N-(4-(imidazo[4,5-b]pyridin-5-YL)-2-pyridyl)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] 3H-IMIDAZO[4,5-B]PYRIDIN-5-YL BENZAMIDE COMPOUNDS AS CAMK2 INHIBITORS

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

[0003] 63 / 721,716, 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 3H-imidazo[4,5-b]pyridin-5-yl benzamide 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. 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;

[0008] 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).

[0009] SUMMARY OF THE INVENTION

[0010] 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.

[0011] The invention also provides processes and intermediates for making the compounds of the present invention.

[0012] 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.

[0013] The compounds of the invention may be used in therapy or the manufacture of a medicament.

[0014] 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.

[0015] 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). These and other features and advantages of the invention will be apparent from the following detailed description and claims.

[0016] DESCRIPTION OF THE INVENTION

[0017] In a first aspect, the present invention provides, inter alia, a compound of Formula (I):

[0018]

[0019] (I),

[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 heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), O, or S(O)P, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 4 Re;

[0022] R2is H, cyano, -OH, -SH, -NH2, C 1-4 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, -NH2,

[0023] -NH(CI-4 alkyl), N(CI-4 alkyl)2, -NH(CI-4 haloalkyl), -NHC(=O)( C1-4 alkyl), -(CRgRgl)o-2-(C3-8cycloalkyl substituted with 0 to 4 Re), or

[0024] -(CRgRgl)o-i-(4- to 6-membered heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), O, or S(O)P, and wherein said heterocycle 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, -NH(CI-4alkyl), -N(CI-4alkyl)2, -C(=O)NH2, -C(=O)N(CI-4alkyl)2,

[0026] C2-6 alkenyl, C2-6 alkynyl, -ORh, or C1-6 alkyl substituted with 0 to 2 Ra; R4is H, halogen, cyano or Ci-4 alkyl;

[0027] R5is halogen, cyano, Ci-4 alkoxy, Ci-4 haloalkyl, Ci-4 haloalkoxy,

[0028] -NH(Ci-4 alkyl), Ci-4 alkyl substituted with 0 to 2 Ra, -SC>2(Ci-4 alkyl substituted with 0 to 1 Rc), -SC>2CH2(C3-4 cycloalkyl), or a 5 to 6-membered heteroaryl containing 1 to 4 ring heteroatoms which are N, N(Rb), O, or S, wherein said heteroaryl is substituted with 0 to 2 Rd;

[0029] R6is halogen, -OH, cyano, Ci-6 alkyl substituted with 0 to 2 Rc, C2-6 alkenyl substituted with 0 to 1 Rc, C2-6 alkynyl substituted with 0 to 1 Rc, C1-4 haloalkyl substituted with 0-1 Rc, C1-4 alkoxy substituted with 0 to 1 Rc, C1-4 haloalkoxy substituted with 0-1 Rc, -NHC(=O)(CI-4alkyl), -NHC(=O)O(CI-4alkyl),

[0030] -(CH2)O-I-(C3-6 cycloalkyl substituted with 0 to 2 Re), a 4- to 8-membered heterocycle including 1 to 2 ring heteroatom which are N, N(Rb), or O, and wherein the heterocycle is monocycle, bridged cycle or spiro cycle, is partially satuated or fully satuated, and is substituted with 0 to 3 Re; or

[0031] -(0)o-i-(5- to 6-membered heteroaryl including 1 to 4 ring heteroatom which are N, N(Rb), O, or S, and is substituted with 0 to 3 Rd);

[0032] Rais halogen, cyano, -OH, -CH2OH, C1-4 alkoxy, C1-4 haloalkyl,

[0033] C1-4 haloalkoxy, NH2, NH(CI-4alkyl), N(CI-4alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;

[0034] Rbis H, C1-4 fluoroalkyl, -C(=O)(Ci-4 alkyl), -C(=O)O(Ci-4 alkyl) or C1-4 alkyl substituted with 0 to 1 Rf;

[0035] Rcis halogen, cyano, -OH, 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;

[0036] Rdis halogen, cyano, -OH, 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;

[0037] Reis oxo or Rd;

[0038] Rfis halogen, cyano, -OH, -CH2OH, C1-4 alkoxy, or N(Ci-4alkyl)2;

[0039] Rgis H, C1-4 alkyl substituted with 0 to 1 Rf, C1-4 alkoxy, or C3-6 cycloalkyl;

[0040] Rglis H or C1-4 alkyl;

[0041] Rhis H or C1-6 alkyl substituted with 0 to 1 Ra; m and n are 0, 1 or 2; and

[0042] p is 0, 1 or 2.

[0043] 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:

[0044] R1is H, Ci-6 alkyl substituted with 0 to 2 Ra, Ci-6 haloalkyl substituted with 0 to 1 Ra, -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re), or a 4- to 6-membered heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), O, or S(O)P, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 2 Re;

[0045] R2is H, Ci-4 alkoxy, Ci-6 alkyl substituted with 0 to 1 Ra, Ci-6 haloalkyl substituted with 0 to 1 Ra, -NH(CI-4 fluoroalkyl), or -NHC(=O)(CI-4 alkyl);

[0046] R3is halogen, -OH, cyano, Ci-6 alkyl, Ci-4 alkoxy, C 1-4 haloalkyl, or

[0047] C1-4 haloalkoxy;

[0048] R4is H, halogen, cyano, or C1-2 alkyl;

[0049] R5is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -SO2(Ci-4 alkyl substituted with 0 to 1 Rc), or a 5 to 6-membered heteroaryl containing 1 to 4 ring atomswhich are N, N(Rb), or O, wherein said heteroaryl is substituted with 0 to 2 Rd;

[0050] Rais halogen, cyano, -OH, -CH2OH, C1-4 alkoxy, C1-4 haloalkyl,

[0051] C1-4 haloalkoxy, NH2, NH(CI-4 alkyl), or N(CI-4 alkyl)2;

[0052] Rbis H, Ci-4 fluoroalkyl, or C1-4 alkyl substituted with 0-1 OH;

[0053] Rcis halogen, cyano, -OH, C1-4 alkoxy, C1-4 haloalkyl, or C1-4 haloalkoxy, -NH2, -NH(C 1-4 alkyl) or -N(Ci-4alkyl)2;

[0054] Rdis halogen, cyano, -OH, -CH2OH, C1-4 alkyl substituted with 0-1 OH,

[0055] 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);

[0056] Rdis F, cyano, C1-4 alkyl substituted with 0-1 OH, C1-4 haloalkyl, or C1-4 haloalkoxy

[0057] Rgis H, C1-2 alkyl or -CH2OH; and

[0058] Rglis H or C1-2 alkyl. 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:

[0059] R1is H, Ci-6 alkyl substituted with 0 to 2 Ra, Ci-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 heterocycle including 1 ring heteroatom which is N, N(Rb), O, or S(O)P, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 2 Re;

[0060] R2is H, Ci-6 alkyl substituted with 0 to 1 Ra, Ci-4 fluoroalkyl substituted with 0 to 1 Ra, -NH(CI-4 fluoroalkyl), or -NHC(=0)(CI-4 alkyl);

[0061] R3is F, Cl or C1-2 alkyl;

[0062] R4is H, F or Cl;

[0063] R5is halogen, Ci-4haloalkyl, -SC>2(Ci-4 alkyl), or a 5 to 6-membered heteroaryl containing 1 to 4 ring atomswhich are N, N(Rb), or O, wherein said heteroaryl is substituted with 0 to 2 Rd;

[0064] R6is halogen, -OH, C1-6 alkyl substituted with 0 to 1 Rc, C2-6 alkynyl substituted with 0 to 1 Rc, C1-4 alkoxy substituted with 0 to 1 Rc, C 1 -4 haloalky 1,

[0065] C1-4 haloalkoxy, -NHC(=0)(CI-4 alkyl), C3-6 cycloalkyl substituted with 0 to 2 Re, a 4- to 6-membered heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), or O, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 2 Re; or a 5- to 6-membered heteroaryl containing 2 to 3 ring heteroatoms which are N, N(Rb), O or S, and wherein said heteroaryl is substituted with 0 to 2 Rd; and

[0066] n is 0 or 1.

[0067] In a fourth aspect, the present invention provides a compound of Formula (II):

[0068]

[0069] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

[0070] R1is H, Ci-6 alkyl, C1-4 fluoroalkyl, -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 1 Re), or a 5- to 6-membered heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), or O, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 1 Re;

[0071] R2is Ci-4 fluoroalkyl, Ci-6 alkyl substituted with 0 to 1 Ra,

[0072] -NH(CI-4 fluoroalkyl), or -NHC(=O)(C 1-4 alkyl);

[0073] R4is H, F, or Cl;

[0074] R5is halogen, C1-4 fluoroalkyl, -SC>2(Ci-4 alkyl), or a 5-membered heteroaryl containing 2 to 3 nitrogen atoms which are N or N(Rb);

[0075] R6is halogen, -OH, C1-6 alkyl substituted with 0 to 1 Rc, C2-6 alkynyl substituted with 0 to 1 Rc, C1-4 alkoxy substituted with 0 to 1 Rc, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, -NHC(=O)(C 1-4 alkyl), C3-6 cycloalkyl substituted with 0 to 1 Re, a 4- to 6-membered heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), or O, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 1 Re; or a 5-to 6-membered heteroaryl containing 2 to 3 nitrogen atoms which are N or N(Rb), and wherein said heteroaryl is substituted with 0 to 1 Rd;

[0076] Rais F, Cl, cyano, -OH, -CH2OH, -NH2, C1-4 alkoxy, or C1-4 fluoroalkyl;

[0077] Rbis H, C1-4 alkyl, or C1-4 fluoroalkyl;

[0078] Rcis F, Cl, cyano, -OH, C1-4 alkoxy, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, -NH2, -NH(C 1-4 alkyl) or -N(Ci-4alkyl)2;

[0079] Rdis F, cyano, C1-4 alkyl substituted with 0-1 OH, C1-4 fluoroalkyl or

[0080] Ci -4 alkoxy; Reis oxo or Rd; and

[0081] m is 0, 1 or 2.

[0082] 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 asepct and wherein, independently for each occurrence:

[0083] R1is C1-4 alkyl, C1-4 fluoroalkyl, -CH(Ci-2alkyl)-cyclopropyl, cyclopentyl, or

[0084]

[0085] R2is Ci-4 fluoroalkyl, C alkyl substituted with 0 to 1 Ra,

[0086] -NH(CI-4 fluoroalkyl), or -NHC(=O)(C 1-4 alkyl);

[0087] R5is Cl, C1-4 alkyl, C1-4 fluoroalkyl, -SC>2(Ci-4 alkyl), or or

[0088]

[0089] ;

[0090] R6is halogen, -OH, C1-6 alkyl substituted with 0 to 1 Rc, C2-6 alkynyl substituted with 0 to 1 Rc, C1-4 alkoxy substituted with 0 to 1 Rc, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, -

[0091] NHC(=O)(C 1-4 alkyl)

[0092]

[0093]

[0094] , or a 5-membered heteroaryl containing 2 to 3 nitrogen atoms which are N or N(Rb), and wherein said heteroaryl is substituted with 0 to 1 Rd;

[0095] Rais cyano, -OH, or -NH2;

[0096] Rbis H, C1-2 alkyl, or C1-2 fluoroalkyl;

[0097] Rcis -OH, -NH2, -NH(CI-4 alkyl), or -N(Ci-4alkyl)2; and

[0098] Rdis F, C1-4 alkyl, C1-4 fluoroalkyl or C1-4 alkoxy.

[0099] 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: R1is -CH(CH3)2, -CH2CHF2, -CH(CH3)CHF2, -CH(CH3)-cyclopropyl,

[0100]

[0101] Rbis H, Cft, or -CF2H.

[0102] 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:

[0103] R1is C1-4 alkyl;

[0104] R2is C1-4 alkyl substituted with OH;

[0105] R4is H orF;

[0106] R5is Cl or -SO2(Ci-2alkyl);

[0107] R6is C1-6 alkyl substituted with 0 to 1 Rc, C2-6 alkynyl substituted with 0 to 1 Rc, C1-4 alkoxy substituted with 0 to 1 Rc, C 1-4 fluoroalkoxy, or a 5-membered heteroaryl containing 2 to 3 nitrogen atoms which are N or N(Rb);

[0108] Rbis H or C1-2 alkyl; and Rcis -OH, -NH2, -NH(CI-4alkyl), or -N(Ci-4alkyl)2.

[0109] 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 any one of the fourth to seventh aspects and wherein, independently for each occurrence:

[0110] R1is -CH(CH3)2;

[0111] R2is -CH2C(CH3)2OH;

[0112] R4is H orF;

[0113] R5is Cl or -SO2CH3;

[0114] R6is -OCH(CH3)2, -OCHF2, -OCH2CHF2, -CH2C(CH3)2NH2,

[0115]

[0116] m is 1 or 2.

[0117] In another aspect, the invention provides a compound selected from:

[0118]

[0119]

[0120] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0121] In another aspect, the invention provides a compound selected from:

[0122]

[0123]

[0124] or a pharmaceutically acceptable salt thereof.

[0125] In an eighth aspect, the invention provides a compound selected from the exemplified Examples 1 to 63 or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0126] 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.

[0127] 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.

[0128] In another embodiment, the present invention provides a process for making a compound of the present invention.

[0129] In another embodiment, the present invention provides an intermediate for making a compound of the present invention.

[0130] DEFINITIONS

[0131] 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. 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.

[0132] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] “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.

[0137] 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".

[0138] 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.

[0139] Where a bonding attachment location is not specified, the bonding may be attached at any appropriate location as understood by practitioners in the art.

[0140] 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.

[0141] 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, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0142] 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.

[0143] 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.

[0144] BIOLOGICAL METHODS

[0145] CAMK2D ECHO MS Activity Assay

[0146] 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%.

[0147] 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 a 712.3 divided by the m / z of internal standard analyte, 605.2 a 713.1.

[0148] 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.

[0149] 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.

[0150] Table 1

[0151] CAMK2D HTRF

[0152] Ex #

[0153] ACT IC50 (nM)

[0154] 1 2.3

[0155] 2 2.5

[0156] 3 3.8

[0157] 4 2.4

[0158] 5 0.78

[0159] 6 0.27

[0160] 7 2.0

[0161] 8 1.5

[0162] 9 1.4

[0163] 10 0.55

[0164] 11 1.0

[0165] 12 0.37

[0166] 13 0.78

[0167] 14 0.29

[0168] 15 0.42

[0169] 16 0.22

[0170] 17 1.9

[0171] 18 3.6

[0172] 19 0.80

[0173] 20 0.67

[0174] 21 0.36

[0175] 22 0.27

[0176] 23 3.8

[0177] 24 3.3

[0178] 25 0.84

[0179] 26 1.3 27 20

[0180] 28 2.7

[0181] 29 1.2

[0182] 30 0.37

[0183] 31 <5

[0184] 32 0.30

[0185] 33 0.82

[0186] 34 5.8

[0187] 35 0.73

[0188] 36 1.1

[0189] 37 0.68

[0190] 38 0.59

[0191] 39 1.7

[0192] 40 2.0

[0193] 41 1.1

[0194] 42 1.3

[0195] 43 1.7

[0196] 44 2.1

[0197] 45 1.0

[0198] 46 0.28

[0199] 47 0.45

[0200] 48 1.6

[0201] 49 6.4

[0202] 50 2.3

[0203] 51 4.8

[0204] 52 0.63

[0205] 53 0.11

[0206] 54 1.5

[0207] 55 1.4

[0208] 56 3.8

[0209] 57 0.23

[0210] 58 2.5

[0211] 59 0.57

[0212] 60 1.4

[0213] 61 0.43

[0214] 62 4.6

[0215] 63 0.22

[0216] Cellular Assay

[0217] 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 Celsius 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 2.

[0218] Table 2. Assay in HEK293 cells measuring inhibition of PLN phosphorylation pPLN HTRF EC50

[0219] Ex #

[0220] (nM)

[0221] 1 19

[0222] 2 0.35

[0223] 3 34

[0224] 4 26

[0225] 5 17

[0226] 6 6.8 ll 37 10 5.3 25 19 23 1.2 6.1 3.2 21 18 7.1 23 12 7.1 32 13 19 32 0.42 32 14 3.3 2.0 2.9 36 8.1 14 36 16 33 7.4 16 39 7.5 12 27 13 16 22 10 50 39 42 12 2.8 5.2

[0227] - lO - 56 2.9

[0228] 57 5.0

[0229] 58 50

[0230] 59 24

[0231] 60 39

[0232] 61 12

[0233] 62 10

[0234] 63 41

[0235] PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE

[0236] 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.

[0237] 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 arrhythmia 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.

[0238] "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 ( / .< ., 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. 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.

[0239] 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.

[0240] "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, / .< ., 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.

[0241] 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.

[0242] 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).

[0243] 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.

[0244] 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.

[0245] 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.

[0246] Another aspect of the invention is a method for treating heart disease wherein the treatment is post myocardial infarction.

[0247] 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.

[0248] 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.

[0249] Another aspect of the invention is a method for treating heart disease wherein the treatment is given to a patient with chronic heart failure. 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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,

[0257] 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 12, 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.

[0258] 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.

[0259] 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 PPARg; 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.

[0260] 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,

[0261] 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).

[0262] 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.

[0263] 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.

[0264] 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).

[0265] CHEMISTRY METHODS 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" for mass 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.

