WO2023183444A1 - Modulators of protein kinases - Google Patents

Abstract

Provided herein are small molecule protein kinase modulators having the formula I Pharmaceutical compositions comprising such, and their uses in treating one or more conditions are also disclosed.

Description

MODULATORS OF PROTEIN KINASES

RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/323,094, filed March 24, 2022, the entire contents of which are incorporated herein by reference.

BACKGROUND

[0002] The more than 523 typical and atypical kinases in the human kinome represent a constellation of enzymes that catalyze the transfer of a phosphate group from ATP to a variety of amino acid residues, such as tyrosine, serine, and threonine. By so doing, these enzymes and their interrelated networks are effectors of cellular signal transduction. In particular, receptor tyrosine kinases (RTKs) coupled with their downstream intracellular kinases and phosphatases mediated cascades and feedback loops establish critical conduits for the transfer and regulation of signals from the cell exterior into the nucleus where transcriptional regulation takes place. Phosphate transfer to specific sites on proteins results in enzyme activation or inactivation, changes in conformation, increased or decreased affinity for other proteins, appropriate localization, and in some cases targeting of proteins for degradation by the proteosome. Kinase inhibitors, design strategies, and various mechanisms of inhibition have been extensively reviewed [Zhang J., et.al. Nature Reviews Cancer (2009) 9: 28-39; Blanc J. et.al., Anti-Cancer Agents in Med. Chem. (2013) 13, 17 pages; Gross S. et.al., J. Clin. Invest. (2015) 125(5); 1780-9; Cosgarea I. et.al., J. der Deutsch. Dermatol. Gesellschaft, (2017) 887-93, DOI: 10.1111/ddg.13321 ]. In addition, mechanistically similar lipid kinases, such as PI3Ks and SPK1, also contribute to the regulatory process (Brown J.R., et.al., BMC Evolutionary Biology (2011) 11(4): 1471-2148; Alvarez S.E., et.al., Nature (2010) 465: 1084-1088).

[0003] Because these processes regulate essential functions in cell growth, proliferation, differentiation and development, division, adhesion, angiogenesis, stress responses, cell-cell or cell-matrix interactions, short range contact-mediated axional guidance and mitogenesis, the activities of RTKs and their downstream kinase partners in signal transduction are tightly regulated and balanced through control of external receptor ligands as well as expression of receptors, receptor antagonists, decoy receptors, and through redundancies or crosstalk between signaling pathways. Therefore, the aberrant expression of kinases or activating mutations in kinases, inactivating mutations in negative regulators, and alterations in phosphatase expression or activity, are known to participate in a variety of diseases, including many cancers.

SUMMARY

[0004] Provided herein are compounds having the Formula I.

and pharmaceutically acceptable salts thereof, wherein R¹, R², and R³ are as defined herein. These compounds act as modulators of protein kinase (e.g., kinase inhibitors) and are useful in treating conditions responsive to the inhibition of protein kinase (e.g., cancer). See e.g., Table 1 and 2.

[0005] Also provided are pharmaceutically acceptable compositions comprising the disclosed protein kinase inhibitors.

DETAILED DESCRIPTION

1. General Description of Compounds

[0006] In a first embodiment, provided is a compound having the Formula I:

or a pharmaceutically acceptable salt thereof, wherein

R¹ and R² are each independently selected from hydrogen, halo and (Ci-C4)alkyl;

R³ is phenyl or heteroaryl, each of which is optionally substituted with 1 to 2 groups selected from R^a;

R^a is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci- C₄)alkoxy, halo(Ci-C₄)alkoxy, halo, -S(O)[(Ci-C₄)alkyl], -S(O)₂[(Ci-C₄)alkyl], -S(Ci- C4)alkyl, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, phenyl, and 4- to 6-membered heteroaryl, wherein said phenyl and 4- to 6-membered heteroaryl are each optionally substituted with 1 to 2 groups selected from R^b; and wherein said (Ci-C4)alkyl, (Ci-C4)alkoxy, and -S(Ci- C4)alkyl are each optionally substituted with -NR^cR^d; R^b is selected from halo and (Ci-C4)alkyl; and

R^c and R^d are each independently selected from hydrogen and (Ci-C4)alkyl.

2. _ Definitions

[0007] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -NH(Ci-C4)alkyl means that the point of attachment for this group occurs on the nitrogen atom.

[0008] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0009] The term “alkyl” when used alone or as part of a larger moiety, such as “haloalkyl”, and the like, means saturated straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-4 carbon atoms, i.e., (Ci-C4)alkyl.

[0010] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, “(Ci-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy.

[0011] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine (e.g., -CF3, - CHF₂, etc.

[0012] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to -OCHF2 or -OCF3.

[0013] The term “heteroaryl” used alone or as part of a larger moiety refers to a 5- to 12- membered (e.g., a 5- to 7-membered or 5- to 6-membered) aromatic radical containing 1-4 heteroatoms selected from N, O, and S. A heteroaryl group may be mono- or bi-cyclic.

Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached.

[0014] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0015] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process e.g., to inhibit the activity of one or more kinases.

[0016] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0017] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0018] For use in medicines, the salts of the compounds described herein refer to nontoxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g. salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[0019] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that will elicit a desired or beneficial biological or medical response of a subject e.g., a dosage of between 0.01 - 100 mg/kg body weight/day.

3. _ Description of Exemplary Compounds:

[0020] In a second embodiment, the compound of Formula I is of the Formula II:

or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0021] In a third embodiment, the compound of Formula I is of the Formula III:

or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0022] In a fourth embodiment, the compound of Formula I is of the Formula IV :

or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for

Formula I.

[0023] In a fifth embodiment, R¹ in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof, is (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I. Alternatively, as part of a fifth embodiment, R¹ in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof, is methyl, wherein the remaining variables are as described above for Formula I.

[0024] In a sixth embodiment, R³ in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof, is selected from phenyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, imidazolyl, indolyl, and pyrrolyl, each of which are optionally substituted with 1 to 2 groups selected from R^a, wherein the remaining variables are as described above for Formula I or the fifth embodiment.

[0025] In a seventh embodiment, R^a in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof, is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, -S(O)[(Ci-C4)alkyl], -S(O)2[(Ci-C4)alkyl], -S(Ci-C4)alkyl, phenyl, and 4- to 6-membered heteroaryl, wherein said phenyl and 4- to 6-membered heteroaryl are each optionally substituted with 1 to 2 groups selected from R^b and wherein said (Ci-C4)alkyl, (Ci- C4)alkoxy, and -S(Ci-C4)alkyl are each optionally substituted with -NR^cR^d, wherein the remaining variables are as described above for Formula I or the fifth or sixth embodiment. Alternatively, as part of a seventh embodiment, R^a in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof, is selected from (Ci-C4)alkyl, halo(Ci- C₄)alkyl, -S(O)[(Ci-C₄)alkyl], -S(O)₂[(Ci-C₄)alkyl], -S[(Ci-C₄)alkyl]N[(Ci-C₄)alkyl]₂, - O[(Ci-C4)alkyl]N[(Ci-C4)alkyl]2, phenyl, pyrazolyl, and imidazolyl wherein said phenyl, pyrazolyl, and imidazolyl are each optionally substituted with 1 to 2 groups selected from R^b, wherein the remaining variables are as described above for Formula I or the fifth or sixth embodiment.

[0026] In an eighth embodiment, R^b in the compound of any one of Formulae I to IV, or a pharmaceutically acceptable salt thereof, is selected from halo and (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I or the fifth, sixth, or seventh embodiment.

[0027] Compounds having the disclosed formulae are further disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included.

4. Uses, Formulation and Administration

[0028] The compounds and compositions described herein are generally useful for modulating the activity of protein kinase. In some aspects, the compounds and pharmaceutical compositions described herein inhibit the activity of protein kinase. [0029] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a disorder associated with protein kinase function. Thus, provided herein are methods of treating a condition associated with protein kinase function, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof. Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a condition associated with protein kinase function. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for use in treating a condition associated with protein kinase function. [0030] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a condition selected from an inflammatory disease, a neurodegenerative disease, cardiovascular disease, metabolic disease, pain, and cancer. [0031] Examples of inflammatory disease include, but are not limited to, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, osteo-arthritis, progression of atherosclerotic plaques, bone metastasis, asthma, interstitial cystitis, atopic dermatitis, psoriasis and systemic lupus erythematosus (SLE).

[0032] Examples of neurodegenerative disease include, but are not limited to, Alzheimer’s, Parkinson's disease, and multiple sclerosis.

[0033] Examples of cardiovascular disease include, but are not limited to, hypertension, coronary and cerebral vasospasm, restenosis, atherosclerosis, stroke, and heart failure [0034] Examples of metabolic disease include, but are not limited to, type 1 diabetes, type 2 diabetes.

[0035] Examples of cancer include, but are not limited to, colon, lung, ovarian, kidney, pancreatic, thyroid, hepatocellular, renal, gastric, breast, and brain cancers.

[0036] In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0037] In some aspects, the pharmaceutical compositions are administered orally.

[0038] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition.

EXEMPLIFICATION

[0039] Kinase compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

ACN: acetonitrile

^<:C: degrees Celsius d: chemical shift in parts per million downfield from tetramethylsilane dichloromethane (CH2CI2)

DCM: dimethylformamide

DMF: dimethylsulfoxide Et20: diethyl ether

EtOAc: ethyl acetate

ES⁺: electro spray ionization

Et: ethyl g: gram(s)

Hex: hexanes h: hour(s)

HPLC: high performance liquid chromatography

Hz: hertz

J: coupling constant (in NMR spectrometry)

LCMS: liquid chromatography mass spectrometry m: micro m: multiplet (spectral); meter(s); milli

M: molar

M⁺: parent molecular ion

Me: methyl

MeOH: methanol

MHz: megahertz min: minute(s) mol: mole(s); molecular (as in mol wt) mL: milliliter

NIS: A- iodosuccinimide

MS: mass spectrometry nm: nanometer(s)

NMR: nuclear magnetic resonance pH: potential of hydrogen; a measure of the acidity or basicity of an aqueous solution

PE: petroleum ether rt: room temperature s: singlet (spectral) t: triplet (spectral)

T: temperature

TFA: trifluoroacetic acid

THF: tetrahydrofuran General Analytical Techniques

[0040] LCMS

[0041] Liquid Chromatography Mass Spectrometry (LCMS) was performed on a

Shimadzu LCMS system consisting of Nexera XR HPLC stack (20 Series) with Nexera X2 SPD-M30A DAD and LCMS-2020 mass spectrometer using LabSolutions, v.5.89 software under the following parameters: Column temp: 45°C, Sample temp: 18°C. Gradient elution methods, mobile phase eluents, and columns are shown below.

[0042] Alternatively, Liquid Chromatography Mass Spectrometry (LCMS) was performed on a Shimadzu SCL-10AVP HPLC/PE SCIEX API 100/365 mass spectrometer under the following parameters: Column: Agilent, Eclipse XDB-C18; Length:50 mm;

Diameter: 3 mm; pore size: 2.7 micron. Column temp: 50 °C, Sample temp: room temperature. Gradient elution methods and mobile phase eluents are shown below.

[0043] Solvent A (0.1% Trifluoroacetic acid in water, pH =2.3)

[0044] Solvent B (0.1% Trifluoroacetic acid in acetonitrile)

[0046] 00951008_BB 1 (0.8 mL/min flow)

[0047] 05991008_BBl (0.8 mL/min flow) - mixed mode column 1

[0048] 05990510_AA0 (1.0 mL/min flow) - RP column 2

[0049] 05991008_BBlHT (0.8 mL/min flow, column temp 50°C) - mixed mode column

2

[0050] Method A-6; polar_6min_100_1500 (1.5 mL/min flow)

[0052] Method A-12; polar_12min_100_1500 (1.5 mL/min flow)

[0053] Neutral mobile phase [0054] Solvent A (20 mM ammonium acetate in 10% MeOH/water, pH 7.4)

[0055] Solvent B (100% acetonitrile)

[0056] Acidic mobile phase

[0057] Solvent A (0.1% formic acid in water, pH 2.3)

[0058] Solvent B (0.1% formic acid in acetonitrile)

[0059] Columns

[0060] RP column 1: ACE EXCEL 3 C18; 3.0 urn, 100 x 3 mm (Mac-Mod Part # EXL- 111-1003U)

[0061] RP column 2: Zorbax Eclipse XDB C8; 1.8 um, 50 x 4.6 mm (Agilent Part # 922975-906)

[0062] Mixed Mode column 1: Scherzo SM-C18; 3.0 um, 100 x 3 mm (Imtakt Part # SM034)

[0063] Mixed Mode column 2: Scherzo SM-C 18; 3.0 um, 75 x 2 mm (Imtakt Part #

SM023)

[0064] HPLC

[0065] Preparative High-performance liquid chromatography (HPLC) was performed on a Shimadzu HPLC equipped with 2 x LC-lOADvp pumps, Rheodyne 7725i manual injection valve, SPD-lOAVvp UV/vis detector, SCL-lOAvp system controller, and FRC-10A fraction follector using LabSolutions Lite, v.6.43 SP1 software and under the following conditions: Column temp: ambient; sample temp: ambient. Elution methods and mobile phase eluents are shown below.

[0066] Preparative isocratic HPLC 1 [Method RP-2525-2080]

[0067] Preparative HPLC gradient [Method RP-2040-2099]

| 30.0 _ | 9.99 _ | 80 _ | 20 _ |

[0068] Neutral mobile phase

[0069] Solvent A (20 mM ammonium acetate in 10% MeOH/water, pH = 7.4)

[0070] Solvent B (100% acetonitrile)

[0071] Acidic mobile phase

[0072] Solvent A (0.1% formic acid in water, pH =2.3)

[0073] Solvent B (100% acetonitrile)

[0074] Columns

[0075] RP: MACCEL PREP2005; 10.0 urn; 50 x 20 mm (Bischoff Part # B052

0F180PS100)

[0076] YMC-Pack ODS-A; 5.0 urn; 150 x 10 mm (YMC Part # AA12S05-1510WT)

[0077] ACE 5 C18-PFP; 5.0 urn; 150 x 10 mm (Avantor-ACE Part # ACE-1210-1510)

[0078] GPC: TSKgel a-2500; 7.0 urn, 300 x 7.8 mm; (TOSOH Part # 0018339)

[0079] ’ H NMR Proton NMR was performed on the Varian Inova 500 spectrometer operating at 500 MHz in CDCI3, DMSO-tfo, or MeOD.

[0080] Synthesis of 2-(4-fhiorophenyl)-N-[4-methyl-3-[[3-(9H-purin-6-yl)-2- pyridyl]amino]phenyl]furan-3-carboxamide [Example 1]:

Intermediate 1 Intermediate 2 Example 1

[0081] A solution of 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]benzene-l,3-diamine Intermediate 1 (50 mg, 0.125 mmol, 1.00 eq) in DMF (1.5 mL, 0.0830 M) and 2-(4-fluorophenyl)furan-3-carboxylic acid Intermediate 2 (31 mg, 0.149 mmol, 1.20 eq) was charged with Diisopropylethylamine (0.065 mL, 0.374 mmol, 3.00 eq) and N - [(Dimethylamino)- 1 H- 1 ,2,3 -triazolo- [4,5-b]pyridin- 1 -ylmethylene] -N- methylmethanaminium hexafluorophosphate N-oxide (95 mg, 0.249 mmol, 2.00 eq) was added. The mixture was stirred at rt for 3h. The reaction mixture was quenched with aq sat NaHCOs (10 mL) and stirred for 1 h. The solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCCh (2 x 5 mL), IM LiCl (10 mL), H2O (2 x 5 mL), Hexanes (2 x 5 mL), and ether (2 x 5 mL). Aqueous layer was extracted with DCM (3 X 10 mL), dried, evaporated and combined with the filter cake. Crude was purified by column chromatography over silica gel, SilicaSep, CombiFlash, 4g cartridge (dry load, 1.0- 1.5% MeOH-DCM as eluent) to afford 2-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9-tetrahydropyran- 2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]furan-3-carboxamide (48 mg, 0.0798 mmol, 64.06 % yield) as a yellow solid. 1H NMR (500 MHz, Chloroform-d) 6 12.15 (s, 1H), 9.70 (d, J = 7.7 Hz, 1H), 8.99 (s, 1H), 8.54 - 8.14 (m, 1H), 7.89 (dd, J = 9.0, 5.4 Hz, 2H), 7.47 (s, 1H), 7.29 - 7.00 (m, 4H), 6.94 (dd, J = 7.9, 4.6 Hz, 1H), 6.82 (s, 1H), 6.08 - 5.65 (m, 1H), 4.22 (d, J = 11.0 Hz, 1H), 4.06 - 3.67 (m, 1H), 2.48 (s, 2H), 2.27 - 2.02 (m, 1H), 2.02 - 1.64 (m, 4H).. MS(ESI⁺) mJz calc'd for [M+H]⁺[C33H28FN7O3+H]⁺: 590.23 found: 590.4, t_R = 2.64 mins. LC-MS Method: Merckmillipore Chromolith SpeedROD C18 column (50 x 4.6 mm) and a dual gradient run from 5-100% mobile phase B over 6 minutes. Mobile phase A = water (0.1 % CF3CO2H). Mobile phase B = acetonitrile (0.1 % CF3CO2H).

