran-

4-yl)methyl)imidazo [ 1 ,2-c]pyrimidin-5 -amine

[0419] Step A: 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.) in THF (1.00 mb) was added cyclopropyl magnesium bromide (0.50 M, 1.55 mb, 6.00 eq.) dropwise at 15 °C, the mixture was stirred at 25 °C for 5 hours, then the reaction mixture was cooled to -10 °C. Methanol (0.50 mb) was added to the reaction mixture, after 15 mins the reaction mixture was added sodium borohydride (19.5 mg, 515 pmol, 4.00 eq.) and stirred at 0 °C for 2 hours. Aqueous sodium bicarbonate (10.0 mb) was added to the reaction mixture and then extracted with ethyl acetate (10.0 mb x 3). combined and dried over sodium sulfate, concentrated to give 2-(amino(cyclopropyl)methyl)-8-bromo- A-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[l,2-c ]pyrimidin-5-amine (50.0 mg, 95.0 pmol, 74.0% yield, 82.0% purity) as yellow oil which was used for the next step without further purification.

[0420] Step B: To a mixture of 2-(amino(cyclopropyl)methyl)-8-bromo-A-((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)imidazo[l,2-c]pyrimidin-5 -amine (61.0 mg, 116 pmol, 1.00 eq.) and TEA (35.1 mg, 347 pmol, 48.3 pL, 3.00 eq.) in THF (2.00 mb) was added di-tert-butyl dicarbonate (50.5 mg, 231 pmol, 53.1 pL, 2.00 eq.) and DMAP (1.41 mg, 11.6 pmol, 0.10 eq.) in one portion at 20 °C under a nitrogen atmosphere. The reaction mixture was stirred at 20 °C for 3 hours. Water (3.00 mL) was added to the reaction mixture and then extracted with ethyl acetate (3.00 mL x 2). The combined organic phase was washed with brine (8.00 mL), dried over anhydrous sodium sulfate, fdtered, and concentrated in vacuo. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/1) to afford the final product tert-butyl ((8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)(cyclopropyl)me thyl)carbamate (40.0 mg, 75.1 pmol, 65.0% yield) as a yellow oil which used for the next step without further purification. LCMS [M+l]: 532.0.

[0421] Step C: tert-butyl ((8-bromo-5-(((5-fhioro-2,3-dihydrobenzofiiran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidin-2-yl)(cyclopropyl)me thyl)carbamate (40.0 mg, 75.1 pmol, 1.00 eq ), l,3-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) -lH-pyrazole (20.0 mg, 90.2 pmol, 1.20 eq.), Pd(dppf)C12 (5.50 mg, 7.51 pmol, 0.10 eq.) and sodium bicarbonate (18.9 mg, 225 pmol, 8.77 pL, 3.00 eq.) in dioxane (1.00 mL) and water (0.20 mL) was degassed and then heated to 100 °C for 2 hours under nitrogen atmosphere. The mixture was cooled to 20 °C and concentrated in reduced pressure. Water (10.0 mL) was added to the reaction mixture and then extracted with ethyl acetate (10.0 mL x 3). The combined organic phases were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/1) to afford tert-butyl (cyclopropyl(8-(l,3-dimethyl-lH-pyrazol-5-yl)- 5-(((5-fhioro-2,3-dihydrobenzofiiran-4-yl)methyl)amino)imida zo[l,2-c]pyrimidin-2- yl)methyl)carbamate (20.0 mg, 36.5 pmol, 48.6% yield) as a yellow oil which was used for the next step without further purification. LCMS [M+l]: 548.4.

[0422] Step D: To a mixture of tert-butyl (cyclopropyl(8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c ]pyrimidin-2-yl)methyl)carbamate (20.0 mg, 36.5 pmol, 1.00 eq.) in DCM (0.50 mL) was added TFA (770 mg, 6.75 mmol, 0.50 mL, 185 eq.) in one portion at 20 °C under a nitrogen atmosphere. The mixture was stirred at 20 °C for 2 hours. The solvent was removed under reduce pressure to give a residue which purified by prep-HPLC (column: Waters Xbridge 150x25mmx5pm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 32%-62%,10min) to give 2-(amino(cyclopropyl)methyl)-8-( l,3-dimethyl-lH-pyrazol-5-yl)-A-((5- fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[l,2-c]pyrim idin-5-amine (10.0 mg, 22.3 pmol, 61.1% yield, 99.9% purity) as a white solid. LCMS [M+l]: 448.4.

[0423] ’H NMR (400 MHz, CD ₃ OD) 5 = 7.95 (s, 1H), 7.73 (s, 1H), 6.91 - 6.82 (m, 1H), 6.66 (dd, J = 4.0, 8.8 Hz, 1H), 6.25 (s, 1H), 4.83 (s, 2H), 4.59 (t, J= 8.8 Hz, 2H), 3.74 (s, 3H), 3.38 (t, J= 8.8 Hz, 2H), 3.29 (br d, J= 8.8 Hz, 1H), 2.30 (s, 3H), 1.28 - 1.17 (m, 1H), 0.67 - 0.62 (m, 2H), 0.50 - 0.32 (m, 2H).

EXAMPLE 42

2-(l-amino-2,2,2-trifluoroethyl)-8-(l,3-dimethyl-lH-pyraz ol-5-yl)-A-((5-fluoro-2,3-dihydrobenzofuran-

[0424] Step A: To a solution of 8-( 1 ,3-dimethyl- lH-pyrazol-5-yl)-5-(((5-fluoro-2,3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine -2-carbaldehyde (80.0 mg, 197 pmol, 1.00 eq.) and di-tert-butyl dicarbonate (47.3 mg, 217 pmol, 49.7 pL, 1.10 eq.) in THF (1.00 mb) was added DMAP (2.40 mg, 19.7 pmol, 0.10 eq.). The reaction mixture was stirred at 35 °C for 1 hour. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiCh, petroleum ether/ethyl acetate = 2/1) to give tert-butyl (8-(l,3-dimethyl-lH-pyrazol-5-yl)-2- formylimidazo[l,2-c]pyrimidin-5-yl)((5-fhioro-2,3-dihydroben zofuran-4-yl)methyl)carbamate (85.0 mg, 168 pmol, 85.3% yield) as a gray solid.

[0425] ’H NMR (400 MHz, DMSO-t/ ₆ ) 5 = 10.08 (s, 1H), 8.40 (s, 1H), 8.20 (s, 1H), 6.82 - 6.76 (m, 1H), 6.61 (dd, J = 4.0, 8.8 Hz, 1H), 6.51 (s, 1H), 5.07 (s, 2H), 4.52 (t, J = 8.8 Hz, 2H), 3.76 (s, 3H), 3.28 - 3.29 (m, 2H), 2.22 (s, 3H), 1.32 (s, 9H).

[0426] Step B: To a solution of tert-butyl (8-(l,3-dimethyl-lH-pyrazol-5-yl)-2-formylimidazo[l,2- c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methy l)carbamate (85.0 mg, 168 pmol, 1.00 eq.) and potassium carbonate (46.4 mg, 336 pmol, 2.00 eq.) in DMF (1.00 mb) was added trimethyl(trifhroromethyl)silane (191 mg, 1.34 mmol, 8.00 eq.) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The reaction was poured into water (3.00 mb) and stirred for 15 mins. The aqueous phase was extracted with ethyl acetate (3.00 mb x 2). The combined organic phases were washed with brine (3.00 mb x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give tert-butyl (8-( l.3-dimcthyl-l7/-pyrazol-5-yl)-2-(2.2.2-trifluoro-l- hydroxyethyl)imidazo [ 1 ,2-c]pyrimidin-5 -y 1) ((5 -fluoro-2, 3 -dihydrobenzofuran -4-yl)methyl)carbamate (85.0 mg, 147 pmol, 87.9% yield) as a gray solid.

[0427] ¹ H NMR (400 MHz, DMSO-t/e) 5 = 8.11 (s, 1H), 7.60 (s, 1H), 7.01 (d, J = 6.8 Hz, 1H), 6.80 - 6.74 (m, 1H), 6.61 (dd, J = 4.0, 8.8 Hz, 1H), 6.46 (s, 1H), 5.34 (t, J = 6.8 Hz, 1H), 5.07 (s, 2H), 4.52 (t, J = 8.8 Hz, 2H), 3.72 (s, 3H), 3.29 - 3.26 (m, 2H), 2.21 (s, 3H), 1.29 (s, 9H).