[0266] Ac Acetic

[0267] AcOH acetic acid

[0268] Acn (or MeCN) Acetonitrile

[0269] BBrs Boron tribromide

[0270] BINAP 2, 2'-bis(diphenylphosphino)- 1,1 '-binaphthyl

[0271] Bispin bis(pinacolato)diboron

[0272] Bn Benzyl

[0273] Boc / c / 7-butyl carbonyl

[0274] BOC2O di- / c77-butyl dicarbonate

[0275] BOP (Benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0276] BTFFH fluoro-N,N,N’,N’-bis(tetramethylene)formamidinium

[0277] hexafluorophosphate Bu Butyl

[0278] CDCh deutero-chloroform

[0279] CD3OD deutero-methanol

[0280] CS2CO3 Cesium carbonate

[0281] dba as in (Pd2(dba)3) Dib enzy li deneacetone

[0282] DCM Dichloromethane

[0283] DEAD diethyl azodi carb oxy late

[0284] DIAD diisopropyl azodicarboxylate

[0285] DIEA or DIPEA Diisopropylethylamine

[0286] DMAP 4-dimethylaminopyridine

[0287] DME Dimethoxy ethane

[0288] DMF Dimethylformamide

[0289] DMSO dimethyl sulfoxide

[0290] DMSO-d6deutero-dimethyl sulfoxide

[0291] dppf 1,1 '-bis(diphenylphosphino)ferrocene

[0292] EDC 3-(Ethyliminomethyleamino)-N-N-dimethylpropan-l- amine

[0293] Et ethyl

[0294] EtOH Ethanol

[0295] EtOAc ethyl acetate

[0296] HATU 2-(7- Aza- IH-benzotri azole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluroni um hexafluorophosphate

[0297] HBTU 2-( 17 / -B enzotri azole- 1 -yl)- 1 , 1 ,3 , 3 -tetramethyluronium hexafluorophosphate

[0298] HC1 hydrochloric acid

[0299] HPLC high-performance liquid chromatography

[0300] z-Bu Isobutyl

[0301] z-Pr Isopropyl

[0302] K2HPO4 Dipotassium phosphate

[0303] LAH lithium aluminum hydride

[0304] LCMS liquid chromatography mass spectrometry Me Methyl

[0305] MeOH Methanol

[0306] MgSO4magnesium sulfate

[0307] NaCl sodium chloride

[0308] Na2CO3sodium carbonate

[0309] NaHCCh sodium bicarbonate

[0310] NaOH sodium hydroxide

[0311] Na2SO4sodium sulfate

[0312] NH4C1 ammonium chloride

[0313] NH4OAC ammonium acetate

[0314] NMM A-methylmorpholine

[0315] NCS N-Chlorosuccinimide

[0316] NBS A-Bromosuccinimide

[0317] NMP N-Methylpyrrolidone

[0318] Pd(OAc)2palladium(II) acetate

[0319] Pd(dppf)Cl2CH2C12[l,l'-Bis(diphenylphosphino)ferrocene]

[0320] dichloropalladium(II), complex with dichloromethane Pd(dba)2Bis(dibenzylideneacetone)palladium(0)

[0321] Ph Phenyl

[0322] PPh3Triphenylphosphine

[0323] Pr Propyl

[0324] RVC Reticulated vitreous carbon

[0325] ABu Zc / V-butyl

[0326] TEA or Et3N Trimethylamine

[0327] TFA trifluoroacetic acid

[0328] THF Tetrahydrofuran

[0329] TMSC1 Trimethyl silyl chloride

[0330] T3P 1-Propanephosphonic anhydride solution

[0331] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0332] 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.

[0333] 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).

[0334] 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 2, 6-di chi oro-3 -nitropyridine la.

[0335] Nucleophilic aromatic substitution of la 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 lb. Additional methods for this transformation include other variations of nucleophilic aromatic substitution using methods known to one skilled in the art.

[0336] Subsequent nitro reduction of lb 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 1c. 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.

[0337] Acylatation of 1c can be prepared from subsequent amide bond coupling between 1c 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,

[0338] 2-(7 -aza- 1 H-benzotriazol e- 1 -yl)- 1 , 1 ,3 , 3 -tetramethyluronium hexafluorophosphate, (benzotri azol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate and 2-(U / -benzotriazole-l-yl)-l,l,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, Id can be converted directly to a compound le in the neat corresponding acid with conventional heating or microwave heating. Alternatively, 1c can be converted directly le with the presence of the corresponding aldehyde with catalytic amount of acetic acid or at room temperature in a suitable solvent such as tetrahydrofuran.

[0339] Miyaura borylation of le 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 If. 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)).

[0340] Subsequent palladium-catalyzed coupling of If to a suitably substituted iodide or bromide or chloride 3f, can provide compounds of general formula (I). 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)).

[0341] Scheme 1

[0342]

[0343] ,

[0344] 85 °C

[0345] Alternatively, as described in Scheme 2, compounds of this invention can be prepared from aldol condensation of acetone with an apporpiately substitued N-alkyl 6-chloro-2-methyl-azabenzimidazole (as prepared from Scheme 1). Subsequent Miyaura borylation and Suzuki similar to that of le to If in Scheme 1, can provide intermediate 2d. Compounds of Formula (II) can be prepared by amide coupling of 2d with a suitably substituted acid similar to that for steps 3d to 3e for Scheme 3. Scheme 2

[0346]

[0347] Additionally, as shown in Scheme 3, compounds of this invention can be prepared by Stille cross-coupling of two prepared intermediates: iodopyridine 3f and stannane 3c.

[0348] Amide coupling of 3d 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 iodopyridine 3f. The amide bond formation can be obtained with a suitable amide coupling reagent such as 1-propanephosphonic anhydride solution,

[0349] 2-(7-aza- IH-benzotriazole-l -yl)- 1 , 1 ,3,3 -tetramethyluronium hexafluorophosphate, (benzotri azol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate and 2-(U / -benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate in a suitable solvent such as dimethylformamide or dichloromethane 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).

[0350] Intermediate 3c is prepared starting from 2,3-diamino-6-bromopyridine 1c outlined in Scheme 1. Treatment of 1c with cyanogenbromide furnished aminobenzimidazole 3a. Subsequent acylation with suitable reagent furnished acyl or carbamoyl 2-aminoazabenzimidazole 3b. Additional methods for this transformation include varients of amide formations using methods known to one skilled in the art for this type of coupling.

[0351] Subsequent palladitive stannylation can be prepared with hexamethylditin in the presence of tri-t-butylphosphine tetrafluoroborate salt and bis(dibenzylidineacetone) palladium (0) in dioxane to furnish stannae 3c. Subsequent Stille cross coupling of 3c with prepared iodopyridine 3f in the presence of tri-t-butylphosphine tetrafluorob orate salt and bis(dibenzylidineacetone) palladium (0) in dioxane prepared compounds of this invention. (See for example. Carlos Cordovilla, Camino Bartolome, Jesus Ma Martinez-Ilarduya, and Pablo Espinet, ACS Catalysis 2015 5 (5), 3040-3053). Scheme 3

[0352] >

[0353]

[0354]

[0355] DIEA, 1.5 eq

[0356] DCE, 80 °C 3f

[0357] 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 NH4OAC) and Solvent B (10% water, 90% MeOH, 10 mM NH4OAC) 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). 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).

[0358] Representative Chiral Purification Methods by SFC and Chiral Columns

[0359] Separation of Example 25 and 26

[0360] Preparative Chromatographic Conditions: Column: Chiralcel OJ-H, 30 mm x 250 mm, 5 pm particles; flow Conditions: 100 mL / min, Detector Wavelength: 220 nm.

[0361] Analytical Chromatographic Conditions: Chiral OJ, 4.6 mm x 100 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: MeOH with 0.1% DEA; flow Conditions: 2 mL / min, Detector Wavelength: 220 nm.

[0362] Example 26 (enantiomer 1): retention time = 4.1 min, >95% ee;

[0363] Example 25 (enantiomer 2): retention time = 8.2 min, >95% ee.

[0364] Analytical HPLC: Methods Employed in Characterization of Examples

[0365] 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 C182.1 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

[0366] 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

[0367] Method C: Sunfire C18, 3.5um x 3.0 xl50 mm, Solvent A: 95% water, 5% Acn, 0.05% TFA; Solvent B: 95% Acn, 5% water, 0.05% TFA; Gradient: 10-100% B over 12 minutes, then a 3 -minute hold at 100% B; Flow: 1 mL / min. Method D: Xbridge C18, 3.5um x 4.6 x 150 mm, Solvent A: 95% water, 5% Acn, 0.05% TFA; Solvent B: 95% ACN, 5% water, 0.05% TFA; Gradient: 0-100% B over 12 minutes, then a 3 -minute hold at 100% B; Flow: 1 mL / min.

[0368] Method E: Linear gradient of 0 to 100% B over 3 min; UV visualization at 220 nm;

[0369] Column: Ascentis Express C182.7pm, 2.1 mm x 50 mm; Flow rate: 1.1 mL / min;

[0370] Solvent A: 10 mM ammonium acetate, 95% water, 5% ACN; Solvent B: 10 mM ammonium acetate, 95% ACN, 5% water.

[0371] Method F: Linear gradient of 0 to 100% B over 3 min; UV visualization at 220 nm;

[0372] Column: Waters XBridge BEH C18 XP 2.5pm, 2.1 mm x 50 mm; Flow rate: 1.1 mL / min; Solvent A: 10 mM ammonium acetate, 95% water, 5% Acn; Solvent B: 10 mM ammonium acetate, 95% ACN, 5% water.

[0373] Method G: Linear gradient of 0 to 100% B over 3 min, with 0.50 min hold time at 100% B; UV visualization at 220 nm; Column: Waters Acquity BEH 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

[0374] Method H: 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.

[0375] Method I: 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.

[0376] Method J: Linear gradient of 5 to 95% 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. Method K: Linear gradient of 5 to 95% B over 2.3 min; UV visualization at 254 nm; Column: HALO C183.0 x 30 mm; Flow rate: 1.5 mL / min; Solvent A: 0.05% TF A, water, Solvent B: 0.05% TFA, ACN.

[0377] Method L: Linear gradient of 5 to 95% B over 1.2 min; UV visualization at 254 nm; Column: Shim-pack Scepter C183.0 x 30 mm; Flow rate: 1.5 mL / min; Solvent A: 0.05% TFA, water, Solvent B: 0.05% TFA, ACN.

[0378] 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 (d 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.

[0379] Intermediate

[0380]

[0381] A solution of 2,6-dichloro-3-nitro pyridine (50 g, 260 mmol) dissolved in ACN (3 L) was added to propan-2-amine (25 g, 420 mmol) and the reaction was stirred at rt for 16 h. The reaction mixture was concentrated and the residue was treated with water (500 mL), and then extracted with DCM (2 x 500 mL). The combined organic layers were washed with brine and then dried over anhydrous magnesium sulfate, filtered and concentrated and the residue was purified by column chromatography (0-100% EtOAc / pet. ether) to obtain the title compound. LC / MS m / z 216.1 (M+H)+.

[0382] Intermediate

[0383]

[0384] To a solution of 6-chloro-N-isopropyl-3-nitropyridin-2-amine (40 g, 190 mmol) dissolved in EtOH (1 L) and water (40 mL) was added ammonium chloride (140 g, 2.6 mol) and activated zinc (49 g, 740 mmol) in portions. The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was filtered through celite and rinsed with water. The filtrate was concentrated and the crude residue was purified by column chromatography (0-100% EtOAc / pet. ether) to obtain the title compound (30 g, 87%). LC / MS m / z 186.0 (M+H)+.

[0385] Intermediate 3 : N-(6-chloro-2-(isopropylamino)pyridin-3-yl)-3-hydroxy-3-methylbutanamide

[0386]

[0387] A mixture of 3 -hydroxy-3 -methylbutanoic acid (22 g, 190 mmol) and 6-chloro-N2-isopropylpyridine-2,3-diamine (32 g, 170 mmol) was dissolved in DMF (320 mL). Then HATU (98 g, 260 mmol) and N-ethyl-N-isopropylpropan-2-amine (36 mL, 210 mmol) were added. The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and then redisolved in DCM and washed with twice with 1.5 N HC1, and then washed with brine. The organic layer was separated and dried over Na2SC>4, filtered concentrated and the crude residue was purified by column chromatography (EtOAc / pet. ether 0-100%) to yield the title compound (30 g, 100 mmol, 60 % yield). LC / MS m / z 268.1 (M+H)+. Intermediate 4: l-(5-chloro-l-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropan-2-ol

[0388]

[0389] Para-toluenesulfonic acid (15 g, 79 mmol) was added to a solution of N-(6-chloro-2-(isopropylamino)pyridin-3-yl)-3-hydroxy-3-methylbutanamide (30 g, 110 mmol) in 2-propanol (500 mL) and the resulting solution was heated to 85 °C and stirred for 16 h. An additional charge of paratoluenesulfonic acid (15 g, 79 mmol) was added and the mixture was heated for an additional 6 h. The reaction mixture was concentrated, reconstituted in EtOAc / THF (9:1) and washed with water. The organic layer was separated, concentrated, and the residue was purified by silica gel column chromatography (EtOAc / pet. ether, 0-100%) to yield the title compound (20 g, 74 mmol, 71 % yield). LC / MS m / z 268.1 (M+H)+.

[0390] Intermediate 5 : l-(3-isopropyl-5-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2yl)-3H-

[0391]

[0392] A mixture of l-(5-chloro-l-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropan-2-ol (20 g, 75 mmol), potassium acetate (15 g, 150 mmol), Pd(dppf)C12 (2.4 g, 3.0 mmol), bispin (24 mg, 93 mmol) was dissolved in 1,4-dioxane (200 mL). The reaction vessel was evacuated and backfilled with nitrogen 3x then heated to 90 °C and stirred for 6 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (500 mL) and water (300 mL). The mixture was then filtered through celite and the layer were separated. The organic layer were dried over anhydrous Na2SC>4, filtered and concentrated. The residue purified by silica gel column chromatography (EtOAc / pet. ether, 10%) to yield the title compound which was used without further purification. Intermediate 6: l-(5-(2-amino-5-fluoropyridin-4-yl)-3-isopropyl-3H- imidazo[4,5-b]pyridin-2-yl)-2-methylpropan-2-ol

[0393]

[0394] A mixture of potassium carbonate (52 g, 380 mmol), 5-fluoro-4-iodopyridin-2-amine (34 g, 150 mmol), l-(3-isopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropan-2-ol (26 g, 72 mmol) in 1,4-di oxane (520 mL) was degassed and then Pd(dppf)C12 (2.4 g, 2.9 mmol) was added. The mixture stirred under nitrogen and heated at 90 °C for 6 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (500 mL) and water (300 mL). The mixture was then filtered through celite and the layer were separated. The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated. The residue purified by silica gel column chromatography (EtOAc / pet. ether,20-100%) to yield the title compound. (10 g, 30 mmol, 41 % yield) as a light brown solid. LC / MS m / z 344.1 (M+H)+.

[0395] Intermediate 7: methyl 2-bromo-5-(difluoromethoxy)benzoate

[0396]

[0397] To a flask containing methyl 2-bromo-5-hydroxybenzoate (5.0 g, 21 mmol), sodium 2-chloro-2,2-difluoroacetate (8.3 g, 54.1 mmol), and CS2CO3 (8.5 g, 26 mmol) was added DMF (44 mL) and water (4.4 mL). The reaction mixture was heated at 100 °C for 3 h, then cooled to rt. The reaction was diluted with water and extracted with EtOAc. The organic extracts were washed with 1 : 1 sat’d aq NaCl and water, dried over MgSCh, filtered and evaporated to dryness in vacuo. The crude product was dissolved in CHCI3 and loaded onto a 120 g silica column pre-conditioned with 5% EtOAc in hexanes. The product was eluted with EtOAc in hexanes to provide title compound (2.5 g, 41% yield). 'HNMR (400 MHz, CDCI3) 87.66 (d, J= 8.8 Hz, 1H), 7.58 (d, J= 3.1 Hz, 1H), 7.14 (dd, J= 8.7, 3.0 Hz, 1H), 6.53 (t, J= 72.8 Hz, 1H), 3.95 (s, 3H). Intermediate 8: 5-(difluoromethoxy)-2-(methylsulfonyl)benzoic acid

[0398]

[0399] To a solution of intermediate 7 (2.5 g, 8.9 mmol) in anhydrous DMSO (18 mL) was added L-proline (0.41 g, 3.5 mmol), NaOH (0.142 g, 3.54 mmol), copper (I) iodide (0.34 g, 1.8 mmol) and sodium methyl sulfinate (1.8 g, 18 mmol). The reaction was heated to 130 °C under nitrogen for 24 h. The reaction mixture was poured into 150 mL of water and 1 N aq NaOH was added to adjust the pH to 11-12. Celite was added to the solution and the celite was filtered and washed with EtOAc. The aqueous layer was acidified with cone. HC1 to pH 1-2 and extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered and evaporated to dryness in vacuo. 5-(Difluoromethoxy)-2-(methylsulfonyl)benzoic acid was obtained by trituration of the solids with DCM to furnish title compound (0.98 g, 37% yield).1H NMR (400 MHz, DMSO-d6) 8 14.01 (s, 1H), 8.07 - 8.02 (m, 1H), 7.54 - 7.52 (m, 1H), 7.51 (s, 1H), 7.48 (t, J = 73 Hz, 1H), 3.37 (s, 3H).