[0082] A solution of 2-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin- 6-yl)-2-pyridyl]amino]-phenyl]furan-3-carboxamide (48 mg, 0.0798 mmol, 1.00 eq) in DCM (1 mL, 0.0814 M) was added trifluoroacetic acid (0.61 mL, 7.98 mmol, 100 eq) and stirred at rt for 24 h. The reaction mixture was evaporated in vacuo, quenched with aq sat NaHCOs (10 mL) and stirred for 1 h. The solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCOs (2 x 5 mL), H2O (2 x 5 mL) and purified under neutral conditions by HPLC purification to afford 2-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9H-purin- 6-yl)-2-pyridyl]amino]phenyl]furan-3-carboxamide Example 1 (9.0 mg, 0.0170 mmol, 21.33 % yield) as a yellow solid. ’ H NMR (500 MHz, DMSO- ₆) 6 12.51 (s, 1H), 10.05 (s, 1H), 9.83 (d, J = 7.8 Hz, 1H), 8.91 (d, 7 = 2.7 Hz, 1H), 8.56 (d, 7 = 2.3 Hz, 1H), 8.47 (d, 7 = 4.1 Hz, 1H), 8.26 (d, 7 = 4.9 Hz, 1H), 7.94 - 7.86 (m, 2H), 7.83 (d, 7 = 2.1 Hz, 1H), 7.38 (d, 7 = 6.7 Hz, 1H), 7.31 - 7.23 (m, 2H), 7.18 (d, 7 = 8.3 Hz, 1H), 7.05 (s, 1H), 6.97 (dd, 7 = 7.8, 4.6 Hz, 1H), 6.50 (s, 1H), 2.41 (s, 3H). MS(ESI+) m/z calc’d for [M+H]⁺[C28H2oFN₇02+H]⁺: 506.17 found: 506.2, t_R = 1.94 mins. [Method B].

[0083] Synthesis of 2-(2-(Dimethylamino)ethylthio)-N-(3-(3-(9H-purin-6-yl)pyridin- 2-ylamino)-4-methylphenyl)-5-(4-fhiorophenyl)-lH-imidazole-4-carboxamide [Example 2]:

Intermediate 1 Intermediate 3 Example 2

[0084] To a solution of 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]benzene-l,3-diamine Intermediate 1 (50 mg, 0.125 mmol, 1.00 eq) and HATU (95 mg, 0.249 mmol, 2.00 eq) in DMF (1.5 mL, 0.0830 M) at rt was added DIPEA (0.065 mL, 0.374 mmol, 3.00 eq) and 2-((2-(dimethylamino)ethyl)thio)-5-(4-fluorophenyl)-lH- imidazole-4-carboxylic acid intermediate 3 (46 mg, 0.149 mmol). The reaction mixture was stirred at this temperature for Ih. Cold water (10 mL) was added to the reaction mixture, solids were filtered, washed with saturated sodium bicarbonate solution (10 mL) followed by IM LiCl (2 x 10 mL), water (2 x 5 mL) and hexanes and dried under reduced pressure. Crude was purified by prep-TLC (Silica gel 60 F254, 2.5% MeOH/ DCM as mobile phase) followed by prep-HPLC (neutral condition) to afford 2-[2-(dimethylamino)ethylsulfanyl]-5-(4- fluorophenyl)-N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]amino]phenyl]-lH-imidazole-4-carboxamide (21 mg, 0.0288 mmol, 23.12 % yield) as yellow solid. ’ H NMR (500 MHz, Chloroform-d) 8 12.03 (s, IH), 9.67 (dd, J = 7.8, 2.0 Hz, IH), 8.97 (s, IH), 8.43 - 8.29 (m, 3H), 7.86 - 7.75 (m, 2H), 7.60 (dd, J = 8.2, 2.3 Hz, IH), 7.18 (d, 7 = 8.4 Hz, IH), 7.11 (t, 7 = 8.7 Hz, 2H), 6.91 (dd, 7 = 7.9, 4.7 Hz, IH), 5.87 (dd, 7 = 10.4, 2.5 Hz, IH), 4.21 (dt, 7 = 11.8, 2.2 Hz, IH), 4.00 - 3.63 (m, IH), 3.12 - 3.02 (m, 2H), 2.99 - 2.88 (m, 2H), 2.43 (s, 3H), 2.38 (s, 6H), 2.32 - 2.14 (m, IH), 2.12 - 2.02 (m, 2H), 1.82 (tq, 7 = 12.9 7.4 Hz, 2H), 1.68 (t, 7 = 2.0 Hz, IH). MS(ESI⁺) mJz calc'd for [M+H]⁺[C36H₃7FNIO0₂S+H]⁺: 693.3 found: 693.4, t_R = 2.11 mins. [Method A-6].

[0085] To a stirred solution of 2-[2-(dimethylamino)ethylsulfanyl]-5-(4-fluorophenyl)- N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]-lH- imidazole-4-carboxamide (20 mg, 0.0289 mmol, 1.00 eq) in DCM (1 mL, 0.0289 M) at rt was added TFA (0.22 mL, 2.89 mmol, 100 eq). The reaction mixture was stirred at rt for 2h. Volatiles were removed, and the residue was diluted with cold water at 0 °C. To this was slowly added aq sat NaHCCh (10 mL). Solids were filtered, washed with water (3 x 10 mL) followed by diethyl ether (2 x 10 mL) and dried under reduced pressure to afford 2-[2- (dimethylamino)ethylsulfanyl]-5-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9H-purin-6-yl)-2-pyri- dyl] amino] -phenyl] -lH-imidazole-4-carboxamide Example 2 (8.0 mg, 0.0123 mmol, 42.71 % yield) as a yellow solid. ’H NMR (500 MHz, DMSO- ₆) 6 13.07 (s, 1H), 10.05 (dd, J = 7.7, 2.0 Hz, 1H), 9.49 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 8.24 (dd, J = 4.8, 2.2 Hz, 3H), 8.07 (s, 1H), 7.53 (d, J = 6.7 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.91 (dd, J = 7.7, 4.7 Hz, 1H), 3.13 (s, 2H), 2.59 (dd, J = 8.7, 6.4 Hz, 2H), 2.42 (s, 3H), 2.20 (s, 6H). MS(ESI⁺) mJz calc'd for [M+H]⁺[C₃IH₂9FNIOOS+H]⁺: 609.2 found: 609.4, t_R = 1.91 mins. [Method B].

[0086] Synthesis of l-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9H-purin-6-yl)-2- pyridyl]amino]phenyl]pyrazole-3-carboxamide [Example 3]:

Intermediate 1 Intermediate 4 Example 3

[0087] To a stirred solution of l-(4-fluorophenyl)-lH-pyrazole-3-carboxylic acid Intermediate 4 (28 mg, 0.137 mmol, 1.10 eq) in 0.5 ml DMF at 25 °C was added a solution of HATU (66 mg, 0.174 mmol, 1.40 eq) in 0.5 ml of DMF, the resulting solution was stirred for 10 minutes, then solution of 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]benzene-l,3-diamine Intermediate 1 (50 mg, 0.125 mmol, 1.00 eq) in 1 ml DMF and N,N-Diisopropylethylamine (0.039 mF, 0.224 mmol, 1.80 eq) was added. The resulting reaction mixture was stirred at 25 °C with LCMS monitoring for Ihour, then quenched with aq. NaHCO3, stirred for 30 minutes, filtered, the solid was washed successively with water, IM LiCl, water and ether afforded l-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9-tetrahydropyran- 2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]pyrazole-3-carboxamide (65 mg, 0.108 mmol, 86.61 % yield) as a bright yellow solid. 1H NMR (500 MHz, Chloroform-d) 6 12.11 (s, 1H), 9.89 - 9.60 (m, 1H), 9.10 - 8.71 (m, 2H), 8.66 - 8.29 (m, 3H), 8.03 - 7.52 (m, 3H), 7.42 - 6.85 (m, 5H), 6.04 - 5.81 (m, 1H), 4.40 - 4.12 (m, 1H), 3.96 - 3.75 (m, 1H), 2.48 (d, J = 3.9 Hz, 3H), 2.33 - 1.97 (m, 3H), 1.97 - 1.47 (m, 5H). [M+H]⁺ MS(ES⁺) m/z cala'd for [M+H] : 590.4 found: 590.3, t_R = 5.17 mins. [Method: B]. [0088] A solution of l-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin- 6-yl)-2-pyridyl]amino]phenyl]pyrazole-3-carboxamide (65 mg, 0.108 mmol, 1.00 eq) in DCM (1 mL, 0.1101 M) and Trifluoroacetic acid (0.83 mL, 10.8 mmol, 100 eq) was stirred at 25 °C for 1.5 hrs with LCMS monitoring, then concentrated under reduced pressure afforded a residue, to the residue was added cold aq. NaHCO3 with vigous stirring to precipitate the desired compound, stirred for 10 minutes, filtered, washed with water and ether, dried in vacuum for overnight afford l-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9H-purin- 6-yl)-2-pyridyl]amino]phenyl]pyrazole-3-carboxamide Example 3 (49 mg, 0.0944 mmol, 87.52 % yield) as a ginger yellow solid.1H NMR (500 MHz, DMSO-d6) 8 12.29 (s, 1H), 10.02 (s, 1H), 9.80 - 9.74 (m, 1H), 9.04 (s, 1H), 8.69 - 8.64 (m, 2H), 8.60 (d, J = 2.6 Hz, 1H), 8.34 (dd, J = 4.6, 2.0 Hz, 1H), 8.10 - 8.02 (m, 2H), 7.46 (dd, J = 8.2, 2.3 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.22 (d, J = 8.5 Hz, 1H), 7.06 - 6.98 (m, 2H), 2.42 (s, 3H). MS(ES⁺) m/z cala'd for [M+H] : 506.2, found LCMS 506.2 t_R= 2.13 min [Method: B],

[0089] Synthesis of N-(3-((3-(9H-purin-6-yl)pyridin-2-yl)amino)-4-methylphenyl)-l- phenyl-lH-pyrazole-5-carboxamide [Example 4]:

Intermediate 1 Intermediate 5 Example 4

[0090] To a stirred solution of 1 -Phenyl- lH-pyrazole-5-carboxylic acid Intermediate 5 (26 mg, 0.137 mmol, 1.10 eq) in 0.5 ml DMF at 25 °C was added a solution of HATU (66 mg, 0.174 mmol, 1.40 eq) in 0.5 ml of DMF, the resulting solution was stirred for 10 minutes, then solution of 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]benzene-l,3- diamine Intermediate 1 (50 mg, 0.125 mmol, 1.00 eq) in 1 ml DMF and N,N- Diisopropylethylamine (0.039 mL, 0.224 mmol, 1.80 eq) was added. The resulting reaction mixture was stirred at 25 °C for 1.5 hrs with LCMS monitoring, then quenched with aq. NaHCO3, stirred for 30 minutes, filtered, the solid was washed successively with water, IM LiCl, water and ether afforded N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]amino]phenyl]-2-phenyl-pyrazole-3 -carboxamide (70 mg, 0.116 mmol, 93.41 % yield) as a bright yellow solid. 1H NMR (500 MHz, Chloroform-d) 6 12.14 (s, 1H), 9.70 (dt, J = 7.9, 2.2, 2.2 Hz, 1H), 8.98 (d, J = 2.2 Hz, 1H), 8.39 - 8.30 (m, 3H), 8.01 (s, 1H), 7.89 (s, 1H), 7.64 (t, J = 2.2, 2.2 Hz, 1H), 7.47 (dd, J = 19.0, 7.4 Hz, 4H), 7.43 - 7.36 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.93 (ddd, J = 7.8, 4.7, 2.1 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 5.91 - 5.85 (m, 1H), 4.25 - 4.19 (m, 1H), 3.83 (td, J = 11.8, 11.8, 2.7 Hz, 1H), 2.99 - 2.93 (m, 3H), 2.88 (d, J = 2.2 Hz, 2H), 2.43 (d, J = 2.2 Hz, 3H), 2.21 (d, J = 11.8 Hz, 1H), 2.10 (s, 1H), 1.83 (tt, J = 10.1, 10.1, 4.1, 4.1 Hz, 2H). MS(ES⁺) m/z cala'd for [M+H] ⁺: 590.4 found: 590.3, t_R = 5.17 mins. [Method: B].

[0091] A solution of N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]amino]phenyl]-2-phenyl-pyrazole-3 -carboxamide (70 mg, 0.120 mmol, 1.00 eq) in DCM (1 mL, 0.1225 M) and trifluoroacetic acid (0.92 mL, 12.0 mmol, 100 eq) was stirred at rt for 1.5 hrs, then concentrated under reduced pressure. The residue was then added cold aq. NaHCOs with vigorous stirring for 10 minutes, filtered, washed with water and ether, dried in vacuum overnight to afford N-(3-((3-(9H-purin-6-yl)pyridin-2-yl)amino)-4- methylphenyl)-l-phenyl-lH-pyrazole-5-carboxamide Example 4 (57 mg, 0.115 mmol, 95.57 % yield) as a ginger yellow solid. ¹ H NMR (500 MHz, DMSO-d6) 8 12.30 (s, 1H), 10.50 (s, 1H), 9.77 (s, 1H), 9.06 (s, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.29 (dd, J = 4.8, 2.0 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 4.9 Hz, 4H), 7.41 - 7.32 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 7.06 - 7.01 (m, 2H), 2.38 (s, 3H). MS(ES⁺) m/z cala'd for [M+H] ⁺: 488.2, found: 488.2, t_R = 1.85 min. [Method: B].

[0092] Synthesis of 3-(4-Fluorophenyl)-N-[4-methyl-3-[[3-(9H-purin-6-yl)-2- pyridyl]amino]phenyl]-lH-pyrrole-2-carboxamide [Example 5]:

Intermediate 1 Intermediate 6 Example 5

[0093] A solution of Diisopropylethylamine (0.037 mL, 0.211 mmol, 2.00 eq) in DMF

(1.5 mL, 0.0703 M) was added benzotriazol-l-yl 3-(4-fluorophenyl)-lH-pyrrole-2- carboxylate Intermediate 6 (34 mg, 0.105 mmol, 1.00 eq), 4-methyl-N3-[3-(9- tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]benzene-l,3-diamine Intermediate 1 (42 mg, 0.105 mmol, 1.00 eq) and the mixture was stirred at rt for 3h and at 50 °C for 18 h. The reaction mixture was quenched with water (10 mL) and the solids were filtered through a fritted funnel and the filter cake was washed with IM LiCl (10 mL), H2O (2 x 5 mL). The cake was dissolved in DCM (10 mL) and was purified by column chromatography over silica gel, SilicaSep, CombiFlash, 4g cartridge (dry load, 40-50% EtOAc-Hexanes as eluent) to afford 3-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]amino]phenyl]-lH-pyrrole-2-carboxamide (26 mg, 0.0420 mmol, 39.78 % yield) as yellow solid. 1H NMR (500 MHz, DMSO-d6) 8 12.12 (s, 1H), 11.71 (s, 1H), 9.72 (dd, J = 7.9, 2.0 Hz, 1H), 9.12 (s, 1H), 9.10 (s, 1H), 8.95 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.31 (dd, J = 4.6, 2.0 Hz, 1H), 7.53 (dd, J = 8.9, 5.6 Hz, 2H), 7.30 (dd, J = 8.1, 2.1 Hz, 1H), 7.22 - 7.11 (m, 3H), 7.03 (dd, J = 7.9, 4.7 Hz, 1H), 6.98 (t, J = 2.7 Hz, 1H), 6.28 (t, J = 2.5 Hz, 1H), 5.97 - 5.80 (m, 1H), 4.05 (d, J = 12.6 Hz, 2H), 3.79 - 3.72 (m, 1H), 2.38 (s, 4H), 2.10 - 1.95 (m, 3H), 1.70 (m, 4H). MS(ESI⁺) m/z calc'd for

[M+H]⁺[C33H29FN8O2+H]⁺:589.24 found: 589.1, t_R = 5.49 mins. LC-MS Method: Merckmillipore Chromolith SpeedROD C18 column (50 x 4.6 mm) and a dual gradient run from 5-100% mobile phase B over 12 minutes. Mobile phase A = water (0.1 % CF3CO2H). Mobile phase B = acetonitrile (0.1 % CF3CO2H).

