WO2023183470A1 - 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. 63/323,095, 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 Z, 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.

[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

Z can be NH or O;

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: N- 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] Eiquid Chromatography Mass Spectrometry (ECMS) was performed on a Shimadzu ECMS 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)

[0045] 05991008_AA0 (0.8 mL/min flow)

[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

[0051] Method B; polar_6min_100_1500 (1.0 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-C18; 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]

[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 um; 50 x 20 mm (Bischoff Part # B052

0F180PS100)

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

[0077] ACE 5 C18-PFP; 5.0 um; 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 5-tert-butyl-N-[4-methyl-3-[(3-methyl-4-oxo-quinazolin-6- yl)amino]phenyl]furan-2-carboxamide [Example 1]:

[0081] A solution of 6-((5-amino-2-methylphenyl)amino)-3-methylquinazolin-4(3H)-one Intermediate 1 (37 mg, 0.131 mmol, 1.00 eq) in DMF (1 mL, 0.1306 M) was added Diisopropylethylamine (0.045 mL, 0.261 mmol, 2.00 eq), 5-tert-Butyl-2-furoic acid

Intermediate 4 (28 mg, 0.164 mmol, 1.26 eq) and HATU (0.074 g, 0.196 mmol, 1.50 eq). The mixture was stirred at rt for 3h and directly purified by HPLC to provide 5-tert-butyl-N-[4- methyl-3-[(3-methyl-4-oxo-quinazolin-6-yl)amino]phenyl]furan-2-carboxamide Example 1 (38 mg, 0.0863 mmol, 66.09 % yield) as a white solid. ¹ H NMR (500 MHz, DMSO-rfe) 8 9.78 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H),

7.45 - 7.37 (m, 2H), 7.35 (dd, J = 8.2, 2.2 Hz, 1H), 7.23 - 7.15 (m, 2H), 6.26 (d, J = 3.4 Hz, 1H), 3.44 (s, 3H), 2.16 (s, 3H), 1.28 (s, 9H). MS(ESI⁺) m/z calc'd for [M+H]⁺[C₂5H₂6N4O3+H]⁺: 431.2 found: 431.8 , t_R = 2.29 mins. [Method: B],

[0082] Synthesis of 3-(4- ethylimidazol- l-yl)- \-|4-methyl-3-|(3-methyl-4-oxo- quinazolin-6-yl)amino]phenyl]-5-(tri-fluoromethyl)benzamide [Example 2]

[0083] To a solution of 3-(4-methylimidazol-l-yl)-5-(trifluoromethyl)benzoic acid Intermediate 3 (40 mg, 0.150 mmol, 1.40 eq) in DMF (1 mL, 0.0535 M) was added Diisopropylethylamine (0.056 mL, 0.321 mmol, 3.00 eq), A-[(Dimethylamino)-l/Z-l,2,3- triazolo-[4,5-b]pyridin-l-ylmethylene]-A-methylmethanaminium hexafluor-ophosphate N- oxide (61 mg, 0.161 mmol, 1.50 eq) and stirred at rt for 10 min. Then a solution of 6-((5- amino-2-methylphenyl)amino)-3-methylquinazolin-4(3H)-one Intermediate 1 (30 mg, 0.107 mmol, 1.00 eq) in DMF (1 mL, 0.0535 M) was added and stirred 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 NaHCOs (2 x 5 mL), IM LiCl (10 mL), H2O (2 x 5 mL). The solid was dried and washed with MeOH (3 x 5 mL), dried overnight under high vacuum to afford 3-(4-methylimidazol-l-yl)-N-[4-methyl-3-[(3- methyl-4-oxo-quinazolin-6-yl)amino]phenyl]-5-(trifluoromethyl)benzamide Example 2 (15 mg, 0.0279 mmol, 26.11 % yield) as an off white solid. ’ H NMR (500 MHz, DMSO-tfo) 6 10.39 (s, 1H), 8.38 (d, J = 13.4 Hz, 2H), 8.20 (s, 1H), 8.15 - 8.09 (m, 2H), 7.98 (s, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.46 - 7.39 (m, 3H), 7.25 (d, J = 8.2 Hz, 1H), 3.44 (d, J = 1.3 Hz, 3H), 2.18 (s, 3H), 2.16 (s, 3H). MS(ESI⁺) m/z calc'd for [M+H]⁺[C28H₂3F3N6O₂+H]⁺: 533.19 found: 532.6, LCMS t_R = 1.82 mins. [Method B],