[0400] Intermediate 9: methyl 2-bromo-5-(2,2-difluoroethoxy)benzoate

[0401]

[0402] To a suspension of methyl 2-bromo-5-hydroxybenzoate (4.9 g, 21 mmol) and CS2CO3 (10 g, 32 mmol) in DMF (42 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (3.4 mL, 26 mmol). The reaction mixture was stirred at rt for 36 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 1 : 1 sat’d aq NaCl and water, dried over MgSO4, filtered and evaporated to dryness to provide title compound (5.4 g, 87% yield). 'HNMR (400 MHz, CDCI3) 67.58 (d, J= 8.8 Hz, 1H), 7.36 (d, J= 3.1 Hz, 1H), 6.94 (dd, J= 8.8, 3.1 Hz, 1H), 6.06 (tt, J= 54.8, 4.2 Hz, 1H), 4.20 (td, J= 12.9, 4.1 Hz, 2H), 3.94 (s, 3H). Intermediate 10:

[0403]

[0404] By application of the same method used for Intermediate 8, methyl 2-bromo-5-(2,2-difluoroethoxy)benzoate (5.46 g, 18.5 mmol) was converted to title compound (2.8 g, 49% yield). ' H NMR (400 MHz, CD3OD) 88.04 (d, J=9.0 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.28 (dd, J=8.9, 2.8 Hz, 1H), 6.22 (dt, J=54.7, 3.7 Hz, 1H), 4.40 (td, J= 13.6, 3.7 Hz, 2H), 3.34 (s, 3H).

[0405] Intermediate

[0406]

[0407] To a solution of 2,6-dibromo-3-nitropyridine (1.5 g, 5.3 mmol) dissolved in ethanol (27 mL) was added isopropylamine (2.3 mL, 27 mmol) and stirred in water bath at rt for 2 h. The reaction was concetrated and then purified over silica gel chromatography (0-100% EtOAc / Hexanes) to furnish title compound (1.2 g, 4.4 mmol, 83 % yield). LCMS m / z 259.7, 261.8 (M+H, M+2+H)+. 'H NMR (400 MHz, CDCI3) 6 8.22 (d, . / =8,6 Hz, 2H), 6.76 (d, J=8.5 Hz, 1H), 4.51 (dquin, J=7.5, 6.5 Hz, 1H), 1.34 (d, J=6.5 Hz, 6H)

[0408] Intermediate 12:

[0409]

[0410] To a solution of Intermediate 11 (1.1 g, 4.3 mmol) dissolved in ethanol (8.7 mL) was added iron (1.2 g, 22 mmol) and 12M HC1 (0.072 mL, 0.87 mmol) and heated to 70 °C for 1 h. LCMS shows mostly SM. Allowed to stand overnight. Added additional HC1 (0.072 mL, 0.87 mmol) and reheated to 70 °C. After 2 h the reaction was complete. The reaction was filteted through celite and then partitioned between EtOAc / phosphate buffer. The organic phase was separated, concentrated, and purified over silica (0-20% MeOH in DCM) to furnish title compound (0.94 g, 4.1 mmol, 94 % yield) which was used without further manipulation. LCMS m / z 229.9, 231.8 (M+H, M+2+H)+.

[0411] Intermediate 13: 5-bromo-3-isopropyl-3H-imidazo [4,5-b]pyridin-2-amme , TFA salt

[0412]

[0413] To a solution of Intermediate 12 (0.94 g, 4.1 mmol) dissolved in ethanol (12 mL) was added dropwise a solution of cyanogen bromide (0.39 g, 3.7 mmol) dissolved in DCM (1.2 mL). The reaction was stirred overnight. LCMS: shows conversion to product. The reaction was concetrated, redissolved in MeOH / water, and loaded onto column directly and purified via reverse phase (5-95% ACN in 0.1% TFA water). Collected desired product 5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-amine, TFA salt (1.0 g, 2.8 mmol, 70 % yield). LCMS m / z 245.9, 256.9 (M+H, M+2+H)+.

[0414] Intermediate

[0415]

[0416] To a solution of intermediate 13 (1.0 g, 4.1 mmol) and pyridine (2.3 mL) dissolved in DCM (11 mL) and cooled with ice bath and was added acetyl chloride (0.32 mL, 4.5 mmol) dropwise. At 1 h - LCMS shows product formation with minimal over acylation. Water was added and the reaction was stirred at rt for 1 h. The reaction was parititoned between water and EtOAc. The organic layer was washed with water, and then brine. The organic layer was separated and then dried over Na2SO4, filtered and concetrated and purified over silica gel from 0-100% EtOAc / Hex to furnish N-(5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)acetamide (410 mg, 1.4 mmol, 34 % yield): LCMS m / z 296.8, 298.9 (M+H, M+2+H)+. 'HNMR (400 MHz, CDC13) 67.51 - 7.35 (m, 1H), 7.31 (d, . / =8,2 Hz, 1H), 5.20 - 4.93 (m, 1H), 2.29 (s, 3H), 1.69 (d, . / =7.0 Hz, 6H). Intermediate 15 : N-(3-isopropyl-5-( trimethylstannyl)-3H-imidazo [ 4, 5-b ]pyridin-2-yl)acetamide

[0417]

[0418] To a solution of intermediate 14 (0.40 g, 1.3 mmol) and 1,1, 1,2, 2, 2-hexamethyldistannane (0.44 g, 1.3 mmol) dissolved in 1,4-dioxane (13 mL) was added Pd(PPh3)4 (78 mg, 0.067 mmol) and heated to 100 °C overnight. The reaction mixture was concetrated and purified over silica gel (0-100% EtOAc / Hexanes) to furnish N-(3-isopropyl-5-(trimethylstannyl)-3H-imidazo[4,5-b]pyridin-2-yl)acetamide (0.40 g, 1.1 mmol, 78 % yield). LCMS m / z 382.7 (M+H)+.

[0419] Intermediate 16: tert-butyl (5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

[0420]

[0421] To a solution of intermediate 13 (0.50 g, 1.5 mmol) dissolved in THF (15 mL) was added EtiN (0.62 mL, 4.5 mmol) followed by boc-anhydride (0.38 mL, 1.6 mmol) and stirred overnight. The reaction mixture was partitioned between 1.5 M pH 7.4 phosphate buffer and EtOAc. The organic phase was separated, dried over Na2SC>4, filtered, and concetrated to furnish tert-butyl (5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.64 g, 1.8 mmol). LC / MS m / z 298.8, 300.7 (M+H, M+2+H)+.

[0422] Intermediate 17: tert-butyl (3-isopropyl-5-(trimethylstannyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

[0423]

[0424] To a solution of intermediate 16 (0.64 g, 1.8 mmol) dissolved in 1-4 dioxane (18 mL) was added hexamethylditin (0.37 mL, 1.8 mmol) and Pd(PhsP)4 (0.10 g, 0.090 mmol) and stirred overnight, at 100 °C. The reaction mixture was concetrated and then purified with a gradient 0-100% Hex / EtOAc to furnish tert-butyl (3-isopropyl-5-(trimethylstannyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (400 mg, 0.91 mmol, 51 % yield). LCMS m / z 440 (M+H)+.

[0425] Intermediate 18 : 6-bromo-N-(2, 2-difluoroethyl)-3-nitro-pyridin-2-amine

[0426]

[0427] To a solution of 2,6-dibromo-3-nitro-pyridine (5.0 g, 18 mmol, 1 equiv) in ethanol (15 mL) was added a solution of 2,2-difluoroethanamine (3.1 g, 39 mmol, 2.2 equiv) in ethanol (15 mL) at 0 °C. The resulting solution was stirred for overnight at rt. The resulting solution was quenched with water (50 mL) and extracted with ethyl acetate (2x60 mL). The combined organic layers were washed with brine (2x40 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure to give title compound (5.0 g, 99%) as a yellow oil. LCMS m / z: 282, 284 (M+H, M+2+H)+.

[0428] Intermediate 19: 6-bromo-N2-(2,2-difluoroethyl)pyridine-2,3-diamme

[0429]

[0430] To a solution of intermediate 18 (5.0 g, 18 mmol, 1 equiv) and NH4CI (9.4 g, 180 mmol, 10 equiv) in ethanol (25 mL) and water (20 mL) was added Fe (4.9 g, 89 mmol, 5 equiv). The resulting mixture was stirred at 70 °C for 3 h under a nitrogen atmosphere. The solid was removed by filtration through a celite pad. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (3x200 mL). The combined organic layers were washed with brine (4x50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give title compound (4.4 g, 98%) as a black solid. LCMS m / z: 252, 254 (M+H, M+2+H)+.

[0431] Intermediate 20 : 5-bromo-3-(2, 2-difluoroethyl)-2-methyl-imidazo[ 4, 5-b ]pyridine

[0432]

[0433] To a solution of intermediate 19 (0.05 g, 2.0 mmol, 1 equiv) in acetic acid (10 mL) was added 1,1,1 -tri ethoxy ethane (640 mg, 4.0 mmol, 2 equiv). The resulting mixture was stirred at 110 °C for 36 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse flash via C18 silica with water (0.05% TFA) / MeCN (2: 1). The solvent was removed under vacuum and then the residue was treated with sodium carbonate solution to pH~10 and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure to give title compound (190 mg, 34%) as an off-white solid. LCMS m / z: 276, 278 (M+H, M+2+H)+.

[0434] Intermediate 21 : l-[5-bromo-3-(2,2-difluoroethyl)imidazo[4,5-b]pyridin-2-yl]-2-methyl-propan-2-ol

[0435]

[0436] To a solution of intermediate 20 (190 mg, 0.69 mmol, 1 equiv) in THF (4.0 mL) was added dropwise 2 M LDA in THF (0.7 mL, 1.4 mmol, 2 equiv) at -78 °C under a nitrogen atmosphere and stirred for 30 min. Acetone (400 mg, 7 mmol, 10 equiv) was added the resulting mixture and stirred at -78 °C for 0.5 h. The resulting mixture was allowed to warm up to rt. The resulting mixture was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with ethyl acetate to give title compound (160 mg, 69%) as an off-white solid. LCMS m / z: 334, 336 (M+H, M+2+H)+.

[0437] Intermediate 22: (3-(2,2-difluoroethyl)-2-(2-hydroxy-2-methylpropyl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid

[0438]

[0439] To a solution of intermediate 21 (120 mg, 0.36 mmol, 1 equiv) and bispin (110 mg, 0.43 mmol, 1.2 equiv) in 1,4-dioxane (4.0 mL) were added KO Ac (110 mg, 1.1 mmol, 3equiv) and Pd(dppf)C12 (29 mg, 0.040 mmol, 0.1 equiv). The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The resulting mixture was used directly for the next step without further purification. LCMS m / z: 300 (M+H)+.

[0440] Intermediate 23: 5-chloro-2-(methylsulfonyl)benzaldehyde

[0441]

[0442] 5-Chloro-2-fluorobenzaldehyde (2.0 g, 13 mmol) and sodium methanesulfmate (1.4 g, 13 mmol) were dissolved in dry DMSO (20 mL) and then heated at 130 °C for 45 min. The reaction mixture was allowed to cool to rt then diluted with EtOAc and washed with water 2x, brine lx, and dried over sodium sulfate. The solvent was removed in vacuo. The product was used in subsequent reaciton without further purifications.!H NMR (500 MHz, CDC13) 6 10.76 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.78 (dd, J=8.5, 2.2 Hz, 1H), 3.28 (s, 3H).

[0443] Intermediate 24: 5-chloro-2-(methylsulfonyl)benzoic acid

[0444]

[0445] To a rapidly stirred mixture of intermediate 23 (2.8 g, 12 mmol) and sulfamic acid (1.8 g, 19 mmol) in THF (30 mL) and water (30 mL) at 0 °C was added sodium chlorite (2.1 g, 19 mmol) solution in water (5 mL) dropwise. The reaction mixture was stirred at 0 °C for 10 min and then allowed to warm to rt and stirred for 1 h. The mixture was partitioned between EtOAc and water. The aq. layer was back-extracted with with EtOAc 2x. The combined organic layers were washed with brine, dried with sodium sulfate, filtered, concentrated onto celite and purified by reverse phase chromatography to deliver 5-chloro-2-(methylsulfonyl)benzoic acid (1.3 g, 5.7 mmol, 45 % yield). 'H NMR (500 MHz, DMSO-d6) 8 14.06 (s, 1H), 8.01 (d, J=9.1 Hz, 1H), 7.87 - 7.83 (m, 2H), 3.40 (s, 3H).

[0446] Intermediate 25 : 5-methoxy-2-(methylsulfonyl)benzoic acid

[0447]

[0448] Methyl 2-bromo-5-methoxybenzoate (6.6 mL, 41 mmol) in DMSO (100 mL) was added L-proline (1.9 g, 16 mmol), NaOH (0.65 g, 16 mmol), sodium methanesulfmate (8.3 g, 82 mmol) and copper(I) iodide (1.6 g, 8.2 mmol) at rt. The mixture was stirred in a sealed tube The reaction mixture was poured into ice cold water (500 mL), then filtered through celite and the collected filtrate was extracted with EtOAc (3 x300 mL).

[0449] Remaining aqueous layer was acidified with cone HC1 to pH 2, extracted with EtOAc (6 x300 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product as a brown liquid. The crude material was taken into 30 mL of water and stirred for 10 min. Solid precipitates formed and were filtered, and dried ON to obtain 5-methoxy-2-(methylsulfonyl)benzoic acid (7.0 g, 29 mmol, 70 % yield). 'HNMR (400MHZ, DMSO-d6) 6 13.75 (s, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.36 - 7.09 (m, 2H), 3.90 (s, 3H), 3.32 (s, 3H).

[0450] Intermediate 26: N-(5-fluoro-4-iodopyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide

[0451]

[0452] To a mixture of Intermediate 25 (1.9 g, 8.4 mmol) and l-(fluoro(pyrrolidin-l-yl)methylene)pyrrolidin-l-ium hexafluorophosphate(V) (2.9 g, 9.2 mmol) suspended in dry DCM (28 mL), was added pyridine (0.8 mL, 9 mmol) and stirred at rt for 1 hr. 5-Fluoro-4-iodopyridin-2-amine (2.0 g, 8.4 mmol) was added followed by addition of DIEA (2.2 mL, 13 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was allowed to cool to rt, then diluted with EtOAc and washed with brine. The organic layer was concentrated residue purified by colum chromatography EtOAc / hexanes gradient (0-100%) to deliver the title compound (3.0 g, 6.73 mmol, 80 % yield). 'HNMR (500 MHz, DMSO-d6) 6 11.34 (s, 1H), 8.66 (d, J=4.7 Hz, 1H), 8.34 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.27 - 7.22 (m, 2H), 3.91 (s, 3H), 3.31 (s, 3H). LC / MS m / z 451.1 (M+H)+

[0453] Intermediate

[0454]

[0455] To a suspension of 4-bromopyridin-2-amine hydrochloride (1.0 g, 4.8 mmol) dissolved in DMF (5 mL) was added Intermediate 25 (1.2 g, 5.0 mmol), TEA (2.0 mL, 14 mmol) and T3P (4.3 mL, 7.2 mmol). The mixture was stirred at R overnight. The reaction was diluted with water and extracted with EtOAc (3x). The combined organics were dried over Na2SC>4 and concentrated. The crude produce was purified by column chromatography (EtOAc / hexanes 0-100%) to deliver the title compound (1.6 g, 89 % yield). LC / MS m / z 386.7 (M+2+H)+

[0456] Intermediate 28 : (5-fluoro-2-(5-methoxy-2-(methylsulfonyl)benzamido)pyridin-4-yl)boronic acid

[0457]

[0458] A mixture of Pd(dppf)Ch.CH2C12 (0.073 g, 0.089 mmol), potassium acetate (0.52 g, 5.3 mmol), bis(pinacolato)diboron (0.68 g, 2.7 mmol) and intermediate 26 (0.80 g, 1.8 mmol) was dissolved in DMSO (3.6 mL). The reaction mixture was degassed and backfilled with N2 (3x) and heated at 85 °C overnight. The reaction mixture was diluted with EtOAc, neutralized with ammonium chloride solution and washed with 10% LiCl solution, and the organic layer was concentrated in vacuo. The residue was purified by column chromatograph (EtOAc / hexanes 0-100%) to recover the unreacted starting material. The column was then eluted with a gradient of DCM / MeOH (0-20%) to deliver the title compound (0.59 g, 1.6 mmol, 90 % yield).XH NMR (500 MHz, CDCI3) 59.56 (s, 1H), 8.52 - 8.20 (m, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.14 - 7.08 (m, 1H), 7.05 (dd, J=8.8, 1.9 Hz, 1H), 3.89 (s, 3H), 3.31 (s, 3H). LC / MS m / z 369.0 (M+H)+

[0459] Intermediate 29:

[0460]

[0461] To a solution of 3-fluoro-5-methoxybenzoic acid (1.25 g, 7.35 mmol) dissolved in DMF (10 mL) was added NBS (2.62 g, 14.7 mmol). The reaction mixture was stirred at rt for 45 min. IM NaOH (14.7 mL, 14.7 mmol) was added, and the reaction mixture was stirred at rt for 3 days. The reaction mixture was quenched with 5% sodium bisulfite, then acidified with cone. HC1, extracted with EtOAc (2x10 mL), washed with water and brine, dried over Na2SO4, and concentrated to give 2-bromo-3-fluoro-5-methoxybenzoic acid as a white solid, which was used directly without purification.1H NMR (400 MHz, CDCI3) 87.39 (d, J=2.5 Hz, 1H), 6.91 (dd, J=11.0, 2.5 Hz, 1H), 3.84 (s, 3H). LC / MS m / z 248.9 (M+H)+, 250.9 (M+2+H)+.

[0462] Intermediate 31 : methyl 5-bromo-2-(methylsulfonyl)benzoate

[0463]

[0464] To a solution of methyl 5-bromo-2-(methylthio)benzoate (720 mg, 2.76 mmol) dissolved in methanol (25 mL) at ice bath temp was added a solution of oxone(R), monopersulfate compound (1.3 g, 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.XH NMR (500 MHz, CDCI3) 8 8.01 (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).