[0094] To a suspension of 3-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9-tetrahydropyran-2- ylpurin-6-yl)-2-pyridyl]-amino]phenyl]-lH-pyrrole-2-carboxamide (26 mg, 0.0420 mmol, 1.00 eq) in methanol (1.3987 mL, 0.0300 M) at 0 °C was added 4 N HC1 in dioxane (0.10 mL, 0.420 mmol, 10.0 eq) and stirred at rt for 3 h. The reaction mixture was evaporated in vacuum and quenched with satd. NaHCCL sol. (10 mL), stirred for 1 h. Then the solids were filtered off and washed with water (20 mL), dried overnight under high vacuum, and purified by HPLC purification under acidic conditions. The solid obtained was neutralized with satd. NaHCCh sol and dried under high vacuum overnight to afford 3-(4-fluorophenyl)-N-[4- methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]-lH-pyrrole-2-carboxamide Example 5 (3.4 mg, 0.00653 mmol, 15.57 % yield) as a yellow solid. ’ H NMR (500 MHz, DMSO- ₆) 8 12.25 (s, 1H), 11.72 (s, 1H), 9.09 (s, 1H), 9.05 (s, 1H), 8.69 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.30 (dd, J = 4.1, 2.0 Hz, 1H), 7.56 - 7.48 (m, 2H), 7.30 (dd, J = 8.3, 2.2 Hz, 1H), 7.22 - 7.11 (m, 4H), 7.02 (dd, J = 7.9, 4.6 Hz, 1H), 6.98 (t, J = 2.7, 2.7 Hz, 1H), 6.27 (t, J = 2.6, 2.6 Hz, 1H), 2.39 (s, 3H). MS(ESI+) m/z calc'd for [M+H]+[C28H2iFN₈O+H]+: 505.19 found: 505.3, tR = 2.00 mins. [Method B].

[0095] Synthesis of 3-(4-Methylimidazol-l-yl)-N-[4-methyl-3-[[3-(9H-purin-6-yl)-2- pyridyl]amino]phenyl]-5-(trifhioro-methyl)benzamide [Example 6]:

Intermediate 1 Intermediate 7 Example 6

[0096] A solution of 3-(4-methylimidazol-l-yl)-5-(trifluoromethyl)benzoic acid Intermediate 7 (47 mg, 0.174 mmol, 1.40 eq) in DMF (1 mL, 0.0623 M) was charged with Diisopropylethylamine (0.065 mL, 0.374 mmol, 3.00 eq) and N-[(Dimethylamino)-lH- l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (71 mg, 0.187 mmol, 1.50 eq), stirred for 10 min at rt. Then was added. 4-methyl- N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]benzene-l,3-diamine Intermediate 71(50 mg, 0.125 mmol, 1.00 eq) in DMF (1 mL, 0.0623 M) and the mixture was stirred at rt for 24h. The reaction mixture was quenched with aq. sat NaHCOs (10 mL) and stirred for 1 h. The solid was filtered through a fritted funnel and the filter cake was washed with aq. sat NaHCCh (2 x 5 mL), IM LiCl (10 mL), H2O (2 x 5 mL) and dried. Crude was purified by column chromatography over silica gel, SilicaSep, CombiFlash, 12g cartridge (dry load, 2.5- 3% MeOH-DCM as eluent) under high vacuum overnight to afford 3-(4-methylimidazol-l- yl)-N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]-5- (trifluoromethyl)benzamide (42 mg, 0.0578 mmol, 46.43 % yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) 8 12.20 (s, 1H), 10.45 (s, 1H), 9.73 (d, J = 7.8 Hz, 1H), 9.14 (s, 1H),8.95 (s, 1H), 8.66 (s, 1H), 8.45 (s, 1H), 8.36 (d, J = 4.6 Hz, 2H), 8.19 (d, J = 22.1 Hz, 2H), 7.70 (s, 1H), 7.47 (d, J = 8.2 Hz,10H), 7.26 (d, J = 8.3 Hz, 1H), 7.03 (dd, J = 7.9, 4.7 Hz, 1H), 5.88 (d, J = 11.1 Hz, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.75 (t, J = 11.0 Hz, 1H), 2.44 (s, 3H), 2.18 (s, 3H), 2.12 - 1.94 (m, 4H), 1.71 (m, 3H). MS(ESI⁺) mJz calc'd for [M+H]⁺[C34H30F3N9O2+H]⁺: 654.2 found: 654.2, t_R = 2.25 mins. [Method B], [0097] A solution of 3-(4-methylimidazol-l-yl)-N-[4-methyl-3-[[3-(9-tetrahydropyran-2- ylpurin-6-yl)-2-pyridyl]amino]phenyl]-5-(trifluoromethyl)benzamide (42 mg, 0.0643 mmol, 1.00 eq) in Methanol (1.28 mL, 0.0500 M) was added 4 N HC1 in dioxane (0.16 mL, 0.643 mmol, 10.0 eq) and stirred at rt for 2 h. The reaction mixture was quenched with aq. sat NaHCOs (10 mL) and stirred for 1 h. The solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCCL (2 x 5 mL), H2O (2 x 5 mL) and dried. Crude was purified by MeOH (3 X 5 mL) wash and dried under high vacuum overnight to afford 3- (4-methylimidazol-l-yl)-N-[4-methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]-5- (trifluoro-methyl)benzamide Example 6 (30 mg, 0.0520 mmol, 82.19 % yield) as a yellow solid. ’ H NMR (500 MHz, DMSO- ₆) 6 13.85 (s, 1H), 12.34 (s, 1H), 10.47 (s, 1H), 9.81 (d, J = 7.8 Hz, 1H), 9.08 (s, 1H), 8.72 - 8.65 (m, 2H), 8.55 (s, 1H), 8.50 - 8.44 (m, 1H), 8.35 (dd, J = 4.7, 2.1 Hz, 1H), 8.26 - 8.16 (m, 2H), 7.76 (s, 1H), 7.46 (dd, J = 8.2, 2.3 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.03 (dd, J = 7.9, 4.7 Hz, 1H), 2.44 (s, 3H), 2.20 (s, 3H). MS(ESI⁺) m/z calc'd for [M+H]⁺[C₂9H₂₂F3N9O+H]⁺: 570.19 found: 570.4, LCMS t_R = 1.53 mins. [Method B],

[0098] Synthesis of N-(3-((3-(6,9-dihydro-lH-purin-6-yl)pyridin-2-yl)amino)-4- methylphenyl)-l-(4-fhiorophenyl)-lH-pyrrole-2-carboxamide [Example 7]:

Intermediate 1 Intermediate 8 Example 7

[0099] A solution of HATU (99 mg, 0.262 mmol, 1.40 eq) and l-(4- fluorophenyl)pyrrole-2-carboxylic acid Intermediate 8 (38 mg, 0.187 mmol, 1.00 eq) in 0.5 ml DMF was stirred for 10 minutes at 25 °C, then a solution of 4-methyl-N3-[3-(9- tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]benzene-l,3-diamine Intermediate 1 (75 mg, 0.187 mmol, 1.00 eq) and N,N-Diisopropylethylamine (0.065 mL, 0.374 mmol, 2.00 eq) in 1ml DMF, the resulting solution was stirred at 25 °C for overnight with LCMS monitoring, 15 mg of HGM was added and continue to stir until full consumption of SCA-HATU intermediate. Quenched with aq. NaHCO3, stirred for Ihr, filtered, washed successively with water, IM LiCl, water and 10% ethyl acetate in hexane, dried in vacuum and afforded a yellow solid, which was purified by flash column chromatography over silica gel, ISCO, CombiFlash, 4g cartridge (eluting with 2% methanol in ethyl acetate) afforded l-(4-fluorophenyl)-N-[4- methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]pyrrole-2- carboxamide (80 mg, 0.129 mmol, 69.11 % yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) 8 12.04 (d, J = 6.6 Hz, 1H), 9.94 (d, J = 6.8 Hz, 1H), 9.70 (d, J = 7.9 Hz, 1H), 9.09 (d, J = 7.1 Hz, 1H), 8.92 (d, J = 7.0 Hz, 1H), 8.39 (d, J = 6.1 Hz, 1H), 8.30 (d, J = 4.9 Hz, 1H), 7.32 (dq, J = 15.3, 8.4, 6.6, 6.6 Hz, 3H), 7.24 - 7.17 (m, 1H), 7.10 (dd, J = 21.0, 6.0 Hz, 2H), 7.04 - 6.93 (m, 1H), 6.29 (q, J = 3.4, 3.4, 3.4 Hz, 1H), 5.86 (d, J = 11.0 Hz, 1H), 4.04 (d, J = 9.4 Hz, 1H), 3.84 - 3.66 (m, 1H), 2.34 (d, J = 6.7 Hz, 4H), 2.01 (dd, J = 28.2, 10.6 Hz, 2H), 1.69 (d, J = 78.6 Hz, 3H). MS(ES⁺) m/z cala'd for [M+H] 589.3 found LCMS 589.2 t_R=2.70 min min. . [Method B], [00100] To a stirred solution of l-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9-tetrahydropyran- 2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]pyrrole-2-carboxamide (80 mg, 0.136 mmol, 1.00 eq) in 1,4-Dioxane (2 mL, 0.0680 M) was added 4N HC1 in dioxane (2.0 mL), the resulting reaction mixture was stirred at 25 °C for 4 hours with LCMS monitoring, then concentrated to dryness under reduced pressure, the residue was added aq. NaHCO3 with vigorous stirring, filtered to afforded a yellow crude compound, purified with by flash column chromatography over silica gel, ISCO, CombiFlash, 4g cartridge (eluting with 0-7% methanol in DCM) afforded N-(3-((3-(6,9-dihydro-lH-purin-6-yl)pyridin-2-yl)amino)-4-methylphenyl)-l-(4- fluoro-phenyl)-lH-pyrrole-2-carboxamide Example 7 (29 mg, 0.0571 mmol, 42.04 % yield) as a yellow solid. ’H NMR (500 MHz, DMSO-d₆) 6 12.16 (s, 1H), 9.95 (s, 1H), 9.74 (s, 1H), 9.04 (s, 1H), 8.68 (s, 1H), 8.42 (d, J = 2.3 Hz, 1H), 8.29 (dd, J = 4.6, 2.1 Hz, 1H), 7.33 (ddt, J = 8.4, 5.9, 2.9, 2.9 Hz, 2H), 7.29 (dd, J = 8.2, 2.3 Hz, 1H), 7.26 - 7.20 (m, 2H), 7.14 - 7.10 (m, 2H), 7.08 (dd, J = 3.9, 1.8 Hz, 1H), 6.99 (dd, J = 7.9, 4.7 Hz, 1H), 6.29 (dd, J = 3.9, 2.6 Hz, 1H), 2.36 (s, 3H). MS(ESI⁺⁾ m/z cala'd for [M+H]⁺ [C28H₂IFN₈O+H]⁺: 505.2, found 505.0, LCMS t_R=2.07 min. [Method B], [00101] Synthesis of N-[4-methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]-lH- indole-3-carboxamide [Example 8]:

Intermediate 1 Intermediate 9 Example 8

[00102] A solution of l-tert-butoxycarbonylindole-3-carboxylic acid Intermediate 9 (40 mg, 0.153 mmol, 1.12 eq) in DMF (1 mL, 0.1370 M) was charged with Diisopropylethylamine (0.040 mL, 0.230 mmol, 1.68 eq) and (Benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (70 mg, 0.158 mmol, 1.16 eq) The mixture was stiired at rt for Ih. Then 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin- 6-yl)-2-pyridyl]benzene-l,3-diamine Intermediate 1 (55 mg, 0.137 mmol, 1.00 eq) was added to the reaction mixture and stirred o/n. The reaction mixture was quenched with aq sat NaHCOs (10 mL) and stirred for 1 h. The solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCCh (2 x 5 mL), IM LiCl (10 mL), H2O (2 x 5 mL), Hexanes (2 x 5 mL), and ether (2 x 5 mL), dried overnight under high vacuum. Crude (including HZ-2020-02-90) was purified by column chromatography over silica gel, SilicaSep, CombiFlash, 40g cartridge (DCM load, 0-50% EtOAc in Hexane) to afford tertbutyl 3-[[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]amino]phenyl]carbamoyl]indole-l-carboxylate (80 mg, 0.114 mmol, 83.33 % yield) as a yellow solid (This yield is based on the scale of HZ-2020-02-91). ¹ H NMR (500 MHz, CDCL3-d) 8 8 12.14 (s, IH), 10.10 (s, IH), 9.82 - 9.69 (m, IH), 9.13 (d, J = 1.8 Hz, IH), 8.95 (d, J = 1.8 Hz, IH), 8.68 (s, IH), 8.61 - 8.51 (m, IH), 8.42 - 8.32 (m, IH), 8.25 (d, J = 7.7 Hz, IH), 8.09 (d, J = 8.5 Hz, IH), 7.49 (d, J = 8.2 Hz, IH), 7.39 (t, J = 7.8, 7.8 Hz, IH), 7.33 (d, J = 7.3 Hz, IH), 7.22 (d, J = 8.1 Hz, IH), 7.02 (dd, J = 8.8, 4.0 Hz, IH), 5.87 (d, J = 11.0 Hz, IH), 4.05 (d, J = 13.2 Hz, 2H), 3.87 - 3.66 (m, IH), 2.39 - 2.29 (m, IH), 2.01 (dd, J = 32.8, 14.2 Hz, 3H), 1.84 - 1.76 (m, OH), 1.73 - 1.48 (m, 8H), 1.27 - 1.09 (m, IH).

MS(ES⁺) m/z cala'd for [M+H]⁺ [C36H₃6N₈O4+H]⁺: 645.3 found 645.4, LCMS t_R= 6.29 min [Method: B].