[0084] Synthesis of 2V-[4-methyl-3-[(3-methyl-4-oxo-quinazolin-6- yl)amino]phenyl]furan-2-carboxamide [Example 3]:

Intermediate 1 Intermediate 6 Example 3

[0085] l-[Bis(dimethylamino)methylene]-l/Z-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.078 g, 0.206 mmol, 1.05 eq) was added to a solution of 6-((5-amino- 2-methylphenyl)amino)-3-methylquinazolin-4(3/Z)-one Intermediate 1 (0.055 g, 0.196 mmol, 1.00 eq), diisopropylethylamine (0.060 mL, 0.343 mmol, 1.75 eq), and 2-furancarboxylic acid Intermediate 6 (0.033 g, 0.294 mmol, 1.50 eq) in DMF (1.962 mL, 0.1000 M) at rt . After 16 hours of stirring, the reaction was quenched with half saturated NaHCOs (aq.). The resulting precipitate was collected via vacuum filtration, rinsed with water (2x), and dried on high vac to afford A-[4-methyl-3-[(3-methyl-4-oxo-quinazolin-6-yl)amino]phenyl]furan-2- carboxamide Example 3 (0.050 g, 0.134 mmol, 68.07 % yield) as an off-white solid. ^!H NMR (600 MHz, DMSO) 8 10.08 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.90 (dd, J = 1.6, 0.7 Hz, 1H), 7.73 (d, 7 = 2.1 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.42 (dd, J = 4.6, 2.4 Hz, 1H), 7.41 (dd, J = 4.1, 2.5 Hz, 1H), 7.28 (dd, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.68 (dd, J = 3.5, 1.7 Hz, 1H), 3.46 (s, 3H), 2.17 (s, 3H); MS(ES⁺) m/z calc'd for [M+H]⁺ [C21H18N4O3]⁺ : 374.39, found 375.0, /R= 3.11 min [Analytical method: 05990510_AA 1.1cm; Column: Zorbax Eclipse XDB-C8 (4.6 mm X 50 mm)]. [0086] Synthesis of N-(4-methyl-3-((3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)amino)phenyl)-6-(trifhioromethyl)-lH-indole-l-carboxamide [Example 4]

Intermediate 1 Intermediate 7

[0087] To a solution of 6-((5-amino-2-methylphenyl)amino)-3-methylquinazolin-4(3H)- one Intermediate 1 (30 mg, 0.107 mmol, 1.00 eq) in THF (2 mL, 0.0535 M) was added DIEA (0.075 mL, 0.428 mmol, 4.00 eq) followed by triphosgene (13 mg, 0.0428 mmol, 0.400 eq) at rt and stirred for 30 min. Then 6-trifluoromethylindole Intermediate 7 (22 mg, 0.118 mmol, 1.10 eq) was added to the reaction mixture and was stirred at rt for 1 h, 40°C o/n and 80°C for 2 days until consumption of aniline. The reaction mixture was concentrated and the residue was purified by column chromatography over silica gel, SilicaSep, CombiFlash, 12g cartridge (dry load, eluting with 2% MeOH in DCM) to afford N-[4-methyl-3-[(3-methyl-4- oxo-quinazolin-6-yl)amino]phenyl]-6-(trifluoromethyl)indole-l -carboxamide Example 4 (0.015 g, 0.0297 mmol, 27.76 % yield) as a white solid. ^!H NMR (500 MHz, Chloroform-d) 8 10.13 (s, 1H), 8.53 (s, 1H), 8.24 (d, J = 3.7 Hz, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 13.4, 8.5 Hz, 2H), 7.48 - 7.40 (m, 2H), 7.34 (dd, J = 8.2, 2.1 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 3.7 Hz, 1H), 3.40 (s, 3H), 2.19 (s, 3H).MS(ESI⁺) m/z calc'd for [M+H]⁺: 492.2 found: 492.4 , t_R = 2.69 mins [Method B],

[0088] Synthesis of N-[2-fhioro-5-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-5-(5- fluoro-2-thienyl)-2-methylsulfanyl-oxazole-4-carboxamide [Example 5] :