[0465] Intermediate 32: 5-bromo-2-(methylsulfonyl)benzoic acid

[0466]

[0467] To a solution of intermediate 31 (1.51 g, 5.15 mmol) dissolved 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 (Na2SO4) filt and concentrated to give the title compound (1.33 g, 4.77 mmol, 93 % yield) as a white solid. 'HNMR (500 MHz, DMSO-d6) 6 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).

[0468] Intermediate 33: 2-bromo-5-[2-(dimethylamino)ethoxy]benzoate

[0469]

[0470] To a solution of 2-(dimethylamino)ethanol (550 mg, 6.5 mmol, 1.5 equiv), methyl 2-bromo-4-hydroxybenzoate (1.0 g, 4.3 mmol, 1 equiv) andPPhs (1.7 g, 6.5 mmol, 1.5 equiv) dissolved in THF (20 mL) was added dropwise DEAD (1.3 g, 6.5 mmol, 1.50 equiv). The resulting mixture was stirred for 2 h at rt under a nitrogen atmosphere. The resulting solution was quenched with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate, decanted, and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (1:9) to give methyl (1.0 g, 77 %) as a yellow oil. LCMS m / z: 302, 304 (M+H, M+2+H)+.

[0471] Intermediate 34: methyl 5-[2-(dimethylamino)ethoxy]-2-ethylsulfonyl-benzoate

[0472]

[0473] To a solution of methyl intermediate 33 (1.0 g, 3.3 mmol, 1 equiv) and ethylsulfmyloxysodium (380 mg, 3.3 mmol, 1 equiv) dissolved in DMSO (15 mL) was added (CuOTf^ CeHe complex (330 mg, 0.66 mmol, 0.2 equiv). The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The residue was purified by reverse flash chromatography on Cl 8 silica with water (0.05% TFA) / MeCN (1:2) to give the title compound (500 mg, 47 %) as a yellow solid. LCMS m / z: 316 (M+H)+.

[0474] Intermediate 35: lithium 4-(2-(dimethylamino)ethoxy)-2-(ethylsulfonyl)benzoate

[0475]

[0476] To a solution of intermediate 34 (480 mg, 1.5 mmol, 1 equiv) disslved in THF (10 mL) and water (2 mL) was added LiOH H2O (130 mg, 3 mmol, 2 equiv). The resulting mixture was stirred for 4 h under a nitrogen atmosphere. The resulting solution was concentrated under reduced pressure to give the title compound (350 mg, 76 %) as a yellow solid. LCMS m / z: 302 (M+H)+. Intermediate 36: 4-[2-(dimethylamino)ethoxy]-2-ethylsulfonyl-N-(5-fluoro-4-iodo-2-pyridyl) benzamide

[0477]

[0478] To a solution of intermediate 35 (250 mg, 0.83 mmol, 1 equiv) and 5-fluoro-4-iodo-pyridin-2-amine (240 mg, 1.0 mmol, 1.2 equiv) dissolved in pyridine (10 mL) was added POCI3 (130 mg, 0.83 mmol, 1 equiv). The resulting mixture was stirred for 2 h at rt under a nitrogen atmosphere. The resulting solution was quenched with water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with DCM / methanol (10: 1) to give the title compound (300 mg, 69 %) as a yellow solid.

[0479] LCMS (ESI, m / z): 522 [M+H]+.

[0480] Intermediate 37 : N- 4-bromo-2-[ ( 2, 2-difluoro-l-methyl-ethyl )amino ]-6-fluoro-phenyl J-3-hydr oxy-3 -methyl-butanamide

[0481]

[0482] To a solution of 2,6-dibromo-3-nitro-pyridine (1.0 g, 3.6 mmol, 1 equiv) dissolved in ethanol (5 mL) was added a solution of l,l-difluoropropan-2-aminium chloride (1.8 g, 14 mmol, 4 equiv) and TEA (1.8 g, 18 mmol, 5 equiv) in ethanol (8.0 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at rt overnight under nitrogen atmosphere. The resulting solution was quenched with water (50 mL) and extracted with ethyl acetate (2x80 mL). The combined organic layers were washed with brine (2x60 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (10: 1) to give the title compound (890 mg, 75%) as a yellow solid. LCMS (ESI, m / z): 296 and 298 [M+H]+. Intermediate

[0483]

[0484] To a solution of intermediate 37 (800 mg, 2.6 mmol, 1 equiv) and NH4CI (1.6 g, 26 mmol, 10 equiv) dissolved in ethanol (20 mL) and water (5 mL) was added Fe (710 mg, 13 mmol, 5 equiv). The reaction mixture was stirred at 70 °C for 3 h under a nitrogen atmosphere. The resulting solid was removed by filtration through a celite pad. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1:2) to afford the title compound (480 mg, 66%) as a black solid. LCMS m / z: 266 and 268 (M+H)+.

[0485] Intermediate 39 : 5-bromo-3-(2, 2-difluoro-l-methyl-ethyl)-2-methyl-imidazo[ 4, 5-b] pyridine

[0486]

[0487] To a solution of intermediate 38 (480 mg, 1.8 mmol, 1 equiv) and 1,1,1-triethoxyethane (590 mg, 3.6 mmol, 2 equiv) dissolved in ethanol (5.0 mL) was added p-TSA (470 mg, 2.7 mmol, 1.5 equiv). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting solution was diluted with saturated aqueous sodium bicarbonate (40 mL) and extracted with ethyl acetate (3x50 mL). The organic layers were washed with brine (2x40 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1 :2) to afford the title compounde (400 mg, 76%) as an off-white solid. LCMS m / z: 290, 292 (M+H, M+2+H)+.

[0488] Intermediate 40 : l-[5-bromo-3-(2, 2-difluoro-l-methyl-ethyl)imidazo[ 4, 5-b ]pyridin-2-yl / -2 -me thyl-propan-2-ol

[0489]

[0490] To a solution of intermediate 39 (400 mg, 1.4 mmol, 1 equiv) dissolved in THF (5 mL) was added 2M LDA in THF (1.4 mL, 2.8 mmol, 2 equiv) at -78 °C. The mixture was stirred at -78 °C for 1 h under a nitrogen atmosphere. Then acetone (800 mg, 14 mmol, 10 equiv) was added the resulting mixture. The resulting mixture was stirred at -78 °C for 1 h and allowed to warm to rt under a nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was quenched with saturated ammonium chloride aqueous (40 mL) and extracted with ethyl acetate (3x50 mL). The organic layers were washed with brine (2x50 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1 : 1) to afford the title compound (180 mg, 37%) as an off-white solid. LCMS m / z: 348, 350 (M+H, M+2+H)+.

[0491] Intermediate 41 : [3-(2,2-difluoro-l-methyl-ethyl)-2-(2-hydroxy-2-methyl-propyl)imidazo[ 4, 5-b ]pyridin-5-yl boronic acid

[0492]

[0493] To a solution of intermediate 40 (90 mg, 0.26 mmol, 1 equiv) and bispin (130 mg, 0.52 mmol, 2 equiv) dissolved in 1,4-dioxane (4 mL) was added KOAc (76 mg, 0.78 mmol, 3 equiv) and Pd(dppf)C12 (21 mg, 0.030 mmol, 0.1 equiv). The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The resulting was directly purified by reverse flash chromatography via C18 silica with water (0.05% TFA) / MeCN (1 : 1) to afford the title compound (60 mg, 74%) as an off-white solid. LCMS m / z: 314 (M+H)+.

[0494] Intermediate 42: methyl 2-bromo-5-[2-(dimethylamino)ethoxy]benzoate

[0495]

[0496] To a solution of 2-(dimethylamino)ethanol (1.1 g, 13 mmol, 1.5 equiv), methyl 2-bromo-5-hydroxy-benzoate (2.0 g, 8.7 mmol, 1 equiv) and DEAD (2.6 g, 13 mmol, 1.5 equiv) dissolved in THF (20 mL) was added PPI13 (3.4 g, 13 mmol, 1.0 equiv). The resulting mixture was stirred for 2 h at rt under a nitrogen atmosphere. The resulting solution was diluted with water (500 mL) and extracted with ethyl acetate (3x500 mL). The combined organic extracts were washed with brine (2x500 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (1:9) to give the title compound (1.5 g, 57 %) as a yellow oil. LC / MS m / z 302 and 304 (M+H, M+2+H)+.

[0497] Intermediate 43: Methyl 5-[2-(dimethylamino)ethoxy]-2-ethylsulfonyl-benzoate SO2Et

[0498] ' - O l CO2Me

[0499] To a solution of intermediate 42 (1.5 g, 5.0 mmol, 1 equiv) and ethylsulfmyloxysodium (576 mg, 5.0 mmol, 1 equiv) dissolved in DMSO (15 mL) was added (CuOTf^ CeHe complex (500 mg, 1.0 mmol, 0.2 equiv). The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The resulting mixture was directly purified by reverse flash chromatography on C18 silica with water (0.05% TFA) / MeCN (1 :2) to give title compound (700 mg, 44 %) as a yellow solid. LC / MS m / z: 316 (M+H)+.

[0500] Intermediate 44: lithium 5-(2-(dimethylamino)ethoxy)-2-(ethylsulfonyl)benzoate

[0501]

[0502] To a solution of methyl intermediate 43 (680 mg, 2.2 mmol, 1 equiv) dissolved in THF (20 mL) and water (5 mL) was added LiOH H2O (180 mg, 4.3 mmol, 2 equiv). The resulting mixture was stirred for 4 h under a nitrogen atmosphere. The resulting solution was concentrated under reduced pressure to give title compound (500 mg, 77 %) as a yellow solid. LCMS m / z: 302 (M+H)+.

[0503] Intermediate 45 : 5-[2-(dimethylamino)ethoxy]-2-ethylsulfonyl-N-(5-fluoro-4-iodo-2-pyridyl) benzamide

[0504]

[0505] To a solution of intermediate 44 (500 mg, 1.7 mmol, 1 equiv) and 5-fluoro-4-iodo-pyridin-2-amine (470 mg, 2.0 mmol, 1.2 equiv) in pyridine (20 mL) was added POCI3 (254 mg, 1.7 mmol, 1 equiv). The resulting mixture was stirred for 2 h at rt under a nitrogen atmosphere. The resulting solution was quenched with water (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic extracts were washed with brine (2x100 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with DCM / methanol (10: 1) to give title compound (500 mg, 57 %) as a yellow solid. LC / MS m / z: 522 (M+H)+.

[0506] Intermediate 46: methyl 5-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-chlorobenzoate

[0507]

[0508] To a vessel containing methyl 2-chloro-5-iodobenzoate (136 mg, 0.460 mmol), l,3-dioxoisoindolin-2-yl 3-((tert-butoxycarbonyl)amino)-3-methylbutanoate (200 mg, 0.552 mmol), Nickel(II) chloride hexahydrate (44 mg, 0.18 mmol), and 22'-bipyridine (29 mg, 0.18 mmol) was added DMF (35 mL), which was stirred and sonicated until all material disolved into a hogenous solution. Then silver nitrate (39 mg, 0.23 mmol) was added, and the reaction was placed in electrosyn using +Mg / graphite- electrodes with 2.5 F / mmol @ 12 mA. Upon completion of the current, the mixture was diluted with EtOAc and filtered through celite. The solution was washed with water and brine, then concentrated. The residue was purified by silica gel chromatography to furnish title compound (103 mg, 0.301 mmol, 65.5 % yield). LCMS m / z: 363.9 (M+Na)+.

[0509] Intermediate 47 : 5-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-chlorobenzoic acid

[0510]

[0511] To a solution of intermediate 46 (0.103 g, 0.301 mmol) dissolved in THF (2.3 mL) was added LiOH (0.025 g, 0.60 mmol) in water (0.75 mL) and the reaction mixture was stirred overnight. The mixture was extracted from 1 N HC1 with EtOAc. The organic layer was concentrated and the residue used without manipulation as title compound (0.099 g, 0.30 mmol, 100 % yield). LCMS m / z: 350.1 (M+Na)+.

[0512] Intermediate 48: tert-butyl (l-(4-chloro-3-((5-fhioro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[ 4, 5-b ]pyridin-5-yl)pyridin-2-yl)carbamoyl)phenyl)-2-methylpropan-2-y I) carbamate

[0513]

[0514] To a solution of intermediate 6 (70 mg, 0.20 mmol) and intermediate 47 (100 mg, 0.305 mmol) dissolved in pyridine (1.1 mL) was added TCFH (86 mg, 0.31 mmol) and heated to 100 °C for 2 h. The reaction mixture was diluted with MeOH and concentrated The residue was purified by silica gel chromatography to furnish title compound (68 mg, 0.10 mmol, 51 % yield). LCMS m / z: 653.2 (M+H)+.

[0515] Intermediate 49: methyl 3-(3-bromo-4-chlorophenyl)cyclobutane-l-carboxylate

[0516]

[0517] A slurry of (3-bromo-4-chlorophenyl)boronic acid (0.659 g, 2.80 mmol), methyl 3 -(2-((4-methoxyphenyl)sulfonyl)hydrazineylidene)cyclobutane-l -carboxylate (0.583 g, 1.87 mmol), CS2CO3 (2.13 g, 6.53 mmol) in 1,4-dioxane (9.3 mL) was heated to 110 °C overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was concentrated and the residue purified by silica gel chromatography to furnish title compound (224 mg, 0.738 mmol, 39.5 % yield, mixture of diastereomers). 'H NMR (500 MHz, CDC13) 67.50 - 7.45 (m, 1H), 7.43 - 7.35 (m, 2H), 7.14 - 7.06 (m, 1H), 6.86 -6.80 (m, 1H), 3.81 (s, 2H), 3.71 (s, 2H), 3.47 - 3.35 (m, 1H), 3.19 - 3.08 (m, 1H), 2.74 -2.67 (m, 1H), 2.65 - 2.57 (m, 1H), 2.45 - 2.32 (m, 2H).

[0518] Intermediate 50:

[0519]

[0520] A solution of intermediate 49 (224 mg, 0.738 mmol) dissoved in THF (3.0 mL) was cooled to -78 °C and treated with methylmagnesium bromide (0.74 mL, 2.2 mmol). The resulting solution was allwoed to slowly warm to rt overnight. The mixture was extracted from aq. NH4CI with EtOAc. The organic layer was filtered through a silica gel plug and concentrated to furnish title compound which was used without further manipulation (224 mg, 0.738 mmol, 100 % yield).

[0521] Intermediate 51: 2-chloro-5-(3-(2-hydroxypropan-2-yl)cyclobutyl)benzoic acid

[0522]

[0523] A slurry of intermediate 50 (224 mg, 0.738 mmol), palladium(II) acetate (17 mg, 0.074 mmol), l,3-bis(diphenylphosphino)propane (30 mg, 0.074 mmol), TEA (0.31 mL, 2.2 mmol) in DMF (6.6 mL) / water (0.7 mL) was blanketed under CO (100 psi) and heated to 100 °C overnight. The mixture was cooled to rt and extracted from 1 N HC1 with EtOAc. The organic layer was concentrated and the residue used without further manipulation as title compound (198 mg, 0.738 mmol, 100 % yield).

[0524] Intermediate 52:

[0525]

[0526] To a solution of methyl 5-bromo-2-fluoro-4-hydroxybenzoate (1.0 g, 4.0 mmol) dissolved in THF (12 mL) was added propan-2-ol (0.34 mlL 4.42mmol) and triphenylphosphine (1.6 g, 6.0 mmol), and then cooled to 0 °C. Then DEAD (2.4 mL, 6.0 mmol) was added dropwise to the reaction mixture and it was stirred and allowed to warm to rt overnight. The reaction mixture was concetrated and purified by flash chromatorgray to furnish a miture of triphhenyl phophine and title compound (1.6 g, 3.3 mmol, 63 % yield). 'H NMR (500 MHz, CDC13) 88.17 (d, . / =7.9 Hz, 1H), 6.66 (d, J=12.8 Hz, 1H), 4.62 (spt, J=6.1 Hz, 1H), 3.92 (s, 3H), 1.45 (d, . / =6,0 Hz, 6H).

[0527] Intermediate 53: methyl 5-bromo-4-isopropoxy-2-(methylthio)benzoate

[0528] ""

[0529]

[0530] To a solution of intermediate 52 (2.0 g, 5.7 mmol) dissolved in DMF (17 mL) was added sodium methanethiolate (0.60 g, 8.6 mmol) and heated to 60 °C for 16 h. The reaction was acidified with IN HC1 (8.5 mL) and then diluted with water. The resulting solid was filtered and then dried under vacuum to furnish title compound (1.6 g, 5.0 mmol, 88 % yield).

[0531] Intermediate 54: methyl 5-bromo-4-isopropoxy-2-(methylsulfonyl)benzoate

[0532]

[0533] To a solution of intermediate 53 (0.75 g, 2.4 mmol) dissolved in DCM (24 mL) was added mCPBA (1.7 g, 6.2 mmol) and stirred 16 h. The reaction mixture was treated with Na2S2O3 solution and the organic layer was separated and dried over sodium sulfate, filtered, concetrated, and the purified by flash chromatography to furnish title compound (730 mg, 2.1 mmol, 89 % yield). LCMS m / z: 351.1, 353.1 (M+H, M+2H)+. Intermediate 55: methyl 4-isopropoxy-2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate

[0534]

[0535] To a solution of intermediate 54 (0.73 g, 2.1 mmol) dissolved in 1,4-dioxane (21 mL) was added bispin (1.1 g, 4.2 mmol), tricyclohexylphosphine tetrafluoroborate (0.038 g, 0.104 mmol), bis(dibenzylideneacetone)palladium(0) (0.060 g, 0.10 mmol), and potassium acetate (0.61 g, 6.2 mmol) and then the mixture was heated to 100 °C under nitrogen atomostphere for 16 h. The reaction mixture was partitioned between EtOAc and phoshate buffer and the organic phase was separated, concetrated to furnish title compound (0.82 g, 2.1 mmol, quant, yield). LCMS m / z: 317.1 (M-bpin+H)+.

[0536] Intermediate 56: methyl 4-isopropoxy-5-(l-methyl-lH-l,2,4-triazol-3-yl)-2- (methylsulfonyl)benzoate

[0537]

[0538] To a solution of intermediate 55 (830 mg, 2.1 mmol) dissolved in 1,4-dioxane (17 mL) was added 3-bromo-l-methyl-lH-l,2,4-triazole (510 mg, 3.11 mmol), water (4.2 mL), potassium carbonate (860 mg, 6.2 mmol), and PdC12(dppf)-CH2C12adduct (170 mg, 0.21 mmol) and then heated ot 100 °C for 1 h. The reaction mixture was diluted with EtOAc, and then the organic phase was separated, dried over sodium sulfate, filtered and concentrated to furnish title compound (840.7 mg, 2.1 mmol, quant yield) which was used without further purification in the next reaction. LCMS m / z: 354.3 (M+H)+. Intermediate 57 : 4-isopropoxy-5-( 1 -methyl-lH-1, 2, 4-triazol-3-yl)-2-(methylsulfonyl)benzoic acid

[0539]

[0540] To a solution of intermediate 56 (0.71 g, 2.0 mmol) dissolved in THF (8 mL) was added lithium hydroxide monohydrate (0.092 g, 2.2 mmol) and water (2 mL) and stirred 16 h. The reaction was concetrated and neutralized with IN HC1. The resultant solid was filtered and dried under high vacuum to furnish title compound (0.68 g, 2.0 mmol, 100 % yield). LCMS m / z: 340.1 (M+H)+.

[0541] Intermediate 58:

[0542]

[0543] To a solution of tert-butyl (5)-4-methyl- 1,2, 3 -oxathiazolidine-3 -carboxylate 2,2-dioxide (0.28 g, 1.2 mmol) and methyl 2-chl oro-5 -hydroxybenzoate (0.20 g, 1.1 mmol) dissolved in DMF (8.1 mL) was added CS2CO3 (1.0 g, 3.2 mmol) and stirred 16 h at 80 °C. The reaction mixture was partitioned between EtOAc / water and then treated with IN HC1. The organic phase was separated, and dried over sodium sulfate, filtered and concetrated to furnish title compound (330 mg, 0.96 mmol, 90 % yield). LCMS m / z: 244.3 (M-Boc+H)+.

[0544] Intermediate 59: methyl (S)-5-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)-2-chlorobenzoate

[0545]

[0546] To a solution intermediate 58 (0.10 g, 0.29 mmol) dissolved DMF (0.51 mL) was added iodomethane (0.13 mL, 2.0 mmol) and cooled to 0 °C. Then was added silver oxide (0.10 g, 0.44 mmol) and the reaction was stirred 16h while warming to rt. The reaction mixture was diluted with DCM and then filtered and purified by flash chromatography to furnish title compound (60 mg, 0.17 mmol, 58 % yield). LCMS m / z: 358.1 (M+H)+.

[0547] Intermediate 60: (S)-5-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)-2-chlorobenzoic acid

[0548]

[0549] To a solution of intermediate 59 (0.066 g, 0.18 mmol) dissolved in THF (1.5 mL) was added water (0.37 mL) and lithium hydroxide monohydrate (0.015 g, 0.37 mmol) and stirred 16 h. The reaction was treated with 2 eq IN HC1 (~0.4 mL) and then extracted into EtOAc. The organic phase was separated, dried over sodium sulfate, filtered and concetrated to dryness to afford title compound (72 mg, 0.18 mmol, quant, yield). LCMS m / z: 366.3 (M+Na)+.

[0550] Intermediate 61: tert-butyl (S)-(l-(4-chloro-3-((5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[ 4, 5-b ]pyridin-5-yl)pyridin-2-

[0551]

[0552] To a solution of intermediate 6 (0.020 g, 0.058 mmol) and intermediate 60 (0.029 g, 0.087 mmol) dissolved in DCM (0.58 mL) was added pyridine (0.047 mL, 0.58 mmol) and cooled to 0 °C. A 10 % solution of POCh (0.11 ml, 0.12 mmol) in DCM was added and the reaction stirred for 5 mm before treatment with MeOH. The mixture was concentrated to furnish title compound (0.038 g, 0.058 mmol, quant, yield) LCMS m / z: 656.1 (M+H)+.

[0553] Intermediate 62: (S)-5-(2-aminopropoxy)-2-chloro-N-(5-fluoro-4-(2-(2-hydroxy-2-

[0554]

[0555] To a vessel containing intermediate 61 (0.038 g, 0.058 mmol) was added DCM (0.46 mL) and TFA (0.12 mL) and stirred for 2 h. The reaction mixture was concetrated to furnish title compound (0.032 g, 0.058 mmol, quant, yield). LCMS m / z: 555.3 (M+H)

[0556] Intermediate 63: tert-butyl 2-(4-chloro-3-(methoxycarbonyl)phenyl)morpholine-4-carboxylate

[0557]

[0558] To a solution of nickel(II) chloride hexahydrate (0.16 g, 0.68 mmol) and 2,2'-bipyridine (0.11 g, 0.68 mmol) stirred in DMA (8.4 mL) for 30 min was added methyl 2-chl oro-5 -iodobenzoate (0.50 g, 1.7 mmol), 4-(tert-butyl) 2-(l,3-dioxoisoindolin-2-yl) morpholine-2,4-dicarboxylate (0.83 g, 2.3 mmol), and then silver nitrate (0.14 g, 0.84 mmol) and submitted to 10 mA constant current, 4 F / mol with Mg working electrode and RVC cathode using an IKA Electrasyn2.0. The reaction was partitioned between EtOAc and diluted IN NaOH. The organic layer was separated, washed with brine, and dried over sodium sulfate. The organic layer was filtered, concetrated, and purified by flash chromatography to furnish title compound (200 mg, 0.56 mmol, 33 % yield).!H NMR (500 MHz, CDC13) 88.09 (s, 0.5H), 8.01 (d, . / =7.8 Hz, 0.5H), 7.88 (d, J=1.5 Hz, 0.5H), 7.60 (d, . / =7,6 Hz, 0.5H), 7.50 - 7.43 (m, 1H), 4.56 - 4.39 (m, 1H), 4.30 - 4.02 (m, 2H), 4.02 - 3.85 (m, 4H), 3.79 - 3.61 (m, 1H), 3.08 (br s, 1H), 2.95 - 2.66 (m, 1H), 1.51 (d, J=l.l Hz, 9H).

[0559] Intermediate 64: methyl (R)-2-chloro-5-(3-(hydroxymethyl)pyrrolidin-l-yl)benzoate

[0560]

[0561] To a solution of (A)-pyrrolidin-3-ylmethanol (0.20 g, 2.0 mmol), methyl 2-chloro-5 -iodobenzoate (0.88 g, 3.0 mmol), L-proline (0.091 g, 0.79 mmol), and copper(I) iodide (0.075 g, 0.40 mmol) dissolved in DMSO (30 mL) was heated to 85 °C for 16 h. The reaction mixture was partitioned between EtOAc and water, the organic phase was washed with sat ammonium chlroide, brine, and then separated, concetrated, and purified by flash chromatography to furnish title compound (240 mg, 0.89 mmol, 45 % yield). LCMS m / z: 269.9 (M+H)+.

[0562] Intermediate 65: (Z)-3-bromo-4-chloro-N-hydroxybenzimidoyl chloride

[0563]

[0564] To a stirred solution of 3-bromo-4-chlorobenzaldehyde (5.0 g, 23 mmol) dissolved in DCM (100 mL) was added hydroxylamine hydrochloride (2.4 g, 34 mmol) and potassium carbonate (2.4 g, 17 mmol) and stirred rt for 16 h. Afterwards, was added DMF (0.709 mL) and NCS (4.6 g, 34 mmol) stirred rt for 3h. The reaction mixture was treated with water, extracted with DCM, washed with brine, dried over sodium sulphate and concentrated to give a yellow oil. Used directly in next step.

[0565] Intermediate 66: (3-(3-bromo-4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)methanol

[0566]

[0567] Intermediate 65 (3.0 g, 11 mmol) was dissolved in DCM (100 mL) and to this solution was addded prop-2-en-l-ol (1.3 g, 22 mmol) followed by TEA (1 mL). the reaction mixture was stirred at rt. The reaction mixture was concentrated and purified by flash chromatography to furnish title compound. (3.1 g, 11 mmol, 98 % yield).XH NMR (500 MHz, CDC13) 87.91 (d, J=1.9 Hz, 1H), 7.57 (dd, J=8.4, 2.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 4.91 (dddd, J=10.9, 7.8, 4.5, 3.1 Hz, 1H), 3.91 (br d, J=12.3 Hz, 1H), 3.73 - 3.66 (m, 1H), 3.38 - 3.24 (m, 2H) 291.7.

[0568] Intermediate 67: 2-chloro-5-(5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)benzoic acid

[0569]

[0570] To a mixture of palladium acetate (0.39 g, 1.7 mmol), xantphos (0.20 g, 0.34 mmol), and intermediate 66 (1.0 g, 3.4 mmol) in a 40 mL pressure vial with septa was sealed and evaluated and backfilled with nitrogen (3 times). Then, a degassed solution of TEA (0.96 mL, 6.9 mmol) di solved in toluene was added and the mixture heated to 100 °C. After 5 min, the reaction was cooled to rt and treated dropwise with a degassed solution 2,4,6-trichlorophenyl formate (2.328 g, 10.33 mmol) in toluene (9 mL) over 1 h. The complete mixture was heated back to 100 °C. After 3 h, the reaction was cooled to rt and concentrated and purified by flash chromatography to give the required intermediate which was dissolved in THF (20 mL) and treated with tithium hydroxide monhydrate (0.43 g, 10 mmol) in water (3 mL) and then heated to 60 °C for 16 h. The reaction mixture was concentrated. The remaining aqueous layer was diluted with water, extracted with EtOAc, and organics discarded. The remaining aqueous layer was acidified with 1.0 N HC1 solution, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to giver a clear, colorless oil. (520 mg, 2.0 mmol, 59%) 255.9 which was separated by SFC. 2-chloro-5-(5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (Peak 1 by chiral SFC) (180 mg, 0.70 mmol, 21 % yield)

[0571] Analytical SFC was used to determine the %ee. Conditions: Column: Chiralpak IC, 4.6 mm x 100 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: MeOH with 10 mM AA; Temperature: 25 °C; Isocratic elution at 25 %B over 10.00 min; Flow: 2.000 mL / min; Detection: UV (220 nm) and UV (254 nm) Injection 1 results: Purity: 100 %ee; Retention Time: 1.81 min.; Waters Acquity BEH Cl 8 1.7um 2.1 x 50mm column, 1-minute gradient; Solvent A: lOmM NFUOAc in CH3CN: H2O (5:95); Solvent B: lOmM NH4OAc in CH3CN: H2O (95:5). Purity: 100% [Method B]

[0572] 'HNMR: (500 MHz, DMSO-d6) 8 13.60 (br s, 1H), 7.99 (d, J=2.1 Hz, 1H), 7.78 (dd, J=8.5, 2.2 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 4.98 (br t, J=5.5 Hz, 1H), 4.78 - 4.71 (m, 1H), 3.56 - 3.47 (m, 2H), 3.46 - 3.38 (m, 1H), 3.21 (dd, J=17.1, 7.6 Hz, 1H)

[0573] 2-chloro-5-(5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (Peak 2 by chiral SFC)

[0574] Analytical SFC was used to determine the %ee. Conditions: Column: Chiralpak IC, 4.6 mm x 100 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: MeOH with 10 mM AA; Temperature: 25 °C; Isocratic elution at 25 %B over 10.00 min; Flow: 2.000 mL / min; Detection: UV (220 nm) and UV (254 nm). Injection 1 results: Purity: 100 %ee; Retention Time: 3.55 min.

[0575] Intermediate 68 and 69: 3-(l,l-difluoropropan-2-yl)-2-(2,2,2-trifluoroethyl)-5-

[0576]

[0577] Prepared from in a similar maner to intermediate 17 from the appropriate starting materials. Preparative Chromatographic Conditions: Column: Whelk-Ol (R,R), 30 mm x 250 mm; flow rate: 90 mL / min; mobile phase: A: Carbon dioxide; B: MeOH / ACN (1:1); detector wavelength: 220 nm. Analytical Chromatographic Conditions: Column: Whelk-01 (R,R), 4.6 mm x 100 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA with 0.1 % DEA, isocratic 8%. Intermediate 68: Peak 1 RT = 0.982 min. Intermediate 69: Peak 2 RT = 1.152 min.

[0578] Intermedi ate 70 : 5-bromo-N -(2, 2-difluoroethyl) -3 -isopropyl-3H-imidazo[ 4, 5-b ]pyridin-2-amine

[0579]

[0580] To a solution of l,l-difluoro-2-isothiocyanatoethane (0.63 g, 5.2 mmol) dissolved in dry MeOH (31 mL) was added intermediate 12 (1.19 g, 5.15 mmol) and stirred at rt for 2 h at rt. The reaction mixture was concetrated, and then the residue was used directly 1-(6-bromo-2-(isopropylamino)pyridin-3-yl)-3-(2,2-difluoroethyl)thiourea (1.82 g, 5.15 mmol, 100 % yield). LCMS m / z: 352.9, 354.9 (M+H, M+2+H)+. The residue was dissolved in DCM (52 mL) and was added diisopropylcarbodiimide (0.96 mL, 6.2 mmol) and stirred 16 hr. The reaction was concentrated and purified by silica gel chromatography to furnish 5-bromo-N-(2,2-difluoroethyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-amine (0.50 g, 1.6 mmol, 30 % yield). LCMS m / z: 318.9, 320.8 (M+H, M+2+H)+.

[0581] Example 1. 4-[2-(dimethylamino)ethoxy]-2-ethylsulfonyl-N-[5-fluoro-4-[2-(2-hydroxy-2-methyl-propyl)-3-isopropyl-imidazo[ 4, 5-b ]pyridin-5-yl ]-2-pyridyl benzamide

[0582]

[0583] To a solution of intermediate 36 (80 mg, 0.15 mmol, 1 equiv) and intermediate 5 (51 mg, 0.18 mmol, 1.2 equiv) dissolved in 1,4-di oxane (5 mL) and water (0.5 mL) was added K2CO3 (63 mg, 0.46 mmol, 3 equiv) and Pd(dppf)C12 (12 mg, 0.015 mmol, 0.10 equiv). The resulting mixture was stirred at 60 °C for 3 h under a nitrogen atmosphere. The resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (1:9) and then further purified by Prep-HPLC (Column: Xselect CSH Prep Fluoro-Phenyl Column, 30*150 mm, 5pm; Mobile Phase A: water(0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min) to give 4-[2-(dimethylamino)ethoxy]-2-ethylsulfonyl-A-[5-fluoro-4-[2-(2-hydroxy-2-methyl-propyl)-3-isopropyl-imidazo[4,5-b]pyridin-5-yl]-2-pyridyl]benzamide (38 mg, 38 %) as an off-white solid. LC / MS m / z: 627.0 (M+H)+, RT = I.09 min (HALO 90A C18 Column 3.0*30 mm, 2.0 pm; Mobile Phase A: water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5000 mL / min; Gradient: 5 % B to 90 % B in 2.30 min; 254 nm).1H NMR (400 MHz, DMSO-d6) 8 II.36 (s, 1H), 9.88 (s, 1H), 8.97 (d, J = 6.0 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.4, 2.4 Hz, 1H), 5.16-5.09 (m, 1H), 4.51-4.48 (m, 2H), 3.61-3.56 (m, 4H), 3.25 (s, 2H), 2.92-2.90 (m, 6H), 1.78 (d, J = 6.4 Hz, 6H), 1.31 (s, 6H), 1.20 (t, J = 7.2 Hz, 3H).

[0584] Example 2. 5-[ 2 -(dime thylamino) ethoxy ]-2-ethylsulfonyl-N-[5-fluoro-4-[ 2-(2-hydroxy-2-

[0585]

[0586] To a solution of Intermediate 45 (80 mg, 0.15 mmol, 1 equiv) and intermediate 5 (42 mg, 0.15 mmol, 1 equiv) in 1,4-dioxane (5 mL) and water (0.5 mL) were added Pd(dppf)C12 (12 mg, 0.015 mmol, 0.1 equiv) and K2CO3 (63 mg, 0.46 mmol, 3 equiv). The resulting mixture was stirred at 60 °C for 3 h under a nitrogen atmosphere. The resulting solution was quenched with water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine (2x20 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by reverse flash chromatography on C18 silica with water (0.05% TFA) / MeCN (1 :2) and then futher purified by Prep-HPLC (Column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 24% B in 10 min; Wave Length: 254nm / 220 nm; RTl(min): 9.42) to give title compound (28.5 mg, 29 %) as an off-white solid.

[0587] LCMS m / z: 627 (M+H)+RT = 0.524 min, method: HALO 90A C18 Column 3.0*30 mm, 2.0 pm; Mobile Phase A: water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5000 mL / min; Gradient: 5 % B to 100 % B in 1.20 min; 254 nm. 1HNMR (400 MHz, DMSO-d6) 8 11.30 (s, 1H), 8.99 (d, J = 6.0 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.8, 2.0 Hz, 1H), 5.07-4.95 (m, 1H), 4.85-4.84 (m, 1H), 4.27 (t, J = 5.6 Hz, 2H), 3.53-3.43 (m, 2H), 3.08 (s, 2H), 2.80-2.77 (m, 2H), 2.31 (s, 6H), 1.74 (d, J = 6.4 Hz, 6H), 1.28 (s, 6H), 1.16 (t, J = 7.2 Hz, 3H).

[0588] Example 3 : 5-(2-amino-2-methylpropyl)-2-chloro-N-(5-fluoro-4-(2-(2-hydroxy-2-

[0589]

[0590] A solution of intermediate 48 (68 mg, 0.10 mmol) in DCM (1 mL) was treated with TFA (0.40 mL, 5.2 mmol). After 2 h, the mixture was diluted with toluene and concentrated. Half of the residue was used without further manipulation to furnish title compound (30 mg, 0.054 mmol). 'HNMR (500 MHz, DMSO-d6) 6 11.11 (s, 1H), 9.06 -8.87 (m, 1H), 8.51 (br s, 1H), 8.02 - 7.84 (m, 4H), 7.59 - 7.32 (m, 3H), 5.18 - 4.91 (m, 1H), 3.57 - 3.33 (m, 1H), 3.17 (s, 2H), 2.98 - 2.81 (m, 2H), 1.74 (br d, . / =5,2 Hz, 6H), 1.35 (br dd, J=7.6, 3.2 Hz, 6H), 1.23 (s, 6H). LCMS m / z 553.2 (M+H)+Method A, RT = 1.32 min.

[0591] Example 4: 2-chloro-5-(2-(dimethylamino)-2-methylpropyl)-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)benzamide

[0592]

[0593] A solution of example 3 (30 mg, 0.054 mmol) dissoved in MeOH (1.1 mL) was treated with formaldehyde soln (37% aq. 0.040 mL, 0.54 mmol) followed by sodium triacetoxyborohydride (35 mg, 0.16 mmol). The reaction was stirred at rt overnight. The mixture was extracted from brine with EtOAc. The organic layer was concentrated and the residue purified by prep rev phase HPLC to furnish title compound (5.5 mg, 8.9 pmol, 16 % yield). 'HNMR (500 MHz, DMSO-d6) 88.93 (br d, J=5.8 Hz, 1H), 8.46 (s, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.45 - 7.25 (m, 3H), 5.08 - 4.93 (m, 1H), 3.55 - 3.42 (m, 1H), 3.06 (s, 2H), 2.69 (s, 2H), 2.20 (s, 6H), 1.72 (d, J=6.7 Hz, 6H), 1.26 (s, 6H), 0.92 (s, 6H). LCMS m / z: 581.2 (M+H)+Method A, RT = 1.32 min.

[0594] Example 5 : 2-chloro-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[ 4, 5-b ]pyridin-5-yl)pyridin-2-yl) -5-(3-( 2-hydroxypropan-2-yl)cyclobutyl)benzamide

[0595]

[0596] To a solution of intermediate 6 (51 mg, 0.15 mmol) and intermediate 51 (60. mg, 0.22 mmol, mixutre of cis-trans isomers) dissolved in pyridine (0.8 mL) was added TCFH (63 mg, 0.22 mmol) and heated to 100 °C for 2 h. The reaction was diluted with MeOH and concentrated. The residue was purified by preparative reverse phase HPLC to furnish title compound (6.1 mg, 9.8 pmol, 6.6 % yield, 1steluting isomer). 'HNMR (500 MHz, DMSO-d6) 68.76 - 8.63 (m, 1H), 8.23 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.54 (br d, J=8.3 Hz, 1H), 7.28 - 7.05 (m, 4H), 4.83 - 4.67 (m, 1H), 3.19 (br d, J=2.1 Hz, 2H), 2.82 (s, 2H), 2.21 - 2.14 (m, 2H), 2.12 - 2.05 (m, 1H), 1.83 - 1.72 (m, 2H), 1.48 (br d, J=6.6 Hz, 6H), 1.02 (s, 6H), 0.80 (s, 6H). LCMS m / z: 594.1 (M+H)+Method A, RT = 1.72 min.

[0597] Exampl e 6 : N-(5 -fluor o-4-( 2-( 2-hydroxy-2-methylpropyl) -3-isopropyl-3H-imidazo[ 4, 5-b ]pyridin-5-yl)pyridin-2-yl)-4-isopropoxy-5-( I -methyl- 1H-1, 2, 4-triazol-3-yl)-2-(methylsulfonyl)benzamide

[0598]

[0599] To a solution of intermediate 6 (0.060 g, 0.18 mmol) and intermediate 57 (0.071 g, 0.21 mmol) dissolved in DCM (1.7 mlL) was added pyridine (0.14 ml, 1.8 mmol) and cooled to 0 °C. A 10% solution of POC13 (0.33 ml, 0.35 mmol) in DCM was added and the reaction stirred for 5 min. The reaction was treated with phosphate buffer, and then extracted with EtOAc. The organic layer was separated, concetrated, and purified by reverse phase chromatography to furnish title compound (14 mg, 0.022 mmol, 12 % yield).XH NMR (500 MHz, DMSO-d6) 5 11.35 (br s, 1H), 9.06 - 8.91 (m, 1H), 8.58 (s, 1H), 8.49 (br s, 1H), 8.17 - 8.07 (m, 2H), 7.81 (br d, J=7.6 Hz, 1H), 7.65 (s, 1H), 5.10 -4.93 (m, 1H), 4.88 - 4.74 (m, 1H), 3.95 (s, 3H), 3.46 (s, 3H), 3.07 (br s, 2H), 1.74 (br d, J=6.6 Hz, 6H), 1.40 - 1.32 (m, 6H), 1.27 (s, 6H). LCMS m / z: 665.0 (M+H)+Method A, RT = 1.37 min.

[0600] Example 7 : (S)-2-chloro-5-(2-(dimethylamino)propoxy)-N-(5-fhioro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)benzamide

[0601]

[0602] To a solution of intermediate 62 (32. mg, 0.058 mmol) dissolved in DMF (520 pL) was added sodium bicarbonate (14.62 mg, 0.174 mmol), acetic acid (58 pL), paraformaldehyde (345 mg, 1.2 mmol), and then sodium triacetoxyborohydride (120 mg, 0.58 mmol) and stirred 16 h. The reaction mixture was purified via reverse phase chromatography to furnish title compound (1.3 mg, 2.2 pmol, 3.8 % yield):XH NMR (500 MHz, DMSO-de) 88.73 (br d, . / =4,2 Hz, 1H), 8.26 (d, . / =2,4 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.57 (d, . / =7,3 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 6.98 (d, J=3.0 Hz, 1H), 6.84 (dd, J=8.9, 3.0 Hz, 1H), 4.79 (dt, J=13.5, 6.5 Hz, 1H), 3.84 (dd, J=10.0, 5.9 Hz, 1H), 3.66 (dd, J=10.0, 6.1 Hz, 1H), 2.85 (s, 2H), 2.73 - 2.61 (m, 1H), 2.00 (s, 6H), 1.51 (d, . / =6,7 Hz, 6H), 1.05 (s, 6H), 0.80 (d, J=6.6 Hz, 3H). LCMS m / z: 582.9 (M+H)+Method A, RT = 1.37 min.

[0603] Example 8: N-(4-(2-acetamido-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)-5-

[0604]

[0605] To a solution of intermediate 15 (0.035 g, 0.092 mmol) and intermediate 26 (0.054 g, 0.11 mmol) dissolved in 1,4-dioxane (1 mL) was added bis(dibenzylideneacetone)palladium(0) (5 mg, 9. pmol) and tri-tert-butylphosphonium tetrafluorob orate (3 mg, 9 pmol). The reaction vessel capped and under an atmosphere of nitrogen and then heated to 100 °C for 16 h. The reaction mixture was then concetrated and purified via reverse phase chromatography to furnish title compound (20 mg, 0.034 mmol, 37 % yeild). ' H NMR (500 MHz, DMSO-d6) 6 11.42 (s, 1H), 9.02 (br d, J=6.0 Hz, 1H), 8.52 (br s, 1H), 8.13 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.86 (br d, J=7.9 Hz, 1H), 7.60 (s, 1H), 7.53 (dd, J=8.6, 2.3 Hz, 1H), 7.67 - 7.31 (m, 1H), 4.69 - 4.52 (m, 1H), 2.20 (s, 3H), 1.72 (br d, J=6.6 Hz, 6H), LCMS m / z: 577.0 (M+H)+Method A, RT = 1.47 min

[0606] The following Examples in Table 3 were made by using the similar procedures as shown above in Intermediates 1-67 and Examples 1-8 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.

[0607] Table 3

[0608] HPLC Method, RT (min) Ex LCMS (M+H)+

[0609] Structure & Name

[0610] #1H NMR (500 MHz, DMSO-d6- ws, unless otherwise indicated) Method A 1.23 min

[0611]

[0612] N-(4-(2-(2 -hydroxy -2-methylpropyl)- J=4.6 Hz, 1H), 7.26 - 7.22 (m, 3-isopropyl-3H-imidazo[4,5-b]pyridin- 2H), 5.16 - 5.02 (m, 1H), 3.90 (s, 5-yl)pyri din-2 -yl)-5-methoxy-2- 3H), 3.65 (br s, 3H), 3.22 (br s, (methylsulfonyl)benzamide 2H), 1.78 (br d, J=6.6 Hz, 6H),

[0613] 1.28 (s, 6H) Method A 1.37 min

[0614]

[0615] 5-(difluoromethoxy)-N-(4-(2-(2- (dd, J=8.6, 2.3 Hz, 1H), 7.58-7.29 hydroxy-2-methylpropyl)-3-isopropyl- (t, 1H), 5.07 (quin, J=6.4 Hz, 1H), H-imidazo[4,5-b]pyridin-5-yl)pyridin- 3.63 - 3.56 (s, 1H), 3.18 (s, 2H), 2-yl)-2-(methylsulfonyl)benzamide 1.77 (d, J=6.6 Hz, 6H), 1.28 (s,

[0616] 6H)WS

[0617]

[0618] 6.5 Hz, 1H), 3.44 (s, 1H), 3.07 (s, N-(5-fluoro-4-(2-(2-hydroxy-2- 2H), 1.74 (d, J=6.8 Hz, 6H), 1.27 methylpropyl)-3-isopropyl-3H- (s, 6H) WS

[0619] imidazo[4,5-b]pyridin-5-yl)pyridin-2- yl)-2-(methylsulfonyl)-5- (trifluoromethyl)benzamide

[0620]

[0621] 1H), 7.41 - 7.14 (t, 1H), 5.05 - 2-(difluoromethyl)-N-(5-fluoro-4-(2- 4.97 (m, 1H), 3.07 (s, 2H), 2.43 (2-hydroxy-2-methylpropyl)-3- (s, 3H), 1.73 (br d, J=6.6 Hz, 6H), isopropyl-3H-imidazo[4,5-b]pyridin-5- 1.27 (s, 6H)

[0622] yl)pyridin-2-yl)-5-methylbenzamide

[0623]

[0624] d, J=7.0 Hz, 2H), 4.98 - 4.89 (m, N-(5-fluoro-4-(3-isopropyl-2-(2,2,2- 1H), 4.33 (q, J=10.8 Hz, 2H), trifluoroethyl)-3H-imidazo[4,5- 2.35 (s, 3H), 2.31 (s, 3H), 1.74 (br b]pyridin-5-yl)pyridin-2-yl)-2,5- d, J=6.6 Hz, 6H)

[0625] dimethylbenzamide

[0626]

[0627] J=8.2 Hz, 1H), 7.86 (br d, J=7.8 N-(4-(2-(2-cyano-2-methylpropyl)-3- Hz, 1H), 5.03 - 4.85 (m, 1H), 3.96 isopropyl-3H-imidazo[4,5-b]pyridin-5- (s, 3H), 3.40 (s, 2H), 3.35 - 3.32 yl)-5-fluoropyridin-2-yl)-5-(l-methyl- (s, 3H), 1.76 (br d, J=6.6 Hz, 6H), lH-l,2,4-triazol-3-yl)-2- 1.55 (s, 6H) (methylsulfonyl)benzamide

[0628]

[0629] 1H), 7.97 (d, J=8.0 Hz, 1H), 7.06 N-(4-(3 -(1,1 -difluoropropan-2-yl)-2- - 6.72 (m, 1H), 5.36 - 5.17 (m, (2,2,2-trifluoroethyl)-3H-imidazo[4,5- 1H), 4.44 - 4.31 (m, 2H), 3.97 (s, b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 2H), 1.84 (br d, J=6.8 Hz, 3H). 5-(l-methyl-lH-l,2,4-triazol-3-yl)-2- WS (methylsulfonyl)benzamide

[0630]

[0631] 7.97 (br d, J=8.1 Hz, 1H), 7.13 - N-(4-(3 -(1,1 -difluoropropan-2-yl)-2- 6.73 (m, 1H), 5.35 - 5.20 (m, 1H), (2,2,2-trifluoroethyl)-3H-imidazo[4,5- 4.49 . 4.32 (m, 2H), 3.99 (s, 3H), b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 1.85 (br d, J=6.6 Hz, 3H). WS. 5-(l-methyl-lH-l,2,4-triazol-3-yl)-2- (methylsulfonyl)benzamide

[0632]

[0633] 2-chloro-N-(5-fluoro-4-(2-(2-hydroxy- 2-methylpropyl)-3-isopropyl-3H- imidazo[4,5-b]pyridin-5-yl)pyridin-2- yl)-4-(l-methylazetidin-3- yl)benzamide

[0634]

[0635] (dimethylamino)propyl)-N-(5-fluoro-4- 3.15 (m, 1H), 3.11 (s, 2H), 2.87 - (2-(2-hydroxy-2-methylpropyl)-3- 2.73 (m, 7H), 1.75 (d, J=6.7 Hz, isopropyl-3H-imidazo[4,5-b]pyridin-5- 6H), 1.28 (s, 6H), 1.12 (br d, yl)pyridin-2-yl)benzamide J=6.6 Hz, 3H)

[0636] 3

[0637]

[0638] (, . z, ), . - . (m, 2-chloro-N-(5-fluoro-4-(2-(2-hydroxy- 1H), 4.80 - 4.73 (m, 1H), 3.29 - 2-methylpropyl)-3-isopropyl-3H- 3.15 (m, 3H), 2.89 (s, 1H), 2.74 - imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2.71 (m, 1H), 1.77 (br d, J=6.7 yl)-5-(5-(hydroxymethyl)-4,5- Hz, 6H), 1.29 (s, 6H) dihydroisoxazol-3-yl)benzamide

[0639]

[0640] s,

[0641] 3H), 3.08 (s, 2H), 2.27 (s, 3H), -(2,5-dimethyl-2H-l,2,3-triazol-4-yl)- 1.74 (br d, J=6.6 Hz, 6H), 1.27 (s, N-(5-fluoro-4-(2-(2-hydroxy-2- 6H)WS

[0642] methylpropyl)-3-isopropyl-3H- imidazo[4,5-b]pyridin-5-yl)pyridin-2- yl)-4-hydroxy-2- (methylsulfonyl)benzamide

[0643]

[0644] ,

[0645] N-(5-fluoro-4-(2-(2-hydroxy-2- 4.10 (s, 3H), 3.08 (s, 2H), 1.74 (br methylpropyl)-3-isopropyl-3H- d, J=6.7 Hz, 6H), 1.28 (s, 6H) WS imidazo[4,5-b]pyridin-5-yl)pyridin-2- yl)-4-methoxy-5-(2-methyl-2H-l,2,3- triazol-4-yl)-2- (methylsulfonyl)benzamide

[0646]

[0647] N-(5-fluoro-4-(2-(2-hydroxy-2- 4.95 (m, 1H), 4.00 (s, 3H), 3.42 methylpropyl)-3-isopropyl-3H- (s, 3H), 3.08 (br s, 2H), 2.78 (s, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 3H), 1.75 (br d, J=6.5 Hz, 6H), yl)-4-methyl-5-(l -methyl-lH- 1,2,4- 1.28 (s, 6H)

[0648] triazol-3-yl)-2- (methylsulfonyl)benzamide

[0649]

[0650] 4.95 (m, 1H), 4.35 - 4.22 (m, 1H), (S)-2-chloro-N-(5-fluoro-4-(2-(2- 4.20 - 4.05 (m, 1H), 3.12 (s, 2H), hydroxy-2-methylpropyl)-3-isopropyl- 2.72 - 2.59 (m, 3H), 1.75 (d, H-imidazo[4,5-b]pyridin-5-yl)pyridin- J=6.7 Hz, 6H), 1.34 - 1.30 (m, 2-yl)-5-(2-(methylamino)propoxy) 3H), 1.28 (s, 6H)

[0651] benzamide

[0652]

[0653] . z, ), . , ., -chloro-5-(2-(dimethylamino)ethoxy)- 2.9 Hz, 1H), 5.02 (dt, J=13.4, 6.7 N-(5-fluoro-4-(2-(2-hydroxy-2- Hz, 1H), 4.11 (t, J=5.6 Hz, 2H), methylpropyl)-3-isopropyl-3H- 3.08 (s, 2H), 2.63 (t, J=5.6 Hz, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2H), 2.21 (s, 6H), 1.74 (d, J=6.7 yl)benzamide Hz, 6H), 1.28 (s, 6H)

[0654] Method A, 1.32 min

[0655]

[0656] (r , . z, , . r , 2-chloro-N-(5-fluoro-4-(2-(2-hydroxy- J=10.8 Hz, 1H), 3.69 - 3.54 (m, 2-methylpropyl)-3-isopropyl-3H- 1H), 3.17 (s, 1H), 3.07 (s, 2H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2.97 (br d, J=13.0 Hz, 1H), 2.73 yl)-5-(morpholin-2-yl)benzamide (br d, J=4.3 Hz, 2H), 1.73 (br d,

[0657] J=6.7 Hz, 6H), 1.27 (s, 6H) Method A, 1.32 min

[0658]

[0659] 1H), 3.88 (br d, J=10.3 Hz, 1H), 2-chloro-N-(5-fluoro-4-(2-(2-hydroxy- 3.66 - 3.56 (m, 1H), 3.16 (s, 1H), 2-methylpropyl)-3-isopropyl-3H- 3.07 (s, 2H), 2.96 (br d, J=12.4 imidazo[4,5-b]pyridin-5-yl)pyridin-2- Hz, 1H), 2.73 (br d, J=3.6 Hz, yl)-5-(morpholin-2-yl)benzamide

[0660] 2H), 1.72 (d, J=6.7 Hz, 6H), 1.26 (s, 6H)

[0661] Method I, 0.719 min

[0662] ,

[0663]

[0664] , . , . , , .0 5 -(3 -amino-3 -methylbut- 1 -yn- 1 -yl)-2- (d, J = 10.8 Hz, 1H), 3.95 (dd, J = chloro-N-(4-(3-(2,2-difluoroethyl)-2- 10.8, 8.0 Hz, 1H), 3.70 (q, J = 8.8 (2-hydroxy-2-methylpropyl)-3H- Hz, 1H), 3.32 (d, J = 6.0 Hz, 2H), imidazo[4,5-b]pyridin-5-yl)-5- 2.52-2.50 (m, 1H), 2.28-2.26 (m, fluoropyridin-2-yl)benzamide 1H), 1.47 (s, 6H), 1.29 (d, J =

[0665] 13.6 Hz, 6H)

[0666] ,

[0667]

[0668] 1H), 7.66 (d, J = 8.4 Hz, 1H), N-(4-(2-(2-aminopropan-2-yl)-3- 5.11-5.03 (m, 1H), 4.02 (s, 3H), isopropyl-3H-imidazo[4,5-b]pyridin-5- 2.09-1.90 (m, 12H)

[0669] yl)-5-fluoropyri din-2 -yl)-2-chloro-5- (1 -methyl- 1H- 1 ,2,4-triazol-3 - yl)benzamide Method K, 1.06 min

[0670]

[0671] . , , . , . (R)-5-(l-(difluoromethyl)-lH-l,2,4- Hz, 1H), 7.79 (t, J = 58.8 Hz, triazol-3-yl)-N-(5-fluoro-4-(2-(2- 1H), 5.64-5.55 (m, 1H), 4.84-4.76 hy droxy-2-methylpropyl)-3 - (m, 1H), 4.38 (t, J = 8.4 Hz, 1H), (tetrahydrofuran-3-yl)-3H-imidazo[4,5- 4.28 (t, J = 8.4 Hz, 1H), 4.20-4.11 b]pyridin-5-yl)pyridin-2-yl)-2- (m, 1H), 3.46 (s, 3H), 3.34 (s, (methylsulfonyl)benzamide 2H), 3.03-2.90 (m, 1H), 2.63-2.48

[0672] (m, 1H), 1.43 (s, 3H), 1.40 (s, 3H) ),

[0673]

[0674] 8.12 (d, J=8.2 Hz, 1H), 7.90 (br d, N-(5-fluoro-4-(3-isopropyl-2-(2,2,2- J=7.9 Hz, 1H), 4.94 (dt, J=13.6, trifluoroethyl)-3H-imidazo[4,5- 6.9 Hz, 1H), 4.34 (q, J=10.7 Hz, b]pyridin-5-yl)pyridin-2-yl)-5-(l- 2H), 3.98 (s, 3H), 1.76 (d, J=6.6 methyl-lH-l,2,4-triazol-3-yl)-2- Hz, 6H) WS

[0675] (m ethyl sulfonyl)

[0676] benzamide

[0677]

[0678] 8.09 (d, J=8.3 Hz, 1H), 7.90 (d, N-(5-fluoro-4-(3-isopropyl-2-(2,2,2- J=8.5 Hz, 1H), 4.95 (dt, J=13.5, trifluoroethyl)-3H-imidazo[4,5- 6.7 Hz, 1H), 4.35 (q, J=10.6 Hz, b]pyridin-5-yl)pyridin-2-yl)-5-(l- 2H), 4.14 (s, 3H), 1.77 (d, J=6.7 methyl-lH-l,2,3-triazol-4-yl)-2- Hz, 6H) WS.

[0679] (m ethyl sulfonyl)

[0680] benzamide

[0681]

[0682] J=8.3 Hz, 1H), 8.07 (CHF2, 1H), -(l-(difluoromethyl)-lH-l,2,4-triazol- 7.84 (br d, J=8.1 Hz, 1H), 5.02 3-yl)-N-(5-fluoro-4-(2-(2-hydroxy-2- (dt, J=13.3, 6.6 Hz, 1H), 3.08 (s, methylpropyl)-3-isopropyl-3H- 2H), 1.75 (br d, J=6.7 Hz, 6H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 1.28 (s, 6H) WS

[0683] yl)-2-(methylsulfonyl)benzamide

[0684]

[0685] 1H), 8.23 (d, J = 1.6 Hz, 1H), N-(4-(2-acetamido-3-cyclopentyl-3H- 8.13-8.11 (m, 2H), 7.93 (d, J = imidazo[4,5-b]pyridin-5-yl)-5- 8.0 Hz, 1H), 5.02-4.80 (m, 1H), fluoropyridin-2-yl)-5 -(1 -methyl- 1 H- 3.98 (s, 3H), 3.43 (s, 3H), 2.58- l,2,4-triazol-3-yl)-2- 2.48 (m, 1H), 2.24 (s, 3H), 2.23- (methylsulfonyl)benzamide 2.00 (m, 5H), 1.70-1.60 (m, 2H)

[0686] Method A, 1.52 min

[0687]

[0688] Hz, 1H), 5.02 (dt, J=13.2, 6.4 Hz, (R)-2-chloro-N-(5-fluoro-4-(2-(2- 1H), 3.90 (s, 1H), 3.41 - 3.23 (m, hydroxy-2-methylpropyl)-3-isopropyl- 1H), 3.18 (s, 1H), 3.11 - 2.99 (m, H-imidazo[4,5-b]pyridin-5-yl)pyridin- 3H), 2.48 - 2.38 (m, 1H), 2.04 (td, 2-yl)-5-(3-(hydroxymethyl)pyrrolidin- J=11.8, 6.4 Hz, 1H), 1.89 (s, 2H), l-yl)benzamide 1.74 (br d, J=6.6 Hz, 7H), 1.28 (s,

[0689] 6H) Method A, 1.67 min

[0690] 5809

[0691]

[0692] (S)-2-chloro-N-(5-fluoro-4-(2-(2- J=13.3, 6.6 Hz, 1H), 3.89 (s, 1H), hydroxy-2-methylpropyl)-3-isopropyl- 3.71 - 3.49 (m, 2H), 3.48 - 3.19 H-imidazo[4,5-b]pyridin-5-yl)pyridin- (m, 3H), 3.17 (d, J=4.7 Hz, 1H), 2-yl)-5-(3-(hydroxymethyl)pyrrolidin- 3.04 (br dd, J=9.5, 6.3 Hz, 1H), l-yl)benzamide 2.48 - 2.37 (m, 1H), 2.12 - 1.99 (m, 1H), 1.73 (br d, J=6.6 Hz, 7H), 1.27 (s, 6H)

[0693]

[0694] 2-chloro-N-(4-(2-((2,2- 7.72 (m, 2H), 7.69 (dd, J=8.4, 2.2 difluoroethyl)amino)-3-isopropyl-3H- Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), imidazo[4,5-b]pyridin-5-yl)-5- 6.44 - 6.11 (m, 1H), 4.78 (dt, fluoropyridin-2-yl)-5 -( 1 -methyl- 1 H- J=13.6, 6.7 Hz, 1H), 3.95 - 3.82 py razol -4-y 1 )b enzami de (m, 5H), 1.70 (d, J=6.8 Hz, 6H)

[0695]

[0696] 1H), 4.84 - 4.67 (m, 1H), 4.11 (s, 2-chloro-N-(4-(2-((2,2- 3 H), 3.85 (ddd, J=14.5, 10.1, 4.4 difluoroethyl)amino)-3-isopropyl-3H- Hz, 2H), 1.69 (br d, J=6.7 Hz, imidazo[4,5-b]pyridin-5-yl)-5- 6H)

[0697] fluoropyridin-2-yl)-5 -( 1 -methyl- 1 H- l,2,3-triazol-4-yl)benzamide

[0698]

[0699] (d, J=8.5 Hz, 1H), 4.79 - 4.61 (m, N-(4-(2-acetamido-3-isopropyl-3H- 1H), 3.94 (s, 3H), 2.18 (s, 3H), imidazo[4,5-b]pyridin-5-yl)-5- 1.70 (d, J=6.8 Hz, 6H) fluoropyri din-2 -yl)-2-chl oro-5-(l- methyl-lH-l,2,4-triazol-3- yl)benzamide

[0700] 31

[0701]

[0702] - 7.21 (m, 1H), 5.05 - 4.93 (m, 6-chloro-2-fluoro-N-(5-fluoro-4-(2-(2- 1H), 4.49 - 4.38 (m, 1H), 3.87 (br hydroxy-2-methylpropyl)-3-isopropyl- d, J=3.7 Hz, 3H), 3.06 (br s, 2H), 3H-imidazo[4,5-b]pyridin-5-yl)pyridin- 1.71 (br d, J=6.3 Hz, 6H), 1.25 2-yl)-3-methoxybenzamide (br s, 6H).

[0703]

[0704] (dd, J=8.8, 2.5 Hz, 1H), 7.47 (d, 5-acetamido-2-chloro-N-(5-fluoro-4- J=8.8 Hz, 1H), 5.13 - 4.97 (m, (2-(2-hydroxy-2-methylpropyl)-3- 1H), 3.11 (s, 2H), 2.07 (s, 3H), isopropyl-3H-imidazo[4,5-b]pyridin-5- 1.74 (d, J=6.8 Hz, 6H), 1.28 (s, yl)pyridin-2-yl)benzamide 6H)

[0705] ,

[0706]

[0707] 7.69 (dd, J=8.3, 1.8 Hz, 1H), 7.51 2-chloro-N-(5-fluoro-4-(2-(2-hydroxy- (d, J=8.3 Hz, 1H), 5.12 - 4.95 (m, 2-methylpropyl)-3-isopropyl-3H- 1H), 3.87 (s, 3H), 3.08 (br s, 2H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 1.75 (br d, J=6.6 Hz, 6H), 1.28 (s, yl)-5 -( 1 -methyl- 1 H-pyrazol-4- 6H)

[0708] yl)benzamide

[0709]

[0710] (, ., . z, ), . (, -chloro-N-(5-fluoro-4-(2-(2-hydroxy- J=7.2 Hz, 1H), 7.64 (d, J=8.4 Hz, 2-methylpropyl)-3-isopropyl-3H- 1H), 5.02 (dt, J=13.4, 6.7 Hz, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 1H), 4.89 (s, 1H), 4.11 (s, 3H), yl)-5-(l-methyl-lH-l,2,3-triazol-4- 3.08 (s, 2H), 1.74 (d, J=6.7 Hz, yl)benzamide 6H), 1.28 (s, 6H)

[0711] ),

[0712]

[0713] 7.81 (d, J=7.5 Hz, 1H), 7.66 (d, -chloro-N-(5-fluoro-4-(2-(2-hydroxy- J=8.4 Hz, 1H), 5.02 (dt, J=13.5, 2-methylpropyl)-3-isopropyl-3H- 6.8 Hz, 1H), 3.94 (s, 3H), 3.08 (s, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2H), 1.75 (d, J=6.7 Hz, 6H), 1.28 yl)-5-(l-methyl-lH-l,2,4-triazol-3- (s, 6H)

[0714] yl)benzamide

[0715]

[0716] (, ., . z, ), . (, -chloro-N-(5-fluoro-4-(2-(2-hydroxy- J=7.3 Hz, 1H), 7.64 (d, J=8.5 Hz, 2-methylpropyl)-3-isopropyl-3H- 1H), 5.09 - 4.96 (m, 1H), 4.21 (s, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 3H), 3.08 (s, 2H), 1.91 (s, 3H), yl)-5-(2-methyl-2H- 1,2,3 -tri azol -4- 1.74 (d, J=6.7 Hz, 6H), 1.27 (s, yl)benzamide 6H) Method J, 1.35 min

[0717]

[0718] , . s, , . , .8 5-(2,2-difluoroethoxy)-N-(4-(2-(2- Hz, 1H), 6.27 (tt, J = 54.8, 3.6 hydroxy-2-methylpropyl)-3-isopropyl- Hz, 1H), 5.30-5.18 (m, 1H), 4.47 H-imidazo[4,5-b]pyridin-5-yl)pyridin- (td, J = 13.6, 3.6 Hz, 2H), 3.50 (s, 2-yl)-2-(methylsulfonyl)benzamide 2H), 3.41 (s, 3H), 1.96 (d, J = 6.8

[0719] Hz, 6H), 1.44 (s, 6H)

[0720]

[0721] Hz, 1H), 5.28-5.16 (m, 1H), 3.50 2-chloro-N-(5-fluoro-4-(2-(2-hydroxy- (s, 2H), 1.95 (d, J = 6.4 Hz, 6H), 2-methylpropyl)-3-isopropyl-3H- 1.36 (s, 6H)

[0722] imidazo[4,5-b]pyridin-5-yl)pyridin-2- yl)-5-( 1H- 1 ,2,4-triazol- 1 -yl)benzamide

[0723] 8

[0724]

[0725] (m, 1H), 7.84 (d, J = 8.8 Hz, 1H), 2-chloro-N-(5-fluoro-4-(2-(2-hydroxy- 7.74 (s, 1H), 5.21-5.18 (m, 1H), 2-methylpropyl)-3-isopropyl-3H- 3.34 (s, 2H), 1.93 (d, J = 6.8 Hz, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 6H), 1.42 (s, 6H)

[0726] yl)-5-(lH-imidazol-l-yl)benzamide

[0727]

[0728] 8.08 (s, 1H), 7.88 (s, 1H), 7.79- 5-chloro-N-(5-fluoro-4-(2-(2-hydroxy- 7.73 (m, 2H), 5.14-5.10 (m, 1H), 2-methylpropyl)-3-isopropyl-3H- 3.50 (s, 2H), 1.90 (d, J = 6.4 Hz, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 6H), 1.43 (s, 6H)

[0729] yl)-2-( 1H- 1 ,2,4-triazol- 1 -yl)benzamide

[0730]

[0731] , ., . , , . , N-(4-(2-acetamido-3-isopropyl-3H- J=8.4 Hz, 1H), 4.74 - 4.51 (m, imidazo[4,5-b]pyridin-5-yl)-5- 1H), 3.87 (s, 3H), 2.19 (s, 3H), fluoropyri din-2 -yl)-2-chloro-5-(l- 1.71 (br d, J=6.6 Hz, 6H) methy 1 - 1 H-py razol -4-y l)b enzami de

[0732] ,

[0733]

[0734] 1H), 7.64 (d, J=8.4 Hz, 1H), 4.85 N-(4-(2-acetamido-3-isopropyl-3H- - 4.60 (m, 1H), 4.11 (s, 3 H), 2.19 imidazo[4,5-b]pyridin-5-yl)-5- (s, 3H), 1.71 (br d, J=6.8 Hz, 6H) fluoropyri din-2 -yl)-2-chl oro-5-(l- methyl-lH-l,2,3-triazol-4- yl)benzamide

[0735]

[0736] d, J=7.9 Hz, 1H), 7.66 (d, J=8.5 N-(4-(2-acetamido-3-isopropyl-3H- Hz, 1H), 4.78 - 4.46 (m, 1H), 3.94 imidazo[4,5-b]pyridin-5-yl)-5- (s, 3H), 2.19 (br s, 3H), 1.71 (br fluoropyri din-2 -yl)-2-chl oro-5-(l - d, J=6.0 Hz, 6H)

[0737] methyl-lH-l,2,4-triazol-3- yl)benzamide

[0738]

[0739] 1H), 2.18 (s, 3H), 1.70 (d, J=6.8 N-(4-(2-acetamido-3-isopropyl-3H- Hz, 6H)

[0740] imidazo[4,5-b]pyridin-5-yl)-5- fluoropyridin-2-yl)-2-chloro-5- (trifluoromethyl)benzamide

[0741]

[0742] (d, J=1.3 Hz, 1H), 8.13 (t, J=8.3 N-(5-fluoro-4-(2-(2-hydroxy-2- Hz, 2H), 7.83 (d, J=7.5 Hz, 1H), methylpropyl)-3-isopropyl-3H- 5.02 (dt, J=13.5, 6.7 Hz, 1H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 4.84 (s, 1H), 3.99 (s, 3H), 3.42 (s, yl)-5-(l-methyl-lH-l,2,4-triazol-3-yl)- 3H), 3.09 (s, 2H), 1.75 (d, J=6.8 2-(methylsulfonyl)benzamide Hz, 6H), 1.28 (s, 6H)

[0743]

[0744] J=13.5, 6.8 Hz, 1H), 4.01 (s, 3H), N-(5-fluoro-4-(2-(2-hydroxy-2- 2.88 (s, 2H), 1.51 (d, J=6.7 Hz, methylpropyl)-3-isopropyl-3H- 6H), 1.04 (s, 6H)

[0745] imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)-5-(2-methyl-2H-l,2,3-triazol-4-yl)- 2-(methylsulfonyl)benzamide

[0746]

[0747] 7.50 (m, 2H), 7.29-6.94 (m, 1H), 5-(difluoromethoxy)-N-(5-fluoro-4-(2- 5.15-5.08 (m, 1H), 3.47 (s, 3H), (2-hydroxy-2-methylpropyl)-3- 3.29 (s, 2H), 1.88 (d, J = 6.8 Hz, isopropyl-3H-imidazo[4,5-b]pyridin-5- 6H), 1.39 (s, 6H)

[0748] yl)pyridin-2-yl)-2- (methylsulfonyl)benzamide Mhd I 073 i

[0749]

[0750] 7.27 (m, 2H), 6.38-6.10 (m, 1H), (R)-N-(4-(3 -(1 -cy clopropylethyl)-2-(2- 4.43 (td, J = 13.6, 3.6 Hz, 2H), hydroxy-2-methylpropyl)-3H- 4.32-4.28 (m, 1H), 3.35-3.25 (m, imidazo[4,5-b]pyridin-5-yl)-5- 5H), 2.42-2.29 (m, 1H), 1.96 (d, J fluoropyridin-2-yl)-5-(2,2- = 6.8 Hz, 3H), 1.40 (s, 3H), 1.37 difluoroethoxy)-2- (s, 3H), 0.87-0.75 (m, 1H), 0.63- (methylsulfonyl)benzamide

[0751] 0.60 (m, 1H), 0.53-0.35 (m, 2H)

[0752]

[0753] . , ., . , , 5-(2,2-difluoroethoxy)-N-(5-fluoro-4- 6.59-6.32 (m, 1H), 5.08 (q, J = (2-(2-hydroxy-2-methylpropyl)-3- 6.8 Hz, 1H), 4.52 (td, J = 14.8, isopropyl-3H-imidazo[4,5-b]pyridin-5- 3.2 Hz, 2H), 3.33 (s, 3H), 3.21 (s, yl)pyridin-2-yl)-2- 2H), 1.76 (d, J = 6.8 Hz, 6H), (methylsulfonyl)benzamide 1.29 (s, 6H)

[0754] Method K, 1.26 min

[0755]

[0756] ), . (r , . z, ), 2-chloro-N-(5-fluoro-4-(2-(2-hydroxy- 5.09 - 4.94 (m, 1H), 3.13 - 3.04 2-methylpropyl)-3-isopropyl-3H- (m, 3H), 2.89 (s, 2H), 2.76 - 2.63 imidazo[4,5-b]pyridin-5-yl)pyridin-2- (m, 4H), 1.81 (br s, 3H), 1.75 - yl)-5-(piperidin-4-yl)benzamide 1.72 (m, 6H), 1.67 - 1.54 (m, 2H),

[0757] 1.27 (s, 6H)

[0758]

[0759] 2-chloro-5-(3- (m, 1H), 3.08 (s, 2H), 2.89 (s, (dimethylamino)cyclobutyl)-N-(5- 2H), 2.73 (s, 1H), 2.49 - 2.41 (m, fluoro-4-(2-(2 -hydroxy -2- 1H), 2.39 - 2.28 (m, 1H), 2.22 - methylpropyl)-3-isopropyl-3H- 2.13 (m, 1H), 2.06 (d, J=7.4 Hz, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 6H), 1.74 (d, J=6.7 Hz, 6H), 1.28 yl)benzamide (s, 6H)

[0760] Method K 1.48 min

[0761]

[0762] (R)-5-(difluoromethoxy)-N-(5-fluoro- Hz, 1H), 3.99 (br dd, J=6.4, 3.1 4-(2-(2 -hydroxy -2-methylpropyl)-3- Hz, 1H), 3.91 - 3.81 (m, 1H), 3.37 (tetrahydro-2H-pyran-3 -yl)-3H- (s, 3H), 3.25 - 3.09 (m, 2H), 3.09 imidazo[4,5-b]pyridin-5-yl)pyridin-2- - 2.94 (m, 1H), 2.14 - 1.99 (m, yl)-2-(methylsulfonyl)benzamide 1H), 1.77 (br s, 2H), 1.29 (br d, J=7.4 Hz, 6H)

[0763]

[0764] 4.95 (m, 1H), 4.07 - 4.01 (m, 2H), 5-(3-(dimethylamino)propoxy)-2- 3.08 (s, 2H), 2.89 (s, 1H), 2.74 (s, fluoro-N-(5-fluoro-4-(2-(2 -hydroxy -2- 1H), 2.37 (s, 2H), 2.15 (s, 6H), methylpropyl)-3-isopropyl-3H- 1.75 (d, J=6.7 Hz, 6H), 1.28 (s, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 6H)

[0765] yl)benzamide Method K, 1.61 min

[0766] 605.2

[0767] ) 62 ,

[0768]

[0769] 8.9 Hz, 1H), 6.78 (dt, J = 6.8, 2-chloro-N-(4-(3-(l,l-difluoropropan- 55.8 Hz, 1H), 5.36 - 5.24 (m, 1H), 2-yl)-2-(2-hydroxy-2-methylpropyl)- 4.92 (br s, 1H), 4.15 - 4.07 (m, 3H-imidazo[4,5-b]pyridin-5-yl)-5- 2H), 3.22 - 3.17 (m, 1H), 3.03 (d, fluoropyridin-2-yl)-5-(2- J = 14.3 Hz, 1H), 2.63 (t, J = 5.8 (dimethylamino)ethoxy)benzamide Hz, 2H), 2.21 (s, 6H), 1.88 (d, J =

[0770] 6.9 Hz, 3H), 1.35 (s, 3H), 1.21 (s, 3H)

[0771] Method K, 1.69 min

[0772] 593.2

[0773]

[0774] N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- 5.50 (m, 1H), 5.14 (br d, J = 5.9 methylpropyl)-3H-imidazo[4,5- Hz, 1H), 4.74 - 4.06 (m, 12H), b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 3.79 (br d, J =10.8 Hz, 1H), 3.66 2-chloro-5-(l-methylpiperidin-4- (d, J = 5.4 Hz, 5H), 2.88 (br s,

[0775] yl)benzamide 1H), 2.64 (br d, J = 11.5 Hz, 2H),

[0776] 2.44 (br d, J = 14.4 Hz, lH),1.2(br s, 1H) 0.79 (d, J = 6.5 Hz, 3H

[0777] 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

1. WE CLAIM:

1. A compound of F ormul a (I) :

4. 6.or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:7.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 heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), O, or S(O)P, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 4 Re;8.R2is H, cyano, -OH, -SH, -NH2, C 1-4 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, -NH2, -NH(CI-4alkyl), N(CI-4alkyl)2, -NH(CI-4haloalkyl), -NHC(=O)( C1-4 alkyl), -(CRgRgl)o-2-(C3-8cycloalkyl substituted with 0 to 4 Re), or9.-(CRgRgl)o-i-(4- to 6-membered heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), O, or S(O)P, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 2 Re);10.R3is halogen, cyano, C1-4 haloalkyl, C1-4 haloalkoxy,11.-C(=O)O(Ci-4alkyl), -NH2, -NH(CI-4alkyl), -N(CI-4alkyl)2, -C(=O)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;12.R4is H, halogen, cyano or C1-4 alkyl;13.R5is halogen, cyano, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -NH(CI-4 alkyl), Ci-4 alkyl substituted with 0 to 2 Ra, -SC>2(Ci-4 alkyl substituted with 0 to 1 Rc), -SC>2CH2(C3-4 cycloalkyl), or a 5 to 6-membered heteroaryl containing 1 to 4 ring heteroatoms which are N, N(Rb), O, or S, wherein said heteroaryl is substituted with 0 to 2 Rd;14.R6is halogen, -OH, cyano, Ci-6 alkyl substituted with 0 to 2 Rc,15.C2-6 alkenyl substituted with 0 to 1 Rc, C2-6 alkynyl substituted with 0 to 1 Rc, C1-4 haloalkyl substituted with 0-1 Rc, C1-4 alkoxy substituted with 0 to 1 Rc, C1-4 haloalkoxy substituted with 0-1 Rc, -NHC(=O)(C 1-4 alkyl),16.-NHC(=O)O(CI-4 alkyl), -(CH2)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re), a 4- to 8-membered heterocycle including 1 to 2 ring heteroatom which are N, N(Rb), or O, and wherein the heterocycle is monocycle, bridged cycle or spiro cycle, is partially satuated or fully satuated, and is substituted with 0 to 3 Re; or -(0)o-i-(5- to 6-membered heteroaryl including 1 to 4 ring heteroatom which are N, N(Rb), O, or S, and is substituted with 0 to 3 Rd);17.Rais halogen, cyano, -OH, -CH2OH, C1-4 alkoxy, C1-4 haloalkyl,18.C1-4 haloalkoxy, NH2, NH(CI-4alkyl), N(CI-4alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;19.Rbis H, C1-4 fluoroalkyl, -C(=O)(Ci-4alkyl), -C(=O)O(Ci-4alkyl) or20.C1-4 alkyl substituted with 0 to 1 Rf;21.Rcis halogen, cyano, -OH, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl substituted with 0 to 2 Rf, or C 1-4 alkoxy substituted with 0 to 1 Rf;22.Rdis halogen, cyano, -OH, 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;23.Reis oxo or Rd;24.Rfis halogen, cyano, -OH, -CH2OH, C1-4 alkoxy, or N(Ci-4alkyl)2;25.Rgis H, C1-4 alkyl substituted with 0 to 1 Rf, C1-4 alkoxy, or C3-6 cycloalkyl; Rglis H or C1-4 alkyl;26.Rhis H or C1-6 alkyl substituted with 0 to 1 Ra;27.m and n are 0, 1 or 2; and28.p 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:29.R1is H, Ci-6 alkyl substituted with 0 to 2 Ra, Ci-6 haloalkyl substituted with 0 to 1 Ra, -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re), or a 4- to 6-membered heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), O, or S(O)P, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 2 Re;30.R2is H, Ci-4 alkoxy, Ci-6 alkyl substituted with 0 to 1 Ra, Ci-6 haloalkyl substituted with 0 to 1 Ra, -NH(CI-4 fluoroalkyl), or -NHC(=O)(C 1-4 alkyl);31.R3is halogen, -OH, cyano, C1-6 alkyl, C1-4 alkoxy, C 1-4 haloalkyl, or32.C1-4 haloalkoxy;33.R4is H, halogen, cyano, or C1-2 alkyl;34.R5is halogen, C1-4 alkyl, C1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -SO2(Ci-4 alkyl substituted with 0 to 1 Rc), or a 5 to 6-membered heteroaryl containing 1 to 4 ring atomswhich are N, N(Rb), or O, wherein said heteroaryl is substituted with 0 to 2 Rd;35.Rais halogen, cyano, -OH, -CH2OH, C1-4 alkoxy, C1-4 haloalkyl,36.C1-4 haloalkoxy, NH2, NH(CI-4 alkyl), or N(CI-4 alkyl)2;37.Rbis H, Ci-4 fluoroalkyl, or C1-4 alkyl substituted with 0-1 OH;38.Rcis halogen, cyano, -OH, C1-4 alkoxy, C1-4 haloalkyl, or39.C1-4 haloalkoxy, -NH2, -NH(CI-4 alkyl) or -N(CI-4 alkyl)2;40.Rdis halogen, cyano, -OH, -CH2OH, C1-4 alkyl substituted with 0-1 OH, 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);41.Rdis F, cyano, C1-4 alkyl substituted with 0-1 OH, C1-4 haloalkyl, or42.C1-4 haloalkoxy43.Rgis H, C1-2 alkyl or -CH2OH; and44.Rglis 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:45.R1is H, Ci-6 alkyl substituted with 0 to 2 Ra, Ci-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 heterocycle including 1 ring heteroatom which is N, N(Rb), O, or S(O)P, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 2 Re;46.R2is H, Ci-6 alkyl substituted with 0 to 1 Ra, Ci-4 fluoroalkyl substituted with 0 to 1 Ra, -NH(CI-4 fluoroalkyl), or -NHC(=O)(C 1-4 alkyl);47.R3is F, Cl or C1-2 alkyl;48.R4is H, F or Cl;49.R5is halogen, Ci-4haloalkyl, -SC>2(Ci-4 alkyl), or a 5 to 6-membered heteroaryl containing 1 to 4 ring atomswhich are N, N(Rb), or O, wherein said heteroaryl is substituted with 0 to 2 Rd;50.R6is halogen, -OH, C1-6 alkyl substituted with 0 to 1 Rc, C2-6 alkynyl substituted with 0 to 1 Rc, C1-4 alkoxy substituted with 0 to 1 Rc, Ci-4haloalkyl, C1-4 haloalkoxy, -NHC(=0)(Ci-4 alkyl), C3-6 cycloalkyl substituted with 0 to 2 Re, a 4-to 6-membered heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), or O, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 2 Re; or a 5- to 6-membered heteroaryl containing 2 to 3 ring heteroatoms which are N, N(Rb), O or S, and wherein said heteroaryl is substituted with 0 to 2 Rd; and51.n is 0 or 1.

4. A compound of Formula (II):

53. 55.or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:56.R1is H, Ci-6 alkyl, C1-4 fluoroalkyl, -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 1 Re), or a 5- to 6-membered heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), or O, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 1 Re;57.R2is Ci-4 fluoroalkyl, Ci-6 alkyl substituted with 0 to 1 Ra,58.-NH(CI-4 fluoroalkyl), or -NHC(=O)(C 1-4 alkyl);59.R4is H, F, or Cl;60.R5is halogen, C1-4 fluoroalkyl, -SC>2(Ci-4 alkyl), or a 5-membered heteroaryl containing 2 to 3 nitrogen atoms which are N or N(Rb);61.R6is halogen, -OH, C1-6 alkyl substituted with 0 to 1 Rc, C2-6 alkynyl substituted with 0 to 1 Rc, C1-4 alkoxy substituted with 0 to 1 Rc, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, -NHC(=O)(C 1-4 alkyl), C3-6 cycloalkyl substituted with 0 to 1 Re, a 4- to 6-membered heterocycle including 1 to 2 ring heteroatoms which are N, N(Rb), or O, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 1 Re; or a 5- to 6-membered heteroaryl containing 2 to 3 nitrogen atoms which are N or N(Rb), and wherein said heteroaryl is substituted with 0 to 1 Rd;62.Rais F, Cl, cyano, -OH, -CH2OH, -NH2, C1-4 alkoxy, or C1-4 fluoroalkyl; Rbis H, C1-4 alkyl, or C1-4 fluoroalkyl;63.Rcis F, Cl, cyano, -OH, C1-4 alkoxy, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, -NH2, -NH(CI-4alkyl) or -N(CI-4alkyl)2;64.Rdis F, cyano, C1-4 alkyl substituted with 0-1 OH, C1-4 fluoroalkyl or C1-4 alkoxy; Reis oxo or R‘ ; and65.m is 1, 1 or 2.

5. The compound of claim 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:67.R1is C1-4 alkyl, C1-4 fluoroalkyl, -CH(Ci-2alkyl)-cyclopropyl, cyclopentyl, or69. 71.R2is Ci-4 fluoroalkyl, C alkyl substituted with 0 to 1 Ra,72.-NH(CI-4 fluoroalkyl), or -NHC(=O)(C 1-4 alkyl);73.R5is Cl, C1-4 alkyl, C1-4 fluoroalkyl, -SC>2(Ci-4 alkyl), or or74.

75. ;76.R6is halogen, -OH, C1-6 alkyl substituted with 0 to 1 Rc, C2-6 alkynyl substituted with 0 to 1 Rc, C1-4 alkoxy substituted with 0 to 1 Rc, C1-4 fluoroalkyl, C1-477.fluoroalkoxy, -NHC(=O)(C 1-4 alkyl),78.

81.

82. , or a 5-membered heteroaryl containing 2 to 3 nitrogen atoms which are N or N(Rb), and wherein said heteroaryl is substituted with 0 to 1 Rd;83.Rais cyano, -OH, or -NH2;84.Rbis H, C1-2 alkyl, or C1-2 fluoroalkyl;85.Rcis -OH, -NH2, -NH(CI-4 alkyl), or -N(Ci-4alkyl)2; and86.Rdis F, C1-4 alkyl, C1-4 fluoroalkyl or C1-4 alkoxy.

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, -CH2CHF2, -CH(CH3)CHF2, -CH(CH3)-cyclopropyl,91.

92. Rbis H, CH3, or -CF2H.

7. The compound of claim 4 or claim 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:94.R1is C1-4 alkyl;95.R2is C1-4 alkyl substituted with OH;96.R4is H orF;97.R5is Cl or -SO2(Ci-2alkyl);98.R6is C1-6 alkyl substituted with 0 to 1 Rc, C2-6 alkynyl substituted with 0 to 1 Rc, C1-4 alkoxy substituted with 0 to 1 Rc, C1-4 fluoroalkoxy, or a 5-membered heteroaryl containing 2 to 3 nitrogen atoms which are N or N(Rb); Rbis H or Ci-2 alkyl; and99.Rcis -OH, -NH2, -NH(CI-4alkyl), or -N(Ci-4alkyl)2.

8. The compound according to claim 1, which is selected from any one of the Examples 1 to 63 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.

11. 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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