5-(pyridin-4-YL)-3h-imidazo[4,5-b]pyridine 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 HETERO ARYL CARBOXAMIDE COMPOUNDS AS CAMK2 INHIBITORS

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

[0003] 63 / 721,727, filed November 18, 2024; the content of which is herein incorporated by reference in its entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to novel 3H-imidazo[4,5-b]pyridin-5-yl heteroaryl carboxamide 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 U S A. 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] or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

[0020] Het is a 5- to 6-membered heteroaryl containing 1 to 3 ring heteroatoms which are N, N(Rb), O, or S, wherein the heteroaryl is substituted with 1 R5and 0 to 3 R6;

[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-3-(C3-8cycloalkyl substituted with 0 to 4 Re), or -(CRgRgl)o-2-(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);

[0024] 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,

[0025] 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;

[0026] R5is halogen, cyano, Ci-4 alkoxy, CM haloalkyl, Ci-4 haloalkoxy,

[0027] -NH(Ci-4 alkyl), CM alkyl substituted with 0 to 2 Ra, -S02(CM 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;

[0028] R6is halogen, -OH, cyano, Ci-6 alkyl substituted with 0-2 Rc, C2-6 alkenyl substituted with 0-2 Rc, C2-6 alkynyl substituted with 0-2 Rc, C1-4 haloalkyl substituted with 0-2 Rc, C1-4 alkoxy substituted with 0-2 Rc, C 1-4 haloalkoxy substituted with 0-2 Rc, -NHC(=O)(CI-4alkyl), -NHC(=O)O(CI-4alkyl),

[0029] -(0)O-I-(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);

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

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

[0032] Rbis H, C1-4haloalkyl, -C(=O)(C1-4alkyl), -C(=O)O(C1-4alkyl), C1-4alkyl substituted with 0-1 Rf, C3-6 cycloalkyl, or a 4- to 8-membered heterocycle including 1 to 2 ring heteroatom which are N, N(Rb), O or S(O)2, and wherein the heterocycle is a monocycle or spiro cycle;

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

[0034] Rdis halogen, cyano, -OH, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, -O(C=O)H, -O(C=O)(C1-4alkyl), -C(=O)O(C1-4alkyl), NH2, N(C1-4alkyl)2, -C(=O)NH2, -C(=O)N(C1-4alkyl)2, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl substituted with 0 to 2 Rc, or a 4- to 6-membered heterocycle including 1 to 2 ring heteroatom which are N, N(Rb), or O, and wherein the heterocycle is a monocycle or spiro cycle and is substituted with 0 to 3 Rf;

[0035] Reis oxo or Rd; Rfis halogen, OH, cyano, -CH2OH, C1-4alkoxy, or N(C1-4alkyl)2;

[0036] Rgis H, CM alkyl substituted with 0 to 1 Rf, C1-4 alkoxy, or C3-6 cycloalkyl;

[0037] Rglis H or CM alkyl;

[0038] Rhis H or C1-6 alkyl substituted with 0 to 1 Ra;

[0039] m and n are 0, 1 or 2; and

[0040] p is 0, 1 or 2.

[0041] In another 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:

[0042] R6is halogen, -OH, cyano, C1-6 alkyl substituted with 0-2 Rc, C2-6 alkenyl substituted with 0-2 Rc, C2-6 alkynyl substituted with 0-2 Rc, Ci-4haloalkyl substituted with 0-2 Rc, C1-4 alkoxy substituted with 0-2 Rc, C 1-4 haloalkoxy substituted with 0-2 Rc, -NHC(=O)(CI-4alkyl), -NHC(=O)O(CI-4alkyl),

[0043] -(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);

[0044] Rbis H, CM haloalkyl, -C(=O)(Ci-4alkyl), -C(=O)O(Ci-4alkyl) or CM alkyl substituted with 0-1 Rf;

[0045] Rcis halogen, cyano, OH, C haloalkyl, CM haloalkoxy, CM alkyl substituted with 0 to 2 Rf, or CM alkoxy substituted with 0 to 1 Rf; and

[0046] Rdis halogen, cyano, -OH, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, -O(C=O)H, -O(C=O)(C1-4alkyl), -C(=O)O(C1-4alkyl), NH2, N(C1-4alkyl)2, -C(=O)NH2, -C(=O)N(C1-4alkyl)2, C2-6 alkenyl, C2-6 alkynyl, or C1-6 alkyl substituted with 0 to 2 Rc.

[0047] 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: 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 independently 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;

[0048] R2is H, Ci-4 alkoxy, Ci-6 alkyl substituted with 0 to 1 Ra, Ci-6 haloalkyl substituted with 0 to 1 Ra, -NH2, -NHC(=0)(CI-4 alkyl) or C3-6 cycloalkyl substituted with 0 to 1 Re;

[0049] R3is halogen, -OH, cyano, C1-6 alkyl, C1-4 alkoxy, C 1-4 haloalkyl, or

[0050] C1-4 haloalkoxy;

[0051] R4is H, halogen, cyano, or C1-2 alkyl;

[0052] R5is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -SO2(C1-4alkyl substituted with 0 to 1 Rc), or -SO2CH2(C3-4cycloalkyl);

[0053] Rais halogen, cyano, -OH, -CH2OH, C1-4 alkoxy, C1-4 haloalkyl, or

[0054] C1-4 haloalkoxy;

[0055] Rbis H, Ci-4 haloalkyl, or C1-4 alkyl substituted with 0-1 OH;

[0056] 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; and

[0057] Rdis halogen, cyano, -OH, -NH2, C1-4 alkyl substituted with 0-1 OH,

[0058] C1-4 alkoxy, C1-4 haloalkyl, or C1-4 haloalkoxy.

[0059] In a third aspect, the present invention provides a compound of Formula (II):

[0060]

[0061] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

[0062] Het is a 5 to 6-membered heteroaryl containing 1 to 2 nitrogen atoms with are N or N(Rb), wherein the heteroaryl is substituted with 1 R5and 0 to 2 R6; R1is Ci-6 alkyl, Ci-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 2 Re;

[0063] R2is Ci-4 fluoroalkyl, Ci-6 alkyl substituted with 0 to 1 Ra, -NH2, -NHC(=O)(CI-4 alkyl) or C3-6 cycloalkyl substituted with 0 to 1 Re;

[0064] R3ais H orR3;

[0065] R3is F, Cl, cyano, C1-4 alkyl, or C1-4 fluoroalkyl;

[0066] R4is H, F or Cl;

[0067] R5is halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, -SO2(C1-4alkyl), or -SO2CH2(C3-4cycloalkyl);

[0068] R6is halogen, cyano, C1-6alkyl substituted with 0-2 Rc, C2-6alkynyl substituted with 0-1 Rc, C1-4haloalkyl substituted with 0-1 Rc, C1-4alkoxy substituted with 0-1 Rc, C1-4haloalkoxy substituted with 0-1 Rc,

[0069] -NHC(=O)O(Ci-4 alkyl), C3-6 cycloalkyl substituted with 0 to 1 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 2 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 2 Rd);

[0070] Rais F, Cl, cyano, -OH, -CH2OH, C1-4 alkoxy, or C1-4 fluoroalkyl;

[0071] Rbis H, C1-4 alkyl, or C1-4 fluoroalkyl;

[0072] Rcis F, Cl, cyano, -OH, C1-4 alkoxy, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, -NH2, -NH(C1-4alkyl) or -N(C1-4alkyl)2;

[0073] Rdis F, cyano, -OH, -NH2, C1-4 alkyl substituted with 0-1 OH, C 1-4 fluoroalkyl or Ci -4 alkoxy;

[0074] Reis oxo or Rd; and

[0075] Rgis H or Ci-2alkyl or -CH2OH.

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

[0077]

[0078] Zk alkyl)

[0079] ) — V(Ci-2 0-2

[0080] w

[0081] cyclohexyl substituted with 0 to 1 -N(CI-4 alkyl)2,

[0082]

[0083] 1-2, or

[0084]

[0085] R2is Ci-4 fluoroalkyl, Ci-6 alkyl substituted with 0 to 1 Ra, -NH2, -NHC(=O)(CI-4 alkyl) or C3-4 cycloalkyl substituted with 0 to 1 cyano;

[0086] R3ais H orR3;

[0087] R3is F or Cl;

[0088] R5is halogen, C1-4alkyl, C1-4fluoroalkyl, -SO2(C1-4alkyl), or -SO2CH2(C3-4cycloalkyl);

[0089] R6is C1-6 alkyl substituted with 0-2 Rc, C2-6 alkynyl substituted with 0-1 Rc, C1-4 haloalkyl substituted with 0-1 Rc, C1-4 alkoxy substituted with 0-1 Rc,

[0090] C1-4 haloalkoxy substituted with 0-1 Rc, -NHC(=O)O(CI-4 alkyl), C3-5 cycloalkyl substituted with 0 to 1 Re, a 4- to 7-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 1 Re; or -(0)o-i-(5- to 6-membered heteroaryl including 1 to 4 ring heteroatom which are N, N(Rb), or O, and is substituted with 0 to 1 Rd);

[0091] R6ais H or cyano;

[0092] Rais cyano or OH; Rcis -OH, -NH2, -NH(C1-4alkyl) or -N(C1-4alkyl)2;

[0093] Rdis F, cyano, -OH, -NH2, C1-4 alkyl, C 1-4 fluoroalkyl, or C1-4 alkoxy; and Reis oxo or Rd.

[0094] 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 third or fourth aspect and wherein, independently for each occurrence:

[0095] Het is

[0096]

[0097] R2is C1-4 fluoroalkyl, C1-6 alkyl substituted with 0 to 1 Ra, -NH2,

[0098] -NHC(=O)(CI-4alkyl) o

[0099]

[0100] r

[0101] R5is Cl, C1-2 alkyl, C1-2 fluoroalkyl, -SO2(Ci-4 alkyl) or -SC>2CH2(cyclopropyl);

[0102] R6is Ci-6 alkyl substituted with 0-1 Rc, C2-6 alkynyl substituted with 0-1 Rc, C1-4 fluoroalkyl substituted with 0-1 Rc, C1-4 alkoxy substituted with 0-1 Rc,

[0103] Rbill N

[0104]

[0105] Rais cyano, -OH, or -NH2;

[0106] Rbis H, C1-4 alkyl or C1-4 fluoroalkyl; and

[0107] Rcis -OH, -NH2, -NH(CI-4alkyl), or -N(Ci-4alkyl)2. 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 third or fourth aspect and wherein, independently for each occurrence:

[0108] R5

[0109]

[0110] In another aspect, the present invention provides a compound of Formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the scope of any of the third to fifth aspects and wherein, independently for each occurrence:

[0111]

[0112] In another aspect, the present invention provides a compound of Formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the third or fourth aspect and wherein, independently for each occurrence:

[0113]

[0114] In another aspect, the present invention provides a compound of Formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the third or fourth aspect and wherein, independently for each occurrence:

[0115] R5

[0116]

[0117] (R )o-i

[0118] 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 of the third to fifth aspects and wherein, independently for each occurrence:

[0119] R5

[0120] Het i

[0121]

[0122] s (R )0-1

[0123] 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 any one of the third to sixth aspects and wherein, independently for each occurrence:

[0124] R5

[0125] Het is

[0126]

[0127] , or

[0128] R1is Ci-4 alkyl, cyclopentyl or cyclohexyl substituted with -N(C1-4alkyl)2;

[0129] R2is Ci-4 fluoroalkyl or Ci-6 alkyl substituted with OH;

[0130] R3ais H orF;

[0131] R4is F;

[0132] R5is Cl, Ci-2 alkyl, or -SO2(C1-2alkyl); and

[0133] R6is C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, lH-l,2,3,4-tetrazol-l-yl, or C3-5 alkynyl substituted with OH or -NH(CI-2 alkyl). 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 of the seventh aspect and wherein, independently for each occurrence:

[0134]

[0135] R1is C1-4 alkyl or cyclohexyl substituted with -N(Ci-2 alkyl)2; and

[0136] R6is C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl, C1-4 fluoroalkoxy or C3-5alkynyl substituted with OH.

[0137] 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 of the seventh aspect and wherein, independently for each occurrence:

[0138] Het is

[0139]

[0140] R1is isoproper or cyclohexyl substituted with -N(CH3)2;

[0141] R2is -CH2CF3or -CH2C(CH3)2OH;

[0142] R3ais H;

[0143] R4is F;

[0144] R5is CH3or -SC>2(Ci-2 alkyl); and

[0145] R

[0146]

[0147] 6is CH3, -OCH3, CF3, -OCHCF2or

[0148] In an eighth aspect, the present invention provides a compound of Formula (III):

[0149]

[0150] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

[0151] R1is Ci-4 alkyl, C1-4 fluoroalkyl, -CH(Ci-2alkyl)-cyclopropyl, cyclopentyl, or alkyl)

[0152] ) - (Cl-2 0-1

[0153] V / 1-2

[0154] R2is C1-4fluoroalkyl, -NH2, -NHC(=O)(C1-4alkyl), C1-4alkyl substituted with 0 to 1 Ra;

[0155] R3ais H orR3;

[0156] R3is F or Cl;

[0157] R4is H orF;

[0158] R5is C1-2 alkyl, -SC>2(Ci-2 alkyl) or -SChCFfclcyclopropyl);

[0159] R6bis H or R6;

[0160] R6is C1-4 alkyl, C1-4 alkoxy, C 1-4 fluoroalkoxy, or cyclopropyl; and

[0161] Rais cyano or -OH.

[0162] In a ninth aspect, the present invention provides a compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the eighth aspect and wherein, independently for each occurrence:

[0163] R1is -CH(CH3)2, -CH(CH3)-cyclopropyl, cyclopentyl,

[0164]

[0165] or

[0166] CH3

[0167]

[0168] R2is -CH2CF3, -CH2C(CH3)2OH, -CH2C(CH3)2CN, -NH2, or -NHC(=O)(CH3);

[0169] R3ais H;

[0170] R5is -SO2CH3, -SO2CH2CH3, or -SO2CH2(cyclopropyl); and

[0171] R6bis H, -CH3, -OCH3, or -OCH2CHF2.

[0172] In another aspect, the invention provides a compound selected from

[0173]

[0174] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0175] In another aspect, the invention provides a compound selected from F

[0176] F F

[0177]

[0178] or a pharmaceutically acceptable salt thereof.

[0179] In a tenth aspect, the invention provides a compound selected from the exemplified Examples 1 to 148 or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0180] 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.

[0181] 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.

[0182] In another embodiment, the present invention provides a process for making a compound of the present invention. In another embodiment, the present invention provides an intermediate for making a compound of the present invention.

[0183] DEFINITIONS

[0184] 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.

[0185] 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.

[0186] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0187] For purposes of clarity and in accordance with standard convention in the art, the symbol I 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.

[0188] 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.

[0189] 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.

[0190] “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.

[0191] 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".

[0192] 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.

[0193] Where a bonding attachment location is not specified, the bonding may be attached at any appropriate location as understood by practitioners in the art.

[0194] 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.

[0195] 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,

[0196] 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0197] 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.

[0198] 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. BIOLOGICAL METHODS

[0199] CAMK2D ECHO MS Activity Assay

[0200] 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 MgCl2, 1 mM CaCl2, 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%.

[0201] 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 DM), 2 DM 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.

[0202] 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.

[0203] 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.

[0204] Table 1

[0205] ECHO MS CAMK2D HTRF

[0206] Ex #

[0207] IC50 (mM) ACT IC50(μM)

[0208] 1 0.001

[0209] 2 0.001

[0210] 3 0.0002

[0211] 4 0.002

[0212] 5 0.0002

[0213] 6 0.003

[0214]

[0215] 7 0.0002 0.004

[0216] 0.001

[0217] 0.013

[0218] 0.0005

[0219] 0.0004 0.001 0.0004 0.002 0.0003

[0220] 0.006

[0221] 0.0001

[0222] 0.001

[0223] 0.0002

[0224] 0.0005

[0225] 0.001

[0226] 0.001

[0227] 0.00007

[0228] 0.0001 0.006

[0229] 0.072

[0230] 0.001 0.028

[0231] 0.009

[0232] 0.009

[0233] 0.001

[0234] 0.001

[0235] 0.0003

[0236] 0.001

[0237] 0.001

[0238] 0.0002

[0239] 0.001

[0240] 0.001

[0241] 0.002

[0242] 0.0004 0.0002

[0243] 0.0005

[0244] 0.010

[0245] 0.001

[0246] 0.001

[0247]

[0248] 0.002 0.0004 0.001 0.0002 0.0005 0.001 0.0002 0.0004 0.0004 0.001 0.002 0.002 0.22 0.0004 0.002 0.006 0.005 0.001 0.003 0.003 0.002 0.002 0.014 0.003 0.0004 0.0004 0.0004 0.009 0.002 0.009 0.001 0.0004 0.003 0.001 0.001 0.001 0.006 0.001 0.002 0.001 0.0004 0.0002

[0249]

[0250] 0.001 0.001 0.002 0.004 0.0003 0.0004 0.001 0.001 0.003 0.001 0.002 0.001 0.001 0.001 0.001 0.00192 0.0002 0.0002 0.0013 0.0047 0.0008 0.0004 0.0002 0.0006 0.0004 0.001 0.001 0.0002 0.0002 0.0001 0.0002 0.0003 0.0003 0.001 0.0002 0.001 0.002 0.001 0.0004 0.0005 0.001 0.0005 0.0002

[0251]

[0252] 0.0001 133 0.0003

[0253] 134 0.0001

[0254] 135 0.0001

[0255] 136 0.0002

[0256] 137 0.0004

[0257] 138 0.0007

[0258] 139 0.0009

[0259] 140 0.0008

[0260] 141 0.0005

[0261] 142 0.0001

[0262] 143 0.0004

[0263] 144 0.0004

[0264] 145 0.0004

[0265] 146 0.0003

[0266] 147 0.0004

[0267]

[0268] 148 0.0002

[0269] Cellular Assay

[0270] 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 μM 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 μL supplemented cell lysis buffer and shaking at room temperature for 30 min. 16 μL of this lysate was transferred to a 384 well plate, and 4 μL 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 inhibition in the cellular assay are reported in Table 2.

[0271] Table 2. Assay in HEK293 cells measuring inhibition of PLN phosphorylation pPLN HTRF EC₅₀

[0272] Ex #

[0273] (μM)

[0274] 1 0.019

[0275] 2 0.030

[0276] 3 0.005

[0277] 4 0.047

[0278] 5 0.009

[0279] 6 0.010

[0280] 7 0.018

[0281] 8 0.037

[0282] 9 0.030

[0283] 10 0.017

[0284] 11 0.011

[0285] 12 0.002

[0286] 13 0.005

[0287] 14 0.012

[0288] 15 0.015

[0289] 16 0.006

[0290] 17 0.029

[0291] 18 0.004

[0292] 19 0.034

[0293] 20 0.022

[0294] 21 0.048

[0295] 22 0.0005

[0296] 23 0.004

[0297] 24 0.007

[0298] 25 0.014

[0299]

[0300] 26 0.014 0.021 0.006 0.034 0.018 0.005 0.021 0.013 0.010 0.012 0.003 0.006 0.032 0.037 0.008 0.004 0.012 0.013 0.003 0.030 0.017 0.034 0.005 0.049 0.001 0.004 0.017 0.006 0.023 0.006 0.005 0.033 0.133 0.12 0.17 0.10 0.10 >0.3 0.076 0.18 >0.3 0.28 0.14 0.31 0.17

[0301]

[0302] 0.004 0.006 0.023 0.005 0.005 0.018 0.008 0.005 0.010 0.004 0.011 0.006 0.048 0.011 0.045 0.005 0.020 0.003 0.027 0.045 0.039 0.016 0.002 0.016 0.041 0.018 0.048 0.034 0.045 0.035 0.041 0.043 0.037 0.890 0.010 0.014 0.053 0.067 0.012 0.044 0.021 0.021 0.036

[0303]

[0304] 0.042 115 0.044

[0305] 116 0.031

[0306] 117 0.015

[0307] 118 0.004

[0308] 119 0.028

[0309] 120 0.007

[0310] 121 0.005

[0311] 122 0.014

[0312] 123 0.015

[0313] 124 0.038

[0314] 125 0.033

[0315] 126 0.035

[0316] 127 0.025

[0317] 128 0.028

[0318] 129 0.016

[0319] 130 0.011

[0320] 131 0.014

[0321] 132 0.007

[0322] 133 0.017

[0323] 134 0.010

[0324] 135 0.013

[0325] 136 0.021

[0326] 137 0.043

[0327] 138 0.039

[0328] 139 0.017

[0329] 140 0.007

[0330] 141 0.023

[0331] 142 0.014

[0332] 143 0.039

[0333] 144 0.028

[0334] 145 0.026

[0335] 146 0.009

[0336] 147 0.021

[0337]

[0338] 148 0.015

[0339] PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE

[0340] 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.

[0341] 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 arrythmia 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.

[0342] " 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 (i.e., prophylaxis and / or risk reduction) of a subclinical disease state in a patient or subject aimed at reducing the probability of the occurrence of a clinical disease state as understood by practitioners in this field. Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. " Therapeutically effective amount" means an amount of a compound that is effective as understood by practitioners in this field.

[0343] 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.

[0344] 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.

[0345] " 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, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.

[0346] 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.

[0347] Pharmaceutically acceptable carriers include both aqueous and nonaqueous liquid media, as well as a variety of solid and semisolid 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).

[0348] 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.

[0349] 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.

[0350] 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.

[0351] Another aspect of the invention is a method for treating heart disease wherein the treatment is post myocardial infarction.

[0352] 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.

[0353] 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.

[0354] Another aspect of the invention is a method for treating heart disease wherein the treatment is given to a patient with chronic heart failure.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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 0.195% 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.

[0360] 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.

[0361] 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.

[0362] 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,

[0363] 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 B6, vitamin B12, 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.

[0364] 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. 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.

[0365] 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,

[0366] β3-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).

[0367] 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.

[0368] 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.

[0369] 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).

[0370] CHEMISTRY METHODS

[0371] 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.

[0372] Ac Acetic

[0373] AcOH acetic acid

[0374] Acn (or MeCN) Acetonitrile

[0375] BBr3 Boron tribromide

[0376] BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0377] Bispin bis(pinacolato)diboron

[0378] Bn Benzyl

[0379] Boc tert-butyl carbonyl

[0380] BOC2O di -te / 7-butyl dicarbonate

[0381] BOP (Benzotriazol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0382] BTFFH fluoro-N, N, N’, N’ -bis(tetramethylene)formamidinium hexafluorophosphate

[0383] Bu Butyl

[0384] CDCI3 deutero-chloroform

[0385] CD3OD deutero-methanol

[0386] Cs2CO3 Cesium carbonate

[0387] dba as in (Pd2(dba)3) Dibenzylideneacetone

[0388] DCM Dichloromethane

[0389] DEAD diethyl azodi carb oxy late

[0390] DIAD diisopropyl azodicarboxylate

[0391] DIEA or DIPEA Diisopropylethylamine

[0392] DMAP 4-dimethylaminopyridine

[0393] DME Dimethoxy ethane

[0394] DMF Dimethylformamide DMSO dimethyl sulfoxide

[0395] DMSO-d6deutero-dimethyl sulfoxide

[0396] dppf 1,1 '-bis(diphenylphosphino)ferrocene

[0397] EDC 3-(Ethyliminomethyleamino)-N-N-dimethylpropan-1-amine

[0398] Et ethyl

[0399] EtOH Ethanol

[0400] EtOAc ethyl acetate

[0401] HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0402] HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0403] HC1 hydrochloric acid

[0404] HPLC high-performance liquid chromatography

[0405] i-Bu Isobutyl

[0406] i-Pr Isopropyl

[0407] K2HPO4 Dipotassium phosphate

[0408] LAH lithium aluminum hydride

[0409] LCMS liquid chromatography mass spectrometry

[0410] Me Methyl

[0411] MeOH Methanol

[0412] MgSO4magnesium sulfate

[0413] NaCl sodium chloride

[0414] Na2CO3sodium carbonate

[0415] NaHCO3 sodium bicarbonate

[0416] NaOH sodium hydroxide

[0417] Na2SO4sodium sulfate

[0418] NH4C1 ammonium chloride

[0419] NH4OAC ammonium acetate

[0420] NMM N-methylmorpholine

[0421] NCS N-Chlorosuccinimide

[0422] NBS N-Bromosuccinimide NMP N-Methylpyrrolidone

[0423] Pd(0Ac)2 palladium(II) acetate

[0424] Pd(dppf)Cl2·CH2Cl2 [1,1'-Bis(diphenylphosphino)ferrocene]

[0425] dichloropalladium(II), complex with dichloromethane Pd(dba)2 Bis(dibenzylideneacetone)palladium(0)

[0426] Ph Phenyl

[0427] PPh3 Triphenylphosphine

[0428] Pr Propyl

[0429] RVC Reticulated vitreous carbon

[0430] t-Bu tert-butyl

[0431] TEA or Et3N Trimethylamine

[0432] TFA trifluoroacetic acid

[0433] THF Tetrahydrofuran

[0434] TMSC1 Trimethyl silyl chloride

[0435] T3P 1-Propanephosphonic anhydride solution

[0436] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0437] 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.

[0438] 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). 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.

[0439] 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.

[0440] 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.

[0441] Acylation 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, 2(7aza1Hbenzotriazole1yl)1,1,3,3tetramethyluronium hexafluorophosphate, (benzotri azol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate and 2(1Hbenzotriazole1yl)1,1,3,3tetramethyluronium 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.

[0442] Miyaura borylation of le in presence of palladium catalysts such as [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2.CH2Cl2) 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)).

[0443] 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 [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (Pd(dppf)Cl2·CH2Cl2) 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)). Scheme 1

[0444] Fe orZn NH^I* BOP or HATU EtOH DIPEA 100 °C DMF B2Pin2, 1.5 eq KOAc, 2 eq Pd(dppf)Cl2 CH2CI2Dioxane, 90 °C

[0445] I

[0446] K3PO4, 2.5 eq Pd(dppf)CI2CH2CI2

[0447]

[0448] Dioxane: water, 10:1 85 °C

[0449] Alternatively, as described in Scheme 2, compounds of this invention can be prepared from aldol condensation of acetone with an appropriately substituted N-alkyl 6-chloro-2-methyl-azabenzimidazole (as prepared from Scheme 1). Subsequent Miy aura borylation and Suzuki similar to that of le to If in Scheme 1, can provide intermediate 2d. Compounds of Formula (la) can be prepared by amide coupling of 2d with a suitably substituted acid similar to that for steps 3d to 3f for Scheme 3. Scheme 2

[0450] B2Pin2, 1.5 eq KOAc, 2 eq Pd(dppf)Cl2 CH2CI2DMF, 90 °C

[0451] K3PO4, 2.5 eq Pd(dppf)Cl2-CH2CI2Dioxane: water, 10:1 85 °C

[0452] HO

[0453] (la)

[0454]

[0455] 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.

[0456] 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,

[0457] 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).

[0458] 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.

[0459] 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

[0460] (MesSn)2Pd (PPh3)4Dioxane, 100 °C

[0461] 3f,, 10 mol% N Pd (dba)2HN—NP(tBu)3’BF4, 10 mol% Dioxane, 100 °C

[0462] I

[0463] 3e BTFFH, 1.1 eq

[0464]

[0465] 3d Pyridine, 1.1 eq

[0466] DIEA, 1.5 eq

[0467] DCE, 80 °C

[0468] 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 NH OAC) 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 NH4O Ac). 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).

[0469] Analytical HPLC: Methods Employed in Characterization of Examples

[0470] Method A: Linear gradient of 0 to 100% B over 3 min, with 0.75 min hold time at 100% B; UV visualization at 220 nm; Column: Waters XBridge C18 2.1 x 50 mm; Flow rate: 1.0 mL / min; Solvent A: 0.1% TFA, 95% water, 5% Acn: Solvent B: 0.1% TFA, 5% water, 95% Acn

[0471] Method B: HALO C18 90A 3.0*30 mm column, 2.0 pm; Mobile Phase A: Water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: 5 % B to 60% B in 1.70 min; 220 nm.

[0472] Method C: HALO C18 Column 30*3.0 mm, 2.0 pm; Mobile Phase A: Water / 0.05% TFA, Mobile PhaseB: Acetonitrile / 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: 5%B to 100% B in 1.20 min; 220 nm.

[0473] Method D: 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: 1.5 mL / min; Gradient: 5% B to 40% B in 1.70 min; 254 nm.

[0474] Method E: 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: 1.5 mL / min; Gradient: 5% B to 50% B in 1.70 min; 254 nm.

[0475] Method F: HALO C18 90A, 3.0*30 mm, 2.0 pm; Mobile Phase A: Water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5 mL / min; Gradient: 5 % B to 60% B in 1.70 min; 254 nm. Method G: HALO C18 90A Column 3.0*30 mm, 2.0 pm; Mobile Phase A: Water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5 mL / min; Gradient: 20 % B to 60% B in 1.70 min; 254 nm.

[0476] Method H: 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: 1.5 mL / min; Gradient: 5 % B to 95 % B in 2.30 min; 254 nm.

[0477] Method I: HALO C18 Column 100*4.6 mm, 2.7 pm; Mobile Phase A: Water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5 mL / min; Gradient: 10 % B to 95% B in 8.00 min; 254 nm.

[0478] Method J: HALO 90A Cl 8, 3.0*30 mm, 2.0 pm; Mobile Phase A: Water / 0.05%TFA, Mobile PhaseB: Acetonitrile / 0.05%TFA; Flow rate: 1.5 mL / min; Gradient: 5 %Bto 100% B in 1.20 min; 254 nm.

[0479] Method K: Shim-pack Scepter C18 120A Column 3.0*33 mm, 3.0 pm; Mobile Phase A: 5% Acetonitrile, 95% Water / 0.05%NH4HC03, Mobile Phase B: Acetonitrile; Flow rate: 1.5000 mL / min; Gradient: 5 % B to 60% B in 1.70 min; 254 nm

[0480] Method L: Shim-pack Scepter C18 120A Column 3.0*33 mm, 3.0 pm; Mobile Phase A: Water / 5mM NH4HCO3, Mobile Phase B: Acetonitrile; Flow rate: 1.5000 mL / min; Gradient: 10% B to 95% B in 1.20 min; 254 nm;

[0481] Method M: 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% Can

[0482] Method N: 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% Can Method O: XBridge C18, 2.1 mm x 50 mm, 1.7 gm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -).

[0483] NMR Employed in Characterization of Examples.XH 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.

[0484] Intermediate 1: 6-chloro-N-isopropyl-3-nitropyridin-2-amine

[0485]

[0486] 2,6-dichloro-3-nitropyridine (50 g, 260 mmol) was dissolved in acetonitrile (3000 mL). Propan-2-amine (25 g, 420 mmol) was added and then the reaction was stirred at rt overnight. The reaction mixture was concentrated and then dissolved in water and extracted with DCM. The combined organic layers were washed with brine and dried over sodium sulfate. The crude residue was purified by column chromatography (ethyl acetate / pet ether, 15%) to yield the title compound (52 g, 93% yield). LC / MS m / z 216.05 (M+H)+.

[0487] Intermediate 2: 6-chloro-N2-isopropylpyridine-2,3-diamine

[0488]

[0489] To a solution of 6-chloro-N-isopropyl-3-nitropyridin-2-amine (40 g, 190 mmol) in ethyl alcohol (1000 mL) and water (40.0 mL) was added

[0490] ammonium chloride (140 g, 2600 mmol) and zinc (48.5 g, 742

[0491] mmol) in portions. The mixture was stirred at 90 °C for 12 h. The reaction mixture was filtered and the resulting solid was washed with water. The crude filtrate was purified by column chromatography (ethyl acetate / pet ether, 30%) to yield the title compound (30 g, 87%). LC / MS m / z 186.03 (M+H)+.

[0492] Intermediate 3: N-(6-chloro-2-(isopropylamino)pyridin-3-yl)-3-hydroxy-3-methylbutanamide

[0493]

[0494] To a solution of 6-chloro-N2-isopropylpyridine-2,3-diamine (32 g, 170 mmol) in DMF (320 mL) was added 3 -hydroxy-3 -methylbutanoic acid (22.4 g, 190 mmol) and HATU (98 g, 260 mmol). DIPEA (36.1 mL, 207 mmol) was added slowly and the resulting reaction mixture was stirred at rt overnight. The reaction was concentrated and redissolved in DCM. The organics were washed twice with 1.5 N HC1, brine, dried over sodium sulfate and concentrated. The resulting crude material was purified by column chromatography (EtOAc / pet ether, 30%) to yield the title compound (29.6 g, 60%). LC / MS m / z 286.1 (M+H)+. Intermediate 4: l-(5-chloro-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropan-2-ol

[0495] ci— i

[0496] N II \x

[0497]

[0498] To a solution of N-(6-chloro-2-(isopropylamino)pyridin-3-yl)-3-hydroxy-3-methylbutanamide (30 g, 105 mmol) in 2-propanol (500 mL) was added p-TSOH (15 g, 79 mmol). The reaction mixture was stirred at 85 °C overnight. After stirring overnight, an additional portion of p-TSOH (15 g, 79 mmol) was added and stirred for another 6 h. The reaction was concentrated and then purified by column chromatography (ethyl acetate / pet ether, 30%) to yield the title compound (20 g, 71%). LC / MS m / z 268.1 (M+H)+.

[0499] Intermediate 5: l-(3-isopropyl-5-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-3H-imidazo[ 4, 5-b ]pyridin-2-yl)-2-methylpropan-2-ol

[0500] 7 — ^5Ozvj- n 1 /

[0501]

[0502] A solution of l-(5-chloro-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropan-2-ol (20 g, 75 mmol), bispin (24 g, 93 mmol) and potassium acetate (14.8 g, 151 mmol) in 1,4-di oxane (200 mL) was added PdC12(dppf)-CH2C12 adduct (2.44 g, 2.99 mmol). The airspace was replaced with nitrogen gas and then the reaction mixture was heated to 90 °C for 6 h. The reaction mixture was diluted with ethyl acetate and water and then filtered through celite. After separation, the organic layer was dried over sodium sulfate and then concentrated. The crude material was purified by column chromatography (ethyl acetate / pet ether, 10%) to yield the title compound. LCMS m / z 277.9 (M+H)+.

[0503] Intermediate 6: 1-(5-(2-amino-5-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropan-2-ol

[0504]

[0505] l-(3-isopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-2-metylpropan-2-ol (26.0 g, 72.4 mmol), 5-fluoro-4-iodopyridin-2-amine (34.4 g, 145 mmol), and K2CO3 (52.0 g, 376 mmol) were dissolved in 1,4-dioxane (520 mL) and water (130 mL). PdC12(dppf)-CH2C12 adduct (2.63 g, 2.89 mmol) was added and the reaction headspace was purged with nitrogen gas. The reaction was heated to 90 °C overnight. The reaction mixture was diluted with ethyl acetate and water and then filtered through celite. After separation, the organic layer was dried over sodium sulfate and concentrated. The crude material was purified by column chromatography (ethyl acetate / pet ether, 0-100%) to yield the title compound (10.4 g, 41%). LC / MS M / Z 344.15 (M+H)+.

[0506] Intermediate 7: 6-bromo-N-( (2R, 3R)-2-methyltetrahydrofuran-3-yl)-3-nitropyridin-2-amine

[0507]

[0508] 2,6-dibromo-3-nitropyridine (0.952 g, 3.38 mmol) was dissolved THF (0.2 M) and chloro((3R)-2-methyltetrahydrofuran-3-yl)-15-azane (0.511 g, 3.71 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (1.76 mL, 10.1 mmol). The reaction was stirred at rt overnight. The reaction was concentrated and the crude was purified via column chromatography (0-5% MeOH / DCM) to afford the title compound (967 mg, 95%). LCMS m / z 301.8, 303.7 (M+H, M+2+H).

[0509] Intermediate 8: 6-bromo-N2-( (2R, 3R)-2-methyltetrahydrofuran-3-yl)pyridine-2, 3-diamine

[0510]

[0511] 6-bromo-N-((3R)-2-methyltetrahydrofuran-3-yl)-3-nitropyridin-2-amine was dissolved AcOH (0.3 M) and then iron (0.566 g, 10.1 mmol) was added. The reaction was heated to 70 °C for 6 h. After cooling to rt, the reaction was diluted with ethyl acetate and then filtered. The filtrate was concentrated and then purified via column chromatography (0-20% MeOH / DCM) to afford the title compound (538 mg, 59%). LCMS m / z 271.8, 273.8 (M+H, M+2+H).

[0512] Intermediate 9: 5-bromo-2-methyl-3-( (2R, 3R)-2-methyltetrahydrofuran-3-yl)-3H-imidazo[ 4, 5-b ]pyridine

[0513]

[0514] 6-bromo-N2-((2R,3R)-2-methyltetrahydrofuran-3-yl)pyridine-2,3-diamine (350 mg, 1.29 mmol) was dissolved 0.2M in ethanol (6.4 mL). 1,1,1-trimethoxyethane (327 pL, 2.57 mmol) was added followed by p-toluenesulfonic acid monoydrate (122 mg, 0.643 mmol). The reaction was heated to 60 °C overnight. The reaction was then cooled to rt before quenching with a saturated potassium phosphate solution. The aqueous layer was extracted 3x with DCM. The resulting organic layer was dried, concentrated, and then purified via column chromatography (0-10% methanol / DCM) to yield the title compound (372 mg, 97%). LCMS m / z 295.8, 297.8 (M+H, M+2+H).

[0515] Intermediate 10: 1-(5-bromo-3-((2R,3R)-2-methyltetrahydrofuran-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropan-2-ol

[0516]

[0517] 5-bromo-2-methyl-3-((2R,3R)-2-methyltetrahydrofuran-3-yl)-3H-imidazo[4,5-b]pyridine (372 mg, 1.26 mmol) was dissolved 0.2 M in THF (6.3 mL) and cooled to -78 °C. A solution of LDA in THF (6.28 mL, 1.51 mmol) was added. After 30 minutes, propan-2-one (279 pL, 3.77 mmol) was added. After 30 min, the reaction was quenched with a saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and then dried, filtered, and concentrated. The resulting material was used crude in the next step. LC / MS m / z 353.8, 355.8 (M+H, M+2+H).

[0518] Intermediate 11: 5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-amine, hydrobromide salt

[0519] NH2

[0520]

[0521] To a solution of 6-bromo-N2-isopropylpyridine-2,3-diamine (1.19 g, 5.17 mmol) dissolved in ethanol (16 mL) was added dropwise a solution of cyanogen bromide (0.49 g, 4.7 mmol) dissolved in DCM (1.6 mL). The reaction was stirred overnight. The reaction mixture was concentrated to yield 5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-amine, hydrobromide (1.65 g, 4.91 mmol, 95 % yield). LCMS m / z 254.9, 256.7 (M+H, M+2+H).

[0522] Intermediate 12: N-(5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)acetamide

[0523] NHAc

[0524]

[0525] To a solution of 5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-amine (1.05 g, 4.11 mmol) and pyridine (2.3 mL) dissolved in DCM (12 mL) was added acetyl chloride (0.322 mL, 4.52 mmol) dropwise at 0 °C. After 1 h, the reaction was quenched with water and then partitioned between water and EtOAc. The organic layer was washed with water and brine, then dried, filtered, and concentrated. The crude mixture was purified via column chromatography (0-100% EtOAc / Hex) to yield to title compound (410 mg, 34%). LCMS m / z 296.8, 298.8 (M+H, M+2+H). 'H NMR (400 MHz, CHLOROFORM-d) 8 7.51 - 7.35 (m, 1H), 7.31 (d, J=8.2 Hz, 1H), 5.20 - 4.93 (m, 1H), 2.29 (s, 3H), 1.69 (d,, / =7.0 Hz, 6H).

[0526] Intermediate 13: N-(3-isopropyl-5-(trimethylstannyl)-3H-imidazo[4,5-b]pyridin-2-yl)acetamide

[0527] NHAc

[0528]

[0529] SnMe3

[0530] To a solution of N-(5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)acetamide (0.4 g, 1.3 mmol) and 1,1,1,2,2,2-hexamethyldistannane (0.441 g, 1.35 mmol) dissolved in 1,4-Dioxane (13.46 mL) was added tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.067 mmol) and heated to 100 °C overnight. The reaction mixture was concentrated and purified via column chromatography (0-100% EtOAc: Hex) to yield the title compound (0.4 g, 78 % yield). LCMS m / z 382.7 (M+H).

[0531] Intermediate 14: tert-butyl (5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

[0532] NHBoc

[0533] N

[0534]

[0535] To a solution of 5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-amine, hydrobromide salt (0.50 g, 1.5 mmol) dissolved in THF (15 mL) was added Et3N (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 concentrated to furnish tert-butyl (5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.641 g, 1.80 mmol, 100 % yield). LCMS m / z 298.8, 300.7 (M+H, M+2+H).

[0536] Intermediate 15: tert-butyl (3-isopropyl-5-(trimethylstannyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

[0537] NHBoc

[0538] N

[0539]

[0540] SnMe3

[0541] To a solution of tert-butyl (5-bromo-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.64 g, 1.8 mmol) dissolved in 1-4 dioxane (18 mL) was added hexamethylditin (0.37 mL, 1.8 mmol) and Pd(Ph3P)4(0.10 g, 0.090 mmol) and stirred overnight at 100°C. The reaction mixture was concentrated and purified with a gradient 0- 100% Hex / EtOAc on a 24g silica column 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 440.0 (M+H).

[0542] Intermediate 16: methyl 5-bromo-2-methoxypyrimidine-4-carboxylate

[0543] N

[0544]

[0545] To a solution of methanol (3.08 mL, 76 mmol) in THF (225 mL) was added LiHMDS (1.0 M in THF, 76 mL, 76 mmol) at -45 °C. The mixture was stirred at -45°C for 45 min, then a solution of methyl 5-bromo-2-(methylsulfonyl)pyrimidine-4-carboxylate (15.0 g, 50.8 mmol) in THF (150 mL) was added. The reaction mixture was allowed to warm to 15 °C and stirred for 2 h. The reaction was quenched with sat. NH4CI sol and extracted with ethyl acetate. The combined organic layers were washed with brine and then dried over Na2SC>4, filtered and concentrated under reduced pressure to afford methyl 5-bromo-2-methoxypyrimidine-4-carboxylate (11 g, 45 mmol, 88% yield) which was used in the next step without purification. LCMS m / z 247.08, 249.06 (M+H, M+2+H).

[0546] Intermediate 17: 2-methoxy-5-(methylthio)pyrimidine-4-carboxylic acid

[0547]

[0548] To a solution of methyl 5-bromo-2-methoxypyrimidine-4-carboxylate (11.0 g, 44.5 mmol) in DMF (250 mL) was added molecular Sieves (4 A, powder, 4.68 g) and then cooled to -30 °C. Thiomethoxide (4.68 g, 66.8 mmol) was added to the mixture and stirred for 2 h at -30 °C. Water was added followed by 10% NaOH solution (11 mL) and then stirred for 2 h at rt. The reaction was filtered and then washed with water. The filtrate was concentrated, redissolved in pH 1-2 water, and the precipitate was collected by filtration. After drying, 2-methoxy-5-(methylthio)pyrimidine-4-carboxylic acid (6.0 g, 30.0 mmol, 67 % yield) was obtained and carried forward without purification. LCMS m / z 201.1 (M+H).

[0549] Intermediate 18: methyl 2-methoxy-5-(methylthio)pyrimidine-4-carboxylate

[0550]

[0551] 2-methoxy-5-(methylthio)pyrimidine-4-carboxylic acid (1000 mg, 4.99 mmol) was dissolved in N, N-dimethylformamide (10 mL, 5.0 mmol). Potassium carbonate (897 mg, 6.49 mmol) was added followed by iodomethane (373 pL, 5.99 mmol). The reaction was stirred at 20 °C for 2 h. The reaction was diluted with 1 N sodium thiosulfate, 1.5 N potassium phosphate, dibasic solution, brine, and DI water. The solid was filtered to yield methyl 2-methoxy-5-(methylthio)pyrimidine-4-carboxylate (1070 mg, 100%) which was used directly in the next step without purification. LCMS m / z 214.8 (M+H).

[0552] Intermediate 19: methyl 2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxylate o

[0553]

[0554] 6'

[0555] Methyl 2-methoxy-5-(methylthio)pyrimidine-4-carboxylate (1070 mg, 4.99 mmol) was dissolved in 1:1 di chloromethane: 1,4-dioxane (10 mL). Acetic acid (2500 pL, 4.99 mmol) was added followed by sodium tungstate dihydrate (2470 mg, 7.49 mmol) and hydrogen peroxide (4990 pL, 4.99 mmol). The reaction was stirred at 20 °C overnight. An additional aliquot of hydrogen peroxide (2.5 mL, 2.5 mmol) was added and stirred for 24 h. The reaction was diluted with 1 N potassium phosphate, dibasic solution, brine, DI water, and ethyl acetate. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate and twice with dichloromethane. The organic layers were combined and dried with sodium sulfate, filtered, and concentrated to yield methyl 2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxylate (750 mg, 61%) which was carried forward without purification. LCMS m / z 246.9 (M+H).

[0556] Intermediate 20: sodium 2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxylate

[0557]

[0558] Methyl 2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxylate (340 mg, 1.381 mmol) was dissolved in water (4600 pL) and 1,4-dioxane (1380 pL) and then sodium hydroxide (1381 pL, 1.381 mmol) was added. The reaction was stirred at 35 °C for 4 h. The reaction mixture was lyophilized to give 380 mg of sodium 2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxylate (351 mg, 100%) which was carried forward crude. LCMS m / z 233.2 (M+H).

[0559] Intermediate 21: tert-butyl 5 -iodo-2 -(trifluor ome thy l)nicotinate

[0560]

[0561] tert-Butyl 5-amino-2-(trifluoromethyl)nicotinate (0.513 g, 1.96 mmol) was added to a 5:1 solution of water (10.9 mL) and cone HCl (2.17 mL) and then cooled in an ice brine bath. Sodium nitrite (0.180 g, 2.60 mmol) was added portionwise and the mixture was stirred for 15 min. A solution of sodium iodide (0.342 g, 2.28 mmol) in 2 mL water was allowed and the mixture was stirred for an hour. The reaction mixture was diluted with EtOAc and the organic layer was separated and dried over Na2SO4and Na2S2O3. The organic layer was filtered, concentrated, then purified as attached to furnish tert-butyl 5-iodo-2-(trifluoromethyl)nicotinate (402.6 mg, 1.079 mmol, 55.2% yield). LCMS m / z 396.4 (M+H+Na).

[0562] Intermediate 22: tert-butyl 5-(2-(dimethylamino)ethoxy)-2-(trifluoromethyl)nicotinate

[0563]

[0564] To a solution of tert-butyl 5-iodo-2-(trifluoromethyl)nicotinate (0.126 g, 0.338 mmol) dissolved in toluene (0.169 mL) was added 1,10-phenanthroline (6.09 mg, 0.034 mmol), copper(I) iodide (3.22 mg, 0.017 mmol), Cs2CO3(0.220 g, 0.675 mmol), and 2-(dimethylamino)ethan-l-ol (0.068 mL, 0.68 mmol). The reaction was blanketed under nitrogen and heated to 90 °C overnight. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, dried over Na2SC>4, filtered, and concentrated to furnish tert-butyl 5-(2-(dimethylamino)ethoxy)-2-(trifluoromethyl)nicotinate (41.7 mg, 0.125 mmol, 36.9 % yield). LCMS m / z 335.5 (M+H)

[0565] Intermediate 23: 5-(2-(dimethylamino)ethoxy)-2-(trifluoromethyl)nicotmic acid, HCl salt

[0566]

[0567] To a solution of tert-butyl 5-(2-(dimethylamino)ethoxy)-2-(trifluoromethyl)nicotinate (0.0471 g, 0.141 mmol) dissolved in DCM (1.1 mL) was added TFA (0.28 mL) and then the mixture was stirred overnight. The reaction mixture was concentrated and the residue was partitioned between 300 pL IN HC1 and ether. The organic layer was separated and concentrated to dryness to afford 5-(2-(dimethylamino)ethoxy)-2-(trifluoromethyl)nicotinic acid, HC1 (41.7 mg, 0.133 mmol, 94 % yield). LC / MS m / z 227.1 (M-H).

[0568] Intermediate 24: ethyl 5-(l-(tert-butoxycarbonyl)azetidin-3-yl)-2-methylnicotinate — ( / \ — Z^N-Boc

[0569]

[0570] EtO2C

[0571] A vial containing ethyl 5-iodo-2-methylnicotinate (191 mg, 0.656 mmol), l-(tert-butyl) 3-(l,3-dioxoisoindolin-2-yl) azetidine-l,3-dicarboxylate (250 mg, 0.722 mmol), (chloro-l5-azaneyl)(5-methoxypyridin-2-yl)methanimine (25 mg, 0.13 mmol), TBAI (242 mg, 0.656 mmol), and zinc (429 mg, 6.56 mmol) was blanketed with N2. The mixture was then solubilized with N, N-Dimethylacetamide (5 mL) containing TFA (0.03 mL, 0.3 mmol) and the resulting mixture was vigorously stirred at rt. After 4 h, the mixture was diluted with EtOAc and filtered through celite. The organic layer was washed with IN NaOH, followed by 10% aq LiCl, and brine then concentrated and the residue purified by silica gel to furnish ethyl 5-(l-(tert-butoxycarbonyl)azetidin-3-yl)-2-methylnicotinate (150 mg, 0.468 mmol, 71.3 % yield). LCMS m / z 321.1 (M+H).

[0572] Intermediate 25: 5-(l-(tert-butoxycarbonyl)azetidin-3-yl)-2-methylnicotinic acid

[0573] OH

[0574] O=Z

[0575] — d p — Z^NBoc

[0576]

[0577] To a solution of ethyl 5-(l-(tert-butoxycarbonyl)azetidin-3-yl)-2-methylnicotinate (0.150 g, 0.468 mmol) in THF (3.5 mL) was added LiOH (0.039 g, 0.94 mmol) in water (1.1 mL). The mixture was treated with 1 eq of IM HC1 then concentrated and the residue used crude as 5-(l-(tert-butoxycarbonyl)azetidin-3-yl)-2-methylnicotinic acid (0.137 g, 0.468 mmol, 100 % yield). LCMS m / z 292.8 (M+H). Intermediate 26: tert-butyl 3-(5-((5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)carbamoyl)-6-methylpyridin-3-yl)azetidine-1-carboxylate

[0578]

[0579] To a solution of 1-(5-(2-amino-5-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropan-2-ol (39.2 mg, 0.114 mmol) and 5-(l-(tert-butoxycarbonyl)azetidin-3-yl)-2-methylnicotinic acid (50 mg, 0.17 mmol) dissolved in DCM (1.1 mL) was added pyridine (0.09 mL, 1 mmol) and cooled to 0 °C. A 10% v / v DCM solution of POCh (21 pL, 0.23 mmol) was added and the reaction stirred for 5 minutes. The mixture was then extracted from phosphate buffer with EtOAc. The organic layer was concentrated and the residue used without further manipulation as tertbutyl 3-(5-((5-fluoro-4-(2-(2 -hydroxy -2-methylpropyl)-3-isopropyl-3H-imidazo[4, 5-b]pyridin-5-yl)pyridin-2-yl)carbamoyl)-6-methylpyridin-3-yl)azetidine-l-carboxylate (70.4 mg, 0.114 mmol, 100 % yield). LCMS m / z 618.4 (M+H).

[0580] Intermediate 27: 5-(azetidin-3-yl)-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[ 4, 5-b ]pyridin-5-yl)pyridin-2-yl)-2-methylnicotinamide

[0581] F

[0582]

[0583] A solution of tert-butyl 3-(5-((5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)carbamoyl)-6-methylpyridin-3-yl)azetidine- 1-carboxylate (70 mg, 0.11 mmol) in DCM (2 mL) was treated with TFA (0.44 mL, 5.7 mmol). After 2 h, the mixture was diluted with toluene and concentrated. The residue was purified by reverse phase HPLC to furnish 5-(azetidin-3-yl)-N-(5-fluoro- 4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)-2-methylnicotinamide (3.1 mg, 6.0 pmol, 5.3 % yield). 'HNMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.17 - 9.04 (m, 1H), 8.97 (br s, 1H), 8.71 (br d, J=2.4 Hz, 1H), 8.54 (br s, 2H), 8.17 (s, 1H), 7.95 - 7.79 (m, 1H), 4.35 - 4.27 (m, 2H), 4.25 - 4.19 (m, 2H), 3.46 (br s, 2H), 3.17 (s, 2H), 2.59 (br s, 3H), 2.51 (br s, 6H), 1.84 - 1.64 (m, 6H). LCMS Method A, RT = 1.11, MW = 518.2 (M+H).

[0584] Intermediate 28: tert-butyl 4-(2-((2-(trifluoromethyl)phenyl)sulfonyl) hydrazineylidene)piperidine-l -carboxylate

[0585]

[0586] CF3

[0587] To a solution of tert-butyl 4-oxopiperidine-l -carboxylate (0.095 g, 0.48 mmol) dissolved in MeOH (2 mL) was added 2-(trifluoromethyl)benzenesulfono

[0588] hydrazide (0.11 g, 0.48 mmol) and the mixture was stirred for 20 min. The reaction mixture was concentrated to furnish tert-butyl 4-(2-((2-(trifluoromethyl)phenyl)sulfonyl)hydrazineylidene)piperidine-l -carboxylate (0.20 g, 0.48 mmol, quant, yield) which was used without further purification. LCMS m / z 422.0 (M+H).

[0589] Intermediate 29: methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-methylpyrazine-2-carboxylate

[0590] o

[0591]

[0592] Yi

[0593] To a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate (0.13 g, 0.71 mmol) dissolved in DMF (1.6 mL) was added tert-butyl 4-(2-((2-(trifluoromethyl)phenyl)sulfonyl)hydrazineylidene)piperidine-l -carboxylate (0.20 g, 0.48 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (0.021 g, 0.095 mmol), 4,4'-diamino-2,2'-bipyridine (0.018 g, 0.095 mmol), dimethylphenylsilane (0.19 g, 1.4 mmol), and 1,2,2,6,6-pentamethylpiperidine (0.22 g, 1.4 mmol), and then heated to 75 °C for 16 h. The reaction mixture was partitioned between EtOAc and phosphate buffer. The organic phase was separated, concentrated and the residue purified by silica gel to furnish methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-methylpyrazine-2-carboxylate (64 mg, 0.19 mmol, 40 % yield). LCMS m / z 336.0 (M+H).

[0594] Intermediate 30: 3,5-difluorobenzenesulfonohydrazide

[0595] F

[0596]

[0597] To a solution of 3,5-difluorobenzenesulfonyl chloride (10. g, 47 mmol) dissolved in THF (70 mL) cooled in an ice bath was added hydrazine hydrate (6.7 mL, 120 mmol) dropwise and stirred for 30 min. The reaction mixture was diluted with EtOAc and washed repeatedly with brine 5 times. The organic phase was separated and dried over Na2SC>4, filtered, concentrated to furnish 3,5-difluorobenzenesulfonohydrazide (10 g, 47 mmol, quant, yield). LCMS m / z 206.9 (M-H), ' H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.64 (tt, J=9.2, 2.3 Hz, 1H), 7.52 - 7.38 (m, 2H), 4.34 (br s, 2H).

[0598] Intermediate 31: tert-butyl 6-(2-((3,5-difluorophenyl)sulfonyl)hydrazineylidene)-2-azabicyclo [2.2.1 ]heptane-2-carboxylate

[0599] F

[0600]

[0601] To a solution of tert-butyl 6-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.19 g, 0.90 mmol) dissolved in MeOH (1.8 mL) was added 3,5-difluorobenzenesulfonohydrazide (0.19 g, 0.90 mmol) and stirred for 20 min. The mixture was concentrated to furnish tert-butyl 6-(2-((3,5-difluorophenyl)sulfonyl)hydrazineylidene)-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.36 g, 0.90 mmol, quant yield) which was used without further manipulation. LCMS m / z 400.0 (M-H). Intermediate 32: tert-butyl 6-(6-(difluoromethyl)-5-(ethoxycarbonyl)pyridin-3-yl)-2-azabicyclo[2.2.1 ]heptane-2-carboxylate

[0602] F

[0603]

[0604] To a solution of ethyl 5-bromo-2-(difluoromethyl)nicotinate (0.21 g, 0.75 mmol) and tert-butyl 6-(2-((3,5-difluorophenyl)sulfonyl)hydrazineylidene)-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.20 g, 0.50 mmol) dissolved in DMF (1.7 mL) was added sodium chloride (30 mg, 0.50 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (0.022 g, 0.10 mmol), 4,4'-diamino-2,2'-bipyridine (0.019 g, 0.10 mmol), dimethylphenylsilane (0.23 mL, 1.5 mmol), and 1,2,2,6,6-pentamethylpiperidine (0.27 mL, 1.5 mmol), then heated to 75 °C for 16 h. The reaction mixture was partitioned between EtOAc and phosphate buffer. The organic phase was separated, concentrated and the residue purified by silica gel to furnish tert-butyl 6-(6-(difluoromethyl)-5-(ethoxycarbonyl)pyridin-3-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (50 mg, 0.13 mmol, 25 % yield). LCMS m / z 396.9 (M+H).

[0605] Example 1: 2-(2,2-difluoroethoxy)-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)-5-(methylsulfonyl)isonicotinamide

[0606]

[0607] 1-(5-(2-amino-5-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-methylpropan-2-ol (20 mg, 0.058 mmol) and 2-(2,2-difluoroethoxy)-5-(methylsulfonyl)isonicotinic acid (18 mg, 0.064 mmol) were dissolved in pyridine (0.2 M). 1,2-dichloro-1,3-dimethylimidazolidin-1-ium-2-ide (11 mg, 0.064 mmol) was added and then the reaction was heated to 100 °C. After 1 h, an additional amount of 1,2- dichloro-1,3-dimethylimidazolidin-1-ium-2-ide (11 mg, 0.064 mmol) was added. The reaction was concentrated and diluted with EtOAc and water. The mixture was extracted 3x with EtOAc and then concentrated. The resulting crude residue was purified via preparative reverse phase chromatograph (95:5 MeCN:H2O and 10 mM ammonium acetate / 5:95 MeCN:H2O and 10 mM ammonium acetate, 25-100%) to obtain the title compound (1.7 mg, 4.8% yield). 'HNMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H), 9.00 (d, J=6.1 Hz, 1H), 8.73 (s, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.16 (d, J=8.3 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 6.60 - 6.32 (m, 1H), 5.06 - 4.99 (m, 1H), 4.77 (td, J=15.1, 3.2 Hz, 2H), 3.11 (s, 2H), 3.00 (s, 3H), 1.74 (d, J=6.7 Hz, 6H), 1.28 (s, 6H). LCMS m / z 607.0 (M+H), Method A, 1.49 min.

[0608] Example 2: N-( 4-( 2-acetamido-3-isopropyl-3H-imidazo[ 4, 5-b ]pyridin-5-yl)-5-fluoropyridin-2-yl)-2-methyl-5-(trifluoromethyl)nicotinamide

[0609] F

[0610] N. / ) — A 'N

[0611] HN N^ NHAG

[0612] IXCH3

[0613] F3C — — CH 3

[0614]

[0615] To a solution of N-(3-isopropyl-5-(trimethylstannyl)-3H-imidazo[4,5-b]pyridin-2- yl)acetamide (0.025 g, 0.066 mmol) and N-(5-fluoro-4-iodopyridin-2-yl)-2-methyl-5- (trifluoromethyl)nicotinamide (0.033 g, 0.079 mmol) dissolved 0.1M in dioxane was added bis(dibenzylideneacetone)palladium(0) (3.77 mg, 6.56 pmol) and tri-tert- butylphosphonium tetrafluorob orate (1.9 mg, 6.6 pmol), then heated to 100 °C overnight. The reaction was diluted with DMF and rinsed twice with hexanes. The DMF layer was purified via reverse phase column chromatography (10-100% 10 / 90 / 1 water / MeCN / TFA and 90 / 10 / 1 water / MeCN / TFA) to yield the title compound (27.5 mg, 65.9 % yield). 'H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 9.00 (d, J=6.2 Hz, 1H), 8.96 (d, J=1.3 Hz, 1H), 8.54 (d, J=2.6 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 8.11 (br d, J=8.3 Hz, 1H), 7.87 (dd, J=8.2, 1.0 Hz, 1H), 4.87 - 4.64 (m, 1H), 2.68 (s, 3H), 2.22 (s, 3H), 1.72 (d, J=6.9 Hz, 6H). LCMS Method M, RT = 1.45 min. m / z = 516.2. Example 3: N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b ]pyridin-5-yl)pyridin-2-yl)-2-methyl-5-( I -methylazetidin-3-yl)nicotinamide

[0616]

[0617] A solution of 5-(azetidin-3-yl)-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)-2-methylnicotinamide (25 mg, 0.048 mmol) in MeOH (1 mL) was treated with 37% aq. formaldehyde (36 pL, 0.48 mmol) followed by sodium triacetoxyborohydride (31 mg, 0.15 mmol). The mixture was stirred overnight and was extracted from brine with EtOAc. The organic layer was concentrated and the residue purified by prep rev phase HPLC to furnish N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)-2-methyl-5-(l-methylazetidin-3-yl)nicotinamide (2.8 mg, 5.0 pmol, 10 % yield).1H NMR (500 MHz, DMSO-d6) δ 11.28 - 11.04 (m, 1H), 8.97 (br d, J=5.5 Hz, 1H), 8.50 (br d, J=13.4 Hz, 2H), 8.13 (br d, J=8.2 Hz, 1H), 7.97 (s, 1H), 7.80 (br d, J=8.2 Hz, 1H), 5.09 - 4.94 (m, 1H), 3.68 - 3.53 (m, 2H), 3.18 (br s, 1H), 3.08 (s, 2H), 2.56 - 2.55 (m, 3H), 2.28 (s, 3H), 1.74 (br d, J=6.6 Hz, 6H), 1.28 (s, 6H). LCMS Method A, 1.06 min. m / z = 532.2.

[0618] Example 4: N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)-5-(3-hydroxyprop-l-yn-l-yl)-2-methylnicotinamide

[0619]

[0620] A slurry of 5-bromo-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)-2-methylnicotinamide (20 mg, 0.037 mmol), prop-2-yn-l-ol (10 mg, 0.19 mmol), Pd(Ph3P)4 (0.9 mg, 0.7 pmol) and copper(I) iodide (0.1 mg, 0.4 pmol) in TEA (0.5 mL) / DMF (0.2 mL) was degassed, blanketed under N2 and heated to 80 °C overnight. The mixture was extracted from water with EtOAc. The organic layer was concentrated and the residue purified by reverse phase HPLC to furnish N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-yl)-5-(3 -hydroxyprop- l-yn-l-yl)-2 -methylnicotinamide (6.2 mg, 0.012 mmol, 32 % yield). 'HNMR (500 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.94 (br d, J=5.9 Hz, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 8.13 (br d, J=7.2 Hz, 1H), 7.95 (s, 1H), 7.81 (br d, J=8.1 Hz, 1H), 5.02 (dt, J=13.6, 6.8 Hz, 1H), 4.34 (s, 2H), 3.08 (br s, 2H), 2.58 (s, 3H), 1.73 (br d, J=6.6 Hz, 6H), 1.27 (s, 6H) Protons missing due to solvent suppression or exchange or overlap with the NMR solvent. LCMS Method O, RT = 1.27 min. m / z = 517.0.

[0621] The following Examples in Table 3 were made by using the similar procedures as shown above in Intermediates 1-31 and Examples 1-4 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.

[0622] Table 3

[0623] HPLC Method, RT (min) Ex LCMS (M+H)+

[0624] Structure & Name

[0625] #1H NMR (500 MHz, DMSO-d6,

[0626]

[0627] unless otherwise indicated) Method A, 1.78 min

[0628] 566.3

[0629] δ 11.48 (s, 1H), 8.98 (d, J=6.2 Hz, 1H), 8.72 (s, 1H), 8.51 (s, 1H), 8.21 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.22 (s, 1H), 4.94 (dt, J=13.2, 6.7 Hz, 1H), 4.01 (s, 3H), 3.37 (s, 2H), 1.76 (d, J=6.6 Hz, 6H), 1.56 (s, 6H). N-(4-(2-(2-cyano-2-methylpropyl)-3- Protons missing due to solvent isopropyl-3H-imidazo[4,5-b]pyridin-5- suppression or exchange or y 1 )- 5 -fluoropyridin-2-yl)-2-methoxy-5 - overlap with the NMR solvent. (methylsulfonyl)isonicotinamide

[0630] Method A, 1.41 min

[0631] 517.2

[0632] δ 11.41 (s, 1H), 8.91 (br d, J=6.0 Hz, 1H), 8.84 (br d, J=4.1 Hz, 1H), 8.49 (br s, 1H), 8.21 (br d, J=7.6 Hz, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.86 - 7.77 (m, 2H), 5.00 (m, J=13.2, 6.7 Hz, 1H), 3.55 (s, 1H), N-(5-fluoro-4-(2-(2-hydroxy-2- 3.06 (s, 2H), 1.71 (br d, J=6.6 Hz, methylpropyl)-3-isopropyl-3H- 6H), 1.26 (s, 6H) imidazo[4,5-b]pyridin-5-yl)pyridin-2- yl)-2-(trifluoromethyl)ni cotinamide

[0633] Method A, 1.83 min

[0634] 550.2

[0635] δ 11.34 (s, 1H), 8.98 (d, J=6.1 Hz, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.25 (d, J=8.9 Hz, 1H), 8.20 (d, J=8.3 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.9 Hz, 1H), 5.10 (dt, J=13.6, 6.8 Hz, 1H), 4.01 (s, 3H), 3.17 - 3.12 (m, 1H), 2.50 - 2.47 (m, 1H), 2.15 - 2.07 (m, 1H), N-(4-(2-(2-cyanocyclopropyl)-3- 1.84 - 1.76 (m, 6H), 1.74 (br dd, isopropyl-3H-imidazo[4,5-b]pyridin-5- <7=8.5, 3.6 Hz, 1H). Protons y 1 )- 5 -fluoropyridin-2-yl)-6-methoxy-3 - missing due to solvent (methylsulfonyl)picolinamide suppression or exchange or

[0636]

[0637] overlap with the NMR solvent. Method A, 1.54 min

[0638] 599.1

[0639] δ 11.29 (s, 1H), 8.89 (d, J=6.0 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.24 (d, J=8.9 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.84 (br d, J=8.2 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 5.57 - 5.43 (m, 1H), 4.97 (s, 1H), 4.70 - 4.59 (m, 1H), 4.10 (br t, N-(5-fluoro-4-(2-(2-hydroxy-2- J=6.1 Hz, 1H), 4.01 (s, 3H), 3.77 methylpropyl)-3-((2R,3R)-2- - 3.69 (m, 1H), 3.46 - 3.36 (m, methyltetrahydrofuran-3 -yl)-3H- 1H), 3.21 - 3.00 (m, 2H), 1.37 - imidazo[4,5-b]pyridin-5-yl)pyridin-2- 1.21 (m, 6H), 0.71 (d, J=6.3 Hz, yl)-6-m ethoxy-3 - 3H). Protons missing due to (methylsulfonyl)picolinamide solvent suppression or exchange or overlap with the NMR solvent.

[0640] Method A, 1.36 min

[0641] 557.2

[0642] δ 11.49 (s, 1H), 8.99 (d, J=6.2 Hz, 1H), 8.72 (s, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.16 (d, J=8.3 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.23 (m, 1H), 5.10 - 4.97 (m, 1H), 4.02 (s, 3H), 3.11 (s, 2H), 1.74 (d, J=6.7 Hz, 6H), 1.28 (s, 6H). N-(5-fluoro-4-(2-(2-hydroxy-2- Protons missing due to solvent methylpropyl)-3-isopropyl-3H- suppression or exchange or imidazo[4,5-b]pyridin-5-yl)pyridin-2- overlap with the NMR solvent. yl)-2-methoxy-5- (methylsulfonyl)isonicotinamide

[0643] Method A, 1.38 min

[0644] 584.1

[0645] δ 9.23 (s, 1H), 8.87 (d, J=6.0 Hz, 1H), 8.54 (d, J=2.4 Hz, 1H), 8.16 (d, J=8.3 Hz, 1H), 7.85 (br d, J=8.1 Hz, 1H), 5.50 (dt, J=9.5, 4.7 Hz, 1H), 4.63 (td, J=8.3, 3.6 Hz, 1H), 4.10 (br t, J=6.2 Hz, 1H), 3.72 (q, J=7.9 Hz, 1H), 3.47 N-(5-fluoro-4-(2-(2-hydroxy-2- (s, 1H), 3.24 - 2.99 (m, 2H), 2.82 methylpropyl)-3-((2R,3R)-2- (s, 3 H), 2.48 - 2.43 (m, 1H), 1.34 methyltetrahydrofuran-3 -yl)-3H- - 1.19 (m, 6H), 0.71 (d, J=6.3 Hz, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 3H). Protons missing due to yl)-2-methyl-5- solvent suppression or exchange (methylsulfonyl)pyrimidine-4- or overlap with the NMR solvent.

[0646]

[0647] carb oxami de Method B, 1.074 min

[0648] 511

[0649] 1H NMR (400 MHz, Methanol- d4) δ 9.32 (s, 1H), 9.07 (d, J= 6.0 Hz, 1H), 8.42 (d, J= 3.2 Hz, 1H), 8.04 (d, J= 8.4 Hz, 1H), 7.88 (d, J= 8.4 Hz, 1H), 4.98-4.78 (m, 1H), 3.54 (s, 3H), 2.91 (s, 3H), 2.78-2.61 (m, 2H), 2.32-2.29 (m, N-(4-(2-amino-3-cyclopentyl-3H- 2H), 2.26-2.18 (m, 2H), 1.88-1.76 imidazo[4,5-b]pyridin-5-yl)-5- (m, 2H). Protons missing due to fluoropyri din-2 -yl)-2-methyl-5- solvent suppression or exchange (methylsulfonyl)pyrimidine-4- or overlap with the NMR solvent.

[0650] carb oxami de

[0651] Method J, 0.689 min

[0652] 584

[0653] 1H NMR (400 MHz, Methanol- d4) δ 9.19 (s, 1H), 9.16 (d, J = 6.0 Hz, 1H), 8.45 (s, 1H), 8.29 (d, J= 8.4 Hz, 1H), 8.20 (d, J= 8.4 Hz, 1H), 4.33-4.29 (m, 1H), 4.22 (s, 3H), 3.50 (s, 3H), 3.32 (s, 2H), 2.39-2.37 (m, 1H), 1.98 (d, J= (R)-N-(4-(3 -(1 -cy clopropylethyl)-2-(2- 6.8 Hz, 3H), 1.42 (s, 3H), 1.39 (s, hydroxy-2-methylpropyl)-3H- 3H), 0.84-0.82 (m, 1H), 0.66-0.64 imidazo[4,5-b]pyridin-5-yl)-5- (m, 1H), 0.55-0.40 (m, 2H). fluoropyri din-2 -yl)-2-methoxy-5- Protons missing due to solvent (methylsulfonyl)pyrimidine-4- suppression or exchange or carb oxami de overlap with the NMR solvent.

[0654] Method F, 1.224 min

[0655] 583

[0656] 1H NMR (400 MHz, Methanol- d4) δ 9.10 (d, J= 6.0 Hz, 1H), 8.81 (s, 1H), 8.43 (d, J= 2.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.21 (d, J= 8.4 Hz, 1H), 7.10 (s, 1H), 4.37-4.27 (m, 1H), 4.10 (s, 3H), 3.39 (s, 3H), 3.36-3.29 (m, 2H), 2.39-2.35 (m, 1H), 1.98 (d, J (R)-N-(4-(3 -(1 -cy clopropylethyl)-2-(2- = 6.8 Hz, 3H), 1.42 (s, 3H), 1.39 hydroxy-2-methylpropyl)-3H- (s, 3H), 0.84-0.80 (m, 1H), 0.64- imidazo[4,5-b]pyridin-5-yl)-5- 0.61 (m, 1H), 0.52-0.39 (m, 2H). fluoropyri din-2 -yl)-2-methoxy-5- Protons missing due to solvent (methylsulfonyl)isonicotinamide suppression or exchange or

[0657]

[0658]

[0659] overlap with the NMR solvent. F Method J, 0.9 min

[0660] 617

[0661] A ZN CN

[0662] W7M H UCH31H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.18 (s, 1H), 8.99 H3CO2S 5=0 13(d, 4= 6.0 Hz, 1H), 8.57 (d, 4 = < M / N FH3CACH= 2.8 Hz, 1H), 8.23 (d, J= 8.4 Hz,

[0663] 1H), 7.88 (d, J = 8.4 Hz, 1H), 6.75-6.16 (m, 1H), 5.01-4.91 (m, N-(4-(2-(2-cyano-2-methylpropyl)-3- 1H), 4.90-4.78 (m, 2H), 3.47 (s, isopropyl-3H-imidazo[4,5-b]pyridin-5- 3H), 3.38 (s, 2H), 1.77 (d, J= 6.8 yl)-5-fluoropyridin-2-yl)-2-(2,2- Hz, 6H), 1.57 (s, 6H). difluoroethoxy)-5- (methylsulfonyl)pyrimidine-4- carb oxami de

[0664] F Method I, 3.721 min

[0665] 557

[0666] A # - C0H1H NMR (400 MHz, Methanol- '1 UCH3

[0667] HI / d4) 69.17 (d, J = 6.0 Hz, 1H), H3CO2S Wo / CH38.43 (d, J = 2.8 Hz, 1H), 8.34 (d,

[0668] J = 8.8 Hz, 1H), 8.29 (d, J = 8.4 MH3cAch= Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H),

[0669] 7.12 (d, J = 8.8 Hz, 1H), 5.30- OCH3

[0670] 5.18 (m, 1H), 4.12 (s, 3H), 3.47 N-(5-fluoro-4-(2-(2-hydroxy-2- (s, 3H), 3.45 (s, 2H), 1.97 (d, J = methylpropyl)-3-isopropyl-3H- 6.8 Hz, 6H), 1.45 (s, 6H). Protons imidazo[4,5-b]pyridin-5-yl)pyridin-2- missing due to solvent

[0671] yl)-6-m ethoxy-3 - suppression or exchange or (methylsulfonyl)picolinamide overlap with the NMR solvent.

[0672] F Method J, 0.88 min

[0673] 618

[0674] {w J'J1H NMR (400 MHz, Methanol-HW N-W <4) 69.35 (s, 1H), 9.14 (4= 6.0 H3CO2S Wo 1 Hz, 1H), 8.48 (s, 1H), 8.41 (d, J= yy H3CACH32.8 Hz, 1H), 8.20 (d, J= 8.4 Hz,

[0675] 1H), 8.09-8.04 (m, 2H), 5.01-4.97 N=( CH3(m, 1H), 4.44 (s, 3H), 4.20 (q, J= >N10.4 Hz, 2H), 3.50 (s, 3H), 1.90N\^N(d, J= 6.8 Hz, 6H). Protons N-(5-fluoro-4-(3-isopropyl-2-(2,2,2- missing due to solvent trifluoroethyl)-3H-imidazo[4,5- suppression or exchange or b]pyridin-5-yl)pyridin-2-yl)-2-(l- overlap with the NMR solvent. methyl-lH-l,2,4-triazol-5-yl)-5-

[0676]

[0677] (methylsulfonyl)isonicotinamide Method J, 0.631 min

[0678] 584

[0679] 1H NMR (400 MHz, Methanol-d4) δ 9.32 (s, 1H), 9.26 (d, J = 6.4 Hz, 1H), 8.46 (d, J = 3.2 Hz, 1H), 8.24-8.20 (m, 2H), 4.99-4.97 (m, 1H), 4.12-3.99 (m, 2H), 3.94-3.88 (m, 1H), 3.54 (s, 3H), 3.37 (s, 2H), 3.28-3.16 (m, 1H), 2.92 (s, (R)-N-(5-fluoro-4-(2-(2 -hydroxy -2- 3H), 2.21-2.19 (m, 1H), 1.96-1.93 methylpropyl)-3-(tetrahydro-2H-pyran- (m, 2H), 1.44 (s, 6H). Protons 3-yl)-3H-imidazo[4,5-b]pyridin-5- missing due to solvent yl)pyridin-2-yl)-2-methyl-5- suppression or exchange or (methylsulfonyl)pyrimidine-4- overlap with the NMR solvent.

[0680] carb oxami de

[0681] Method A, 1.56 min

[0682] 500.2

[0683] δ 9.07 - 8.98 (m, 1H), 8.94 (s, 1H), 8.42 (br s, 1H), 8.34 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 6.98 (s, 2H), 3.83 - 3.70 (m, 1H), 2.67 (s, 3H), 2.11 - 1.99 (m, 1H), 1.74 (br d, J=6.6 (R)-N-(4-(2-amino-3-(l- Hz, 3H), 0.70 - 0.57 (m, 1H), 0.45 cyclopropylethyl)-3H-imidazo[4,5- - 0.32 (m, 2H), 0.29 (br d, J=5.6 b]pyridin-5-yl)-5-fluoropyridin-2-yl)- Hz, 1H). Protons missing due to 2-methyl-5- solvent suppression or exchange (trifluoromethyl)nicotinamide or overlap with the NMR solvent.

[0684] Method K, 1.528 min

[0685] 533

[0686] 1H NMR (400 MHz, Methanol- d4) δ 9.32 (s, 1H), 9.19 (d, J= 6.4 Hz, 1H), 8.41 (d, J= 3.2 Hz, 1H), 8.03-8.00 (m, 2H), 3.96-3.78 (m, 1H), 3.56 (s, 3H), 2.92 (s, 3H), 2.25 (s, 3H), 2.29-2.18 (m, 1H), 1.92 (d, J = 6.4 Hz, 3H), 0.82- N-(4 -(2 -acetami do-3 - ( 1 - 0.71 (m, 1H), 0.56-0.41 (m, 2H), cyclopropylethyl)-3H-imidazo[4,5- 0.37-0.28 (m, 1H). Protons b]pyridin-5-yl)-5-fluoropyridin-2-yl)- missing due to solvent

[0687] 2-methyl-5- suppression or exchange or (methylsulfonyl)pyrimidine-4- overlap with the NMR solvent.

[0688]

[0689] carb oxami de F Method J, 0.845 min

[0690] 618

[0691] 1H NMR (400 MHz, DMSO-d6+D2O) δ 9.04 (d, J= 6.0 Hz, H3CO2S WO / 1H), 8.70 (s, 1H), 8.56 (d, J= 2.4

[0692] H3C^CH3

[0693] Hz, 1H), 8.53 (d, J= 8.4 Hz, 1H), 8.40 (d, J= 8.4 Hz, 1H), 8.26 (d, J= 8.4 Hz, 1H), 7.92 (d, J= 8.4 VN Hz, 1H), 4.99-4.89 (m, 1H), 4.35 N h (q, J= 10.4 Hz, 2H), 4.01 (s, 3H),SCH3

[0694] 3.46 (s, 3H), 1.77 (d, J= 6.4 Hz, N-(5-fluoro-4-(3-isopropyl-2-(2,2,2- 6H). Protons missing due to trifluoroethyl)-3H-imidazo[4,5- solvent suppression or exchange b]pyridin-5-yl)pyridin-2-yl)-6-(l- or overlap with the NMR solvent. methyl-lH-l,2,4-triazol-3-yl)-3- (methylsulfonyl)picolinamide

[0695] F Method A, 1.5 min

[0696] 542.3

[0697] 6 11.33 (s, 1H), 9.01 (d, J=6.3 Hz, HN N^NHAc 1H), 8.52 (d, J=2.4 Hz, 1H), 8.25

[0698] (d, J=8.8 Hz, 1H), 8.20 - 8.02 (m,HICO!Q ° 1H), 7.86 (br d, J=8.1 Hz, 1H),

[0699] 7.18 (d, J=8.9 Hz, 1H), 4.72 - 4.46 (m, 1H), 4.02 (s, 3H), 3.40 OCH3(brm, 3 H), 2.19 (br s, 3H), 1.71 N-(4-(2-acetamido-3-isopropyl-3H- (br d, J=6.3 Hz, 6H) imidazo[4,5-b]pyridin-5-yl)-5- fluoropyri din-2 -yl)-6-methoxy-3- (methylsulfonyl)picolinamide

[0700] F Method J, 0.631 min

[0701] 556

[0702] \ # — C # ~N 0H

[0703] M |1 i CH31H NMR (400 MHz, Methanol- Hl / N> X / VH d4) δ 9.25 (s, 1H), 9.13 (d, J = 6.4 EtO2S )=O j3Hz, 1H), 8.44 (d, J= 2.8 Hz, 1H), W H3C^CH38.29 (d, J= 8.4 Hz, 1H), 8.19 (d,

[0704] J= 8.4 Hz, 1H), 5.23-5.18 (m, 1H), 3.70 (q, J = 7.6 Hz, 2H), Un3

[0705] 3.37 (s, 2H), 2.89 (s, 3H), 1.92 (d, 5-(ethylsulfonyl)-N-(5-fluoro-4-(2-(2- J= 6.8 Hz, 6H), 1.41 (s, 6H), hydroxy-2-methylpropyl)-3-isopropyl- 1.34 (t, J= 7.6 Hz, 3H). Protons H-imidazo[4,5-b]pyridin-5-yl)pyridin- missing due to solvent

[0706] 2-yl)-2-methylpyrimidine-4- suppression or exchange or

[0707]

[0708] carb oxami de overlap with the NMR solvent. F Method J, 0.779 min

[0709] 579

[0710] A # — 4 / T'N

[0711] Uc

[0712] 1n

[0713] CH31H NMR (400 MHz, DMSO-d6) 8 Hl / N^^VH 11.49 (s, 1H), 9.24 (s, 1H), 8.90 H3CO2S \=O:3(d, J = 6.0 Hz, 1H), 8.57 (d, J =

[0714] 2.4 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 5.48-5.33 (M, Ih), 4.58-4.52 (m, ^CH3

[0715] 1H), 4.17-4.12 (m, 2H), 4.05-4.01 (R)-N-(4-(2-(2-cyano-2-methylpropyl)- (m, IH), 3.50-3.39 (m, 5H), 2.89- 3 -(tetrahydrofuran-3 -yl)-3H- 2.78 (m, 4H), 2.47-2.38 (m, IH), imidazo[4,5-b]pyridin-5-yl)-5- 1.56 (s, 6H). Protons missing due fluoropyri din-2 -yl)-2-methyl-5- to solvent suppression or (methylsulfonyl)pyrimidine-4- exchange or overlap with the carb oxami de NMR solvent.

[0716] F Method A, 1.82 min

[0717] 552.2

[0718] δ 11.52 (s, IH), 9.24 (s, IH), 8.97Hf / A|VF3 (d, J=6.1 Hz, IH), 8.56 (d, J=2.4 H3CO2S \=O 1 Hz, IH), 8.26 (d, J=8.4 Hz, IH), V / H3C-ACH7.91 (br d, J=8.4 Hz, IH), 5.03 - 4.88 (m, IH), 4.35 (q, J=10.6 Hz, 2H), 3.47 (s, 3H), 2.83 (s, 3H), Un31.76 (br d, J=6.7 Hz, 6H) N-(5-fluoro-4-(3-isopropyl-2-(2,2,2- trifluoroethyl)-3H-imidazo[4,5- b]pyridin-5-yl)pyridin-2-yl)-2-methyl- 5-(methylsulfonyl)pyrimidine-4- carb oxami de

[0719] F Method D, 1.438 min

[0720] 558

[0721] y \—U / / N 0H

[0722] ACH,1H NMR (400 MHz, DMSO-d6) δ HN 11.56 (s, IH), 9.13 (s, IH), 8.97 H3CO2S 5=O J3(d, J = 6.0 Hz, IH), 8.57 (d, J =H=CACH32.8 Hz, IH), 8.24 (d, J = 8.4 Hz,

[0723] IH), 7.94 (d, J = 8.4 Hz, IH), ACH35.11-5.04 (m, IH), 4.11 (s, 3H),

[0724] 3.17 (s, 2H), 1.76 (d, J = 6.8 Hz, N-(5-fluoro-4-(2-(2-hydroxy-2- 6H), 1.29 (s, 6H). Protons methylpropyl)-3-isopropyl-3H- missing due to solvent imidazo[4,5-b]pyridin-5-yl)pyridin-2- suppression or exchange or yl)-2-methoxy-5-(methylsulfonyl)

[0725] overlap with the NMR solvent.

[0726]

[0727] pyrimidine-4-carboxamide Method J, 0.736 min

[0728] 530

[0729] 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 9.00 (d, J = 6.0 Hz, 1H), 8.96 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.16 (s, 2H), 7.88 (d, J = 8.0 Hz, 1H), 5.02 - 4.88 (m, 1H), 3.37 (s, 2H), N-(4-(2-(2-amino-2-methylpropyl)-3- 2.68 (s, 3H), 1.77 (d, J = 6.4 Hz, isopropyl-3H-imidazo[4,5-b]pyridin-5- 6H), 1.43 (s, 6H)

[0730] yl)-5-fluoropyridin-2-yl)-2-methyl-5- (trifluoromethyl)nicotinamide

[0731] Method D, 1.37 min

[0732] 484

[0733] 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.97-8.96 (m, 2H), 8.51 (d, J = 5.2 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), N-(4 -(2 -acetami do-3 -ethy 1 -3 H- 7.91 (dd, J = 5.2, 2.0 Hz, 1H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 4.34 (q, J = 6.8 Hz, 2H), 2.70 (s, yl)-2-methyl-5- 3H), 2.28 (s, 3H), 1.45 (t, J = 6.8 (trifluoromethyl)nicotinamide Hz, 3H) _

[0734] Method G, 1.421 min

[0735] 567

[0736] 1H NMR (400 MHz, Methanol-d4) δ 9.09 (d, J = 6.0 Hz, 1H), 8.81 (s, 1H), 8.40 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 5.02-4.84 (m, 1H), 4.28-4.10 (m, 1H), 4.10 (s, 3H), 3.40 (s, 3H), 1.90 (d, J = N-(5-fluoro-4-(3-isopropyl-2-(2,2,2- 6.8 Hz, 6H). Protons missing due trifluoroethyl)-3H-imidazo[4,5- to solvent suppression or b]pyridin-5-yl)pyridin-2-yl)-2- exchange or overlap with the methoxy-5- NMR solvent.

[0737]

[0738] (methylsulfonyl)isonicotinamide Method J, 0.572 min

[0739] 521

[0740] 1H NMR (400 MHz, Methanol- d4) δ 9.10 (d, J = 6.0 Hz, 1H), 8.50-8.40 (m, 2H), 8.34 (s, 1H), 8.22-8.10 (m, 2H), 5.78-5.57 (m, 1H), 4.81-4.78 (m, 1H), 4.40-4.32 (m, 1H), 4.31-4.23 (m, 1H), 4.18- (R)-N-(5-fluoro-4-(2-(2 -hydroxy -2- 4.08 (m, 1H), 4.04 (s, 3H), 3.45 methylpropyl)-3 -(tetrahy drofuran-3 - (s, 2H), 3.03-2.90 (m, 1H), 2.76 yl)-3H-imidazo[4,5-b]pyridin-5- (s, 3 H), 2.65-2.53 (m, 1H),1.43 yl)pyridin-2-yl)-5-methoxy-2- (s, 6H). Protons missing due to methylnicotinamide solvent suppression or exchange or overlap with the NMR solvent. Method A, 1.22 min

[0741] 604.4

[0742] δ 9.01 - 8.89 (m, 1H), 8.52 (br s, 2H), 8.13 (br d, J=8.2 Hz, 1H), 7.86 (br s, 1H), 7.81 (br d, J=8.1 Hz, 1H), 5.13 - 4.95 (m, 1H), 4.29 (br s, 2H), 3.08 (s, 2H), 2.68 (br s, 2H), 2.23 (s, 6H), 1.91 (s, 1H), 5-(2-(dimethylamino)ethoxy)-N-(5- 1.73 (br d, J=6.6 Hz, 6H), 1.28 (s, fluoro-4-(2-(2 -hydroxy -2- 6H). Protons missing due to methylpropyl)-3-isopropyl-3H- solvent suppression or exchange imidazo[4,5-b]pyridin-5-yl)pyridin-2- or overlap with the NMR solvent. yl)-2-(trifluoromethyl)ni cotinamide

[0743] Method A, 1.79 min

[0744] 550.5

[0745] δ 10.60 (s, 1H), 8.96 (d, J=6.1 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.28 (d, J=2.6 Hz, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.46 (d, J=2.2 Hz, 1H), 5.03 (dt, J=13.6, 6.8 Hz, 1H), 4.24 (t, J=5.6 Hz, 2H), 3.09 (s, 2H), 2.74 5-(2-(dimethylamino)ethoxy)-N-(5- - 2.64 (m, 5H), 2.23 (s, 6H), 1.80 fluoro-4-(2-(2 -hydroxy -2- - 1.69 (m, 6H), 1.28 (s, 6H). methylpropyl)-3-isopropyl-3H- Protons missing due to solvent imidazo[4,5-b]pyridin-5-yl)pyridin-2- suppression or exchange or overlap with the NMR solvent.

[0746]

[0747]

[0748] yl)-3-methylpicolinamide F Method E, 1.094 min

[0749] 529

[0750] 1H NMR (400 MHz, Methanol- HN T^^NHAC

[0751] Vo J d4) δ 9.12 (d, J = 5.2 Hz, 1H), / =\H3CCH, 8.73 (d, J = 2.0 Hz, 1H), 8.42 (d, / - 4 Z>—CH3 J = 2.8 Hz, 1H), 8.16-8.10 (m, H3C-N

[0752] " CH33H), 5.04-4.93 (m, 1H), 4.40 (s,

[0753] 2H), 3.06 (s, 6H), 2.74 (s, 3H), N-(4-(2-acetamido-3-isopropyl-3H- 2.40 (s, 3H), 1.90 (d, J = 6.8 Hz, imidazo[4,5-b]pyridin-5-yl)-5- 6H). Protons missing due to fluoropyridin-2-yl)-5 -(3 - solvent suppression or exchange (dimethylamino)prop- 1 -yn- 1 -yl)-2- or overlap with the NMR solvent. methylnicotinamide

[0754] F Method J, 0.694 min

[0755] 596

[0756] 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.93 (s, 1H), 8.80 (d, J = 6.0 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.28 (d, J = 8.4 Hz,F3C^=4CH3 1H), 8.27 (s, 1H), 7.84 (s, 1H),

[0757] 5.00-4.84 (m, 1H), 4.32 (q, J = H36

[0758] 10.8 Hz, 2H), 3.70-3.50 (m, 2H), N-(5-fluoro-4-(3-(l-methylpiperidin-4- 3.44-3.20 (m, 4H), 2.95-2.90 (m, yl)-2-(2,2,2-trifluoroethyl)-3H- 3H), 2.73 (s, 3H), 2.22-2.08 (m, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2H)

[0759] yl)-2-methyl-5- (trifluoromethyl)nicotinamide

[0760] F Method I, 4.08 min

[0761] 624

[0762] 1H NMR (400 MHz, Methanol-d4) δ 9.44 (d, J = 6.0 Hz, 1H), yo 8.90 (d, J = 2.4 Hz, 1H), 8.40- 8.39 (m, 1H), 8.18 (s, 1H), 8.18- F3C— y CH3L J 8.15 (m, 2H), 4.88-4.85 (m, 1H),

[0763] 4.69-4.67 (m, 1H), 4.22-3.94 (m, H3C'CH31H), 3.91-3.89 (m, 1H), 3.34-3.32

[0764] (m, 1H), 3.33-3.27 (m, 1H), 2.84 N-(4-(3-((lr,4r)-4- (s, 6H), 2.77 (s, 3H), 2.32-2.29 (dimethylamino)cyclohexyl)-2-(2,2,2- (m, 2H), 2.19-2.11 (m, 2H), 1.91- trifluoroethyl)-3H-imidazo[4,5- 1.82 (m, 2H). Protons missing b]pyridin-5-yl)-5-fluoropyridin-2-yl)- due to solvent suppression or 2-methyl-5- exchange or overlap with the (trifluoromethyl)nicotinamide

[0765]

[0766] NMR solvent. Method A, 1.45 min

[0767] 474

[0768] δ 11.26 (s, 1H), 9.02 (br d, J=5.7 Hz, 1H), 8.94 (s, 1H), 8.43 (d, J=2.9 Hz, 1H), 8.35 (s, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.05 (s, 2H), 4.76 - 4.62 (m, 1H), 2.67 (s, 3H), 1.66 (d, N-(4-(2-amino-3-isopropyl-3H- J=6.7 Hz, 6H)

[0769] imidazo[4,5-b]pyridin-5-yl)-5- fluoropyri din-2 -yl)-2-methyl-5- (trifluoromethyl)nicotinamide

[0770] F Method A, 1.5 min

[0771] 564.2

[0772] δ 11.01 (s, 1H), 8.92 (br d, J=6.0 Hz, 1H), 8.52 (s, 1H), 8.21 (br d, J=8.3 Hz, 1H), 7.89 (br dd, CH3J=16.5, 8.4 Hz, 2H), 6.73 (d, J=8.4 Hz, 1H), 5.14 - 4.99 (m, 1H), 4.38 (brt, J=6.0 Hz, 2H), 3.24 (br d, J=2.2 Hz, 2H), 3.16 (s, 'CH3

[0773] 2H), 2.83 (br s, 6H), 2.56 - 2.55 6-(3-(dimethylamino)propoxy)-N-(5- (m, 3H), 2.20 - 2.07 (m, 2H), 1.75 fluoro-4-(2-(2-hydroxy-2- (br d, J=6.6 Hz, 6H), 1.29 (s, 6H). methylpropyl)-3-isopropyl-3H- Protons missing due to solvent imidazo[4,5-b]pyridin-5-yl)pyridin-2- suppression or exchange or yl)-2-methylnicotinamide overlap with the NMR solvent.

[0774] Method A, 1.1 min

[0775] 477.2

[0776] δ 11.07 (s, 1H), 8.94 (br d, J=5.6 Hz, 1H), 8.49 (d, J=2.4 Hz, 1H), 8.39 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.79 (br d, J=8.4 Hz, 1H), 7.73 (s, 1H), 5.09 - 4.95 (m, 1H), 3.07 (s, 2H), 2.53 (s, 3H), 2.31 (s, 3H), 1.73 (br d, J=6.6 Hz, 6H), N-(5-fluoro-4-(2-(2-hydroxy-2- 1.27 (s, 6H). Protons missing due methylpropyl)-3-isopropyl-3H- to solvent suppression or imidazo[4,5-b]pyridin-5-yl)pyridin-2- exchange or overlap with the yl)-2,5-dimethylnicotinamide

[0777]

[0778] NMR solvent. Method A, 1.39 min

[0779] 560.3

[0780] δ 8.94 (br d, J=5.7 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.28 (d, J=2.7 Hz, 1H), 8.24 (d, J=8.3 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 4.94 (m, J=13.1, 6.7 Hz, 1H), 4.34 (q, J=10.6 Hz, 5-(2-amino-2-methylpropoxy)-N-(5- 2H), 3.81 (s, 2H), 1.88 (s, 3H), fluoro-4-(3-isopropyl-2-(2,2,2- I.75 (br d, J=6.8 Hz, 6H), 1.14 (s, trifluoroethyl)-3H-imidazo[4,5- 6H). Protons missing due to b]pyridin-5-yl)pyridin-2-yl)-2- solvent suppression or exchange methylnicotinamide or overlap with the NMR solvent.

[0781] Method H, 1.343 min

[0782] 567

[0783] 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.02 (d, J = 6.0 Hz, 1H), 8.95 (dd, J = 4.8, 1.6 Hz, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.44 (dd, J = 8.4, 1.6 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.89- 7.80 (m, 2H), 5.04-5.01 (m, 1H), 4.83 (s, 1H), 3.58 (d, J = 7.2 Hz, 2H), 3.08 (s, 2H), 1.74 (d, J = 6.4 3-((cyclopropylmethyl)sulfonyl)-N-(5- Hz, 6H), 1.28 (s, 6H), 0.98-0.94 fluoro-4-(2-(2 -hydroxy -2- (m, 1H), 0.55-0.46 (m, 2H), 0.24- methylpropyl)-3-isopropyl-3H- 0.14 (m, 2H). Protons missing imidazo[4,5-b]pyridin-5-yl)pyridin-2- due to solvent suppression or yl)picolinamide exchange or overlap with the NMR solvent.

[0784] Method E, 1.372 min

[0785] 582

[0786] 1H NMR (400 MHz, Methanol- d4) δ 9.31 (s, 1H), 9.16 (d, J = 6.0 Hz, 1H), 8.44 (d, J = 2.8 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 5.19 (m, 1H), 3.66 (d, J = 7.2 Hz, 2H), 2.92 (s, 3H), 1.92 (d, J = 6.8 Hz, 6H), 1.42 (s, 6H), 1.13 (m, 1H), 0.63- 5-((cyclopropylmethyl)sulfonyl)-N-(5- 0.60 (m, 2H), 0.33-0.31 (m, 2H). fluoro-4-(2-(2 -hydroxy -2- Protons missing due to solvent methylpropyl)-3-isopropyl-3H- suppression or exchange or imidazo[4,5-b]pyridin-5-yl)pyridin-2- overlap with the NMR solvent.

[0787]

[0788]

[0789] yl)-2-methylpyrimidine-4-carboxamide Method M, 1.81 min

[0790] 568

[0791] δ 11.54 (s, 1H), 9.13 (s, 1H), 8.97 (d, J=6.1 Hz, 1H), 8.57 (d,. / =2,6 Hz, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.91 (dd, J=8.3, 0.9 Hz, 1H), 5.00 - 4.88 (m, 1H), 4.36 (q, J=10.8 Hz, 2H), 4.12 (s, 3H), 3.44 (s, 3H), 1.76 (d, J=6.7 Hz, 6H). N-(5-fluoro-4-(3-isopropyl-2-(2,2,2- trifluoroethyl)-3H-imidazo[4,5- b]pyridin-5-yl)pyridin-2-yl)-2- methoxy-5- (methylsulfonyl)pyrimidine-4- carb oxami de

[0792] Method A, 1.02 min

[0793] 463.5

[0794] δ 11.14 (s, 1H), 8.94 (br d, J=5.6 Hz, 1H), 8.55 (dd, J=4.8, 1.5 Hz, 1H), 8.49 (d, J=2.6 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.80 (br d, J=8.3 Hz, 1H), 7.34 (dd, J=7.7, 4.9 Hz, 1H), 5.07 - 4.96 (m, 1H), 3.54 (br s, 3H), N-(5-fluoro-4-(2-(2-hydroxy-2- 3.08 (s, 2H), 1.74 (br s, 3H), 1.72 methylpropyl)-3-isopropyl-3H- (s, 3H), 1.27 (s, 6H). Protons imidazo[4,5-b]pyridin-5-yl)pyridin-2- missing due to solvent

[0795] yl)-2-methylnicotinamide suppression or exchange or overlap with the NMR solvent.

[0796] Method N, 1.8 min

[0797] 541.2

[0798] δ 11.28 (s, 1H), 8.97 (d, J=1.4 Hz, 1H), 8.49 (s, 1H), 8.30 (s, 1H), 7.97 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.45 (br d, J=8.0 Hz, 1H), 5.12 - 5.00 (m, 1H), 4.95 (s, 1H), 3.06 (s, 2H), 2.66 (s, 3H), 1.61 (d,. / =6,9 Hz, 6H), 1.27 (s, N-(5-fluoro-4-(2-(2-hydroxy-2- 6H). Protons missing due to methylpropyl)-3-isopropyl-3H- solvent suppression or exchange imidazo[4,5-b]pyridin-5-yl)pyridin-2- or overlap with the NMR solvent.

[0799] yl)-6-methyl-3-

[0800]

[0801] (methylsulfonyl)picolinamide Cl Method N, 1.78 min

[0802] 543.2

[0803] A # — C0Hδ 8.92 (br d, J=4.6 Hz, 1H), 8.57 NA '1 ACH3

[0804] Hl / (s, 1H), 8.55 (s, 1H), 8.42 (d, H3CO2S \=O

[0805] 31. / =8,0 Hz, 1H), 8.12 (d, J=8.3 Hz, H CACH3

[0806] 1H), 7.83 (dd, J=7.9, 4.9 Hz, 1H), 7.67 (d,. / =8,2 Hz, 1H), 5.06 - 4.94 (m, 1H), 3.07 (s, 2H), 1.69 N-(5-chloro-4-(2-(2-hydroxy-2- (br d, J=6.6 Hz, 6H), 1.27 (s, 6H). methylpropyl)-3-isopropyl-3H- Protons missing due to solvent imidazo[4,5-b]pyridin-5-yl)pyridin-2- suppression or exchange or yl)-3-(methylsulfonyl)picolinamide

[0807] overlap with the NMR solvent. F Method A, 1.33 min

[0808] 542.2

[0809] A # - C0H

[0810] NA '1 UCH3δ 9.23 (s, 1H), 8.98 (d, J=6.1 Hz, Hl / 1H), 8.55 - 8.51 (m, 1H), 8.14 (d, H3CO2S )=O / 3. / =8,2 Hz, 1H), 7.84 (br d,. / =7,6 W H3C^CH3Hz, 1H), 5.11 - 4.93 (m, 1H), 3.08 / / AI

[0811] (s, 2H), 2.83 (s, 3H), 1.74 (br d, ^CHg J=6.6 Hz, 6H), 1.28 (s, 6H).

[0812] Protons missing due to solvent N-(5-fluoro-4-(2-(2-hydroxy-2- suppression or exchange or methylpropyl)-3-isopropyl-3H- overlap with the NMR solvent. imidazo[4,5-b]pyridin-5-yl)pyridin-2- yl)-2-methyl-5- (methylsulfonyl)pyrimidine-4- carb oxami de

[0813] Method N, 1.65 min

[0814] F

[0815] 526.9

[0816] N. z> — 4 A--N OH δ 11.34 (s, 1H), 9.01 (d, J=6.2 A^7M || ACH3Hz, 1H), 8.96 - 8.92 (m, 1H), 8.52 HN (d,.7=2.4 Hz, 1H), 8.44 (dd, H3CO2S )=O / 3

[0817] H3CACJ=8.1, 1.3 Hz, 1H), 8.13 (d, J=8.3 / / AI Hz, 1H), 7.84 (br d, J=8.0 Hz,

[0818] 2H), 5.01 (dt, J=13.5, 6.7 Hz, N-(5-fluoro-4-(2-(2-hydroxy-2- 1H), 4.89 (s, 1H), 3.08 (s, 2H), methylpropyl)-3-isopropyl-3H- 1.74 (d,.7=6.6 Hz, 6H), 1.27 (s, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 6H). Protons missing due to yl)-3-(methylsulfonyl)picolinamide solvent suppression or exchange

[0819]

[0820] or overlap with the NMR solvent. F Method N, 1.56 min

[0821] 528.2

[0822] \ °H

[0823] ii i CH3δ 9.61 (s, 1H), 9.38 (s, 1H), 8.99HN (d, J=5.9 Hz, 1H), 8.54 (s, 1H), H3CO2S \=O 138.14 (d,. / =8,2 Hz, 1H), 7.85 (br W H3C^CH3d,. / =8,2 Hz, 1H), 5.07 - 4.97 (m, / / UM

[0824] 1H), 4.89 (s, 1H), 3.08 (s, 2H), 1.74 (br d, J=6.6 Hz, 6H), 1.28 (s, N-(5-fluoro-4-(2-(2-hydroxy-2- 6H). Protons missing due to methylpropyl)-3-isopropyl-3H- solvent suppression or exchange imidazo[4,5-b]pyridin-5-yl)pyridin-2- or overlap with the NMR solvent. yl)-5-(methylsulfonyl)pyrimidine-4- carb oxami de

[0825] F Method N, 1.78 min

[0826] 572.2

[0827] \ # — C / / n°

[0828] |l Uh

[0829] CH3δ 8.85 (s, 1H), 8.71 (d, J=6.3 Hz, IW 1H), 8.29 (d,. / =2,4 Hz, 1H), 7.89 EtO2S )=O 13(d, J=8.4 Hz, 1H), 7.59 (d, J=8.1 yy H3C'ACH3Hz, 1H), 4.82 - 4.72 (m, 1H), 4.61

[0830] (s, 1H), 3.86 (s, 3H), 2.83 (s, 2H), ACH31.49 (d,. / =6,8 Hz, 6H), 1.03 (s,

[0831] 6H), 0.97 (t,.7=7.4 Hz, 3H).

[0832] 5 -(ethyl sulfonyl)-N -(5 -fluoro-4-(2-(2- Protons missing due to solvent hydroxy-2-methylpropyl)-3-isopropyl- suppression or exchange or H-imidazo[4,5-b]pyridin-5-yl)pyridin- overlap with the NMR solvent.

[0833] 2-yl)-2-methoxypyrimidine-4- carb oxami de

[0834] F Method A, 1.73 min

[0835] 551.2

[0836] δ 11.51 (br s, 1H), 9.00 - 8.94 (m, 2H), 8.54 (s, 1H), 8.25 (d, J=8.4 H3CO2S y / 5=O Hz, 1H), 7.89 (d, J=8.4 Hz, 1H),

[0837] H3C / \ 1CH37.71 (s, 1H), 5.01 - 4.87 (m, 1H),

[0838] 4.34 (q, J=10.5 Hz, 2H), 2.66 (s, 3H), 1.76 (d, <7=6.6 Hz, 6H). CH3Protons missing due to solvent N-(5-fluoro-4-(3-isopropyl-2-(2,2,2- suppression or exchange or trifluoroethyl)-3H-imidazo[4,5- overlap with the NMR solvent. b]pyridin-5-yl)pyridin-2-yl)-2-methyl-

[0839]

[0840] 5-(methylsulfonyl)isonicotinamide Method A, 1.4 min

[0841] 623.1

[0842] δ 11.37 (s, 1H), 8.96 (br d, J=6.1 Hz, 1H), 8.55 (s, 1H), 8.38 (d, J=8.8 Hz, 1H), 8.27 (br d, J=8.3 Hz, 1H), 7.98 (br d, J=8.1 Hz, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 7.37 (d, J=8.8 Hz, 1H), 5.17 - 5.02 (m, 1H), 3.81 (s, 3H), 3.21 N-(5-fluoro-4-(2-(2-hydroxy-2- (s, 2H), 1.76 (br d, 7=6.6 Hz, 6H), methylpropyl)-3-isopropyl-3H- 1.29 (s, 6H).

[0843] imidazo[4,5-b]pyridin-5-yl)pyridin-2- yl)-6-((l-methyl-lH-pyrazol-4-yl)oxy)- 3-(methylsulfonyl)picolinamide

[0844] Method A, 1.35 min

[0845] 545.2

[0846] δ 11.19 (s, 1H), 8.95 (br d, J=5.6 Hz, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.93 (s, 1H), 7.80 (br d, J=8.3 Hz, 1H), 5.09 - 4.95 (m, 1H), 4.88 (s, 1H), N-(5-fluoro-4-(2-(2-hydroxy-2- 3.43 (br s, 1H), 3.08 (s, 2H), 2.58 methylpropyl)-3-isopropyl-3H- (s, 3H), 1.74 (br d, J=6.7 Hz, 6H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 1.49 (s, 6H), 1.28 (s, 6H) yl)-5 -(3 -hydroxy-3 -methylbut- 1 -yn- 1 - yl)-2-methylnicotinamide

[0847] Method A, 1.21 min

[0848] 544.4

[0849] δ 8.92 (br d, J=6.0 Hz, 1H), 8.51 (dd, J=17.4, 2.1 Hz, 2H), 8.12 (d, J=8.3 Hz, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.83 - 7.75 (m, 1H), 5.05 - 4.95 (m, 1H), 3.07 (s, 2H), 2.57 5 -(3 -amino-3 -methylbut- 1 -yn- 1 -yl)-N- (s, 3H), 1.72 (d, J=6.7 Hz, 6H), (5-fluoro-4-(2-(2-hydroxy-2- 1.41 (s, 6H), 1.27 (s, 6H) Protons methylpropyl)-3-isopropyl-3H- missing due to solvent imidazo[4,5-b]pyridin-5-yl)pyridin-2- suppression or exchange or yl)-2-methylnicotinamide

[0850]

[0851]

[0852] overlap with the NMR solvent. Method A, 1.1 min

[0853] F 544.3

[0854] δ 11.24 (s, 1H), 8.97 (br d, J=5.3 A # — (

[0855] U0

[0856] L-H

[0857] CH3Hz, 1H), 8.69 (d, J=1.9 Hz, 1H), CH3\=Q 138.52 (d, J=2.2 Hz, 1H), 8.20 - Hl4 / = / H3CACH38.03 (m, 2H), 7.89 - 7.75 (m, 1H), ) = / VCH35.12 - 4.96 (m, 1H), 4.59 - 4.39 H3C W

[0858] (m, 1H), 3.09 (br s, 2H), 2.73 (s, (S)-N-(5-fluoro-4-(2-(2-hydroxy-2- 3H), 2.61 (s, 3H), 1.74 (d, J=6.7 methylpropyl)-3-isopropyl-3H- Hz, 6H), 1.57 (d, J=6.8 Hz, 3H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 1.28 (s, 6H) Protons missing due yl)-2-methyl-5-(3 -(methylamino)but- 1 - to solvent suppression or

[0859] yn-l-yl)nicotinamide exchange or overlap with the NMR solvent.

[0860] Method A, 1.06 min F 532.3

[0861] 6 11.28 (s, 1H), 9.00 (br d, J=5.0 y—V ii0

[0862] iH

[0863] CH3Hz, 1H), 8.59 - 8.46 (m, 2H), 8.23 (s, 1H), 8.21 - 8.19 (m, 1H), 7.94 >0 13

[0864] Z\ / =\H3CX}H3- 7.83 (m, 1H), 5.15 - 5.00 (m,H2N\ / A / CHs1H), 3.17 (d, J=1.2 Hz, 2H), 2.69

[0865] - 2.63 (m, 1H), 2.60 (d, J=6.3 Hz, 5-(3-aminocyclobutyl)-N-(5-fluoro-4- 3H), 2.30 (br d, J=9.3 Hz, 1H), (2-(2-hydroxy-2-methylpropyl)-3- 1.76 (d, J=6.7 Hz, 6H), 1.30 (s, isopropyl-3H-imidazo[4,5-b]pyridin-5- 6H) Protons missing due to yl)pyridin-2-yl)-2-methylnicotinamide solvent suppression or exchange or overlap with the NMR solvent. F Method A, 1.1 min

[0866] 534.3

[0867] A

[0868] r-7 0H

[0869] >1 _UCH36 11.15 (s, 1H), 8.98 (br d, J=5.3

[0870] Hz, 1H), 8.54 (d, J=2.3 Hz, 1H), X3

[0871] / = / H3C^CH38.46 (d, J=1.8 Hz, 1H), 8.23 (br d,H2N, — <( VCH3J=8.2 Hz, 1H), 7.89 (d, J=7.7 Hz, H3C^\ 1H), 7.86 - 7.81 (m, 1H), 5.13 - OH34.98 (m, 1H), 3.20 - 3.13 (m, 3H), 5-(2-amino-2-methylpropyl)-N-(5- 2.93 (s, 2H), 2.60 (s, 3H), 1.76 (d, fluoro-4-(2-(2 -hydroxy -2- J=6.7 Hz, 6H), 1.28 (d, J=13.7 methylpropyl)-3-isopropyl-3H- Hz, 12H) Protons missing due to imidazo[4,5-b]pyridin-5-yl)pyridin-2- solvent suppression or exchange

[0872]

[0873] yl)-2-methylnicotinamide or overlap with the NMR solvent. F Method A, 1.1 min

[0874] 544.3

[0875] ’v XN OH

[0876] H || KCH38 11.24 (s, 1H), 8.96 (br d, J=5.1 HN N>\ / V Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), CH3VO 138.51 (s, 1H), 8.25 (s, 1H), 8.08 (d, Hl4 / = / H3C'' OH3

[0877] J=2.0 Hz, 1H), 7.86 - 7.70 (m, ) = (\ / kCH3

[0878] H3C* W 1H), 5.15 - 4.92 (m, 1H), 4.63 - 4.33 (m, 1H), 3.20 - 3.01 (m, 1H), 2.73 (s, 2H), 2.61 (s, 2H), 1.74 (br (R)-N-(5-fluoro-4-(2-(2-hydroxy-2- d, J=6.6 Hz, 6H), 1.57 (d, J=6.8 methylpropyl)-3-isopropyl-3H- Hz, 2H), 1.30 (br s, 6H) Protons imidazo[4,5-b]pyridin-5-yl)pyridin-2- missing due to solvent yl)-2-methyl-5-(3 -(methylamino)but- 1 - suppression or exchange or yn-l-yl)nicotinamide

[0879] overlap with the NMR solvent. F Method A, 1.46 min

[0880] 613.1

[0881] \\ A V

[0882] NV 1|0

[0883] UHCH3δ 8.80 - 8.71 (m, 1H), 8.28 (br s, HNNAAH1H), 8.09 - 7.98 (m, 1H), 7.90 (br EtO2S Vo / 3

[0884] d, J=8.4 Hz, 1H), 7.64 - 7.54 (m, HHscAch’ 1H), 7.51 - 7.43 (m, 1H), 4.85 - \= / OH 4.67 (m, 1H), 2.84 (s, 2H), 2.79 - V I CH3

[0885] 2.74 (m, 2H), 1.56 - 1.45 (m, 6H), CH3

[0886] 1.04 (s, 6H), 0.98 - 0.85 (m, 9H) 3-(ethylsulfonyl)-N-(5-fluoro-4-(2-(2- Protons missing due to solvent hydroxy-2-methylpropyl)-3-isopropyl- suppression or exchange or 3H-imidazo[4,5-b]pyridin-5-yl)pyridin- overlap with the NMR solvent.

[0887] 2-yl)-6-(2 -hydroxy -2- methylpropyl)picolinamide

[0888] Method A, 1.11 min

[0889] F 547.3

[0890] δ 10.79 (s, 1H), 9.01 (br d, J=5.0 A VV V~

[0891] V 'N VN

[0892] ||0

[0893] 1H

[0894] CH3Hz, 1H), 8.73 (s, 2H), 8.54 (br s, 1H), 8.50 - 8.37 (m, 1H), 8.21 (br Vo 1CH3

[0895] / — \ N= / H3C" \; H3d, J=7.9 Hz, 1H), 7.89 (br d, J=8.2 Hz, 1H), 5.07 (quin, J=6.6h CH3

[0896] Hz, 1H), 3.44 (br dd, J=11.2, 1.7 N-(5-fluoro-4-(2-(2-hydroxy-2- Hz, 1H), 3.27 - 3.19 (m, 1H), 3.17 methylpropyl)-3-isopropyl-3H- (s, 1H), 3.15 (s, 1H), 3.13 - 3.01 imidazo[4,5-b]pyridin-5-yl)pyridin-2- (m, 2H), 2.79 (s, 3H), 2.12 (br d, yl)-3-methyl-6-(piperidin-4- J=13.3 Hz, 2H), 2.07 - 1.93 (m, yl)pyrazine-2-carboxamide 2H), 1.76 (d, J=6.7 Hz, 6H), 1.29

[0897]

[0898] (s, 6H). F Method A, 1.13 min

[0899] 561.4

[0900] A

[0901] '10

[0902] DHCH3

[0903] Hl / δ 9.07 - 8.89 (m, 1H), 8.71 (s,

[0904] 1H), 8.52 (br s, 1H), 8.13 (d, y y N= / >° H3C^ 1CH33J=8.4 Hz, 1H), 7.81 (br d, J=7.9 H3C-N \ \ — CH3

[0905] Hz, 1H), 5.10 - 4.95 (m, 1H), 3.08 N-(5-fluoro-4-(2-(2-hydroxy-2- (s, 2H), 2.90 (br d, J=10.5 Hz, methylpropyl)-3-isopropyl-3H- 2H), 2.86 - 2.75 (m, 4H), 2.22 (s, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 3H), 2.09 - 1.99 (m, 2H), 1.95 - yl)-3-methyl-6-(l-methylpiperidin-4- 1.79 (m, 4H), 1.75 (br d, J=6.6 yl)pyrazine-2-carboxamide Hz, 6H), 1.28 (s, 6H).

[0906] Method A, 1.14 min

[0907] F

[0908] 559.3

[0909] \ XN OH δ 10.87 (s, 1H), 9.06 - 8.97 (m,

[0910] ECH3

[0911] HR\I^I1H), 8.72 - 8.59 (m, 3H), 8.54 (br '^XXCH3

[0912] s, 1H), 8.20 (d,. / =8,2 Hz, 1H), ^ ^ 7.88 (d,. / =8,2 Hz, 1H), 5.06 (dt, OOA J=13.4, 6.7 Hz, 1H), 4.12 (brt, N-(5-fluoro-4-(2-(2-hydroxy-2- J=5.9 Hz, 2H), 4.01 (br t, J=5.6 methylpropyl)-3-isopropyl-3H- Hz, 2H), 3.72 - 3.63 (m, 1H), 3.21 imidazo[4,5-b]pyridin-5-yl)pyridin-2- - 3.11 (m, 3H), 2.75 (s, 3H), 2.72 yl)-3-methyl-6-(2-azaspiro[3.3]heptan- - 2.63 (m, 2H), 2.62 - 2.53 (m, 6-yl)pyrazine-2-carboxamide 2H), 1.76 (d, J=6.6 Hz, 6H), 1.29

[0913] (s, 6H).

[0914] F Method A, 1.11 min

[0915] 559.4

[0916] A0Hδ 10.86 (s, 1H), 8.98 (br d, J=1.2

[0917] UCH3

[0918] Hz, 1H), 8.78 (s, 2H), 8.60 - 8.46 >° (m, 2H), 8.19 (d, J=8.5 Hz, 1H), H3C- / 1\CH337.87 (d,. / =7,8 Hz, 1H), 5.14 - 4.98 (m, 1H), 4.20 (br s, 1H), 3.23 - 3.08 (m, 4H), 2.89 (br s, 6-(2-azabicyclo[2.2.1]heptan-5-yl)-N- 1H), 2.75 (s, 3H), 2.43 - 2.30 (m, (5-fluoro-4-(2-(2-hydroxy-2- 1H), 2.25 - 2.16 (m, 1H), 2.02 (br methylpropyl)-3-isopropyl-3H- d, J=11.7 Hz, 1H), 1.76 (d, J=6.1 imidazo[4,5-b]pyridin-5-yl)pyridin-2- Hz, 6H), 1.62 (br d, J=10.8 Hz, yl)-3-methylpyrazine-2-carboxamide

[0919] 1H), 1.29 (s, 6H).

[0920]

[0921] Method A, 1.12 min

[0922] 573.3

[0923] δ 9.02 - 8.92 (m, 1H), 8.78 - 8.68 (m, 1H), 8.50 (br s, 1H), 8.12 (d, J=8.2 Hz, 1H), 7.80 (br d, J=8.2 Hz, 1H), 5.09 - 4.93 (m, 1H), 3.20 - 3.12 (m, 1H), 3.10 - 3.01 (m, N-(5-fluoro-4-(2-(2-hydroxy-2- 2H), 2.85 - 2.77 (m, 1H), 2.75 (s, methylpropyl)-3-isopropyl-3H- 3H), 2.67 - 2.59 (m, 1H), 2.39 (s, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2H), 2.29 - 1.87 (m, 2H), 1.79 (s, yl)-3-methyl-6-(2-methyl-2- 3H), 1.73 (br d, J=6.6 Hz, 6H), azabicyclo[2.2.1]heptan-5-yl)pyrazine- 1.68 - 1.53 (m, 1H), 1.27 (s, 6H).

[0924] 2-carboxamide

[0925] Method A, 1.20 min

[0926] 612.3

[0927] δ 8.94 (br d, J=6.2 Hz, 1H), 8.77 (s, 1H), 8.50 (br s, 1H), 8.17 - 8.08 (m, 2H), 7.81 (br d, J=7.7 Hz, 1H), 5.06 - 4.96 (m, 1H), 3.78 (br d, J=1.9 Hz, 1H), 3.58 - 3.50 (m, 1H), 3.26 - 3.19 (m, 1H), 3.08 5-(2-azabicyclo[2.2.1]heptan-5-yl)-N- (s, 2H), 3.03 - 2.96 (m, 1H), 2.95 (5-fluoro-4-(2-(2-hydroxy-2- - 2.86 (m, 1H), 2.70 (br s, 1H), methylpropyl)-3-isopropyl-3H- 2.26 - 2.15 (m, 1H), 1.97 - 1.87 imidazo[4,5-b]pyridin-5-yl)pyridin-2- (m, 1H), 1.78? (s, 4H), 1.72 (d, yl)-2-(trifluoromethyl)ni cotinamide. / =6,7 Hz, 7H), 1.56 - 1.50 (m,

[0928] 1H), 1,27 (s, 6H). _

[0929] Method A, 1.22 min

[0930] 596.3

[0931] δ 11.54 (s, 1H), 9.03 - 8.83 (m, 2H), 8.78 - 8.63 (m, 2H), 8.54 (s, 1H), 8.19 (d, J=8.3 Hz, 1H), 8.00 (s, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.31 - 7.03 (m, 3H), 5.05 (dt, J=13.7, 6.8 Hz, 1H), 3.50 - 3.34 2-(difluoromethyl)-N-(5-fluoro-4-(2- (m, 1H), 3.06 - 2.95 (m, 1H), 2.76 (2-hydroxy-2-methylpropyl)-3- - 2.65 (m, 2H), 2.24 - 2.10 (m, isopropyl-3H-imidazo[4,5-b]pyridin-5- 1H), 2.03 - 1.87 (m, 2H), 1.75 (d, yl)pyridin-2-yl)-5-(3-methylpiperidin- J=6.6 Hz, 6H), 1.29 (s, 6H), 0.73

[0932] 4-yl)nicotinamide

[0933]

[0934]

[0935] (br d, J=6.6 Hz, 3H). Method A, 1.16 min

[0936] 596.3

[0937] δ 11.46 (s, 1H), 8.98 - 8.90 (m, 1H), 8.54 (d, J=2.1 Hz, 2H), 8.21 (d, J=8.4 Hz, 1H), 8.09 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.33 - 7.02 (m, 1H), 5.06 (dt, J=13.6, 6.9 Hz, 1H), 3.68 (br dd, J=5.6, 2-(difluoromethyl)-N-(5-fluoro-4-(2- 2.9 Hz, 1H), 3.39 - 3.20 (m, 1H), (2-hydroxy-2-methylpropyl)-3- 3.15 (s, 3H), 2.21 - 2.12 (m, 1H), isopropyl-3H-imidazo[4,5-b]pyridin-5- 2.11 - 1.98 (m, 2H), 1.97 - 1.88 yl)pyridin-2-yl)-5-((2S,4R)-2- (m, 1H), 1.75 (d, J=6.7 Hz, 6H), methylpiperidin-4-yl)nicotinamide 1.38 (d, J=6.8 Hz, 3H), 1.28 (s,

[0938] 6H).

[0939] Method A, 1.18 min

[0940] 594.1

[0941] 6 8.93 (br d, J=5.3 Hz, 1H), 8.74 (d, J=1.7 Hz, 1H), 8.52 (d,. / =2,0 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.07 (s, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.30 - 7.00 (m, 1H), 5.08 - 4.89 (m, 1H), 3.82 (br s, 1H), 5 -(2 -azabi cy cl o [2.2.1 ] heptan- 5 -y l)-2- 3.08 (s, 2H), 3.04 - 2.98 (m, 1H), (difluoromethyl)-N-(5-fluoro-4-(2-(2- 2.97 - 2.87 (m, 1H), 2.71 (br s, hydroxy-2-methylpropyl)-3-isopropyl- 1H), 2.24 - 2.14 (m, 1H), 2.00 - 3H-imidazo[4,5-b]pyridin-5-yl)pyridin- 1.91 (m, 1H), 1.83 (s, 3H), 1.79 - 2-yl)nicotinamide 1.68 (m, 7H), 1.52 (br d, J=10.8

[0942] Hz, 1H), 1,28 (s, 6H). _ Method A, 1.11 min

[0943] 594.5

[0944] 1H NMR (500 MHz, DMSO-d6-ws) δ 11.43 (s, 1H), 8.95 (br d, J=5.3 Hz, 2H), 8.75 (s, 1H), 8.54 (br s, 1H), 8.20 - 8.08 (m, 2H), 7.80 (d, J=8.2 Hz, 1H), 7.34 - 6.99 (m, 1H), 5.10 - 4.95 (m, 1H), 5-(2-azabicyclo[2.2.1]heptan-6-yl)-2- 4.28 (br s, 1H), 3.16 - 3.01 (m, (difluoromethyl)-N-(5-fluoro-4-(2-(2- 3H), 2.80 (br s, 1H), 2.14 - 1.99 hydroxy-2-methylpropyl)-3-isopropyl- (m, 2H), 1.98 - 1.89 (m, 2H), 1.74 3H-imidazo[4,5-b]pyridin-5-yl)pyridin- (br d, J=6.7 Hz, 6H), 1.66 (br d, 2-yl)nicotinamide

[0945]

[0946]

[0947] J=11.2 Hz, 1H), 1.28 (s, 6H). Method A, 1.12 min 594.2 δ 11.47 (s, 1H), 9.23 - 9.04 (m, 2H), 8.98 - 8.88 (m, 1H), 8.84 (s, 1H), 8.55 (s, 1H), 8.28 - 8.15 (m, 2H), 7.90 (d, J=8.3 Hz, 1H), 7.33 - 7.01 (m, 1H), 5.16 - 5.03 (m, 1H), 3.71 - 3.57 (m, 2H), 3.26 (br 5-((1R,5S,6R)-3- d, J=5.2 Hz, 1H), 3.21 - 3.11 (m, azabicyclo[3.1.1]heptan-6-yl)-2- 3H), 2.85 (br d, J=5.6 Hz, 2H), (difluoromethyl)-N-(5-fluoro-4-(2-(2- 2.46 - 2.34 (m, 1H), 1.75 (br d, hydroxy-2-methylpropyl)-3-isopropyl- J=6.6 Hz, 6H), 1.29 (s, 6H). 3H-imidazo[4,5-b]pyridin-5-yl)pyridin- 2-yl)nicotinamide Method A, 1.12 min 594.2 δ 11.38 (s, 1H), 9.08 - 8.92 (m, 2H), 8.64 (s, 1H), 8.54 (s, 1H), 8.26 - 8.12 (m, 2H), 8.03 (s, 1H), 7.85 (br d, J=7.0 Hz, 1H), 7.33 - 7.08 (m, 1H), 5.05 (dt, J=13.4, 6.5 Hz, 1H), 3.75 (br s, 1H), 3.12 5-((1R,5S,6S)-3- (br s, 2H), 3.05 (br t, J=5.3 Hz, azabicyclo[3.1.1]heptan-6-yl)-2- 2H), 2.40 - 2.28 (m, 1H), 1.86 - (difluoromethyl)-N-(5-fluoro-4-(2-(2- 1.69 (m, 8H), 1.29 (br s, 6H). hydroxy-2-methylpropyl)-3-isopropyl- 3H-imidazo[4,5-b]pyridin-5-yl)pyridin- 2-yl)nicotinamide Method A, 1.18 min 596.4 δ 11.45 (s, 1H), 8.97 - 8.90 (m, 1H), 8.62 - 8.55 (m, 1H), 8.53 (s, 1H), 8.19 (d, J=8.2 Hz, 1H), 8.09 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.27 - 7.04 (m, 1H), 5.05 (dt, J=13.4, 6.6 Hz, 1H), 3.68 - 3.49 (m, 1H), 3.39 - 3.30 (m, 1H), 3.24 2-(difluoromethyl)-N-(5-fluoro-4-(2- (br dd, J=6.3, 2.4 Hz, 1H), 3.13 (2-hydroxy-2-methylpropyl)-3- (s, 2H), 2.16 (ddd, J=14.2, 10.3, isopropyl-3H-imidazo[4,5-b]pyridin-5- 4.0 Hz, 1H), 2.10 - 1.99 (m, 2H), yl)pyridin-2-yl)-5-((2R,4R)-2- 1.97 - 1.86 (m, 1H), 1.74 (m, 7H), methylpiperidin-4-yl)nicotinamide 1.38 (d, J=6.9 Hz, 3H), 1.28 (s,

[0948]

[0949] 6H). Method M, 0.92 min

[0950] 568.1

[0951] δ 11.54 (s, 1H), 9.13 (s, 1H), 8.97 A, (d, J=6.1 Hz, 1H), 8.57 (d, J=2.6 MeO. zA / ^0NA,FHz, 1H), 8.26 (d, J=8.3 Hz, 1H), \\ \zo _ / ^rr

[0952] N7.91 (dd, J=8.3, 0.9 Hz, 1H), 5.00 ^St0k

[0953] - 4.88 (m, 1H), 4.36 (q, J=10.8 N-(5-fluoro-4-(3-isopropyl-2-(2,2,2- Hz, 2H), 4.12 (s, 3H), 3.44 (s, trifluoroethyl)-3H-imidazo[4,5- 3H), 1.76 (d, J=6.7 Hz, 6H). b]pyridin-5-yl)pyridin-2-yl)-2- methoxy-5- (methylsulfonyl)pyrimidine-4- carb oxami de

[0954] F Method M, 1.10 min

[0955] 534.3

[0956] \ NH2~XN6 11.15 (s, 1H), 9.06 - 8.92 (m,

[0957] 1H), 8.54 (d, J=2.3 Hz, 1H), 8.46 NA / (d, J=1.8 Hz, 1H), 8.23 (br d, J=8.2 Hz, 1H), 8.00 (br s, 3H), ^"hr " OH

[0958] 7.89 (d, J=7.7 Hz, 1H), 7.85 (s, 5-(2-amino-2-methylpropyl)-N-(5- 1H), 5.18 - 4.99 (m, 1H), 3.18 (s, fluoro-4-(2-(2-hydroxy-2- 2H), 2.60 (s, 3H), 1.76 (d, J=6.7 methylpropyl)-3-isopropyl-3H- Hz, 7H), 1.28 (d, J=13.7 Hz, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 12H).

[0959] yl)-2-methylnicotinamide

[0960] F Method M, 1.06 min

[0961] 523.3

[0962] 6 11.28 (s, 1H), 9.00 (br d, J=5.0 A

[0963] H2N^\ LNA^N Hz, 1H), 8.59 - 8.46 (m, 2H), 8.26 XA / A"0A / - 8.16 (m, 3H), 8.06 (br s, 3H),

[0964] 7.90 (d, J=8.3 Hz, 1H), 5.16 - 5.00 (m, 1H), 3.17 (d, J=1.2 Hz, 5-(3-aminocyclobutyl)-N-(5-fluoro-4- 3H), 2.74 - 2.64 (m, 1H), 2.61 - (2-(2-hydroxy-2-methylpropyl)-3- 2.57 (m, 4H), 2.30 (br d, J=9.3 isopropyl-3H-imidazo[4,5-b]pyridin-5- Hz, 1H), 1.76 (d, J=6.7 Hz, 6H), yl)pyridin-2-yl)-2-methylnicotinamide

[0965]

[0966] 1.30 (s, 6H). Method M, 1.79 min

[0967] 550.5

[0968] δ 10.60 (s, 1H), 8.96 (d, J=6.1 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.28 (d, J=2.6 Hz, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.46 (d, J=2.2 Hz, 1H), 5.03 (dt, 5-(2-(dimethylamino)ethoxy)-N-(5- J=13.6, 6.8 Hz, 1H), 4.24 (t, fluoro-4-(2-(2 -hydroxy -2- J=5.6 Hz, 2H), 3.09 (s, 2H), 2.74 methylpropyl)-3-isopropyl-3H- - 2.64 (m, 5H), 2.23 (s, 6H), 1.80 imidazo[4,5-b]pyridin-5-yl)pyridin-2- - 1.69 (m, 6H), 1.28 (s, 6H). yl)-3-methylpicolinamide

[0969] Method M, 1.10 min

[0970] 564.2

[0971] δ 11.00 (s, 1H), 8.91 (d, J=6.0 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.18 (d, J=8.3 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 5.13 - 6-(3-(dimethylamino)propoxy)-N-(5- 4.96 (m, 1H), 4.37 (t, J=6.1 Hz, fluoro-4-(2-(2-hydroxy-2- 2H), 3.23 (br d, J=4.5 Hz, 2H), methylpropyl)-3-isopropyl-3H- 3.12 (s, 2H), 2.83 (br d, J=2.7 Hz, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 6H), 2.55 (s, 3H), 2.21 - 2.05 (m, yl)-2-methylnicotinamide 2H), 1.74 (d, J=6.6 Hz, 6H), 1.28

[0972] (s, 6H). _

[0973] Method M, 1.22 min

[0974] 604.4

[0975] δ 9.01 - 8.89 (m, 1H), 8.52 (br s, 2H), 8.13 (br d, J=8.2 Hz, 1H), 7.86 (br s, 1H), 7.81 (br d, J=8.1 Hz, 1H), 5.13 - 4.95 (m, 1H), 4.29 (br s, 2H), 3.08 (s, 2H), 2.68 (br s, 5-(2-(dimethylamino)ethoxy)-N-(5- 2H), 2.23 (s, 6H), 1.73 (br d, fluoro-4-(2-(2 -hydroxy -2- J=6.6 Hz, 6H), 1.28 (s, 6H). methylpropyl)-3-isopropyl-3H- imidazo[4,5-b]pyridin-5-yl)pyridin-2-

[0976]

[0977]

[0978] yl)-2-(trifluoromethyl)ni cotinamide Method M, 1.31 min

[0979] 586.2

[0980] δ 11.03 (s, 1H), 8.90 (d, J=6.1 Hz, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.21 (d, J=8.3 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 6.76 - 6.71 (m, 1H), 6.93 - 6.64 N-(4-(3 -(1,1 -difluoropropan-2-yl)-2-(2- (m, 1H), 5.39 - 5.22 (m, 1H), 4.92 hydroxy-2-methylpropyl)-3H- (s, 1H), 4.50 (br t, J=5.0 Hz, 2H), imidazo[4,5-b]pyridin-5-yl)-5- 3.21 - 3.00 (m, 4H), 2.55 (s, 3H), fluoropyridin-2-yl)-6-(2- 1.87 (br d, J=6.8 Hz, 3H), 1.40 - (dimethylamino)ethoxy)-2- 1.16 (m, 6H).

[0981] methylnicotinamide

[0982] Method M, 1.78 min

[0983] 572.2

[0984] δ 8.85 (s, 1H), 8.71 (d, J=6.3 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 4.82 - 4.72 (m, 1H), 4.61 (s, 1H), 3.86 (s, 2H), 2.83 (s, 2H), 1.49 (d, J=6.8 Hz, 6H), 1.03 (s, 5-(ethylsulfonyl)-N-(5-fluoro-4-(2-(2- 6H), 0.97 (t, J=7.4 Hz, 3H). hydroxy-2-methylpropyl)-3-isopropyl- Protons missing due to solvent 3H-imidazo[4,5-b]pyridin-5-yl)pyridin- suppression or exchange or 2-yl)-2-methoxypyrimidine-4- overlap with the NMR solvent. carb oxami de

[0985] Method M, 1.11 min

[0986] 548.2

[0987] δ 11.12 (s, 1H), 8.94 (br d, J=5.5 Hz, 1H), 8.49 (s, 1H), 8.37 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.80 (br d, J=8.3 Hz, 1H), 7.76 - 7.63 (m, 1H), 5.09 - 4.90 (m, 1H), 3.08 (S)-5-(2-(dimethylamino)propyl)-N-(5- (s, 2H), 2.91 - 2.73 (m, 2H), 2.20 fluoro-4-(2-(2 -hydroxy -2- (s, 6H), 1.90 (s, 3H), 1.73 (br d, methylpropyl)-3-isopropyl-3H- J=6.6 Hz, 6H), 1.28 (s, 6H), 0.89 imidazo[4,5-b]pyridin-5-yl)pyridin-2- (br d, J=6.0 Hz, 3H).

[0988]

[0989] yl)-2-methylnicotinamide Method M, 1.06 min

[0990] 560.3

[0991] δ 8.99 - 8.90 (m, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.83 - 7.75 (m, 2H), 5.07 - 4.95 (m, N-(5-fluoro-4-(2-(2-hydroxy-2- 1H), 3.08 (s, 2H), 2.91 - 2.82 (m, methylpropyl)-3-isopropyl-3H- 2H), 2.74 (s, 1H), 2.20 (s, 3H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2.02 - 1.93 (m, 2H), 1.80 - 1.71 yl)-2-methyl-5-(l-methylpiperidin-4- (m, 13H), 1.28 (s, 6H).

[0992] yl)nicotinamide

[0993] Method M, 1.34 min

[0994] 564.2

[0995] δ 8.90 (br d, J=6.0 Hz, 1H), 8.49 (br s, 1H), 8.34 (s, 1H), 8.13 (br d, J=8.3 Hz, 1H), 7.78 (br d, J=7.9 Hz, 1H), 6.75 (s, 1H), 5.10 - 4.95 (m, 1H), 4.32 (brt, J=6.4 N-(4-(3 -(1,1 -difluoropropan-2-yl)-2-(2- Hz, 2H), 3.08 (br s, 2H), 2.40 (s, hydroxy-2-methylpropyl)-3H- 3H), 2.34 (br t, J=6.6 Hz, 2H), imidazo[4,5-b]pyridin-5-yl)-5- 2.14 (s, 6H), 1.85 (brt, J=6.7 Hz, fluoropyridin-2-yl)-6-(3 - 2H), 1.73 (br d, J=6.6 Hz, 6H), (dimethylamino)propoxy)-4- 1.28 (s, 6H).

[0996] methylnicotinamide

[0997] Method M, 1.39 min

[0998] 580.4

[0999] δ 8.97 - 8.89 (m, 1H), 8.60 (s, 1H), 8.54 (br s, 1H), 8.13 (br d, J=8.3 Hz, 1H), 7.82 (br d, J=8.3 Hz, 1H), 6.70 - 6.38 (m, 1H), 5.08 - 4.97 (m, 1H), 4.92 - 4.77 (m, l-(2,2-difluoroethyl)-N-(5-fluoro-4-(2- 2H), 3.49 (br s, 1H), 3.08 (s, 2H), (2-hydroxy-2-methylpropyl)-3- 1.74 (br d, J=6.6 Hz, 6H), 1.28 (s, isopropyl-3H-imidazo[4,5-b]pyridin-5- 6H). Protons missing due to yl)pyridin-2-yl)-4-(methylsulfonyl)- solvent suppression or exchange or overlap with the NMR solvent.

[1000]

[1001]

[1002] lH-pyrazole-3-carboxamide Method M, 1.28 min

[1003] F

[1004] 466.4

[1005] δ 10.36 (br s, 1H), 8.84 - 8.80 (m, 1H), 8.47 (br d, J=5.8 Hz, 2H), 8.16 - 8.08 (m, 1H), 7.74 (br d, N-^ / J=8.3 Hz, 1H), 5.08 - 4.94 (m, 'V\ 1H), 3.81 (s, 2H), 3.08 (br s, 2H),

[1006] 2.37 (s, 3H), 1.80 - 1.68 (m, 6H), N-(5-fluoro-4-(2-(2-hydroxy-2- 1.28 (br s, 6H). Protons missing methylpropyl)-3-isopropyl-3H- due to solvent suppression or imidazo[4,5-b]pyridin-5-yl)pyridin-2- exchange or overlap with the yl)- 1, 3 -dimethyl- 1 H-pyrazole-4- NMR solvent.

[1007] carb oxami de

[1008] _FMethod N, 1.77 min

[1009] 658.1

[1010] A CXv-i δ 11.38 (s, 1H), 8.94 (d, J=6.0 Hz, OHN; LX 1H), 8.48 (dd, J=18.3, 1.9 Hz, ° < / / 0 / 2H), 8.15 (br d, J=8.2 Hz, 1H),

[1011] 7.88 - 7.78 (m, 2H), 5.02 (dt, 'LhA'CF3- J=13.3, 6.6 Hz, 1H), 4.64 - 4.55

[1012] (m, 1H), 3.30 - 3.20 (m, 1H), 3.16 5-(((lr,4r)-4- (s, 1H), 3.09 (s, 2H), 2.76 - 2.69 (dimethylamino)cyclohexyl)oxy)-N-(5- (m, 6H), 2.25 (br d, J=10.2 Hz, fluoro-4-(2-(2-hydroxy-2- 2H), 2.06 (br d, J=11.0 Hz, 2H), methylpropyl)-3-isopropyl-3H- 1.72 (d, J=6.6 Hz, 6H), 1.68 - imidazo[4,5-b]pyridin-5-yl)pyridin-2- 1.58 (m, 2H), 1.55 - 1.44 (m, 2H), yl)-2-(trifluoromethyl)ni cotinamide

[1013] 1.26 (s, 6H).

[1014] Method M, 1.45 min

[1015] 618.1

[1016] δ 8.93 (br d, J=6.2 Hz, 1H), 8.50 (br s, 2H), 8.13 (br d, J=8.4 Hz, AACF31H), 7.87 - 7.69 (m, 2H), 5.12 - Ai

[1017] 4.90 (m, 1H), 4.33 - 4.12 (m, 2H), 5-(3-(dimethylamino)propoxy)-N-(5- 3.08 (s, 2H), 2.45 - 2.33 (m, 2H), fluoro-4-(2-(2-hydroxy-2- 2.16 (s, 6H), 1.91 (br s, 2H), 1.73 methylpropyl)-3-isopropyl-3H- (br d, J=6.6 Hz, 6H), 1.27 (s, 6H). imidazo[4,5-b]pyridin-5-yl)pyridin-2-

[1018]

[1019] yl)-2-(trifluoromethyl)ni cotinamide F Method N, 1.73 in

[1020] 544.1

[1021] XX / ^

[1022] δ 10.60 (s, 1H), 8.89 (d, J=6.3HV XX Hz, 1H), 8.53 (d,.7=2.4 Hz, 1H), N. X^O 11 J / /

[1023] 8.49 (s, 1H), 8.21 (d, J=8.4 Hz, — i\l X _ /

[1024] 1H), 7.91 (br d,.7=7,9 Hz, 1H), ' j<=0 X 5.12 - 4.96 (m, 1H), 4.00 (s, 2H),

[1025] 3.20 - 3.11 (m, 2H), 1.75 (d, 4-(ethylsulfonyl)-N-(5-fluoro-4-(2-(2- J=6.9 Hz, 6H), 1.28 (s, 6H), 1.18 hydroxy-2-methylpropyl)-3-isopropyl- (t, J=7.4 Hz, 3H).

[1026] 3H-imidazo[4,5-b]pyridin-5-yl)pyridin- 2-yl)- 1 -methyl- lH-pyrazole-3 - carboxamide

[1027] Method M, 1.38 min

[1028] F 630.1

[1029] xXxx δ 11.29 (s, 1H), 8.97 (br d, J=5.8

[1030] Hz, 1H), 8.53 (dd, J=12.2, 2.0 Hz, I \H1 L

[1031] I N> A

[1032] j / NN

[1033] \ / 2H), 8.25 (d, J=8.3 Hz, 1H), 7.98 Vx-CF3- 7.86 (m, 2H), 5.08 (dt, J=13.6,

[1034] 6.7 Hz, 1H), 4.04 - 3.96 (m, 2H), N-(5-fluoro-4-(2-(2-hydroxy-2- 3.51 - 3.44 (m, 1H), 3.34 (br t, methylpropyl)-3-isopropyl-3H- J=11.4 Hz, 2H), 3.22 - 3.15 (m, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2H), 3.15 - 3.07 (m, 2H), 3.03 - y 1 )- 5 -( 1 -(tetrahy dro-2H-pyran-4- 2.94 (m, 1H), 2.60 (s, 3H), 2.53 - yl)piperidin-4-yl)-2- 2.49 (m, 4H), 2.19 - 2.09 (m, 2H), (trifluoromethyl)nicotinamide 2.04 - 1.95 (m, 3H), 1.80 - 1.66 (m, 8H), 1.29 (s, 6H).

[1035] F Method M, 1.36 min

[1036] 566.1

[1037] XX / ^

[1038] HV XX1H NMR (400 MHz, DMSO-d6) δ

[1039] 11.16 (s, 1H), 9.05 (s, 1H), 8.91 F N^ X^O Y. / / /

[1040] (d, J=6.2 Hz, 1H), 8.59 (d,.7=2,7 Vi\l X / AX'

[1041] X -Xt° X A Hz, 1H), 8.24 (d, J=8.4 Hz, 1H),

[1042] 8.13 - 7.83 (m, 2H), 5.17 - 5.01 l-(difluoromethyl)-N-(5-fluoro-4-(2- (m, 1H), 3.50 (s, 3H), 3.18 (s, (2-hydroxy-2-methylpropyl)-3- 2H), 1.77 (d, <7=6.8 Hz, 6H), 1.30 isopropyl-3H-imidazo[4,5-b]pyridin-5- (s, 6H). Protons missing due to yl)pyridin-2-yl)-4-(methylsulfonyl)- solvent suppression or exchange or overlap with the NMR solvent.

[1043]

[1044] lH-pyrazole-3-carboxamide Method N, 1.77 min

[1045] 533.1

[1046] δ 10.49 (s, 1H), 8.91 (d, J=6.0 Hz, 1H), 8.54 - 8.47 (m, 2H), 8.13 (d,. / =8,2 Hz, 1H), 7.81 (d,. / =8,2 Hz, 1H), 5.07 - 4.97 (m, 1H), 4.86 (s, 1H), 3.46 (s, 1H), 3.09 (s, 2H), N-(5-fluoro-4-(2-(2-hydroxy-2- 1.74 (br d,. / =6,7 Hz, 6H), 1.28 (s, methylpropyl)-3-isopropyl-3H- 6H). Protons missing due to imidazo[4,5-b]pyridin-5-yl)pyridin-2- solvent suppression or exchange yl)-l-(methyl-d3)-4-(methylsulfonyl)- or overlap with the NMR solvent.

[1047] lH-pyrazole-3-carboxamide

[1048] Method M, 1.23 min

[1049] 588.2

[1050] δ 8.98 - 8.88 (m, 1H), 8.67 (s, 1H), 8.50 (br s, 1H), 8.13 (d, J=8.2 Hz, 1H), 8.06 (s, 1H), 7.81 (br d, J=8.0 Hz, 1H), 5.05 - 4.95 (m, 1H), 3.53 (br s, 1H), 3.17 (s, N-(5-fluoro-4-(2-(2-hydroxy-2- 1H), 3.12 - 3.04 (m, 2H), 2.85 (br methylpropyl)-3-isopropyl-3H- s, 2H), 1.73 (br d, J=6.7 Hz, 6H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 1.27 (s, 6H), 1.12 (s, 6H). yl)-5-(2 -hydroxy -2-methylpropyl)-2- (trifluoromethyl)nicotinamide

[1051] Method M, 1.33 min

[1052] 600

[1053] δ 9.11 (s, 1H), 8.86 (d, J=6.0 Hz, 1H), 8.53 (d, J=2.3 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.85 (d, J=7.9 Hz, 1H), 5.54 - 5.43 (m, 1H), 4.62 (td, J=8.4, 4.4 Hz, 1H), 4.09 (s, 3H), 3.72 (q, J=8.0 Hz, 1H), 3.22 N-(5-fluoro-4-(2-(2-hydroxy-2- - 2.99 (m, 2H), 2.48 - 2.39 (m, methylpropyl)-3-((2R,3R)-2- 1H), 1.31 (s, 3H), 1.24 (s, 3H), methyltetrahydrofuran-3 -yl)-3H- 0.70 (d, J=6.3 Hz, 3H). imidazo[4,5-b]pyridin-5-yl)pyridin-2- yl)-2-methoxy-5- (methylsulfonyl)pyrimidine-4-

[1054]

[1055]

[1056] carb oxami de Method M, 1.18 min

[1057] 565.3

[1058] δ 9.02 - 8.91 (m, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.41 (s, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 5.09 - 4.94 (m, 1H), 4.44 (br t, J=6.4 Hz, 2H), 3.08 (s, 2H), 6-(3-(dimethylamino)propoxy)-N-(5- 2.70 (s, 3H), 2.39 (brt, J=7.1 Hz, fluoro-4-(2-(2-hydroxy-2- 2H), 2.15 (s, 6H), 1.97 - 1.90 (m, methylpropyl)-3-isopropyl-3H- 2H), 1.74 (d, J=6.7 Hz, 6H), 1.27 imidazo[4,5-b]pyridin-5-yl)pyridin-2- (s, 6H).

[1059] yl)-3-methylpyrazine-2-carboxamide

[1060] Method N, 1.94 min

[1061] 580.2

[1062] δ 11.20 (s, 1H), 9.01 (s, 1H), 8.91 - 8.85 (m, 1H), 8.55 (br s, 1H), 8.26 (br d, J=8.4 Hz, 1H), 8.05 - 7.76 (m, 2H), 5.12 - 5.00 (m, 1H), 3.21 (br s, 2H), 1.76 (br d, J=6.6 Hz, 6H), 1.29 (s, 6H), 1.22 (brt, 1 -(difluoromethyl)-3 -(ethyl sulfonyl)- J=7.3 Hz, 3H). Protons missing N-(5-fluoro-4-(2-(2-hydroxy-2- due to solvent suppression or methylpropyl)-3-isopropyl-3H- exchange or overlap with the imidazo[4,5-b]pyridin-5-yl)pyridin-2- NMR solvent.

[1063] yl)-lH-pyrazole-4-carboxamide

[1064] Method M, 1.16 min

[1065] 599.9

[1066] δ 8.89 (br d, J=5.4 Hz, 1H), 8.50 (s, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.12 (d, J=8.2 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.75 (br s, 1H), 7.26 - 6.90 (m, 1H), 5.00 (dt, J=13.4, 6.6 Hz, 1H), 4.21 (brt, 2-(difluoromethyl)-5-(3- J=6.1 Hz, 2H), 3.07 (s, 2H), 2.42 (dimethylamino)propoxy)-N-(5-fluoro- (br t, J=7.0 Hz, 2H), 2.18 (s, 6H), 4-(2-(2 -hydroxy -2-methylpropyl)-3- 1.96 - 1.90 (m, 2H), 1.72 (br d, isopropyl-3H-imidazo[4,5-b]pyridin-5- J=6.6 Hz, 6H), 1.27 (s, 6H).

[1067]

[1068] yl)pyridin-2-yl)nicotinamide Method M, 1.50 min

[1069] 594.1

[1070] δ 11.06 (s, 1H), 9.05 (s, 1H), 8.91 (d, J=6.1 Hz, 1H), 8.57 (d, J=2.8 Hz, 1H), 8.18 (d, J=8.3 Hz, 1H), 7.88 (dd, J=8.3, 1.2 Hz, 1H), 8.10 - 7.85 (m, 1H), 5.49 - 5.33 (m, 1H), 4.80 (s, 1H), 4.60 - 4.51 (m, (R)- 1 -(difluoromethyl)-N-(5-fluoro-4- 1H), 4.11 (d, J=7.9 Hz, 2H), 4.03 (2-(2-hydroxy-2-methylpropyl)-3- (td, J=8.3, 4.9 Hz, 1H), 3.52 (s, (tetrahydrofuran-3-yl)-3H-imidazo[4,5- 3H), 3.15 (d, J=2.8 Hz, 2H), 2.89 b]pyridin-5-yl)pyridin-2-yl)-3- - 2.79 (m, 1H), 2.42 - 2.36 (m, (methylsulfonyl)-lH-pyrazole-4- 1H), 1.29 (s, 3H), 1.26 (s, 3H). carb oxami de

[1071] Method N, 1.58 min

[1072] 684.1

[1073] 1H NMR (400 MHz, DMSO-d6) δ 11.43 - 11.33 (m, 1H), 8.99 - 8.89 (m, 1H), 8.77 (s, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.13 (s, 2H), 7.86 N-(5-fluoro-4-(2-(2-hydroxy-2- - 7.75 (m, 1H), 5.08 - 4.96 (m, methylpropyl)-3-isopropyl-3H- 1H), 4.84 (s, 1H), 3.96 - 3.85 (m, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2H), 3.31 - 3.23 (m, 2H), 3.08 (s, y 1 )- 5 -( 1 -(tetrahy dro-2H-pyran-4- 4H), 2.82 - 2.69 (m, 1H), 2.31 - yl)piperidin-4-yl)-2- 2.18 (m, 2H), 1.73 (d, J=6.8 Hz, (trifluoromethyl)nicotinamide 12H), 1.54 - 1.41 (m, 2H), 1.28

[1074] (s, 6H). _

[1075] Method N, 1.6 min

[1076] 614.4

[1077] δ 11.51 - 11.36 (m, 1H), 8.98 - 8.91 (m, 1H), 8.78 (s, 1H), 8.56 - 8.51 (m, 1H), 8.25 - 8.19 (m, 1H), 8.14 - 8.09 (m, 1H), 7.95 - 7.88 N-(5-fluoro-4-(2-(2-hydroxy-2- (m, 1H), 5.12 - 5.00 (m, 1H), 3.63 methylpropyl)-3-isopropyl-3H- - 2.65 (m, 9H), 2.14 (br d, J=13.7 imidazo[4,5-b]pyridin-5-yl)pyridin-2- Hz, 2H), 2.01 - 1.88 (m, 2H), 1.79 yl)-5-(l-methylpiperidin-4-yl)-2- - 1.69 (m, 6H), 1.29 (s, 6H).

[1078]

[1079] (trifluoromethyl)nicotinamide Method N, 1.77 min

[1080] 684.2

[1081] δ 8.94 (br d, J=6.0 Hz, 1H), 8.75 (s, 1H), 8.55 - 8.46 (m, 1H), 8.18 - 8.05 (m, 2H), 7.86 - 7.76 (m, < ZCF3 X bH 1H), 5.08 - 4.94 (m, 1H), 3.95 - 3.69 (m, 2H), 3.26 - 3.15 (m, 2H), N-(5-fluoro-4-(2-(2-hydroxy-2- 3.08 (s, 2H), 3.01 (br d, J=10.1 methylpropyl)-3-isopropyl-3H- Hz, 2H), 2.80 - 2.66 (m, 1H), 2.43 imidazo[4,5-b]pyridin-5-yl)pyridin-2- - 2.23 (m, 3H), 1.97 - 1.89 (m, y 1 )- 5 -( 1 -(tetrahy dro-2H-pyran-3 - 1H), 1.87 - 1.80 (m, 3H), 1.73 (br yl)piperidin-4-yl)-2- d, J=6.6 Hz, 8H), 1.68 - 1.62 (m, (trifluoromethyl)nicotinamide 1H), 1.54 - 1.38 (m, 2H), 1.28 (s,

[1082] 6H).

[1083] Method N, 1.61 min

[1084] 666.2

[1085] F

[1086] δ 11.51 - 11.37 (m, 1H), 8.93 (br d, J=5.1 Hz, 1H), 8.73 (s, 1H),l8.54 (s, 1H), 8.19 (d, J=8.3 Hz, ^XX / X^° -x M ^X / r 1H), 8.09 - 7.93 (m, 1H), 7.86 (d,

[1087] \ OH J=8.3 Hz, 1H), 5.12 - 4.99 (m,

[1088] 1H), 4.05 - 3.96 (m, 2H), 3.70 - 2-(difluoromethyl)-N-(5-fluoro-4-(2- 3.61 (m, 1H), 3.52 - 3.29 (m, 2H), (2-hydroxy-2-methylpropyl)-3- 3.13 (s, 4H), 2.89 (s, 1H), 2.73 (s, isopropyl-3H-imidazo[4,5-b]pyridin-5- 1H), 2.25 - 2.13 (m, 2H), 2.10 - yl)pyridin-2-yl)-5-(l-(tetrahydro-2H- 1.92 (m, 4H), 1.74 (br d, J=6.7 pyran-4-yl)piperidin-4-yl)nicotinamide Hz, 8H), 1.28 (s, 6H), 2 protons presumed supressed along with water.

[1089] Method N, 1.73 min

[1090] 654.4

[1091] δ 8.94 - 8.87 (m, 1H), 8.73 (s, 1H), 8.47 (br s, 1H), 8.13 - 8.08 (m, 1H), 8.07 - 8.01 (m, 1H), 7.86 < XCF3 X OH - 7.74 (m, 1H), 5.05 - 4.91 (m, 5-(l-cyclobutylpiperidin-4-yl)-N-(5- 1H), 3.11 - 3.02 (m, 2H), 2.99 - fluoro-4-(2-(2 -hydroxy -2- 2.88 (m, 2H), 2.83 - 2.70 (m, 2H), methylpropyl)-3-isopropyl-3H- 2.01 - 1.94 (m, 2H), 1.91 - 1.86 imidazo[4,5-b]pyridin-5-yl)pyridin-2- (m, 4H), 1.86 - 1.78 (m, 4H), 1.78 yl)-2-(trifluoromethyl)ni cotinamide - 1.72 (m, 2H), 1.71 (s, 6H), 1.65

[1092]

[1093] - 1.55 (m, 2H), 1.25 (s, 6H). Method N, 1.75 min

[1094] 564.2

[1095] δ 8.97 - 8.88 (m, 2H), 8.54 (d, J=2.4 Hz, 1H), 8.44 (dd, J=8.1, 1.3 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.85 (dd, J=8.1, 4.9Hz, 1H), 5.45 - 5.31 (m, 1H), 4.56 (q, J=7.7 Hz, 1H), 4.22 - 4.10 (m, 2H), 4.07 - (R)-N-(4-(2-(2-cyano-2-methylpropyl)- 4.00 (m, 1H), 2.89 - 2.79 (m, 1H), 3 -(tetrahydrofuran-3 -yl)-3H- 2.48 - 2.39 (m, 1H), 1.56 (s, 3H), imidazo[4,5-b]pyridin-5-yl)-5- 1.55 (s, 3H). Protons missing due fluoropyridin-2-yl)-3 - to solvent suppression or (methylsulfonyl)picolinamide exchange or overlap with the NMR solvent.

[1096] Method N, 1.74 min

[1097] 594.2

[1098] δ 11.32 (s, 1H), 8.92 (d, J=6.2 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.18 (d, J=8.9 Hz, 1H), 5.47 - 5.31 (m, 1H), 4.63 - 4.51 (m, 1H), 4.20 - 4.15 (m, 1H), (R)-N-(4-(2-(2-cyano-2-methylpropyl)- 4.14 - 4.09 (m, 1H), 4.01 (s, 3H), 3 -(tetrahydrofuran-3 -yl)-3H- 2.89 - 2.78 (m, 1H), 2.48 - 2.39 imidazo[4,5-b]pyridin-5-yl)-5- (m, 1H), 1.56 (s, 3H), 1.55 (s, fluoropyri din-2 -yl)-6-methoxy-3- 3H). Protons missing due to (methylsulfonyl)picolinamide solvent suppression or exchange or overlap with the NMR solvent.

[1099] Method N, 1.69 min

[1100] 594.2

[1101] δ 8.90 (d, J=6.0 Hz, 1H), 8.72 (s, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.22 (s, 1H), 5.45 - 5.33 (m, 1H), 4.55 (q, J=7.8 Hz, 1H), 4.20 - 4.14 (m, 1H), 4.14 - 4.09 (R)-N-(4-(2-(2-cyano-2-methylpropyl)- (m, 1H), 4.07 - 3.97 (m, 4H), 2.88 3 -(tetrahydrofuran-3 -yl)-3H- - 2.80 (m, 1H), 2.47 - 2.37 (m, imidazo[4,5-b]pyridin-5-yl)-5- 1H), 1.56 (s, 3H), 1.55 (s, 3H). fluoropyri din-2 -yl)-2-methoxy-5-

[1102]

[1103]

[1104] (methylsulfonyl)isonicotinamide Method M, 1.50 min

[1105] 599.2

[1106] δ 11.27 (s, 1H), 9.03 (d, J=6.2 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 5.02 (N-(5-fluoro-4-(2-(2 -hydroxy -2- (quin, J=6.7 Hz, 1H), 3.43 (s, methylpropyl)-3-isopropyl-3H- 3H), 3.09 (s, 2H), 3.00 (s, 2H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 1.75 (d, J=6.7 Hz, 6H), 1.28 (s, yl)-3 -(methyl sulfonyl)-6- 6H), 1.18 (s, 6H). neopentylpicolinamide

[1107] Method N, 1.86 min

[1108] 541.1

[1109] δ 9.01 (d, J=6.3 Hz, 1H), 8.94 (dd, J=4.8, 1.4 Hz, 1H), 8.52 (d,.7=2.7 Hz, 1H), 8.44 (dd, J=8.1, 1.4 Hz, 1H), 8.15 (d,.7=8.3 Hz, 1H), 7.89 - 7.81 (m, 2H), 4.80 - 4.70 (m, 1H), 3.47 (s, 1H), 3.22 - 3.11 (m, 1H), 3.03 (d, J=14.3 Hz, 1H), 2.46 - 2.34 (m, 1H), 2.14 - (S)-N-(4-(3-(sec-butyl)-2-(2-hydroxy- 2.02 (m, 1H), 1.75 (br d, J=6.7 2-methylpropyl)-3H-imidazo[4,5- Hz, 3H), 1.31 (s, 3H), 1.25 (s, b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 3H), 0.75 (t, J=7.4 Hz, 3H).

[1110] 3-(methylsulfonyl)picolinamide Protons missing due to solvent suppression or exchange or overlap with the NMR solvent. Method N, 1.78 min

[1111] 541,4

[1112] δ 9.01 (d, J=6.2 Hz, 1H), 8.94 (dd, J=4.8, 1.4 Hz, 1H), 8.52 (d,.7=2,7 Hz, 1H), 8.44 (dd, J=8.0, 1.3 Hz, 1H), 8.15 (d,.7=8,3 Hz, 1H), 7.88 - 7.81 (m, 2H), 4.84 - 4.70 (m, 1H), 3.47 (s, 1H), 3.20 - 3.11 (m, 1H), 3.03 (d, J=14.3 Hz, 1H), 2.46 - 2.36 (m, 1H), 2.14 - (R)-N-(4-(3-(sec-butyl)-2-(2-hydroxy- 2.03 (m, 1H), 1.75 (brd, J=6.6 2-methylpropyl)-3H-imidazo[4,5- Hz, 3H), 1.31 (s, 3H), 1.25 (s, b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 3H), 0.75 (t,.7=7,3 Hz, 3H).

[1113] 3-(methylsulfonyl)picolinamide Protons missing due to solvent suppression or exchange or

[1114]

[1115]

[1116] overlap with the NMR solvent. Method M, 1.60 min

[1117] 613.2

[1118] δ 11.07 (s, 1H), 8.80 (d, J=6.3 Hz, 1H), 8.32 (d, J=2.5 Hz, 1H), 8.10 (d, J=8.2 Hz, 1H), 8.04 (br d, J=8.2 Hz, 1H), 7.74 (br d, J=7.1 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 4.67 - 4.54 (m, 1H), 3.22 (s, 3H), (R)-N-(4-(3-(sec-butyl)-2-(2-hydroxy- 3.07 - 2.87 (m, 2H), 2.79 (s, 2H), 2-methylpropyl)-3H-imidazo[4,5- 2.26 - 2.09 (m, 1H), 1.98 - 1.87 b]pyridin-5-yl)-5-fluoropyridin-2-yl)- (m, 1H), 1.55 (d, J=6.7 Hz, 3H), 6-(2-hydroxy-2-methylpropyl)-3- 1.15 - 1.01 (m, 6H), 0.96 (s, 6H), (methylsulfonyl)picolinamide 0.57 (t, J=7,4 Hz, 3H). _ Method M, 1.16 min

[1119] 551.5

[1120] δ 10.72 (s, 1H), 9.04 - 8.93 (m, 1H), 8.55 (s, 1H), 8.50 - 8.39 (m, 3H), 8.20 (br d, J=8.5 Hz, 1H), 7.87 (br d, J=8.4 Hz, 1H), 5.16 - 4.96 (m, 1H), 4.52 (brt, J=5.5 N-(5-fluoro-4-(2-(2-hydroxy-2- Hz, 2H), 3.18 - 3.05 (m, 4H), 2.73 methylpropyl)-3-isopropyl-3H- (s, 3H), 2.62 (br t, J=5.2 Hz, 3H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2.14 (quin, J=6.6 Hz, 2H), 1.76 yl)-3-methyl-6-(3- (br d, J=6.7 Hz, 6H), 1.29 (s, 6H). (methylamino)propoxy)

[1121] pyrazine-2-carboxamide

[1122] Method N, 1.62 min

[1123] 658.4

[1124] δ 8.97 - 8.89 (m, 1H), 8.49 (br d, J=5.7 Hz, 2H), 8.12 (d, J=8.4 Hz, 1H), 7.87 - 7.76 (m, 2H), 5.01 (dt, J=13.0, 6.3 Hz, 1H), 4.82 (br s, 1H), 3.07 (s, 2H), 2.21 - 2.12 (m, 5-(((ls,4s)-4- 7H), 1.97 (br s, 2H), 1.72 (br d, (dimethylamino)cyclohexyl)oxy)-N-(5- J=6.6 Hz, 6H), 1.67 - 1.56 (m, fluoro-4-(2-(2 -hydroxy -2- 4H), 1.48 - 1.33 (m, 2H), 1.27 (s, methylpropyl)-3-isopropyl-3H- 6H).

[1125] imidazo[4,5-b]pyridin-5-yl)pyridin-2-

[1126]

[1127]

[1128] yl)-2-(trifluoromethyl)ni cotinamide Method N, 1.65 min

[1129] 594.1

[1130] 1H NMR (400 MHz, DMSO-d6) δ = 11.54 (s, 1H), 9.13 (s, 1H), 8.94 (d, J = 6.0 Hz, 1H), 8.56 (d, J = 2.8 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 7.5

[1131] Hz, 1H), 6.80 (dt, J = 7.3, 58.5 N-(4-(3 -(1,1 -difluoropropan-2-yl)-2-(2- Hz, 1H), 5.40 - 5.21 (m, 1H), 4.91 hydroxy-2-methylpropyl)-3H- (s, 1H), 4.11 (s, 3H), 3.43 (s, 3H), imidazo[4,5-b]pyridin-5-yl)-5- 3.23 - 3.14 (m, 1H), 3.03 (d, J = fluoropyri din-2 -yl)-2-methoxy-5- 14.3 Hz, 1H), 1.87 (d, J (methylsulfonyl)pyrimidine-4- = 7.0 Hz, 3H), 1.35 (s, 3H), 1.22 carb oxami de (s, 3H).

[1132] Enantiomer 1

[1133] Method N, 1.65 min

[1134] 594.1

[1135] 1H NMR (400 MHz, DMSO-d6) δ = 11.54 (s, 1H), 9.13 (s, 1H), 8.94 (d, J = 6.0 Hz, 1H), 8.56 (d, J = 2.8 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 7.5

[1136] Hz, 1H), 6.80 (dt, J = 7.3, 58.5 N-(4-(3 -(1,1 -difluoropropan-2-yl)-2-(2- Hz, 1H), 5.40 - 5.21 (m, 1H), 4.91 hydroxy-2-methylpropyl)-3H- (s, 1H), 4.11 (s, 3H), 3.43 (s, 3H), imidazo[4,5-b]pyridin-5-yl)-5- 3.23 - 3.14 (m, 1H), 3.03 (d, J = fluoropyri din-2 -yl)-2-methoxy-5- 14.3 Hz, 1H), 1.87 (d, J (methylsulfonyl)pyrimidine-4- = 7.0 Hz, 3H), 1.35 (s, 3H), 1.22 carb oxami de (s, 3H).

[1137] Enantiomer 2

[1138] Method N, 1.34 min

[1139] 572.3

[1140] 1H NMR (400 MHz, DMSO-d6) δ = 11.14 (s, 1H), 8.97 (d, J = 6.3 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.84 -7.76 (m, N-(5-fluoro-4-(2-(2-hydroxy-2- 2H), 5.02 (quin, J = 6.7 Hz, 1H), methylpropyl)-3-isopropyl-3H- 4.85 (br s, 1H), 3.65 (s, 2H), 3.45 imidazo[4,5-b]pyridin-5-yl)pyridin-2- (br s, 5H), 3.08 (s, 4H), 2.54 (s, yl)-2-methyl-5-(2-methyl-2- 3H), 2.45 - 2.41 (m, 3H), 2.38 - azaspiro [3.3 ] heptan-6-yl )ni cotinami de 2.29 (m, 2H),1.74 (d, J = 6.8 Hz,

[1141]

[1142]

[1143] 7H), 1.28 (s, 7H). Method N, 1.78 min

[1144] 1H NMR (400 MHz, DMSO-d6) 8 F

[1145] = 11.27 (s, 1H), 9.01 (d, J = 6.3 Hz, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.14 (d, \ \ N^ / ^O \. II / J = 8.3 Hz, 1H), 7.83 (d, J = 7.3

[1146] X° \ 6H Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H),

[1147] 5.02 (quin, J = 6.8 Hz, 1H), 4.84 3-(ethylsulfonyl)-N-(5-fluoro-4-(2-(2- (s, 1H), 3.58 (br d, J = 7.3 Hz, hydroxy-2-methylpropyl)-3-isopropyl- 6H), 3.08 (s, 2H), 2.82 (brt, J = H-imidazo[4,5-b]pyridin-5-yl)pyridin- 12.0 Hz, 1H), 2.33 (br s, 1H),

[1148] 2-yl)-6-(4- 2.00 (brt, J = 13.1 Hz, 4H), 1.75 morpholinocyclohexyl)picolinamide (d, J = 6.8 Hz, 7H), 1.70 - 1.58 (m, 2H), 1.46 - 1.32 (m, 2H), 1.28 (s, 7H), 1.19 (t, J = 7.4 Hz, 3H). Method N, 1.71 min

[1149] 732.3

[1150] F1H NMR (400 MHz, DMSO-d6) δ

[1151] = 11.39 (br s, 1H), 8.89 (d, J = 6.0 °'V\ 1 Hz, 1H), 8.76 (d, J = 1.0 Hz, 1H), AAA vNAN

[1152] I ° NA / 8.52 (d, J = 2.0 Hz, 1H), 8.21 (d, < N X^CCFF3 H \_FOH J = 8.5 Hz, 1H), 8.10

[1153] (s, 1H), 7.86 (d, J = 7.5 Hz, 1H), 6.76 (dt, J = 7.5, 56.5 Hz, 1H), 5 -( 1 -(2-oxaspiro[3.3 ]heptan-6- 5.44 - 5.21 (m, 1H), 4.90 (br s, yl)piperidin-4-yl)-N -(4 - (3 -( 1, 1 - 1H), 4.58 (s, 2H), 4.44 (s, 2H), difluoropropan-2-yl)-2-(2-hydroxy-2- 3.18 (br d, J = 14.5 Hz, 1H), methylpropyl)-3H-imidazo[4,5- 3.02 (d, J = 14.5 Hz, 1H), 2.89 (br b]pyridin-5-yl)-5-fluoropyridin-2-yl)- d, J = 11.0 Hz, 2H), 2.79 - 2.68 2-(trifluoromethyl)nicotinamide

[1154] (m, 1H), 2.39 - 2.26 (m, 2H), 1.98 Isomer 1

[1155] - 1.90 (m, 2H), 1.89 - 1.66 (m, 11H), 1.34 (s, 3H), 1.21

[1156]

[1157] (s, 3H). Method N, 1.72 min

[1158] 732.2

[1159] 1H NMR (400 MHz, DMSO-d6) δ = 11.40 (s, 1H), 8.90 (d, J = 6.3 Hz, 1H), 8.76 (d, J = 1.5 Hz, 1H), 8.53 (d, J = 2.5 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.11

[1160] (s, 1H), 7.92 - 7.82 (m, 1H), 7.02 5 -( 1 -(2-oxaspiro[3.3 ]heptan-6- - 6.57 (m, 1H), 5.39 - 5.23 (m, yl)piperidin-4-yl)-N -(4-(3 -( 1, 1 - 1H), 4.91 (s, 1H), 4.59 (s, 2H), difluoropropan-2-yl)-2-(2-hydroxy-2- 4.45 (s, 2H), 3.23 - 3.16 (m, 1H), methylpropyl)-3H-imidazo[4,5- 3.03 (d, J = 14.0 Hz, 1H), b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 2.92 (br dd, J= 1.9, 8.1 Hz, 2H), 2-(trifluoromethyl)nicotinamide

[1161] 2.75 (br s, 1H), 2.34 (dt, J = 1.6, Isomer 2

[1162] 3.6 Hz, 2H), 2.00 - 1.65 (m, 12H), 1.35 (s, 3H), 1,21 (s, 3H). _ Method N, 1.48 min

[1163] 678.2

[1164] 1H NMR (400 MHz, DMSO-d6) 8 = 11.14 (s, 1H), 8.93 (d, J = 6.3 Hz, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 8.3 Hz, 1H), 7.86 (dd, J = 1.3, 8.3 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 6.79 (dt, J = 10.0, 58.3 Hz, 1H), 5.37 - 5.23 (m, 1H), 4.91 (s, 5 -( 1 -(2-oxaspiro[3.3 ]heptan-6- 1H), 4.58 (s, 2H), 4.45 (s, 2H), yl)piperidin-4-yl)-N -(4 - (3 -( 1, 1 - 3.23 - 3.15 (m, 1H), 3.03 (d, J = difluoropropan-2-yl)-2-(2-hydroxy-2- 14.3 Hz, 1H), 2.88 (br d, J= 10.5 methylpropyl)-3H-imidazo[4,5- Hz, 2H), 2.55 (s, 4H), 2.33 (ddd, J b]pyridin-5-yl)-5-fluoropyridin-2-yl)- = 2.8, 7.1, 9.4 Hz, 2H), 1.98 - 2-methylnicotinamide

[1165] 1.90 (m, 2H), 1.87 (d, J = 7.0 Hz, 3H), 1.84 - 1.74 (m, 4H), 1.68 (dt, J = 3.3, 12.4 Hz, 2H), 1.35 (s,

[1166]

[1167]

[1168] 3H), 1.21 (s, 4H). Method N, 1.55 min

[1169] 656.2

[1170] 1H NMR (400 MHz, DMSO-d6) δ = 11.11 (s, 1H), 8.95 (d, J = 6.3 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.84 - 7.72 (m, 2H), 4.92 (s, 1H), 4.80 - 4.71 (m, 5 -( 1 -(2-oxaspiro[3.3 ]heptan-6- 1H), 4.58 (s, 2H), 4.45 (s, 2H), yl)piperidin-4-yl)-N-(4-(3-(sec-butyl)- 3.15 (d, J = 14.3 Hz, 1H), 3.07 - 2-(2 -hydroxy -2-methylpropyl)-3H- 2.98 (m, 1H), 2.93 - 2.84 (m, 2H), imidazo[4,5-b]pyridin-5-yl)-5- 2.55 (s, 3H), 2.45 - 2.30 (m, 3H), fluoropyridin-2-yl)-2- 2.14 - 2.00 (m, 1H), 1.97 - 1.89 methylnicotinamide (m, 2H), 1.85 - 1.62 (m, 11H),

[1171] 1.31 (s, 3H), 1.25 (s, 3H), 0.74 (t, J = 7.4 Hz, 3H).

[1172] Method N, 1.51 min

[1173] 644.4

[1174] 1H NMR (400 MHz, DMSO-d6) δ = 11.13 (s, 1H), 8.95 (d, J = 6.3 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.82 - 7.78 (m, 2H), 4.92 (s, 1H), 4.80 - 4.71 (m, 1H), 3.93 - 3.87 (m, 2H), 3.32 - N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- 3.25 (m, 3H), 3.21 - 3.10 (m, 1H), methylpropyl)-3H-imidazo[4,5- 3.08 - 2.96 (m, 3H), 2.58 (br d, J b]pyridin-5-yl)-5-fluoropyridin-2-yl)- = 3.5 Hz, 1H), 2.55 (s, 3H), 2.48 - -methyl-5-(l-(tetrahydro-2H-pyran-4- 2.35 (m, 2H), 2.28 - 2.18 (m, 2H), yl)piperidin-4-yl)nicotinamide 2.14 - 2.00 (m, 1H), 1.86 - 1.65 (m, 8H), 1.46 (dq, J = 4.4, 12.0 Hz, 2H), 1.31 (s, 3H), 1.25 (s,

[1175]

[1176]

[1177] 3H), 0.74 (t, J = 7.4 Hz, 3H). Method N, 1.74 min

[1178] 698.3

[1179] 1H NMR (400 MHz, DMSO-d6) 8 = 11.37 (s, 1H), 8.92 (d, J = 6.3 Hz, 1H), 8.77 (s, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.12 (s, 1H), 7.81 (dd, J = 1.3, 8.3 Hz, 1H), 4.91 (s, 1H), 4.75 (td, J = 6.6, 8.8 Hz, 1H), N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- 3.90 (br dd, J = 3.6, 10.6 Hz, 2H), methylpropyl)-3H-imidazo[4,5- 3.30 - 3.25 (m, 2H), 3.15 (d, J = b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 14.3 Hz, 1H), 3.10 - 2.98 (m, 3H), 5-(l -(tetrahydro-2H-pyran-4- 2.76 (br s, 1H), 2.44 - 2.35 (m, yl)piperidin-4-yl)-2- 1H), 2.27 (br s, 1H), 2.12 - 2.02 (trifluoromethyl)nicotinamide (m, 1H), 1.85 (br s, 2H), 1.73 (d,

[1180] J = 6.8 Hz, 9H), 1.53 - 1.41 (m, 2H), 1.31 (s, 3H), 1.25 (s, 3H), 0.74 (t, J = 7.4 Hz, 3H).

[1181] Method N, 1.73

[1182] 572.2

[1183] 1H NMR (400 MHz, DMSO-d6) δ = 11.50 (s, 1H), 9.13 (s, 1H), 8.98 (d, J = 6.3 Hz, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 1.3, 8.3 Hz, 1H), 4.90 (s, 1H), 4.80 - 4.71 (m, N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- 1H), 4.12 (s, 3 H), 3.44 (s, 3H), methylpropyl)-3H-imidazo[4,5- 3.21 - 3.10 (m, 1H), 3.08 - 2.97 b]pyridin-5-yl)-5-fluoropyridin-2-yl)- (m, 1H), 2.45 - 2.36 (m, 1H), 2.14 2-methoxy-5- - 2.04 (m, 1H), 1.74 (d, J = 6.8 (methylsulfonyl)pyrimidine-4- Hz, 3H), 1.31 (s, 3H), 1.25 (s, carb oxami de

[1184] 3H), 0.75 (t, J = 7.4 Hz, 3H).

[1185]

[1186]

[1187] Enantiomer 1 Method N, 1.73

[1188] 572.2

[1189] 1H NMR (400 MHz, DMSO-d6) δ = 11.50 (s, 1H), 9.13 (s, 1H), 8.98 (d, J = 6.3 Hz, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 1.3, 8.3 Hz, 1H), 4.90 (s, 1H), 4.80 - 4.71 (m, N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- 1H), 4.12 (s, 3 H), 3.44 (s, 3H), methylpropyl)-3H-imidazo[4,5- 3.21 - 3.10 (m, 1H), 3.08 - 2.97 b]pyridin-5-yl)-5-fluoropyridin-2-yl)- (m, 1H), 2.45 - 2.36 (m, 1H), 2.14 2-methoxy-5- - 2.04 (m, 1H), 1.74 (d, J = 6.8 (methylsulfonyl)pyrimidine-4- Hz, 3H), 1.31 (s, 3H), 1.25 (s, carb oxami de

[1190] 3H), 0.75 (t, J = 7.4 Hz, 3H). Enantiomer 2

[1191] Method N, 1.42 min

[1192] 588.3

[1193] 1H NMR (400 MHz, DMSO-d6) δ = 11.15 (s, 1H), 8.97 (d, J = 6.0 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.84 - 7.74 (m, 2H), 5.02 (td, J = 6.7, 13.4 Hz, N-(5-fluoro-4-(2-(2-hydroxy-2- 1H), 4.85 (s, 1H), 3.08 (s, 2H), methylpropyl)-3-isopropyl-3H- 2.95 (br s, 1H), 2.76 (br s,lH) imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2.55 (s, 3H), 2.36 (br s, 1H), 1.81 yl)-2-methyl-5-(l,2,2- (br d, J = 6.5 Hz, 2H), 1.74 (d, J = trimethylpiperidin-4-yl)nicotinamide 6.8 Hz, 10H), 1.28 (s, 8H), 1.20

[1194] (br s, 3H), 1.16 - 1.05 (m, 2H). Method N, 1.93 min

[1195] 708.3

[1196] 1H NMR (400 MHz, DMSO-d6) 8 ppm 11.27 (s, 1 H) 9.01 (d, J=6.25 Hz, 1 H) 8.49 - 8.58 (m, 1 H) 8.24 - 8.32 (m, 1 H) 8.11 - 8.17 (m, 1 H) 7.79 - 7.87 (m, 1 H) 7.65 - 7.73 (m, 1 H) 4.96 - 5.10 (m, 1 H) 4.80 - 4.87 (m, 1 H) 3.87 - 4.00 (m, 1 H) 3.55 - 3.63 (m, 2 3-(ethylsulfonyl)-N-(5-fluoro-4-(2-(2- H) 3.45 - 3.54 (m, l H) 3.16 (s, 3 hydroxy-2-methylpropyl)-3-isopropyl- H) 3.08 (s, 2 H) 2.75 - 2.88 (m, 2 H-imidazo[4,5-b]pyridin-5-yl)pyridin- H) 2.68 (dt, J=3.60, 1.77 Hz, 1 H) 2-yl)-6-(4-(3 -m ethoxy azeti din- 1 - 2.30 - 2.36 (m, 1 H) 1.84 - 2.00 yl)cyclohexyl)picolinamide

[1197] (m, 4 H) 1.75 (d, J=6.75 Hz, 6 H) 1.53 - 1.67 (m, 2 H) 1.28 (s, 6 H) 1.16 - 1.22 (m, 3 H) 1.00 - 1.14

[1198]

[1199]

[1200] (m, 2 H). Method N, 2.16 min

[1201] 744.3

[1202] 1H NMR (400 MHz, DMSO-d6) δ ppm 11.24 - 11.35 (m, 1 H) 8.92 - 9.04 (m, 1 H) 8.49 - 8.59 (m, 1 H) 8.28 (d, J=8.25 Hz, 1 H) 8.19 - 8.25 (m, 1 H) 7.87 - 7.93 (m, 1 H) 7.66 - 7.73 (m, 1 H) 6.65 - 6.99 (m, 1 H) 5.24 - 5.38 (m, 1 H) 4.88 - 4.93 (m, 1 H) 3.87 - 3.97 (m, 1 N-(4-(3 -(1,1 -difluoropropan-2-yl)-2-(2- H) 3.58 (q, J=7.30 Hz, 2 H) 3.49 hydroxy-2-methylpropyl)-3H- (br s, 2 H) 3.12 - 3.22 (m, 4 H) imidazo[4,5-b]pyridin-5-yl)-5- 3.04 (d, J=14.26 Hz, 1 H) 2.73 - fluoropyridin-2-yl)-3-(ethylsulfonyl)-6- 2.85 (m, 3 H) 2.65 - 2.70 (m, 2 H) (4-(3 -methoxy azeti din- 1 - 2.30 - 2.36 (m, 1 H) 1.90 - 2.06 yl)cyclohexyl)picolinamide

[1203] (m, 4 H) 1.87 (br d, J=6.88 Hz, 5 H) 1.53 - 1.67 (m, 2 H) 1.32 - 1.37 (m, 3 H) 1.15 - 1.25 (m, 6 H) 0.99 - 1.13 (m, 2 H).

[1204] Method N, 1.83 min

[1205] 720.3

[1206] 1H NMR (400 MHz, DMSO-d6) 8 = 11.41 (s, 1H), 8.90 (d, J = 6.3 Hz, 1H), 8.77 (d, J = 1.3 Hz, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.12

[1207] (s, 1H), 7.94 - 7.80 (m, 1H), 6.77 N-(4-(3 -(1,1 -difluoropropan-2-yl)-2-(2- (dt, J = 7.3, 57.8 Hz, 1H), 5.30 (br hydroxy-2-methylpropyl)-3H- s, 1H), 4.91 (s, 1H), 3.65 - 3.52 imidazo[4,5-b]pyridin-5-yl)-5- (m, 1H), 3.23 - 3.10 (m, 4H), 3.03 fluoropyridin-2-yl)-5-(l-(3- (d, J = 14.3 Hz, 1H), methoxycyclobutyl)piperidin-4-yl)-2- 2.95 (br s, 2H), 2.77 (br s, 2H), (trifluoromethyl)nicotinamide 1.87 (br d, J = 7.0 Hz, 8H), 1.63

[1208] (br s, 4H), 1.35 (s, 4H), 1.21 (s,

[1209]

[1210]

[1211] 4H). Method N, 1.48 min

[1212] 696.3

[1213] 1H NMR (400 MHz, DMSO-d6) δ F = 11.37 (s, 1H), 8.94 (d, J = 6.3 Hz, 1H), 8.76 (d, J = 1.8 Hz, 1H), °rv\ A 8.51 (d, J = 2.8 Hz, 1H), 8.14 (d, nA'N \NAN

[1214] J = 8.5 Hz, 1H), 8.11

[1215] v~"iT XCCFF3 A \ OH (s, 1H), 7.80 (dd, J = 1.1, 8.1 Hz,

[1216] 1H), 5.02 (t, J = 6.9 Hz, 1H), 4.84 5 -( 1 -(2-oxaspiro[3.3 ]heptan-6- (s, 1H), 4.59 (s, 2H), 4.45 (s, 2H), yl)piperidin-4-yl)-N-(5-fluoro-4-(2-(2- 3.18 (d, J = 5.3 Hz, 1H), 3.08 (s, hydroxy-2-methylpropyl)-3-isopropyl- 2H), 2.91 (br d, J =

[1217] H-imidazo[4,5-b]pyridin-5-yl)pyridin- 11.0 Hz, 2H), 2.74 (brt, J= 11.4 2-yl)-2-(trifluoromethyl)nicotinamide

[1218] Hz, 1H), 2.39 - 2.29 (m, 2H), 2.00 - 1.89 (m, 2H), 1.88 - 1.78 (m, 3H), 1.73 (d, J = 6.8 Hz, 8H), 1.28 (s, 6H).

[1219] Method N, 1.72 min

[1220] 656.3

[1221] 1H NMR (400 MHz, DMSO-d6) 8 F = 11.37 (br s, 1H), 8.92 (d, J = 6.3

[1222] Hz, 1H), 8.76 (d, J = 1.8 Hz, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 8.11

[1223] (s, 1H), 7.87 - 7.71 (m, 1H), 4.91 CAA° VA L.

[1224] M' CF-; OH (br s, 1H), 4.83 - 4.60 (m, 1H),

[1225] 3.15 (br d, J = 14.5 Hz, 4H), 3.02 N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- (br d, J = 14.3 Hz, 3H), 2.18 (s, methylpropyl)-3H-imidazo[4,5- 3H), 1.89 (s, 3H), 1.83 - 1.75 (m, b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 2H), 1.73 (d, J = 6.8 Hz, 3H), 2-(trifluoromethyl)-5-(l,2,2- 1.63 (d, J = 8.5 Hz, 2H), 1.31 (s, trimethylpiperidin-4-yl)nicotinamide 3H), 1.25 (s, 2H), 1.12

[1226] (s, 2H), 1.05 (t, J = 7.1 Hz, 1H), 1.01 (s, 1H), 0.74 (t, J = 7.4 Hz, 1H).

[1227]

[1228] Method N, 1.68 min

[1229] 726.3

[1230] 1H NMR (400 MHz, DMSO-d6) δ = 11.38 (s, 1H), 8.93 (d, J = 6.3 Hz, 1H), 8.76 (d, J = 1.8 Hz, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 8.11

[1231] (s, 1H), 7.82 (d, J = 7.0 Hz, 1H), 5.07 - 4.99 (m, 1H), 4.88 (s, 1H), 5 -( 1 -(2-oxaspiro[3.3 ]heptan-6- 4.59 (s, 2H), 4.45 (s, 2H), 4.23 (t, yl)piperidin-4-yl)-N-(5-fluoro-4-(2-(2- J = 9.4 Hz, 1H), 3.84 (dd, J = 5.4, hy droxy-2-methylpropyl)-3 -( 1 - 9.6 Hz, 1H), 3.21 - methoxypropan-2-yl)-3H-imidazo[4,5- 3.12 (m, 3H), 2.99 (d, J= 14.3 b]pyridin-5-yl)pyridin-2-yl)-2- Hz, 1H), 2.90 (br d, J = 11.8 Hz, (trifluoromethyl)nicotinamide 2H), 2.79 - 2.69 (m, 1H), 2.55 (s,

[1232] 1H), 2.39 - 2.30 (m, 2H), 1.98 - 1.89 (m, 2H), 1.87 - 1.73

[1233] (m, 4H), 1.71 (d, J = 6.8 Hz, 4H), 1.32 (s, 3H), 1,23 (s, 3H). _ Method N, 1.59 min

[1234] 666.3

[1235] 1H NMR (400 MHz, DMSO-d6) δ = 11.15 (s, 1H), 8.93 (d, J = 6.3 Hz, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 8.3 Hz, 1H), 7.86

[1236] (dd, J = 1.3, 8.3 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 6.79 (dt, J = 6.5, 59.3 Hz, 1H), 5.40 - 5.22 (m, 1H), N-(4-(3 -(1,1 -difluoropropan-2-yl)-2-(2- 4.91 (s, 1H), 3.58 (quin, J = 7.3 hydroxy-2-methylpropyl)-3H- Hz, 1H), 3.19 (d, J = imidazo[4,5-b]pyridin-5-yl)-5- 14.3 Hz, 1H), 3.12 (s, 3H), 3.03 fluoropyridin-2-yl)-5-(l-(3- (d, J = 14.3 Hz, 1H), 2.91 (br d, J methoxycyclobutyl)piperidin-4-yl)-2- = 11.0 Hz, 2H), 2.58 (br d, J = 4.0 methylnicotinamide Hz, 1H), 2.55 (d, J = 2.3 Hz, 4H), Isomer 1 2.44 - 2.35 (m, 2H),

[1237] 2.33 - 2.27 (m, 1H), 1.91 (s, 1H), 1.88 (d, J = 7.0 Hz, 2H), 1.85 - 1.56 (m, 7H), 1.35 (s, 3H), 1.22

[1238]

[1239]

[1240] (s, 3H). Method N, 1.59 min

[1241] 666.3

[1242] 1H NMR (400 MHz, DMSO-d6) 8 = 11.14 (s, 1H), 8.93 (d, J = 6.3 Hz, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.86 (dd, J = 1.3, 8.5 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 6.79 (dt, J = 6.5, 56.3 Hz, N-(4-(3 -(1,1 -difluoropropan-2-yl)-2-(2- 1H), 5.39 - 5.23 (m, 1H), 4.91 (s, hydroxy-2-methylpropyl)-3H- 1H), 3.65 - 3.51 (m, 1H), 3.19 (br imidazo[4,5-b]pyridin-5-yl)-5- d, J = 14.3 Hz, 2H), 3.12 (s, 3H), fluoropyridin-2-yl)-5-(l-(3- 3.03 (d, J = 14.3 Hz, 1H), 2.91 (br methoxycyclobutyl)piperidin-4-yl)-2- d, J = 10.8 Hz, 2H), 2.58 (br s, methylnicotinamide 1H), 2.55 (d, J = 2.3 Hz, 4H), Isomer 2 2.44 - 2.35 (m, 2H), 2.32 - 2.25 (m, 1H), 1.88 (d, J = 7.0 Hz, 3H), 1.84 - 1.54 (m, 6H), 1.35 (s, 3H), 1.22 (s, 3H).

[1243] Method N, 1.57 min

[1244] 630.3

[1245] 1H NMR (400 MHz, DMSO-d6) δ = 11.13 (s, 1H), 8.96 (d, J = 6.0 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.85 - 7.75 (m, N-(5-fluoro-4-(2-(2-hydroxy-2- 2H), 5.09 - 4.95 (m, 1H), 4.86 (s, methylpropyl)-3-isopropyl-3H- 1H), 3.58 (quin, J = 7.2 Hz, 1H), imidazo[4,5-b]pyridin-5-yl)pyridin-2- 3.12 (s, 3H), 3.08 (s, 2H), 2.91 (br yl)-5-(l-(3- d, J = 10.8 Hz, 2H), 2.58 (br s, methoxycyclobutyl)piperidin-4-yl)-2- 1H), 2.55 (s, 3H), 2.44 - 2.35 (m, methylnicotinamide 2H), 2.31 - 2.27 (m, 1H), 1.88 - 1.67 (m, 11H), 1.65 - 1.55 (m,

[1246]

[1247]

[1248] 2H), 1.28 (s, 6H), 1.24 (s, 1H). Method N, 1.80 min

[1249] 722.3

[1250] 1H NMR (400 MHz, DMSO-d6) δ = 11.26 (s, 1H), 9.01 (d, J = 6.3 Hz, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 4.91 (s, 1H), 4.84 - 4.69 (m, 1H), 3.93 (t, J = 5.8 Hz, 1H), 3.59 (q, J N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- = 7.5 Hz, 3H), 3.53 (br s, 2H), methylpropyl)-3H-imidazo[4,5- 3.16 (s, 4H), 3.07 - 2.98 (m, 1H), b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 2.88 - 2.76 (m, 2H), 2.41 (td, J = 3 -(ethyl sulfonyl)-6-(4-(3 - 7.8, 13.9 Hz, 1H), 2.16 - 2.03 (m, methoxyazetidin- 1 - 2H), 2.00 - 1.82 (m, 4H), 1.75 (d, yl)cyclohexyl)picolinamide J = 6.8 Hz, 3H), 1.68 - 1.53 (m,

[1251] 2H), 1.31 (s, 3H), 1.25 (s, 3H), 1.19 (t, J = 7.5 Hz, 3H), 1.08 (q, J = 11.0 Hz, 2H), 0.75 (t, J = 7.4 Hz, 3H).

[1252] Method N, 1.64 min

[1253] 738.2

[1254] 1H NMR (400 MHz, DMSO-d6) δ = 11.27 (d, J = 2.5 Hz, 1H), 10.36 - 9.77 (m, 1H), 9.00 (d, J = 6.3 Hz, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.93 - 7.80 (m, 1H), 7.71 (dd, J = 2.0, 8.3 Hz, 1H), 5.15 - 4.92 (m, 1H), 4.47 - 3-(ethylsulfonyl)-N-(5-fluoro-4-(2-(2- 4.12 (m, 4H), 4.10 - 3.97 (m, 2H), hy droxy-2-methylpropyl)-3 -( 1 - 3.83 (dd, J = 5.4, 9.6 Hz, 1H), methoxypropan-2-yl)-3H-imidazo[4,5- 3.60 (q, J = 7.3 Hz, 2H), 3.30 (s, b]pyridin-5-yl)pyridin-2-yl)-6-(4-(3- 2H), 3.26 (s, 2H), 3.19 (s, 4H), methoxyazetidin- 1 - 3.15 (s, 1H), 3.00 (d, J = 14.3 Hz, yl)cyclohexyl)picolinamide 1H), 2.95 - 2.84 (m, 1H), 2.20 - 1.98 (m, 4H), 1.73 (d, J = 7.0 Hz, 3H), 1.66 (br d, J = 13.3 Hz, 2H), 1.33 (s, 5H), 1.23 (s, 3H), 1.20 (t,

[1255]

[1256]

[1257] J = 7.4 Hz, 3H). Method N, 1.91 min

[1258] 678.3

[1259] 1H NMR (400 MHz, DMSO-d6) δ = 11.12 (s, 1H), 8.95 (d, J = 6.0 Hz, 1H), 8.50 (d, J = 2.5 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.85 - 7.74 (m, 2H), 4.92 (s, 1H), 4.82 - 4.68 (m, 1H), 3.20 - 3.11 (m, 1H), 3.02 (d, N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- J = 14.5 Hz, 1H), 2.96 (br d, J = methylpropyl)-3H-imidazo[4,5- 11.3 Hz, 2H), 2.55 (s, 4H), 2.40 b]pyridin-5-yl)-5-fluoropyridin-2-yl)- (ddd, J = 7.5, 8.8, 13.8 Hz, 1H), -(l-(4,4-difluorocyclohexyl)piperidin- 2.31 - 2.22 (m, 2H), 2.13 - 1.99 4-yl)-2-methylnicotinamide

[1260] (m, 3H), 1.92 - 1.64 (m, 12H), 1.63 - 1.50 (m, 2H), 1.31 (s, 3H), 1.25 (s, 3H), 0.75 (t, J = 7.4 Hz, 3H).

[1261] Method N, 1.63 min

[1262] 692.2

[1263] 1H NMR (400 MHz, DMSO-d6) δ = 11.13 (s, 1H), 8.96 (d, J = 6.3 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.87 - 7.74 (m, 2H), 4.92 (s, 1H), 4.82 - 4.68 (m, N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- 1H), 3.23 - 2.99 (m, 6H), 2.92 (br methylpropyl)-3H-imidazo[4,5- d, J = 11.3 Hz, 2H), 2.75 - 2.62 b]pyridin-5-yl)-5-fluoropyridin-2-yl)- (m, 1H), 2.61 - 2.53 (m, 4H), 2.40 5-(l -(1, 1 -dioxidotetrahydro-2H- (ddd, J = 7.5, 8.9, 13.6 Hz, 1H), thiopyran-4-yl)piperidin-4-yl)-2- 2.32 - 2.23 (m, 2H), 2.12 - 1.96 methylnicotinamide

[1264] (m, 5H), 1.84 - 1.65 (m, 7H), 1.31 (s, 3H), 1.25 (s, 3H), 0.74 (t, J =

[1265]

[1266]

[1267] 7.4 Hz, 3H). Method N, 1.63 min

[1268] 656.3

[1269] 1H NMR (400 MHz, DMSO-d6) δ = 11.30 (s, 1H), 8.99 (d, J = 6.3 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 4.91 (s, 1H), 4.82 - 4.71 (m, 1H), 4.45 (t, J = 6.6 Hz, 2H), 3.53 (q, J N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- = 7.4 Hz, 2H), 3.16 (d, J = 14.3 methylpropyl)-3H-imidazo[4,5- Hz, 1H), 3.03 (d, J = 14.3 Hz, b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 1H), 2.47 - 2.36 (m, 3H), 2.19 (s, 6-(3-(dimethylamino)propoxy)-3- 5H), 2.14 - 2.04 (m, 1H), 2.00 - (ethylsulfonyl)picolinamide 1.88 (m, 2H), 1.74 (d, J = 6.8 Hz,

[1270] 3H), 1.31 (s, 3H), 1.25 (s, 3H), 1.19 (t, J = 7.4 Hz, 3H), 0.75 (t, J = 7.4 Hz, 3H).

[1271] Method N, 2.03 min

[1272] 718.3

[1273] 1H NMR (400 MHz, DMSO-d6) δ = 11.37 (s, 1H), 8.94 (d, J = 6.0 Hz, 1H), 8.76 (d, J = 1.5 Hz, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.20 - 8.04 (m, 2H), 7.80 (dd, J

[1274] = 1.3, 8.3 Hz, 1H), 5.02 (quin, J = -(l-(4,4-difluorocyclohexyl)piperidin- 6.8 Hz, 1H), 4.85 (s, 1H), 3.08 (s, 4-yl)-N-(5-fluoro-4-(2-(2-hydroxy-2- 2H), 3.00 (br d, J = 10.0 Hz, 2H), methylpropyl)-3-isopropyl-3H- 2.81 - 2.71 (m, 1H), 2.31 (br s, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 1H), 2.13 - 2.00 (m,

[1275] yl)-2-(trifluoromethyl)ni cotinamide

[1276] 2H), 1.92 - 1.75 (m, 7H), 1.73 (d, J = 6.8 Hz, 6H), 1.65 - 1.50 (m,

[1277]

[1278]

[1279] 2H), 1.28 (s, 6H). Method N, 2.05 min

[1280] 754.1

[1281] 1H NMR (400 MHz, DMSO-d6) δ = 11.40 (s, 1H), 8.90 (d, J = 6.3 Hz, 1H), 8.77 (d, J = 1.5 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.12

[1282] (s, 1H), 7.87 (d, J = 7.5 Hz, 1H), 5-(l-(4,4-difluorocyclohexyl)piperidin- 6.77 (dt, J = 7.8, 57.8 Hz, 1H), 4-yl)-N-(4-(3 -(1,1 -difluoropropan-2- 5.39 - 5.21 (m, 1H), 4.91 (s, 1H), yl)-2-(2 -hydroxy -2-methylpropyl)-3H- 3.19 (d, J = 14.0 Hz, 1H), 3.07 - imidazo[4,5-b]pyridin-5-yl)-5- 2.94 (m, 3H), 2.80 - 2.69 fluoropyridin-2-yl)-2- (m, 2H), 2.36 - 2.22 (m, 2H), 2.11 (trifluoromethyl)nicotinamide - 1.99 (m, 3H), 1.93 - 1.69 (m,

[1283] 11H), 1.65 - 1.51 (m, 3H), 1.35 (s, 3H), 1.21 (s, 3H).

[1284] Method N, 2.13 min

[1285] 732.2

[1286] 1H NMR (400 MHz, DMSO-d6) δ = 11.37 (s, 1H), 8.92 (d, J = 6.3 Hz, 1H), 8.76 (d, J = 1.5 Hz, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 8.12

[1287] (s, 1H), 7.81 (dd, J= 1.0, 8.3 Hz, 1H), 4.91 (s, 1H), 4.82 - 4.68 (m, N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- 1H), 3.15 (d, J = 14.0 Hz, 1H), methylpropyl)-3H-imidazo[4,5- 3.07 - 2.92 (m, 3H), 2.81 - 2.70 b]pyridin-5-yl)-5-fluoropyridin-2-yl)- (m, 1H), 2.44 - 2.35 (m,

[1288] 5-(l-(4,4-difluorocyclohexyl)piperidin- 1H), 2.33 - 2.24 (m, 2H), 2.13 - 4-yl)-2-(trifluoromethyl)nicotinamide

[1289] 1.96 (m, 3H), 1.89 - 1.69 (m, 11H), 1.65 - 1.51 (m, 2H), 1.31 (s, 3H), 1.25 (s, 3H), 0.74 (t, J =

[1290]

[1291]

[1292] 7.4 Hz, 3H). Method N, 1.84 min

[1293] 746.2

[1294] 1H NMR (400 MHz, DMSO-d6) δ = 11.37 (s, 1H), 8.92 (d, J = 6.0 Hz, 1H), 8.77 (d, J = 1.5 Hz, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.22 - 8.06 (m, 2H), 7.81 (dd, J

[1295] = 1.0, 8.3 Hz, 1H), 4.91 (s, 1H), N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- 4.81 - 4.70 (m, 1H), 3.22 - 3.00 methylpropyl)-3H-imidazo[4,5- (m, 6H), 2.95 (br d, J = 11.3 Hz, b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 2H), 2.84 - 2.63 (m, 2H), 2.45 - 5-( 1 -( 1, 1 -dioxidotetrahydro-2H- 2.21 (m, 3H), 2.12 - 1.97 thiopyran-4-yl)piperidin-4-yl)-2- (m, 5H), 1.90 - 1.83 (m, 2H), 1.82 (trifluoromethyl)nicotinamide

[1296] - 1.76 (m, 1H), 1.73 (d, J = 6.8 Hz, 3H), 1.31 (s, 3H), 1.25 (s, 3H), 0.74 (t, J = 7.4 Hz, 3H). Method N, 1.74 min

[1297] 744.3

[1298] 1H NMR (400 MHz, DMSO-d6) δ = 11.30 (s, 1H), 8.98 (d, J = 6.3 Hz, 1H), 8.54 (d, J = 2.5 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 6.81 (dt, J = 5.8, 57.0 Hz, 1H), 5.41 - 5.21 (m, 1H), 4.91 (s, 1H), N-(4-(3 -(1,1 -difluoropropan-2-yl)-2-(2- 3.92 (quin, J = 5.8 Hz, 1H), 3.58 hydroxy-2-methylpropyl)-3H- (q, J = 7.3 Hz, 2H), 3.54 - 3.45 imidazo[4,5-b]pyridin-5-yl)-5- (m, 2H), 3.24 - 3.12 (m, 5H), 3.04 fluoropyridin-2-yl)-3-(ethylsulfonyl)-6- (d, J = 14.0 Hz, 1H), 2.88 - 2.75 (4-(3 -methoxy azeti din- 1 - (m, 3H), 2.06 (br d, J = 11.8 Hz, yl)cyclohexyl)picolinamide

[1299] 1H), 1.99 - 1.82 (m, 7H), 1.70 - 1.52 (m, 2H), 1.35 (s, 3H), 1.24 - 1.15 (m, 6H), 1.07 (q, J= 11.7

[1300]

[1301]

[1302] Hz, 2H). Method N, 1.79 min

[1303] 722.3

[1304] 1H NMR (400 MHz, DMSO-d6) δ = 11.27 (s, 1H), 9.01 (d, J = 6.3 Hz, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 4.91 (s, 1H), 4.82 - 4.69 (m, 1H), N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- 3.94 (br t, J = 5.8 Hz, 1H), 3.66 - methylpropyl)-3H-imidazo[4,5- 3.51 (m, 4H), 3.20 - 3.11 (m, 5H), b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 3.02 (d, J = 14.5 Hz, 1H), 2.91 - 3 -(ethyl sulfonyl)-6-(4-(3 - 2.75 (m, 2H), 2.46 - 2.37 (m, 1H), methoxyazetidin- 1 - 2.16 - 2.04 (m, 2H), 2.01 - 1.84 yl)cyclohexyl)picolinamide (m, 4H), 1.75 (d, J = 6.8 Hz, 3H),

[1305] 1.68 - 1.53 (m, 2H), 1.31 (s, 3H), 1.25 (s, 3H), 1.19 (t, J = 7.4 Hz, 3H), 1.14 - 1.02 (m, 2H), 0.75 (t, J = 7,4 Hz, 3H), _

[1306] Method N, 1.70 min

[1307] 718.1

[1308] 1H NMR (400 MHz, DMSO-d6) δ = 8.94 (d, J = 6.0 Hz, 1H), 8.77 (d, J = 1.5 Hz, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.19 - 8.09 (m, 2H), 7.87 - 7.74 (m, 1H), 5.02 (quin, J = 6.8 Hz, 1H), 4.85 (br s, 5-(l -(1, 1 -di oxidotetrahydrothi ophen-3 - 1H), 3.27 - 3.22 (m, 2H), 3.14 - yl)piperidin-4-yl)-N-(5-fluoro-4-(2-(2- 3.05 (m, 4H), 3.04 - 2.94 (m, 2H), hydroxy-2-methylpropyl)-3-isopropyl- 2.85 - 2.72 (m, 1H), 2.40 - 2.34 H-imidazo[4,5-b]pyridin-5-yl)pyridin- (m, 1H), 2.27 - 2.13 (m,

[1309] 2-yl)-2-(trifluoromethyl)nicotinamide 2H), 2.06 (s, 1H), 2.05 - 1.95 (m,

[1310] 1H), 1.91 - 1.84 (m, 2H), 1.82 - 1.67 (m, 7H), 1.28 (s, 6H), 1.11

[1311]

[1312]

[1313] (s, 1H), 1.03 (s, 1H). Method N, 1.72 min

[1314] 656.3

[1315] 1H NMR (400 MHz, DMSO-d6) 8 = 11.37 (br s, 1H), 8.92 (d, J = 6.3 Hz, 1H), 8.76 (d, J = 1.5 Hz, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 8.11

[1316] (s, 1H), 7.86 - 7.76 (m, 1H), 4.91 (br s, 1H), 4.75 (td, J = 6.6, 8.5 Hz, 1H), 3.19 - 3.12 (m, 2H), 3.02 N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- (br d, J = 14.3 Hz, 2H), 2.65 - methylpropyl)-3H-imidazo[4,5- 2.54 (m, 2H), 2.44 - 2.35 b]pyridin-5-yl)-5-fluoropyridin-2-yl)- (m, 1H), 2.18 (s, 2H), 2.12 - 2.00 2-(trifluoromethyl)-5-(l,2,2- (m, 1H), 1.85 (s, 2H), 1.78 (br s, trimethylpiperidin-4-yl)nicotinamide 1H), 1.73 (d, J = 6.8 Hz, 2H),

[1317] 1.63 (d, J = 8.3 Hz, 2H), 1.31 (s, 3H), 1.25 (s, 3H), 1.12 (s, 3H), 1.00 (s, 2H), 0.74 (t, J = 7.4

[1318] Method N, 1.80 min

[1319] 720.3

[1320] 1H NMR (400 MHz, DMSO-d6) δ = 11.40 (s, 1H), 8.90 (d, J = 6.3 Hz, 1H), 8.74 (d, J = 1.5 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.10

[1321] (s, 1H), 7.93 - 7.80 (m, 1H), 6.77 (dt, J = 8.0, 56.5 Hz, 1H), 5.41 - N-(4-(3 -(1,1 -difluoropropan-2-yl)-2-(2- 5.22 (m, 1H), 4.91 (s, 1H), 3.94 hydroxy-2-methylpropyl)-3H- (br t, J = 6.0 Hz, 1H), 3.54 (br s, imidazo[4,5-b]pyridin-5-yl)-5- 2H), 3.23 - 3.14 (m, 3H), fluoropyridin-2-yl)-5-(4-(3- 3.03 (d, J = 14.3 Hz, 2H), 2.83 (br methoxyazetidin- 1 -yl)cy clohexyl)-2- s, 1H), 2.76 - 2.69 (m, 1H), 2.55 (trifluoromethyl)nicotinamide (s, 1H), 2.08 (s, 2H), 1.87 (br d, J = 6.8 Hz, 7H), 1.68 - 1.48 (m, 2H), 1.35 (s, 3H), 1.21 (s,

[1322]

[1323]

[1324] 3H), 1.15 - 0.99 (m, 2H). Method N, 1.90 min

[1325] 698.3

[1326] 1H NMR (400 MHz, DMSO-d6) 8 = 11.37 (s, 1H), 8.92 (d, J = 6.3 Hz, 1H), 8.74 (d, J = 1.5 Hz, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 8.10

[1327] V N-^ / (s, 1H), 7.81 (dd, J= 1.3, 8.3 Hz, < N^CF3 ~^V_ C> H 1H), 4.91 (s, 1H), 4.83 - 4.67 (m,

[1328] 1H), 3.93 (quin, J = 5.4 Hz, 1H), N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- 3.52 (br s, 1H), 3.20 - 3.12 (m, methylpropyl)-3H-imidazo[4,5- 2H), 3.02 (d, J = 14.3 Hz, b]pyridin-5-yl)-5-fluoropyridin-2-yl)- 1H), 2.80 (br s, 2H), 2.76 - 2.67 5-(4-(3 -m ethoxy azeti din- 1 - (m, 1H), 2.55 (s, 2H), 2.45 - 2.34 yl)cyclohexyl)-2- (m, 1H), 2.12 - 2.01 (m, 2H), 1.91 (trifluoromethyl)nicotinamide (s, 1H), 1.87 (br d, J = 11.0 Hz,

[1329] 2H), 1.73 (d, J = 6.8 Hz, 2H), 1.64 - 1.51 (m, 2H), 1.31 (s, 3H), 1.25 (s, 2H), 1.16 - 1.01 (m, 2H), 0.74 (t, J = 7.4 Hz, 2H). Method N, 1.64 min

[1330] 694.3

[1331] 1H NMR (400 MHz, DMSO-d6) δ = 11.27 (s, 1H), 9.04 (d, J = 6.3 Y\, 0^ A Hz, 1H), 8.53 (d, J = 2.8 Hz, 1H), \ \ N^ / ^O \. II / 8.32 (d, J = 8.3 Hz, 1H), 8.14 (d,

[1332] A. -° 8H J = 8.0 Hz, 1H), 7.84

[1333] (d, J = 7.3 Hz, 1H), 7.70 (d, J = N-(5-fluoro-4-(2-(2-hydroxy-2- 8.3 Hz, 1H), 5.02 (quin, J = 6.8 methylpropyl)-3-isopropyl-3H- Hz, 1H), 4.84 (s, 1H), 3.61 (br s, imidazo[4,5-b]pyridin-5-yl)pyridin-2- 2H), 3.44 (s, 4H), 3.17 (s, 3H), yl)-6-(4-(3 -methoxy azeti din- 1 - 3.08 (s, 2H), 2.95 (br s, 2H), 2.55 yl)cyclohexyl)-3- (s, 1H), 2.21 (br s, 1H), 2.02 - (methylsulfonyl)picolinamide 1.85 (m, 2H), 1.75 (d, J = 6.8 Hz,

[1334] 4H), 1.69 - 1.54 (m, 2H), 1.28 (s,

[1335]

[1336] 6H), 1.18 - 1.03 (m, 2H). Method N, 1.63 min

[1337] 632.2

[1338] 1H NMR (400 MHz, DMSO-d6) δ = 11.38 (s, 1H), 8.93 (d, J = 6.3 Hz, 1H), 8.53 - 8.49 (m, 2H), 8.15 (d, J = 8.5 Hz, 1H), 7.85 - 7.80 (m, 2H), 4.92 (s, 1H), 4.83 - 4.67 148 (m, 1H), 4.24 (t, J = 6.4 Hz, 2H),

[1339] 3.16 (d, J = 14.3 Hz, 2H), 3.02 (d, N-(4-(3-(sec-butyl)-2-(2-hydroxy-2- J = 14.3 Hz, 1H), 2.41 (brt, J = methylpropyl)-3H-imidazo[4,5- 6.9 Hz, 2H), 2.18 (s, 6H), 2.07 b]pyridin-5-yl)-5-fluoropyridin-2-yl)- (td, J = 6.9, 13.4 Hz, 1H), 1.92 5-(3-(dimethylamino)propoxy)-2- (quin, J = 6.6 Hz, 2H), 1.74 (d, J (trifluoromethyl)nicotinamide

[1340] = 6.8 Hz, 3H), 1.31 (s, 3H), 1.24

[1341]

[1342] (s, 3H), 0.74 (t, J = 7.4 Hz, 3H).

[1343] It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

WE CLAIM:

1. A compound of F ormul a (I):or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:Het is a 5- to 6-membered heteroaryl containing 1 to 3 ring heteroatoms which are N, N(Rb), O, or S, wherein the heteroaryl is substituted with 1 R5and 0 to 3 R6;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;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-4 alkyl), N(CI-4 alkyl)2, -NH(CI-4 haloalkyl), -NHC(=O)( C1-4 alkyl), -(CRgRgl)o-3-(C3-8cycloalkyl substituted with 0 to 4 Re), or -(CRgRgl)o-2-(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);R3is halogen, cyano, C1-4 haloalkyl, C1-4 haloalkoxy,-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;R4is H, halogen, cyano or C1-4 alkyl;R5is halogen, cyano, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy,-NH(CI-4 alkyl), CM alkyl substituted with 0 to 2 Ra, -S02(CM 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;R6is halogen, -OH, cyano, Ci-6 alkyl substituted with 0-2 Rc,C2-6 alkenyl substituted with 0-2 Rc, C2-6 alkynyl substituted with 0-2 Rc,Ci-4haloalkyl substituted with 0-2 Rc, C1-4 alkoxy substituted with 0-2 Rc,C1-4 haloalkoxy substituted with 0-2 Rc, -NHC(=O)(CI-4 alkyl),-NHC(=O)O(CI-4 alkyl), -(0)O-I-(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);Rais halogen, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 haloalkyl,C1-4haloalkoxy, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;Rbis H, C1-4haloalkyl, -C(=O)(C1-4alkyl), -C(=O)O(C1-4alkyl), C1-4alkyl substituted with 0-1 Rf, C3-6 cycloalkyl, or a 4- to 8-membered heterocycle including 1 to 2 ring heteroatom which are N, N(Rb), O or S(O)2, and wherein the heterocycle is a monocycle or spiro cycle;Rcis halogen, cyano, OH, C1-4haloalkyl, C1-4haloalkoxy, N(C1-4alkyl)2, C1-4alkyl substituted with 0 to 2 Rf, or C1-4alkoxy substituted with 0 to 1 Rf;Rdis halogen, cyano, -OH, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, -O(C=O)H, -O(C=O)(C1-4alkyl), -C(=O)O(C1-4alkyl), NH2, N(C1-4alkyl)2, -C(=O)NH2, -C(=O)N(C1-4alkyl)2, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl substituted with 0 to 2 Rc, or a 4- to 6-membered heterocycle including 1 to 2 ring heteroatom which are N, N(Rb), or O, and wherein the heterocycle is a monocycle or spiro cycle and is substituted with 0 to 3 Rf;Reis oxo or Rd;Rfis halogen, OH, cyano, -CH2OH, C1-4alkoxy, or N(C1-4alkyl)2;Rgis H, C1-4 alkyl substituted with 0 to 1 Rf, C1-4 alkoxy, or C3-6 cycloalkyl; Rglis H or C1-4 alkyl;Rhis H or C1-6 alkyl substituted with 0 to 1 Ra;m and n are 0, 1 or 2; andp is 0, 1 or 2.

2. The compound of claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is H, C1-6 alkyl substituted with 0 to 2 Ra, C1-6 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 independently 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;R2is H, C1-4alkoxy, C1-6alkyl substituted with 0 to 1 Ra, C1-6haloalkyl substituted with 0 to 1 Ra, -NH2, -NHC(=O)(C1-4alkyl) or C3-6cycloalkyl substituted with 0 to 1 Re;R3is halogen, -OH, cyano, C1-6 alkyl, C1-4 alkoxy, C 1-4 haloalkyl, orC1-4 haloalkoxy;R4is H, halogen, cyano, or C1-2 alkyl;R5is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C 1-4 haloalkoxy, -SO2(C1-4alkyl substituted with 0 to 1 Rc), or -SO2CH2(C3-4cycloalkyl);Rais halogen, cyano, -OH, -CH2OH, C1-4 alkoxy, C1-4 haloalkyl, orC1-4 haloalkoxy;Rbis H, Ci-4 haloalkyl, or C1-4 alkyl substituted with 0-1 OH;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; andRdis halogen, cyano, -OH, -NH2, C1-4 alkyl substituted with 0-1 OH,C1-4 alkoxy, C1-4 haloalkyl, or C1-4 haloalkoxy.

3. The compound of claim 1 or claim 2, wherein the compound is represented by Formula (II):or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:Het is a 5 to 6-membered heteroaryl containing 1 to 2 nitrogen atoms with are N or N(Rb), wherein the heteroaryl is substituted with 1 R5and 0 to 2 R6;R1is Ci-6 alkyl, Ci-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 2 Re;R2is C1-4fluoroalkyl, C1-6alkyl substituted with 0 to 1 Ra, -NH2, -NHC(=O)(C1-4alkyl) or C3-6cycloalkyl substituted with 0 to 1 Re;R3ais H orR3;R3is F, Cl, cyano, C1-4 alkyl, or C1-4 fluoroalkyl;R4is H, F or Cl;R5is halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, -SO2(C1-4alkyl), or -SO2CH2(C3-4cycloalkyl);R6is halogen, cyano, C1-6alkyl substituted with 0-2 Rc, C2-6alkynyl substituted with 0-1 Rc, C1-4haloalkyl substituted with 0-1 Rc, C1-4alkoxy substituted with 0-1 Rc, C1-4haloalkoxy substituted with 0-1 Rc,-NHC(=O)O(Ci-4 alkyl), C3-6 cycloalkyl substituted with 0 to 1 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 2 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 2 Rd);Rais F, Cl, cyano, -OH, -CH2OH, C1-4 alkoxy, or C1-4 fluoroalkyl;Rbis H, C1-4 alkyl, or C1-4 fluoroalkyl;Rcis F, Cl, cyano, -OH, C1-4 alkoxy, C1-4 fluoroalkyl, C1-4 fluoroalkoxy,-NH2, -NH(C1-4alkyl) or -N(C1-4alkyl)2;Rdis F, cyano, -OH, -NH2, C1-4 alkyl substituted with 0-1 OH,C1-4 fluoroalkyl or C1-4 alkoxy;Reis oxo or Rd; andRgis H or C1-2 alkyl or -CH2OH.

4. The compound of any one of claims 1 to 3, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R5R1is C1-4 alkyl, C1-4 fluoroalkyl, -CH(Ci-2alkyl)-cyclopropyl, cyclopentyl,cyclohexyl substituted with 0 to 1 -N(CI-4 alkyl)?,R2is C1-4fluoroalkyl, C1-6alkyl substituted with 0 to 1 Ra, -NH2, -NHC(=O)(C1-4alkyl) or C3-4cycloalkyl substituted with 0 to 1 cyano;R3ais H orR3;R3is F or Cl;R5is halogen, C1-4alkyl, C1-4fluoroalkyl, -SO2(C1-4alkyl), or -SO2CH2(C3-4cycloalkyl);R6is C1-6 alkyl substituted with 0-2 Rc, C2-6 alkynyl substituted with 0-1 Rc, C1-4 haloalkyl substituted with 0-1 Rc, C1-4 alkoxy substituted with 0-1 Rc,C1-4 haloalkoxy substituted with 0-1 R, -NHC(=O)O(CI-4 alkyl), C3-5 cycloalkyl substituted with 0 to 1 Re, a 4- to 7-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 1 Re; or -(0)o-i-(5- to 6-membered heteroaryl including 1 to 4 ring heteroatom which are N, N(Rb), or O, and is substituted with 0 to 1 Rd);R6ais H or cyano;Rais cyano or OH;Rcis -OH, -NH2, -NH(C1-4alkyl) or -N(C1-4alkyl)2;Rdis F, cyano, -OH, -NH2, C1-4 alkyl, C 1-4 fluoroalkyl, or C1-4 alkoxy; and Reis oxo or Rd.

5. The compound of claim 1 or claim 2, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R2is C1-4 fluoroalkyl, C1-6 alkyl substituted with 0 to 1 Ra, -NH2,—CN-NHC(=O)(CI-4alkyl) or;R5is Cl, C1-2alkyl, C1-2fluoroalkyl, -SO2(C1-4alkyl) or -SO2CH2(cyclopropyl);R6is C1-6 alkyl substituted with 0-1 Rc, C2-6 alkynyl substituted with 0-1 Rc, C1-4fluoroalkyl substituted with 0-1 Rc, C1-4 alkoxy substituted with 0-1 Rc,V— Rb / ill N.Rais cyano, -OH, or -NH2;Rbis H, C1-4 alkyl or C1-4 fluoroalkyl; andRcis -OH, -NH2, -NH(C1-4alkyl), or -N(C1-4alkyl)2.

6. The compound of claim 1 or claim 2, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R57. The compound of any one of claims 3 to 6, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is C1-4alkyl, cyclopentyl or cyclohexyl substituted with -N(C1-4alkyl)2; R2is C1-4 fluoroalkyl or C1-6 alkyl substituted with OH;R3ais H orF;R4is F;R5is Cl, C1-2alkyl, or -SO2(C1-2alkyl); andR6is C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, lH-l,2,3,4-tetrazol-l-yl, or C3-5 alkynyl substituted with OH or -NH(CI-2 alkyl).

8. The compound of claim 1 or claim 2, wherein the compound is represented by Formula (III):R3aN-^R2or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is C1-4alkyl, C1-4fluoroalkyl, -CH(C1-2alkyl)-cyclopropyl, cyclopentyl, orR2is C1-4fluoroalkyl, -NH2, -NHC(=O)(C1-4alkyl), C1-4alkyl substituted with 0 to 1 Ra;R3ais H orR3;R3is F or Cl;R4is H orF;R5is C1-2alkyl, -SO2(C1-2alkyl) or -SO2CH2(cyclopropyl);R6bis H or R6;R6is C1-4 alkyl, C1-4 alkoxy, C 1-4 fluoroalkoxy, or cyclopropyl; andRais cyano or -OH.

9. The compound of claim 8, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is -CH(CH3)2, -CH(CH3)-cyclopropyl, cyclopentyl,1-2, orCH3R2is -CH2CF3, -CH2C(CH3)2OH, -CH2C(CH3)2CN, -NH2, or -NHC(=O)(CH3);R3ais H;R5is -SO2CH3, -SO2CH2CH3, or -SO2CH2(cyclopropyl); andR6bis H, -CH3, -OCH3, or -OCH2CHF2.

10. The compound according to claim 1, which is selected from any one of the Examples 1 to 148 as described in the specification, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

11. A composition comprising a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and one or more a pharmaceutically acceptable carriers, diluents, or excipients.

12. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10 or a composition according to claim 11 for use in therapy.

13. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10 or a composition according to claim 11 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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