[00103] To a solution of tert-butyl 3-[[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)- 2-pyridyl]amino]phen-yl]carbamoyl]indole-l-carboxylate (80 mg, 0.114 mmol, 1.00 eq) in DCM (1 mL, 0.1241 M) was added TFA (1.0 mL, 13.1 mmol, 114 eq). The reaction was stirred for Ih. The reaction mixture was evaporated and triturated with sat. aq NaHCOs. The precipitate was collected, washed with H2O and dried under vacuum to provide N-[4- methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]-lH-indole-3-carboxamide Example 8 (21 mg, 0.0456 mmol, 39.95 % yield) as a yellow solid. ¹ H NMR (500 MHz, DMSO-tfo) 6 12.21 (s, IH), 11.66 (d, J = 3.2 Hz, IH), 9.76 (d, J = 7.9 Hz, IH), 9.64 (s, IH), 9.06 (s, IH), 8.68 (s, IH), 8.53 (d, J = 2.4 Hz, IH), 8.34 (dd, J = 5.2, 1.6 Hz, IH), 8.31 (d, J = 3.2 Hz, IH), 8.18 (d, J = 7.8 Hz, IH), 7.49 (dd, J = 8.1, 2.6 Hz, IH), 7.45 (d, J = 7.9 Hz, IH), 7.21 - 7.08 (m, 3H), 7.00 (dd, J = 7.9, 4.6 Hz, IH), 2.40 (s, 3H). MS(ESI⁺) mJz calc'd for [M+H]⁺[C26H2ON₈0+H]⁺: 461.2, found:461.2, t_R = 1.62 mins. [Method: B],

[00104] Synthesis of N-[4-methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]-3-(4- methylpyrazol-l-yl)-5-(trifhioro-methyl)benzamide [Example 9]:

Intermediate 1 Intermediate 10 Example 9

[00105] A solution of Diisopropylethylamine (0.043 mL, 0.249 mmol, 2.00 eq) in DMF (1 mL, 0.1245 M) was charged with 3-(4-methylpyrazol-l-yl)-5-(trifluoromethyl)benzoic acid Intermediate 10 (40 mg, 0.149 mmol, 1.20 eq) and HATU (71 mg, 0.187 mmol, 1.50 eq) The mixture was stirred at rt for 15min. Then 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)- 2-pyridyl]benzene-l,3-diamine Intermediate 1 (50 mg, 0.125 mmol, 1.00 eq) was added to the reaction mixture and stirred o/n. The reaction mixture was quenched with aq. sat NaHCOs (10 mL) and stirred for 1 h. The solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCCL (2 x 5 mL), IM LiCl (10 mL), H2O (2 x 5 mL), Hexanes (2 x 5 mL), and ether (2 x 5 mL), dried overnight under high vacuum. Crude was dissolved in MeOH (2ml). The mixture was added 4N HC1 in Dioxane (0.5 ml) and stirred o/n. The mixture was filtered. The cake was washed with Et20, Sat. NaHCO3, H2O, dried under vacuum to afford N-[4-methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]-3- (4-methylpyrazol-l-yl)-5-(trifluoromethyl)benzamide Example 9 (40 mg, 0.0701 mmol, 56.28 % yield) as a yellow solid. ’ H NMR (500 MHz, CDCL3-d) 8 12.53 (s, 1H), 10.61 (s, 1H), 9.86 (d, J = 8.8 Hz, 1H), 9.09 (s, 1H), 8.74 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 8.32 - 8.26 (m, 2H), 8.16 (s, 1H), 7.67 (s, 1H), 7.57 (dd, J = 8.2, 2.3 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 7.9, 5.1 Hz, 1H), 2.40 (s, 3H), 2.12 (s, 3H).

MS(ES⁺) m/z cala'd for [M+H]⁺ [C29H₂₂F3N9O+H]⁺: 570.2 found 570.4, LCMS t_R= 2.18 min. [Method: B].

[00106] Synthesis of N-[4-methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]-6- (trifluoromethyl)indole-l -carboxamide [Example 10]:

Example 10

[00107] To a stirred solution of 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]benzene-l,3-diamine Intermediate 1 (0.20 g, 0.498 mmol, 1.00 eq) in anhydrous DCM (5 mL, 0.0996 M) was added (4-nitrophenyl) carbonochloridate 1-10 (0.12 g, 0.598 mmol, 1.20 eq). The resulting solution was stirred at rt o/n. The mixture was filtered and washed with DCM. The resulting cake was dried under high vacuum to provide crude (4- nitrophenyl) N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]amino]phenyl]carbamate;hydrochloride 2-10 (0.28 g, 0.426 mmol, 85.44 % yield) as a solid which was used directly for the next step without further purification. ^!H NMR (500 MHz, Chloroform-d) 8 12.26 (s, 1H), 10.38 (s, 1H), 9.76 (d, J = 7.9 Hz, 1H), 9.12 (s, 1H), 8.96 (s, 1H), 8.42 (s, 1H), 8.29 (d, J = 8.9 Hz, 3H), 7.52 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 6.2 Hz, 2H), 7.15 - 7.02 (m, 1H), 5.87 (d, J = 10.5 Hz, 1H), 4.07 - 4.00 (m, 1H), 3.78 - 3.71 (m, OH), 2.41 - 2.31 (m, 3H), 2.10 - 1.94 (m, 3H), 1.83 - 1.74 (m, 1H), 1.66 - 1.54 (m, 3H).

MS(ESI⁺) mJz calc'd for [M+H]⁺[C₂3Hi9N₅O5+H-HCl]⁺: 567.2 found: 567.5 , t_R = 5.15 mins. [Method: B]

[00108] To a solution of (4-nitrophenyl) N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin- 6-yl)-2-pyridyl]amino]phenyl]carbamate;hydrochloride 2-10 (100 mg, 0.166 mmol, 1.00 eq) in THF (3 mL, 0.0415 M) was added sodium hydride (21 mg, 0.514 mmol, 3.10 eq). The mixture was stirred at rt for 0.5h. The solution was added to a solution of 6-

Trifluoromethylindole 3-10 (92 mg, 0.497 mmol, 3.00 eq) in THF (1 mL, 0.0415 M) dropwise. The mixture was stirred for overnight. Solution change from trace suspension to cloudy. The mixture was evaporated to get THP protected product. The intermediate was dissolved in MeOH (2ml) and added 4M HC1 in dioxane (0.5 ml). The mixture was stirred for Ih and solvent was evaporated. The crude was purified by HPLC under acidic condition to give HC1 salt, which was dissolved in MeOH and passed through Amberlite IRA-67 resin. The filtrate was evaporated and dried to afford N-[4-methyl-3-[[3-(9H-purin-6- yl)-2-pyridyl]amino]phenyl]-6-(trifluoromethyl)indole-l -carboxamide Example 10 (6.0 mg, 0.0113 mmol, 6.83 % yield) as a yellow solid. ’H NMR (500 MHz, DMSO-d6) 812.45 (s, IH), 10.18 (s, IH), 9.81 (d, J = 8.3 Hz, IH), 9.02 (s, IH), 8.66 - 8.60 (m, 2H), 8.57 (s, IH), 8.36 - 8.29 (m, 2H), 7.86 (d, J = 8.2 Hz, IH), 7.53 (dd, J = 8.2, 2.0 Hz, IH), 7.31 (dd, J = 8.1, 2.3 Hz, IH), 7.26 (d, J = 8.3 Hz, IH), 7.02 (dd, J = 7.8, 4.8 Hz, IH), 6.88 (d, J = 3.7 Hz, IH), 6.50 (s, IH), 2.46 (s, 3H). MS(ES⁺) m/z cala'd for [M+H]⁺ [C27Hi9F3N₈O+H]⁺: 529.2 found 529.0, LCMS t_R= 2.17 min [Method: B]

[00109] Synthesis of N-(3-((3-(9H-purin-6-yl)pyridin-2-yl)amino)-4-methylphenyl)-l- (4-fhiorophenyl)-5-(methylsulfonyl)-lH-pyrazole-3-carboxamide [Example 11] :

Intermediate 1 Intermediate 11 Example 11

[00110] 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]benzene-l,3- diamine Intermediate 1 (1.00 eq.), l-(4-fluorophenyl)-5-(methylsulfonyl)-lH-pyrazole-3- carboxylic acid Intermediate 11 (1.2 eq.), and BOP (2.00 eq.) were dissolved in DMF (0.1 M). DIPEA (3.0 eq.) was added and stirred for 3o min. The reaction was quenched with saturated aqueous sodium bicarbonate. The precipitate was filtered off and washed with water. The product was dry loaded onto a 40g silica column and purified over a 0-10% MeOH in DCM gradient to yield l-(4-fluorophenyl)-N-(4-methyl-3-((3-(9-(tetrahydro-2H- pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)amino)phenyl)-5-(methylsulfonyl)-lH-pyrazole-3- carboxamide. The solid was dissolved in DCM (0.1 M) and TFA (3 equiv) was added dropwise and stirred overnight to yield N-(3-((3-(9H-purin-6-yl)pyridin-2-yl)amino)-4- methylphenyl)-l-(4-fluorophenyl)-5-(methylsulfonyl)-lH-pyrazole-3-carboxamide Example 11 (56 mg, 48 % yield) as an orange solid. ¹ H NMR (500 MHz, DMSO-d6) 8 = 12.27 (s, 1H), 10.32 (s, 1H), 9.77 (s, 1H), 9.07 (s, 1H), 8.71 (s, 1H),8.65 (s, 1H), 8.32 (d, J = 3.4 Hz, 1H), 7.76 (dd, J = 8.7, 4.8 Hz, 2H), 7.67 (s, 1H), 7.48 - 7.42 (m, 3H), 7.22 (d, J = 8.2 Hz, 1H), 7.02 (dd, J = 7.9, 4.7 Hz, 1H), 3.33 (s, 3H), 2.41 (s, 3H).; MS (ES+): m/z = 584.4 [M + H]⁺; LCMS: fa = 1.81 min [Method A-6].

[00111] Synthesis of N-(3-((3-(9H-purin-6-yl)pyridin-2-yl)amino)-4-methylphenyl)-l- (4-fhiorophenyl)-5-(methylsulfinyl)-lH-pyrazole-3-carboxamide [Example 12] :

Intermediate 1 Intermediate 12 Example 12

[00112] Nl-(3-(9H-purin-6-yl)pyridin-2-yl)-6-methylbenzene-l,3-diamine Intermediate 1 (150 mg, 0.47 mmol, 1.00 eq), l-(4-fluorophenyl)-5-(methylsulfinyl)-lH-pyrazole-3- carboxylic acid Intermediate 12 (142 mg, 0.57 mmol, 1.20 eq) and BOP (415 mg, 0.93 mmol, 2.00 eq) were dissolved in 3 ml DMF (3 ml, 0.10 M). DIPEA (0.25 ml, 1.4 mmol, 3.0 eq) was added and stirred for 30 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate. The precipitate was filtered off and washed with water. The precipitate was triturated with ether/EtOAc and DCM/MeOH, filtered. The solid was washed with IM LiCl then water, dried to afford N-(3-((3-(9H-purin-6-yl)pyridin-2-yl)amino)-4-methylphenyl)-l- (4-fluorophenyl)-5-(methylsulfinyl)-lH-pyrazole-3-carboxamide Example 12 (151 mg, 56 % yield) as a beige solid. ’ H NMR (500 MHz, DMSO-d6) 8 13.84 (s, 1H), 12.28 (s, 1H), 9.81 (s, 2H), 9.07 (s, 1H), 8.71 (s, 1H),8.58 (s, 1H), 8.34 (d, J = 4.7 Hz, 1H), 8.24 - 8.18 (m, 2H), 7.45 (d, J = 8.3 Hz, 1H), 7.34 (t, J = 8.7, 8.7Hz, 2H), 7.23 (d, J = 8.2 Hz, 1H), 7.02 (dd, J = 8.0, 4.6 Hz, 1H), 5.36 (q, J = 8.7, 8.6, 8.6 Hz, 2H), 2.41(s, 3H); MS (ES⁺) m/ = 605.5 [M+H]⁺; LCMS: fa= 2.33 min [Method A-6].

[00113] Synthesis of 5-(4-fhiorophenyl)-N-[4-methyl-3-[[3-(9H-purin-6-yl)-2- pyridyl]amino]phenyl]-2-methylsulfinyl-thiazole-4-carboxamide [Example 13] :

Intermediate 1 Intermediate 13

[00114] 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]benzene-l,3- diamine Intermediate 1, 5-(4-fluorophenyl)-2-(methylsulfinyl)thiazole-4-carboxylic acid Intermediate 13, and HATU were dissolved in 3 ml DMF. DIPEA was added and stirred for 30 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate. The precipitate was filtered off and washed with water. The product was dry loaded onto a 40g silica column and purified over a 0-10% MeOH in DCM gradient to yield 5-(4-fluorophenyl)- 2-methylsulfinyl-N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]amino]phenyl]thiazole-4-carboxamide. The solid was dissolved in 3 mL DCM and TFA was added dropwise and stirred overnight to yield 5-(4-fluorophenyl)-N-[4-methyl-3- [[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]-2-methylsulfinyl-thiazole-4-carboxamide. Most of the solution was evaporated (-80%) under reduced pressure. The remaining solution was quenched with saturated sodium bicarbonate aqueous solution (dropwise). The product precipitated and was filtered. It was then triturated with 2 mL MeOH/Ether (1:4) then washed with water. It was then dried under a high vacuum over the weekend to afford 5-(4- fluorophenyl)-N-[4-methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]-2-methylsulfinyl- thiazole-4-carboxamide Example 13 (67 mg, 38 % yield) as a deep orange solid. 1H NMR (500 MHz, DMSO-d6) 8 10.32 (s, 1H), 9.06 (s, 1H), 8.71 (s, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.30 (dd, J = 4.8, 2.0 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.39 (dd, J = 8.2, 2.2 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 7.9, 4.7 Hz, 1H), 3.16 (s, 3H), 2.39 (s, 3H); MS (ES⁺) m/z calc'd for [M+H]⁺[C₂8H2iFN₈O2S2+H]⁺: 585.1 found. LCMS: f_R=1.82 min [Method A-6].

[00115] Synthesis of afford 5-tert-butyl-N-[4-methyl-3-[[3-(9H-purin-6-yl)-2- pyridyl]amino]phenyl]oxazole-4-carboxamide [Example 14]

[00116] A solution of 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]benzene-l,3-diamine Intermediate 1 (70 mg, 0.174 mmol, 1.00 eq) in DMF (1.5 mL, 0.0581 M) and was added 5-tert-butyloxazole-4-carboxylic acid Intermediate 14 (29 mg, 0.174 mmol, 1.00 eq), Diisopropylethylamine (0.062 mL, 0.349 mmol, 2.00 eq) and HATU (99 mg, 0.262 mmol, 1.50 eq). The mixture was stirred at rt for 3h. The reaction mixture was quenched with aq sat NaHCOs (5 mL) and stirred for 1 h. The solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCOs (5 mL), IM LiCl (2 x 5 mL), H2O (2 x 5 mL). The cake was dried o/n and triturated with ether (5 ml), filtered and dried overnight under high vacuum to afford 80mg of THP protected product, which was dissolved in DCM (1.5ml) and TFA (1.5 mL, 19.6 mmol, 112 eq) was added drop wise. The mixture was stirred 3h until consumption of the starting material. The organic solvent was evaporated and quenched with Sat. NaHCOs (11 ml) drop wise at 0 °C. The precipitate was filtered and dried. The cake was triturated with Et2O and dried to afford 5-tert-butyl-N-[4- methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]oxazole-4-carboxamide Example 14 (52 mg, 0.109 mmol, 62.65 % yield) as a yellow solid. ’ H NMR (500 MHz, DMSO-d6) 8 12.25 (s, 1H), 9.88 (s, 1H), 9.77 (s, 1H), 9.06 (s, 1H), 8.70 (s, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.38 (s, 1H), 8.32 (dd, J = 4.8, 2.0 Hz, 1H), 7.46 (dd, J = 8.2, 2.2 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.01 (dd, J = 7.9, 4.7 Hz, 1H), 2.39 (s, 3H), 1.41 (s, 9H). MS(ESI⁺) mJz calc'd for [M+H]⁺[C25H₂4N₈O2+H]⁺: 469.2 found: 469.3 , t_R = 2.03 mins. [Method: B],

[00117] Synthesis of 3-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9H-purin-6-yl)-2- pyridyl]amino]phenyl]furan-2-carboxamide [Example 15]:

Intermediate 1 Intermediate 15

[00118] A solution of 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]benzene-l,3-diamine Intermediate 1 (50 mg, 0.125 mmol, 1.00 eq) in DMF (1.5 mL, 0.0830 M) and Diisopropylethylamine (0.065 mL, 0.374 mmol, 3.00 eq) was charged with 3- (4-fluorophenyl)furan-2-carboxylic acid Intermediate 15 (31 mg, 0.149 mmol, 1.20 eq) and N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (95 mg, 0.249 mmol, 2.00 eq) was added. The mixture was stirred at rt for 3h. The reaction mixture was quenched with aq sat NaHCOs (10 mL) and stirred for 1 h. The solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCCh (2 x 5 mL), IM LiCl (10 mL), H2O (2 x 5 mL), Hexanes (2 x 5 mL), and ether (2 x 5 mL), dried overnight under high vacuum. Crude was purified by column chromatography over silica gel, SilicaSep, CombiFlash, 4g cartridge (dry load, 1.0- 1.5% MeOH in DCM as eluent) to afford 3-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9- tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]furan-2-carboxamide (52 mg, 0.0864 mmol, 69.40 % yield) as a yellow solid. ’ H NMR (500 MHz, Chloroform-7) 6 12.12 (s, 1H), 9.70 (d, J = 8.2 Hz, 1H), 8.99 (s, 1H), 8.38 (dt, J = 6.6, 4.2, 4.2 Hz, 3H), 8.29 - 8.07 (m, 1H), 7.74 (td, J = 5.5, 5.4, 2.4 Hz, 3H), 7.58 (dd, J = 8.2, 2.3 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.11 (td, J = 9.0, 8.7, 2.6 Hz, 2H), 6.94 (dd, 7 = 7.9, 4.7 Hz, 1H), 6.65 (d, J = 1.8 Hz, 1H), 5.89 (dd, 7 = 10.4, 2.5 Hz, 1H), 4.23 (d, 7 = 11.1 Hz, 1H), 3.84 (t, 7 = 11.5, 11.5 Hz, 1H), 2.47 (s, 3H), 2.21 (d, 7 = 12.9 Hz, 1H), 2.17 - 2.00 (m, 2H), 1.97 - 1.76 (m, 1H), 1.70 (d, 7 = 10.5 Hz, 1H). MS(ESI⁺) m/z calc’d for [M+H]⁺[C33H₂₈FN7O3+H]⁺: 590.23 found: 590.2, t_R = 5.22 mins. [Method A-12], [00119] A solution of 3-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9-tetrahydropyran-2-ylpurin- 6-yl)-2-pyridyl]amino]-phenyl]furan-2-carboxamide (0.052 g, 0.0882 mmol, 1.00 eq) in DCM (1.5 mL, 0.0830 M) was added Trifluoroacetic acid (0.68 mL, 8.82 mmol, 100 eq) and stirred at rt for 24 h. The reaction mixture was evaporated in vacuo, quenched with aq sat NaHCO3 (10 mL) and stirred for 1 h. The solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCO3 (2 x 5 mL), H2O (2 x 5 mL), Hexanes (2 x 5 mL), and ether (2 x 5 mL), dried overnight under high vacuum to afford 3-(4-fluorophenyl)- N-[4-methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]furan-2-carboxamide Example 15 (39 mg, 0.0769 mmol, 87.69 % yield) as a orange solid. ¹ H NMR (500 MHz, DMSO-7₆) 6 12.30 (s, 1H), 10.16 (s, 1H), 9.79 (s, 1H), 9.06 (s, 1H), 8.71 (s, 1H), 8.51 - 8.47 (m, 1H), 8.29 (dd, 7 = 4.8, 2.0 Hz, 1H), 7.95 (d, 7 = 1.8 Hz, 1H), 7.83 - 7.75 (m, 2H), 7.44 (dd, 7 = 8.2, 2.3 Hz, 1H), 7.26 - 7.18 (m, 3H), 7.04 (dd, 7 = 7.8, 4.8 Hz, 1H), 6.95 (d, 7 = 1.8 Hz, 1H), 2.38 (s, 3H). MS(ESI⁺) m/z calc’d for [M+H]⁺[C28H2oFN₇02+H]⁺: 506.17 found: 505.9, t_R = 2.06 mins. [Method B].

[00120] Synthesis of 2-[2-(dimethylamino)ethylsulfanyl]-5-(4-fhiorophenyl)-N-[4- methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]oxazole-4-carboxamide [16]:

Intermediate 1 Intermediate 16 Example 16

[00121] A solution of 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]benzene-l,3-diamine Intermediate 1 (50 mg, 0.125 mmol, 1.00 eq) in DMF (1.5 mL, 0.0830 M) and 2-((2-(dimethylamino)ethyl)thio)-5-(4-fluorophenyl)oxazole-4-carboxylic acid Intermediate 16 (46 mg, 0.149 mmol, 1.20 eq) was charged with Diisopropylethylamine (0.065 mL, 0.374 mmol, 3.00 eq) and N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin- l-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (95 mg, 0.249 mmol, 2.00 eq) was added. The mixture was stirred at rt for 3h. The reaction mixture was quenched with aq sat NaHCOs (10 mL) and stirred for 1 h. The solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCOs (2 x 5 mL), IM LiCl (10 mL), H2O (2 x 5 mL), Hexanes (2 x 5 mL), and ether (2 x 5 mL), dried overnight under high vacuum to afford 2-[2-(dimethylamino)ethylsulfanyl]-5-(4-fluorophenyl)-N-[4-methyl-3-[[3- (9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]oxazo-le-4-carboxamide (75 mg, 0.105 mmol, 84.19 % yield) as a yellow solid. ’ H NMR (500 MHz, Chloroform- /) 6 12.10 (s, 1H), 9.70 (d, J = 5.7 Hz, 1H), 9.34 - 8.80 (m, 2H), 8.65 - 8.00 (m, 4H), 7.61 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 8.8, 3.5 Hz, 2H), 6.94 (dd, J = 7.9, 3.8 Hz, 1H), 5.91 (d, J = 4.5 Hz, 1H), 4.24 (s, 1H), 3.84 (s, 1H), 3.65 - 3.03 (m, 16H), 2.77 (d, J = 7.1 Hz, 2H), 2.48 (s, 1H), 2.43 - 2.07 (m, 6H), 2.17 (d, J = 44.4 Hz, 4H), 1.78 (d, J = 58.7 Hz, 2H), 1.22 (dd, J = 7.0, 3.3 Hz, 20H). MS(ESI⁺) m/z calc’d for [M+H]⁺[C36H36FN₉O3S+H]+: 694.27 found: 694.0, t_R = 4.71 mins [Method A- 12].

[00122] A solution of 2-[2-(dimethylamino)ethylsulfanyl]-5-(4-fluorophenyl)-N-[4- methyl-3-[[3-(9-tetrahydropy-ran-2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]oxazole-4- carboxamide (0.075 g, 0.108 mmol, 1.00 eq) in DCM (1.5 mL, 0.0700 M), was added trifluoroacetic acid (0.72 mL, 9.37 mmol, 100 eq) and stirred at rt for 24 h. The reaction mixture was evaporated in vacuo, quenched with aq sat NaHCCh (10 mL) and stirred for 1 h. The solid was filtered through a fritted funnel and the filter cake was washed with aq sat NaHCCh (2 x 5 mL), H2O (2 x 5 mL), Hexanes (2 x 5 mL), and ether (2 x 5 mL), dried overnight under high vacuum to afford 2-[2-(dimethylamino)ethylsulfanyl]-5-(4- fluorophenyl)-N- [4-methyl-3 - [ [3 -(9H-purin-6-yl)-2-pyridyl] amino] phenyl] oxazole-4- carboxamide Example 16 (58 mg, 0.0888 mmol, 82.14 % yield) as a brown solid. ’H NMR (500 MHz, DMSO-rfc) 8 12.26 (s, IH), 9.94 (s, IH), 9.75 (d, 7= 38.9 Hz, IH), 9.07 (s, IH), 8.70 (s, IH), 8.60 (d, 7 = 2.2 Hz, IH), 8.33 (dd, 7 = 4.7, 2.0 Hz, IH), 8.25 - 8.17 (m, 2H), 7.45 (dd, 7 = 8.1, 2.3 Hz, IH), 7.39 - 7.30 (m, 2H), 7.22 (d, 7 = 8.4 Hz, IH), 7.02 (dd, 7 = 7.9, 4.7 Hz, IH), 3.56 (t, 7 = 7.0, 7.0 Hz, 2H), 2.90 (s, 2H), 2.40 (d, 7 = 8.4 Hz, 9H).

MS(ESI⁺) m/z calc’d for [M+H]⁺[C36H₃6FN9O4S+H]⁺: 610.21 found: 610.3, t_R = 1.84 mins. [Method B],

[00123] Synthesis of A^-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-4-methylphenyl)-5-(3- chlorophenyl)oxazole-4-carboxamide [Example 17]:

Intermediate 1 Intermediate 17 Example 17

[00124] To a solution of 4-methyl-/V3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]benzene-l,3-diamine Intermediate 1 (50 mg, 0.125 mmol, 1.00 eq), 5-(3- chlorophenyl)oxazole-4-carboxylic acid Intermediate 17 (33 mg, 0.149 mmol, 1.20 eq) and HATU (95 mg, 0.249 mmol, 2.00 eq) in DMF (1.5 mL, 0.0830 M) at rt was added DIPEA (0.065 mL, 0.374 mmol, 3.00 eq). The reaction mixture was stirred at this temperature for Ih. Cold water (10 mL) was added to the reaction mixture, solids were filtered, washed with aq sat NaHCCh (10 mL) followed by IM LiCl (2 x 10 mL), water (2 x 5 mL) and hexanes and dried under high vacuum to afford 5-(3-chlorophenyl)-N-[4-methyl-3- [[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]amino]phen-yl]oxazole-4-carboxamide (70 mg, 0.110 mmol, 87.96 % yield) as yellow solid. ’H NMR (500 MHz, DMSO-rfc) 8 12.15 (s, IH), 10.12 (s, IH), 9.72 (dd, 7 = 7.9, 2.0 Hz, IH), 9.13 (s, IH), 8.95 (s, IH), 8.63 (d, J = 2.3 Hz, IH), 8.35 (d, 7= 1.8 Hz, IH), 8.08 (d, 7 = 4.4 Hz, IH), 7.47 (dd, 7= 8.1, 2.0 Hz, IH), 7.23 (d, 7 = 8.5 Hz, IH), 7.02 (dd, 7 = 7.9, 4.6 Hz, IH), 5.88 (dd, 7 = 10.9, 2.2 Hz, IH), 4.05 (d, 7 = 11.1 Hz, IH), 3.75 (d, 7= 3.2 Hz, IH), 2.38 - 2.30 (m, 3H), 2.03 (t, 7= 18.7 Hz, 2H), 1.79 (d, 7= 12.3 Hz, IH), 1.62 (s, 2H). MS(ESI⁺) m/z calc'd for [M+H]⁺[C32H₂7C1N₈O3+H]⁺: 607.2 found: 607.4, tR = 5.65 mins. [Method: A- 12]. [00125] To a stirred solution of 5-(3-chlorophenyl)-A-[4-methyl-3-[[3-(9-tetrahydropyran- 2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]oxazole-4-carboxamide (83 mg, 0.130 mmol, 1.00 eq) in DCM (1.5 mL, 0.0637 M) at rt was added TFA (0.9 mL, 11.36 mmol, 100 eq.). The reaction mixture was stirred at rt for 2h. Volatiles were removed; residue was diluted with cold water at 0 °C. To this was slowly added aq sat NaHCCL (10 mL). Solids were filtered, washed with water (3 x 10 mL) followed by diethyl ether (2 x 10 mL) and dried under reduced pressure followed by lyophilization to afford 5-(3-chlorophenyl)-A-[4-methyl-3-[[3- (9H-purin-6-yl)-2-pyridyl]amino]phenyl]oxazole-4-carboxamide Example 17 (53 mg, 0.0999 mmol, 87.96 % yield) as a yellow solid. ’ H NMR (500 MHz, DMSO-rfc) 8 13.82 (s, 1H), 12.25 (s, 1H), 10.16 (s, 1H), 9.78 (s, 1H), 9.06 (s, 1H), 8.77 (s, 1H), 8.70 (s, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 8.5 Hz, 2H), 8.34 (dd, J = 4.7 , 2.0 Hz, 1H), 7.89 (d, J = 8.7 Hz, 2H), 7.47 (dd, J = 8.2, 2.2 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 7.8, 4.6 Hz, 1H), 2.41 (s, 3H). MS(ESI⁺) m z calc'd for [M+H]⁺[C28Hi9F₃N₈O2+H]⁺: 557.2 found: 557.2, t_R = 2.29 mins. [Method: B].

[00126] Synthesis of 2-(2-(dimethylamino)ethoxy)-N-(3-(3-(9H-purin-6-yl)pyridin-2- ylamino)-4-methylphen-yl)-5-(4-fhiorophenyl)oxazole-4-carboxamide [Example 18] :

Intermediate 1 Intermediate 18 Example 18

[00127] To a solution of 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]benzene-l,3-diamine Intermediate 1 (50 mg, 0.125 mmol, 1.00 eq), 2-(2- (dimethylamino)ethoxy)-5-(4-fluorophenyl)oxazole-4-carboxylic acid Intermediate 18 (44 mg, 0.149 mmol, 1.20 eq) and HATU (95 mg, 0.249 mmol, 2.00 eq) in DMF (1.5 mL, 0.0830 M) at rt was added DIPEA (0.065 mL, 0.374 mmol, 3.00 eq). The reaction mixture was stirred at this temperature for Ih. Cold water (10 mL) was added to the reaction mixture, solids were filtered, washed with aq sat NaHCCh (10 mL) followed by IM LiCl (2 x 10 mL), water (2 x 5 mL) and hexanes and dried under reduced pressure. Crude was purified by column chromatography over silica gel, ISCO, CombiFlash, 4g cartridge (dry load, 0-10% MeOH in DCM as eluent) to afford 2-[2-(dimethyl-amino)ethoxy]-5-(4-fluorophenyl)-N-[4- methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]-amino]phenyl]oxazole-4- carboxamide (51 mg, 0.0715 mmol, 57.40 % yield) as a yellow solid. ’ H NMR (500 MHz, DMSO-7₆) 6 12.13 (s, 1H), 10.12 - 9.39 (m, 2H), 9.12 (s, 1H), 8.94 (s, 1H), 8.55 (d, 7 = 2.3 Hz, 1H), 8.34 (dd, 7 = 4.6, 2.0 Hz, 1H), 8.24 - 8.12 (m, 2H), 7.45 (dd, 7 = 8.1, 2.3 Hz, 1H), 7.31 (t, 7 = 8.9 Hz, 2H), 7.22 (d, 7 = 8.5 Hz, 1H), 7.01 (dd, 7 = 7.9, 4.7 Hz, 1H), 5.87 (dd, 7 = 11.0, 2.3 Hz, 1H), 4.63 (t, 7 = 5.5 Hz, 2H), 4.27 - 3.95 (m, 1H), 3.75 (td, 7 = 11.5, 3.4 Hz, 1H), 2.71 (t, 7 = 5.5 Hz, 2H), 2.43 - 2.31 (m, 3H), 2.24 (s, 6H), 2.14 - 1.93 (m, 2H), 1.77 (dd, 7 = 14.6, 10.9 Hz, 2H), 1.62 (d, 7 = 4.2 Hz, 2H). MS(ESI⁺) mJz calc'd for [M+H]⁺[C36H36FN₉O4+H]⁺: 678.3 found: 678.4, t_R = 2.27 mins.[Method: A-6].

[00128] To a stirred solution of in 2-[2-(dimethylamino)ethoxy]-5-(4-fluorophenyl)-N-[4- methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]oxazole-4- carboxamide (51 mg, 0.0753 mmol, 1.00 eq) in DCM (1.5 mL, 0.0502 M) at rt was added TFA (0.58 mL, 7.53 mmol, 100 eq). The reaction mixture was stirred at rt for 2h. Volatiles were removed, and the residue was diluted with cold water at 0 °C. To this was slowly added aq sat NaHCCL (10 mL). Solids were filtered, washed with water (3 x 10 mL) followed by diethyl ether (2 x 10 mL) and dried under reduced pressure. Crude was purified by prep- HPLC, and the purified material was taken in water before aq sat NaHCO was added to it. Solids were filtered, washed with water (3 x 10 mL) followed by diethyl ether (2 x 10 mL) and dried under reduced presure 2-[2-(dimethylamino)ethoxy]-5-(4-fluorophenyl)-N-[4- methyl-3-[[3-(9H-purin-6-yl)-2-pyridyl]amino]phenyl]oxazole-4-carboxamide Example 18 (21 mg, 0.0353 mmol, 46.87 % yield) as a yellow solid. ¹ H NMR (500 MHz, DMSO-7₆) 6 13.12 (s, 1H), 10.04 (dd, 7 = 7.7, 2.0 Hz, 1H), 9.67 (s, 1H), 8.68 - 8.62 (m, 2H), 8.22 - 8.14 (m, 3H), 8.07 (s, 1H), 7.40 (dd, 7 = 8.1, 2.3 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.18 (d, 7 = 8.4 Hz, 1H), 6.93 (dd, 7 = 7.7, 4.7 Hz, 1H), 4.63 (t, 7 = 5.5 Hz, 2H), 2.70 (t, 7 = 5.5 Hz, 2H), 2.45 (s, 3H), 2.23 (s, 6H). MS(ESI⁺) m/z calc'd for [M+H]⁺[C3iH₂₈FN9O3+H]⁺: 594.2 found:

594.1, t_R = 1.82 mins. [Method B].