[0428] Step C: To a solution of tert-butyl (8-( l.3-dimcthyl-l7/-pyrazol-5-yl)-2-(2.2.2-trifluoro-l- hydroxyethyl)imidazo [ 1 ,2-c]pyrimidin-5 -y 1) ((5 -fluoro-2, 3 -dihydrobenzofuran -4-yl)methyl)carbamate (22.0 mg, 38.2 pmol, 1.00 eq.) in DCE (1.00 mb) was added manganese dioxide (6.60 mg, 76.3 pmol, 2.00 eq.). The mixture was stirred at 40 °C for 1 hour. The mixture was filtered and concentrated in vacuo to give tert-butyl (8-( l.3-dimcthyl-l7/-pyrazol-5-yl)-2-(2.2.2-trifluoroacctyl)imid azo| 1,2- c]pyrimidin-5-yl)((5-fluoro-2,3-dihydrobenzofuran-4-yl)methy l)carbamate (16.0 mg, crude) as a white solid which was used without further purification in the next step.

[0429] Step D: To a solution of tert-butyl (8-( l.3-dimcthyl-IT/-pyrazol-5-yl)-2-(2.2.2- trifluoroacetyl)imidazo [ 1 ,2-c]pyrimidin-5 -yl)((5-fluoro-2,3 -dihydrobenzofuran-4-yl)methyl)carbamate (12.0 mg, 20.9 pmol, 1.00 eq.) in THF (0.50 mL) was added ammonia (711 pg, 41.8 pmol, 2.00 eq.) and titanium isopropoxide (11.9 mg, 41.8 pmol, 12.3 pL, 2.00 eq. ), the mixture was to adjust pH=4 with acetic acid (0.10 mL) and stirred at 40 °C for 30 minutes. Then the mixture was added sodium cyanoborohydride (2.63 mg, 41.8 pmol, 2.00 eq.) and stirred at 40 °C for another 2 hours. The mixture was poured into saturated ammonium chloride (3.00 mL) and stirred for 15 mins. The aqueous phase was extracted with dichloromethane (3.00 mL x 5). The combined organic phases were washed with brine (3.00 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give tert-butyl (2-( l-amino-2,2,2-trifluoroethyl)-8-( l.3-dimcthyl-IT/-pyrazol-5-yl)imidazo| l,2-c]pyrimidin- 5 -yl)((5 -fluoro-2, 3 -dihydrobenzofuran-4-yl)methyl)carbamate (12.0 mg, crude) as a white solid. LCMS [M+l]: 576.5.

[0430] Step E: To a solution of tert-butyl (2-( l-amino-2.2.2-trifluorocthyl)-8-( l.3-dimcthyl-l7/- pyrazol-5-yl)imidazo[l,2-c]pyrimidin-5-yl)((5-fluoro-2,3-dih ydrobenzofuran-4-yl)methyl)carbamate (10.0 mg, 17.4 pmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (0.30 mL). The mixture was stirred at 25 °C for 30 minutes. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25mm x 5pm; mobile phase: [water(10 mM NHJTCCLj-ACN]; B%: 27%-57%, lOmin) to give 2-(l-amino-2,2,2- trifluorocthyl)-8-( l.3-dimcthyl-l7/-pyrazol-5-yl)-A'-((5-fluoro-2.3-dihydrobcnz ofuran-4- yl)methyl)imidazo[l,2-c]pyrimidin-5-amine (6.00 mg, 12.2 pmol, 70.0% yield, 96.4% purity) as a white solid. LCMS [M+l]: 476.4.

[0431] Tf NMR (400 MHz, DMSO-t/ ₆ ) 5 = 8.42 (br s, 1H), 8.20 (s, 1H), 7.71 (s, 1H), 6.98 - 6.89 (m, 1H), 6.70 (dd, J = 4.0, 8.8 Hz, 1H), 6.20 (s, 1H), 4.71 (br s, 2H), 4.68 - 4.60 (m, 1H), 4.55 (t, J = 8.8 Hz, 2H), 3.68 (s, 3H), 3.31 - 3.27 (m, 2H), 2.43 (br d, J = 7.2 Hz, 2H), 2.18 (s, 3H). EXAMPLE 43

8-( l .3-dimcthyl- l//-pyrazol-5-yl)-A'-((5-fluoro-2.3-dihydrobcnzofiiran-4-yl) mcthyl)-2-(2//-tctrazol-5- yl)imidazo[ 1 ,2-c]pyrimidin-5 -amine

[0432] Step A: A mixture of 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (250 mg, 644 pmol, 1.00 eq.), 1,3-dimethyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (215 mg, 966 pmol, 1.50 eq.), Pd(dppf)C12 (47.1 mg, 64.4 pmol, 0.10 eq.) and sodium bicarbonate (162 mg, 1.93 mmol, 75.1 pL, 3.00 eq.) in dioxane (1.70 mL) and water (0.30 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 95 °C for 1 hour under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled and filtered, the filtrate was concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiCE, petroleum ether/ethyl acetate=3/l to 1/1) to give 8-( 1 ,3 -dimethyl- 1 H-pyrazol -5 -y 1) -5 -(((5 -fluoro-2,3 -dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbonitrile (170 mg, 379 pmol, 58.9% yield, 90% purity) as a yellow solid.

[0433] ’H NMR (400MHz, DMSO-t/ ₆ ) 5 = 8.92 (s, 1H), 8.63 (t, J = 4.8 Hz, 1H), 7.86 (s, 1H), 7.02 - 6.90 (m, 1H), 6.71 (dd, J = 4.0, 8.8 Hz, 1H), 6.23 (s, 1H), 4.72 (d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.67 (s, 3H), 3.32 - 3.30 (m, 2H), 2.18 (s, 3H).

[0434] Step B: To a mixture of -( 1,3 -dimethyl- lH-pyrazol-5-yl)-5 -(((5 -fluoro-2, 3 -dihydrobenzofuran- 4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbonitrile (20.0 mg, 44.6 pmol, 1.00 eq.) and ammonium chloride (2.50 mg, 46.7 pmol, 1.05 eq.) in DMF (1.00 mL) was added sodium azide (3.00 mg, 46.1 pmol, 1.03 eq.). The reaction mixture was heated at 100 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled and diluted with water (3.00 mL) and extracted with ethyl acetate (5.00 mLx 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25* 10pm; mobile phase: [water(0.05%HCl)- ACN]; B%: 20%-40%) to afford 8-(l,3-dimethyl-lH-pyrazol-5-yl)-A-((5-fluoro-2,3-dihydroben zofuran- 4-yl)methyl)-2-(2H-tetrazol-5-yl)imidazo[ l,2-c]pyrimidin-5-amine (19.7 mg, 43.1 pmol, 96.6% yield, 97.7% purity) as a white solid. LCMS [M+l]: 447.1.

[0435] ‘H NMR (400MHz, DMSO-t/ ₆ ) 5 = 8.99 (s, 1H), 8.64 (s, 1H), 7.80 (s, 1H), 7.04 - 6.87 (m, 1H), 6.71 (dd, J = 4.0, 8.8 Hz, 1H), 6.26 (s, 1H), 4.75 (d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.71 (s, 3H), 3.37 - 3.31 (m, 2H), 2.20 (s, 3H).

8-( l.3-dimcthyl-l//-pyrazol-5-yl)-A'-((5-fluoro-2.3-dihydrobcnz ofiiran-4-yl)mcthyl)-2-( 1,3,4-oxadiazol-

[0436] Step A: A mixture of ethyl 8-bromo-5-(((5-fluoro-2,3-dihydrobenzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carboxylate (800 mg, 1.84 mmol, 1.00 eq ), 1,3-dimethyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (612 mg, 2.76 mmol, 1.50 eq.), NaHCCh (463 mg, 5.51 mmol, 214 pL, 3.00 eq.) and Pd(dppf)C12 (134 mg, 184 pmol, 0.10 eq.) in water (1.60 mL) and dioxane (8.00 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 105 °C for 2 hours under a nitrogen atmosphere. The mixture was fdtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate=l/O to 0/1) to give 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 (750 mg, 1.66 mmol, 90.6% yield) as a yellow solid. LCMS [M+l]: 451.0.

[0437] Step B: To a solution of ethyl 8-( 1,3 -dimethyl- lH-pyrazol-5-yl)-5 -(((5 -fluoro-2, 3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine -2-carboxylate (400 mg, 888 pmol, 1.00 eq.) in ethanol (4.00 mL) was added hydrazine hydrate (178 mg, 3.55 mmol, 173 pL, 4.00 eq.) at 25 °C. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with methanol (3.00 mL), filtered, the filter cake was collected and dried to give 8-( 1 ,3-dimethyl- l//-pyrazol-5-yl)-5-(((5-fluoro-2.3- dihydrobenzofuran-4-yl)methyl)amino)imidazo[l,2-c]pyrimidine -2-carbohydrazide (190 mg, 435pmol, 49.0% yield) as a white solid.

[0438] ’H NMR (400MHz, DMSO-t/ ₆ ) 5 = 9.48 (br s, 1H), 8.65 (s, 1H), 8.48 (br s, 1H), 7.75 (s, 1H), 6.93 (brt, J = 8.8 Hz, 1H), 6.74 - 6.65 (m, 1H), 6.27 (s, 1H), 4.71 (br d, J = 3.6 Hz, 2H), 4.54 (brt,J = 8.8 Hz, 2H), 4.48 (br s, 2H), 3.72 (s, 3H), 3.30 - 3.28 (m, 2H), 2.18 (s, 3H).

[0439] Step C: To a solution 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobe nzofuran- 4-yl)methyl)amino)imidazo[l,2-c]pyrimidine-2 -carbohydrazide (50.0 mg, 97.4 pmol, 1.00 eq.) in triethoxymethane (2.00 mL) and DMSO (2.00 mL) was added ammonium chloride (20.8 mg, 390 pmol, 4.00 eq.), the reaction mixture was stirred at 130 °C for 1 hour. The reaction was concentrated in vacuo to give a residue, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25 5pM; mobile phase: [phase A: water(10mM NH4HCO3), phase B: ACN])and lyophilization to give 8-( 1 ,3- dimethyl-lH-pyrazol-5-yl)-/V-((5-fluoro-2,3-dihydrobenzofura n-4-yl)methyl)-2-(l,3,4-oxadiazol-2- yl)imidazo[l,2-c]pyrimidin-5 -amine (10.3 mg, 21.1 pmol, 21.7% yield, 91.4% purity) as a white solid. LCMS [M+l]: 447.3.

[0440] ’H NMR (400 MHz, DMSO-t/ ₆ ) 5 = 9.34 (s, 1H), 8.91 (br s, 1H), 8.62 (br s, 1H), 7.79 (s, 1H), 6.95 (br t, J = 9.2 Hz, 1H), 6.70 (br dd, J = 3.6, 8.4 Hz, 1H), 6.24 (s, 1H), 4.73 (s, 2H), 4.55 (br t, J = 8.4 Hz, 2H), 3.72 (s, 3H), 3.37 - 3.34 (m, 2H), 2.20 (s, 3H).

EXAMPLE 45

8-(l,3-dimethyl-lH-pyrazol-5-yl)-/V-((5-fluoro-2,3-dihydr obenzofuran-4-yl)methyl)-2-(oxazol-5- yl)imidazo[ 1 ,2-c]pyrimidin-5 -amine

[0441] To a solution of 8-(l,3-dimethyl-lH-pyrazol-5-yl)-5-(((5-fluoro-2,3-dihydrobe nzofuran-4- yl)methyl)amino)imidazo[l,2-c]pyrimidine-2-carbaldehyde (80.0 mg, 196 pmol, 1.00 eq.) in methanol (2.00 mb) were added p-toluene sulfonylmethyl isocyanide (64.0 mg, 328 pmol, 1.67 eq.) and potassium carbonate (81.6 mg, 590 pmol, 3.00 eq.). The reaction was stirred at 65 °C for 2 hours. The suspension was fdtered, the cake was collected and triturated with methanol (5.00 mL), then dried under vacuum to give 8-(l,3-dimethyl-lH-pyrazol-5-yl)-A-((5-fluoro-2,3-dihydroben zofuran-4-yl)methyl)-2-(oxazol-5- yl)imidazo[l,2-c]pyrimidin-5 -amine (37.4 mg, 80.2 pmol, 40.7% yield, 95.5% purity) as a white solid. LCMS [M+l]: 446.2.

[0442] ’H NMR (400 MHz, CD ₃ OD) 5 = 8.31 (s, 1H), 8.26 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 6.85 (t, J = 9.2 Hz, 1H), 6.64 (dd, J = 3.6, 8.8Hz, 1H), 6.26 (s, 1H), 4.83 - 4.80 (m, 2H), 4.57 (t, J = 8.8 Hz, 2H), 3.74 (s, 3H), 3.38 ( t, J = 8.8 Hz, 2H), 2.29 (s, 3H).

[0443] The compounds of the present disclosure may have one or more chiral center and, if so, are synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures or the individual components/isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer’s instructions, as well as methods described herein, e.g., EXAMPLES 11 and 12. Alternatively, compounds of the present disclosure may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the disclosure.

[0444] Also contemplated within the scope of the disclosure are variants of compounds of the present disclosure in which one or more hydrogen atoms have been replaced with deuterium. As exemplified herein, Intermediates B-7, B-8, C-7, C-8, and D-31 have one or more hydrogen atom replaced with deuterium. By substituting one or more hydrogen for deuterium on the Intermediates A - D exemplified herein, deuterated versions of the compounds of the present disclosure can be readily generated using methods well known in the art.

EXAMPLE A

[0445] This Example illustrates that exemplary compounds of the present disclosure inhibit PRC2 enzymatic activity. [0446] Ten-point dose-response curves for compounds of the present disclosure were determined using a Hot Spot HMT assay (Reaction Biology Corp; see Horiuchi et al., Assay Drug Dev Technol. (2013) 4: 227-236 doi: 10.1089/adt.2012.480). The assay uses purified human, His-tagged PRC2 complex, including N-terminal His-tagged EZH2 enzyme, N-terminal Flag-tagged embryonic ectoderm development protein (EED), N-terminal His-tagged suppressor of zeste 12 (SUZ12), N-terminal His- tagged AEBP2, and N-terminal His-tagged RbAp48. In this assay, the transfer of the tritiated methyl group from radiolabeled S-adenosyl methionine (SAM) to purified core histone protein by EZH2 is quantitated after filtration to determine the activity of the core PRC2 complex in the presence and absence of compound.

[0447] Briefly, compounds of the present disclosure were solubilized in DMSO and a series of 10, three-fold serial dilutions were made for each compound in 15% DMSO. The initial starting concentration for the serial dilutions of each compound was 1.0 pM. Control samples lacking compound, EZH2 enzyme or various reaction components also were prepared and processed in parallel with compound test samples. SAH (S-(5-adenosyl)-L-homocysteine) was used as a positive control for assay validation.

[0448] An aliquot of each serial dilution of test compound was added to deep 384 well plate using Acoustic Technology instrument (Echo 550, LabCyte) containing reaction buffer (50 mM Tris-HCl (pH 8.)), 0.01% Brij35, 1 mM EDTA, 1 mM DTT, 1 mM PMSF and 1% DMSO), 10 nM purified PRC2 complex and 0.05 mg/ml core histone H3 in a 5 pl volume. The reaction was mixed gently and then preincubated for 20 min at 30°C. The enzymatic reaction was initiated by adding 1 uM S-Adenosyl-L- [methyl - ³ H]methionine and incubated for 1 hr at 30°C. After 1 hr, the reaction product was detected using a filter binding method and the amount of tritiated H3 core histone was quantitated using a scintillation counter. The IC50 value for each compound was determined from each 10-point doseresponse curve using GraphPad Prism software and the results for exemplary compounds of Formula (I) are shown in Table 5. Key: A = <250 nM; B = >250 nM - <500 nM; and C = >500 nM - <2 pM.

Table 5

Inhibition of PRC2 -mediated Enzymatic Activity by Exemplary Compounds of Formula (I)

[0449] While the disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the present disclosure as come within known or customary practice within the art to which the disclosure pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.