N-(4-(1h-benzo[d[imidazol-6-yl)-pyridin-2-yl)benzamide derivatives as CAMK2 inhibitors for the treatment of heart failure

Abstract

The present invention relates to a compound of formula (I), as inhibitors of calcium calmodulin dependent protein kinase 2 (CAMK2) for the treatment of for the treatment of heart failure, fibrosis, cardiomyopathies, atrial fibrillation, catecholaminergic polymeric ventricular tachycardia, heart block, cardiac arrhythmias, contraception, anxiety, post-traumatic stress disorder, hypertension, tachycardia, diabetes, allergy, and asthma.

Description

[0001] BENZIMIDAZOLE COMPOUNDS AS CAMK2 INHIBITORS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the priority benefit of U.S. Provisional Application No.

[0003] 63 / 721,691, filed November 18, 2024; the content of which is herein incorporated by reference in its entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to novel benzimidazole compounds, compositions containing them, and methods of using them, for example, for the treatment of diseases or disorders associated with Calcium calmodulin dependent protein kinase 2 (CAMK2) kinases, including CAMK2A, CAMK2B, CAMK2G and CAMK2D.

[0006] BACKGROUND OF THE INVENTION CAMK2D belongs to the CAMK2 family, a family of calmodulin dependent kinases, which are serine and threonine kinases regulated by the calcium and calmodulin complex. Members of the CAMK2 family are generally expressed in most tissues in mammals, with CAMK2A and CAMK2B predominating in brain, and CAMK2D and G predominating in cardiac and skeletal muscle (for review, see Tombes et al., Gene 2003, 322: 17-31). CAMK2 proteins’ kinase activity is induced by increased local concentrations of calcium (Hanson et al., Neuron 1989, 3(1):59— 7. doi: 10.1016 / 0896- 6273(89) 90115-3). Increased calcium (or calcium complexed with calmodulin) occurs in excitable cells such as neurons and muscle cells during or just after depolarization; under normal physiological conditions, this is part of the process followed by neurons firing and muscle cells contracting. CAMK2 proteins, activated by a recent increase in calcium, will then phosphorylate a number of downstream target proteins, altering their activity or properties.

[0007] Various forms of cardiac stress result in dysregulation of calcium in heart tissue (Lenhart et al., Heart Fail Rev. 2009, 14(4):213-24); moreover, animal models of cardiac stress have elevated levels of CAMK2 activity in heart tissue (e.g., Ling et al., Circ Res.

[0008] 2013, 112:935-944). Inhibition of CAMK2 via genetic manipulation or treatment with a small molecule enzyme inhibitor improves cardiac function in multiple rodent cardiac stress models (e.g., Backs et al, Proc Natl Acad Sci USA. 2009, 106(7):2342-47;

[0009] Dewenter et al., Circ Heart Fail. 2017 May; 10(5):e003840; Purohit et al., Circulation 2013 Oct 15; 128(16): 1748-57; Mustroph et al., Clin Res Cardiol (abstract V826) 2016, 105). CAMK2 activity has also been shown to be involved in diabetes (Ozcan et al., Cell Metab. 2013, 18(6): 803-15), neointima formation (Li et al., J Biol. Chem 2011, 286(10):7990-9), fertility (Backs et al., Proc Natl Acad Sci USA 2010, 107(l):81-6), fear conditioning (Fang et al., Brain Res Bull 2017, 134: 18-23), memory or learning (Ohno et al., Eur JNeurosci 2006, 23(8):2235-40) and asthma (Morris et al., Mol Pharm 2017 14(6):2166-2175).

[0010] SUMMARY OF THE INVENTION

[0011] The invention encompasses compounds of Formulae (I) and (II), including stereoisomers, pharmaceutically acceptable salts, or solvates thereof, which are useful as inhibitors of calcium calmodulin dependent protein kinase 2 (CAMK2), and inhibit the CAMK2D isoform as well as CAMK2A, CAMK2B, and / or CAMK2G.

[0012] The invention also provides processes and intermediates for making the compounds of the present invention.

[0013] The invention also provides pharmaceutical compositions comprising at least a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, pharmaceutically acceptable salts, or solvates thereof.

[0014] The compounds of the invention may be used in therapy or the manufacture of a medicament.

[0015] The compounds of the invention may be used in the treatment and / or prophylaxis of one or more diseases or disorders associated with CAMK2 kinases, such as heart failure, fibrosis, cardiomyopathies, atrial fibrillation, catecholaminergic polymeric ventricular tachycardia, heart block, cardiac arrhythmias, contraception, anxiety, post-traumatic stress disorder, hypertension, tachycardia, diabetes, allergy, asthma, and related diseases.

[0016] The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s).

[0017] These and other features and advantages of the invention will be apparent from the following detailed description and claims. DESCRIPTION OF THE INVENTION

[0018] In a first aspect, the present invention provides, inter alia, a compound of Formula (I):

[0019]

[0020] or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:

[0021] R1is H, Ci-6 alkyl substituted with 0 to 3 Ra, Ci-6 haloalkyl substituted with 0 to 2 Ra, -(CRgRgl)o-2-(C3-8cycloalkyl substituted with 0 to 4 Re), or a 4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re;

[0022] R2is H, cyano, OH, SH, NH2, C1-4 alkylthio, C1-4 alkoxy, C1-8 alkyl substituted with 0 to 2 Ra, C2-6 alkenyl substituted with 0 to 1 Ra, C2-6 alkynyl substituted with 0 to 1 Ra, C1-6 haloalkyl substituted with 0 to 1 Ra,

[0023] -(CRgRgl)o-3-(C3-8cycloalkyl substituted with 0 to 4 Re), or

[0024] -(CRgRgl)o-2-(4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re);

[0025] R3is halogen, cyano, C1-4 haloalkyl, C1-4 haloalkoxy, -C(=O)O(Ci-4 alkyl), NH2, N(Ci-4 alkyl)2, -C(=0)NH2, -C(=0)N(CI-4 alkyl)2, C2-6 alkenyl, C2-6 alkynyl, ORh, or C1-6 alkyl substituted with 0 to 2 Ra;

[0026] R4is H, halogen, cyano or C1-4 alkyl;

[0027] R5is a 4- to 9-membered monocyclic or bicyclic heterocyclic ring including 1 to 4 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 3 Re, or a 5 to 6-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), or O, wherein the heteroaryl is substituted with 0 to 3 Rd;

[0028] R6is halogen, cyano, Ci-4 alkoxy, Ci-4 haloalkyl, Ci-4 haloalkoxy,

[0029] -NH(CI-4 alkyl), Ci-4 alkyl substituted with 0 to 2 Ra, or -SC>2(Ci-4 alkyl substituted with 0 to 1 Rc);

[0030] Rais halogen, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 haloalkyl,

[0031] C1-4 haloalkoxy, NH2, NH(CI-4alkyl), N(CI-4alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;

[0032] Rbis H, C1-4 fluoroalkyl, -C(=O)(Ci-4 alkyl), -C(=O)O(Ci-4 alkyl) or C1-4 alkyl substituted with 0-1 OH;

[0033] Rcis halogen, OH, cyano, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl substituted with 0 to 2 Rf, or C1-4 alkoxy substituted with 0 to 1 Rf;

[0034] Rdis halogen, OH, cyano, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -O(C=O)H, -O(C=O)(C 1-4 alkyl), -C(=O)O(Ci-4alkyl), NH2, N(CI-4alkyl)2, -C(=O)NH2, -C(=O)N(CI-4 alkyl)2, C2-6 alkenyl, C2-6 alkynyl, or C1-6 alkyl substituted with 0 to 2 Rc;

[0035] Reis oxo or Rd;

[0036] Rfis halogen, OH, cyano, -CH2OH, C1-4 alkoxy, or N(Ci-4alkyl)2;

[0037] Rgis H, C1-4 alkyl substituted with 0 to 1 Rf, C1-4 alkoxy, or C3-6 cycloalkyl;

[0038] Rglis H or C1-4 alkyl;

[0039] Rhis H or C1-6 alkyl substituted with 0 to 1 Ra;

[0040] m and n are 0, 1 or 2; and

[0041] p is 0, 1 or 2.

[0042] In a second aspect, the present invention provides a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the first aspect and wherein, independently for each occurrence:

[0043] R1is H, C1-6 alkyl substituted with 0 to 2 Ra, C1-6 fluoroalkyl substituted with 0 to 1 Ra, -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re), or a 4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re;

[0044] R2is H, Ci-4 alkoxy, Ci-6 alkyl substituted with 0 to 1 Ra, or Ci-6 fluoroalkyl substituted with 0 to 1 Ra;

[0045] R3is halogen, OH, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 fluoroalkyl, or

[0046] Ci-4 fluoroalkoxy;

[0047] R4is H, F, Cl, cyano, or C1-2 alkyl;

[0048] R6is H, halogen, C1-4 alkyl, C1-4 alkoxy, Ci-4haloalkyl, C 1-4 haloalkoxy, or -SO2(Ci-4 alkyl substituted with 0 to 1 Rc);

[0049] Rais halogen, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 fluoroalkyl,

[0050] C1-4 fluoroalkoxy, NH2, NH(CI-4 alkyl), N(CI-4 alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;

[0051] Rbis H, Ci-4 fluoroalkyl, or C1-4 alkyl substituted with 0-1 OH;

[0052] Rcis F, Cl, cyano, OH, C1-4 alkoxy, C1-4 fluoroalkyl, or C1-4 fluoroalkoxy;

[0053] Rdis halogen, cyano, OH, -CH2OH, C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, -O(C=O)H, -O(C=O)(Ci-4alkyl), or -C(=O)O(Ci-4alkyl);

[0054] Rgis H, C1-2 alkyl or -CH2OH; and

[0055] Rglis H or C1-2 alkyl.

[0056] In a third aspect, the present invention provides a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the first or second aspect and wherein, independently for each occurrence:

[0057] R1is H, C1-6 alkyl substituted with 0 to 2 Ra, C1-4 fluoroalkyl substituted with 0 to 1 Ra, -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re), or a 4- to 6-membered heterocyclic ring including 1 ring heteroatom which is independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re;

[0058] R2is H, C1-6 alkyl substituted with 0 to 1 Ra, or C1-4 fluoroalkyl substituted with 0 to 1 Ra;

[0059] R3is F, Cl or C1-2 alkyl;

[0060] R4is H, F or Cl; R5is a 4- to 9-membered monocyclic or bicyclic heterocyclic ring including 1 to 4 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is is partially satuated or fully satuated, and is substituted with 0 to 2 Re, or a 5 to 6-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), or O, wherein the heteroaryl is substituted with 0 to 2 Rd;

[0061] R6is halogen, Ci-4 alkyl, Ci-4 alkoxy, C 1-4 fluoroalkyl, C 1-4 fluoroalkoxy, or -SO2(C 1-4 alkyl); and

[0062] m and n are 0 or 1.

[0063] In a fourth aspect, the present invention provides a compound of Formula (II):

[0064]

[0065] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:

[0066] R1is H, C1-6 alkyl, C1-4 fluoroalkyl, -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 1 Re), or a 5-membered heterocyclic ring including 1 ring heteroatom which is independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 1 Re;

[0067] R2is C1-6 alkyl substituted with 0 to 1 Ra;

[0068] R4is H, F or Cl;

[0069] R5is a 4- to 8-membered monocyclic or bicyclic heterocyclic ring including 1 to 3 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re, or a 5 to 6-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), or O, wherein the heteroaryl is substituted with 0 to 2 Rd;

[0070] R6is halogen, C1-4 fluoroalkoxy, or -SC>2(Ci-4 alkyl); Rais F, Cl, cyano, OH, -CH2OH, C1-4 alkoxy, or C1-4 fluoroalkyl;

[0071] Rbis H, C1-4 alkyl, C1-4 fluoroalkyl, or -CH2C(CH3)2OH; and

[0072] Rdis F, cyano, C1-4 alkyl substituted with 0-1 OH, C1-4 fluoroalkyl or

[0073] Ci -4 alkoxy;

[0074] Reis oxo or Rd; and

[0075] m is 0 or 1.

[0076] In a fifth aspect, the present invention provides a compound of Formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the fourth aspect and wherein, independently for each occurrence:

[0077] R1is C1-4 alkyl, -CH(CH3)-cyclopropyl, C4-5 cycloalkyl substituted with 0-1 OH,

[0078]

[0079] R2is -CH2C(CH3)2OH or -CH2C(CH3)2CN;

[0080] R4is F;

[0081] R5is a 4- to 6-membered monocyclic heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is is partially satuated or fully satuated, and is substituted with 0 to 1 Re, a 5 to 6-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), or

[0082] O, wherein the heteroaryl is substituted

[0083]

[0084] & and

[0085] R6is Cl, C1-4 fluoroalkoxy, or -SO2(Ci-4 alkyl).