[00129] Synthesis of A^-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-4-methylphenyl)-l-(4- fhiorophenyl)-lH-pyrazole-5-carboxamide [Example 19]:

Intermediate 1 Intermediate 19 Example 19

[00130] To a solution of 4-methyl-V3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]benzene-l,3-diamine Intermediate 1 (50 mg, 0.125 mmol, 1.00 eq) , 2-(4- fluorophenyl)pyrazole-3-carboxylic acid Intermediate 19 (43 mg, 0.209 mmol, 1.20 eq) and HATU (133 mg, 0.349 mmol, 2.00 eq) in DMF (1.5 mL, 0.1162 M) at rt was added DIPEA (0.091 mL, 0.523 mmol, 3.00 eq). The reaction mixture was stirred at this temperature for Ih. Cold water (10 mL) was added to the reaction mixture, solids were filtered, washed with aq sat NaHCCh (10 mL) followed by IM LiCl (2 x 10 mL), water (2 x 5 mL) and hexanes and dried under reduced pressure. Crude was purified by column chromatography over silica gel, ISCO, CombiFlash, 4g cartridge (dry load, 0-10% MeOH in DCM as eluent) to afford 2-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9-tetrahydropyran-2- ylpurin-6-yl)-2-pyridyl]amino]phenyl]pyrazole-3-carboxamide (101 mg, 0.163 mmol, 93.33 % yield) as a yellow solid. ^!H NMR (500 MHz, Chloroform- /) 6 12.18 (s, IH), 9.71 (dd, J = 7.8, 2.0 Hz, IH), 8.99 (s, IH), 8.46 - 8.39 (m, IH), 8.37 (s, IH), 8.34 (dd, J = 4.7, 2.0 Hz, IH), 7.95 (s, IH), 7.64 (d, J = 2.0 Hz, IH), 7.51 - 7.33 (m, 2H), 7.17 (d, J = 8.5 Hz, IH), 7.12 (t, J = 8.6 Hz, 2H), 6.94 (dd, J = 7.9, 4.7 Hz, IH), 6.73 (d, J = 2.0 Hz, IH), 5.89 (dd, J = 10.6, 2.5 Hz, IH), 4.46 - 4.01 (m, IH), 4.01 - 3.70 (m, IH), 2.45 (s, 3H), 2.20 (t, J = 13.1 Hz, IH), 2.12 - 2.01 (m, 2H), 1.93 - 1.76 (m, 2H), 1.71 (d, J = 10.7 Hz, IH). MS(ESI⁺) m/z calc'd for [M+H]⁺[C32H₂₈FN9O2+H]⁺: 590.2 found: 590.4, t_R = 2.44 mins. [Method: (A-6].

[00131] To a stirred solution of in 2-(4-fluorophenyl)-A-[4-methyl-3-[[3-(9- tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]pyrazole-3-carboxamide (101 mg, 0.163 mmol, 1.00 eq) in DCM (1.5 mL, 0.1085 M) at rt was added TFA (1.2 mL, 16.3 mmol, 100 eq). The reaction mixture was stirred at rt for 2h. Volatiles were removed; residue was diluted with cold water at 0 °C. To this was slowly added aq sat NaHCCh (10 mL). Solids were filtered, washed with water (3 x 10 mL) followed by diethyl ether (2 x 10 mL) and dried under reduced pressure. Crude was purified by prep-HPLC, and the purified material was taken in water before saturated sodium bicarbonate was added to it. Solids were filtered, washed with water (3 x 10 mL) followed by diethyl ether (2 x 10 mL) and dried under reduced presure 2-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9H-purin-6-yl)-2- pyridyl]amino]phenyl]pyrazole-3-carboxamide Example 19 (84 mg, 0.161 mmol, 99.05 % yield) as yellow solid. ¹ H NMR (500 MHz, DMSO-d6) 8 12.29 (s, 1H), 10.46 (s, 1H), 9.77 (s, 1H), 9.06 (s, 1H), 8.71 (s, 1H), 8.51 - 8.48 (m, 1H), 8.29 (dd, J = 4.8, 2.0 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.34 (dd, J = 8.2, 2.3 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 7.8, 4.8 Hz, 1H), 2.39 (s, 3H). MS(ESI⁺) mJz calc'd for [M+H]⁺[C₂7H₂oFN90+H]⁺: 506.2 found: 506.2, t_R = 1.88 mins. [Method B].

[00132] Synthesis of A^-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-4-methylphenyl)-5-(4- fluorophenyl)thiazole-4-carboxamide [Example 20]:

Intermediate 1 Intermediate 20 Example 20

[00133] To a solution of 4-methyl-N3-[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2- pyridyl]benzene-l,3-diamine Intermediate 1 (50 mg, 0.125 mmol, 1.00 eq), 5-(4- fluorophenyl)thiazole-4-carboxylic acid Intermediate 20 (29 mg, 0.131 mmol, 1.05 eq) and HATU (59 mg, 0.156 mmol, 1.25 eq) in DMF (1.5 mF, 0.0830 M) at rt was added DIPEA (0.043 mL, 0.249 mmol, 2.00 eq). The reaction mixture was stirred at this temperature for Ih. Cold water (10 mL) was added to the reaction mixture, solids were filtered, washed with aq sat NaHCCh (10 mL) followed by IM LiCl (2 x 10 mL), water (2 x 5 mL) and hexanes and dried under reduced pressure. Crude was purified by column chromatography over silica gel, ISCO, CombiFlash, 4g cartridge (dry load, 0-10% MeOH in DCM as eluent) to afford 5-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9-tetrahydropyran-2- ylpurin-6-yl)-2-pyridyl]amino]phenyl]thiazole-4-carboxamide (71 mg, 0.111 mmol, 89.27 % yield) as a yellow solid. ’ H NMR (500 MHz, Chloroform-<7) 6 12.06 (s, IH), 9.69 (dd, J = 7.9, 2.1 Hz, IH), 9.48 (s, IH), 8.98 (s, IH), 8.72 (s, IH), 8.51 - 8.27 (m, 3H), 7.63 (ddd, J = 10.3, 7.1, 2.9 Hz, 3H), 7.20 (d, J = 8.2 Hz, IH), 7.16 - 7.05 (m, 2H), 6.92 (dd, J = 7.9, 4.7 Hz, IH), 5.89 (dd, J = 10.6, 2.6 Hz, IH), 4.22 (d, J = 9.9 Hz, IH), 3.97 - 3.67 (m, IH), 2.45 (s, 3H), 2.21 (d, J = 11.7 Hz, 1H), 2.11 (d, J = 8.9 Hz, 2H), 1.83 (q, J = 12.5 Hz, 2H), 1.69 (s, 1H). MS(ESI⁺) m z calc'd for [M+H]⁺[C3₂H₂₇FN₈O₂S+H]⁺: 607.2 found: 607.3, t_R = 2.68 mins. [Method: A-6].

[00134] To a stirred solution of 2-[2-(dimethylamino)ethoxy]-5-(4-fluorophenyl)-A-[4- methyl-3-[[3-(9-tetrahydropyran-2-ylpurin-6-yl)-2-pyridyl]amino]phenyl]oxazole-4- carboxamide (51 mg, 0.0753 mmol, 1.00 eq) in DCM (1.5 mL, 0.0522 M) at rt was added TFA (0.60 mL, 7.83 mmol, 100 eq). The reaction mixture was stirred at rt for 2h. Volatiles were removed; residue was diluted with cold water at 0 °C. To this was slowly added aq sat NaHCOs (10 mL). Solids were filtered, washed with water (3 x 10 mL) followed by diethyl ether (2 x 10 mL) and dried under reduced pressure. Crude was purified by prep- HPLC, and the purified material was taken in water before aq sat NaHCOs was added to it. Solids were filtered, washed with water (3 x 10 mL) followed by diethyl ether (2 x 10 mL) and dried under reduced pressure to afford 5-(4-fluorophenyl)-N-[4-methyl-3-[[3-(9H-purin- 6-yl)-2-pyridyl]amino]phenyl]-thiazole-4-carboxamide Example 20 (26 mg, 0.0467 mmol, 59.61 % yield) as a yellow solid. ’ H NMR (500 MHz, DMSO- ₆) 6 12.26 (s, 1H), 10.24 (s, 1H), 9.77 (s, 1H), 9.20 (s, 1H), 9.06 (s, 1H), 8.70 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.29 (dd, J = 4.8, 2.1 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.43 (dd, J = 8.3, 2.3 Hz, 1H), 7.31 - 7.22 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.02 (dd, 7 = 7.9, 4.7 Hz, 1H), 2.38 (s,

3H). MS(ESI⁺) mJz calc'd for [M+H]⁺[C₂7HI₉FN₈OS+H]⁺: 523.2 found: 523.6, t_R = 2.12 mins. [Method B].

[00135] Synthesis of 6-methyl-N¹-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)- pyridin-2-yl)benzene-l,3-diamine [Intermediate 1]:

[00136] 6-( 2-fluoropy ridin-3-yl )-9-( let rahydro-2/7-py ran-2-yl )-9H-purine [3-1] :

[00137] To a stirred solution of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine 1-1 (75.00 g, 314.2 mmol) in dioxane (1050 ml) and H2O (105 ml) was added 2-[3-(2- fluoro)pyridine]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane 2-1 (91 g, 408 mmol) and the reaction flask was purged with nitrogen gas for 30 min. Then Pd(dppf)C12 (6.9 g, 9.4 mmol) and CS2CO3 (256 g, 785 mmol) were added, and the reaction was heated at 100 °C for 3 h under a nitrogen atmosphere. The reaction was quenched with H2O (500 ml) and the resulting mixture was extracted with EtOAc (3 x 500 ml). The combined organic layers were washed with saturated brine solution (1 x 200 ml), separated, dried over Na2SO4, filtered, and concentrated to dryness in vacuo to get a black oil. The crude oil was then treated with Et20 (500 ml) and filtered to give 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H- purine 3-1 as a gray solid (72 g, 76%). ’ H NMR (500 MHz, Chloroform-7) 6 9.11 (s, 1H), 8.51 (t, 7 = 9.0, 9.0 Hz, 1H), 8.41 (s, 2H), 7.47 -7.38 (m, 1H), 5.88 (d, J = 12.4 Hz, 1H), 4.22 (d, J = 13.3 Hz, 1H), 3.83 (t, J = 12.8, 12.8 Hz, 1H), 2.22(d, J = 12.3 Hz, 1H), 2.11 (t, J = 11.7, 11.7 Hz, 2H), 1.92 - 1.66 (m, 3H). MS (ES+) m/z calcd for [M+H]⁺ [C15H14FN5O +H]⁺: 299.1 found 300.6, LCMS tR= 2.98 min. [Method: A]

[00138] A^-(2-methyl-5-nitrophenyl)-3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6- yl)pyridin-2-amine [5-1]:

[00139] A stirred solution of 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H- purine 3-1 (45.00 g, 143 mmol) and 2-methyl-5 -nitroaniline 4-1 (25.00 g, 161 mmol) in anhydrous THF (750 ml) was cooled to 0 °C in an ice-bath. To this solution was added NaHMDS in THF (314 mL, 314 mmol) dropwise over 30 min. The ice-bath was removed, and the reaction was stirred at room temperature for 4 h and monitored by LCMS for completion. The reaction was then quenched with H2O (500 ml). The precipitate obtained was filtered and washed with H2O (2 x 100 ml) to get some of the product (17 g) as a dark yellowish solid. The filtrate was then extracted with EtOAc (2 x 500 ml) to extract more product from the water layer. The combined organic layers were washed (l x 200 ml) saturated brine solution. The organics were then separated and dried over Na2SO4, filtered, and concentrated to dryness in vacuo. The crude solid obtained was further purified using ISCO, Combiflash companion, Siliasep 330 g column (dry loaded in DCM) (eluting 0 to 50 % DCM/EtOAc gradient over 50 min to give another 22 g of N-(2-methyl-5-nitrophenyl)-3- (9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine 5-1 (39.00 g, 62.02% ) as a bright yellow solid. 1H NMR (500 MHz, DMSO-d6) 8 12.67 (s, 1H), 9.81 (dd, J = 7.9, 1.9 Hz, 1H), 9.56 (d, J = 2.5 Hz, 1H), 9.15 (s, 1H), 8.98 (s, 1H), 8.48 (dd, J = 4.7, 1.9 Hz, 1H), 7.79 (dd, J = 8.3, 2.5 Hz, 1H), 7.53 (d, J =8.4 Hz, 1H), 7.16 (dd, J = 7.9, 4.7 Hz, 1H), 5.88 (dd, J = 11.0, 2.3 Hz, 1H), 4.05 (d, J = 12.3 Hz, 1H), 3.76 (td, J = 11.3, 11.2, 3.9 Hz, 1H), 2.61 (s, 3H), 2.39 - 2.31 (m, 1H), 2.09 - 1.98 (m, 2H), 1.62 (d, J =4.8 Hz, 2H).MS (ES+) m/z calcd for [M+H]+ [C22H21N7O3 +H]⁺: 431.4 found 432.4, LCMS tR= 2.50 min [Method: B] [00140] 6-methyl-A^¹-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2- yl)benzene-l,3-diamine [Intermediate 1]:

[00141] A 2 L-hydrogenation bottle was charged with N-(2-methyl-5-nitrophenyl)-3-(9- (tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine 5-1 (25.00 g, 56.8 mmol). This was suspended in a mixture of 500 ml of THF and MeOH (60 mL, 0.0860 M), and a suspension of 10% Pd/C (3.02 g, 2.84 mmol) in 100 ml THF was slowly added to the hydrogenation bottle under a steady flow of nitrogen. The bottle was then purged with nitrogen gas for 10 mins, and then subjected to hydrogenation in a Parr shaker at 40 psig for 6 h. The reaction mixture was then filtered through Celite. The Celite was washed with THF (100 ml), MeOH (100 ml), and EtOAc (300 ml). The filtrate was evaporated to get a greenish yellow residue. The crude solid was further purified using ISCO, Combiflash Siliasep 330 g column (dry loaded in DCM, eluting 0 to 100 % DCM/EtOAc gradient over 60 min). Product fractions were combined and concentrated in vacuo to give 6-methyl-N¹-(3-(9-(tetrahydro- 2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-l,3-diamine Intermediate 1 (14.00 g, 60.2 % yield) as an orange solid. ’ H NMR (500 MHz, DMSO-d6) 8 11.94 (s, 1H), 9.68 (dd, J = 7.9, 2.0 Hz, 1H), 9.08 (s, 1H), 8.93 (s, 1H), 8.32 (dd, J = 4.6, 1.9 Hz, 1H), 7.59 (s, 1H), 6.96 (dd, J = 7.9, 4.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.22 (dd, J = 8.0, 2.3 Hz, 1H), 5.86 (dd, J = 10.9, 2.2 Hz, 1H), 4.79 (s, 2H), 4.08 - 4.01 (m, 1H), 3.79 - 3.71 (m, 1H), 2.41 - 2.29 (m, 1H), 2.26 (s, 3H), 2.03 (t, J = 15.2, 15.2 Hz, 2H), 1.81 - 1.75 (m, 1H), 1.70 - 1.58 (m, 2H). MS (ES+) m/z calcd for [M+H]⁺ [C22H23N7O +H]⁺: 401.46 found 402.4, LCMS tR= 1.46 min [Method: B]

[00142] Synthesis of 2-(4-fluorophenyl)furan-3-carboxylic add [Intermediate 2]:

1-2 2-2 Intermediate 2

[00143] To a solution of 2-iodofuran-3 -carboxylic acid 1-2 (2.10 g, 4.85 mmol, 1.00 eq), and 4-Fluorophenylboronic acid 2-2 (0.75 g, 5.34 mmol, 1.10 eq) in dioxane: water (3:1,40 mL) under argon, was added Palladium(II) acetate (0.018 g, 0.0791 mmol, 0.0163 eq) and reaction mixture was stirred for 4 h at room temperature and then filterd through Celite, filtrate was diluted with 10 mL water and acidified with 4 mL of 2 M HC1, crude product was isolated by filtration, washed with cold water and dried under reduced pressure to afford 2-(4-fluorophenyl)furan-3-carboxylic acid Intermediate 2 as a brown solid. (0.650 g, 92.6 % Yield) 1H NMR (400 MHz, DMSO-d₆): 6 12.75 (br s, 1H), 8.00 (dd, J = 8.9, 5.6 Hz, 2H), 7.81 (d, J = 2.0 Hz, 1H), 7.32 (t, 7 = 8.9 Hz, 2H), 6.84 (d, J = 1.9 Hz, 1H). MS (ES- ) m/z calc’d for [M-H]’ [CIIH₇F03-H] :205.04 found 205.25, LCMS: fa = 1.922min, [Method: [LCMS 7 STD (XselectF.Acid) (+ ar )], Column : X-Select CSH C18 (3.0*50) mm 2.5um, Mobile Phase: A: 0.05% Formic acid in water: ACN(95:05) B: 0.05% Formic acid in ACN , Flow Rate : 1.2. mL/minute, Column oven Temp: 50°C.