[0089] To a stirred mixture of6-(3-amino-4-fluorophenoxy)-3-methylquinazolin-4(3H)- one Intermediate 2 (32 mg, 0.111 mmol, 1.00 eq) and 5-(5-fluorothiophen-2-yl)-2-

(methylthio)oxazole-4-carboxylic acid Intermediate 5 (34 mg, 0.133 mmol, 1.20 eq) in DMF at 25C was added HATU (63 mg, 0.166 mmol, 1.50 eq) and N,N-Diisopropylethylamine (0.058 mL, 0.332 mmol, 3.00 eq). The reaction mixture was stirred at room temperature with LCMS monitoring, the reaction was complete after overnight, quenched with aq. Na2CO3, stirred for 30 minutes, filtered, washed with IM LiCl and water, afforded a crude 39 mg which was triturated with ethyl acetate-ether twice. The crude material was purified by flash chromatography over silica gel, ISCO, CombiFlash, 4g cartridge (dry load, 0-10% MeOH in DCM)to provide solid which then recrystallized from DCM-hexane, dried on high vacuum pump over the weekend to afford N-[2-fluoro-5-(3-methyl-4-oxo-quinazolin-6-yl)oxy- phenyl]-5-(5-fluoro-2-thienyl)-2-methylsulfanyl-oxazole-4-carboxamide Example 5 (23 mg, 0.0426 mmol, 38.55 % yield) as a beige solid. ¹ H NMR (500 MHz, DMSO- d₆) 69.76 (s, 1H), 8.32 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 6.4, 3.0 Hz, 1H), 7.62 (t, J = 4.3, 4.3 Hz, 1H), 7.58 (dd, J = 8.8, 2.9 Hz, 1H), 7.50 (d, J = 2.9 Hz, 1H), 7.42 (dd, J = 10.3, 9.0 Hz, 1H), 7.03 (dt, J = 8.9, 3.5, 3.5 Hz, 1H), 6.88 (dd, J = 4.3, 2.0 Hz, 1H), 3.47 (s, 3H), 2.77 (s, 3H). MS(ES⁺) m/z cala'd for [M+H] 527.06: found 527.2 , LCMS t_R = 3.13 min [Method:B], [0090] Synthesis of 6-((5-amino-2-methylphenyl)amino)-3-methylquinazolin-4(3H)- one [Intermediate 1]:

[0091] Tert-butyl (3-amino-4-methylphenyl)carbamate [1-1]:

[0092] Available from commercial sources

[0093] 6-bromo-3-methylquinazolin-4(3H)-one [1A]:

[0094] Available from commercial sources

[0095] Tert-butyl (4-methyl-3-((3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)amino)phenyl)carbamate [2-1]:

[0096] A stirred mixture of tert-butyl N-(3-amino-4-methyl-phenyl)carbamate 1-1 (8.9 g, 40.04 mmol), 6-bromo-3-methylquinazolin-4(3H)-one 1A (9.3 g, 39.2 mmol), CS2CO3 (39.1 g, 120.1 mmol), BINAP (2.49 g, 4.04 mmol) in dioxane (180 ml) was treated with Pd2(dba)3 (1.83 mg, 4.04 mmol). The reaction mixture was heated to 80 °C for 23h. The reaction was then quenched with 10% NaOH(aq) and extracted with EtOAc. The organics were washed with NaCl(sat) and then Na2SO4(S). The organics were removed under reduced pressure and the resulting solid was treated with DCM (300 ml). The resulting precipitate was collected by vacuum filtration to provide tert-butyl N-[4-methyl-3-[(3-methyl-4-oxo- quinazolin-6-yl)amino]phenyl]carbamate 1-2 (10.60 g, 27.6 mmol, 70.36 % yield) an off white solid. ’ H NMR (500 MHz, DMSO-d6) 89.22 (s, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 7.11 (q, J = 8.7, 8.7, 8.3 Hz, 2H), 3.44 (s, 3H), 2.09 (s, 3H), 1.43 (s, 9H). MS(ES⁺) m/z cala'd for [M+H]⁺ [C8H7BrN2O+H]⁺: 381.2 found 381.1 , LCMS t_R— 4.40 min [Method:B],

[0097] 6-((5-amino-2-methylphenyl)amino)-3-methylquinazolin-4(3H)-one [Intermediate 1]:

[0098] A solution of tert-butyl (4-methyl-3-((3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)amino)phenyl)carbamate 2 (60.0 g, 158 mmol, 1.00 eq) in HCl/MeOH (4 M, 960 mL, 24.4 eq) was stirred at 20 °C for 12 h. LC-MS showed that 2 was consumed completely and one main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with EtOAc (30 mL * 2), then it was filtered and the filter cake was dried in vacuo. The residue was dissolved by water (1000 mL), then saturated aqueous NaHCOs solution was added to the mixture to adjust pH ~ 8. The aqueous phase was extracted with EtOAc (500 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with MTBE (30 mL * 2), then it was filtered, and the filter cake was dried in vacuo. 6-((5-amino-2-methylphenyl)amino)-3-methylquinazolin-4(3H)-one Intermediate 1 (25.7 g, 90.1 mmol, 57.1% yield, 98.4% purity) was obtained as a white solid. ’ H NMR (500 MHz, DMSO-d6) 8 8.09 (s, 1H), 7.71 (s, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.35 - 7.28 (m, 2H), 6.88 (d, J = 8.1 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 6.28 (dd, J = 8.0, 2.3 Hz, 1H), 4.84 (s, 2H), 3.44 (s, 3H), 2.00 (s, 3H). MS(ES⁺) m/z cala'd for [M+H]⁺ [Ci₆Hi₇N4O+H]⁺: 281.1 found 281.2 ,

LCMS t_R— 1.08 min [Method:B],

[0099] Synthesis of 6-(3-amino-4-fluoro-phenoxy)-3-methyl-quinazolin-4-one

[Intermediate 2] :

[00100] An oven dried round -bottom flask was charged with 6-bromo-3-methylquinazolin-

4(3H)-one 2-1 (35.00 g, 146 mmol), 3-amino-4-fluorophenol 2-2 (37.20 g, 293 mmol), K3PO4 (62.10 g, 293 mmol), Cui (2.79 g, 14.6 mmol) and picolinic acid (3.60 g, 29.2 mmol). To this mixture was added DMSO (500 ml), and the flask was purged with nitrogen gas for 20 min. The reaction was then heated at 100 °C for 12 h. The reaction was cooled to room temperature, and crushed ice (500 ml) was added. The precipitate obtained was filtered and washed with EtOAc (500 ml), then suspended in a mixture of 20% methanol in DCM solution (1500 ml), and filtered to remove the residual copper iodide. The filtrate was evaporated to get 6-(3-amino-4-fluoro-phenoxy)-3-methyl-quinazolin-4-one Intermediate 2 (31.00 g, 72.22 %) as a greyish brown solid. ’ H NMR (500 MHz, DMSO-d6) 8 8.29 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.50 (dd, J = 8.8, 2.9 Hz, 1H), 7.44 (d, J = 2.9 Hz, 1H), 7.02 (dd, J =

11.2, 8.7 Hz, 1H), 6.46 (dd, J = 7.7, 2.9 Hz, 1H), 6.22 (dt, J = 8.6, 3.2, 3.2 Hz, 1H), 5.35 (s, 2H), 3.46 (s, 3H). MS (ES⁺) m/z calcd for [M+H]⁺ [C15H12FN3O2 +H]⁺: 285.1 found 286.0,

LCMS t_R— 1.60 min [Method: B]

[00101] Synthesis of 3-(4-methylimidazol-l-yl)-5-(trifluoromethyl)benzoic acid [Intermediate 3]:

Intermediate 3

[00102] 3-(4-Methylimidazol- l-yl)-5-(trifluoromethyl)benzonitrile [3-3] :

[00103] A stirred solution of 4-Methyl-lH-imidazole 3-2 (1.45 g, 17.7 mmol, 3.10 eq) and 3-Fluoro-5-(trifluoromethyl)benzonitrile 3-1 (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 3-3 (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], [00104] Synthesis of 3-(4-Methylimidazol-l-yl)-5-(trifluoromethyl)benzoic acid [Intermediate 3]:

[00105] To a solution of 3-(4-methylimidazol-l-yl)-5-(trifluoromethyl)benzonitrile 3-3 (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 3 (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⁺) m/z calc'd for [M+H]⁺[Ci₂H9F3N₂O2+H]⁺: 271.1, found:271.1, t_R = 1.12 mins. [Method: B],

[00106] Synthesis of 5-(tert-butyl)furan-2-carboxylic add [Intermediate 4]:

[00107] Available from commercial sources

[00108] Synthetic Scheme of 5-(5-fluorothiophen-2-yl)-2-(methylthio)oxazole-4- carboxylic acid [Intermediate 5]:

[00109] (5-fluorothiophen-2-yl)(lH-imidazol-l-yl)methanone [5-2]:

[00110] To a solution of 5-fluorothiophene-2-carboxylic acid 5-1 (20.0 g, 137 mmol) in THF (0.3 M) was added CDI (27 g, 166.6 mol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solution was diluted with EtOAc (3.0 L), washed with water, brine, dried with MgSCU, and concentrated. The crude material was recrystallized from EtOAc : hexane (1 : 10 ) to afford (5-fluorothiophen-2-yl)(lH-imidazol-l-yl)methanone 5-2 as pale yellow solid (24 g).

[00111] methyl 5-(5-fhiorothiophen-2-yl)-2-(methylthio)oxazole-4-carboxylate [5-4]:

[00112] To a mixture of methyl 2-((bis(methylthio)methylene)amino)acetate 5-2 (28.0 g, 144 mmol) in THF (400 mL) at -78 °C was added NaOtBu (18 g, 184.8 mmol) and the mixture was stirred for 30 min. A solution of (5-fluorothiophen-2-yl)(lH-imidazol-l- yl)methanone 5-3 (crude) in THF (125 mL) was then added dropwise, and the mixture was allowed to warm slowly to room temperature and stirred for 2 h. The solution was then diluted with EtOAc, washed with water, brine, and dried with MgSO4. The solvent was removed by rotary evaporation, and the crude was triturated with 10 : 1 hexane : ethyl acetate twice to afford methyl 5-(5-fluorothiophen-2-yl)-2-(methylthio)oxazole-4-carboxylate 5-4 as beige solid (27.3 g, 73% yield). MS (ES⁺) m/z calcd. for

[M+H]⁺ [C10H8FNO3S2+H]⁺: 274.3 found 274.3, LCMS t_R= 2.85 min [Method B], [00113] Synthesis of 5-(5-fhiorothiophen-2-yl)-2-(methylthio)oxazole-4-carboxylic acid [Intermediate 5]:

HO N^/^S^ 0 J"⁰ 0^s

F

[00114] Methyl 5-(5-fluorothiophen-2-yl)-2-(methylthio)oxazole-4-carboxylate 5-4 (37 g, 135.4 mmol) was dissolved in THF (900 mL) and 2N LiOH (400 mL, 808 mmol, 2N aqueous solution) was added to the reaction mixture dropwise and degassed with nitrogen for 5 min. The reaction mixture was stirred for 3 h at room temperature and volatiles were removed under reduced pressure. Water (100 mL) was added to the residue and reaction mixture was gradually acidified with 2N HC1 (pH ~ 2), stirred for 15 min and filtered. The filter cake was dried under high vacuum and then azeotroped with toluene (3 X 100 mL) to afford pure 5-(5- fluorothiophen-2-yl)-2-(methylthio)oxazole-4-carboxylic acid Intermediate 5 (32.6 g, 93% yield). ’ H NMR (300 MHz, CDC1₃ 67.82 (d, J = 3.8 Hz, 1H), 6.96 (d, J = 3.8 Hz, 1H), 2.69 (s, 3H). MS (ES⁺) m/z calcd. for [M+H]⁺ [C9H6FNO3S2+H]⁺: 260.0 found 260.2, LCMS t_R= 2.39 min [Method B].

[00115] Synthesis of Furan-2-carboxylic add [Intermediate 6]:

^HOyQ o

[00116] Available from commercial sources

[00117] Synthesis of 6-(trifhioromethyl)-lH-indole [Intermediate 7]:

^HN ZL F/F [00118] Available from commercial sources

Biochemical Assays

1. Kinase Panel

[00119] 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.

[00120] 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. 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

[00121] 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.

[00122] 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

Z can be NH or O;

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

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:

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.