[0086] In a sixth aspect, the present invention provides a compound of Formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the fourth or fifth aspect and wherein, independently for each occurrence:

[0087] R1is -CH(CH3)2, -CH(CH3)-cyclopropyl, cyclobutyl substituted with 0-1 OH,

[0088] cyclopentyl,

[0089]

[0090]

[0091] R6is Cl, -OCF2H, -OCH2CF2H, or -SO2CH3;

[0092] Rbis H, CH3, -CH(CH3)2, -CF2H, -CH2CF2H, or -CH2C(CH3)2OH; and

[0093] Rdis independently F, cyano, CH3, -OCFF, CF3, -CH2OH, or -C(CH3)2OH.

[0094] In a seventh aspect, the present invention provides a compound of Formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the fourth or fifth aspect and wherein, independently for each occurrence:

[0095] R1is independently -CH(CH3)2, -CH(CH3)-cyclopropyl, cyclobutyl substituted

[0096]

[0097] R6is independently Cl, -OCF2H, -OCH2CF2H, or -SO2CH3;

[0098] Rbis independently H, CH3, -CH(CH3)2, -CF2H, -CH2CF2H, or -CH2C(CH3)2OH; and

[0099] Rdis independently F, cyano, CH3, -OCH3, CF3, -CH2OH, or -C(CH3)2OH. In another aspect, the present invention provides a compound of Formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the fourth or fifth aspect and wherein, independently for each occurrence:

[0100]

[0101] R6is -OCF2H or -SO2CH3; and

[0102] Rbis CH3or -CH(CH3)2.

[0103] In another aspect, the invention provides a compound selected from

[0104]

[0105]

[0106] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0107] In another aspect, the invention provides a compound selected from

[0108]

[0109] or a pharmaceutically acceptable salt thereof.

[0110] In another aspect, the invention provides a compound selected from

[0111] or a stereoisomer or a pharmaceutically acceptable salt thereof. In an eighth aspect, the invention provides a compound selected from the exemplified Examples 1 to 64 or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0112] In another aspect, the present invention provides a compound selected from any subset list of compounds or a single compound from the exemplified examples within the scope of any of the above aspects.

[0113] In some embodiments, presented herein are compounds selected from active metabolites, stereoisomers, tautomers, pharmaceutically acceptable salts or solvates of at least one of the compounds of the invention.

[0114] In another embodiment, the present invention provides a process for making a compound of the present invention.

[0115] In another embodiment, the present invention provides an intermediate for making a compound of the present invention.

[0116] DEFINITIONS

[0117] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0118] Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, "a" and "an" may refer to either one, or one or more.

[0119] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0120] For purposes of clarity and in accordance with standard convention in the art, the symbol is used in formulas and tables to show the bond that is the point of attachment of the moiety or substituent to the core / nucleus of the structure. Additionally, for purposes of clarity, where a substituent has a dash (-) that is not between two letters or symbols; this is used to indicate a point of attachment for a substituent. For example, -OCH3 is attached through the oxygen atom.

[0121] Unless specified otherwise, these terms have the following meanings. “Alkyl” means a straight or branched alkyl group composed of 1 to 6 carbons. “Alkenyl” means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. “Alkynyl” means a straight or branched alkyl group composed of 2 to 6 carbons with at least one triple bond. Terms with a hydrocarbon moiety (e.g. alkoxy or alkylthio) include straight and branched isomers for the hydrocarbon portion. “Halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” and “haloalkoxy” include all halogenated isomers from monohalo to perhalo.

[0122] “Aryl” means a monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms, or a bicyclic fused ring system wherein one or both of the rings is aromatic. Bicyclic fused ring systems consist of a phenyl group fused to a four- to sevenmembered aromatic or non-aromatic carbocyclic ring. Representative examples of aryl groups include but are not limited to phenyl, indanyl, indenyl, naphthyl, and tetrahydronaphthyl. “Heteroaryl” means a 5 to 8 membered monocyclic or 8 to 12 membered bicyclic aromatic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. “Cycloalkyl” means a monocyclic ring system composed of 3 to 8 carbons, wherein the cycloalkyl group may be a spirocyclic ring or contain one or more bridged linker(s), and may be optionally substituted. The term "heterocycle" or "cycloheteroalkyl" refers to a nonaromatic 3-8 membered monocyclic or 7-10 membered bicyclic ring system having 1-3 heteroatoms if monocyclic, or 1-4 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent, optionally contains a spirocyclic ring. Examples of heterocyclyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

[0123] As used herein, "carbocycle", "carbocyclyl", or "carbocyclic ring" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered polycyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic or may contain a spirocyclic or bridged ring. When the term "carbocycle" is used, it is intended to include "aryl". As used herein, the term "heterocycle", "heterocyclyl", or "heterocyclic ring" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13 -membered polycyclic heterocyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.

[0124] Where a bonding attachment location is not specified, the bonding may be attached at any appropriate location as understood by practitioners in the art.

[0125] Combinations of substituents and bonding patterns are only those that result in stable compounds as understood by practitioners in the art. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.

[0126] The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine,

[0127] 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0128] Some of the compounds of the invention exist in stereoisomeric forms including the structure below with the indicated carbon. The invention includes all stereoisomeric forms of the compounds including enantiomers and diastereomers. Methods of making and separating stereoisomers are known in the art. The invention includes all tautomeric forms of the compounds. The invention includes atropisomers and rotational isomers.

[0129] The invention is intended to include all isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include13C and14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

[0130] BIOLOGICAL METHODS

[0131] CAMK2D ECHO MS Activity Assay

[0132] The inhibitory activity of compounds was tested in the CAMK2D ECHO MS activity assays carried out in 20 mM Hepes (pH 7.5), 10 mM MgCh, 1 mM CaCh, 50 ug / mL BSA, 0.015 % Brij-35 and 2 mM DTT. Compounds were solubilized at 10 mM in dimethylsulfoxide (DMSO) and serially diluted 3-fold for a total of eleven concentrations; final DMSO percentage in the reactions remained below 1%.

[0133] Reaction mixtures containing 0.05 nM full length CAMK2D (CARNA Product Number 02-111), 0.01 mg / mL His-TVMV-hCalmodulin (1-149, in-house synthesized), ATP at the kinase ATP Km (5 uM), 2 uM of the PLN peptide fragment (MEKVQYLTRSAIRRASTIEMPQQARQKLQN) were incubated with test compounds for 60 min. Following, the reactions were quenched with 0.1% formic acid. Endpoint data was collected by determining the ratio of the m / z of product analyte using mass spectrometry, 731.7

[0134]

[0135] 712.3 divided by the m / z of internal standard analyte, 605.2

[0136]

[0137] 713.1.

[0138] Inhibition data were calculated from the product conversion generated by the no enzyme control reactions for 100% inhibition and vehicle-only reactions for 0% inhibition. Dose response curves were fit to a 4-parameter logistic curve in order to determine the concentration required for inhibiting 50% of the enzyme activity.

[0139] Cellular Assay Some compounds of the invention were tested in a cellular assay to measure inhibition of the phosphorylation of phospholamban (PLN). In this assay, HEK 293T cells were transfected using Lipofectamine LTX according to manufacturer’s protocols and the following expression plasmids were delivered into the cells: CAMK2D, PLN and / or empty vector in control wells. In some cases, CAMK2D and PLN were misexpressed in 293T cells using the BacMam mammalian transduction system, again according to manufacturer’s protocols. In some cases, CAMK2D and PLN were stably co-transfected into HEK293T cells and a single clone was selected and expanded based on CAMK2D and PLN expression levels and assay performance. Cells were plated onto poly-D-lysine coated 96 well plates and grown to sub -confluence (24-48 hours). Test compounds were diluted in dimethyl sulfoxide to desired final concentrations. The growth medium was removed from the HEK 293 T cells, and was replaced with Opti-MEM without phenol red. Compounds were added directly to the wells; 96 or 384 well cell plates were shaken briefly by hand and returned to the growth incubator to be incubated at 37 degrees C under a humidified 5% CO2 atmosphere for 1 hour. Cells were then stimulated with 1 uM ionomycin final concentration for 15 minutes. Cell lysates were prepared and analyzed using the CisBio pPLN HTRF Assay Kit, following manufacturer’s protocols. Briefly, cell lysates were prepared by adding 50 uL supplemented cell lysis buffer and shaking at room temperature for 30 min. 16 uL of this lysate was transferred to a 384 well plate, and 4 uL of combined HTRF antibodies, and this was incubated overnight at room temperature in the dark. Plates were read for HTRF ratios 16-22 hours later on an Envision plate reader. Results were normalized as maximal inhibition observed in a staurosporin concentration-response curve representing 100% inhibition, and 0% inhibition representing vehicle-only (DMSO) treated cells. These data points were then fit to a to a 4-parameter logistic curve. In some cases, the upper plateau of this curve was assumed to be 100% inhibition. In some cases, the lower plateau of this curve was assumed to be 0% inhibition. Potencies were then recorded as the inflection point of this curve. Examples of inhibiton in the cellular assay are reported in Table 1. Table 1 lists IC50 values measured for the examples described in the invention. A range of IC50 values of <250 nM was observed for compounds described in the invention in one of the two CAMK2D in vitro activity assays.

[0140] Table 1. ECHO MS and Cellular Assays

[0141]

[0142] <

[0143] <

[0144] <

[0145] <

[0146] < <

[0147]

[0148] PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE

[0149] The compounds of the present invention may be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders including heart failure, cardiomyopathies, atrial fibrillation, catecholaminergic polymeric ventricular tachycardia, heart block, cardiac arrhythmias, contraception, anxiety, post-traumatic stress disorder, hypertension, tachycardia, diabetes, allergy, asthma, and related diseases.

[0150] Unless otherwise specified, the following terms have the stated meanings. The term "subject" refers to any human or other mammalian species that could potentially benefit from treatment with a CAMK2D, CAMK2A, CAMK2B, CAMK2G inhibitor as understood by practitioners in this field. Some subjects include human beings of any age with risk factors for cardiovascular disease. Common risk factors include age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity arrthymia or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). The term "patient" means a person suitable for therapy as determined by practitioners in the field. As used herein, the term "patient" encompasses all mammalian species.

[0151] "Treating" or "treatment" cover the treatment of a patient or subject as understood by practitioners in this field. "Preventing" or "prevention" cover the preventive treatment (z.e., prophylaxis and / or risk reduction) of a subclinical disease-state in a patient or subject aimed at reducing the probability of the occurrence of a clinical disease-state as understood by practitioners in this field. Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. "Therapeutically effective amount" means an amount of a compound that is effective as understood by practitioners in this field.

[0152] Another aspect of the invention are pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I in combination with a pharmaceutical carrier.

[0153] Another aspect of the invention are pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I in combination with at least one other therapeutic agent and a pharmaceutical carrier.

[0154] "Pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, z.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.

[0155] Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted.

[0156] Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L.V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0157] Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and / or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. Another aspect of the invention is a method for treating heart disease comprising administering a therapeutically effective amount of a compound of formula I to a patient.

[0158] Another aspect of the invention is a method for treating heart disease wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, heart failure, acute coronary disease, fibrosis, and cardiac iatrogenic damage.

[0159] Another aspect of the invention is a method for treating heart disease wherein the treatment is post myocardial infarction.

[0160] Another aspect of the invention is a method for treating heart disease wherein the treatment is given to a patient with heart failure with preserved ejection fraction.

[0161] Another aspect of the invention is a method for treating heart disease wherein the treatment is given to a patient with acute decompensated heart failure.

[0162] Another aspect of the invention is a method for treating heart disease wherein the treatment is given to a patient with chronic heart failure.

[0163] Another aspect of the invention is a method for treating heart disease comprising administering a therapeutically effective amount of a compound of formula I to a patient in conjunction with other therapeutic agents.

[0164] The compounds of this invention can be administered by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0165] The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.

[0166] By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.01 to about 5000 mg per day, preferably between about 0.1 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0167] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition. A typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.

[0168] The compounds of the present invention may be employed in combination with other suitable therapeutic agents useful in the treatment of the aforementioned diseases or disorders including: anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, anorectic agents, memory enhancing agents, anti-dementia agents, cognition promoting agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral arterial disease, agents for treating malignant tumors, and anti-inflammatory agents. The compounds of the invention may be used with at least one of the following heart failure agents selected from loop diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNI), beta blockers, mineralocorticoid receptor antagonists, nitroxyl donors, RXFP1 agonists, APJ agonists, SGLT2 inhibitors, HCN potassium-sodium channel inhibitors, myosin modulators, calcium channel inhibitors, chymase inhibitors, and cardiotonic agents. These agents include, but are not limited to furosemide, bumetanide, torsemide, sacubitrial-valsartan, thiazide diruetics, captopril, enalapril, lisinopril, carvedilol, metopolol, bisoprolol, serelaxin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irbestarain, losartan, olmesartan, telmisartan, and valsartan.

[0169] The compounds of the present invention may be employed in combination with at least one of the following therapeutic agents in treating cardiovascular or metabolic diseases: anti-hyperlipidemic agents, plasma HDL-raising agents,

[0170] anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors (such as HMG CoA reductase inhibitors), LXR agonist, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (such as anion exchange resins, or quaternary amines (e.g., cholestyramine or colestipol)), low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin Bg, vitamin B ^2, anti-oxidant vitamins, P-blockers, anti-diabetes agents, angiotensin II antagonists, angiotensin converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives.

[0171] The compounds of the present invention may be employed in combination at least one of the following therapeutic agents in treating cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor. Examples of suitable HMG-CoA reductase inhibitors include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin.

[0172] The compounds of the invention may be used in combination with at least one of the following anti-diabetic agents depending on the desired target therapy. Studies indicate that diabetes and hyperlipidemia modulation can be further improved by the addition of a second agent to the therapeutic regimen. Examples of anti-diabetic agents include, but are not limited to, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone), and related insulin sensitizers, such as selective and non-selective activators of PPARa, PPARP and PPARy; dehydroepiandrosterone (also referred to as DHEA or its conjugated sulphate ester, DHEA-SO4); anti-glucocorticoids; TNFa inhibitors; dipeptidyl peptidase IV (DPP4) inhibitor (such as sitagliptin, saxagliptin), GLP-1 agonists or analogs (such as exenatide), a-glucosidase inhibitors (such as acarbose, miglitol, and voglibose), pramlintide (a synthetic analog of the human hormone amylin), other insulin secretagogues (such as repaglinide, gliquidone, and nateglinide), insulin, as well as the therapeutic agents discussed above for treating atherosclerosis.

[0173] The compounds of the invention may be used in combination with at least one of the following anti-obesity agents selected from phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentiramine,

[0174] P3 -adrenoreceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptins. Other agents used in treating obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, histamine H3 receptors, dopamine D2 receptor modulators, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA).

[0175] The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving CAMK2 kinases. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving CAMK2 activity. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness. The compounds of the present invention may also be used in diagnostic assays involving CAMK2.

[0176] In some embodiments, the compounds of the invention may be used in therapy. In certain embodiments, the present invention provides a combined preparation of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy. In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, may be used as a medicament. In certain embodiments, the compounds of the invention may be used for the manufacture of a medicament for the treatment.

[0177] The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises a first therapeutic agent, comprising a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of dyslipidemias and the sequelae thereof. In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent for the treatment of dyslipidemias and the sequelae thereof. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries. The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and / or individual / bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product. The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached. The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).

[0178] CHEMISTRY METHODS

[0179] Abbreviations as used herein, are defined as follows: "lx" for once, "2x" for twice, "3x" for thrice, " °C" for degrees Celsius, "aq" for aqueous, "Col" for column, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, "pL" for microliter or microliters, "N" for normal, "M" for molar, "nM" for nanomolar, "mol" for mole or moles, "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "RT" for retention time, "ON" for overnight, "atm" for atmosphere, "psi" for pounds per square inch, "cone." for concentrate, "aq" for "aqueous", "sat" or "sat'd " for saturated, "MW" for molecular weight, "mw" or "pwave" for microwave, "mp" for melting point, "Wt" for weight, "MS" or "Mass Spec" formass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid chromatography, "RP HPLC" for reverse phase HPLC, "TLC" or "tic" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser effect spectroscopy, "1H" for proton, "6 " for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" forbroad, "Hz" for hertz, and "a", "0", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art. Ac Acetic

[0180] AcOH acetic acid

[0181] Acn (or MeCN) Acetonitrile

[0182] BBrs Boron tribromide

[0183] BINAP 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl Bispin bis(pinacolato)diboron

[0184] Bn Benzyl

[0185] Boc tert-butyl carbonyl

[0186] BOC2O di -te / 7-butyl dicarbonate

[0187] BOP (Benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0188] BTFFH fluoro-N,N,N’,N’-bis(tetramethylene)formamidinium hexafluorophosphate

[0189] Bu Butyl

[0190] CDCI3 deutero-chloroform

[0191] CD3OD deutero-methanol

[0192] CS2CO3 Cesium carbonate

[0193] dba as in (Pd2(dba)3) Dib enzy li deneacetone

[0194] DCM Dichloromethane

[0195] DEAD diethyl azodi carb oxy late

[0196] DIAD diisopropyl azodicarboxylate

[0197] DIEA or DIPEA Diisopropylethylamine

[0198] DMAP 4-dimethylaminopyridine

[0199] DME Dimethoxy ethane

[0200] DMF Dimethylformamide

[0201] DMSO dimethyl sulfoxide

[0202] DMSO-d6deutero-dimethyl sulfoxide

[0203] dppf 1,1 '-bis(diphenylphosphino)ferrocene

[0204] EDC 3-(Ethyliminomethyleamino)-N-N-dimethylpropan-l- amine

[0205] Et ethyl EtOH Ethanol

[0206] EtOAc ethyl acetate

[0207] HATU 2-(7- Aza- IH-benzotri azole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluroni um hexafluorophosphate

[0208] HBTU 2-( 177-B enzotri azole- 1 -yl)- 1 , 1 ,3 , 3 -tetramethyluronium hexafluorophosphate

[0209] HC1 hydrochloric acid

[0210] HPLC high-performance liquid chromatography

[0211] z-Bu Isobutyl

[0212] z-Pr Isopropyl

[0213] K2HPO4 Dipotassium phosphate

[0214] LAH lithium aluminum hydride

[0215] LCMS liquid chromatography mass spectrometry

[0216] Me Methyl

[0217] MeOH Methanol

[0218] MgSO4magnesium sulfate

[0219] NaCl sodium chloride

[0220] Na2CO3sodium carbonate

[0221] NaHCCh sodium bicarbonate

[0222] NaOH sodium hydroxide

[0223] Na2SO4sodium sulfate

[0224] NH4C1 ammonium chloride

[0225] NH4OAC ammonium acetate

[0226] NMM A-methylmorpholine

[0227] NCS N-Chlorosuccinimide

[0228] NBS AMSromosuccinimide

[0229] NMP N-Methylpyrrolidone

[0230] Pd(OAc)2palladium(II) acetate

[0231] Pd(dppf)Cl2CH2C12[1,1 '-Bis(diphenylphosphino)ferrocene]

[0232] dichloropalladium(II), complex with dichloromethane Pd(dba)2Bis(dibenzylideneacetone)palladium(0)

[0233] Ph Phenyl PPhs Triphenylphosphine

[0234] Pr Propyl

[0235] RVC Reticulated vitreous carbon

[0236] t-Bu tert-butyl

[0237] TEA or EtsN Trimethylamine

[0238] TFA trifluoroacetic acid

[0239] THF Tetrahydrofuran

[0240] TMSC1 Trimethyl silyl chloride

[0241] T3P 1-Propanephosphonic anhydride solution

[0242] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0243] The disclosed compounds can be made by various methods known in the art including those of the following schemes and in the specific embodiments section. The structure numbering and variable numbering shown in the synthetic schemes are distinct from and should not be confused with the structure or variable numbering in the claims or the rest of the specification. The variables in the schemes are meant only to illustrate how to make some of the compounds of this invention.

[0244] The disclosure is not limited to the foregoing illustrative examples and the examples should be considered in all respects as illustrative and not restrictive, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced. A consideration in the planning of any synthetic route in this field is the choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene, T.W. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007).

[0245] Compounds having the general Formula (I) can be prepared by the following one or more of the synthetic schemes. Compounds of this invention can be prepared by the general route shown in Scheme 1, starting from 4-bromo-2-fluoro-l -nitrobenzene la. Miyaura borylation of la in presence of palladium catalysts such as [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)C12.CH2C12) under suitable solvents such as dioxane or dimethyl sulfoxide in presence of a base such as potassium acetate with conventional heating or microwave heating can provide 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane, intermediate lb. Additional methods for this transformation include other variations of Miyaura borylation using methods known to one skilled in the art for this type of coupling, (see for example Ishimaya & Miyaura, J. Org. Chem. 1995, 60, 7508).; Kurti, L. and Czako, B. Strategies and Applications of Named Reactions in Organic Synthesis, Elsevier (2005)).

[0246] Subsequent palladium-catalyzed coupling of lb to a suitably substituted iodide or bromide or chloride 1c, can provide intermediate Id. The coupling can be performed in presence of palladium catalysts such as [l,l’-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (Pd(dppf)C12 CH2CI2) or 2nd gen XPhos precatalyst under suitable solvents such as dioxane and water in presence of a base such as potassium phosphate. Additional methods for this transformation include other variations of Suzuki -Miyaura cross coupling using methods known to one skilled in the art for this type of coupling, (see for example Miyaura & Suzuki, Chem. Rev. 1995, 95, 2457; Ashcroft & Wilford, Tett. Lett, 2013, 54, 4529).; Kurti, L. and Czako, B. Strategies and Applications of Named Reactions in Organic Synthesis, Elsevier (2005)).

[0247] Nucleophilic aromatic substitution of Id with a suitably substituted amine in presence of a suitable solvent such as THF or DMF with or without Hunig’s base can provide intermediate le. Additional methods for this transformation include other variations of nucleophilic aromatic substitution using methods known to one skilled in the art. Subsequent nitro reduction of le in presence of a suitable reductant such as iron or zinc and a suitable acid such as HC1 or ammonium chloride in a suitable solvent such as ethanol under heating can provide intermediate If. This transformation can also be done in presence of sodium hydrosulfite and ammonia in THF at rt. Additional methods for this transformation include other variations of nitro reduction using methods known to one skilled in the art.

[0248] Compounds of this invention can be obtained from subsequent amide bond coupling between If and a suitably substituted acid followed by cyclization of the resulting intermediate in presence of a suitable acid. The amide bond formation can be obtained with a suitable amide coupling reagent such as 1-propanephosphonic anhydride solution, 2-(7-aza- IH-benzotri azole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate, (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate and 2-( l / / -benzotri azole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate in a suitable solvent such as dimethylformamide or di chloromethane in presence of a base such as pyridine and N,N-diisopropylethylamine or triethyl amine. Additional methods for this transformation include other variations of amide coupling conditions, using methods known to one skilled in the art for this type of coupling, (see for example Due-Hansen et al. Org. Biomol. Chem. 2016, 14, 430; El-Faham & Albericio, Chem. Rev. 2011,111, 6557; Ferrins et al. J. Med. Chem. 2014, 57, 6393). The resulting amide can be cyclized by condensation in presence of a suitable acid such as acetic acid or HC1 or p-toluenesulfonic acid in a suitable solvent such as dioxane under heating to obtain compounds of this invention. In certain cases R2can be replaced by methyl when acetic acid is used under prolonged heating. Additional methods for this transformation include other variations of amide condensation, using methods known to one skilled in the art. Alternatively, If can be converted directly to a compound of Formula (I) in the neat corresponding acid with conventional heating or microwave heating. Alternatively, If can be converted directly to a compound of Formula (I) with the presence of the corresponding aldehyde with catalytic amount of acetic acid at room temperature in a suitable solvent such as tetrahydrofuran. Scheme 1

[0249] "

[0250]

[0251] Alternatively, as described in Scheme 2, compounds of this invention can be prepared starting with nucleophilic aromatic substitution of 4-bromo-2-fluoro-l-nitrobenzene la, with a suitably substituted amine using conditions similar to the transformation of Id to le in Scheme 1. Subsequent nitro reduction of 2a using conditions similar to the transformation of le to If in Scheme 1, can provide intermediate 2b. Amide coupling of 2b with a suitably substituted acid, followed by acid-catalyzed condensation using conditions similar to the transformation of If to a compound of Formula (I) in Scheme 1 can provide intermediate 2d. Subsequent Miyaura borylation of 2d using similar conditions to the transformation of la to lb in Scheme 1 can provide intermediate 2e. Compounds of Formula (I) can be prepared by palladium-catalyzed coupling of 2e to a suitably substituted iodide or bromide or chloride 1c using conditions similar to the transformation of lb to Id in Scheme 1.

[0252] Scheme 2

[0253]

[0254] 85 °C

[0255] Additionally, as shown in Scheme 3, compounds of this invention can be prepared starting from 2-chl oro-5 -fluoro-4-iodopyri dine 3a. Suzuki -Miyaura cross-coupling of 3a with a suitably substituted boronic ester 2e using conditions similar to the transformation of lb to Id in Scheme 1 can deliver intermediate 3b. The resulting biaryl intermediate 3b can be converted to intermediate 3c by Buchwald-Hartwig cross-coupling followed by acid-catalyzed deprotection. The palladium catalyzed cross-coupling can be performed in presence of a suitable palladium catalyst such bis(dibenzylidineacetone) palladium (0) in suitable solvents such as dioxane or dimethylacetamide and / c / V-butyl alcohol in presence of a base such as cesium carbonate or potassium carbonate and ligands such as (9,9- dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and second generation BrettPhos precatalyst. Additional methods for this transformation include other variations of Buchwald-Hartwig cross-coupling using methods known to one skilled in the art for this type of coupling. (See for example. Hicks, J, D.; Buchwald, S. L. et al. J. Am. Chem. Soc.

[0256] 2009, 131, 16720.; B.P. Fors & Buchwald, S. L Tetrahedron. 2009, 65, 6576.; Yin, J. & Buchwald, S. L J. Am. Chem. Soc. 2002, 124, 6043). The resulting tert-butyl carbonyl protected amine can be deprotected with acid such as HC1 or trifluoroacetic acid in presence of a suitable solvent such as dioxane or methylene chloride to obtain intermediate 3c. Alternatively 3c can be prepared directly from 3d by Buchwald-Hartwig cross-coupling using methods known to one skilled in the art for this type of coupling.

[0257] Subsequent amide coupling of 3c with a suitably substituted acid intermediate 3e using a suitable amide coupling reagent such as 1-propanephosphonic anhydride solution, 2-chloro-l,3-dimethylimidazolinium chloride and fluoro-N,N,N’,N’-bis(tetramethylene)formamidinium hexafluorophosphate (BTFFH) in a suitable solvent such as dimethylformamide or di chloromethane in presence of a base such as pyridine and N,N-diisopropylethylamine or triethyl amine or 2,4,6-trimethylpyridine can provide compounds of this invention. Scheme 3

[0258]

[0259] The following methods were used in the exemplified examples, except where noted otherwise. Purification of intermediates and final products was carried out via normal or reverse phase chromatography. Normal phase chromatography was carried out using prepacked SiO2cartridges eluting with either gradients of hexanes and ethyl acetate or DCM and MeOH unless otherwise indicated. Reverse phase preparative HPLC was carried out using C18 columns with UV 220 nm or prep LCMS detection eluting with gradients of Solvent A (90% water, 10% MeOH, 0.1% TFA) and Solvent B (10% water, 90% MeOH, 0.1% TFA) or with gradients of Solvent A (90% water, 10% MeOH, 10 mM NHqOAc) and Solvent B (10% water, 90% MeOH, 10 mM NHqOAc) or with gradients of Solvent A (95% water, 5% Acn, 0.1% TFA) and Solvent B (5% water, 95% Acn, 0.1% TFA) or with gradients of Solvent A (95% water, 5% Acn, 10 mM NH4OAC) and Solvent B (95% Acn 2% water, 10 mM NH4OAC).

[0260] LC / MS Methods Employed in Characterization of Intermediates: Waters Acquity SDS -BEH C18 2.1x50mm; Flow rate: 1 min gradient from 2-98 %B. Solvent A: H2O + 0.05%TFA; Solvent B: Acn + 0.05%TFA).

[0261] Analytical HPLC: Methods Employed in Characterization of Examples

[0262] Method A: Linear gradient of 0 to 100% B over 3 min, with 0.75 min hold time at 100% B; UV visualization at 220 nm; Column: Waters XBridge C18 2.1 x 50 mm; Flow rate: 1.0 mL / min; Solvent A: 0.1% TFA, 95% water, 5% Acn: Solvent B : 0.1% TFA, 5% water, 95% Acn

[0263] Method B: Linear gradient of 0 to 100% B over 3 min, with 0.75 min hold time at 100% B; UV visualization at 220 nm; Column: Waters XBridge Cl 8, 2.1 mm x 50 mm; Flow rate: 1.0 mL / min; Solvent A: 10 mM ammonium acetate, 95% water, 5% Acn

[0264] Method C: Linear gradient of 5 to 55% B over 1.7 min; UV visualization at 254 nm; Column: HALO C183.0 x 30 mm; Flow rate: 1.5 mL / min; Solvent A: 0.05% TFA, water, Solvent B: 0.05% TFA, Acn.

[0265] Method D: Linear gradient of 5 to 95% B over 1.2 min; UV visualization at 254 nm; Column: HALO C183.0 x 30 mm; Flow rate: 1.5 mL / min; Solvent A: 0.05% TFA, water, Solvent B: 0.05% TFA, Acn.

[0266] NMR Employed in Characterization of Examples.1H NMR spectra were obtained with Bruker or JEOL® Fourier transform spectrometers operating at frequencies as follows: 1H NMR: 400 MHz (Bruker or JEOL®) or 500 MHz (Bruker or JEOL®). 13C NMR: 100 MHz (Bruker or JEOL®). Spectra data are reported in the format: chemical shift (multiplicity, coupling constants, and number of hydrogens). Chemical shifts are specified in ppm downfield of a tetramethylsilane internal standard (5 units, tetramethylsilane = 0 ppm) and / or referenced to solvent peaks, which in1H NMR spectra appear at 2.49 ppm for (CDs^SO, 3.30 ppm for CD3OD, 1.94 for CD3CN, 7.24 ppm for CDCI3, and 8.03 ppm, 2.92 ppm and 2.75 ppm for C3D7NO and which in13C NMR spectra appear at 39.7 ppm for (CD3)2SO, 49.0 ppm for CD3OD, and 77.0 ppm for CDCI3. All13C NMR spectra were proton decoupled. In some cases, when solvents such as DMSO that required water suppression were used, exchangeable protons were not observed. The water suppression in DMSO-d6 was performed on the tallest peak in the rage 3-5 ppm. In some cases the methyl sulfone peak was obscured or diminished due to the water suppression.

[0267] Intermediate

[0268]

[0269] A solution of 4-bromo-2-fluoro-l -nitrobenzene (0.73 g, 3.3 mmol) in THF (5 mL) was added to cyclopentanamine (0.65 mL, 6.6 mmol) and the reaction was stirred at rt for 5 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was used in the next step without purification. LC / MS m / z 284.9, 286.9 (M+H, M+2+H)+.

[0270] Intermediate

[0271]

[0272] To a solution of 5-bromo-N-cyclopentyl-2-nitroaniline (460 mg, 1.6 mmol) in EtOH (5 mL) under N2 was added iron (360 mg, 6.4 mmol) and saturated NH4CI solution (~0.5 mL). The reaction mixture was stirred at 90 °C overnight. The reaction mixture was then cooled to rt, filtered through celite and rinsed with EtOAc. The filtrate was concentrated and the crude residue was purified by column chromatography (0-100%EtOAc / Hex) to obtain the title compound (0.37 g, 91%). LC / MS m / z 255.0, 257.0 M+H, M+2+H)+.

[0273] Intermediate 3 : N-(4-bromo-2-(cyclopentylamino)phenyl)-3-hydroxy-3-methylbutanamide

[0274]

[0275] A mixture of HATU (830 mg, 2.2 mmol) and 5-bromo-Nl-cyclopentylbenzene-1,2-diamine (370 mg, 1.5 mmol) was dissolved in DMF (5 mL). Then 3-hydroxy-3-methylbutanoic acid (0.18 mL, 1.5 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.51 mL, 2.9 mmol) were added. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% LiCl. The organic layer was concentrated and the crude residue was purified by column chromatography (EtOAc-Hexanes0-100%) to yield the title compound (470 mg, 1.3 mmol, 91 % yield).!H NMR (500 MHz, DMSO-de) 87.14 (d, J=8.9 Hz, 1H), 6.94 (d, J=8.9 Hz, 1H), 6.90 (s, 1H), 3.66 (m, 1H), 2.51 (s, 2H), 1.93 (m, 2H), 1.63 (m, 2H), 1.51 (m, 2H), 1.49 (m, 2H), 1.33 (s, 6H). LC / MS m / z 355.0, 357.0 (M+H, M+2+H)+.

[0276] Intermediate 4 : l-( 6-bromo-l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol

[0277]

[0278] A solution of N-(4-bromo-2-(cy cl opentylamino)phenyl)-3 -hydroxy-3 -methylbutanamide (450 mg, 1.3 mmol) in acetic acid (3 mL) was heated to 90 °C and stirred at this temperature overnight. The reaction mixture was allowed to cool to rt, diluted with ethyl acetate and washed with K2HPO4 solution. The organic layer was dried over Na2SC>4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc / Hexanes,0-100%) to yield the title compound (0.36 g, 1.1 mmol, 84 % yield). 'H NMR (400 MHz, CDC13) 67.57 (d, J=8.6 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.34 (dd, J=8.5, 1.9 Hz, 1H), 4.78 (m, 1H), 2.99 (s, 2H), 2.22 - 2.09 (m, 4H), 1.88 - 1.76 (m, 2H), 1.57 - 1.47 (m, 2H), 1.35 (s, 6H). LC / MS m / z 336.9, 339.0 (M+H, 4M+2+H)+.

[0279] Intermediate 5 : 1-(1 -cyclopentyl-6-(4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol

[0280]

[0281] A mixture of l-(6-bromo-l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (210 mg, 0.62 mmol), potassium acetate (180 mg, 1.9 mmol), Pd(dppf)C12 (51 mg, 0.062 mmol), bispin (240 mg, 0.93 mmol) was dissolved in dioxane (3 mL). The sealed reaction vessel was evacuated and backfilled with nitrogen 3x then heated to 85 °C and stirred for 16 h. The reaction mixture was cooled to rt, diluted with ethyl acetate andwashed with brine. The organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was used in the next step without further purification. LC / MS m / z 385.2 (M+H)+.

[0282] Intermediate 6: l-(6-(2-chloro-5-fluoropyridin-4-yl)-l-(tetrahydrofuran-3-yl)-lH-

[0283]

[0284] A stirred suspension of l-(6-bromo-l-(tetrahydrofuran-3-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (15 g, 41 mmol) (prepared from a similar procedure as intermediate 4) was added 2-chloro-5-fluoro-4-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)pyridine (12 g, 45 mmol) and potassium phosphate tribasic anhydrous (26 g, 120 mmol). The reaction mixture was degassed under Argon for 5 min, then 1,1'-bi s(diphenylphosphino)

[0285] ferrocenepalladium (II) di chloride (3.0 g, 4.1 mmol) was added and the reaction mixture was stirred for 2 h at 85 °C. The reaction mixture was cooled to rt, filtered through celite and the celite bed was washed with EtOAc. The collected filtrate was washed with water and the water layer was back extracted with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulphate and concentrated. The crude residue was purified by column chromatography (EtOAc / petroleum ether, 80-100% EtOAc) to deliver the title compound (11 g, 23 mmol, 56 % yield). LC / MS m / z 390.41 (M+H)+.!H NMR (400 MHz, DMSO-d6) 88.55 (d, . / =2,5 Hz, 1H), 7.98 (s, 1H), 7.82 (d, J=5.5 Hz, 1H), 7.74 (d, . / =8,5 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 5.63 - 5.52 (m, 1H), 4.30 (m, 1H), 4.13 - 4.07 (m, 1H), 3.93 (m, 1H), 3.74 - 3.65 (m, 1H), 3.10 (m, 2H), 2.22 (m, 1H), 1.24 (s, 3H), 1.22 (s, 3H). One CH was obscured by solvent peak.

[0286] Intermediate 7: tert-butyl (5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-(tetrahydrofuran-

[0287]

[0288] A stirred suspension of l-(6-(2-chloro-5-fluoropyridin-4-yl)-l-(tetrahydrofuran-3-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (11 g, 28 mmol), tert-butyl carbamate (6.6 g, 56 mmol), potassium phosphate (12 g, 56 mmol) and X-Phos (2.7 g, 5.6 mmol) in 1,4-di oxane (110 mL) was degassed with Argon for 15 min.

[0289] Bis(dibenzylideneacetone)palladium(0) (1.6 g, 2.8 mmol) was added and the reaction mixture was stirred for 2 h at 100 °C. The reaction mixture was cooled to rt, filtered through celite and the celite bed was washed with EtOAc. The collected filtrate was washed with water and the water layer was back extracted with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulphate and concentrated. The crude residue was purified by column chromatography (EtOAc / petroleum ether, 80-100%) to deliver the title compound (11 g, 19 mmol, 66 % yield) as a pale brown solid. LC / MS m / z 471.46 (M+H)+, RT = 1.53 min. 'HNMR (400 MHz, DMSO-d6) 69.93 (s, 1H), 8.33 (d, .7=2.5 Hz, 1H), 8.04 - 7.96 (m, 2H), 7.75 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 5.64 - 5.53 (m, 1H), 4.30 (m, 1H), 4.11 - 4.04 (m, 1H), 3.96 - 3.87 (m, 1H), 3.76 - 3.63 (m, 1H), 3.10 (d, J=15.6 Hz, 2H), 2.26 - 2.12 (m, 1H), 1.49 (s, 9H), 1.24 (s, 3H), 1.22 (s, 3H). One CH was obscured by solvent peak.

[0290] Intermediate 8: l-(6-(2-amino-5-fluoropyridin-4-yl)-l-(tetrahydrofuran-3-yl)-lH-

[0291]

[0292] Trifluoroacetic acid (14 mL) was added to a stirred solution of tert-butyl (5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-(tetrahydrofuran-3-yl)-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate (11 g, 19 mmol) at 0 °C and stirred for 5 h at rt. The reaction mixture was concentrated and the crude residue was diluted with DCM and washed with 10% aqueous NaHCOs solution and brine. The organic layer was concentrated and the crude residue was purified by column chromatography (methanol / DCM, 0-20%).

[0293] Trituration with EtOAc / MTBE delivered the title compound l-(6-(2-amino-5-fluoropyridin-4-yl)-l-(tetrahydrofuran-3-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (5.0 g, 13 mmol, 70 % yield) as an off white solid. 'H NMR (400 MHz, DMSO-de) 8 8.01 - 7.91 (m, 1H), 7.89 - 7.81 (m, 1H), 7.75 - 7.61 (m, 1H), 7.42 - 7.18 (m, 1H), 6.72 - 6.50 (m, 1H), 5.98 - 5.83 (m, 2H), 5.67 - 5.39 (m, 1H), 4.80 (s, 1H), 4.39 - 4.24 (m, 1H), 4.17 - 3.99 (m, 1H), 3.97 - 3.84 (m, 1H), 3.79 - 3.60 (m, 1H), 3.19 - 2.99 (m, 2H), 2.27 - 2.09 (m, 1H), 1.34 - 1.14 (m, 6H).

[0294] Intermediate 9 : l-( 6-(2-amino-5-fluor opyridin-4-yl)-l -cyclopentyl- lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol

[0295]

[0296] A mixture of potassium phosphate tribasic (0.69 g, 3.3 mmol), 5-fluoro-4-iodopyridin-2-amine (0.31 g, 1.3 mmol), l-(l-cyclopentyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (0.50 g, 1.3 mmol) in dioxane (10 ml) and water (1.0 ml) were degassed and then Pd(dppf)C12 (0.11 g, 0.13 mmol) was added. The mixture stirred under nitrogen and heated at 85 °C for 3 h. The reaction mixture was filtered through celite. The filtrate was diluted with EtOAc and water and extracted with EtOAc (3x). The combined extracts were dried and concentrated in vacuo. The crude product was purified by silica column chromatography (0-20% MeOH / DCM) to give l-(6-(2-amino-5-fluoropyridin-4-yl)-l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (0.39 g, 1.1 mmol, 81 % yield) as a light brown solid. LC / MS m / z 369.5 (M+H)+.

[0297] Intermediate 10. methyl 5-bromo-2-(methylsulfonyl)benzoate

[0298]

[0299] To a solution of methyl 5-bromo-2-(methylthio)benzoate (720 mg, 2.76 mmol) in methanol (25 mL) at ice bath temp was added a solution of oxone(R), monopersulfate compound (5.09 mg, 8.27 mmol) in water (25 mL). The ice bath was removed and the mixture stirred for 20 h. The mixture was evaporated under reduced pressure to remove most of the MeOH then poured into water and extracted with EtOAc (3x). The extracts were dried over Na2SO4, filtered and concentrated to give the title compound (0.80 g, 2.7 mmol, 99 % yield) as a white solid. 'HNMR (500 MHz, CDC13) 88.01 (d, J=8.3 Hz, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.83 (dd, J=8.4, 1.8 Hz, 1H), 4.01 (s, 3H), 3.37 (s, 3H).

[0300] Intermediate 11: 5-bromo-2-(methylsulfonyl)benzoic acid

[0301]

[0302] To a solution of methyl 5-bromo-2-(methylsulfonyl)benzoate (1.51 g, 5.15 mmol) in THF (25.8 ml) was added IM LiOH (10.3 ml, 10.3 mmol) and the mixture stirred at 45 °C for 45 min. The mixture was evaporated to remove most of the THF then the mixture acidified with IN HC1 and extracted with EtOAc (3x). The extracts were dried (Na2SC>4) filt and concentrated to give the title compound (1.33 g, 4.77 mmol, 93 % yield) as a white solid. ' H NMR (500 MHz, DMSO-d6) 8 14.09 (br s, 1H), 8.00 - 7.96 (m, 1H), 7.95 (s, 1H), 7.93 - 7.89 (m, 1H), 3.40 (s, 3H).

[0303] Intermediate 12. 5-bromo-N-(4-(l -cyclopentyl-2-(2-hydroxy-2-methylpropyl)-lH-

[0304]

[0305] l-(6-(2-amino-5-fluoropyridin-4-yl)-l -cyclopentyl- lH-benzo[d]imidazol -2 -yl)-2-methylpropan-2-ol (250 mg, 0.679 mmol), 5-bromo-2-(methylsulfonyl)benzoic acid (208 mg, 0.746 mmol), 2-chloro-l,3-dimethylimidazolinium chloride (149 mg, 0.882 mmol) were dissolved in pyridine (0.5 mL). The reaction mixture was stirred to 100 °C for 1 h. The mixture was evaporated and satd NH4CI added and extracted with EtOAc (3x) the extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel chromatography (EtOAc / Hex 0-100%) to obtain the title compound (0.36 g, 0.57 mmol, 84% yield) as a white solid. LC / MS m / z 629.2 (M+H)+, 631.1 (M+2+H)+.

[0306] Intermediate 13. 5-bromo-2-chloro-N-(4-(l-cyclopentyl-2-(2-hydroxy-2-methylpropyl)~ lH-benzo[ d]imidazol-6-yl)-5-fluoropyridin-2-yl) benzamide

[0307]

[0308] By application of the same method used for Intermediate 33, 5-bromo-2-chlorobenzoic acid (105 mg, 0.448 mmol) was converted to Intermediate 34 (188 mg, 78.7% yield). LC / MS m / z 585.2 (M+H)+, 587.2 (M+2+H)+.

[0309] Intermediate 14: 2-bromo-4-(difluoromethoxy)benzaldehyde

[0310]

[0311] To a solution of KOH (6.7 g, 119 mmol) dissolved in water (34.1 mL) was added a solution of 2-bromo-4-hydroxybenzaldehyde (4 g, 19.9 mmol) dissolved in DCM (80 mL). Subsequently (bromodifluoromethyl)trimethylsilane (6.17 mL, 39.8 mmol) was added and stirred for 2 hours. The reaction was transfered to a sep funnel, acidified with HC1, and extracted into EtOAc. The organic phase was separated, washed with brine, and dried over Na2SO4, decanted, concentrated onto Celite and purified by normal phase chromatography (EtOAc / Hexanes, 0-100%) to yield the title compound (3.18 g, 12.67 mmol, 63.7 % yield) as an amber oil. 'H NMR: (400 MHz, CHLOROFORM-d) 8 10.29 (d, J=0.8 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.42 (d, J=2.3 Hz, 1H), 7.21 - 7.17 (m, 1H), 6.81 - 6.43 (m, 1H).

[0312] Intermediate 15: (Z)-2-bromo-4-(difluoromethoxy)-N-hydroxybenzimidoyl chloride

[0313]

[0314] TEA was added to 2-bromo-4-(difluoromethoxy)benzaldehyde (3.18 g, 12.67 mmol) in DCM (100 mL). To this solution was added hydroxylamine hydrochloride and the reaction stirred at r.t. overnight. The reaction mixture was concentrated, water (100 mL) was added, and the solids filtered, washed water, and dried under vacuum.!H NMR: (400 MHz, CHLOROFORM-d) 68.49 (s, 1H), 7.86 - 7.82 (m, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.13 - 7.09 (m, 1H), 6.73 - 6.36 (m, 1H).

[0315] The oxime was re-dissolved in DMF (25 mL), cooled to 0 °C and NCS (1.69 g, 12.67 mmol) added and allowed to gradually come to rt. After 12 h, the reaction mixture was partitioned with EtOAc / water / brine and extracted with EtOAc. Combined organic layers were washed with water, brine, dried (Na2SO4), concentrated, and purified by (EtOAc / Hexanes, 0-100%) to furnish the title compound (3.37 g, 11.22 mmol, 89 % yield) as a white solid. 'HNMR (400 MHz, CHLOROFORM-d) 68.54 (s, 1H), 7.51 -7.42 (m, 2H), 7.15 (dd, J=8.5, 2.2 Hz, 1H), 6.75 - 6.37 (m, 1H).

[0316] Intermediate 16 : 3-(2-bromo-4-(difluoromethoxy)phenyl)-3a, 4, 6, 6a-tetrahydrofuro[ 3, 4-d]isoxazole

[0317]

[0318] To (Z)-2-bromo-4-(difluoromethoxy)-N-hydroxybenzimidoyl chloride (1 g, 3.33 mmol) and 2, 5 -dihydrofuran (583 mg, 8.32 mmol) in DCM (33 mL) was added TEA (1.39 mL, 9.98 mmol). After stirring overnight, the reaction mixture was concentrated onto Celite and purified by normal phase chromatography (EtOAc / Hexanes, 0-100%) to give the title compound as an amber oil which slowly solidified overtime.XH NMR (400 MHz, CHLOROFORM-d) 87.54 (d, J=8.6 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.15 (dd, J=8.5, 2.4 Hz, 1H), 6.74 - 6.37 (m, 1H), 5.42 (dd, J=9.2, 4.0 Hz, 1H), 4.75 - 4.70 (m, 1H), 4.33 (d, J=10.8 Hz, 1H), 3.97 - 3.91 (m, 1H), 3.76 - 3.66 (m, 2H). LC / MS m / z 334.0, 335.7 (M+H, 4M+2+H)+.

[0319] Intermediate 17 : 5-(difluoromethoxy)-2-(3a, 4, 6, 6a-tetrahydrofuro[ 3, 4-d]isoxazol-3-yl)benzoic acid (diaster comer ic mixture)

[0320]

[0321] (diastereomeric mixture) 3-(2-bromo-4-(difluoromethoxy)phenyl)-3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazole (690 mg, 2.07 mmol), PdOAc? (93 mg, 0.41 mmol, 0.2 eq), dppf (229 mg, 0.41 mmol, 0.2 eq), and TEA (0.29 mL, 2.07 mmol) were added to DMSO (3 mL) / MeOH (1.5 mL) and heated to 80 °C under CO at 80 psi for 12 h. The crude reaction mixture was concentrated onto Celite purified by normal phase chromatography (EtOAc / Hexanes, 0- 100%) to give the desired product.!H NMR: (400 MHz, DMSO-d6) 67.60 - 7.54 (m, 2H), 7.50 - 7.19 (m, 2H), 5.37 (dd, J=9.2, 3.6 Hz, 1H), 4.42 (t, J=7.4 Hz, 1H), 4.10 (d, J=10.7 Hz, 1H), 3.80 (s, 4H), 3.65 - 3.56 (m, 2H). LC / MS m / z 313.8 (M+H)+.

[0322] The benzoate was dissolved in THF / MeOH (20 mL; 1 : 1) and treat with LiOH monohydrate (260 mg, 6.20 mmol) in H2O (5 mL). After 12 h, the reaction mixture was diluted with water (10 mL) and concentrated. The remaining aqueous layer was extracted with EtOAc (25 mL). The aqueous layer was acidified with IM HC1 solution, extracted with EtOAc (3x), dried over sodium sulfate, filtered, and concentrated to give the title compound (351 mg, 56.8%) as a diastereomeric mixture. 'H NMR: (400 MHz, DMSO-d6) 8 13.52 (br s, 1H), 7.63 - 7.56 (m, 1H), 7.51 - 7.19 (m, 3H), 5.35 (dd, J=9.2, 3.6 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.12 - 4.06 (m, 1H), 3.80 - 3.71 (m, 1H), 3.65 - 3.51 (m, 2H). LC / MS m / z 299.8 (M+H)+.

[0323] Intermediate 18 : 5 -(difluoromethoxy) -2 -(3 a, 4, 6, 6a-tetrahydrofuro[ 3, 4-d]isoxazol-3-ylfbenzoic acid (homochiral, Peak 1)

[0324] Intermediate 19 : 5-(difhioromethoxy)-2-( 3a, 4, 6, 6a-tetrahydrofuro[ 3, 4-d]isoxazol-3-ylfbenzoic acid (homochiral, Peak 2)

[0325]

[0326] Intermediate 17 Intermediate 18 Intermediate 19 (diastereomeric mixture) SFC (1st Peak) SFC (2nd Peak) (fast eluting) (slow eluting) Separation of Intermediate 18 and Intermediate 19

[0327] Preparative Chromatographic Conditions: Column: Whelk-01 (R,R), 30 mm x 250 mm, 5 pm particles; Flow Rate: 90 mL / min; Column Temperature: 45 °C. Fraction collection was triggered by UV (220 nm).

[0328] Analytical Chromatographic Conditions: Column: Whelk-01 (R,R), 4.6 mm x 100 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: MeOH; Temperature: 25 °C; Isocratic elution at 20 %B over 10.00 min; Flow: 2.00 mL / min; Detection: UV (220 nm) and UV (254 nm).

[0329] Intermediate LMS5 (diastereomer 1): retention time = 1.88 min, 99% de;

[0330] Intermediate LMS6 (diastereomer 2): retention time = 2.83 min, 97.8% de.

[0331] Intermediate 20: 5-(difluoromethoxy)-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-(pyrrolidin-3-yl)benzamide Intermediate BV5-1. 1 -(tert-butyl) 3-(l,3-dioxoisoindolin-2-yl) pyrrolidine-1, 3-di carb oxy late

[0332] "

[0333]

[0334] To a solution of 2-hydroxyisoindoline-l, 3-dione (1.5 g, 9.3 mmol) and l-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.0 g, 9.3 mmol) dissolved in DCM (50 mL) was added DMAP (0.06 g, 0.5 mmol) and N,N’ -diisopropylcarbodiimide (1.6 mL, 10 mmol) and stirred overnight. The reaction mixture was filtered through celite and concentrated, then the residue was purified on silica gel chromatography to furnish 1-(tert-butyl) 3-(l,3-dioxoisoindolin-2-yl) pyrrolidine- 1, 3 -dicarboxylate (3.1 g, 8.5 mmol, 92 % yield): 'H NMR (400 MHz, CDC13) 87.92 (dd, J=5.6, 3.1 Hz, 2H), 7.87 - 7.76 (m, 2H), 3.89 - 3.40 (m, 5H), 2.37 (q, J=6.8 Hz, 2H), 1.49 (s, 9H).

[0335] Intermediate 21. 5-(difluoromethoxy)-2-iodobenzaldehyde

[0336]

[0337] To a solution of KOH (3.6 g, 65 mmol) dissolved in water (14 mL) was added a solution of 5-hydroxy-2-iodobenzaldehyde (2.0 g, 8.1 mmol) dissolved in DCM (50 mL) at 0 °C and rapidly stirred. To this slurry was added (bromodifluoromethyl)trimethylsilane (3.8 mL, 24 mmol) was added and stirred 1 hour at rt. Once all the solids were dissolved, the reaction was neutralized with IM HC1 and the reaction mixture was extracted into EtOAc. The organic phase was separated and dried over sodium sulfate, decanted, concentrated, and purified on silica gel chromatography to furnish 5-(difluoromethoxy)-2-iodobenzaldehyde (1.6 g, 5.4 mmol, 67 % yield) 'H NMR (400 MHz, CDCh) 69.99 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.71 - 7.59 (m, 1H), 7.47 (dd, J=8.0, 1.8 Hz, 1H), 6.86 - 6.44 (m, 1H)

[0338] Intermediate 22. 5-(difluoromethoxy)-2-iodobenzoic acid

[0339]

[0340] To a solution of 5-(difluoromethoxy)-2-iodobenzaldehyde (1.6 g, 5.4 mmol) dissolved in n-BuOH (14 mL) and water (14 mL) was added sodium dihydrogen phosphate (3.3 g, 27 mmol), 2-methyl-2 -butene (13 mL, 120 mmol), and then sodium chlorite (3.4 g, 38 mmol) and vigorously stirred for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was then acidified with HC1 and extracted with ether. The combined organic layers were dried over sodium sulfate, filtered, and concentrated and pumped under high vacuum and used without further purification to furnish 5-(difluoromethoxy)-2-iodobenzoic acid (2.05 g, 5.4 mmol, quantitative yield wet with trace n-BuOH)XH NMR (400 MHz, CDCh) 88.02 (d, J=8.3 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.69 (dd, J=8.2, 1.9 Hz, 1H), 6.83 - 6.43 (m, 1H)

[0341] Intermediate 23. methyl 5-(difluoromethoxy)-2 -iodobenzoate

[0342]

[0343] To a solution of 5-(difluoromethoxy)-2-iodobenzoic acid (1.7 g, 5.4 mmol) dissolved in MeOH (5.4 mL) was added 4-toluenesulfonic acid monohydrate (0.10 g, 0.54 mmol) and heated to 65 °C overnight. The reaction mixture was partitioned between EtOAc / phosphate buffer. The organic phase was separated and dried over sodium sulfate, and then decanted and concentrated to furnish methyl 5-(difluoromethoxy)-2-iodobenzoate (1.80 g, quantitative yield): 'HNMR (400 MHz, CDCI3) 67.97 (d, J=8.2 Hz, 1H), 7.82 - 7.76 (m, 1H), 7.63 (dd, J=8.3, 1.9 Hz, 1H), 6.84 - 6.39 (m, 1H), 3.95 (s, 3H).

[0344] Intermediate 24. tert-butyl 3-(4-(difluoromethoxy)-2-(methoxycarbonyl) phenyl)pyrrolidine- 1 -carboxylate

[0345]

[0346] Prepared according to procedures in Journal of the American Chemical Society 2022 144 (38), 17709-17720. To an Electrasyn2.0 10 mL vessel containing methyl 5-(difluoromethoxy)-2-iodobenzoate (0.43 g, 1.3 mmol), 1 -(tert-butyl) 3-(l,3-dioxoisoindolin-2-yl) pyrrolidine- 1, 3 -di carb oxy late (0.57 g, 1.6 mmol), nickel (II) chloride hexahydrate (0.13 g, 0.52 mmol), and 22'-bipyridyl (0.082 g, 0.52 mmol) was added DMF (9.9 mL), stirred and sonicated until a homogenous solution was obtained. Then silver nitrate (0.11 g, 0.66 mmol) was added, and the Electrasyn2.0 with +Mg / RVC-was set to 2.5F / mmol @ 16 mA. Upon completion of reaction, the reaction mixture was partitioned between EtOAc and 0.1M HC1, the organic phase was washed with phosphate buffer, concentrated and purified with silica gel chromatography to furnish tert-butyl 3-(4-(difluoromethoxy)-2-(methoxycarbonyl)phenyl)pyrrolidine-l-carboxylate (140 mg, 0.37 mmol, 28 % yield): 'H NMR (400 MHz, CDC13) 87.89 (dd, J=8.2, 1.5 Hz, 1H), 7.78 (s, 1H), 7.39 (br d, J=8.0 Hz, 1H), 6.85 - 6.42 (m, 1H), 3.95 (s, 3H), 3.88 - 3.23 (m, 5H), 2.28 (br d, J=3.1 Hz, 1H), 2.09 - 1.93 (m, 1H), 1.50 (s, 9H).

[0347] Intermediate 25: 2-(l-(tert-butoxycarbonyl)pyrrolidin-3-yl)-5-(difluoromethoxy)benzoic acid

[0348]

[0349] To a solution of tert-butyl 3-(4-(difluoromethoxy)-2-(methoxycarbonyl) phenyl)pyrrolidine-l -carboxylate (0.090 g, 0.24 mmol) dissolved in THF (1 mL) was added water (0.25 mL) and lithium hydroxide (0.020 g, 0.49 mmol) and stirred overnight. The reaction mixture was acidified with IN HC1 and extracted into EtOAc. The organic layer was separated and dried over sodium sulfate. The organic phase was decanted and concentrated. The residue was dried under high vacuum to furnish 2-(l-(tert-butoxycarbonyl)pyrrolidin-3-yl)-5-(difluoromethoxy)benzoic acid (76 mg, 0.21 mmol, 88 % yield). LC / MS m / z 356.1 (M-H)’.

[0350] Intermediate 26: tert-butyl 3-(4-(difluoromethoxy)-2-((5-fluoro-4-iodopyridin-2-yl)carbamoyl)phenyl)pyrrolidine-l -carboxylate.

[0351]

[0352] To a solution of 2-(l-(tert-butoxycarbonyl)pyrrolidin-3-yl)-5-(difluoromethoxy)benzoic acid (0.076 g, 0.21 mmol) and 5-fluoro-4-iodopyridin-2-amine (0.042 g, 0.18 mmol) dissolved in a mixture or pyridine (1.8 mL) and DCM (1.8 mL) was cooled to 0 °C and POCh (0.033 mL, 0.35 mmol) was added dropwise. The reaction was stirred 15 min, then quenched with MeOH (0.1 mL). The reaction mixture was concentrated and the residue was purified with flash chromatography to furnish tert-butyl 3-(4-(difluoromethoxy)-2-((5-fluoro-4-iodopyridin-2-yl)carbamoyl)phenyl)pyrrolidine-l-carboxylate (60 mg, 0.10 mmol, 59 % yield): LC / MS m / z 576.0 (M-H)'.

[0353] Intermediate 27: tert-butyl 3-(4-(difluoromethoxy)-2-((5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamoyl)phenyl)pyrrolidine-l -carboxylate

[0354]

[0355] To a solution of tert-butyl 3-(4-(difluoromethoxy)-2-((5-fluoro-4-iodopyridin-2-yl)carbamoyl)phenyl)pyrrolidine-l -carboxylate (0.010 g, 0.017 mmol) and 1-(1-isopropyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (0.012 g, 0.017 mmol) dissolved in Dioxane (0.08 mL) was added water (8 pL), tripotassium phosphate (9 mg, 0.04 mmol), and PdC12(dppf)-DCM adduct (0.7 mg, 0.9 pmol). The reaction was heated to 80 °C overnight. The reaction mixture was diluted with MeOH and purified on reverse phase chromatography to furnish tertbutyl 3-(4-(difluoromethoxy)-2-((5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamoyl)phenyl)pyrrolidine-l-carboxylate (1.3 mg, 1.9 pmol, 11 % yield): 1HNMR (500 MHz, DMSO-d6) 88.26 (d, J=1.8 Hz, 1H), 8.19 (d, J=6.2 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.63 (s, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.32 (br d, J=6.5 Hz, 1H), 7.20 (br d, J=8.4 Hz, 1H), 7.28 - 6.95 (m, 1H), 4.87 - 4.75 (m, 1H), 4.00 (dd, J=5.4, 3.7 Hz, 1H), 3.51 - 3.36 (m, 2H), 3.29 - 3.05 (m, 1H), 3.02 - 2.91 (m, 1H), 2.81 (s, 2H), 2.04 - 1.91 (m, 1H), 1.88 - 1.73 (m, 1H), 1.37 (d, J=6.8 Hz, 6H), 1.19 (br d, J=5.5 Hz, 9H), 1.03 (s, 6H), missing 2 exchangeable protons.

[0356] Intermediate 28: Mixture of tert-butyl 4-(4-(difluoromethoxy)-2-(methoxycarbonyl)phenyl)-2-oxopyrrolidine-l -carboxylate and tert-butyl 3-(4-(difluoromethoxy)-2-(methoxycarbonyl)phenyl)-2-oxopyrrolidine-l-carboxylate

[0357]

[0358] To a solution of tert-butyl 3-(4-(difluoromethoxy)-2-(methoxycarbonyl) phenyl)pyrrolidine-l -carboxylate (0.14 g, 0.37 mmol) dissolved in EtOAc (2.6 mL) was added sodium periodate solution (10 %wt) (7.9 mL, 3.7 mmol) followed by ruthenium (III) chloride hydrate (0.021 g, 0.092 mmol) and stirred rapidly overnight. The reaction mixture was partitioned between EtOAc / water containing Na2S20s, and then the organic phase was separated concentrated. The residue was purified on silica gel chromatography to furnish a mixture of tert-butyl 3-(4-(difluoromethoxy)-2-(methoxycarbonyl)phenyl)-2-oxopyrrolidine-1 -carboxylate compound with tert-butyl 4-(4-(difluoromethoxy)-2-(methoxycarbonyl)phenyl)-2-oxopyrrolidine-l -carboxylate (90 mg, 0.12 mmol, 63 % yield). LC / MS m / z 283.8 (M-Boc-H)’.

[0359] Intermediate 28: 5-bromo-A-[(l R)-l -cyclopropyl ethyl]-2-nitro-ani line

[0360]

[0361] To a solution of 4-bromo-2-fluoro-l -nitro-benzene (5.0 g, 23 mmol) and (1R)-1 -cyclopropylethanamine (4.0 g, 45 mmol) in MeCN (20 mL) was added K2CO3 (5.0 g, 34 mmol). The resulting mixture was stirred overnight at room temperature. The resulting solution was diluted with water (50 mL), extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (2x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure to give 5-bromo-7V-[(lR)-l-cyclopropylethyl]-2-nitro-aniline (5.0 g, 77%) as a yellow solid crude. LCMS (ESI, m / z): 285 and 287 [M+H]+.

[0362] Intermediate 29: 4-bromo-7V2-[(lR)-l-cyclopropylethyl]benzene-l,2-diamine

[0363]

[0364] To a solution of 5-bromo-7V-[(lR)-l-cyclopropylethyl]-2-nitro-aniline (5.0 g, 18 mmol) in acetic acid (50 mL) was added Fe (4.9 g, 180 mmol). The resulting mixture was stirred at 70 °C for 2 h under a nitrogen atmosphere. The resulting solution was diluted with ethyl acetate (150 mL). The mixture was filtered and the filtrate was concentrated under reduce pressure. The residue was diluted with water (40 mL), then adjusted to pH 8~9 with saturated aqueous sodium carbonate, and extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with brine (2x40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure to give 4-bromo-A2-[(lR)-l-cyclopropylethyl]benzene-l,2-diamine (4.0 g, 89%) as a red solid crude. LCMS (ESI, m / z): 255 and 257 [M+H]+.

[0365] Intermediate 30: A-(2-amino-5-bromo-phenyl)-A-[(lR)-l-cyclopropylethyl]-3-hydroxy-3-methyl-butanamide

[0366] <

[0367]

[0368] To a solution of 4-bromo-A2-[(lR)-l-cyclopropylethyl]benzene-l,2-diamine (2.0 g, 7.8 mmol), 3 -hydroxy-3 -methyl-butanoic acid (1.1 g, 9.4 mmol) in DMF (10 mL) were added HATU (4.5 g, 12 mmol, 1.5) and DIPEA (4.1 g, 31 mmol). The resulting solution was stirred for 2 h at room temperature. LThe resulting solution was directly purified by reverse flash chromatography on C18 silica with water (0.05% TFA) / MeCN (2: 1) to give A-(2-amino-5-bromo-phenyl)-A-[(lR)-l-cyclopropylethyl]-3-hydroxy-3-methyl-butanamide (2.0 g, 71%) as a yellow solid. LCMS (ESI, m / z): 355 and 357 [M+H]+.

[0369] Intermediate 30 : 1 -[6-bromo- 1 -[( 1R)- 1 -cyclopropylethyl]benzimidazol-2-yl]-2-methyl-propan-2-ol

[0370]

[0371] A solution of A-(2-amino-5-bromo-phenyl)-A-[(lR)-l-cyclopropylethyl]-3- hydroxy-3-methyl-butanamide (2.0 g, 5.6 mmol) in acetic acid (20 mL) was stirred at 80 °C for 36 h under a nitrogen atmosphere. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse flash chromatography on C18 silica with water (0.05% TFA) / MeCN (2:1) to give l-[6-bromo-l-[(lR)-l- cyclopropylethyl]benzimidazol-2-yl]-2-methyl-propan-2-ol (1.4 g, 73%) as a yellow solid. LCMS (ESI, m / z): 337 and 339 [M+H]+.1H NMR (400 MHz, Methanol- A 6 7.96 (d, J= 2.0 Hz, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.36 (dd, J= 8.4, 2.0 Hz, 1H), 4.19- 4.12 (m, 1H), 3.06-2.97 (m, 2H), 1.69 (d, J= 6.8 Hz, 3H), 1.68-1.61 (m, 1H), 1.35 (s, 3H), 1.28 (s, 3H), 0.83-0.76 (m, 1H), 0.60-0.53 (m, 1H), 0.49-0.42 (m, 1H), 0.33-0.27 (m, 1H).

[0372] Intermediate 31 : (R)-l-(l-(l-cyclopropylethyl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol

[0373]

[0374] To a solution of l-[6-bromo-l-[(lR)-l-cyclopropylethyl]benzimidazol-2-yl]-2-methyl-propan-2-ol (1.4 g, 4.2 mmol), Bis(pinacolato)diboron (1.3 g, 5.0 mmol) and KO Ac (813 mg, 8.30 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf)C12 (680 mg, 0.83 mmol). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting solution was used directly without further purification. LCMS (ESI, m / z): 385 [M+H]+.

[0375] Intermediate 32: (R)-l-(6-(2-amino-5-fluoropyridin-4-yl)-l-(l-cyclopropylethyl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol

[0376]

[0377] To the solution of l-[l-[(lR)-l-cyclopropylethyl]-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzimidazol-2-yl]-2-methyl-propan-2-ol (3.6 mmol), 5-fluoro-4-iodo-pyridin-2-amine (1.0 g, 4.4 mmol) in 1,4-dioxane (20 mL) from the previous step were added K2CO3 (1.5 g, 11 mmol, 3.0 equiv.), water (2 mL) and Pd(dppf)C12 (590 mg, 0.73 mmol). The resulting mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was diluted with water (60 mL), extracted with ethyl acetate (3x60 mL). The organic layers were washed with brine (2x60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by reverse flash chromatography on C18 silica with water (1 mmol NH4HCO3) / MeCN (2: 1) to give l-[6-(2-amino-5-fluoro-4-pyridyl)-l-[(lR)-l-cyclopropylethyl]benzimidazol-2-yl]-2-methyl-propan-2-ol (800 mg, 59%) as a yellow solid. LCMS (ESI, m / z): 369 [M+H]+.

[0378] Intermediate 33: Mixture of methyl 5-(difluoromethoxy)-2-(5-oxopyrrolidin-3-yl)benzoate with methyl 5-(difluoromethoxy)-2-(2-oxopyrrolidin-3-yl)benzoate

[0379]

[0380] To a solution of a mixture of tert-butyl 3-(4-(difluoromethoxy)-2-(methoxycarbonyl)phenyl)-2-oxopyrrolidine-l -carboxylate and tert-butyl 4-(4-(difluoromethoxy)-2-(methoxycarbonyl)phenyl)-2-oxopyrrolidine-l-carboxylate (0.090 g, 0.23 mmol) dissolved in DCM (1.9 mL) was added TFA (0.47 mL) and stirred 2 hours. The reaction mixture was concentrated and then pumped overnight on high vacuum to furnish a mixture of methyl 5-(difluoromethoxy)-2-(2-oxopyrrolidin-3-yl)benzoate mixed with methyl 5-(difluoromethoxy)-2-(5-oxopyrrolidin-3-yl)benzoate which was used without further purification assuming quantitative yield. LC / MS m / z 285.9 (M+H)+.

[0381] Chiral Separation conditions for Intermediates 34 and 35: methyl 5-(difluoromethoxy)-2-(2-oxoazeti din-3 -yl)benzoate

[0382]

[0383] Preparative Chromatographic Conditions: Column: Chiralpak AD-H, 30 mm x 250 mm, 5 micron; mobile phase: 85% CO2 / 15% MeOH w / 0.1% NF OH; flow Conditions: 90 mL / min, Detector Wavelength: 220 nm.

[0384] Analytical Chromatographic Conditions: Chiralpak AD-H, 4.6 mm x 100 mm, 5 micron; mobile phase: 85% CO2 / 15% MeOH w / 0.1% NH4OH; flow Conditions: 2 mL / min, Detector Wavelength: 220 nm.

[0385] Intermediate 30 (isomer 1): retention time = 2.13 min, 89.0 % ee; Intermediate (isomer 2): retention time = 2.26 min, 91.6 % ee.

[0386] Example 1. N-(4-(l-cyclopentyl-2-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)-2-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzamide

[0387]

[0388] POCh (5.06 pL, 0.054 mmol) in DCM (0.5 mL) was added dropwise to a solution of Intermediate 13 (20 mg, 0.054 mmol), 5-(difluoromethoxy)-2-(3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazol-3-yl)benzoic acid (Intermediate LS5, 16.24 mg, 0.054 mmol), and pyridine (300 pL, 3.71 mmol) in DCM (1 mL) at 0 °C. After 1 h, the reaction was quench with MeOH (0.5 mL) and concentrated. The residue was dissolved in DMF (2 mL) and purified by reverse phase chromatography to afford the title compound (10.2 mg, 28.9%). 'HNMR (500 MHz, DMSO-d6) Shift 11.25 - 11.20 (m, 1H), 8.50 (s, 1H), 8.40 - 8.33 (m, 1H), 8.06 - 8.01 (m, 1H), 8.00 - 7.96 (m, 1H), 7.75 (br d, J=8.6 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.24 - 7.03 (m, 1H), 5.35 - 5.26 (m, 2H), 4.45 - 4.38 (m, 1H), 3.98 (br dd, J=35.9, 9.8 Hz, 2H), 3.67 - 3.58 (m, 2H), 3.35 - 3.27 (m, 2H), 2.19 (br d, J=6.6 Hz, 4H), 2.09 - 1.99 (m, 2H), 1.81 - 1.73 (m, 2H), 1.28 (s, 6H). LC / MS m / z 650.2 (M+H)+, RT = 1.94 min (Method B).

[0389] Example 2. N-{4-[l-cyclopentyl-2-(2-hydroxy-2-methylpropyl)-lH-l,3-benzodiazol-6-yl]-5-fluoropyridin-2-yl}-2-methanesulfonyl-5-[l-(propan-2-yl)-lH-pyrazol-4-yl]benzamide

[0390]

[0391] Intermediate 12 (50 mg, 0.079 mmol), potassium acetate (23.4 mg, 0.238 mmol) and bispin (30.3 mg, 0.119 mmol) were dissolved in degassed dioxane (2 ml) and the mixture degassed then Pd(dppf)C12 (6.49 mg, 7.94 pmol) added. The reaction mixture was backfilled with nitrogen then heated at for ON. The mixture was allowed to cool to room temperature then potassium phosphate (42.1 mg, 0.199 mmol), 4-bromo-l-isopropyl-lH-pyrazole (19.5 mg, 0.103 mmol) and water (0.200 ml) were added and the mixture degassed then Pd(dppf)C12 (6.49 mg, 7.94 pmol) added and the mixture placed under nitrogen and heated at 85 °C for 3 h. The reaction mixture was diluted with EtOAc and water and extracted with EtOAc (3x). The organics were combined and dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography to give the title compound (11 mg, 20%). LC / MS m / z 658.9 (M+H)+, RT = 1.93 min (Method B). 'H NMR (500 MHz, DMSO-d6-ws) 6 11.42 (s, 1H), 8.55 -8.53 (m, 1H), 8.53 - 8.51 (m, 1H), 8.46 - 8.42 (m, 1H), 8.12 - 8.09 (m, 1H), 8.07 - 8.03 (m, 1H), 8.02 - 7.99 (m, 1H), 7.94 (s, 3H), 7.78 (br d, J=8.7 Hz, 1H), 5.39 - 5.27 (m, 1H), 4.58 - 4.49 (m, 1H), 3.34 (s, 2H), 3.00 (s, 1H), 2.29 - 2.17 (m, 4H), 2.10 - 1.99 (m, 2H), 1.84 - 1.74 (m, 2H), 1.47 (s, 3H), 1.46 (s, 3H), 1.29 (s, 6H).

[0392] Example 3 : 5-(difluoromethoxy)-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-(pyrrolidin-3-yl)benzamide

[0393] >

[0394]

[0395] To a solution of tert-butyl 3-(4-(difluoromethoxy)-2-((5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamoyl)phenyl)pyrrolidine-l -carboxylate (0.05 g, 0.07 mmol) was added MeOH (1.8 mL) and water (1.8 mL) and heated in microwave to 120 °C for 1 hour. The reaction mixture was purified with reverse phase chromatography to furnish title compound (1.0 mg, 1.5 pmol, 2.0 % yield) 'H NMR (500 MHz, DMSO-d6) 68.48 (d, J=2.0 Hz, 1H), 8.40 (d, J=6.0 Hz, 1H), 7.95 (s, 1H), 7.90 (br d, J=8.1 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.46 - 7.12 (m, 2H), 5.03 (dt, J=13.6, 6.8 Hz, 1H), 3.27 - 3.19 (m, 1H), 3.04 (s, 2H), 3.01 - 2.91 (m, 2H), 2.75 - 2.66 (m, 1H), 2.14 (br d, , / =7.3 Hz, 1H), 1.74 (s, 3H), 1.59 (d, J=6.8 Hz, 6H), 1.25 (s, 6H). ). m / z = 582.0 (M+H)+, RT = 1.51 min (Method B).

[0396] Example 4: (R)-N-(4-(l-(l-cyclopropylethyl)-2-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-5-(l-methyl-lH-l,2,3-triazol-4-yl)-2- (methylsulfonyl)benzamide

[0397]

[0398] To a solution of l-[6-(2-amino-5-fluoro-4-pyridyl)-l-[(lR)-l-cyclopropylethyl]benzimidazol-2-yl]-2-methyl-propan-2-ol (300 mg, 0.81 mmol, 1.0 equiv.) and 2-methylsulfonyl-5-(l -methyltriazol -4-yl)benzoic acid (274 mg, 0.98 mmol, 1.2 equiv.) in pyridine (4 mL) was added dropwise POCI3 (371 mg, 2.44 mmol, 3.0 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 3 h. LCMS showed the reaction was completed. The resulting mixture was quenched with water (30 mL), extracted with ethyl acetate (4x30 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by Prep-HPLC (Column: SunFire Prep C18 OBD Column, 19*150 mm, 5 pm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: MeCN; Flow rate: 25 mL / min; Gradient: 30% B to 50% B in 5.32 min; Wave Length: 254 / 210 nm) to giveA-[4-[3-[(lR)-l-cyclopropylethyl]-2-(2-hydroxy-2-methyl-propyl)benzimidazol-5-yl]-5-fluoro-2-pyridyl]-2-methylsulfonyl-5-(l -methyltri azol -4-yl)benzamide (29.8 mg, 5%) as a white solid. LCMS (ESI, m / z): 632 [M+H]+. Rt: 1.31 min. (Method C) 'HNMR (400 MHz, DMSO-tL) 6 11.48 (s, 1H), 8.82 (s, 1H), 8.48 (d, = 2.0 Hz, 1H), 8.41 (d, = 6.0 Hz, 1H), 8.21 (dd, J= 8.0, 2.0 Hz, 1H), 8.17 (s, 1H), 8.08 (d, J= 8.0 Hz, 1H), 8.07 (s, 1H), 7.78 (d, J= 8.4 Hz, 1H), 7.44 (d, J= 8.4 Hz, 1H), 5.12-4.96 (m, 1H), 4.28-4.12 (m, 1H), 4.14 (s, 3H), 3.37 (s, 3H), 3.05-2.96 (m, 2H), 1.72-1.64 (m, 1H), 1.63 (d, J= 6.8 Hz, 3H), 1.27 (s, 3H), 1.22 (s, 3H), 0.76-0.68 (m, 1H), 0.62-0.54 (m, 1H), 0.45-0.38 (m, 1H), 0.41-0.23 (m, 1H). Example 53 : N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-5-(2-methyl-2H-l,2,3-triazol-4-yl)-2-(methylsulfonyl)benzamide

[0399]

[0400] To a solution of 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-l,2,3-triazole (0.017 g, 0.080 mmol) in dioxane (0.66 mL) was added Intermediate 12 (0.04 g, 0.066 mmol), K2CO3 (0.037 g, 0.27 mmol), and water (0.133 ml). The mixture was stirred under nitrogen atmosphere in a sealed vessel at 80 C overnight. The reaction was filtered and purified by reverse phase chromatography to yield the title compound (7.2 mg).

[0401] The following Examples in Table 3 were made by using the similar procedures as shown above in Intermediates 1-29 and Examples 1-4 and Example 53 with the appropriate starting materials. Water suppression pulse sequences were used in the proton NMR experiments for many of the reported examples. Use of water suppression in a particular example is indicated with the abbreviation “ws” preceding the NMR peak listing. In these cases, proton resonances with chemical shifts near the water peak may be suppressed entirely or partially, and consequently are either not reported or their integrated intensities are omitted in the peak listings.

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[0458] It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

WE CLAIM:

1. A compound of F ormul a (I) :or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is H, Ci-6 alkyl substituted with 0 to 3 Ra, Ci-6 haloalkyl substituted with 0 to 2 Ra, -(CRgRgl)o-2-(C3-8cycloalkyl substituted with 0 to 4 Re), or a 4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re;R2is H, cyano, OH, SH, NH2, C1-4 alkylthio, C1-4 alkoxy, C1-8 alkyl substituted with 0 to 2 Ra, C2-6 alkenyl substituted with 0 to 1 Ra, C2-6 alkynyl substituted with 0 to 1 Ra, C1-6 haloalkyl substituted with 0 to 1 Ra,-(CRgRgl)o-3-(C3-8cycloalkyl substituted with 0 to 4 Re), or-(CRgRgl)o-2-(4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re);R3is halogen, cyano, C1-4 haloalkyl, C1-4 haloalkoxy,-C(=O)O(Ci-4alkyl), NH2, N(CI-4alkyl)2, -C(=O)NH2, -C(=O)N(CI-4alkyl)2,C2-6 alkenyl, C2-6 alkynyl, ORh, or C1-6 alkyl substituted with 0 to 2 Ra;R4is H, halogen, cyano or C1-4 alkyl;R5is a 4- to 9-membered monocyclic or bicyclic heterocyclic ring including 1 to 4 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 3 Re, ora 5 to 6-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), or O, wherein the heteroaryl is substituted with 0 to 3 Rd;R6is halogen, cyano, Ci-4 alkoxy, Ci-4 haloalkyl, Ci-4 haloalkoxy,-NH(CI-4 alkyl), Ci-4 alkyl substituted with 0 to 2 Ra, or -SC>2(Ci-4 alkyl substituted with 0 to 1 Rc);Rais halogen, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 haloalkyl,C1-4 haloalkoxy, NH2, NH(CI-4alkyl), N(CI-4alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;Rbis H, C1-4 fluoroalkyl, -C(=O)(Ci-4alkyl), -C(=O)O(Ci-4alkyl) orC1-4 alkyl substituted with 0-1 OH;Rcis halogen, OH, cyano, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl substituted with 0 to 2 Rf, or C1-4 alkoxy substituted with 0 to 1 Rf;Rdis halogen, OH, cyano, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -O(C=O)H, -O(C=O)(C 1-4 alkyl), -C(=O)O(Ci-4alkyl), NH2, N(CI-4alkyl)2, -C(=O)NH2, -C(=O)N(CI-4 alkyl)2, C2-6 alkenyl, C2-6 alkynyl, or C1-6 alkyl substituted with 0 to 2 Rc;Reis oxo or Rd;Rfis halogen, OH, cyano, -CH2OH, C1-4 alkoxy, orN(Ci-4alkyl)2;Rgis H, C1-4 alkyl substituted with 0 to 1 Rf, C1-4 alkoxy, or C3-6 cycloalkyl; Rglis H or C1-4 alkyl;Rhis H or C1-6 alkyl substituted with 0 to 1 Ra;m and n are 0, 1 or 2; andp is 0, 1 or 2.

2. The compound of claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is H, C1-6 alkyl substituted with 0 to 2 Ra, C1-6 fluoroalkyl substituted with 0 to 1 Ra, -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re), or a 4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re;R2is H, C1-4 alkoxy, C1-6 alkyl substituted with 0 to 1 Ra, orCi-6 fluoroalkyl substituted with 0 to 1 Ra;R3is halogen, OH, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 fluoroalkyl, orCi-4 fluoroalkoxy;R4is H, F, Cl, cyano, or C1-2 alkyl;R6is H, halogen, C1-4 alkyl, C1-4 alkoxy, Ci-4haloalkyl, C 1-4 haloalkoxy, or -SO2(Ci-4 alkyl substituted with 0 to 1 Rc);Rais halogen, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 fluoroalkyl,C1-4 fluoroalkoxy, NH2, NH(Ci-4 alkyl), N(CI-4 alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;Rbis H, Ci-4 fluoroalkyl, or C1-4 alkyl substituted with 0-1 OH;Rcis F, Cl, cyano, OH, C1-4 alkoxy, C1-4 fluoroalkyl, orC1-4 fluoroalkoxy;Rdis halogen, cyano, OH, -CH2OH, C1-4 alkyl, C1-4 alkoxy,C1-4 fluoroalkyl, C1-4 fluoroalkoxy, -O(C=O)H, -O(C=O)(Ci-4 alkyl), or-C(=O)O(Ci-4alkyl);Rgis H, C1-2 alkyl or -CH2OH; andRglis H or C1-2 alkyl.

3. The compound of claim 1 or claim 2, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is H, C1-6 alkyl substituted with 0 to 2 Ra, C1-4 fluoroalkyl substituted with 0 to 1 Ra, -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re), or a 4- to 6-membered heterocyclic ring including 1 ring heteroatom which is independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re;R2is H, C1-6 alkyl substituted with 0 to 1 Ra, or C1-4 fluoroalkyl substituted with 0 to 1 Ra;R3is F, Cl or C1-2 alkyl;R4is H, F or Cl;R5is a 4- to 9-membered monocyclic or bicyclic heterocyclic ring including 1 to 4 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is is partially satuated or fully satuated, and is substituted with 0 to 2 Re,or a 5 to 6-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), or O, wherein the heteroaryl is substituted with 0 to 2 Rd;R6is halogen, C1-4 alkyl, C1-4 alkoxy, C 1-4 fluoroalkyl, C 1-4 fluoroalkoxy, or - SO2(C 1-4 alkyl); andm and n are 0 or 1.

4. A compound of Formula (II):or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is H, Ci-6 alkyl, C1-4 fluoroalkyl, -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 1 Re), or a 5-membered heterocyclic ring including 1 ring heteroatom which is independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 1 Re;R2is Ci-6 alkyl substituted with 0 to 1 Ra;R4is H, F or Cl;R5is a 4- to 8-membered monocyclic or bicyclic heterocyclic ring including 1 to 3 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re, or a 5 to 6-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), or O, wherein the heteroaryl is substituted with 0 to 2 Rd;R6is halogen, Ci-4 fluoroalkoxy, or -SC>2(Ci-4 alkyl);Rais F, Cl, cyano, OH, -CH2OH, CM alkoxy, or Ci-4fluoroalkyl;Rbis H, C1-4 alkyl, C1-4 fluoroalkyl, or -CH2C(CH3)2OH; andRdis F, cyano, C1-4 alkyl substituted with 0-1 OH, Ci-4fluoroalkyl orCi -4 alkoxy;Reis oxo or Rd; andm is 0 or 1.

5. The compound of claim 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is Ci-4 alkyl, -CH(CH3)-cyclopropyl, C4-5 cycloalkyl substituted with 0-1 OH,R5is a 4- to 6-membered monocyclic heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is is partially satuated or fully satuated, and is substituted with 0 to 1 Re, a 5 to 6-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), orO, wherein the heteroaryl is substituted& andR6is Cl, C1-4 fluoroalkoxy, or -SO2(Ci-4 alkyl).

6. The compound of claim 4 or claim 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is -CH(CH3)2, -CH(CH3)-cyclopropyl, cyclobutyl substituted with 0-1 OH,cyclopentyl,R6is Cl, -OCF2H, -OCH2CF2H, or -SO2CH3;Rbis H, CH3, -CH(CH3)2, -CF2H, -CH2CF2H, or -CH2C(CH3)2OH; and Rdis independently F, cyano, CH3, -OCFF, CF3, -CH2OH, or -C(CH3)2OH.

7. The compound of claim 4 or claim 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is independently -CH(CH3)2, -CH(CH3)-cyclopropyl, cyclobutyl substitutedR6is independently Cl, -OCF2H, -OCH2CF2H, or -SO2CH3;Rbis independently H, CH3, -CH(CH3)2, -CF2H, -CH2CF2H, or -CH2C(CH3)2OH; andRdis independently F, cyano, CH3, -OCH3, CF3, -CH2OH, or-C(CH3)2OH.

8. The compound according to claim 1, which is selected from any one of the Examples 1 to 64 as described in the specification, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

9. A composition comprising a compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, and one or more a pharmaceutically acceptable carriers, diluents, or excipients.

10. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 or a composition according to claim 9 for use in therapy.

10. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 or a composition according to claim 9 for use in treating one or more diseases or disorders selected heart failure, fibrosis, cardiomyopathies, atrial fibrillation, catecholaminergic polymeric ventricular tachycardia, heart block, cardiac arrhythmias, contraception, anxiety, post-traumatic stress disorder, hypertension, tachycardia, diabetes, allergy, and asthma.

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