[00144] Synthesis of 2-((2-(dimethylamino)ethyl)thio)-5-(4-fhiorophenyl)-lH- imidazole-4-carboxylic acid [Intermediate 3]: was made according to procedures to which one of skil in the art would be aware.

[00145] Synthesis of l-(4-fluorophenyl)-lH-pyrazole-3-carboxylic acid [Intermediate 4]:

[00146] Available from commercial sources.

[00147] Synthesis of l-phenyl-lH-pyrazole-5-carboxylic add [Intermediate 5]:

[00148] Available from commercial sources

[00149] Synthesis of 3-(4-fluorophenyl)-lH-pyrrole-2-carboxylic acid [Intermediate

1-6 Intermediate 6

[00150] To a solution ethyl 3-(4-fluorophenyl)-lH-pyrrole-2-carboxylate 1-6 (0.64 g, 2.75 mmol, 1.00 eq) of in Methanol (10 mL, 0.2746 M) and H2O (4.0 mL, 4.00 mmol, 1.46 eq) was added LiOH (0.82 g, 7.15 mmol, 2.61 eq) under N2. The mixture was stirred at 80 C for 17h. The solution was cool to 23 C and concentrated under vacuo, the solution was acidified to pH2 with 2N HC1 and stirred for 2h. The precipitate was filtered and crystalized with Et20: Hex to afford 3-(4-fluorophenyl)-lH-pyrrole-2-carboxylic acid Intermediate 6 (0.31 g, 1.51 mmol, 55.00 % yield). ’ H NMR (600 MHz, DMSO) 8 12.27 (s, 1H), 11.71 (s, 1H), 7.59 - 7.52 (m, 2H), 7.19 - 7.13 (m, 2H), 6.97 (t, J = 2.7 Hz, 1H), 6.26 (t, J = 2.7 Hz, 1H).

MS (ES-) mJz calc’d for [M-H]⁺ [CiiH7F0₃-H] :205.04 found 206.0 LCMS: fa = 5.41 min. [Method: 05991008_AA0.1cm, Buff A - 0.1% FA/H2O, Buff B - 0.1% FA/AcN]

[00151] Synthesis of 3-(4-methyl-lH-imidazol-l-yl)-5-(trifhioromethyl)benzoic acid [Intermediate 7]:

[00152] 3-(4-Methylimidazol-l-yl)-5-(trifluoromethyl)benzonitrile [3-7] :

[00153] A stirred solution of 4-Methyl-lH-imidazole 2-7 (1.45 g, 17.7 mmol, 3.10 eq) and 3-Fluoro-5-(trifluoromethyl)benzonitrile 7-1 (1.08 g, 5.70 mmol, 1.00 eq) in DMA (5 mL, 1.1401 M) was heated to 145 °C for 24h. Reaction mixture was cooled to rt, water (10 mL) was added to it before it was extracted with ethyl acetate (3 x 10 mL). Organic part was washed with water followed by brine and concentrated. Crude was purified by column chromatography over silica gel, ISCO, 40g cartridge, eluting with 0-40% EtOAc in Hexane to give 3-(4-methylimidazol-l-yl)-5-(trifluoromethyl)benzonitrile 3-7 (730 mg, 2.87 mmol, 50.42 % yield) as a white solid. ¹ H NMR (500 MHz, DMSO-d6) 8 8.53 (s, 1H), 8.40 (s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 7.71 (s, 1H), 2.15 (s, 3H). MS(ESI⁺) m/z calc'd for [M+H]⁺[Ci₂H₈F3N3+H]⁺: 252.2, found: 252.2 , t_R = 2.75 mins. [Method: A- 12],

[00154] Synthesis of 3-(4-Methylimidazol-l-yl)-5-(trifhioromethyl)benzoic acid [Intermediate 7]:

[00155] To a solution of 3-(4-methylimidazol-l-yl)-5-(trifluoromethyl)benzonitrile 3-7 (696 mg, 2.77 mmol, 1.00 eq) in 1,4-Dioxane (15 mL, 0.1847 M) was added IN NaOH (14 mL, 13.8 mmol, 5.00 eq). The mixture was stirred at 95°C o/n. The reaction mixture was evaporated and diluted with H2O. The mixture was acidified with 3N HC1 and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine, dried, filtered and evaporated to afford 3-(4-methylimidazol-l-yl)-5-(trifluoromethyl)benzoic acid Intermediate 7 (0.70 g, 2.59 mmol, 93.53 % yield) as an off white solid. ’H NMR (500 MHz, DMSO- d6) 8 9.71 (s, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 8.27 (s, 1H), 8.21 - 8.17 (m, 1H), 2.34 (s, 3H). MS(ESI⁺) mJz calc'd for [M+H]⁺[Ci₂H₉F3N2O2+H]⁺: 271.1, found:271.1, t_R = 1.12 mins. [Method: B],

[00156] Synthesis of l-(4-fluorophenyl)-lH-pyrrole-2-carboxylic add [Intermediate 8]:

[00157] Available from commercial sources

[00158] Synthesis of l-(tert-butoxycarbonyl)-lH-indole-3-carboxylic add

[Intermediate 9]:

[00159] Available from commercial sources

[00160] Synthesis of 3-(4-methylpyrazol-l-yl)-5-(trifluoromethyl)benzoic acid

[Intermediate 10]:

[00161] A mixture of 3-Fluoro-5-(trifluoromethyl)benzonitrile (1.50 g, 7.93 mmol, 1.00 eq), 4-Methylpyrazole (0.65 g, 7.93 mmol, 1.00 eq) and Sodium hydroxide (793 mg, 19.8 mmol, 2.50 eq) in DMF (10 mL, 0.1586 M) was heated at 110 °C for 2hours with LCMS monitoring. The reaction mixture was cooled to room temperature, and poured to ice- water, acidified to PH 6 with cone. HC1, extracted with ethyl acetate (X2), combined organic phase was washed with water (X4) and brine, dried with anhydrous Na2SO4, filtered, concentrated to dryness under reduced pressure afforded a yellowish white solid , combined with the crude from FY-2021-02-44 and FY-2021-02-45, then was taken to 1,4-Dioxane (40 mL, 0.1586 M) and Sodium hydroxide (40 mL, 39.7 mmol, 5.00 eq), the resulting reaction mixture was stirred at 70°C for over the weekend, concentrated under reduced pressure to remove dioxane, then diluted with water, acidified to PH4 with cone. HC1, extracted with ethyl acetate (X3), combined organic phase was washed with brine, dried with Na2SO4, filtration and concentration afforded 3-(4-methylpyrazol-l-yl)-5-(trifluoromethyl)benzoic acid Intermediate 10 (1.91 g, 6.98 mmol, 87.95 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 13.69 (s, 1H), 8.61 - 8.56 (m, 2H), 8.36 (d, J = 2.1 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.66 (d, J = 3.0 Hz, 1H), 2.09 (d, J = 2.7 Hz, 3H). MS(ES⁺) m/z cala'd for [M+H] :271.1, found LCMS 271.3 t_R=2.43 min [Method: B] .

[00162] Synthesis of l-(4-fhiorophenyl)-5-(methylsulfonyl)-lH-pyrazole-3-carboxylic add [Intermediate 11], and l-(4-fhiorophenyl)-5-(methylsulfinyl)-lH-pyrazole-3- carboxylic add [Intermediate 12]:

i) MeMgCI, THF

O C

[00163] l,l-Bis(methylthio)ethylene [2-11]:

— S — s^z

[00164] Methyl magnesium chloride (426 mL, 1278 mmol) in anhydrous THF (852 ml) was added to a mechanically stirred 5 L round bottom flask. To this was added carbon disulfide 1-11 (116 ml, 1917 mmol) in 116 ml of anhydrous THF with an addition rate such that the internal temperature did not exceed 40 °C. The reaction mixture was stirred at 40 °C for 2 h. The reaction was then cooled to -78 °C using an acetone / dry ice bath, and to this was added LDA 2.0 M solution in ethyl benzene (639 ml, 1278 mmol) in 640 ml of THF. The reaction was then stirred at -78 °C for 2 h. To this was added a solution of dimethyl sulfate (243 mL, 2556 mmol,) in 246 ml of THF, and the reaction was allowed to warm to room temperature and stirred for 17 h. Then 700 ml of Et20 was added, and the reaction was stirred for 10 min and allowed to stand during which time the inorganic salts precipitated. The supernatant was decanted, and the salts were rinsed with Et2O (500 ml). The combined Et2O fractions were then washed with H2O (2 x 1500 ml), brine (1000 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to get a dark brown oil. The crude oil was then distilled at 50 °C, 3 Torr, to afford l,l-bis(methylthio)ethylene 2-11 (60.00 g, 37.09 %) as a yellow oil. ’ H NMR (500 MHz, Chloroform-^) 8 5.24 (s, 2H), 2.36 (s, 6H). LCMS: No ionization or UV signal observed.

[00165] Methyl 4,4-bis(methylthio)-2-oxo-but-3-enoate [3-11]:

[00166] A stirred solution of l,l-bis(methylthio)ethylene 2-11 (60.0 g, 474 mmol) in anhydrous Et2O (600 ml) was cooled to -60 °C using an Et2O / dry ice bath. To this solution was added oxalyl chloride (50 mL, 569 mmol) dropwise. During the addition of oxalyl chloride the solution turned into a yellow suspension. The suspension was allowed to warm up to -15 °C , and MeOH (115 ml, 2859 mmol) was added. The reaction was then allowed to warm to room temperature and stirred for 2 h. Et2O (400 ml) was added, and the precipitate obtained was filtered and dried in vacuo to give 49.00 g, 47.60 % yield of Methyl 4,4- bis(methylthio)-2-oxo-but-3-enoate 3-11 as a yellow solid. ’ H NMR (500 MHz, chloroform- d) 8 6.83 (s, 1H), 3.86 (s, 3H), 2.56 (s, 3H), 2.54 (s, 3H). LCMS: No ionization or UV signal observed.

[00167] Methyl l-(4-fluorophenyl)-5-(methylthio)-lH-pyrazole-3-carboxylate [4-11]:

[00168] To a stirred solution of 4-fluorophenyhydrazine hydrochloride (22.00 g, 135 mmol) in a dry 500 ml round-bottom flask was added THF (150 ml) and EtsN (19 ml, 135 mmol). The solution was stirred 10 min after which was added a solution of methyl 4,4- bis(methylthio)-2-oxo-but-3-enoate 3-11 (28.60 g, 132 mmol) in THF (150 mL). Molecular sieves (3 A, 8-12 mesh) were added, and the reaction was heated at reflux (80 °C) for 5 h. The reaction was cooled and then filtered through Celite. The Celite was washed with EtOAc (200 ml), and the combined organic layers were evaporated in vacuo to get a crude yellow solid. This solid was further purified using ISCO, Combiflash companion, Siliasep 330 g column, (dry loaded in DCM), eluting 0 to 50 % hexane / EtOAc gradient over 60 min). The product fractions were combined and concentrated in vacuo to give 13.00 g, 36.08 % yield of Methyl l-(4-fluorophenyl)-5-(methylthio)-l/Z-pyrazole-3-carboxylate 4-11. ’ H NMR (500 MHz, DMSO-^6) 6 13.00 (s, 1H), 7.64 - 7.57 (m, 2H), 7.44 - 7.37 (m, 2H), 6.92 (s, 1H), 2.47 (s, 3H). MS (ES+) m/z calcd for [M+H]⁺ [C12H11FN2O2S +H]⁺: 252.03 found 253.0, LCMS tR= 1.95 min. [Analytical Method: B]

[00169] Methyl l-(4-fluorophenyl)-5-(methylsulfonyl)-lH-pyrazole-3-carboxylate [5 Methyl l-(4-fluorophenyl)-5-(methylsulfonyl)-lH-pyrazole-3-carboxylate [5-11] :

[00170] To a stirred solution of methyl l-(4-fluorophenyl)-5-(methylthio)-lH-pyrazole-3- carboxylate 4-11 (17.00 g, 63.8 mmol) in DCM (500 mL, 0.1277 M) was added 3- chloroperoxybenzoic acid (62.95 g, 255 mmol) and the reaction was stirred at room temperature for 2 h. The mixture was then washed with saturated NaHCOs solution (2 x 200 ml), brine (100 ml), dried over Na2SO4, filtered, and evaporated to give 12.50 g, 62.36 % yield of Methyl l-(4-fluorophenyl)-5-(methylsulfonyl)-l/Z-pyrazole-3-carboxylate 5-11 as a yellow solid. ’ H NMR (500 MHz, DMSO- ₆) 67.73 - 7.66 (m, 2H), 7.60 (s, 1H), 7.42 (t, J = 8.7, 8.7 Hz, 2H), 3.86 (s, 3H), 3.33 (s, 3H). MS (ES+) m/z calcd for [M+H]⁺ [C12H11FN2O4S +H]⁺: 298.29 found 299.50, LCMS t_R= 5.42 min. [Analytical Method: A]

[00171] l-(4-fluorophenyl)-5-(methylsulfonyl)-lH-pyrazole-3-carboxylic add [Intermediate 11]:

[00172] To a stirred solution of methyl l-(4-fluorophenyl)-5-(methylsulfonyl)-lH- pyrazole-3 -carboxylate 11-5 (11.00 g, 35.0 mmol) in THF (100 ml) was added a solution of LiOH (1.68 g, 70.1 mmol) in H2O (100 ml). The reaction was allowed to stir for 2 h. After completion, 2N HCL was added to the reaction mixture, which was then extracted with EtOAc (500 ml). The organic layer was washed with brine (200 ml), dried over Na2SO4, filtered, and evaporated to get a yellowish oil. The oil was triturated with EtOAc: hexane (1:3) to afford l-(4-fluorophenyl)-5-(methylsulfonyl)-l/Z-pyrazole-3-carboxylic acid Intermediate 11 as a pale yellow solid {8.60 g, 28.5 mmol, 81.35 %). ’ H NMR (500 MHz, DMSO-d₆) 6 7.68 (ddd, J = 8.9, 4.7, 1.8 Hz, 2H), 7.52 (d, J = 1.9 Hz, 1H), 7.42 (td, J = 8.8, 8.7, 1.9 Hz, 2H), 3.31 (s, 3H). MS (ES+) m/z calcd for [M+H]⁺ [C11H9FN2O4S

+H]⁺: 284.3 found 285.4, LCMS t_R= 2.02 min. [Analytical Method: B]]:

[00173] Methyl l-(4-fluorophenyl)-3-(methylsulfinyl)-lH-pyrazole-5-carboxylate [6- 11]:

[00174] To a stirred solution of methyl l-(4-fluorophenyl)-5-(methylthio)-lH-pyrazole-3- carboxylate 4-11 (13.00 g, 48.8 mmol) in DCM (200 ml) was added 3 -chloroperoxybenzoic acid 4-11 (12.00 g, 48.7 mmol), and the reaction was stirred at room temperature for 2 h. The reaction mixture was then washed with saturated NaHCOs solution (2 x 200 ml), brine (100 ml), dried over Na2SO4, filtered, and concentrated to dryness in vacuo to provide 11.50 g, 79.28 % yield of Methyl l-(4-fluorophenyl)-3-(methylsulfinyl)-l/Z-pyrazole-5-carboxylate 6- 11 as an orange solid. ’ H NMR (500 MHz, DMSO- ₆) 67.76 - 7.69 (m, 2H), 7.68 (s, 1H), 7.47 (t, J = 8.7, 8.7 Hz, 2H), 3.87 (s, 3H), 3.06 (s, 3H). MS (ES+) m/z calcd for

[M+H]⁺ [C12H11FN2O3S +H]⁺: 282.29 found 283.6, LCMS t_R= 4.91 min. [Analytical Method: A-6]

[00175] l-(4-fluorophenyl)-5-(methylsulfinyl)-lH-pyrazole-3-carboxylic add [Intermediate 12]:

[00176] To a stirred solution / suspension of methyl l-(4-fluorophenyl)-5-(methylsulfinyl)- l/Z-pyrazole-3-carboxylate 6-11 (11.50 g, 40.7 mmol) in THF (100 ml) was added a solution of LiOH (1.90 g, 79.3 mmol) in H2O (100 ml). The reaction was stirred for 1 h. After completion, 5% HC1 (100 ml) was added to the reaction mixture until pH=l. The mixture was then extracted with EtOAc (500 ml). The organic layer was washed with brine (200 ml), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. The oil was triturated with EtOAc:hexane (1:3), then filtered to afford 9.20 g, 80.65 % of l-(4- fluorophenyl)-5-(methylsulfinyl)-l/Z-pyrazole-3-carboxylic acid Intermediate 12 as an orange solid. ’ H NMR (500 MHz, DMSO-d₆) 6 13.2-13.4(s,lH), 87.75 - 7.68 (m, 2H), 7.60 (d, J = 0.9 Hz, 1H), 7.46 (t, J = 8.8, 8.8 Hz, 2H), 3.04 (s, 3H).MS (ES+) m/z calcd for

[M+H]⁺ [C11H9FN2O3S +H]⁺: 268.02 found 268.9, LCMS t_R= 1.17 min. [Analytical Method: B]

[00177] Synthesis of 5-(4-fluorophenyl)-2-(methylsulfinyl)thiazole-4-carboxylic add [Intermediate 13]:

[00178] Made according to procedures descrbied in WO2013/22766

[00179] Synthesis of 5-(tert-butyl)oxazole-4-carboxylic add [Intermediate 14]:

[00180] Available from commercial sources

[00181] Synthesis of 3-(4-fluorophenyl)furan-2-carboxylic add [Intermediate 15]:

1-15 Intermediate 15

[00182] A well stirred mixture of ethyl 3-bromofuran-2-carboxylate (6 g, 27.3 mmol, 1 eq.), Pd(PPh₃)₄ (0.3 g, 0.27 mmol, 0.01 eq.), and Cs2CO3 (8.9 g, 27.3 mmol, 1 eq.) in THF: Water (1:1 - v/v) was treated with 4-Fluorophenylboronic acid (5.7 g, 41.1 mmol, 1.5 eq.) at room temperature and then reaction mixture was stirred at 70 °C for 8 h. Reaction mixture was cooled to room temperature upon completion, as judged by TLC, before extracting with ethyl acetate twice. Solvent evaporated under reduced pressure. Crude reaction mixture was purified over gravity column using silica gel (100-200 mesh) with a gradient of 0 to 10% ethyl acetate in hexane as an eluent to afford ethyl 3-(4-fluorophenyl)furan-2-carboxylate 1- 15 (4.5 g (61%) as colorless liquid.

[00183] To a well stirred mixture of ethyl 3-(4-fluorophenyl)furan-2-carboxylate 1-15 (5 g, 21.3 mmol, 1 eq.) was added 2M NaOH (30 mL) at room temperature and the reaction mixture was stirred at room temperature for 4 h. after completion of the reaction as judged by TLC, reaction mixture was acidified using IM HC1 (~60 mL) and then reaction mixture was extracted using Ethyl acetate(100 mL) twice, organic layer was evaporated under reduced pressure to afford 3-(4-fluorophenyl)furan-2-carboxylic acid Intermediate 15 (4.1 g, 90.7%) as a white colored solid.¹!! NMR (400 MHz, DMSO-d₆): 6 13.00 (br s, 1H), 7.87-7.84 (m, 2H), 7.38-7.26 (m, 3H), 7.12 (d, J = 3.4 Hz, 1H). MS (ES+) m/z calc’d for [M-H]-

[C11H7FO3-H]-: 205.0 found 205.00, LCMS: tR = 1.910 min [Method: LCMS 7 STD (XselectF.Acid) (+ an]. Column: X-Select CSH C18 (3.0*50) mm 2.5um. Mobile Phase: A: 0.05% Formic acid in water: ACN(95:05) B: 0.05% Formic acid in ACN. Inj Volume: 2.0 pL. Flow Rate: 1.2. mL/minute Column oven Temp: 50°C.

[00184] Synthesis of 2-((2-(dimethylamino)ethyl)thio)-5-(4-fhiorophenyl)oxazole-4- carboxylic add [Intermediate 16]:

5-16 Intermediate 16

[00185] Methyl 5-(4-fhiorophenyl)-2-(methylthio)oxazole-4-carboxylate [3-16]:

[00186] To a stirred solution of methyl 2- [bis(methylsulfanyl)methyleneamino] acetate 2- 16 (75.0 g, 388.02 mmol) in THF (3.0 L) at -78 °C was added NaCTBu (44.7 g, 465.62 mmol) in portions, and the reaction mixture was stirred for 30 min. To this was added l-(4- fluorobenzoyl)-lH-imidazole 1-16 (77.5 g, 407.42 mmol) in THF (880 ml) dropwise, and the mixture was allowed to warm slowly to room temperature and stir overnight. The solution was then diluted with EtOAc, washed with H2O, brine, and dried with MgSCU. The solvent was removed by rotary evaporation, and the crude material was triturated with a mixture of hexane: Et20 (12:1, 2 x 800 ml) to afford methyl 5-(4-fluorophenyl)-2-(methylthio)oxazole- 4-carboxylate 3-16 (92.0 g, 327.0 mmol, 84.3% yield) as a white solid. ¹ H NMR (500 MHz, DMSO-d6) 87.75 - 7.62 (m, 2H), 7.44 - 7.31 (m, 2H), 3.36 (s, 3H). MS(ESI⁺) mJz calcd for [M+H]⁺[Ci2HioFN03S+H]⁺: 268.28 found: 268.1, t_R = 2.76 mins. [Method: A-6]. [00187] 5-(4-fhiorophenyl)-2-(methylthio)oxazole-4-carboxylic add [4-16]:

[00188] Methyl 5-(4-fluorophenyl)-2-(methylthio)oxazole-4-carboxylate 3-16 (1.0 g, 3.74 mmol) was dissolved in THF (14 mL) and cooled to 0 °C and LiOH (180.0 mg, 7.48 mmol) was dissolved in H2O and cooled to 0 °C, and the solution was added to the reaction mixture dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3 h The reaction mixture was then gradually acidified with IN HC1 (pH ~ 1) and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with brine, dried with Na2SO4 and concentrated in vacuo to afford pure 5-(4-fluorophenyl)-2-(methylthio)oxazole-4-carboxylic acid 4-16 (916.0 mg, 97% yield).

[00189] 5-(4-fluorophenyl)-2-(methylsulfonyl)oxazole-4-carboxylic add [5-16]:

[00190] Oxone (681 g, 2.12 mol) in H2O (2.5 L) was added to a solution of 5-(4- fluorophenyl)-2-(methylthio)oxazole-4-carboxylic acid 4-16 (85 g, 0.336 mol) in MeOH (2.5 L) at room temperature and stirred 3 days. Then 12 L H2O was added, and the mixture was extracted with EtOAc (2 x 12 L). The organic layer was dried and evaporated to provide 5-(4- fluorophenyl)-2-(methylsulfonyl)oxazole-4-carboxylic acid 5-16 as an off white solid (92 g, 95% yield) which was used directly without further purification in the following step.

[00191] 2-(2-(dimethylamino)ethoxy)-5-(4-fhiorophenyl)oxazole-4-carboxylic add [Intermediate 16]:

[00192] Using the same procedure described for the displacement reaction with sodium methoxide, the sodium salt of 2-(dimethylamino)ethan-l-ol was reacted with 5-(4- fluorophenyl)-2-methoxyoxazole-4-carboxylic acid 5-16 to afford 2-(2- (dimethylamino)ethoxy)-5-(4-fluorophenyl)oxazole-4-carboxylic acid Intermediate 16.

[00193] Synthesis of 5-(3-chlorophenyl)oxazole-4-carboxylic add [Intermediate 17]:

[00194] Available from commercial sources

[00195] Synthesis of 2-(2-(dimethylamino)ethoxy)-5-(4-fluorophenyl)oxazole-4- carboxylic add [Intermediate 18]:

[00196] Using the same procedure described for the displacement reaction with sodium methoxide, the sodium salt of 2-(dimethylamino)ethane-l -thiol was reacted with 5-(4- fluorophenyl)-2-methoxyoxazole-4-carboxylic acid 5-16 to afford 2-((2- (dimethylamino)ethyl)thio)-5-(4-fluorophenyl)oxazole-4-carboxylic acid Intermediate 18.

[00197] Synthesis of l-(4-fluorophenyl)-lH-pyrazole-5-carboxylic add [Intermediate 19]:

[00198] Available from commercial sources

[00199] Synthesis of 5-(4-fluorophenyl)thiazole-4-carboxylic add [Intermediate 20]:

1-20 Intermediate 20

[00200] To a Ethyl 5-bromothiazole-4-carboxylate (5.00 g, 21.2 mmol, 1.00 eq),Na2CO3 (3.37 g, 31.8 mmol, 1.50 eq),4-Fluorophenylboronic acid (4.44 g, 31.8 mmol, 1.50 eq), 1,4- Dioxane (47 mL, 0.4506 M) was added and purged with nitrogen for 10 min and Pd Tetrakis (2.45 g, 2.12 mmol, 0.100 eq)was added and purged with Nitrogen for 5 min, refluxed the reaction mixture for 12hrs at 100°C. upon completion of reaction, It was cooled to RT, Extracted with water and EtOAc, organic layer was washed with Saturated aqueous NaCl. Organic layer was evaporated under reduced pressure. Crude reaction mixture was purified under Combi flash using silica gel (100-200mesh) with gradient of 0-35%Ethylacetae in hexane as an eluent. The obtained mixture of 5-(4-fluorophenyl)thiazole-4-carboxylate 1-20 was concentrated under vacuum.

[00201] To a well stirred mixture of 5-(4-fluorophenyl)thiazole-4-carboxylate 1-20 (1.50 g, 5.97 mmol, 1.00 eq) in Ethanol (15 mL), 2N NaOH (15 mL) was added and reaction mixture was refluxed at 80 °C for 6 h. Upon completion of the reaction, the reaction mixture was cooled to RT and was extracted with ethyl acetate (1x10 mL) acidified. Aqueous layer was then acidified using IM HC1 to pH =1. Precipitation formed was filtered and washed with water and dried under vacuum to afford 5-(4-fluorophenyl)thiazole-4-carboxylic acid Intermediate 20 as pale brown solid (1 g, 74.07%). LCMS: MS(ES⁺) m/z calc'd for

[M+H]⁺ [CioH₆FN0₂S+H]⁺ 224.01, found: 223.85, LCMS: t_R = 2.45 min, LCMS: [7 STD METHOD (XseleCT.) 10 min]. Column: X-Select CSH C18 (3.0*50) mm 2.5um Mobile Phase: A: 0.05% Formic acid in water: ACN(95:05) B: 0.05% Formic acid in ACN Inj Volume: 2.0pL Flow Rate : 1.2. mL/minute Column oven Temp: 50°C. ^!H NMR (400 MHz, CHLOROFORM-d) 8 = 8.72 - 8.68 (m, 1H), 7.60 (br dd, J = 5.3, 8.6 Hz, 2H), 7.11 (br t, J = 8.6 Hz, 2H).

Biochemical Assays

1. Kinase Panel

[00202] The disclosed compounds were tested for activity against a panel of at least 300 kinases. Kinase panel screening was conducted by Nanosyn (Santa Clara, CA 95051) using an enzymatic inhibition assay accepted as valid by those skilled in the art (e.g., the Caliper LabChip® mobility shift assay, an ADP detection assay, or time-resolved fluorescence detection technology. Compounds were screened at a concentration of 5 pM using an ATP concentration at the Km for each of the respective kinases and a 30-minute pre-incubation time-point.

[00203] A selection of kinases from that panel in which one or more of the disclosed compounds showed inhibition of kinase activity is shown below in Table 1 and Table 2. In the table, kinase inhibition is classified by: A = 95% or greater, B = 90%-94%, C = 80%- 89%, and D = 79% and less with a compound concentration of 5 pM.

Table 1

Table 2

[00204] While we have described a number of embodiments, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[00205] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

Claims

Listing of Claims:

1. A compound having the Formula I:

or a pharmaceutically acceptable salt thereof, wherein

R¹ and R² are each independently selected from hydrogen, halo, and (Ci-C4)alkyl;

R³ is phenyl or heteroaryl, each of which is optionally substituted with 1 to 2 groups selected from R^a;

R^a is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci- C₄)alkoxy, halo(Ci-C₄)alkoxy, halo, -S(O)[(Ci-C₄)alkyl], -S(O)₂[(Ci-C₄)alkyl], -S(Ci- C4)alkyl, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, phenyl, and 4- to 6-membered heteroaryl, wherein said phenyl and 4- to 6-membered heteroaryl are each optionally substituted with 1 to 2 groups selected from R^b; and wherein said (Ci-C4)alkyl, (Ci-C4)alkoxy, and -S(Ci- C4)alkyl are each optionally substituted with -NR^cR^d;

R^b is selected from halo and (Ci-C4)alkyl; and

R^c and R^d are each independently selected from hydrogen and (Ci-C4)alkyl.

2. The compound of Claim 1, wherein the compound is of the Formula II:

or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 or 2, wherein the compound is of the Formula III:

or a pharmaceutically acceptable salt thereof.

4. The compound of any one of Claims 1 to 3, wherein the compound is of the Formula

IV:

or a pharmaceutically acceptable salt thereof.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R¹ is (Ci-C4)alkyl.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl.

7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from phenyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, imidazolyl, indolyl, and pyrrolyl, each of which are optionally substituted with 1 to 2 groups selected from R^a.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R^a is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, - S(O)[(Ci-C4)alkyl], -S(O)2[(Ci-C4)alkyl], -S(Ci-C4)alkyl, phenyl, and 4- to 6-membered heteroaryl, wherein said phenyl and 4- to 6-membered heteroaryl are each optionally substituted with 1 to 2 groups selected from R^b and wherein said (Ci-C4)alkyl, (Ci-C4)alkoxy, and -S(Ci-C4)alkyl are each optionally substituted with -NR^cR^d.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R^a is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, -S(O)[(Ci-C4)alkyl], - S(O)2[(Ci-C4)alkyl], -S[(Ci-C4)alkyl]N[(Ci-C₄)alkyl]2, -O[(Ci-C4)alkyl]N[(Ci-C₄)alkyl]2, phenyl, pyrazolyl, and imidazolyl wherein said phenyl, pyrazolyl, and imidazolyl are each optionally substituted with 1 to 2 groups selected from R^b.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R^b is selected from halo and (Ci-C4)alkyl.

11. The compound of Claim 1, wherein the compound is selected from:

, and

, or a pharmaceutically acceptable salt of any of the foregoing.

12. A pharmaceutical composition comprising a compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

13. A method of treating a condition responsive to the inhibition of the serine/threonine protein kinase Raf family comprising administering to the subject a therapeutically effective amount of the compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof.