6-(pyridin-4-yl)-1h-benzo[d]imidazole derivatives as CAMK2 inhibitors for the treatment of heart failure

Abstract

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

Description

[0001] BENZIMIDAZOLE COMPOUNDS AS CAMK2 INHIBITORS

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

[0003] 63 / 721,704, filed November 18, 2024; the content of which is herein incorporated by reference in its entirety.

[0004] FIELD OF THE INVENTION

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

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

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

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

[0016] These and other features and advantages of the invention will be apparent from the following detailed description and claims. 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 2 nitrogen atoms, 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, C2-6 alkenyl, C2-6 alkynyl, ORh, or C1-6 alkyl substituted with 0 to 2 Ra;

[0025] R4is H, halogen, cyano or C1-4 alkyl;

[0026] 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;

[0027] R6is halogen, 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)O(CI-4alkyl), -NHC(=O)O(CI-4alkyl),

[0028] -(O)0-1-(CH2)0-1-(C3-6cycloalkyl 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 a monocycle, bridged cycle or spiro cycle, is partially satuated or fully satuated, and is substituted with 0 to 3 Re; or

[0029] -(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] CM haloalkoxy, NH2, NH(CI-4alkyl), N(CI-4alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;

[0032] Rbis H, C1-4 haloalkyl, -C(=O)(Ci-4alkyl), -C(=O)O(Ci-4alkyl), C alkyl substituted with 0-1 Rf, or a 4- to 8-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;

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

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

[0035] Reis oxo or Rd;

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

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

[0038] Rhis H or C1-6 alkyl substituted with 0 to 1 Ra; m and n are 0, 1 or 2; and

[0039] p is 0, 1 or 2.

[0040] 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:

[0041] R6is halogen, 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)O(CI-4alkyl), -NHC(=O)O(CI-4alkyl),

[0042] -(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 a monocycle, bridged cycle or spiro cycle, is partially satuated or fully satuated, and is substituted with 0 to 3 Re; or

[0043] -(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; and

[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.

[0046] 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:

[0047] Het is a 6-membered heteroaryl containing 1 to 2 nitrogen atoms, wherein the heteroaryl is substituted with 1 R5and 0 to 3 R6;

[0048] 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, Ci-4 alkoxy, Ci-6 alkyl substituted with 0 to 1 Ra, Ci-6 haloalkyl substituted with 0 to 1 Ra, or -NHC(=O)( Ci-4 alkyl);

[0049] R3is halogen, -OH, cyano, Ci-6 alkyl, Ci-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, or -SO2(Ci-4 alkyl substituted with 0 to 1 Rc);

[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, C1-4 alkyl substituted with 0-1 OH, C1-4 alkoxy, C1-4 haloalkyl, or C1-4 haloalkoxy.

[0058] In a third aspect, the present invention provides a compound of Formula (II):

[0059]

[0060] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

[0061] Het is a 6-membered heteroaryl containing 1 to 2 nitrogen atoms, wherein the heteroaryl is substituted with 1 R5and 0 to 2 R6;

[0062] R1is C1-6 alkyl, C1-4 fluoroalkyl, -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 1 Re), or a 5-to 6-membered heterocycle including 1 ring heteroatom which is N, N(Rb), O, or S(O)P, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 2 Re;

[0063] R2is C1-4 fluoroalkyl or C1-6 alkyl substituted with 0 to 1 Ra, or

[0064] -NHC(=O)( C 1-4 alkyl);

[0065] R3ais H orR3; R3is F, Cl, cyano, Ci-4 alkyl, or Ci-4 fluoroalkyl;

[0066] R4is H, F or Cl;

[0067] R5is halogen, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 fluoroalkyl, Ci-4 fluoroalkoxy, or -SO2(Ci-4alkyl);

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

[0069] -NHC(=O)O(Ci-4 alkyl), C3-6 cycloalkyl, a 5- to 6-membered heteroaryl including 1 to 4 ring heteroatom which are N, N(Rb), O, or S(O)P, and is substituted with 0 to 2 Rd; or a 5-to 6-membered heterocycle including 1 to 4 ring heteroatom which are N, N(Rb), O, or S(O)P, and wherein the heterocycle is partially satuated or fully satuated, and is substituted with 0 to 2 Re;

[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(C 1-4 alkyl) or -N(Ci-4alkyl)2;

[0073] Rdis F, cyano, C1-4 alkyl substituted with 0-1 OH, C1-4 fluoroalkyl or

[0074] Ci -4 alkoxy;

[0075] Reis oxo, F, Cl, OH, C1-4 alkyl, or C1-4 fluoroalkyl;

[0076] Rgis H or C1-2 alkyl or -CH2OH; and

[0077] p is 0, 1 or 2.

[0078] 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: R5

[0079] o

[0080]

[0081] r (r6)°-1;

[0082] R1is Ci-4 alkyl, C1-4 fluoroalkyl, -CH(Ci-2alkyl)-cyclopropyl, cyclopentyl,

[0083] xC alkyl)

[0084] V-n / (Ci-2 0-2

[0085] cyclohexyl substituted with 0 to 1 -N(C1-4alkyl)2

[0086]

[0087] ?,1-2, or

[0088] N

[0089] xRb.

[0090]

[0091] 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;

[0092] R3ais H orR3;

[0093] R3is F or Cl;

[0094] R4is H, F or Cl;

[0095] R5is halogen, C1-4 alkyl, C1-4 fluoroalkyl, -SC>2(CM alkyl), or

[0096] -SC>2CH2(C3-4 cycloalkyl);

[0097] 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, C alkoxy substituted with 0-1 Rc,

[0098] C haloalkoxy substituted with 0-1 Rc, -NHC(=0)0(CM alkyl), C3-4 cycloalkyl, •CH2OH 'N— RblH-l,2,3-triazol-l-yl, lH-l,2,3,4-tetrazol-l-yl,

[0099]

[0100] HX, or

[0101]

[0102] R6ais H or cyano;

[0103] Rais cyano or OH;

[0104] Rbis H, C1-4alkyl or C1-4fluoroalkyl; and

[0105] Rcis -OH, -NH2, -NH(C1-4alkyl) or -N(C1-4alkyl)2.

[0106] 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 fouth aspect and wherein, independently for each occurrence:

[0107] R6a’6

[0108]

[0109] :6)o-i R1is C1-4alkyl, C1-4fluoroalkyl, -CH(C1-2alkyl)-cyclopropyl, cyclopentyl, or

[0110] ) - V(Cl-2 0-2

[0111]

[0112] o

[0113] R2is CM fluoroalkyl or Ci-6 alkyl substituted with 0 to 1 Ra, or

[0114] -NHC(=O)( C i-4 alkyl); and

[0115] R5is halogen, C1-4alkyl, or -SO2(C1-4alkyl).

[0116] 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 any of the third to fifth aspects and wherein, independently for each occurrence: R5

[0117]

[0118] (R6)o-1

[0119] 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:

[0120]

[0121] 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:

[0122]

[0123] 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:

[0124]

[0125] 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:

[0126] R5

[0127] Het i

[0128]

[0129] s (R )0-1

[0130] 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 of the third to fifth aspects and wherein, independently for each occurrence:

[0131] R5

[0132] Het is

[0133]

[0134] , or

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

[0136] R2is Ci-4 fluoroalkyl or Ci-6 alkyl substituted with OH;

[0137] R3ais H orF;

[0138] R4is F;

[0139] R5is Cl, Ci-2 alkyl, or -SO2(C1-2 alkyl); and

[0140] 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).

[0141] In an eighth aspect, the present invention provides a compound of Formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the seventh aspect and wherein, independently for each occurrence:

[0142] R1is C1-4 alkyl or cyclopentyl; R2is Ci-6 alkyl substituted with OH; and

[0143] R6is Ci-4 alkyl, C3-5 alkynyl substituted with -NH(C1-2 alkyl), Ci-4 alkoxy, or 1 H- 1, 2, 3, 4 -tetr azol - 1 -y 1.

[0144] 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 seventh aspect and wherein, independently for each occurrence:

[0145] R1is isoproper or cyclopentyl;

[0146] R2is -CH2C(CH3)2OH;

[0147] R3ais H;

[0148] R4is F;

[0149] R5is Cl, CH3or -SO2CH3; and

[0150] R6is CH3, -OCH3, lH-l,2,3,4-tetrazol-l-yl,

[0151]

[0152] or ^CH3.

[0153] In a ninth aspect, the present invention provides a compound of Formula (III):

[0154]

[0155] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:

[0156] R1is Ci-4 alkyl, C1-4 fluoroalkyl, -CH(Ci-2alkyl)-cyclopropyl, cyclopentyl, or

[0157]

[0158] R2 is C1-4 fluoroalkyl, C1-4 alkyl substituted with 0 to 1 Ra or

[0159]

[0160] F; R3ais H orR3;

[0161] R3is F or Cl;

[0162] R4is F;

[0163] R5 is C1-2 alkyl, -SO2(C1-2 alkyl) or -SO2CH2(cyclopropyl);

[0164] R6bis H or R6;

[0165] v alkyl R6is Ci-4 alkyl, Ci-4 alkoxy, Ci-4 fluoroalkoxy, cyclopropyl, o

[0166]

[0167] r1'4; and

[0168] Rais cyano or -OH.

[0169] In a tenth aspect, the present invention provides a compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the ninth aspect and wherein, independently for each occurrence:

[0170] R1is -CH2CH3, -CH(CH3)2, -CH2CHF2, -CH(CH3)CHF2,

[0171] -CH(CH3)-cyclopropyl, cyclopentyl, o

[0172]

[0173] r 1-2

[0174] R2is -CH2CF3, -CH2C(CH3)2OH, -CH2C(CH3)2CN, orFR3ais H, F or Cl;

[0175] R5is -CH3, -SO2CH3, -SO2CH2CH3, or -SO2CH2(cyclopropyl); and

[0176]

[0177] R6bis H, -CH3, -OCH3, -OCH2CHF2, cyclopropyl, or

[0178] In another aspect, the invention provides a compound selected from:

[0179]

[0180] or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0181] In another aspect, the invention provides a compound selected from:

[0182]

[0183]

[0184] In an eleventh aspect, the invention provides a compound selected from the exemplified Examples 1 to 150 or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0185] 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.

[0186] 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.

[0187] In another embodiment, the present invention provides a process for making a compound of the present invention.

[0188] In another embodiment, the present invention provides an intermediate for making a compound of the present invention.

[0189] DEFINITIONS

[0190] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, "a" and "an" may refer to either one, or one or more.

[0191] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0192] For purposes of clarity and in accordance with standard convention in the art, the symbol is used in formulas and tables to show the bond that is the point of attachment of the moiety or substituent to the core / nucleus of the structure.

[0193] 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.

[0194] 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.

[0195] “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.

[0196] 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".

[0197] 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.

[0198] Where a bonding attachment location is not specified, the bonding may be attached at any appropriate location as understood by practitioners in the art.

[0199] 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.

[0200] The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0201] 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.

[0202] 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.

[0203] BIOLOGICAL METHODS

[0204] CAMK2D ECHO MS Activity Assay

[0205] 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%.

[0206] Reaction mixtures containing 0.05 nM full length CAMK2D (CARNA Product Number 02-111), 0.01 mg / mL His-TVMV-hCalmodulin (1-149, in-house synthesized), ATP at the kinase ATP Km (5 uM), 2 uM of the PLN peptide fragment (MEKVQYLTRSAIRRASTIEMPQQARQKLQN) were incubated with test compounds for 60 min. Following, the reactions were quenched with 0.1% formic acid. Endpoint data was collected by determining the ratio of the m / z of product analyte using mass spectrometry, 731.7 a 712.3 divided by the m / z of internal standard analyte, 605.2 a 713.1.

[0207] 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.

[0208] 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.

[0209] Table 1

[0210] ECHO MS CAMK2D HTRF

[0211] Ex #

[0212] IC50 (mM) ACT IC50 (□M)

[0213] 1 0.005

[0214] 2 0.001

[0215] 3 0.004

[0216] 4 0.005

[0217] 5 0.008

[0218] 6 0.002

[0219] 7 0.002

[0220] 8 0.004

[0221] 9 0.003

[0222] 10 0.001

[0223] 11 0.003

[0224] 12 0.002

[0225] 13 0.002

[0226] 14 0.002

[0227] 15 0.004

[0228] 16 0.001

[0229] 17 0.001

[0230] 18 0.001

[0231] 19 0.002

[0232] 20 0.001

[0233] 21 0.001

[0234] 22 0.003

[0235] 23 0.001

[0236]

[0237] 24 0.002 0.002

[0238] 0.001

[0239] 0.001

[0240] 0.0004

[0241] 0.001

[0242] 0.0001

[0243] 0.008 0.001 0.0002 0.008 0.001 0.0008 0.002 0.002 0.007 0.002 0.008 0.0006 0.002 0.004 0.0008 0.0008 0.0006 0.004 0.0003 0.0008 0.001 0.0003 0.0007 0.0006 0.005 0.0006 0.0005 0.001 0.005 0.0005 0.002 0.005 0.005 0.001

[0244]

[0245] 0.003 0.002 0.008 0.005 0.008 0.002 0.004 0.0002 0.007 0.0006 0.002 0.0009 0.003 0.003 0.003 0.02 0.004 0.003 0.02 0.0004 0.007 0.0005 0.001 0.001 0.002 0.0002 0.0006 0.002 0.004 0.01 0.003 0.0005 0.002 0.005 0.002 0.001 0.002 0.001 0.002 0.003 0.0006

[0246]

[0247] 0.0006 0.0003 0.0003 0.0003 0.0003 0.003 0.002 0.0002 0.003 0.009 0.001 0.002 0.0004 0.0007 0.007 0.001 0.003 0.007 0.008

[0248] 0.002

[0249] 0.004

[0250] 0.002

[0251] 0.004

[0252] 0.001

[0253] 0.003

[0254] 0.001

[0255] 0.001

[0256] 0.023

[0257] 0.001

[0258] 0.002

[0259] 0.0002

[0260] 0.006

[0261] 0.007

[0262] 0.002

[0263] 0.003

[0264] 0.003

[0265] 0.0004

[0266] 0.0004

[0267] 0.001

[0268] 0.001

[0269] 0.001

[0270]

[0271] 0.001 148 0.004

[0272] 149 0.000

[0273]

[0274] 150 0.000

[0275] Cellular Assay

[0276] 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% CO2atmosphere for 1 hour. Cells were then stimulated with 1 uM ionomycin final concentration for 15 minutes. Cell lysates were prepared and analyzed using the CisBio pPLN HTRF Assay Kit, following manufacturer’s protocols. Briefly, cell lysates were prepared by adding 50 uL supplemented cell lysis buffer and shaking at room temperature for 30 min. 16 uL of this lysate was transferred to a 384 well plate, and 4 uL of combined HTRF antibodies, and this was incubated overnight at room temperature in the dark. Plates were read for HTRF ratios 16-22 hours later on an Envision plate reader. Results were normalized as maximal inhibition observed in a staurosporin concentration-response curve representing 100% inhibition, and 0% inhibition representing vehicle-only (DMSO) treated cells. These data points were then fit to a to a 4-parameter logistic curve. In some cases, the upper plateau of this curve was assumed to be 100% inhibition. In some cases, the lower plateau of this curve was assumed to be 0% inhibition. Potencies were then recorded as the inflection point of this curve. Examples of inhibiton in the cellular assay are reported in Table 2. Table 2. Assay in HEK293 cells measuring inhibition of PLN phosphorylation pPLN HTRF EC50

[0277] Ex #

[0278] (□M)

[0279] 1 0.025

[0280] 2 0.008

[0281] 3 0.017

[0282] 4 0.015

[0283] 5 0.026

[0284] 6 0.025

[0285] 7 0.013

[0286] 8 0.05

[0287] 9 0.016

[0288] 10 0.023

[0289] 11 0.036

[0290] 12 0.002

[0291] 13 0.041

[0292] 14 0.026

[0293] 15 0.04

[0294] 16 0.006

[0295] 17 0.007

[0296] 18 0.011

[0297] 19 0.003

[0298] 20 0.014

[0299] 21 0.009

[0300] 22 0.02

[0301] 23 0.016

[0302] 24 0.012

[0303] 25 0.018

[0304] 26 0.007

[0305] 27 0.017

[0306] 28 0.009

[0307] 29 0.003

[0308] 30 0.004

[0309] 31 0.044

[0310] 32 0.006

[0311] 33 0.013

[0312] 34 0.046

[0313] 35 0.031

[0314] 36 0.015

[0315] 37 0.013

[0316] 38 0.047

[0317] 39 0.048

[0318] 40 0.01

[0319] 41 0.05

[0320]

[0321] 42 0.006 0.019 0.034 0.011 0.014 0.047 0.025 0.039 0.01 0.024 0.005 0.004 0.004 0.06 0.023 0.012 0.017 0.025 0.026 0.025 0.036 0.031 0.009 0.014 0.017 0.015 0.041 0.030 0.029 0.014 0.005 0.037 0.01 0.009 0.005 0.016 0.024 0.017 0.016 0.005 0.018 0.005 0.001 0.037 0.022 0.004 0.02

[0322]

[0323] 0.03 0.009 0.014 0.006 0.0003 0.024 0.02 0.006 0.029 0.027 0.022 0.022 0.019 0.006 0.024 0.007 0.015 0.007 0.008 0.005 0.005 0.007 0.013 0.001 0.007 0.017 0.029 0.012 0.008 0.007 0.006 0.008 0.01 0.014 0.06 0.023 0.001 0.062 0.054 0.015 0.015 0.023 0.010 0.006 0.016 0.006 0.031

[0324]

[0325] 0.007 137 0.007

[0326] 138 0.045

[0327] 139 0.016

[0328] 140 0.032

[0329] 141 0.051

[0330] 142 0.003

[0331] 143 0.011

[0332] 144 0.019

[0333] 145 0.042

[0334] 146 0.052

[0335] 147 0.099

[0336] 148 0.047

[0337] 149 0.017

[0338]

[0339] 150 0.006

[0340] PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE

[0341] 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.

[0342] Unless otherwise specified, the following terms have the stated meanings. The term "subject" refers to any human or other mammalian species that could potentially benefit from treatment with a CAMK2D, CAMK2A, CAMK2B, CAMK2G inhibitor as understood by practitioners in this field. Some subjects include human beings of any age with risk factors for cardiovascular disease. Common risk factors include age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity arrhythmia or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). The term "patient" means a person suitable for therapy as determined by practitioners in the field. As used herein, the term "patient" encompasses all mammalian species.

[0343] " Treating" or "treatment" cover the treatment of a patient or subject as understood by practitioners in this field. " Preventing" or "prevention" cover the preventive treatment ( / .<., prophylaxis and / or risk reduction) of a subclinical diseas estate 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.

[0344] 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.

[0345] 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.

[0346] " Pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, / .<., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.

[0347] 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.

[0348] 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). 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. Another aspect of the invention is a method for treating heart disease wherein the treatment is given to a patient with chronic heart failure.

[0354] 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.

[0355] 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 nonaqueous 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] 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, 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, β-blockers, anti-diabetes agents, angiotensin II antagonists, angiotensin converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives.

[0362] 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.

[0363] 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 PPARα, PPARβ and PPARg; dehydroepiandrosterone (also referred to as DHEA or its conjugated sulphate ester, DHEA-SO4); anti-glucocorticoids; TNFα 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.

[0364] 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, 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 H3receptors, dopamine D2receptor modulators, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA).

[0365] 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.

[0366] 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.

[0367] 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).

[0368] CHEMISTRY METHODS Abbreviations as used herein, are defined as follows: "lx" for once, "2x" for twice, "3x" for thrice, " °C" for degrees Celsius, "aq" for aqueous, " Col" for column, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, " L" for liter or liters, "mL" for milliliter or milliliters, "pL" for microliter or microliters, " N" for normal, " M" for molar, "nM" for nanomolar, "mol" for mole or moles, "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, " RT" for retention time, " ON" for overnight, "atm" for atmosphere, "psi" for pounds per square inch, "cone." for concentrate, "aq" for "aqueous", "sat" or "sat'd " for saturated, " MW" for molecular weight, "mw" or "pwave" for microwave, "mp" for melting point, " Wt" for weight, " MS" or " Mass Spec" for mass spectrometry, " ESI" for electrospray ionization mass spectroscopy, " HR" for high resolution, " HRMS" for high resolution mass spectrometry, " LCMS" for liquid chromatography mass spectrometry, " HPLC" for high pressure liquid chromatography, " RP HPLC" for reverse phase HPLC, " TLC" or "tic" for thin layer chromatography, " NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser effect spectroscopy, "1H" for proton, "6 " for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" forbroad, " Hz" for hertz, and "a", "0", " R", " S", " E", and " Z" are stereochemical designations familiar to one skilled in the art.

[0369] Ac Acetic

[0370] AcOH acetic acid

[0371] Acn (or MeCN) Acetonitrile

[0372] BBr3Boron tribromide

[0373] BINAP 2, 2'-bis(diphenylphosphino)- 1,1 '-binaphthyl

[0374] Bispin bis(pinacolato)diboron

[0375] Bn Benzyl

[0376] Boc tert-butyl carbonyl

[0377] Boc2O di-tert-butyl dicarbonate

[0378] BOP (Benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0379] BTFFH fluoro-N, N, N’, N’-bis(tetramethylene)formamidinium

[0380] hexafluorophosphate Bu Butyl

[0381] CDCl3deutero-chloroform

[0382] CD3OD deutero-methanol

[0383] Cs2CO3Cesium carbonate

[0384] DAST Diethylaminosulfur trifluoride

[0385] dba as in (Pd2(dba)3) Dibenzylideneacetone

[0386] DCM Dichloromethane

[0387] DEAD diethyl azodicarboxylate

[0388] DIAD diisopropyl azodicarboxylate

[0389] DIEA or DIPEA Diisopropylethylamine

[0390] DMAP 4-dimethylaminopyridine

[0391] DME Dimethoxy ethane

[0392] DMF Dimethylformamide

[0393] DMSO dimethyl sulfoxide

[0394] DMSO-d6deutero-dimethyl sulfoxide

[0395] dppf 1,1′-bis(diphenylphosphino)ferrocene

[0396] EDC 3-(Ethyliminomethyleamino)-N-N-dimethylpropan-1-amine

[0397] Et ethyl

[0398] EtOH Ethanol

[0399] EtOAc ethyl acetate

[0400] HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0401] HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0402] HC1 hydrochloric acid

[0403] HPLC high-performance liquid chromatography

[0404] z-Bu Isobutyl

[0405] z-Pr Isopropyl

[0406] K2HPO4 Dipotassium phosphate

[0407] LAH lithium aluminum hydride

[0408] LCMS liquid chromatography mass spectrometry Me Methyl

[0409] MeOH Methanol

[0410] MgSO4magnesium sulfate

[0411] NaCl sodium chloride

[0412] Na2CO3sodium carbonate

[0413] NaHCO3sodium bicarbonate

[0414] NaOH sodium hydroxide

[0415] Na2SO4sodium sulfate

[0416] NH4Cl ammonium chloride

[0417] NH4OAC ammonium acetate

[0418] NMM A-methylmorpholine

[0419] NCS N-Chlorosuccinimide

[0420] NBS A-Bromosuccinimide

[0421] NMP N-Methylpyrrolidone

[0422] Pd(OAc)2palladium(II) acetate

[0423] Pd(dppf)Cl2·CH2Cl2[l,l'-Bis(diphenylphosphino)ferrocene]

[0424] dichloropalladium(II), complex with dichloromethane Pd(dba)2Bis(dibenzylideneacetone)palladium(0)

[0425] Ph Phenyl

[0426] PPh3Triphenylphosphine

[0427] Pr Propyl

[0428] RVC Reticulated vitreous carbon

[0429] t-Bu tert-butyl

[0430] TEA or Et3N Trimethylamine

[0431] TFA trifluoroacetic acid

[0432] THF Tetrahydrofuran

[0433] TMSCl Trimethyl silyl chloride

[0434] T3P 1-Propanephosphonic anhydride solution

[0435] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0436] 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.

[0437] 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).

[0438] Compounds having the general Formula (I) can be prepared by the following one or more of the synthetic schemes. Additional methods or variations for the following transformations using methods known to one skilled in the art provide alternative means to accessing the following described compounds. Compounds of this invention can be prepared by the general route shown in Scheme 1, starting from a substituted 5-bromo-l-fluoro-2-nitrobenzene. Nucleophilic aromatic substitution of la dissolved in THF with a suitably substituted amine in the presence of Hiinig’s base can provide intermediate lb. Subsequent iron reduction of lb in presence of HC1 in ethanol under heating can provide intermediate aniline 1c.

[0439] HATU coupling of 1c with a suitable carboxylic acid 2 in the presence of Hiinig’s base in DMF provides the amide Id. The resulting amide can be cyclized by condensation under heating in isopropanol in presence of a p-toluenesulfonic acid to provide le.

[0440] Miyaura borylation of le in presence of bis(pinacolato)diboron, Pd(dppf)Cl2·CH2Cl2and potassium acetate in dioxane under heating provides an intermediate boronate. Addition of a substituted 4-iodopyrin-2-amine, potassium phosphate (tribasic), and water, generates the aniline If under typical Suzuki coupling conditions. Scheme 1

[0441] o pTSA / -PrOH 100 °C

[0442] 4

[0443]

[0444] \

[0445] Compounds of Formula (I) can be prepared by amide coupling of If with a suitable carboxylic acid 4. Accordingly, treatment of a solution of If and 4 in pyridine with 2-chloro-l,3-dimethyl-4,5-dihydro-lH-imidazol-3-ium chloride followed by heating yields compounds of Formula (I).

[0446] Alternatively, compounds of Formula (I) can be accessed through the intermediate 1g as described in Scheme 2 (vide infra). The stannane 1g is formed upon treatment of le with 1,1,1,2,2,2-hexamethyldistannane and palladium tetrakis in dioxane under heating. Subsequent Stille coupling with a suitable iodopyridine 5 then yields compounds of Formula (I). As mentioned above, methods or variations for the abovementioned transformations in Scheme 2 using methods known to one skilled in the art provide additional means to accessing the described compounds.

[0447] Scheme 2 2b (I) (f-Bii3PH)BF4 Pd2(dba)3

[0448]

[0449] dioxane

[0450] 100 °C

[0451] Additionally, as shown in Scheme 3, compounds of this invention can be prepared by Stille cross-coupling of two prepared intermediates: iodopyridine 2b and stannane 2a.

[0452] Amide coupling of 3d with a suitably substituted acid intermediate 4 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 dichloromethane in presence of a base such as pyridine and N, N-diisopropylethylamine or triethyl amine or 2,4,6-trimethylpyridine can provide iodopyridine 2b The amide bond formation can be obtained with a suitable amide coupling reagent such as 1-propanephosphonic anhydride solution,

[0453] 2-(7-aza- IH-benzotriazole-l -yl)- 1, 1,3,3 -tetramethyluronium hexafluorophosphate, (benzotri azol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate and 2-(1H-benzotriazole-1-yl)-1,1,3,3-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).

[0454] Intermediate 3c is prepared starting from l,2-diamino-4-bromobenzene 1c outlined in Scheme 1. Treatment of 1c with cyanogenbromide furnished aminobenzimidazole 3a. Subsequent acylation with a suitable reagent furnished acyl or carbamoyl 2-aminobenzimidazole 3b. Additional methods for this transformation include variants of amide formations using methods known to one skilled in the art for this type of coupling. 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 stannane 3c. Subsequent Stille cross coupling of 3c with prepared iodopyridine 2b in the presence of tri-t-butylphosphine tetrafluoroborate 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).

[0455] Scheme 3

[0456] H

[0457] o

[0458]

[0459] qpi Pyridine, 1.1 eq 2b

[0460] DIEA, 1.5 eq

[0461] DCE, 80 °C

[0462] 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 NH4OAC).

[0463] 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).

[0464] Analytical HPLC: Methods Employed in Characterization of Examples

[0465] Method A: HALO C18 Column 3.0*30 mm, 2.7 pm; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 50% B in 1.70 min; 254 nm

[0466] Method B: HALO 100A C18 Column 4.6*100 mm, 2.7 pm; Mobile Phase A:

[0467] Water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5000 mL / min; Gradient: 10% B to 95% B in 6.0 min; 254 nm

[0468] Method C: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA;

[0469] 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 + / -).

[0470] Method D: HALO C18, 3.0*30 mm, 2.0 pm; Mobile Phase A: Water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5000 mL / min; Gradient: 5 % B to 60% B in 1.70 min; 220 nm

[0471] 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: 1.5000 mL / min; Gradient: 5% B to 50% B in 1.70 min; 254 nm Method F: HALO 90A C18 Column 3.0*30 mm, 2.0 pm; Mobile Phase A:

[0472] Water / 0.1%FA, Mobile Phase B: Acetonitrile / 0.1%FA; Flow rate: 1.5000 mL / min; Gradient: 5 % B to 100% B in 1.20 min; 254 nm

[0473] Method G: HALO 90A C18 Column 30*3.0 mm, 2.0 pm; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 60% B in 1.70 min; 254 nm

[0474] Method H: 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;

[0475] Gradient: 10% B to 95% B in 1.20 min; 254 nm

[0476] Method I: HALO C18 90A Column 3.0*30 mm, 2.0 pm; Mobile Phase A:

[0477] Water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5000 mL / min; Gradient: 5 % B to 100% B in 1.20 min; 254 nm

[0478] Method J: HALO 90A C18, 3.0*30 mm, 2.0 pm; Mobile Phase A: water / 0.05%TFA, Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 100% B in 1.20 min; 254 nm

[0479] Method K: HALO 90A C18, 3.0*30 mm, 2.0 pm; Mobile Phase A: water / 0.05%TFA, Mobile Phase B: MeCN / 0.05%TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 60% B in 1.70 min; 254 nm

[0480] Method L: Acquity BEH C18 1.7um 2.1 x 50mm; Mobile Phase A: 0.05% TFA in CH3CN: Water (5:95); Mobile Phase B: 0.05% TFA in CH3CN: Water (95:5);

[0481] 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 + / -).

[0482] Method M: XBridge C18, 2.1 mm x 50 mm, 1.7 µm particles; Mobile Phase A:

[0483] 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 + / -).

[0484] Method N: XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A:

[0485] ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Temperature: 50 °C; Gradient: 0-100 %B (0-3 min), 100 %B (3-3.5 min); Flow: 1 mL / min; Detection: UV (220 nm) and MS (ESI + / -).

[0486] Method O: HALO C18, 4.6*100 mm, 2.7 pm; Mobile Phase A: Water / 0.1%TFA, Mobile Phase B: Acetonitrile / 0.1%TFA; Flow rate: 1.500 mL / min; Gradient: 10 % B to 95% B in 8.00 min; 254 nm

[0487] Method P: HALO 90A C18 Column 30*3.0 mm, 2.0 pm; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 40% B in 1.70 min; 254 nm

[0488] Method Q: HALO 90A C18 Column 3.0*30 mm, 2.0 pm; Mobile Phase A: water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5000 mL / min; Gradient: 5 % B to 95% B in 2.30 min; 254 nm

[0489] Method R: HALO 90A C18, 3.0*30 mm, 2.0 pm; Mobile Phase A: Water / 0.05%TFA, Mobile Phase B: Acetonitrile / 0.05%TFA; Flow rate: 1.5000 mL / min; Gradient: 5 % B to 50% B in 1.70 min; 254 nm

[0490] Method S: HALO 90A C18 Column 30*3.0 mm, 2.0 pm; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 100% B in 1.70 min; 254 nm

[0491] Method T: HALO 90A C18 Column 30*3.0 mm, 2.0 pm; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 100% B in 1.20 min; 254 nm; Method U: HALO 90A C18 Column 30*3.0 mm, 2.0 pm; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 50% B in 1.70 min; 254 nm

[0492] Method V: Shim-pack Scepter C18-120, 30*3.0 mm, 3.0 pm; Mobile Phase A: 5 mM NH4HCO3 in water / acetonitrile(95:5, v:v), Mobile Phase B: Acetonitrile; Flow rate:

[0493] 1.5000 mL / min; Gradient: 5% B to 90% B in 1.20 min; 254 nm

[0494] Method W: HALO 90A C18 Column 3.0*30 mm, 2.0 pm; Mobile Phase A: water / 0.05%TFA, Mobile Phase B: ACN / 0.05%TFA; Flow rate: 1.5000 mL / min;

[0495] Gradient: 5 % B to 100 % B in 1.20 min; 254 nm

[0496] NMR Employed in Characterization of Examples.1H NMR spectra were obtained with Bruker or JEOL® Fourier transform spectrometers operating at frequencies as follows: 1H NMR: 400 MHz (Bruker or JEOL®) or 500 MHz (Bruker or JEOL®). 13C NMR: 100 MHz (Bruker or JEOL®). Spectra data are reported in the format: chemical shift (multiplicity, coupling constants, and number of hydrogens). Chemical shifts are specified in ppm downfield of a tetramethylsilane internal standard (d units, tetramethylsilane = 0 ppm) and / or referenced to solvent peaks, which in1H NMR spectra appear at 2.49 ppm for (CD3)2SO, 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.

[0497] Intermediate 1: 5-bromo-3-fluoro-N-isopropyl-2-nitroaniline

[0498]

[0499] To a solution of 5-bromo-l,3-difluoro-2-nitrobenzene (2000 mg, 8.4 mmol) in tetrahydrofuran (28 mL) was added N-ethyl-N-isopropylpropan-2-amine (3.0 mL, 17 mmol) and propan-2-amine (860 pL, 10 mmol). A reflux condenser was added, and the reaction was stirred at 70 °C for 24 h. The reaction was cooled to 20 °C and 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. The organic layers were collected and dried using sodium sulfate. The dried organic layers were filtered and concentrated in vacuo. The crude material was used directly in the next step without further purification.

[0500] Intermediate 2: 5-bromo-3-fluoro-N1-isopropylbenzene-1,2-diamine

[0501] NH

[0502] 12

[0503] 2H

[0504] H

[0505] F. 1 N /

[0506]

[0507] To a solution of 5-bromo-3-fluoro-N-isopropyl-2-nitroaniline (2500 mg, 9.0 mmol) in ethanol (30 mL) was added hydrogen chloride (1.5 mL, 18 mmol) and iron (1500 mg, 27 mmol). A reflux condenser was added, and the reaction was stirred at 75 °C for 3 h. The reaction was cooled to 20 °C and concentrated under a stream of nitrogen. The reaction was diluted with 1 N potassium phosphate, dibasic solution, brine, DI water, and ethyl acetate. The solution was filtered, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were layers were dried using sodium sulfate and concentrated in vacuo. The material was used directly in the next step without further purification.

[0508] Intermediate 3: N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-3-hydroxy-3-methylbutanamide

[0509] HOT — '^ NH

[0510] H F J JII N

[0511]

[0512] To a solution of 3 -hydroxy-3 -methylbutanoic acid (1.5 mL, 14 mmol) inN, N-dimethylformamide (20 mL) was added N-ethyl-N-isopropylpropan-2-amine (3.1 mL, 18 mmol). The mixture was cooled to 0 °C. 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (5150 mg, 13.5 mmol) was added, and the reaction was stirred for 15 min at 0 °C. A solution of 5-bromo-3-fluoro-Nl-isopropylbenzene-l,2-diamine (2200 mg, 9.0 mmol) in N, N-dimethylformamide (10 mL) was added dropwise to the reaction. The reaction was moved to 20 °C 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. The organic layers were collected, and the collected organic layers were dried using sodium sulfate. The dried organic layers were filtered, and the mixture was concentrated in vacuo. The material was loaded onto a prepacked silica gel column. The material was purified by silica gel chromatography with a gradient from 0% to 100% ethyl acetate: hexanes to provide N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-3-hydroxy-3-methylbutanamide (2500 mg, 80% yield) as a solid.

[0513] Intermediate 4: l-(6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol

[0514] II

[0515] hr

[0516]

[0517] To a solution of N-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)-3-hydroxy-3-methylbutanamide (2500 mg, 7.2 mmol) in propan-2-ol (24 mL) was added 4-methylbenzenesulfonic acid (3720 mg, 21.6 mmol). A reflux condenser was added, and the reaction was stirred at 100 °C for 5 h. The reaction was concentrated under a stream of nitrogen. The concentrated crude material 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. The combined organic layers were dried using sodium sulfate. The combined organic layers were concentrated in vacuo. The crude material was purified by silica gel chromatography with a gradient from 0% to 100% ethyl acetate: hexanes to provide l-(6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (1800 mg, 76% yield) as a solid.

[0518] Intermediate 5: l-(6-(2-amino-5-fluoropyridin-4-yl)-4-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol

[0519]

[0520] To a solution of l-(6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (2500 mg, 7.6 mmol) in 1,4-dioxane (38 mL) was added potassium acetate (1500 mg, 15 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2900 mg, 11 mmol). The mixture was sparged with nitrogen for 3 minutes. Pd(dppf)C12 (280 mg, 0.4 mmol) was added, and the reaction was sparged with nitrogen for 1 min. The reaction was stirred at 85 °C for 18 h. The reaction was moved to 20 °C. The reaction was filtered through celite and diluted with 1.5 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. The combined organic layers were dried using sodium sulfate and concentrated in vacuo. The mixture was dissolved in 1,4-dioxane (38 mL) and water (3.7 mL). 5-fluoro-4-iodopyridin-2-amine (2350 mg, 9.9 mmol), potassium phosphate, tribasic (3220 mg, 15.2 mmol), and Pd(dppf)Ch (280 mg, 0.4 mmol) was added. The reaction was sparged with nitrogen for 5 min. The reaction was stirred at 85 °C for 18 h. The reaction was filtered through celite and diluted with 1.5 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. The combined organic layers were dried using sodium sulfate and concentrated in vacuo. The material was purified by silica gel chromatography with a gradient from 0% to 20%

[0521] methanol: di chloromethane to provide l-(6-(2-amino-5-fluoropyridin-4-yl)-4-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol. The material was further purified by reverse phase chromatography to provide l-(6-(2-amino-5-fluoropyridin-4-yl)-4-fluoro-l -isopropyl- lH-benzo[d]imidazol -2 -yl)-2-methylpropan-2-ol (1500 mg, 55% yield) as a solid. 'H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J=2.8 Hz, 1H), 7.68 (s, 1H), 7.16 (d, J=11.7 Hz, 1H), 6.65 (d, J=5.5 Hz, 1H), 5.91 (s, 2H), 5.10 - 5.01 (m, 1H), 4.81 (s, 1H), 3.05 (s, 2H), 1.58 (d, J=6.9 Hz, 6H), 1.26 (s, 6H).

[0522] Intermediate 6: 1-(4-fluoro-1-isopropyl-6-(trimethylstannyl)-1H-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol

[0523] N

[0524] 11

[0525]

[0526] To a solution of l-(6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (500 mg, 1.5 mmol) in 1,4-dioxane (7.6 mL) was added 1, 1,1, 2,2,2-hexamethyldistannane (380 pL, 1.8 mmol) and Pd(PPhs)4 (180 mg, 0.15 mmol). The reaction was sparged with nitrogen for 1 min. The reaction was stirred at 100 °C for 18 h. The mixture was concentrated under a stream of nitrogen. The material was purified by silica gel chromatography with a gradient from 0% to 100% ethyl acetate: hexanes to provide l-(4-fluoro-l-isopropyl-6-(trimethylstannyl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (550 mg, 88% yield) as a solid. 'H NMR (500 MHz, DMSO-de) 57.51 (s, 1H), 7.01 (d, J=9.8 Hz, 1H), 5.05 - 4.91 (m, 1H), 3.01 (s, 2H), 2.00 (s, 1H), 1.57 (s, 3H), 1.55 (s, 3H), 1.23 (s, 6H), 0.32 (s, 9H).

[0527] Intermediates 7 and 8: 3-( 1,1 -difluor opropan-2-yl)-2-(2, 2, 2-trifluoroethyl)-5-( trimethylstannyl)-3H-imidazo[ 4, 5-b ]pyridine

[0528] Me3Sn h-N

[0529] II CF

[0530] / *

[0531]

[0532] To a solution of 5-chloro-3-(l,l-difluoropropan-2-yl)-2-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridine (180 mg, 0.57 mmol) in 1,4-dioxane (2.9 mL) was added 1,1,1,2,2,2-hexamethyldistannane (150 pL, 0.7 mmol). The reaction was sparged with nitrogen for 3 min. Tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) was added, and the reaction was sparged with nitrogen for 1 min. The reaction was stirred at 100 °C for 18 h. The reaction was concentrated under a stream of nitrogen. The reaction was diluted with DMF and hexanes. The layers were separated, and the DMF layer was extracted twice with hexanes. The DMF layer was concentrated under a stream of nitrogen. The crude material was purified via preparative SFC chromatography with the following conditions: Column: ES GreenSep Diol 1.8uM, 30 mm x 150 mm, 5 pm particles; Flow Rate: 90.5 mL / min; Column Temperature: 35 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative SFC with the following conditions: Column: Whelk-01 (R, R), 30 mm x 250 mm, 5 µm particles; Flow Rate: 90.5 mL / min; Column Temperature: 35 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the first isolate of 3-(l,l-difluoropropan-2-yl)-2-(2,2,2-trifluoroethyl)-5-(trimethylstannyl)-3H-imidazo[4,5-b]pyridine (13.1 mg, 5% yield) and the second isolate of 3-(l,l-difluoropropan-2-yl)-2-(2,2,2-trifluoroethyl)-5-(trimethylstannyl)-3H-imidazo[4,5-b]pyridine (14.8 mg, 6% yield). The material was used directly in the next step without any further purification. Analytical SFC was used to determine the %ee. Conditions: Column: Whelk-01 (R, R), 4.6 mm x 100 mm, 5 pm particles; Mobile Phase A: CO2; Mobile Phase B: IPA with 0.1 % DEA; Temperature: 25 °C; Isocratic elution at 8 %B over 10.00 min; Flow: 2.400 mL / min; Detection: UV (220 nm) and UV (254 nm). Isolate 1 results: Purity: 99 %ee; Retention Time: 0.98 min. Isolate 2 results: Purity: 90.6 %ee; Retention Time: 1.02 min.

[0533] Intermediate 9: methyl 2-methoxy-5-(methylthio)pyrimidine-4-carboxylate

[0534] O SCH3

[0535]

[0536] To a solution of methyl 5-bromo-2-methoxypyrimidine-4-carboxylate (710 mg, 2.9 mmol) in N, N-dimethylformamide (8.2 mL) was added sodium methanethiolate (300 mg, 4.3 mmol). The reaction was stirred at 20 °C for 3 h. Potassium carbonate (800 mg, 5.8 mmol) and iodomethane (360 pL, 5.8 mmol) were added, and the reaction mixture was stirred at 20 °C for 18 h. The reaction was diluted with saturated aqueous hydrogen bicarbonate solution, brine, DI water, and ethyl acetate. The layers were separated, and the aqueous layer was extracted twice more with ethyl acetate. The organic layers were collected, and the collected organic layers were dried using sodium sulfate. The dried organic layers were filtered, and celite was added. The mixture was concentrated in vacuo. The material was purified by silica gel chromatography with a gradient from 0% to 100% ethyl acetate: hexanes to provide methyl 2-methoxy-5-(methylthio)pyrimidine-4-carboxylate (420 mg, 68% yield).

[0537] Intermediate 10: methyl 2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxylate

[0538]

[0539] To a solution of methyl 2-methoxy-5-(methylthio)pyrimidine-4-carboxylate (1070 mg, 5.0 mmol) in dichloromethane (5 mL), 1,4-dioxane (12.5 mL), and acetic acid (2.5 mL) was added sodium tungstate dihydrate (2500 mg, 7.5 mmol) and 30% w / w hydrogen peroxide (5 mL). The reaction was stirred at 20 °C for 36 h. Ice was added, and 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. The organic layers were collected, and the collected organic layers were dried using sodium sulfate. The dried organic layers were filtered and concentrated in vacuo to provide methyl 2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxylate (750 mg, 61% yield) as a solid.

[0540] Intermediate 11: N-(5-fluoro-4-iodopyridin-2-yl)-2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxamide

[0541]

[0542] To a solution of 5-fluoro-4-iodopyridin-2-amine (460 mg, 1.95 mmol) in tetrahydrofuran (11 mL) at 0 °C was added lithium bis(trimethylsilyl)amide (1 M, 2.4 mL, 2.4 mmol) dropwise. The reaction was stirred for 10 min at 0 °C. Methyl 2 -methoxy -5-(methylsulfonyl)pyrimidine-4-carboxylate (400 mg, 1.6 mmol) was added, and the reaction was moved to 20 °C. The reaction was stirred at 20 °C for 2 h. The reaction was diluted with 1 N HC1, DI water, and ethyl acetate. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried using sodium sulfate. The dried organic layers were filtered, and the mixture was concentrated in vacuo. The material was purified by silica gel chromatography with a gradient from 0% to 50% ethyl acetate:dichloromethane to provide N-(5-fluoro-4-iodopyridin-2-yl)-2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxamide (340 mg, 46% yield) as a solid. 'H NMR (500 MHz, DMSO-d6) 6 11.54 (s, 1H), 9.13 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.37 (s, 1H), 4.09 (s, 3H), 3.42 (s, 3H).

[0543] Intermediate 12: sodium 2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxylate

[0544]

[0545] To a solution of methyl 2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxylate (340 mg, 1.4 mmol) in deionized water (4.6 mL) and 1,4-dioxane (1.4 mL) was added sodium hydroxide (1 N, 1.4 mL, 1.4 mmol). The reaction was stirred at 35 °C for 18 h. The reaction was lyophilized to give sodium 2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxylate (352 mg, 100% yield) as a solid.

[0546] Intermediate 13: methyl 3,6-bis(methylthio)picolinate

[0547] O SCH3

[0548]

[0549] To a solution of methyl 3,6-dibromopicolinate (1500 mg, 5.1 mmol) in N, N-dimethylformamide (17 mL) was added sodium methanethiolate (784 mg, 11.2 mmol) was added. The reaction was stirred at 60 °C for 48 h. The reaction was cooled to 20 °C. lodomethane (2.2 mL, 5.1 mmol) was added. The reaction was stirred at 20 °C for 30 min. 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. The combined organic layers were dried using sodium sulfate and concentrated in vacuo. The material was purified by silica gel chromatography with a gradient from 0% to 100% ethyl acetate:hexanes.to provide methyl 3,6-bis(methylthio)picolinate (900 mg, 77% yield) as a solid. The material was used directly in the next step.

[0550] Intermediate 14: methyl 3,6-bis(methylsulfonyl)picolinate

[0551] O SO2CH3

[0552]

[0553] To a solution of methyl 3,6-bis(methylthio)picolinate (500 mg, 2.2 mmol) in dichloromethane (22 mL) at 0 °C was added 3-chlorobenzoperoxoic acid (2400 mg, 9.8 mmol). The reaction stirred at 20 °C for 2 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. The combined organic layers were dried using sodium sulfate and concentrated in vacuo. The material was purified by silica gel chromatography with a gradient from 0% to 100% ethyl acetate:dichloromethane to give methyl 3,6-bis(methylsulfonyl)picolinate (470 mg, 74% yield) as a solid. The material was used directly in the next step.

[0554] Intermediate 15: methyl 6-(2,2-difluoroethoxy)-3-(methylsulfonyl)picolinate

[0555]

[0556] To a solution of 2,2-difluoroethan-l-ol (130 pL, 2.1 mmol) in tetrahydrofuran (11 mL) at 0 °C was added lithium bis(trimethylsilyl)amide (1 M, 2400 pL, 2.4 mmol). The reaction was stirred for 10 min. Methyl 3,6-bis(methylsulfonyl)picolinate (470 mg, 1.6 mmol) was added. The reaction was moved to 20 °C. 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. The combined organic layers were dried using sodium sulfate and concentrated in vacuo. The material was purified by silica gel chromatography (ISCO1, M.2110) with a gradient from 0% to 100% ethyl acetate:dichloromethane to provide methyl 6-(2,2-difluoroethoxy)-3-(methylsulfonyl)picolinate (300 mg, 63% yield). The material was used directly in the next step.

[0557] Intermediate 16: 5-chloro-2-(lH-tetrazol-l-yl)isonicotinic acid

[0558]

[0559] A suspension of 5-amino-2-methylbenzoic acid (500 mg, 2.7 mmol) in AcOH (3 mL) was heated to 75 °C under nitrogen and the triethyl orthoformate (1.3 mL, 8.0 mmol) was slowly added. The reaction mixture was heated for 2 h before adding sodium azide (520 mg, 8.0 mmol) in 5 portions over 75 min. The mixture was allowed to stir for an additional 40 min. The reaction mixture was cooled to rt. The reaction mixture was partitioned between ethyl acetate and water and neutralized with saturated bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give an off white solid. The material was dissolved in THF / MeOH (1:1, 15 mL) and treated with LiOH-H₂O (340 mg, 8.0 mmol) in water (2 mL). After 3 hrs, the reaction mixture was diluted with water (5 mL). The organics were removed under vacuum and the remaining aqueous layer extracted with EtOAc (15 mL). The aqueous layer was acidified with 1.0M HC1 solution and extracted with EtOAc (2 x 15 mL) The combined organics were washed with water followed by brine, dried over sodium sulfate, filtered, and concentrated. The material was used directly as 5-chloro-2-(IH-tetrazol-l-yl)isonicotinic acid (390 mg, 65% yield).XH NMR (400 MHz, DMSO-de) 8 10.23 (s, 1H), 8.90 - 8.85 (m, 1H), 8.34 - 8.33 (m, 1H).

[0560] Intermediate 17: methyl 5-(l-methyl-lH-l,2,4-triazol-3-yl)-2-(methylsulfonyl)benzoate

[0561] N SO2CH3

[0562]

[0563] To a solution of methyl 2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (13 g, 38 mmol) and 3-bromo-l-methyl-lH-l,2,4-triazole (6.8 g, 42 mmol) dissolved in Dioxane (150 mL) was added potassium carbonate (15.8 g, 114 mmol), water (38 ml), and PdCl₂(dppf)-CH₂Cl₂ (930 mg, 1.14 mmol). The mixture was stirred at 95 °C for 4 h. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The collected organic layers were dried with sodium sulfate and concentrated in vacuo. The material was purified via silica gel chromatography to provide the crude product. The residue was taken up in ~50 mL of MeOH and heated to reflux. The flask was cooled in an ice bath, and the solids were filtered off and washed with cold MeOH. The off-white solids were collected as methyl 5-(l-methyl-lH-l,2,4-triazol-3-yl)-2-(methylsulfonyl)benzoate (2.6 g, 24 % yield). 'H NMR (400 MHz, CHLOROFORM-d) 88.47 (d, J=1.5 Hz, 1H), 8.38 (dd, J=8.3, 1.7 Hz, 1H), 8.21 (d, J=8.3 Hz, 1H), 8.14 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H), 3.41 (s, 3H).

[0564] Intermediate 18: 5-(l-methyl-lH-l,2,4-triazol-3-yl)-2-(methylsulfonyl)benzoic acid

[0565] HO

[0566]

[0567] To a solution of methyl 5-(l-methyl-lH-l,2,4-triazol-3-yl)-2-(methylsulfonyl)benzoate (2.0 g, 6.9 mmol) in THF (28 mL) was added lithium hydroxide (580 mg, 13.9 mmol) and Water (7 mL). The mixture was stirred for 18 h at 20 °C. The reaction mixture was heated to 50 °C for 1 h. The reaction was cooled to 0 °C and then treated with HC1 (12 N, 1.2 ml, 14 mmol) dropwise. The reaction mixture was diluted with ether, and an off-white precipitate formed. The mixture was filtered, and the solids washed with water. The solid was then dried to provide 5-(l-methyl-lH-l,2,4-triazol-3-yl)-2-(methylsulfonyl)benzoic acid (1.53 g, 5.44 mmol, 78 % yield).XH NMR (400 MHz, DMSO-d6) 6 13.91 (br s, 1H), 8.65 (s, 1H), 8.31 (dd, J=8.3, 1.6 Hz, 1H), 8.26 (d, J=1.6 Hz, 1H), 8.11 (d, J=8.2 Hz, 1H), 3.98 (s, 3H), 3.43 (s, 3H).

[0568] Intermediate 19: N-(5 -fluor o-4-iodopyridin-2-yl)-5-( I -methyl- 1H-1, 2, 4-triazol-3-yl)-2-(methylsulfonyl)benzamide I

[0569]

[0570] To a solution of 5-(l-methyl-lH-l,2,4-triazol-3-yl)-2-(methylsulfonyl)benzoic acid (250 mg, 0.9 mmol) in dichloromethane (4.4 mL) and pyridine (100 pL) at 0 °C was added phosphoryl trichloride (90 pL, 1.0 mmol) dropwise. The reaction was stirred at 0 °C for 15 min. The mixture was added to a solution of 5-fluoro-4-iodopyridin-2-amine (230 mg, 1.0 mmol) in dichloromethane (4.5 mL). The reaction was stirred at 20 °C for 4 h. The reaction was diluted with ice, 1 N potassium phosphate, dibasic solution, brine, DI water, and ethyl acetate. A solid triturated out upon quenching. The solid was collected and washed with di chloromethane to provide N-(5-fluoro-4-iodopyri din-2 -yl)-5-(l -methyl-lH-l,2,4-triazol-3-yl)-2-(methylsulfonyl)benzamide (400 mg, 90%) as a solid.!H NMR (500 MHz, DMSO-d6) 6 11.51 (s, 1H), 8.68 - 8.65 (m, 2H), 8.35 (s, 1H), 8.31 (dd, J=8.3, 1.7 Hz, 1H), 8.20 (d, J=1.2 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 3.98 (s, 3H), 3.41 (s, 3H).

[0571] Intermediate 20: ethyl 2-cyclopropyl-5-fluoropyrimidine-4-carboxylate

[0572]

[0573] To a nitrogen sparged solution of ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate (200 mg, 0.98 mmol), cyclopropylboronic acid (126 mg, 1.5 mmol), potassium carbonate (270 mg, 2.0 mmol) in 1,4-di oxane (5 mL) was added 1,1'-Bis(diphenylphosphino)ferrocene dichloropalladium (II) (70 mg, 0.1 mmol). The mixture was sparged with nitrogen for 1 min. The reaction was stirred at 85 °C for 18 h. The reaction was cooled to 20 °C and diluted with saturated aqueous hydrogen bicarbonate solution, brine, DI water, and ethyl acetate. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combinded organic layers were dried using sodium sulfate. The dried organic layers were filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography with a gradient from 0% to 100% ethyl acetate: hexanes to provide ethyl 2-cyclopropyl-5-fluoropyrimidine-4-carboxylate (170 mg, 83% yield) as an oil.XH NMR (500 MHz, DMSO-de) 58.94 (d,.7=2.4 Hz, 1H), 4.42 - 4.39 (m, 2H), 2.34 - 2.26 (m, 1H), 1.35 - 1.32 (m, 3H), 1.11 - 1.07 (m, 2H), 1.01 - 0.98 (m, 2H).

[0574] Intermediate 21: 2-cyclopropyl-5-(methylthio)pyrimidine-4-carboxylic acid

[0575] O SCH3

[0576]

[0577] I

[0578] To a solution of ethyl 2-cyclopropyl-5-fluoropyrimidine-4-carboxylate (120 mg, 0.6 mmol) in N, N-dimethylformamide (1.9 mL) was added sodium methanethiolate (90 mg, 1.3 mmol). The reaction was stirred at 20 °C for 18 h. The reaction was diluted with deionized water, and 1 N HC1 was added. A solid precipitated, and the resulting solid was filtered and washed with deionized water, hexanes, and ether. The solid was collected to give 2-cyclopropyl-5-(methylthio)pyrimidine-4-carboxylic acid (120 mg, 100% yield).

[0579] Intermediate 22: (Z)-4-bromo-N-hydroxy-5-methylpicolinimidoyl chloride

[0580]

[0581] To a stirred solution of 4-bromo-5-methylpicolinaldehyde (650 mg, 3.3 mmol) in dichloromethane (13 mL) was added hydroxylamine hydrochloride (340 mg, 4.9 mmol) and potassium carbonate (340 mg, 2.4 mmol). The reaction was stirred at 20 °C for 18 h. N, N-dimethylformamide (260 pL) and N-chlorosuccinimide (650 mg, 4.9 mmol) was added. The reaction was stirred at 20 °C for 3 h. The reaction was diluted with deionized water and dichloromethane. The layers were separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine and dried using sodium sulfate. The dried organic layers were filtered and concentrated in vacuo. The crude material was used directly in the next step. Intermediate 23: (3-(4-bromo-5-methylpyridin-2-yl)-4,5-dihydroisoxazol-5-yl)methanol

[0582]

[0583] To a solution of (Z)-4-bromo-N-hydroxy-5-methylpicolinimidoyl chloride (880 mg, 3.3 mmol) in di chloromethane (20 mL) was added prop-2-en-l-ol (380 mg, 6.5 mmol) and triethylamine (1.4 mL). The reaction was stirred at 20 °C for 4 h. The mixture was concentrated in vacuo and purified via silica gel chromatography with a gradient from 0% to 100% ethyl acetate: hexanes to provide (3-(4-bromo-5-methylpyridin-2-yl)-4,5-dihydroisoxazol-5-yl)methanol (393 mg, 45% yield) as a solid.XH NMR (500 MHz, DMSO-de) 88.55 (s, 1H), 8.04 (s, 1H), 4.99 (t, J=5.7 Hz, 1H), 4.80 - 4.73 (m, 1H), 3.57 -3.47 (m, 2H), 3.38 (d, J=11.1 Hz, 1H), 3.26 - 3.20 (m, 1H), 2.37 (s, 3H).

[0584] Intermediate 24: 2-(5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)-5-methylisonicotinic acid

[0585]

[0586] Palladium(II) acetate (160 mg, 0.7 mmol), 9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine (83 mg, 0.14 mmol), and (3-(4-bromo-5-methylpyridin-2-yl)-4,5-dihydroisoxazol-5-yl)methanol (390 mg, 1.4 mmol) were added to a large pressure vial. The vial was sealed and evaluated and backfilled with nitrogen three times. Then, a degassed solution of triethylamine (400 pL) in toluene (5 mL) was added and the mixture heated to 100 °C. After 5 min, the reaction was cooled to 20 °C and treated dropwise with a degassed solution 2,4,6-trichlorophenyl formate (1.0 g, 4.3 mmol) in toluene (5 mL) over 1 h. The reaction was stirred at 100 °C for 18 h. The reaction was cooled to 20 °C, filtered through celite, and purified via silica gel chromatography with a gradient from 0% to 100% ethyl acetate: hexanes to provide the intermediate ester. To a solution of the ester in THF (6 mL) was added lithium hydroxide monohydrate (180 mg, 4.3 mmol) in water (1 mL). The reaction was heated to 60 °C for 4 h. The mixture was cooled to 20 °C, and the mixture was diluted with ethyl acetate and deionized water. The layers were separated, and the aqueous layer was lyophilized to provide 2-(5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)-5-methylisonicotinic acid (302 mg, 77%).

[0587] Intermediate 25: ethyl 5-bromo-6-methylnicotinate

[0588] ■"6 CO2Et

[0589] A solution of 5-bromo-6-methylnicotinic acid (500 mg, 2.3 mmol) in ethanol (14 mL) was treated with 12 N HC1 (0.7 mL, 3 mmol) then heated to 70 °C overnight. The mixture was cooled to rt and extracted from phosphate buffer with EtOAc. The organic layer was filtered through a silica gel plug and concentrated to furnish ethyl 5-bromo-6-methylnicotinate (292 mg, 1.2 mmol, 52 % yield) which was used without further manipulation.

[0590] Intermediate 26: 2-(5-bromo-6-methylpyridin-3-yl)propan-2-ol

[0591]

[0592] To a solution of ethyl 5-bromo-6-methylnicotinate (290 mg, 1.2 mmol) in THF (6 mL) at 0 °C was added methylmagnesium bromide (0.4 mL, 1.2 mmol) in ether. The solution was allowed to slowly warm to rt and stir overnight. The mixture was extracted from brine with EtOAc. The organic layer was concentrated and the residue purified by silica gel chromatography to furnish 2-(5-bromo-6-methylpyridin-3-yl)propan-2-ol (147 mg, 0.639 mmol, 53.4 % yield). LCMS = 229.9 (M+H).

[0593] Intermediate 27: 2,4,6-trichlorophenyl 5-(2-hydroxypropan-2-yl)-2-methylnicotinate

[0594]

[0595] To a chemglass pressure vessel with septum containing 2-(5-bromo-6-methylpyri din-3 -yl)propan-2-ol (130 mg, 0.6 mmol), 2,4,6-trichlorophenyl formate (200 mg, 0.9 mmol) and a stir bar was added a solution of xantphos (20 mg, 0.03 mmol), PdOAc₂ (6 mg, 0.03 mmol) dissolved in DMF (1.1 mL). The vessel was sealed under nitrogen, and then Et₃N (0.2 mL, 1.1 mmol) was added via syringe and the vessel heated to 60 °C overnight. The mixture was extracted from 0.1 N HC1 with EtOAc. The organic layer was washed with water and brine, then concentrated. The residue was purified by silica gel chromatography to furnish 2,4,6-trichlorophenyl 5-(2-hydroxypropan-2-yl)-2-methylnicotinate (110 mg, 0.29 mmol, 51 % yield). LCMS = 375.7 (M+H).

[0596] Intermediate 28: 5-(2-hydroxypropan-2-yl)-2-methylnicotinic acid

[0597] Me O

[0598] n J

[0599]

[0600] HC<\

[0601] To a solution of 2,4,6-trichlorophenyl 5-(2-hydroxypropan-2-yl)-2-methylnicotinate (110 mg, 0.3 mmol) in THF (2.2 mL) was added LiOH (25 mg, 0.6 mmol) in water (0.7 mL) and the reaction was stirred overnight. The mixture was extracted from 1 N HC1 with EtOAc. The aqueous layer was concentrated and the residue used without manipulation as 5-(2-hydroxypropan-2-yl)-2-methylnicotinic acid (57 mg, 0.29 mmol, 100 % yield), LCMS = 196.0.

[0602] Intermediate 29: tert-butyl (S)-(4-(5-((5-fhioro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamoyl)-6-methylpyridin-3-yl)but-3-yn-2-yl) (methyl) carbamate

[0603]

[0604] A slurry of 5-bromo-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl- lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methylnicotinamide (25 mg, 0.05 mmol), tert- butyl (S)-but-3-yn-2-yl(methyl)carbamate (42 mg, 0.23 mmol), Pd(Ph3P)4 (1 mg, 0.9 pmol) and copper(I) iodide (0.1 mg, 0.5 pmol) in TEA (0.5 mL) / DMF (0.2 mL) was degassed, blanketed under N2 and heated to 70 °C overnight. The mixture was extracted from water with EtOAc. The organic layer was concentrated and the residue used without further manipulation tert-butyl (S)-(4-(5-((5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamoyl)-6-methylpyridin-3-yl)but-3-yn-2-yl)(methyl)carbamate (29.7 mg, 0.046 mmol, 100 % yield). LCMS = 643.3 (M+H).

[0605] Intermediate 30: N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methyl-5-(2-methylprop-l-en-l-yl)nicotinamide

[0606]

[0607] A mixture of 5-bromo-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methylnicotinamide (300 mg, 0.56 mmol), 4,4,5,5-tetramethyl-2-(2-methylprop-l-en-l-yl)-l,3,2-dioxaborolane (200 mg, 1.1 mmol), PdCh(dppf) (20 mg, 0.03 mmol) in 1,4-dioxane (2.5 mL) / water (1.2 mL) was blanketed under N2 and heated to 90 °C. After 2 h, the mixture was extracted from brine with EtOAc. The organic layer was concentrated and the residue purified by silica gel chromatography to furnish N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methyl-5-(2-methylprop-l-en-l-yl)nicotinamide (286 mg, 0.555 mmol, 100 % yield). LCMS = 516.2 (M+H).

[0608] Intermediate 31: 3-bromo-5-(difluoromethyl)-2-methylpyridine

[0609] Br

[0610] F / = /

[0611] ) — -

[0612]

[0613] To a solution of 5-bromo-6-methylnicotinaldehyde (210 mg, 1.1 mmol) dissolved in DCM (10.5 ml) at -20 °C was added DAST (0.5 mL, 3.7 mmol). The reaction was allowed to warm to 20 °C. The reaction was cooled to 0 °C and quenched using aqueous sodium bicarbonate solution. Ethyl acetate was added, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried using sodium sulfate and concentrated in vacuo. The material was purified by silica gel chromatography to furnish 3-bromo-5-(difluoromethyl)-2-methylpyridine (139 mg, 60% yield).

[0614] Intermedate 32: 5-(difluoromethyl)-2-methylnicotinic acid

[0615] ? I

[0616]

[0617] F^F

[0618] A slurry of 3-bromo-5-(difluoromethyl)-2-methylpyridine (140 mg, 0.6 mmol), palladium II acetate (40 mg, 0.2 mmol), l,3-bis(diphenylphosphino)

[0619] propane (80 mg, 0.2 mmol), triethylamine (0.3 mL, 1.9 mmol) in DMF (3 mL) / Water (300 pL) was blanketed under CO (80 psi) and heated to 100 °C for 18 h. The reaction was cooled to 20 °C, acidified with IM HC1, and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate. The organic layer was filtered and concentrated in vacuo to furnish 5-(difluoromethyl)-2-methylnicotinic acid (200 mg, 100 % yield).

[0620] Intermediate 33: 5-(4-hydroxy-l-methylpiperidin-4-yl)-2-methylnicotinic acid

[0621] HO

[0622]

[0623] To a solution of 5-bromo-2-methylnicotinic acid (500 mg, 2.3 mmol) dissolved in tetrahydrofuran (12 mL) at 0 °C was added sodium hydride (100 mg, 2.6 mmol). The reaction was stirred at 0 °C for 30 min. The solution was then canulated into a solution of tBuLi (2.9 mL, 4.9 mmol) dissolved in tetrahydrofuran (12 mL) at -78 °C. The reaction mixture was stirred for 1 h, and l-methylpiperidin-4-one (0.3 mL, 2.8 mmol) was added. The reaction was allowed to warm to 20 °C. The reaction mixture was treated with HC1 in dioxane (4 N). The reaction mixture was diluted with ether. A solid precipitated to furnish 5-(4-hydroxy-l-methylpiperidin-4-yl)-2-methylnicotinic acid, HC1 (930 mg, 85 % yield).

[0624] Intermediate 34: methyl 5-(2,2-difluoroethoxy)-2-methylnicotinate

[0625] o.0

[0626]

[0627] To a solution of methyl 5-hydroxy-2-methylnicotinate (190 mg, 1.1 mmol) and 2-bromo- 1,1 -difluoroethane (165 mg, 1.1 mmol) in DMF (3 mL) was added cesium carbonate (740 mg, 2.3 mmol). The mixture was stirred at 80 °C for 18 h. The material was concentrated in vacuo and purified via silica gel chromatography to provide methyl 5-(2,2-difluoroethoxy)-2-methylnicotinate (203 mg, 77% yield) as an oil. 'HNMR (400 MHz, CDC13) 88.39 (d, J=3.1 Hz, 1H), 7.77 (d, J=3.1 Hz, 1H), 6.12 (tt, J=54.9, 4.0 Hz, 1H), 4.27 (td, J=12.9, 4.0 Hz, 2H), 3.95 (s, 3H), 2.80 (s, 3H).

[0628] Intermediate 35: 5-(2,2-difluoroethoxy)-2-methylnicotinic acid

[0629]

[0630] To a solution of methyl 5-(2,2-difluoroethoxy)-2-methylnicotinate (200 mg, 0.9 mmol) in THF / methanol / water at 0 °C was added LiOH (60 mg, 2.6 mmol). The reaction was stirred at 20 °C for 18 h. The reaction was partitioned with water, IN HC1, and ethyl acetate. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried with magnesium sulfate to provide 5-(2,2-difluoroethoxy)-2-methylnicotinic acid (188 mg, 100% yield). 'HNMR (400 MHz, CDC13) 68.48 (d, J=3.1 Hz, 1H), 7.95 (br d, J=1.9 Hz, 1H), 6.14 (tt, J=54.8, 4.0 Hz, 1H), 4.31 (td, J=12.9, 3.9 Hz, 2H), 2.89 (s, 3H), 1.98 - 1.89 (m, 1H).

[0631] Intermediate 36: 3-bromo-5-(difluoromethoxy)-2-methylpyridine Br

[0632]

[0633] To a solution of 5-bromo-6-methylpyridin-3-ol (1.0 g, 5.3 mmol) in DMF (3 mL) was added sodium chlorodifluoroacetate (1.2 g, 8.0 mmol) and cesium carbonate (2.6 g, 8.0 mmol). The reaction was stirred at 65 °C for 18 h. The material was concentrated in vacuo and purified via silica gel chromatography to provide 3-bromo-5-(difluoromethoxy)-2-methylpyridine (434 mg, 34% yield) as an oil.XH NMR (400 MHz, CDC13) 88.35 (d,. / =2,4 Hz, 1H), 7.69 (d,. / =2,4 Hz, 1H), 6.54 (t, J=72.4 Hz, 1H), 2.68 (s, 3H).

[0634] Intermediate 37: methyl 5 -(difluoromethoxy) -2 -me thy Inicotinate

[0635] Me°2CX|p^N

[0636]

[0637] To a solution of 3-bromo-5-(difluoromethoxy)-2-methylpyridine (434 mg, 1.8 mmol) in DMSO (4.4 mL) and methanol (4.4 mL) was added palladium(II) acetate (80 mg, 0.4 mmol), l,l'-bis(diphenylphosphino)ferrocene (300 mg, 0.5 mmol), and triethylamine (250 pL, 1.8 mmol). The reaction was stirred at 100 °C under 60 psi of CO for 4 h. The reaction was cooled to 20 °C and silica was added. The mixture was concentrated in vacuo and purified via silica gel chromatography to provide methyl 5-(difluoromethoxy)-2-methylnicotinate (300 mg, 76% yield) as an oil.1H NMR (400 MHz, CDC13) 68.52 (d, J=2.6 Hz, 1H), 8.01 (d, J=2.5 Hz, 1H), 6.57 (t, J=72.5 Hz, 1H), 3.96 (s, 3H), 2.85 (s, 3H).

[0638] Intermediate 38: 5-(difluoromethoxy)-2-methylnicotinic acid

[0639] HO*cyU

[0640] O F

[0641]

[0642] To a solution of methyl 5-(difluoromethoxy)-2-methylnicotinate (300 mg, 1.4 mmol) in THF, methanol, and water was added LiOH (100 mg, 4.1 mmol). The reaction was stirred at 20 °C for 18 h. The reaction was partitioned with water, IN HC1, and ethyl acetate. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated in vacuo to provide 5-(difluoromethoxy)-2-methylnicotinic acid (133 mg, 47% yield). 'HNMR (400 MHz, CDC13) 88.57 (d, J=3.3 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H), 6.59 (t, J=72.4 Hz, 1H), 2.89 (s, 3H). One proton was not observed, most likely due to exchange with the H NMR solvent.

[0643] Intermediate 39: methyl 6-(difluoromethyl)-3-(methylsulfonyl)picolinate

[0644] SO2Me

[0645]

[0646] A solution of methyl 6-chloro-3-(methylsulfonyl)picolinate (57 mg, 0.23 mmol), [l,3-Bis[2,6-bis(i-propyl)phenyl]-2-imidazolidinylidene]difluoromethyl

[0647] silver(I) (160 mg, 0.3 mmol), (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine (26 mg, 0.046 mmol), and Pd2(dba)3 (21 mg, 0.02 mmol) in toluene (4.0 mL) was sparged with nitrogen for 1 min. The reaction was stirred at 80 °C for 18 h. The reaction was cooled to 20 °C and diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography to provide methyl 6-(difluoromethyl)-3-(methylsulfonyl)picolinate (43 mg, 71 % yield). 'HNMR (400 MHz, CHLOROFORM-d) 6 8.60 (d, J=8.3 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 6.74 (t, J=54.7 Hz, 1H), 4.09 (s, 3H), 3.40 (s, 3H).

[0648] Intermediate 40: lithium 6-(difluoromethyl)-3-(methylsulfonyl)picolinate

[0649] 2

[0650] l_iO2C,

[0651]

[0652] HF. To a solution of methyl 6-(difluoromethyl)-3-(methylsulfonyl)picolinate (42 mg, 0.16 mmol) in methanol / THF (1:3) (2.0 mL) was added 1 N lithium hydroxide (240 pL, 240 mmol). The reaction was stirred at 20 °C for 2 h. The reaction was lyophilized to provide lithium 6-(difluoromethyl)-3-(methylsulfonyl)picolinate. The material was used directly in the next step without further purification.

[0653] Example 3: (R)-N-(4-(l -(1 -cyclopropylethyl)-2-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-6-(2,2-difluoroethoxy)-3-(methylsulfonyl)picolinamide

[0654] V

[0655] N''

[0656] SO2Me

[0657]

[0658] To a solution of (R)-l-(6-(2-amino-5-fluoropyridin-4-yl)-l-(l-cyclopropylethyl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (29 mg, 0.08 mmol) and sodium 6-(2,2-difluoroethoxy)-3-(methylsulfonyl)picolinate (20 mg, 0.066 mmol) in pyridine (330 pL, 0.07 mmol) was added 2-chloro-l,3-dimethyl-4,5-dihydro-lH-imidazol-3-ium chloride (15 mg, 0.09 mmol). The reaction was moved to 100 °C for 20 min. The reaction was moved to 20 °C. The reaction was quenched with methanol. The reaction was concentrated under a stream of nitrogen. The reaction was dissolved in DMF, filtered through a syringe filter, and purified via reverse phase chromatography to provide (R)-N-(4-(l-(l-cyclopropylethyl)-2-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-6-(2,2-difluoroethoxy)-3-(methylsulfonyl)picolinamide (23.2 mg, 56% yield). Proton NMR report as follows. Some protons in the NMR may be missing due to water suppression or overlap with the NMR solvent residual peaks.

[0659] Example 8: N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methyl-5-(methylsulfonyl)pyrimidine-4-carboxamide F

[0660]

[0661] To a solution of l-(6-(2-amino-5-fluoropyridin-4-yl)-l-isopropyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (102 mg, 0.3 mmol) and 2-methyl-5-(methylthio)pyrimidine-4-carboxylic acid (50 mg, 0.27 mmol) in pyridine (1.4 mL) was added 2-chloro-l,3-dimethyl-4,5-dihydro-lH-imidazol-3-ium chloride (60 mg, 0.35 mmol). The reaction was stirred at 100 °C for 20 min. The reaction was moved to 20 °C. The reaction was concentrated under a stream of nitrogen. The reaction was diluted with saturated aqueous hydrogen bicarbonate solution, brine, DI water, and ethyl acetate. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried using sodium sulfate. The dried organic layers were filtered and celite was added. The mixture was concentrated in vacuo. The material was passed through a silica gel plug with a gradient from 0% to 10%

[0662] methanol: di chloromethane. The material was dissolved in dichloromethane (1.4 mL). The mixture was cooled to 0 °C. 3-chlorobenzoperoxoic acid (134 mg, 0.6 mmol) was added, and the reaction was warmed to 20 °C. The reaction was stirred at 20 °C for 30 min. The reaction was diluted with 1 N sodium thiosulfate solution, saturated aqueous hydrogen bicarbonate solution, brine, DI water, and ethyl acetate. The layers were separated, and the aqueous layer was extracted twice more with ethyl acetate. The organic layers were collected, and the collected organic layers were dried using sodium sulfate. The dried organic layer was filtered and concentrated in vacuo. The material was purified via reverse phase chromatography to provide N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-1 -isopropyl- lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methyl-5-(methylsulfonyl)pyrimidine-4-carboxamide (51.3 mg, 34% yield) as a solid.

[0663] Example 12: 5-chloro-N-( 4-( 1 -cyclopentyl-2-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-2-(lH-tetrazol-l-yl)isonicotinamide

[0664]

[0665] To a solution of l-(6-(2-amino-5-fluoropyridin-4-yl)-l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (20 mg, 0.05 mmol) and 5-chloro-2-(lH-tetrazol-l-yl)isonicotinic acid (12 mg, 0.05 mmol) in pyridine (300 pl) was added 2-chloro-l,3-dimethyl-4,5-dihydro-lH-imidazol-3-ium chloride (12 mg, 0.07 mmol). The reaction mixture was stirred at 100 °C for 1 h. The reaction was dissolved in DMF, filtered through a syringe filter, and purified via reverse phase chromatography to provide 5-chloro-N-(4-(l-cyclopentyl-2-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-2-(lH-tetrazol-l-yl)isonicotinamide (16 mg, 51% yield).

[0666] Example 23: N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxamide

[0667]

[0668] To a solution of l-(4-fluoro-l-isopropyl-6-(trimethylstannyl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (230 mg, 0.56 mmol) and N-(5-fluoro-4-iodopyridin-2-yl)-2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxamide (280 mg, 0.6 mmol) in 1,4-di oxane (5.6 mL) was added tri-tert-butylphosphonium tetrafluoroborate (16 mg, 0.06 mmol) and Pd(dba)2 (32 mg, 0.06 mmol). The reaction was sparged with nitrogen for 1 min. The reaction was stirred at 100 °C for 18 h. The reaction was filtered over celite and concentrated under a stream of nitrogen. The material was purified by silica gel chromatography with a gradient from 0% to 100% ethyl acetate:dichloromethane and further purified by reverse phase chromatography to provide N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy-2-methylpropyl)-l -isopropyl- 1H-benzo[d]imidazol-6-yl)pyri din-2 -yl)-2-methoxy-5-(methylsulfonyl)pyrimidine-4-carboxamide (140 mg, 42% yield) as a solid.

[0669] Example 42: N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-5-(4-(2-hydroxypropan-2-yl)phenyl)-2-methylnicotinamide

[0670]

[0671] To a solution of l-(6-(2-amino-5-fluoropyridin-4-yl)-l-isopropyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (30 mg, 0.09 mmol) and 5-(2-hydroxypropan-2-yl)-2-methylnicotinic acid (26 mg, 0.13 mmol) dissolved in pyridine (0.5 mL) was added TCFH (37 mg, 0.13 mmol) and heated to 100 °C for 2 h. The reaction was diluted with MeOH and concentrated. The residue was purified by preparative reverse phase HPLC to furnish N-(5-fluoro-4-(2-(2 -hydroxy -2-methylpropyl)- l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-5-(2-hydroxypropan-2-yl)-2-methylnicotinamide (3.6 mg, 6.7 pmol, 7.7 % yield).

[0672] Example 66: (S)-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methyl-5-(3-(methylamino)but-l-yn-l-yl)nicotinamide

[0673]

[0674] A solution of tert-butyl (S)-(4-(5 -((5 -fluoro-4-(2-(2-hydroxy-2-m ethylpropyl)- 1-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamoyl)-6-methylpyridin-3-yl)but-3-yn-2-yl)(methyl)carbamate (30 mg, 0.05 mmol) in DCM (1 mL) was treated with TFA (0.2 mL, 2.3 mmol). After 2 h, the mixture was diluted with toluene and concentrated. The residue was dissolved in MeOH and purified by preparative rev phase HPLC to furnish (S)-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methyl-5-(3-(methylamino)but-l-yn-l-yl)nicotinamide (9.4 mg, 0.017 mmol, 37 % yield).

[0675] Exampl e 74: 5-(l, 2-dihydroxy-2-methylpropyl) -N-(5 -fluor o-4-( 2-(2-hydroxy-2-methylpropyl)-l-isopropyl-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methylnicotinamide

[0676]

[0677] A solution ofN-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l -isopropyl- 1H-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methyl-5-(2-methylprop-l-en-l-yl)nicotinamide (50 mg, 0.1 mmol) and NMO (34 mg, 0.3 mmol) in acetone (1.2 mL) / water (0.8 mL) was treated with a few drops of osmium tetroxide (approximately 0.9 pL, 3 pmol) and allowed to stir overnight. The mixture was quenched with sodium thiosulfate solution and extracted with EtOAc. The organic layer was concentrated and the residue purified by prep reverse phase HPLC to furnish 5-(l,2-dihydroxy-2-methylpropyl)-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l -isopropyl- lH-benzo[d]imidazol-6-yl)pyridin-2-yl)-2-methylnicotinamide (6.0 mg, 11 pmol, 11 % yield).

[0678] The following Examples in Table 3 were made by using the similar procedures as shown above Intermediates and Examples 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. HPLC Method, RT (min) Ex LCMS (M+H)+

[0679] Structure & Name

[0680] #1H NMR (500 MHz, DMSO-d6, unless otherwise indicated) Method A, 1.214

[0681] 556

[0682] / =\

[0683] N 2 — A / / NOH1H NMR (400 MHz, DMSO-d6) δ

[0684] Il j _ 11.54 (s, 1H), 8.73 (s, 1H), 8.54 HN

[0685] (s, 1H), 8.34-8.30 (m, 2H), 7.99 )=O

[0686] (dd, J= 8.0, 3.2 Hz, 1H), 7.59 (d, 1 \) — / — SO2Me J= 8.0 Hz, 1H), 7.19 (s, 1H),

[0687] 5.23-5.20 (m, 1H), 4.02 (s, 3H), 3.44 (s, 3H), 3.34-3.31 (m, 2H), N-(5-fluoro-4-(2-(2-hydroxy-2- 1.68 (d, J = 6.4 Hz, 6H), 3.30 (s, methylpropyl)- 1 -i sopropyl- 1 H- 6H).

[0688] benzo[d]imidazol-6-yl)pyridin-2-yl)-2- methoxy-5- (methylsulfonyl)isonicotinamide

[0689] F Method B, 2.69

[0690] 556

[0691] \\ # — A -7N 0H1H NMR (400 MHz, DMSO4) 6 )Z' NiJk U-CH311.41 (s, 1H), 8.55 (d, J= 1.6 Hz, \=0JL 1H), 8.37 (d, J = 6.0 Hz, 1 H) H3C N=(H3C"\H38.36 (s, 1H), 8.25 (d, J= 8.8 Hz, 2 b— K SO2CH31H), 8.01 (d, J= 8.4 Hz, 1H),

[0692] 7.76 (d, J= 8.4 Hz, 1H), 7.19 (d, N-(5-fluoro-4-(2-(2-hydroxy-2- J= 8.8 Hz, 1H), 5.26-5.10 (m, methylpropyl)- 1 -i sopropyl- 1 H- 1H), 4.00 (s, 3H), 3.34 (s, 3 H), benzo[d]imidazol-6-yl)pyridin-2-yl)-6- 3.33 (s, 2H), 1.69 (d, J= 6.8 Hz, methoxy-3- 6H), 1.30 (s, 6H)

[0693] (methylsulfonyl)picolinamide

[0694]

[0695] Method C, 2.1

[0696] 632.5

[0697] δ 8.49 (br s, 1H), 8.38 (br d, J=5.8 Hz, 1H), 8.32 (br d, J=8.9 Hz, 1H), 8.07 (br s, 1H), 7.78 (br d, J=8.0 Hz, 1H), 7.45 (br d, J=7.5 Hz, 1H), 7.31 (br d, J=8.8 Hz, 1H), 6.65 - 6.33 (m, 1H), 5.05 (br s, 1H), 4.76 (br t, J=14.3 Hz, 2H), 4.27 - 4.11 (m, 1H), 3.07 - 2.91 (m, 2H), 1.70 - 1.65 (R)-N-(4-(l-(l-cyclopropylethyl)-2-(2- (m, 1H), 1.63 (br d, J=6.7 Hz, hydroxy-2-methylpropyl)- 1H- 3H), 1.27 (s, 3H), 1.22 (s, 3H), benzo[d]imidazol-6-yl)-5- 0.77 - 0.67 (m, 1H), 0.63 - 0.54 fluoropyridin-2-yl)-6-(2,2- (m, 1H), 0.44 - 0.35 (m, 1H), 0.31 difluoroethoxy)-3 - - 0.24 (m, 1H). Protons missing (methylsulfonyl)picolinamide

[0698] due to solvent suppression or exchange or overlap with the NMR solvent. _

[0699] Method D, 1.463

[0700] 633

[0701] 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.17 (s, 1H), 8.50 (d, J= 2.0 Hz, 1H), 8.43-8.39 (m, 1H), 8.33 (d, J = 6.0 Hz, 1H), 8.08 (s, 1H), 7.77 (d, J= 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.72-6.33 (m, 1H), 5.18-4.92 (m, (R)-N-(4-(l-(l-cyclopropylethyl)-2-(2- 1H), 4.92-4.75 (m, 2H), 4.19 (t, J hydroxy-2-methylpropyl)- 1H- = 8.0 Hz, 1H), 3.43 (s, 3H), 3.07- benzo[d]imidazol-6-yl)-5- 2.93 (m, 2H), 1.70-1.54 (m, 4H), fluoropyridin-2-yl)-2-(2,2- 1.27 (s, 3H), 1.21 (s, 3H), 0.75- difluoroethoxy )- 5 - 0.62 (m, 1H), 0.61-0.52 (m, 1H), (methylsulfonyl)pyrimidine-4- 0.42-0.32 (m, 1H), 0.31-0.20 (m, carb oxami de

[0702]

[0703] 1H) _ Method C, 1.65

[0704] 601.2

[0705] δ 9.21 (s, 1H), 8.52 (br s, 1H), 8.35 (br d, J=5.2 Hz, 1H), 7.90 (br s, 1H), 7.34 (br d, J=10.7 Hz, 1H), 5.69 - 5.57 (m, 1H), 4.38 - 4.29 (m, 1H), 4.10 (br d, J=9.6 Hz, 1H), 3.93 (br t, J=9.0 Hz, 1H), 3.70 (q, J=8.6 Hz, 1H), 3.56 (q, J=6.3 Hz, 1H), 3.22 - 3.13 (m, (R)-5-(ethylsulfonyl)-N-(5-fluoro-4-(4- 1H), 3.13 - 3.06 (m, 1H), 2.83 (s, fluoro-2-(2 -hydroxy -2 -methylpropyl)- 3 H), 2.24 - 2.13 (m, 1H), 1.28 (s, 1 -(tetrahydrofuran-3 -yl)- 1H- 3H), 1.23 (br s, 3H), 1.23 - 1.19 benzo[d]imidazol-6-yl)pyridin-2-yl)-2- (m, 3H). Protons missing due to methylpyrimidine-4-carboxamide solvent suppression or exchange or overlap with the NMR solvent. Method C, 1.77

[0706] 594.2

[0707] δ 8.95 (br d, J=4.5 Hz, 1H), 8.52 (s, 1H), 8.38 (br d, J=8.0 Hz, 1H), 8.34 (br d, J=5.8 Hz, 1H), 7.83 (br dd, J=7.8, 5.1 Hz, 1H), 7.79 (s, 1H), 7.33 (br d, J=11.2Hz, 1H), 6.68 - 6.31 (m, 1H), 5.13 - 4.97 (m, 2H), 3.97 - 3.84 (m, 1H), N-(4-(l-(2,2-difluoroethyl)-4-fluoro-2- 3.09 (s, 2H), 1.28 (s, 6H), 1.21 (2-hydroxy-2-methylpropyl)- 1H- (br d, J=6.7 Hz, 6H). Protons benzo[d]imidazol-6-yl)-5- missing due to solvent fluoropyri din-2 -yl)-3- suppression or exchange or (isopropylsulfonyl)picolinamide overlap with the NMR solvent.

[0708] Method F, 0.694

[0709] 582

[0710] 1H NMR (400 MHz, Methanol- d4) 68.79 (s, 1H), 8.46 (d, J= 6.0 Hz, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.90 (d, J= 8.4 Hz, 1H), 7.07 (s, 1H), 4.61-4.48 (m, 1H), 4.08 (s, 3H), 3.35 (s, 3H), 1.81(d, J= 6.8 Hz, 3H), 1.82-1.75 (m, 1H), 1.38 (R)-N-(4-(l-(l-cyclopropylethyl)-2-(2- (s, 3H), 1.37 (s, 3H), 0.96-0.86 hydroxy-2-methylpropyl)- 1H- (m, 1H), 0.80-0.71 (m, 1H), 0.64- benzo[d]imidazol-6-yl)-5- 0.53 (m, 1H), 0.48-0.36 (m, 1H). fluoropyridin-2-yl)-2-methoxy-5- Protons missing due to solvent (methylsulfonyl)isonicotinamide suppression or exchange or

[0711]

[0712] overlap with the NMR solvent. F Method C, 1.69

[0713] 541

[0714] δ 11.46 (s, 1H), 9.24 (s, 1H), 8.50

[0715] (d, J=2.1 Hz, 1H), 8.33 (d, J=6.1 Hz, 1H), 7.97 (s, 1H), 7.77 (d, vo / A

[0716] J=8.5 Hz, 1H), 7.42 (d, J=8.5 Hz,N=\ / x

[0717] 1H), 5.13 - 4.98 (m, 1H), 4.93 (s, 1H), 3.44 (s, 3H), 3.05 (s, 2H), 2.83 (s, 3H), 1.60 (d, J=6.8 Hz, N-(5-fluoro-4-(2-(2-hydroxy-2- 6H), 1.26 (s, 6H). Protons methylpropyl)- 1 -i sopropyl- 1 H- benzo[d]imidazol-6-yl)pyridin-2-yl)-2- missing due to solvent suppression or exchange or methyl-5-(methylsulfonyl)pyrimidine- overlap with the NMR solvent.

[0718] 4-carboxamide

[0719] F Method C, 1.76

[0720] 540.3

[0721] δ 8.47 (s, 1H), 8.35 (br d, J=5.6 Hz, 1H), 8.29 (d, J=7.7 Hz, 1H), 7.99 - 7.93 (m, 1H), 7.76 (br d, J=8.2 Hz, 1H), 7.68 (br d, J=8.3N=\ zxHz, 1H), 7.43 (br d, J=8.4 Hz,

[0722] 1H), 5.11 - 4.94 (m, 1H), 3.37 (s, 2H), 2.64 (s, 3H), 1.60 (br d, N-(5-fluoro-4-(2-(2-hydroxy-2- J=6.6 Hz, 6H), 1.25 (s, 6H). methylpropyl)- 1 -i sopropyl- 1 H- Protons missing due to solvent benzo[d]imidazol-6-yl)pyridin-2-yl)-6- suppression or exchange or methyl-3-(methylsulfonyl)picolinamide overlap with the NMR solvent.

[0723] Method G, 1.171

[0724] F

[0725] 607

[0726] 1H NMR (400 MHz, Methanol- A # — \ °h

[0727] d4) δ 8.61 (d, J= 8.4 Hz, 1H), HN N^X / ^ 8.59 (d, J= 6.0 Hz, 1H), 8.46 (s, 8=0

[0728] 1H), 8.44 (s, 1H), 8.41 (s, 1H), 8.35 (d, J= 8.4 Hz, 1H), 8.00 (d, J= 8.4 Hz, 1H), 7.95 (d, J= 8.4 Hz, 1H), 5.40-5.28 (m, 1H), 4.32 (s, 3H), 3.53 (s, 3H), 3.43 (s, 2H), N-(5-fluoro-4-(2-(2-hydroxy-2- 1.84 (d, J= 6.8 Hz, 6H), 1.43(s, methylpropyl)- 1 -i sopropyl- 1 H- 6H). Protons missing due to benzo[d]imidazol-6-yl)pyridin-2-yl)-6- solvent suppression or exchange (2-methyl-2H-l,2,3-triazol-4-yl)-3- or overlap with the NMR solvent. (methylsulfonyl)picolinamide

[0729]

[0730] F Method H, 0.916

[0731] 607

[0732] 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 9.14 (s, 1H), 8.50 Vo A °H(s, 1H), 8.48 (s, 1H), 8.37 (d, J = N^\ OX6.0 Hz, 1H), 8.20 (s, 1H), 7.97 (s,

[0733] 1H), 7.78 (d, J = 8.4 Hz, 1H), >rTA=Mb 7.43 (d, J= 8.4 Hz, 1H), 5.14- N-(5-fluoro-4-(2-(2-hydroxy-2- 5.00 (m, 1H), 4.93 (s, 1H), 4.30 methylpropyl)- 1 -i sopropyl- 1 H- (s, 3H), 3.45 (s, 3H), 3.05 (s, 2H), benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 1.61 (d, J = 6.4 Hz, 6H), 1.26 (s, (2-methyl-2H-l,2,3-triazol-4-yl)-5- 6H).

[0734] (methylsulfonyl)isonicotinamide

[0735] F Method, 2.06

[0736] 576.1

[0737] N /

[0738] / - \=\ 6 10.25 (s, 1H), 8.91 (s, 1H), 8.51 W '1 _ (br s, 1H), 8.46 (br d, J=5.0 Hz,

[0739] 1H), 8.39 (s, 1H), 7.84 (s, 1H), >° A6h7.79 (d, J=8.3 Hz, 1H), 7.49 (br N^=\ / =\ I / d, J=8.0 Hz, 1H), 5.27 - 5.11 (m,N^N' 1H), 3.09 (s, 2H), 2.19 - 2.09 (m,

[0740] 4H), 2.06 - 1.95 (m, 2H), 1.81 - 5-chloro-N-(4-(l-cyclopentyl-2-(2- 1.72 (m, 2H), 1.26 (s, 6H). hydroxy-2-methylpropyl)- 1H- benzo[d]imidazol-6-yl)-5- Protons missing due to solvent suppression or exchange or fluoropyri din-2 -y l)-2-( 1 H-tetrazol- 1 - overlap with the NMR solvent. yl)isonicotinamide

[0741] F Method I, 0.636

[0742] 593

[0743] / ==\

[0744] \ \ / / NHO,1H NMR (400 MHz, Methanol- '1 V d4) δ 9.03 (s, 1H), 8.81 (d, J= 8.8 HN N^\A\

[0745] Hz, 1H), 8.62-8.56 (m, 1H), 8.47 v=o

[0746] (s, 1H), 8.41 (s, 1H), 8.01-7.93 N=z

[0747] L N— <( 2>— SO2CH3(m, 3H), 5.41-5.26 (m, 1H), 3.55 VJ' (s, 3H), 3.43 (s, 2H), 1.84 (d, J =

[0748] 6.8 Hz, 6H), 1.28 (s, 6H). Protons N-(5-fluoro-4-(2-(2-hydroxy-2- missing due to solvent methylpropyl)- 1 -i sopropyl- 1 H- suppression or exchange or benzo[d]imidazol-6-yl)pyridin-2-yl)-3- overlap with the NMR solvent. (methylsulfonyl)-6-(lH-l,2,3-triazol-l-

[0749]

[0750] yl)picolinamide Method C, 1.79

[0751] 574.4

[0752] δ 11.35 (s, 1H), 8.49 (s, 1H), 8.35 (d, J=5.8 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 7.31 (br d, J=11.6Hz, 1H), 7.18 (d, J=8.9 Hz, 1H), 5.11 - 5.04 (m, 1H), 4.01 (s, 3H), 3.35 (s, 2H), 3.09 (s, N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- 2H), 1.60 (d, J=6.9 Hz, 6H), 1.27 2-m ethylpropyl)- 1 -i sopropyl- 1 H- (s, 6H). Protons missing due to benzo[d]imidazol-6-yl)pyridin-2-yl)-6- solvent suppression or exchange methoxy-3- or overlap with the NMR solvent. (methylsulfonyl)picolinamide

[0753] Method C, 1.91

[0754] 567.2

[0755] δ 9.24 (s, 1H), 8.50 (s, 1H), 8.37 (br d, J=6.0 Hz, 1H), 7.84 - 7.81 (m, 1H), 7.79 (br d, J=8.3 Hz, 1H), 7.49 (br d, J=8.3 Hz, 1H), 5.23 - 5.13 (m, 1H), 3.08 (s, 2H), 2.83 (s, 3H), 2.13 (br s, 4H), 2.00 N-(4-(l-cyclopentyl-2-(2-hydroxy-2- (br s, 2H), 1.84 - 1.70 (m, 2H),

[0756] 1.25 (s, 6H). Protons missing due methylpropyl)-lH-benzo[d]imidazol-6- yl)-5-fluoropyri din-2 -yl)-2-methyl-5- to solvent suppression or (methylsulfonyl)pyrimidine-4- exchange or overlap with the carb oxami de NMR solvent.

[0757] Method C, 1.69

[0758] 550.2

[0759] δ 11.48 (s, 1H), 9.24 (s, 1H), 8.50 (d, J=1.7 Hz, 1H), 8.33 (d, J=6.0 Hz, 1H), 8.01 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.46 (br d, J=8.2 Hz, 1H), 5.04 - 4.95 (m, 1H), 3.31 (s, 1H), 2.83 (s, 3H), 1.64 (br d, J=6.8 Hz, 6H), 1.56 (s, 6H). N-(4-(2-(2-cyano-2-methylpropyl)- 1 - isopropyl-lH-benzo[d]imidazol-6-yl)- Protons missing due to solvent suppression or exchange or 5-fluoropyridin-2-yl)-2-methyl-5- (methylsulfonyl)pyrimidine-4- overlap with the NMR solvent.

[0760]

[0761] carb oxami de F Method J, 0.723

[0762] 546

[0763] 1H NMR (400 MHz, Methanol- d4) δ 8.53 (d, J= 5.2 Hz, 1H), Hr / 'NVF'.

[0764] 8.45 (s, 1H), 8.41 (s, 1H), 8.29 (d, 0 >o A

[0765] J= 5.2 Hz, 1H), 7.95 (d, J= 8.8 °=< f=C Hz, 1H), 7.82 (d, J= 8.8 Hz, 1H),

[0766] 5.30-5.10 (m, 1H), 4.48-4.32 (m, 2H), 3.84 (s, 3H), 2.75 (s, 3H), methyl (5 -((5 -fluoro-4-( 1 -i sopropyl-2- 1.81 (d, J= 6.8 Hz, 6H). Protons (2,2,2-trifluoroethyl)-lH- missing due to solvent benzo[d]imidazol-6-yl)pyridin-2- suppression or exchange or yl)carbamoyl)-6-methylpyridazin-3- overlap with the NMR solvent. yl)carbamate

[0767] F Method K, 0.963

[0768] 536

[0769] A # -OH1H NMR (400 MHz, Methanol- y—v II I _ d4) δ 8.54 (d, J = 6.0 Hz, 1H), HN

[0770] 8.44 (s, 1H), 8.40 (d, J= 4.4 Hz, 0 )=o U

[0771] 1H), 8.39 (s, 1H), 8.00 (d, J= 8.8 °=< / =\ Hz, 1H), 7.94 (d, J= 8.8 Hz, 1H),

[0772] 5.40-5.28 (m, 1H), 3.84 (s, 3H), 3.44 (s, 2H), 2.74 (s, 3H), 1.83 (d, methyl (5-((5-fluoro-4-(2-(2-hydroxy- J= 6.8 Hz, 6H), 1.43 (s, 6H). 2-methylpropyl)- 1 -i sopropyl- 1 H- Protons missing due to solvent benzo[d]imidazol-6-yl)pyridin-2- suppression or exchange or yl)carbamoyl)-6-methylpyridazin-3- overlap with the NMR solvent. yl)carbamate

[0773] Method M, 1.52

[0774] F 566.9

[0775] δ 11.48 (s, 1H), 9.23 (s, 1H), 8.49 (d, J=1.7 Hz, 1H), 8.33 (d, J=6.0

[0776] HN P Hz, 1H), 8.11 (s, 1H), 7.79 (d, \ _ Q Jabs J=8.3 Hz, 1H), 7.47 (br d, J=8.4

[0777] Hz, 1H), 4.25 - 4.18 (m, 1H),N=\

[0778] — — SO2CH3'' 3.08 - 2.96 (m, 2H), 2.82 (s, 3H),

[0779] 1.72 - 1.65 (m, 1H), 1.63 (d, (R)-N-(4-(1-(1-cyclopropylethyl)-2-(2- J=6.8 Hz, 3H), 1.27 (s, 3H), 1.22 hydroxy-2-methylpropyl)- 1H- (s, 3H), 0.75 - 0.67 (m, 1H), 0.64 benzo[d]imidazol-6-yl)-5- - 0.56 (m, 1H), 0.43 - 0.35 (m, fluoropyridin-2-yl)-2-methyl-5- 1H), 0.28 (br dd, J=9.6, 4.5 Hz, (methylsulfonyl)pyrimidine-4- 1H). Protons missing due to carb oxami de solvent suppression or exchange

[0780]

[0781] or overlap with the NMR solvent. Method M, 1.45

[0782] 567.2

[0783] δ 11.46 (s, 1H), 9.14 (s, 1H), 8.50 (d, J=1.8 Hz, 1H), 8.33 (br d, J=6.1 Hz, 1H), 7.97 (s, 1H), 7.77 (br d, J=8.3 Hz, 1H), 7.43 (br d, J=8.0 Hz, 1H), 5.05 (spt, J=6.9 Hz, 1H), 3.06 (s, 2H), 2.47 - 2.37 (m, 1H), 1.61 (br s, 3H), 1.60 (s, 2-cyclopropyl-N-(5-fluoro-4-(2-(2- 3H), 1.30 - 1.27 (m, 2H), 1.26 (s, hydroxy-2-methylpropyl)- 1 -isopropyl- 6H), 1.25 - 1.21 (m, 2H). Protons lH-benzo[d]imidazol-6-yl)pyridin-2- missing due to solvent yl)-5-(methylsulfonyl)pyrimidine-4- suppression or exchange or carb oxami de overlap with the NMR solvent.

[0784] Method M, 1.61

[0785] 609.1

[0786] δ 8.61 (s, 1H), 8.47 (d, J=1.8 Hz, 1H), 8.43 (br d, J=5.5 Hz, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 5.23 - 5.11 (m, 1H), 4.83 - 4.75 (m, 1H), 3.08 (s, 2H), 2.99 (s, 1H), 2.41 (s, 3H), 2.18 - 2.08 N-(4-(l-cyclopentyl-2-(2-hydroxy-2- (m, 4H), 2.06 - 1.94 (m, 2H), 1.81 methylpropyl)-lH-benzo[d]imidazol-6- - 1.71 (m, 2H), 1.25 (s, 6H). yl)-5 -fluoropyridin-2-yl)-2-(5 - Protons missing due to solvent (hydroxymethyl)-4,5-dihydroisoxazol- suppression or exchange or 3-yl)-5-methylisonicotinamide

[0787] overlap with the NMR solvent. Method M, 1.35

[0788] 559

[0789] δ 11.52 (s, 1H), 9.23 (s, 1H), 8.51 (s, 1H), 8.30 (br d, J=6.0 Hz, 1H), 7.87 (s, 1H), 7.33 (br d, J=11.4 Hz, 1H), 5.13 - 5.04 (m, 1H), 3.10 (s, 2H), 2.82 (s, 3H), 1.60 (br d, J=6.8 Hz, 6H), 1.27 (s, 6H). N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- Protons missing due to solvent suppression or exchange or 2-m ethylpropyl)- 1 -i sopropyl- 1 H- benzo[d]imidazol-6-yl)pyridin-2-yl)-2- overlap with the NMR solvent. methyl-5-(methylsulfonyl)pyrimidine-

[0790]

[0791]

[0792] 4-carboxamide Method L, 1.391

[0793] 575.2

[0794] δ 11.52 (s, 1H), 9.13 (s, 1H), 8.52 (d, J=1.9 Hz, 1H), 8.31 (d, J=6.0 Hz, 1H), 7.83 (s, 1H), 7.27 (d, J=11.4Hz, 1H), 5.13 - 5.01 (m, 1H), 4.81 (s, 1H), 4.11 (s, 3H), 3.40 (s, 3H), 3.07 (s, 2H), 1.60 (d, J=6.9 Hz, 6H), 1.27 (s, 6H). N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- 2-m ethylpropyl)- 1 -i sopropyl- 1 H- benzo[d]imidazol-6-yl)pyridin-2-yl)-2- methoxy-5- (methylsulfonyl)pyrimidine-4- carb oxami de

[0795] Method M, 1.49

[0796] 625.2

[0797] δ 9.17 (s, 1H), 8.52 (br s, 1H), 8.36 - 8.25 (m, 1H), 7.82 (s, 1H), 7.27 (br d, J=11.3 Hz, 1H), 6.70 - 6.32 (m, 1H), 5.07 (spt, J=6.9 Hz, 1H), 4.83 (br t, J=13.7 Hz, 2H), 3.07 (s, 2H), 1.59 (d, J=6.9 Hz, 2-(2,2-difluoroethoxy)-N-(5-fluoro-4- 6H), 1.27 (s, 6H). Protons

[0798] (4-fluoro-2-(2-hydroxy-2- missing due to solvent suppression or exchange or methylpropyl)- 1 -i sopropyl- 1 H- benzo[d]imidazol-6-yl)pyridin-2-yl)-5- overlap with the NMR solvent.

[0799] (methylsulfonyl)pyrimidine-4- carb oxami de

[0800] Method L, 1.266

[0801] 553.1

[0802] δ 9.36 (s, 1H), 9.13 (s, 1H), 8.25 (s, 1H), 8.09 (d, J=6.0 Hz, 1H), 7.83 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.20 (br d, J=8.6 Hz, 1H), 4.03 - 3.90 (m, 1H), 2.75 (br d, J=8.9 Hz, 2H), 1.66 (s, 3H), 1.44 - 1.39 (m, 1H), 1.38 (br d, J=6.9 (R)-N-(4-( 1 -(1 -cyclopropylethyl)-2-(2- Hz, 3H), 1.02 (s, 3H), 0.97 (s, hydroxy-2-methylpropyl)- 1H- 3H), 0.51 - 0.41 (m, 1H), 0.38 - benzo[d]imidazol-6-yl)-5- 0.29 (m, 1H), 0.17 - 0.10 (m, 1H), fluoropyridin-2-yl)-5- 0.06 - -0.02 (m, 1H). Protons (methylsulfonyl)pyrimidine-4- missing due to solvent carb oxami de suppression or exchange or

[0803]

[0804]

[0805] overlap with the NMR solvent. Method, 1.51

[0806] F 632.1

[0807] δ 11.53 - 11.51 (m, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 8.32 (br d, J=5.6 Hz, 1H), 8.27 (br s, 1H), 7.91 (br d, J=7.5 Hz, 1H), 7.63 (br d, J=8.2 Hz, 1H), 7.29 (s, 1H), 6.56 - 6.29 (m, 1H), 4.80 - 4.70 (m, 2H), 4.38 - 4.31 (m, 1H), 3.35 (R)-N-(4-(l-(l -cyclopropyl ethyl )-2-(2- (s, 3H), 3.21 - 3.10 (m, 2H), 1.72 hydroxy-2-methylpropyl)- 1H- (m, 1H), 1.66 (br d, J=6.8 Hz, benzo[d]imidazol-6-yl)-5- 3H), 1.25 (br d, J=16.0 Hz, 6H), fluoropyridin-2-yl)-2-(2,2- 1.15 (t, J=7.3 Hz, 1H), 0.77 - 0.28 difluoroethoxy )- 5 - (m, 4H).

[0808] (methylsulfonyl)isonicotinamide

[0809] F F Method M, 1.88

[0810] 568.9

[0811] δ 9.23 (s, 1H), 8.52 (d, J=1.6 Hz,

[0812] HF / ACF. 1H), 8.30 (d, J=6.0 Hz, 1H), 7.91

[0813] (s, 1H), 7.35 (d, J=ll.l Hz, 1H), )=o -"k

[0814] N=ZX4.98 (spt, J=6.9 Hz, 1H), 4.31 (q, — — S O2C H 3 J=10.7 Hz, 2H), 2.82 (s, 3H),

[0815] 1.61 (d, J=6.9 Hz, 6H). Protons missing due to solvent

[0816] N-(5 -fluoro-4-(4-fluoro- 1 -isopropyl-2- suppression or exchange or (2,2,2-trifluoroethyl)-lH- benzo[d]imidazol-6-yl)pyridin-2-yl)-2- overlap with the NMR solvent. methyl-5-(methylsulfonyl)pyrimidine- 4-carboxamide

[0817] F F Method C, 1.96

[0818] 595.1

[0819] δ 11.28 (s, 1H), 9.00 (s, 1H), 8.28 (s, 1H), 8.07 (d, J=5.9 Hz, 1H),

[0820] 7.78 (s, 1H), 7.13 (br d, J=11.3 \ Q _ [abs

[0821] Hz, 1H), 4.10 - 3.95 (m, 2H),N=\ 3.95 - 3.88 (m, 1H), 3.25 - 3.10 — — SO2CH3

[0822] (m, 2H), 2.59 (s, 3H), 1.53 - 1.43 (m, 1H), 1.39 (br d, J=6.8 Hz, (R)-N-(4-(l-(l-cyclopropylethyl)-4- 3H), 0.51 - 0.44 (m, 1H), 0.44 - fluoro-2-(2,2,2-trifluoroethyl)-lH- 0.38 (m, 1H), 0.20 - 0.12 (m, 1H), benzo[d]imidazol-6-yl)-5- 0.06 - -0.02 (m, 1H). Protons fluoropyridin-2-yl)-2-methyl-5- missing due to solvent (methylsulfonyl)pyrimidine-4- suppression or exchange or carb oxami de

[0823]

[0824] overlap with the NMR solvent. Method N, 1.96

[0825] 601.2

[0826] 6 11.55 (s, 1H), 9.11 (s, 1H), 8.50 (d, J=1.7 Hz, 1H), 8.30 (d, J=6.0 Hz, 1H), 7.93 (s, 1H), 7.30 (d, J=11.4Hz, 1H), 4.27 - 4.20 (m, 1H), 4.09 (s, 3H), 3.38 (s, 2H), 1.68 - 1.63 (m, 1H), 1.61 (d, J=6.9 Hz, 3H), 1.27 (s, 3H), 1.21 (R)-N-(4-(l-(l-cyclopropylethyl)-4- (s, 3H), 0.74 - 0.66 (m, 1H), 0.62 fluoro-2-(2 -hydroxy -2 -methylpropyl)- - 0.56 (m, 1H), 0.40 - 0.35 (m, lH-benzo[d]imidazol-6-yl)-5- 1H), 0.31 - 0.24 (m, 1H). Protons fluoropyridin-2-yl)-2-methoxy-5- missing due to solvent (methylsulfonyl)pyrimidine-4- suppression or exchange or carb oxami de overlap with the NMR solvent.

[0827] Method N, 1.96

[0828] 585.2

[0829] 6 11.51 (s, 1H), 9.23 (s, 1H), 8.51 (s, 1H), 8.31 (d,. / =6,0 Hz, 1H), 7.97 (s, 1H), 7.33 (br d, J=11.2 Hz, 1H), 4.32 - 4.20 (m, 1H), 2.82 (s, 2H), 1.70 - 1.65 (m, 1H), 1.62 (br d, J=6.8 Hz, 3H), 1.28 (s, 3H), 1.22 (s, 3H), 0.74 - 0.65 (m, (R)-N-(4-(l-(l-cyclopropylethyl)-4- 1H), 0.65 - 0.56 (m, 1H), 0.45 - fluoro-2-(2 -hydroxy -2 -methylpropyl)- 0.33 (m, 1H), 0.33 - 0.25 (m, 1H). lH-benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-2-methyl-5- Protons missing due to solvent (methylsulfonyl)pyrimidine-4- suppression or exchange or overlap with the NMR solvent. carb oxami de

[0830] Method C, 1.75

[0831] 629.1

[0832] δ 9.18 (s, 1H), 8.52 (s, 1H), 8.32 (d, J=6.0 Hz, 1H), 7.92 (s, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.47 (br d, J=8.2 Hz, 1H), 6.77 - 6.24 (m, 2H), 5.02 - 4.94 (m, 2H), 4.83 (td, J=15.0, 2.8 Hz, 2H), 3.07 (s, 2H), 1.27 (s, 6H). Protons missing due 2-(2,2-difluoroethoxy)-N-(4-(l-(2,2- difluoroethyl)-2-(2-hydroxy-2- to solvent suppression or methylpropyl)-lH-benzo[d]imidazol-6- exchange or overlap with the yl)-5-fluoropyridin-2-yl)-5- NMR solvent.

[0833] (methylsulfonyl)pyrimidine-4-

[0834]

[0835]

[0836] carb oxami de Method C, 1.9

[0837] 559.1

[0838] 6 11.51 (s, 1H), 9.24 (s, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.32 (d, J=6.0 Hz, 1H), 8.11 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 4.97 - 4.88 (m, 1H), 3.39 - 3.30 (m, 1H), 3.24 - 3.17 (m, 1H), 2.30 - 2.18 (m, 1H), 1.82 - 1.70 N-(4-(2-((2,2- (m, 1H), 1.64 (br s, 3H), 1.64 - difluorocyclopropyl)methyl)-l- 1.62 (m, 3H), 1.50 - 1.38 (m, 1H). isopropyl-lH-benzo[d]imidazol-6-yl)- 5-fluoropyridin-2-yl)-2-methyl-5- Protons missing due to solvent suppression or exchange or (methylsulfonyl)pyrimidine-4- overlap with the NMR solvent. carb oxami de

[0839] Method M, 1.44

[0840] 574.9

[0841] 6 11.56 (s, 1H), 9.12 (s, 1H), 8.54 - 8.49 (m, 1H), 8.31 (br d, J=5.9 Hz, 1H), 8.13 (br s, 1H), 7.91 - 7.87 (m, 1H), 7.59 (br d, J=7.5 Hz, 1H), 5.09 - 4.78 (m, 1H), 4.10 (s, 3H), 3.39 (s, 3H), 3.23 - N-(4-(2-((2,2- 3.17 (m, 1H), 2.31 - 2.19 (m, 1H),

[0842] 1.82 - 1.71 (m, 1H), 1.67 - 1.62 difluorocyclopropyl)methyl)-l- isopropyl-lH-benzo[d]imidazol-6-yl)- (m, 6H), 1.53 - 1.40 (m, 1H). 5-fluoropyri din-2 -yl)-2-methoxy-5- Protons missing due to solvent (methylsulfonyl)pyrimidine-4- suppression or exchange or overlap with the NMR solvent. carb oxami de

[0843] Method M, 1.58

[0844] 495

[0845] 6 10.91 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 8.39 (br d,. / =5,2 Hz, 1H), 7.90 (s, 1H), 7.36 (d, J=11.2Hz, 1H), 5.23 - 4.95 (m, 1H), 3.11 (s, 2H), 2.69 (s, 3H), 2.49 (s, 3H), 1.60 (d,. / =6,9 Hz, 6H), 1.27 (s, N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- 6H). Protons missing due to solvent suppression or exchange 2-m ethylpropyl)- 1 -i sopropyl- 1 H- benzo[d]imidazol-6-yl)pyridin-2-yl)- or overlap with the NMR solvent.

[0846]

[0847] ,

[0848]

[0849] 5-dimethylpyrimidine-4-carboxamide F Method 0, 4.109

[0850] / = / 7=\ N 536

[0851] 1H NMR (400 MHz, Methanol- \ # — C Z^N 1 1

[0852] y—V '1 d4) 89.32 (s, 1H), 8.51 (d, J= 6.0 HN N-'V / ’V Hz, 1H), 8.38 (s, 1H), 7.94 (s, \=O 1H), 7.84 (d, J = 8.4 Hz, 1H),N=\ 7.64 (d, J= 8.4 Hz, 1H), 4.53 (q, — — SO2CH3

[0853] J= 7.2 Hz, 2H), 3.53 (s, 3H), 3.33 (s, 2H), 2.91 (s, 3H), 1.61 (s, 6H), N-(4-(2-(2-cyano-2-methylpropyl)- 1 - 1.50 (d, J = 7.2 Hz, 3H). Proton ethyl-lH-benzo[d]imidazol-6-yl)-5- missing due to solvent fluoropyridin-2-yl)-2-methyl-5- suppression or exchange or (methylsulfonyl)pyrimidine-4- overlap with the NMR solvent. carb oxami de

[0854] F Method C, 1.66

[0855] 536.2

[0856] 6 11.55 (s, 1H), 9.61 (s, 1H), 9.38 (s, 1H), 8.50 (s, 1H), 8.34 (br d, HN

[0857] J=5.7 Hz, 1H), 8.01 (s, 1H), 7.83 )=O

[0858] N=Z ' (br d,. / =8,2 Hz, 1H), 7.46 (br d, ^^-SO2CH3J=8.1 Hz, 1H), 5.04 - 4.93 (m,

[0859] 1H), 3.31 (s, 1H), 2.89 (s, 1H), 1.63 (br d, J=6.8 Hz, 6H), 1.56 (s, N-(4-(2-(2-cyano-2-methylpropyl)- 1 - isopropyl-lH-benzo[d]imidazol-6-yl)- 6H). Protons missing due to 5 -fluoropyri din-2 -yl)-5 - solvent suppression or exchange (methylsulfonyl)pyrimidine-4- or overlap with the NMR solvent.

[0860] carb oxami de

[0861] F Method C, 1.69

[0862] 553.4

[0863] δ 9.61 (s, 1H), 9.38 (s, 1H), 8.50 (s, 1H), 8.37 (br d, J=6.2 Hz, 1H), HN N^^ / ^OH

[0864] 7.82 (br s, 1H), 7.78 (br d, J=8.4 )=O J.

[0865] Hz, 1H), 7.49 (br d, J=8.1 Hz,N=\ 1 /

[0866] ^^-SO2CH31H), 5.24 - 5.12 (m, 1H), 3.08 (s,

[0867] 2H), 2.18 - 2.07 (m, 4H), 2.06 - 1.96 (m, 2H), 1.80 - 1.71 (m, 2H), N-(4-(l-cyclopentyl-2-(2-hydroxy-2- 1.25 (s, 6H). Protons missing due methylpropyl)-lH-benzo[d]imidazol-6- to solvent suppression or yl)-5-fluoropyridin-2-yl)-5- (methylsulfonyl)pyrimidine-4- exchange or overlap with the NMR solvent.

[0868]

[0869] carb oxami de Method M, 1.28

[0870] 545.3

[0871] δ 9.61 (s, 1H), 9.38 (s, 1H), 8.52 (s, 1H), 8.31 (d, J=5.7 Hz, 1H), 7.83 (s, 1H), 7.27 (br d, J=11.2 Hz, 1H), 5.16 - 4.98 (m, 1H), 3.07 (s, 2H), 1.59 (d, J=6.8 Hz, 6H), 1.26 (s, 6H). Protons N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- missing due to solvent suppression or exchange or 2-m ethylpropyl)- 1 -i sopropyl- 1 H- benzo[d]imidazol-6-yl)pyridin-2-yl)-5- overlap with the NMR solvent.

[0872] (methylsulfonyl)pyrimidine-4- carb oxami de

[0873] Method M, 1.33

[0874] 587.3

[0875] 6 11.53 (s, 1H), 9.23 (s, 1H), 8.51 (d, J=1.9 Hz, 1H), 8.35 (d, J=5.9 Hz, 1H), 7.91 (s, 1H), 7.36 (br d, J=11.7Hz, 1H), 5.66 - 5.52 (m, 1H), 4.37 - 4.27 (m, 1H), 4.12 - 4.04 (m, 1H), 3.99 - 3.87 (m, 1H), 3.75 - 3.64 (m, 1H), 3.44 (s, 1H), (R)-N-(5-fluoro-4-(4-fluoro-2-(2- 3.22 - 3.14 (m, 1H), 3.14 - 3.05 hydroxy-2-methylpropyl)- 1 - (m, 1H), 2.82 (s, 2H), 2.24 - 2.11 (tetrahy drofuran-3 -yl)- 1 H- (m, 1H), 1.27 (s, 3H), 1.22 (s, benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 3H). Protons missing due to methyl-5-(methylsulfonyl)pyrimidine- solvent suppression or exchange 4-carboxamide or overlap with the NMR solvent.

[0876] Method, 1.16

[0877] 520.2

[0878] 6 11.15 (s, 1H), 8.64 (d, J=2.1 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.41 (br d, J=5.6 Hz, 1H), 7.98 (s, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.46 (br d, J=8.5 Hz, 1H), 5.10 - 4.96 (m, 1H), 3.06 (s, 2H), 2.53 - 2.45 (m, 3H), N-(5-fluoro-4-(2-(2-hydroxy-2- 1.60 (d, J=6.9 Hz, 6H), 1.48 (s, methylpropyl)- 1 -i sopropyl- 1 H- 6H), 1.26 (s, 6H). Protons benzo[d]imidazol-6-yl)pyridin-2-yl)-5- missing due to solvent

[0879] (2-hydroxypropan-2-yl)-2- suppression or exchange or

[0880] methylnicotinamide

[0881]

[0882]

[0883] overlap with the NMR solvent. Method L, 1.485

[0884] 581.2

[0885] 1H NMR (500 MHz, DMSO-d6) 6 11.49 (s, 1H), 9.24 (s, 1H), 8.54 (d, J=1.8 Hz, 1H), 8.31 (d, J=6.0 Hz, 1H), 7.80 (s, 1H), 7.33 (d, J=11.4Hz, 1H), 6.66 - 6.31 (m, 1H), 5.09 - 4.98 (m, 2H), 4.92 (s, 1H), 3.44 (s, 3H), 3.09 (s, 2H), N-(4-(l-(2,2-difluoroethyl)-4-fluoro-2- 2.83 (s, 3H), 1.28 (s, 6H).

[0886] (2-hydroxy-2-methylpropyl)- 1H- benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-2-methyl-5- (methylsulfonyl)pyrimidine-4- carb oxami de

[0887] Method M, 1.29

[0888] 596.2

[0889] δ 8.86 (d, J=2.3 Hz, 1H), 8.54 - 8.41 (m, 2H), 8.18 (d, J=2.1 Hz, 1H), 7.96 (s, 1H), 7.80 - 7.75 (m, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 1H), 5.10 - 4.98 (m, 1H), N-(5-fluoro-4-(2-(2-hydroxy-2- 3.05 (s, 2H), 2.63 (s, 3H), 1.60 (d, methylpropyl)- 1 -i sopropyl- 1 H- J=6.9 Hz, 6H), 1.47 (s, 6H), 1.26 benzo[d]imidazol-6-yl)pyridin-2-yl)-5- (s, 6H). Protons missing due to (4-(2-hydroxypropan-2-yl)phenyl)-2- solvent suppression or exchange methylnicotinamide

[0890] or overlap with the NMR solvent.

[0891] Method L, 1.279

[0892] 593.1

[0893] 6 11.50 (s, 1H), 9.12 (s, 1H), 8.50 (s, 1H), 8.32 (d, J=6.0 Hz, 1H), 7.98 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.46 (d,. / =8,3 Hz, 1H), 6.70 - 6.39 (m, 1H), 5.45 - 5.27 (m, 1H), 4.94 (s, 1H), 4.11 (s, 3H), 3.41 (s, 3H), 3.17 - 3.10 (m, 1H), (R)-N-(4-(l -(1, 1 -difluoropropan-2-yl)- 3.08 - 2.98 (m, 1H), 1.71 (d, 2-(2-hydroxy-2-methylpropyl)-lH- J=7.1 Hz, 3H), 1.32 (s, 3H), 1.22 benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-2-methoxy-5- (s, 3H).

[0894] (methylsulfonyl)pyrimidine-4-

[0895]

[0896]

[0897] carb oxami de Method L, 1.311

[0898] 577.2

[0899] 6 11.47 (s, 1H), 9.24 (s, 1H), 8.50 (s, 1H), 8.32 (d, J=6.1 Hz, 1H), 7.98 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.47 (d,. / =8,3 Hz, 1H), 6.76 - 6.41 (m, 1H), 5.43 - 5.28 (m, 1H), 4.94 (s, 1H), 3.44 (s, 3H), 3.16 - 3.09 (m, 1H), 3.06 - 2.96 (R)-N-(4-(l -(1, 1 -difluoropropan-2-yl)- (m, 1H), 2.83 (s, 3H), 1.71 (d, 2-(2-hydroxy-2-methylpropyl)-lH- J=7.1 Hz, 3H), 1.32 (s, 3H), 1.22 benzo[d]imidazol-6-yl)-5- (s, 3H).

[0900] fluoropyridin-2-yl)-2-methyl-5- (methylsulfonyl)pyrimidine-4- carb oxami de

[0901] Method M, 1.35

[0902] 512.4

[0903] 6 11.38 (s, 1H), 8.77 (s, 1H), 8.54 (s, 1H), 8.42 (br d, J=5.9 Hz, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 8.01 (br d, J=8.4 Hz, 1H), 7.80 (br d, J=9.0 Hz, 1H), 7.31 - 7.01 (m, 1H), 5.36 - 5.10 (m, 1H), 3.34 (s, 1H), 2.64 (s, 3H), 1.69 (br d, 5-(difluoromethyl)-N-(5-fluoro-4-(2- J=6.8 Hz, 6H), 1.31 (s, 6H). (2-hydroxy-2-methylpropyl)- 1 - Protons missing due to solvent isopropyl-lH-benzo[d]imidazol-6- suppression or exchange or yl)pyri din-2 -yl)-2-methylnicotinamide overlap with the NMR solvent.

[0904] Method M, 1.14

[0905] 601.4

[0906] δ 8.41 (d, J=2.2 Hz, 1H), 8.21 (s, 1H), 8.17 (br d, J=5.3 Hz, 1H), 7.82 (br s, 1H), 7.67 (s, 1H), 7.52 (br d, J=8.4 Hz, 1H), 7.21 (br d, J=7.9 Hz, 1H), 4.03 - 3.85 (m, 1H), 2.81 - 2.68 (m, 2H), 2.37 - 2.32 (m, 2H), 2.21 - 2.07 (m, 2H), 1.97 (s, 3H), 1.84 - 1.69 (m, 2H), (R)-N-(4-( 1 -(1 -cyclopropylethyl)-2-(2- 1.62 (br s, 4H), 1.42 - 1.37 (m, hydroxy-2-methylpropyl)- 1H- 5H), 1.03 (s, 3H), 0.97 (s, 3H), benzo[d]imidazol-6-yl)-5- 0.53 - 0.41 (m, 1H), 0.38 - 0.31 fluoropyridin-2-yl)-5 -(4-hydroxy- 1 - (m, 1H), 0.21 - 0.10 (m, 1H), 0.08 methylpiperidin-4-yl)-2- - -0.03 (m, 1H). Protons missing methylnicotinamide due to solvent suppression or exchange or overlap with the

[0907]

[0908]

[0909] NMR solvent. Method M, 1.06

[0910] 601.3

[0911] 6 11.16 (s, 1H), 8.66 (s, 1H), 8.52 - 8.42 (m, 2H), 7.92 (s, 1H), 7.82 (s, 1H), 7.78 (d,. / =8,5 Hz, 1H), 7.49 (br d, J=8.2 Hz, 1H), 5.26 - 5.03 (m, 1H), 3.08 (s, 2H), 2.57 (s, 5H), 2.43 - 2.31 (m, 2H), 2.21 (s, 3H), 2.18 - 2.09 (m, 4H), 2.06 N-(4-(l-cyclopentyl-2-(2-hydroxy-2- - 1.97 (m, 4H), 1.81 - 1.71 (m, methylpropyl)-lH-benzo[d]imidazol-6- 2H), 1.67 - 1.60 (m, 2H), 1.25 (s, yl)-5-fluoropyri din-2 -yl)-5-(4-hydroxy- 6H). Protons missing due to 1 -methylpiperidin-4-yl)-2- solvent suppression or exchange methylnicotinamide or overlap with the NMR solvent.

[0912] Method M, 1.22

[0913] 585

[0914] 6 11.17 (s, 1H), 8.66 (d, J=1.5 Hz, 1H), 8.48 (s, 1H), 8.42 (br d,. / =6,7 Hz, 1H), 8.04 (s, 1H), 7.93 (d, J=1.9 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.50 (br d, J=8.9 Hz, 1H), 5.04 (s, 1H), 5.00 - 4.93 (m, N-(5-fluoro-4-(l-isopropyl-2-(2,2,2- 1H), 4.28 (q, J=10.8 Hz, 2H), trifluoroethyl)-lH-benzo[d]imidazol-6- 2.63 - 2.55 (m, 5H), 2.43 - 2.31 yl)pyridin-2-yl)-5-(4-hydroxy- 1 - (m, 2H), 2.21 (s, 3H), 2.06 - 1.96 methylpiperidin-4-yl)-2- (m, 2H), 1.77 - 1.53 (m, 8H). methylnicotinamide

[0915] Method M, 1.09

[0916] 584.2

[0917] 6 11.27 - 11.01 (m, 1H), 8.65 (s, 1H), 8.47 (s, 1H), 8.42 (br d, J=5.6 Hz, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.47 (br d,. / =8,2 Hz, 1H), 5.04 - 4.92 (m, 1H), 3.30 (s, 2H), 2.71 - 2.63 (m, 2H), 2.56 (s, 3H), 2.49 - N-(4-(2-(2-cyano-2-methylpropyl)- 1 - 2.42 (m, 2H), 2.28 (s, 3H), 2.10 - isopropyl-lH-benzo[d]imidazol-6-yl)- 1.99 (m, 2H), 1.72 - 1.65 (m, 2H), 5-fluoropyridin-2-yl)-5-(4-hydroxy-l- 1.63 (br d, J=6.8 Hz, 6H), 1.55 (s, methylpiperidin-4-yl)-2- 6H). Protons missing due to methylnicotinamide solvent suppression or exchange

[0918]

[0919]

[0920] or overlap with the NMR solvent. F Method M, 1.79

[0921] 602.9

[0922] / / =\

[0923] N / — X / / N8 9.10 (s, 1H), 8.49 (s, 1H), 8.29

[0924] (d, J=6. Q Hz, 1H), 8.03 (s, 1H), \ — 0 - / abs 7.87 (d, J=8.4 Hz, 1H), 7.53 (br d,. / =8,2 Hz, 1H), 6.72 - 6.42 (m, \N=\ / / 'F

[0925] 1H), 5.35 - 5.16 (m, 1H), 4.37 - 4.17 (m, 2H), 4.09 (s, 2H), 3.38 (s, 2H), 1.72 (br d,. / =7,0 Hz, 3H). (R)-N-(4-(l -(1, 1 -difluoropropan-2-yl)- 2-(2,2,2-trifluoroethyl)- 1 H- Protons missing due to solvent suppression or exchange or benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-2-methoxy-5- overlap with the NMR solvent. (methylsulfonyl)pyrimidine-4- carb oxami de

[0926] F Method L, 1.691

[0927] / =\ 587.1

[0928] N / — X / / N6 11.48 (s, 1H), 9.24 (s, 1H), 8.52

[0929] (d, J=1.9 Hz, 1H), 8.32 (d, J=6.1 \ — Q / abs Hz, 1H), 8.07 (s, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.5 Hz,N=\ / X-F

[0930] 1H), 6.76 - 6.50 (m, 1H), 5.37 - 5.21 (m, 1H), 4.44 - 4.21 (m, 2H), 3.44 (s, 3H), 2.83 (s, 3H), 1.73 (d, (R)-N-(4-(l -(1, 1 -difluoropropan-2-yl)- J=7.1 Hz, 3H).

[0931] 2-(2,2,2-trifluoroethyl)- 1 H- benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-2-methyl-5- (methylsulfonyl)pyrimidine-4- carb oxami de

[0932] Method C, 1.71

[0933] 552.1

[0934] F

[0935] 8.68 (d,.7=4,7 Hz, 1H), 8.22 (s, 1H), 8.19 (d, <7=8.0 Hz, 1H), 8.12 (d, J=6. Q Hz, 1H), 7.82 (s, 1H), HN 7.60 (dd, <7=8.0, 4.8 Hz, 1H), 7.53 \ Q Jabs (d, <7=8.2 Hz, 1H), 7.21 (br d,N=\ <7=8.2 Hz, 1H), 4.05 - 3.84 (m, z J^SO2CH3V1H), 3.17 (s, 2H), 2.80 - 2.70 (m,

[0936] 2H), 1.53 - 1.29 (m, 4H), 1.02 (s, (R)-N-(4-(l-(l-cyclopropylethyl)-2-(2- 3H), 0.97 (s, 3H), 0.54 - 0.40 (m, hydroxy-2-methylpropyl)- 1H- 1H), 0.40 - 0.27 (m, 1H), 0.18 - benzo[d]imidazol-6-yl)-5- 0.09 (m, 1H), 0.09 - -0.02 (m, fluoropyri din-2 -yl)-3- 1H). Protons missing due to (methylsulfonyl)picolinamide

[0937] solvent suppression or exchange

[0938]

[0939] or overlap with the NMR solvent. Method C, 1.67

[0940] 535.1

[0941] 6 11.33 (s, 1H), 8.92 (br d, J=4.5 Hz, 1H), 8.46 (s, 1H), 8.43 (br d, J=8.1 Hz, 1H), 8.34 (br d,. / =6,0 Hz, 1H), 7.99 (s, 1H), 7.85 - 7.79 (m, 2H), 7.46 (br d, J=8.2 Hz, 1H), 5.02 - 4.88 (m, 1H), 3.40 (s, N-(4-(2-(2-cyano-2-methylpropyl)- 1 - 3 H), 3.28 (s, 2H), 1.62 (br d, isopropyl-lH-benzo[d]imidazol-6-yl)-. / =6,8 Hz, 6H), 1.54 (s, 6H).

[0942] 5 -fluoropyri din-2 -y 1 ) -3 - Method C, 1.71

[0943] 552.1

[0944] δ 8.93 (br d, J=4.7 Hz, 1H), 8.47 (s, 1H), 8.43 (br d, J=8.2 Hz, 1H), 8.40 (br d, J=6.0 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.78 (br d, J=8.4 Hz, 1H), 7.50 (br d, J=8.6 Hz, 1H), 5.21 - 5.11 (m, 1H), 3.56 (br s, 2H), 3.08 (s, 2H), 2.20 - 2.06 N-(4-(l-cyclopentyl-2-(2-hydroxy-2- (m, 4H), 2.05 - 1.95 (m, 2H), 1.85 methylpropyl)- 1 H-benzo [d]imidazol -6- - 1.71 (m, 2H), 1.24 (s, 6H). yl)-5-fluoropyridin-2-yl)-3- Protons missing due to solvent (methylsulfonyl)picolinamide suppression or exchange or overlap with the NMR solvent. Method L, 1.201

[0945] 554.2

[0946] 6 11.33 (s, 1H), 8.94 (dd, J=4.8, 1.5 Hz, 1H), 8.50 (d, J=2.1 Hz, 1H), 8.44 (dd, J=8.1, 1.5 Hz, 1H), 8.41 (d, J=6.1 Hz, 1H), 8.07 (br s, 1H), 7.85 (dd, J=8.0, 4.9 Hz, 1H), 7.80 (br d, J=8.3 Hz, 1H), 7.52 (br d,. / =6,7 Hz, 1H), 5.69 - 5.54 (m, 1H), 4.90 - 4.72 (m, 1H), 4.40 (R)-N-(5-fluoro-4-(2-(2 -hydroxy -2- - 4.27 (m, 1H), 4.17 - 4.06 (m, methylpropyl)- 1 -(tetrahy drofuran-3 - 1H), 4.00 - 3.88 (m, 1H), 3.77 - yl)-lH-benzo[d]imidazol-6-yl)pyridin- 3.65 (m, 1H), 3.45 - 3.43 (m, 3H), 2-yl)-3-(methylsulfonyl)picolinamide 3.19 - 3.06 (m, 2H), 2.58 - 2.53 (m, 1H), 2.28 - 2.18 (m, 1H), 1.28

[0947]

[0948]

[0949] (s, 3H), 1,23 (s, 3H). Method P, 1.379

[0950] 554

[0951] 1H NMR (400 MHz, Methanol- d4) δ 9.22 (s, 1H), 8.67-8.52 (m, 3H), 8.42 (s, 1H), 8.35 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.87 (d, J= 8.4 Hz, 1H), 4.35-4.30 (m, 1H), 4.04 (s, 3H), 2.76 (s, 3H), (R)-N-(4-(2-acetamido-l-(l- 2.44 (s, 3H), 1.84 (d, J= 6.8 Hz, cyclopropylethyl)-lH- 3H), 1.83-1.82 (m, 1H), 0.96-0.93 benzo[d]imidazol-6-yl)-5- (m, 1H), 0.73-0.71 (m, 1H), 0.70- fluoropyridin-2-yl)-2-methyl-5-(l- 0.63 (m, 1H), 0.46-0.40 (m, 1H).

[0952] methyl-lH-l,2,4-triazol-3- Protons missing due to solvent yl)nicotinamide suppression or exchange or overlap with the NMR solvent.

[0953] Method Q, 1.283

[0954] 561

[0955] 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 9.12 (s, 1H), 8.62 (s, 1H), 8.53-8.33 (m, 3H), 7.83 (s, 1H), 7.30 (d, J = 11.6 Hz, 1H), 5.13-5.03 (m, 1H), 4.82 (s, 1H), N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- 3.96 (s, 3H), 3.07 (s, 2H), 2.64 (s, 2-m ethylpropyl)- 1 -i sopropyl- 1 H- 3H), 1.60 (d, J = 8.0 Hz, 6H), benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 1.27 (s, 6H).

[0956] methyl-5-(l-methyl-lH-l,2,4-triazol-3- yl)nicotinamide

[0957] Method L, 1.525

[0958] 6 11.50 (s, 1H), 9.24 (s, 1H), 8.53 (d, J=1.9 Hz, 1H), 8.30 (d, J=6.1 Hz, 1H), 7.83 (s, 1H), 7.34 (d, J=11.2 Hz, 1H), 6.76 - 6.36 (m, 1H), 5.50 - 5.33 (m, 1H), 4.89 (s, 1H), 3.44 (s, 3H), 3.17 - 3.11 (m, 1H), 3.08 - 3.03 (m, 1H), 2.83 (s, 3H), 1.71 (d, J=7.4 Hz, 3H), 1.33 N-(4-(l -( 1, 1 -difluoropropan-2-yl)-4- (s, 3H), 1.22 (s, 3H).

[0959] fluoro-2-(2 -hydroxy -2 -methylpropyl)- lH-benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-2-methyl-5- (methylsulfonyl)pyrimidine-4-

[0960]

[0961]

[0962] carb oxami de F F Method M, 1.69

[0963] / =\ δ 9.22 (s, 1H), 8.50 (s, 1H), 8.28N / \\ / / ~N1 (br d, J=5.5 Hz, 1H), 7.81 (s, 1H), )= / \ X b" 7.33 (br d, J=11.5 Hz, 1H), 6.67 - HN

[0964] 6.35 (m, 1H), 5.49 - 5.32 (m, 1H), ^0 — \

[0965] N=Z / Z~~F 3.45 - 3.38 (m, 1H), 3.16 - 3.10 (m, 1H), 3.07 - 3.02 (m, 1H), 2.81 (s, 2H), 1.69 (br d, J=7.1 Hz, 3H), 1.32 (s, 3H), 1.21 (s, 3H). Protons N-(4-(l -( 1, 1 -difluoropropan-2-yl)-4- fluoro-2-(2 -hydroxy -2 -methylpropyl)- missing due to solvent suppression or exchange or lH-benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-2-methyl-5- overlap with the NMR solvent. (methylsulfonyl)pyrimidine-4- carb oxami de

[0966] F F Method L, 1.78

[0967] 6 11.51 (s, 1H), 9.24 (s, 1H), 8.54N / - NX / / N(d, J=1.8 Hz, 1H), 8.30 (d, J=6.0 Hz, 1H), 7.93 (s, 1H), 7.42 (d, J=11.2Hz, 1H), 6.86 - 6.48 (m, ko (

[0968] N1H), 5.44 - 5.20 (m, 1H), 4.48 - =< / z~~-F

[0969] 4.27 (m, 2H), 3.43 (s, 3H), 2.83 (s, 3H), 1.73 (d,. / =7,2 Hz, 3H). N-(4-(l -( 1, 1 -difluoropropan-2-yl)-4- fluoro-2-(2,2,2-trifluoroethyl)-lH- benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-2-methyl-5- (methylsulfonyl)pyrimidine-4- carb oxami de

[0970] F F Method L, 1.774

[0971] 605.2

[0972] 6 11.51 (s, 1H), 9.24 (s, 1H), 8.54 (d, J=1.8 Hz, 1H), 8.30 (d, J=6. Q HN N'-'V / '^ F

[0973] Hz, 1H), 7.93 (s, 1H), 7.42 (d, kO (

[0974] NJ=11.2Hz, 1H), 6.77 - 6.48 (m, =< / / " F

[0975] 1H), 5.45 - 5.26 (m, 1H), 4.47 - 4.26 (m, 2H), 3.43 (s, 3H), 2.83 (s, 3H), 1.73 (d, J=7.1 Hz, 3H). N-(4-(l -( 1, 1 -difluoropropan-2-yl)-4- fluoro-2-(2,2,2-trifluoroethyl)-lH- benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-2-methyl-5- (methylsulfonyl)pyrimidine-4-

[0976]

[0977] carb oxami de Method, 1.5

[0978] 612.2

[0979] 6 11.52 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.37 (d, J=5.9 Hz, 1H), 8.29 (br s, 1H), 8.01 - 7.61 (m, 2H), 7.19 (s, 1H), 5.30 (br d, J=6.9 Hz, 1H), 4.58 - 4.50 (m, 1H), 4.41 - 4.33 (m, 1H), 4.01 (s, 3H), 3.83 (d,.7=8.5 Hz, 1H), 3.73 (d, 7=8.5 Hz, 1H), 3.30 (br d, N-(4-(l-(4,4-dimethyltetrahydrofuran- 7=15.0 Hz, 1H), 3.18 (br d, 7=8.5 3-yl)-2-(2-hydroxy-2-methylpropyl)- Hz, 1H), 1.34 (s, 6H), 1.25 (s, lH-benzo[d]imidazol-6-yl)-5- 3H), 0.65 (s, 3H). Protons fluoropyridin-2-yl)-2-methoxy-5- missing due to solvent (methylsulfonyl)isonicotinamide suppression or exchange or overlap with the NMR solvent. Method N, 1.8

[0980] 591.2

[0981] δ 9.12 (s, 1H), 8.51 (s, 1H), 8.28 (d, 7=6.1 Hz, 1H), 7.95 (s, 1H), 7.49 (s, 1H), 5.15 - 5.03 (m, 1H), 4.91 (s, 1H), 4.10 (s, 3H), 3.39 (s, 2H), 3.08 (s, 2H), 1.59 (br d, 7=6.9 Hz, 6H), 1.26 (s, 6H). N-(4-(4-chloro-2-(2 -hydroxy -2- Protons missing due to solvent suppression or exchange or methylpropyl)- 1 -i sopropyl- 1 H- benzo[d]imidazol-6-yl)-5- overlap with the NMR solvent. fluoropyridin-2-yl)-2-methoxy-5- (methylsulfonyl)pyrimidine-4- carb oxami de

[0982] Method C, 1.63

[0983] 580.1

[0984] δ 8.96 - 8.88 (m, 1H), 8.50 (s, 1H), 8.46 - 8.41 (m, 1H), 8.33 (br d, J=6.0 Hz, 1H), 7.91 - 7.69 (m, 2H), 7.34 (br d, 7=10.9 Hz, 1H), 6.70 - 6.32 (m, 1H), 5.48 - 5.32 (m, 1H), 4.95 (s, 1H), 3.42 (s, 1H), 3.17 - 3.11 (m, 1H), 3.10 - N-(4-(l -( 1, 1 -difluoropropan-2-yl)-4- 2.99 (m, 1H), 1.70 (br d, 7=6.8 fluoro-2-(2 -hydroxy -2 -methylpropyl)- Hz, 3H), 1.32 (s, 3H), 1.22 (s, lH-benzo[d]imidazol-6-yl)-5- 3H). Protons missing due to fluoropyri din-2 -yl)-3- solvent suppression or exchange (methylsulfonyl)picolinamide

[0985]

[0986]

[0987] or overlap with the NMR solvent. Method M, 1.37

[0988] 562.2

[0989] δ 8.97 - 8.89 (m, 1H), 8.48 (s, 1H), 8.44 (br d, J=8.1 Hz, 1H), 8.36 (br d, J=6.0 Hz, 1H), 7.98 (s, 1H), 7.87 - 7.82 (m, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.48 (br d, J=8.4 Hz, 1H), 6.76 - 6.31 (m, 1H), 5.47 - 5.29 (m, 1H), 4.98 (s, 1H), (R)-N-(4-( 1 -(1, 1 -difluoropropan-2-yl)- 3.17 - 3.08 (m, 1H), 3.06 - 2.98 2-(2-hydroxy-2-methylpropyl)-lH- (m, 1H), 1.71 (br d, J=7.0 Hz, benzo[d]imidazol-6-yl)-5- 3H), 1.31 (s, 3H), 1.22 (s, 3H). fluoropyri din-2 -yl)-3- Protons missing due to solvent (methylsulfonyl)picolinamide suppression or exchange or overlap with the NMR solvent.

[0990] Method M, 1.08

[0991] 543.3

[0992] 6 11.06 (s, 1H), 8.46 (s, 1H), 8.29 (s, 1H), 8.18 (br d, J=5.7 Hz, 1H), 8.04 - 7.96 (m, 1H), 7.82 (s, 1H), 7.78 - 7.66 (m, 1H), 7.46 (br d, J=6.3 Hz, 1H), 5.05 - 4.85 (m, (S)-N-(5-fluoro-4-(2-(2-hydroxy-2- 1H), 4.38 - 4.18 (m, 1H), 3.04 (br methylpropyl)- 1 -i sopropyl- 1 H- s, 1H), 2.50 (s, 3H), 2.38 (s, 3H), benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 2.32 (s, 3H), 1.44 (br d, J=6.6 Hz, methyl-5-(3-(methylamino)but-l-yn-l- 6H), 1.34 (d, J=6.7 Hz, 3H), 1.07 yl)nicotinamide (br s, 6H).

[0993] Method, 1.07

[0994] 543.5

[0995] 8 11.06 (s, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.40 (br d, J=5.9 Hz, 1H), 7.96 (br d, J=3.7 Hz, 2H), 7.82 (br d, J=8.2 Hz, 1H), 7.46 (br d, J=8.1 Hz, 1H), 5.10 - 4.97 (m, (R)-N-(5-fluoro-4-(2-(2 -hydroxy -2- 1H), 3.91 - 3.76 (m, 1H), 3.04 (s, methylpropyl)- 1 -i sopropyl- 1 H- 2H), 2.59 (s, 3H), 2.47 (s, 3H), benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 1.91 (s, 2H), 1.60 (br d, J=6.7 Hz, methyl-5 -(3 -(methylamino)but- 1 -yn- 1 - 6H), 1.39 (d, J=6.6 Hz, 3H), 1.26

[0996] (s, 6H).

[0997]

[0998] Method M, 1.44

[0999] 600

[1000] δ 9.00 - 8.90 (m, 1H), 8.51 (s, 1H), 8.43 - 8.36 (m, 2H), 7.90 (s, 1H), 7.87 - 7.79 (m, 1H), 7.34 (br d, J=11.0 Hz, 1H), 5.68 - 5.56 (m, 1H), 4.39 - 4.28 (m, 1H), 4.10 (br d, J=10.8 Hz, 1H), 3.98 - 3.88 (m, 2H), 3.77 - 3.66 (m, 1H), 3.22 - 3.13 (m, 1H), 3.13 - 3.07 (m, 1H), (R)-N-(5-fluoro-4-(4-fluoro-2-(2- 2.24 - 2.13 (m, 1H), 1.28 (s, 3H), hydroxy-2-methylpropyl)- 1 - 1.25 - 1.18 (m, 9H). Protons (tetrahy drofuran-3 -yl)- 1 H- missing due to solvent benzo[d]imidazol-6-yl)pyridin-2-yl)-3- suppression or exchange or (isopropylsulfonyl)picolinamide overlap with the NMR solvent.

[1001] Method S, 0.597

[1002] 582

[1003] 1H NMR (400 MHz, Methanol- d4) δ 9.32 (s, 1H), 8.55 (d, J= 6.0 Hz, 1H), 8.52 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.00-7.97 (m, 1H), 7.95-7.93 (m, 1H), 5.14-5.08 (m, 1H), 4.30 (t, J= 10.8 Hz, 1H), 4.18 (dd, J= 10.8, 4.4 Hz, 1H), (R)-N-(5-fluoro-4-(2-(2 -hydroxy -2- 4.03 (d, J= 11.2 Hz, 1H), 3.79- methylpropyl)- 1 -(tetrahydro-2H-pyran- 3.73 (m, 1H), 3.51 (s, 3H), 3.46 3-yl)-lH-benzo[d]imidazol-6- (s, 2H), 2.91 (s, 3H), 2.69-2.62 yl)pyridin-2-yl)-2-methyl-5- (m, 1H), 2.34-2.30 (m, 1H), 2.01- (methylsulfonyl)pyrimidine-4- 1.95 (m, 2H), 1.44 (s, 3H), 1.41 carb oxami de (s, 3H). Protons missing due to solvent suppression or exchange or overlap with the NMR solvent.

[1004] Method T, 0.619

[1005] 555

[1006] 1H NMR (400 MHz, Methanol- d4) δ 9.27 (s, 1H), 8.51 (d, J= 6.0 Hz, 1H), 8.45 (d, J= 2.0 Hz, 1H), 8.39 (s, 1H), 8.01-7.97 (m, 1H), 7.93-7.91 (m, 1H), 5.36-5.29 (m, 1H), 3.68 (q, J = 7.6 Hz, 2H), 3.43 (s, 2H), 2.91 (s, 3H), 1.83 (d, 5-(ethylsulfonyl)-N-(5-fluoro-4-(2-(2- J= 6.8 Hz, 6H), 1.43 (s, 6H), hydroxy-2-methylpropyl)- 1 -isopropyl- 1.34 (t, J= 7.6 Hz, 3H). Protons lH-benzo[d]imidazol-6-yl)pyridin-2- missing due to solvent yl)-2-methylpyrimidine-4-carboxamide

[1007] suppression or exchange or

[1008]

[1009]

[1010] overlap with the NMR solvent. Method U, 1.305

[1011] 581

[1012] 1H NMR (400 MHz, Methanol- d4) δ 9.31 (s, 1H), 8.47 (d, J= 6.0 Hz, 1H), 8.38 (d, J= 2.4 Hz, 1H), 8.05 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 5.17-5.10 (m, 1H), 3.64 (d, J= 7.2 Hz, 2H), 3.16 (s, 2H), 2.92 (s, 5-((cyclopropylmethyl)sulfonyl)-N-(5- 3H), 1.72 (d, J = 6.8 Hz, 6H), fluoro-4-(2-(2-hydroxy-2- 1.38 (s, 6H), 1.12 (m, 1H), 0.60- methylpropyl)- 1 -i sopropyl- 1 H- 0.59 (m, 2H), 0.31-0.30 (m, 2H). benzo[d]imidazol-6-yl)pyridin-2-yl)-2- Protons missing due to solvent methylpyrimidine-4-carboxamide

[1013] suppression or exchange or overlap with the NMR solvent.

[1014] Method M, 1.86

[1015] 551.3

[1016] 6 11.13 (s, 1H), 8.48 (s, 1H), 8.43 (br d, J=6.0 Hz, 1H), 8.34 (d, J=2.9 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.65 (d, J=2.8 Hz, 1H), 7.46 (br d, J=8.3 Hz, 1H), 6.58 - 6.24 (m, 1H), 5.08 - 4.91 (m, 1H), 4.46 (td, J=14.6, N-(4-(2-(2-cyano-2-methylpropyl)- 1 - 3.4 Hz, 2H), 3.31 (s, 1H), 1.63 (d, isopropyl-lH-benzo[d]imidazol-6-yl)- J=6.9 Hz, 6H), 1.56 (s, 6H).

[1017] 5 -fluoropyri din-2 -yl)-5 -(2,2- Protons missing due to solvent difluoroethoxy)-2-methylnicotinamide suppression or exchange or overlap with the NMR solvent.

[1018] Method M, 1.17

[1019] 570.1

[1020] 6 11.12 (s, 1H), 8.46 (s, 1H), 8.43 (br d, J=6.0 Hz, 1H), 8.32 (d, J=2.8 Hz, 1H), 8.03 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.64 (d, J=2.9 Hz, 1H), 7.49 (br d, J=8.5 Hz, 1H), 6.54 - 6.23 (m, 1H), 5.66 - 5.50 (m, 1H), 4.45 (td, J=14.7, 3.2 Hz, 2H), 4.34 - 4.24 (m, 1H), 4.08 (br dd, J=10.4, 2.7 Hz, 1H), (R)-5-(2,2-difluoroethoxy)-N-(5- 3.97 - 3.87 (m, 1H), 3.60 (s, 2H), fluoro-4-(2-(2-hydroxy-2- 3.20 - 3.10 (m, 1H), 3.10 - 3.01 methylpropyl)- 1 -(tetrahy drofuran-3 - (m, 1H), 2.22 - 2.10 (m, 1H), 1.26 yl)-lH-benzo[d]imidazol-6-yl)pyridin- (s, 3H), 1.21 (s, 3H). Protons 2-yl)-2-methylnicotinamide missing due to solvent suppression or exchange or

[1021]

[1022] overlap with the NMR solvent. Method, 1.05

[1023] F 550.2

[1024] / =\ δ 8.46 (br d, J=18.1 Hz, 2H), 8.40N / — \\ / / "N(br d, J=5.8 Hz, 1H), 7.95 (s, 1H),

[1025] '1 _

[1026] HN 7.81 - 7.66 (m, 2H), 7.48 - 7.41 >° A6h(m, 1H), 5.14 - 4.96 (m, 1H), 4.39ho / =\x(br d, J=2.9 Hz, 1H), 3.53 (br s, ) — 4 -7 — 1H), 3.05 (s, 2H), 2.51 (br d, HO— 4— N

[1027] J=1.6 Hz, 5H), 1.59 (d, J=6.9 Hz, 5-(l,2-dihydroxy-2-methylpropyl)-N- 6H), 1.25 (s, 6H), 1.12 (s, 3H), (5-fluoro-4-(2-(2-hydroxy-2- 0.99 (s, 3H). Protons missing due methylpropyl)- 1 -i sopropyl- 1 H- to solvent suppression or benzo[d]imidazol-6-yl)pyridin-2-yl)-2- exchange or overlap with the methylnicotinamide NMR solvent.

[1028] Method, 1.18

[1029] F 561.3

[1030] 6 11.26 (s, 1H), 8.69 (s, 1H), 8.49 (s, 1H), 8.38 (br d, J=5.0 Hz, 1H), ). "p Ql

[1031] 8.05 (s, 1H), 7.83 (s, 1H), 7.31 (br d, J=ll.l Hz, 1H), 5.17 - 4.99HI X -x \ V OrH (m, 1H), 4.56 - 4.44 (m, 1H), 3.55 (S)-N-(5-fluoro-4-(4-fluoro-2-(2- - 3.42 (m, 2H), 2.72 (br s, 3H), hydroxy-2-methylpropyl)- 1 -isopropyl- 2.61 (s, 3H), 1.66 - 1.51 (m, 9H), lH-benzo[d]imidazol-6-yl)pyridin-2- 1.27 (s, 6H). Protons missing due yl)-2-methyl-5-(3 -(methylamino)but- 1 - to solvent suppression or

[1032] yn- 1 -yl)nicotinamide exchange or overlap with the NMR solvent.

[1033] Method W, 0.668

[1034] F 566

[1035] 1H NMR (400 MHz, DMSO-t / e) 6 V2O FT

[1036] 11.36 (s, 1H), 8.75 (s, 1H), 8.52 (s, 1H), 8.43 (d, J= 6.0 Hz, 1H), n 1HCF3

[1037] 8.28 (s, 1H), 8.06 (s, 1H), 7.88 (d, J= 8.4 Hz, 1H), 7.54 (d, J = 8.0 5 -(3 -amino-3-methylbut- 1 -yn- 1 -yl)-N- Hz, 1H), 6.62 (td, J= 54.8, 3.6 (4-(l -( 1, 1 -difluoropropan-2-yl)-2- Hz, 1H), 5.38-5.20 (m, 1H), 4.43- (2,2,2-trifluoroethyl)-lH- 4.21 (m, 2H), 2.66 (s, 3H), 1.73 benzo[d]imidazol-6-yl)-5- (d, J= 7.2 Hz, 3H), 1.52 (s, 6H). fluoropyridin-2-yl)-2- Protons missing due to solvent methylnicotinamide

[1038] suppression or exchange or

[1039]

[1040] overlap with the NMR solvent. Method M, 1.74

[1041] 625.1

[1042] δ 9.10 - 9.08 (m, 1H), 8.52 (s, 1H), 8.29 (br d, J=5.6 Hz, 1H), 7.82 (s, 1H), 7.33 (br d, J=11.3 Hz, 1H), 6.71 - 6.38 (m, 1H), 5.45 - 5.35 (m, 1H), 4.13 - 4.07 (m, 3H), 3.18 - 3.12 (m, 1H), 3.08 - 3.03 (m, 1H), 1.70 (d, J=7.0 Hz, N-(4-(l -( 1, 1 -difluoropropan-2-yl)-4- 3H), 1.32 (s, 3H), 1.23 - 1.21 (m, fluoro-2-(2 -hydroxy -2 -methylpropyl)- 3H), 1.21 - 1.18 (m, 3H). Protons lH-benzo[d]imidazol-6-yl)-5- missing due to solvent fluoropyridin-2-yl)-5-(ethylsulfonyl)-2- suppression or exchange or methoxypyrimidine-4-carboxamide

[1043] overlap with the NMR solvent. Method C, 1.34

[1044] 606.1

[1045] 6 11.20 (s, 1H), 8.51 (s, 1H), 8.47 (d, J=1.9 Hz, 1H), 8.39 (br d, J=5.6 Hz, 1H), 7.83 (s, 1H), 7.30 (br d, J=11.5 Hz, 1H), 5.17 - 4.99 (m, 1H), 4.61 - 4.41 (m, 2H), 3.25 5-cyano-6-(3- (br s, 2H), 3.09 (s, 2H), 2.84 (br s, (dimethylamino)propoxy)-N-(5-fluoro- 6H), 2.62 (d, J=2.1 Hz, 3H), 2.28 4-(4-fluoro-2-(2-hydroxy-2- - 2.11 (m, 2H), 1.67 - 1.51 (m, methylpropyl)- 1 -i sopropyl- 1 H- 6H), 1.28 (s, 6H). Protons benzo[d]imidazol-6-yl)pyridin-2-yl)-2- missing due to solvent methylnicotinamide suppression or exchange or overlap with the NMR solvent. Method N, 1.67

[1046] 617.2

[1047] δ 9.10 (s, 1H), 8.53 (s, 1H), 8.35 (br d, J=5.9 Hz, 1H), 7.90 (s, 1H), 7.34 (brd, J=11.1 Hz, 1H), 5.71 - 5.53 (m, 1H), 4.36 - 4.28 (m, 1H), 4.11 (s, 3H), 4.09 - 4.05 (m, 1H), 3.98 - 3.89 (m, 1H), 3.75 - 3.66 (m, 1H), 3.56 - 3.47 (m, 1H), 3.19 - 3.13 (m, 1H), 3.13 - 3.05 (m, (R)-5-(ethylsulfonyl)-N-(5-fluoro-4-(4- 1H), 2.25 - 2.13 (m, 1H), 1.28 (s, fluoro-2-(2 -hydroxy -2 -methylpropyl)- 3H), 1.23 (br s, 3H), 1.23 - 1.19 1 -(tetrahydrofuran-3 -yl)- 1H- (m, 3H). Protons missing due to benzo[d]imidazol-6-yl)pyridin-2-yl)-2- solvent suppression or exchange methoxypyrimidine-4-carboxamide

[1048] or overlap with the NMR solvent.

[1049]

[1050]

[1051] Method C, 1.33

[1052] 581.3

[1053] δ 10.61 (s, 1H), 8.50 - 8.37 (m, 2H), 8.27 (br s, 1H), 7.82 (br s, 1H), 7.44 (br s, 1H), 7.28 (br s, 1H), 5.16 - 4.99 (m, 1H), 4.24 (br s, 2H), 3.26 (br d, J=6.7 Hz, 2H), 5-(3-(dimethylamino)propoxy)-N-(5- 3.07 (br s, 2H), 2.83 (br s, 6H), fluoro-4-(4-fluoro-2-(2-hydroxy-2- 2.69 (s, 3H), 2.16 (br s, 2H), 1.59 methylpropyl)- 1 -i sopropyl- 1 H- (br d, J=6.6 Hz, 6H), 1.26 (s, 6H). benzo[d]imidazol-6-yl)pyridin-2-yl)-3- Protons missing due to solvent methylpicolinamide suppression or exchange or overlap with the NMR solvent. Method M, 1.64

[1054] 556.2

[1055] 8 11.23 (s, 1H), 8.47 (s, 2H), 8.44 (br d, J=6.1 Hz, 1H), 8.03 (s, 1H), 7.82 (d, J=2.6 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.48 (br d, J=8.2 Hz, 1H), 7.46 - 7.13 (m, 1H), 5.66 - 5.51 (m, 1H), 4.83 (s, 1H), 4.35 - 4.26 (m, 1H), 4.08 (dd, J=10.1, 3.2 Hz, 1H), 3.97 - 3.86 (R)-5-(difluoromethoxy)-N-(5-fluoro- (m, 1H), 3.78 - 3.65 (m, 1H), 3.19 4-(2-(2-hydroxy-2-methylpropyl)- 1 - - 3.10 (m, 1H), 3.08 - 3.00 (m, (tetrahy drofuran-3 -yl)- 1 H- 1H), 2.56 (s, 3 H), 2.25 - 2.13 (m, benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 1H), 1.26 (s, 3H), 1.21 (s, 3H).

[1056] methylnicotinamide Proton missing due to solvent suppression or exchange or overlap with the NMR solvent. Method M, 1.6

[1057] 582.1

[1058] δ 8.92 (br s, 1H), 8.57 (br s, 1H), 8.42 (br d, J=7.9 Hz, 1H), 8.27 (br s, 1H), 7.87 - 7.80 (m, 1H), 7.66 (br s, 1H), 7.23 (br d, J=10.5 Hz, 1H), 6.61 - 6.30 (m, 1H), 5.12 - 4.91 (m, 2H), 3.08 (br s, N-(5-chloro-4-(l-(2,2-difluoroethyl)-4- 2H), 1.27 (s, 6H). Protons fluoro-2-(2 -hydroxy -2 -methylpropyl)- missing due to solvent lH-benzo[d]imidazol-6-yl)pyridin-2- suppression or exchange or

[1059]

[1060]

[1061] yl)-3-(methylsulfonyl)picolinamide overlap with the NMR solvent. Method M, 1.05

[1062] 476

[1063] δ 8.45 (s, 1H), 8.40 (s, 2H), 7.95 (s, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.42 (br d, J=7.6 Hz, 1H), 7.34 (s, 1H), 5.11 - 4.98 (m, 1H), 3.04 (s, 2H), 2.48 (s, 3H), 2.32 (s, 3H), N-(5-fluoro-4-(2-(2-hydroxy-2- 1.59 (br d, J=6.9 Hz, 6H), 1.25 (s, methylpropyl)- 1 -i sopropyl- 1 H- 6H). Protons missing due to benzo[d]imidazol-6-yl)pyridin-2-yl)- solvent suppression or exchange or overlap with the NMR solvent. Method M, 1.42

[1064] 8 11.38 (s, 1H), 8.53 (s, 1H), 8.37 (d, J=8.9 Hz, 1H), 8.34 - 8.29 (m, 2H), 7.98 (br d, J=8.5 Hz, 1H), 7.92 (s, 1H), 7.73 (br d, J=8.1 Hz, 1H), 7.59 (s, 1H), 7.37 (d, J=8.7 Hz, 1H), 5.25 - 5.16 (m, 1H), N-(5-fluoro-4-(2-(2-hydroxy-2- 3.81 (s, 3H), 3.35 (s, 2H), 1.67 methylpropyl)- 1 -i sopropyl- 1 H- (br d, J=6.8 Hz, 6H), 1.29 (s, 6H). benzo[d]imidazol-6-yl)pyridin-2-yl)-6- Protons missing due to solvent ((1 -methyl- IH-pyrazol -4-yl)oxy)-3- suppression or exchange or (methylsulfonyl)picolinamide overlap with the NMR solvent.

[1065] Method M, 1.09

[1066] 549.3

[1067] 6 11.02 (s, 1H), 8.33 (s, 1H), 8.22 (br d, J=5.8 Hz, 1H), 8.15 (d, J=2.7 Hz, 1H), 8.09 (s, 1H), 7.79 (br d, J=8.4 Hz, 1H), 7.53 (br d, J=8.5 Hz, 1H), 7.40 (d, J=2.7 Hz, 1H), 5.08 - 4.93 (m, 1H), 3.88 (s, 5-(2-amino-2-methylpropoxy)-N-(5- 2H), 3.11 (s, 1H), 2.32 (s, 3H), fluoro-4-(2-(2-hydroxy-2- 1.48 (br d, J=6.9 Hz, 6H), 1.16 (s, methylpropyl)- 1 -i sopropyl- 1 H- 6H), 1.10 (s, 6H). Protons benzo[d]imidazol-6-yl)pyridin-2-yl)-2- missing due to solvent methylnicotinamide suppression or exchange or

[1068]

[1069]

[1070] overlap with the NMR solvent. Method M, 1.2

[1071] 558.2

[1072] 6 11.16 (s, 1H), 8.48 (s, 1H), 8.42 (br d, J=6.0 Hz, 1H), 8.35 (d, 8.35 (d, J=2.7 Hz, 1H), 8.04 (s, 1H), 7.85

[1073] (d, J=8.5 Hz, 1H), 7.62 (d,.7=2,7 Hz, 1H), 7.50 (br d, J=8.4 Hz, \ CN

[1074] 1H), 5.07 - 4.91 (m, 1H), 4.08 (s, 5-(2-amino-2-methylpropoxy)-N-(4-(2- 2H), 3.36 (s, 1H), 3.17 (s, 1H), (2-cyano-2-methylpropyl)-l-isopropyl- 2.89 (s, 1H), 2.73 (s, 1H), 1.64 (d, lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-2-methylnicotinamide fluoropyridin-2-yl)-2- (s, 6H). Protons missing due to methylnicotinamide solvent suppression or exchange or overlap with the NMR solvent. Method M, 1.13

[1075] 575.2

[1076] F

[1077] 6 10.98 (s, 1H), 8.29 (br s, 1H), 8.18 (br s, 1H), 8.14 - 8.12 (m, 1H), 7.52 (br s, 1H), 7.36 (s, 1H), 4.41 - 4.14 (m, 1H), 3.85 (s, 2H), 3.33 - 3.19 (m, 1H), 3.10 - 2.97 H, N \ \\ \ OH

[1078] (m, 1H), 2.94 (s, 1H), 2.66 (s, 1H), 2.50 (s, 1H), 1.58 - 1.50 (m, (R)-5-(2-amino-2-methylpropoxy)-N- 1H), 1.47 (br d,.7=5,2 Hz, 3H), (4-(l-(l-cyclopropylethyl)-2-(2- 1.17 - 1.03 (m, 12H), 0.54 - 0.47 hydroxy-2-methylpropyl)- 1H- (m, 1H), 0.47 - 0.42 (m, 1H), 0.21 benzo[d]imidazol-6-yl)-5- - 0.15 (m, 1H), 0.15 - 0.09 (m, fluoropyridin-2-yl)-2- 1H). Protons missing due to methylnicotinamide

[1079] solvent suppression or exchange or overlap with the NMR solvent. Method M, 1.17

[1080] 575.3

[1081] F 6 11.22 (s, 1H), 8.53 (s, 1H), 8.45

[1082] (br d, J=5.7 Hz, 1H), 8.35 (d,.7=2,7 Hz, 1H), 8.06 (s, 1H), 8.00 HIST /

[1083] (d, J=8.5 Hz, 1H), 7.77 (br d, J=8.2 Hz, 1H), 7.60 (d,.7=2,5 Hz, 1H), 5.36 - 5.24 (m, 1H), 4.08 (s, X / 2H), 3.34 (s, 1H), 3.17 (s, 1H), 5-(2-amino-2-methylpropoxy)-N-(4-(l- 2.89 (s, 1H), 2.73 (s, 1H), 2.52 (s, cyclopentyl-2-(2-hydroxy-2- 3H), 2.26 - 2.16 (m, 4H), 2.08 - methylpropyl)-lH-benzo[d]imidazol-6- 1.99 (m, 2H), 1.84 - 1.74 (m, 2H), yl)-5-fluoropyridin-2-yl)-2- 1.35 (s, 6H), 1.29 (s, 6H). Protons methylnicotinamide missing due to solvent suppression or exchange or

[1084]

[1085] overlap with the NMR solvent. Method M, 1.03

[1086] 476.3

[1087] δ 11.08 (s, 1H), 8.46 (s, 1H), 8.42 (br d, J=5.7 Hz, 1H), 8.40 (br s, 1H), 7.96 (s, 1H), 7.76 (br d, J=8.2 Hz, 1H), 7.73 (s, 1H), 7.43 (br d, J=8.1 Hz, 1H), 5.04 (dt, J=13.9, 6.9 Hz, 1H), 3.05 (s, 2H), N-(5-fluoro-4-(2-(2-hydroxy-2- 2.54 (br s, 3H), 2.32 (s, 3H), 1.60 methylpropyl)- 1 -i sopropyl- 1 H- (br d, J=6.8 Hz, 6H), 1.26 (s, 6H). benzo[d]imidazol-6-yl)pyridin-2-yl)- Protons missing due to solvent 2,5-dimethylnicotinamide suppression or exchange or overlap with the NMR solvent. Method M, 1.41

[1088] δ 11.33 (s, 1H), 8.47 (s, 1H), 8.36 (d, J=8.8 Hz, 1H), 8.30 (d, J=5.8 Hz, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.58 (s, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.28 - 7.25 (m, 1H), 5.10 - 4.98 (m, 1H), 3.80 (s, 2H), N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- 3.34 (s, 2H), 3.05 (s, 2H), 1.57 (d, 2-m ethylpropyl)- 1 -i sopropyl- 1 H- J=6.9 Hz, 6H), 1.24 (s, 6H). benzo[d]imidazol-6-yl)pyridin-2-yl)-6- Protons missing due to solvent ((1 -methyl- IH-pyrazol -4-yl)oxy)-3- suppression or exchange or (methylsulfonyl)picolinamide

[1089] overlap with the NMR solvent. Method N, 1.7

[1090] δ 8.47 (s, 1H), 8.37 (d, J=8.8 Hz, 1H), 8.32 (br d, J=6.1 Hz, 1H), 7.96 (br s, 1H), 7.93 (s, 1H), 7.78 (br d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.45 (br d, J=7.9 Hz, 1H), 7.36 (br d, J=8.7 Hz, 1H), 6.71 - 6.35 (m, 1H), 5.44 - 5.28 (m, 1H), 3.81 (R)-N-(4-(l -(1, 1 -difluoropropan-2-yl)- (s, 3H), 3.36 (s, 1H), 3.15 - 3.08 2-(2-hydroxy-2-methylpropyl)-lH- (m, 1H), 3.04 - 2.95 (m, 1H), 1.69 benzo[d]imidazol-6-yl)-5- (br d, J=6.9 Hz, 3H), 1.30 (s, 3H), fluoropyridin-2-yl)-6-((l-methyl-lH- 1.20 (s, 3H). Protons missing due pyrazol-4-yl)oxy)-3 - to solvent suppression or (methylsulfonyl)picolinamide exchange or overlap with the

[1091]

[1092]

[1093] NMR solvent. Method, 1.64

[1094] 553.3

[1095] δ 11.20 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.48 (s, 1H), 8.40 (br d, J=6.0 Hz, 1H), 8.03 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.49 (br d, J=8.5 Hz, 1H), 4.97 (dt, J=13.7, 6.6 Hz, (S)-N-(5-fluoro-4-(l-isopropyl-2- 1H), 4.28 (q, J=10.7 Hz, 2H), (2,2,2-trifluoroethyl)-lH- 3.70 - 3.56 (m, 1H), 2.58 (s, 3H), benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 2.39 (br s, 3H), 1.62 (d, J=6.9 Hz, methyl-5-(3-(methylamino)but-l-yn-l- 6H), 1.34 (d, J=6.8 Hz, 3H).

[1096] yl)nicotinamide Protons missing due to solvent suppression or exchange or overlap with the NMR solvent. Method M, 1.7

[1097] 476

[1098] δ 10.82 (s, 1H), 8.51 - 8.47 (m, 1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.75 (br s, 1H), 7.74 (br d, J=8.5 Hz, 1H), 7.45 (d, J=3.1 Hz, 1H), 7.44 (br d, J=3.4 Hz, 1H), 5.13 - 4.98 (m, 1H), 3.05 (s, 2H), 2.62 N-(5-fluoro-4-(2-(2-hydroxy-2- (s, 3H), 2.57 (s, 3H), 1.60 (br d, methylpropyl)- 1 -i sopropyl- 1 H- J=6.9 Hz, 6H), 1.26 (s, 6H). benzo[d]imidazol-6-yl)pyridin-2-yl)- Protons missing due to solvent 3,6-dimethylpicolinamide suppression or exchange or overlap with the NMR solvent. Method M, 1.36

[1099] 594.4

[1100] δ 11.05 (s, 1H), 8.38 (s, 1H), 8.32 (br d, J=5.3 Hz, 1H), 8.22 (d, J=2.7 Hz, 1H), 7.96 (br s, 1H), 7.73 (br d, J=8.5 Hz, 1H), 7.50 (br s, 1H), 7.43 (br d, J=8.5 Hz, 1H), 5.06 - 4.93 (m, 1H), 4.33 (br 5-(2-(dimethylamino)ethoxy)-N-(5- s, 2H), 3.52 - 3.39 (m, 1H), 3.04 fluoro-4-(2-(2-hydroxy-2- (s, 1H), 2.77 (s, 6H), 2.42 (br s, methylpropyl)- 1 -i sopropyl- 1 H- 3H), 1.52 (br d, J=6.8 Hz, 6H), benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 1.16 (s, 6H). Protons missing due methylnicotinamide to solvent suppression or exchange or overlap with the

[1101]

[1102]

[1103] NMR solvent. Method M, 1.41

[1104] δ 11.47 (s, 1H), 8.97 (s, 1H), 8.48 (s, 1H), 8.35 (br d, J=5.9 Hz, 1H), 8.06 (br s, 1H), 7.78 (br d, J=8.2 Hz, 1H), 7.67 (s, 1H), 7.43 (br d, J=8.5 Hz, 1H), 4.26 - 4.13 (m, 1H), 3.08 - 2.93 (m, 2H), 2.65 (s, 3H), 1.69 - 1.64 (m, 1H), 1.62 (br d, J=6.8 Hz, 3H), 1.27 (s, 3H), (R)-N-(4-(l-(l-cyclopropylethyl)-2-(2- 1.22 (s, 3H), 0.76 - 0.64 (m, 1H), hydroxy-2-methylpropyl)- 1H- 0.64 - 0.55 (m, 1H), 0.43 - 0.35 benzo[d]imidazol-6-yl)-5- (m, 1H), 0.32 - 0.24 (m, 1H). fluoropyridin-2-yl)-2-methyl-5- Protons missing due to solvent (methylsulfonyl)isonicotinamide suppression or exchange or overlap with the NMR solvent. Method, 1.81

[1105] δ 8.40 (br d, J=8.2 Hz, 1H), 8.26 (s, 1H), 8.13 (br d, J=6.0 Hz, 1H), 7.90 (br d, J=8.2 Hz, 1H), 7.74 (s, 1H), 7.53 (br d, J=8.4 Hz, 1H), 7.20 (br d, J=8.2 Hz, 1H), 7.10 - 6.78 (m, 1H), 4.90 - 4.76 (m, 1H), 2.82 (s, 2H), 1.37 (br d, J=6.8 Hz, 6-(difluoromethyl)-N-(5-fluoro-4-(2- 6H), 1.02 (s, 6H). Protons (2-hydroxy-2-methylpropyl)- 1 - missing due to solvent isopropyl-lH-benzo[d]imidazol-6- suppression or exchange or yl)pyri din-2 -yl)-3- overlap with the NMR solvent. (methylsulfonyl)picolinamide

[1106] Method C, 1.62

[1107] δ 8.97 (s, 1H), 8.49 (br s, 1H), 8.35 (br d, J=5.2 Hz, 1H), 7.98 (br s, 1H), 7.83 (br d, J=8.4 Hz, 1H), 7.68 (s, 1H), 7.44 (br d, J=8.3 Hz, 1H), 5.08 - 4.83 (m, 1H), 2.66 (s, 3H), 1.63 (br d, N-(4-(2-(2-cyano-2-methylpropyl)- 1 - J=6.8 Hz, 6H), 1.56 (s, 6H). isopropyl-lH-benzo[d]imidazol-6-yl)- Protons missing due to solvent 5-fluoropyridin-2-yl)-2-methyl-5- suppression or exchange or

[1108]

[1109] (methylsulfonyl)isonicotinamide overlap with the NMR solvent. Method C, 1.7

[1110] δ 8.96 (s, 1H), 8.47 (br s, 2H), 8.38 (br d, J=6.0 Hz, 1H), 7.81 (s, 1H), 7.78 (br d, J=8.3 Hz, 1H), 7.67 (s, 1H), 7.48 (br d, J=8.2 Hz, 1H), 5.24 - 5.12 (m, 1H), 3.38 (d, J=7.9 Hz, 1H), 3.08 (s, 2H), 2.65 (s, 3H), 2.22 - 2.05 (m, 4H), 2.03 N-(4-(l-cyclopentyl-2-(2-hydroxy-2- - 1.94 (m, 2H), 1.80 - 1.71 (m, methylpropyl)-lH-benzo[d]imidazol-6- 2H), 1.25 (s, 6H). Protons yl)-5-fluoropyri din-2 -yl)-2-methyl-5- missing due to solvent (methylsulfonyl)isonicotinamide suppression or exchange or overlap with the NMR solvent.

[1111] Method C, 1.92

[1112] δ 8.50 (s, 1H), 8.35 (d, J=5.9 Hz, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.27 (br d, J=11.2 Hz, 1H), 6.69 - 6.29 (m, 1H), 5.07 (s, 1H), 4.85 (s, 1H), 4.75 (td, J=15.1, 3.2 Hz, 6-(2,2-difluoroethoxy)-N-(5-fluoro-4- 2H), 3.07 (s, 2H), 1.59 (d, J=6.9 (4-fluoro-2-(2-hydroxy-2- Hz, 6H), 1.27 (s, 6H). Protons methylpropyl)- 1 -i sopropyl- 1 H- missing due to solvent benzo[d]imidazol-6-yl)pyridin-2-yl)-3- suppression or exchange or (methylsulfonyl)picolinamide overlap with the NMR solvent.

[1113] Method N, 1.9

[1114] δ 11.37 (s, 1H), 8.50 (s, 1H), 8.37 (br d, J=6.0 Hz, 1H), 8.32 (d, J=8.8 Hz, 1H), 7.98 (br s, 1H), 7.81 (br d, J=6.9 Hz, 1H), 7.47 (br d, J=7.3 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.78 - 6.34 (m, 2H), 5.50 - 5.28 (m, 1H), 4.97 (br (R)-6-(2,2-difluoroethoxy)-N-(4-(l- s, 1H), 4.76 (br t, <7=15.0 Hz, 2H), (1,1 -difluoropropan-2-yl)-2-(2- 3.16 - 3.08 (m, 1H), 3.06 - 2.98 hydroxy-2-methylpropyl)- 1H- (m, 1H), 1.71 (br d, <7=7.0 Hz, benzo[d]imidazol-6-yl)-5- 3H), 1.32 (br s, 3H), 1.22 (br s, fluoropyri din-2 -yl)-3- 3H). Protons missing due to (methylsulfonyl)picolinamide solvent suppression or exchange

[1115]

[1116]

[1117] or overlap with the NMR solvent. Method M, 1.63

[1118] 571.2

[1119] 6 11.14 (s, 1H), 8.48 (s, 1H), 8.42 (br d, J=2.6 Hz, 1H), 8.22 (br s, 1H), 8.03 (br s, 1H), 7.84 (br d, J=8.2 Hz, 1H), 7.49 (br d, J=7.8 Hz, 1H), 7.44 (br s, 1H), 5.02 - (S)-N-(5-fluoro-4-(l-isopropyl-2- 4.88 (m, 2H), 4.28 (q, J=11.0 Hz, (2, 2, 2-tri fluoroethyl)- 1H- 2H), 2.82 - 2.74 (m, 1H), 2.72 - benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 2.62 (m, 2H), 2.49 (s, 3H), 2.37 - methyl-5-((l-methylpyrrolidin-3- 2.29 (m, 2H), 2.27 (s, 3H), 1.85 - yl)oxy)nicotinamide 1.77 (m, 1H), 1.62 (br d, J=6.7

[1120] Hz, 6H), _ Method M, 1.62

[1121] 587.3

[1122] 6 11.28 - 11.17 (m, 1H), 8.54 (s, 1H), 8.44 (br d, J=5.7 Hz, 1H), 8.41 (s, 1H), 8.30 (m, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.75 (br d, J=8.3 Hz, 1H), 7.58 (br d, J=0.7 Hz, 1H), 5.34 - 5.21 (m, 1H), 4.49 - 4.36 (m, 1H), 3.33 - 3.23 (m, 2H), 2.96 (s, 1H), 2.90 (s, 3H), 2.74 (s, 1H), 2.67 - 2.58 (m, N-(4-(l-((R)-l-cyclopropylethyl)-2-(2- 1H), 2.52 (br s, 3H), 2.33 - 2.26 hydroxy-2-methylpropyl)- 1H- (m, 1H), 2.13 (ddd, J=7.0, 4.6, 2.4 benzo[d]imidazol-6-yl)-5- Hz, 1H), 1.78 (td, J=8.1, 4.1 Hz, fluoropyri din-2 -yl)-2-methyl-5-(((S)- 1 - 1H), 1.73 - 1.69 (m, 1H), 1.71 (d, methylpyrrolidin-3- J=6.9 Hz, 3H), 1.28 (br d, J=12.7 yl)oxy)nicotinamide Hz, 6H), 0.80 - 0.63 (m, 2H), 0.50 - 0.29 (m, 2H). Protons missing due to solvent suppression or exchange or overlap with the NMR solvent.

[1123] Method U, 1.156

[1124] 607

[1125] 1H NMR (400 MHz, Methanol-d4) δ 9.52 (s, 1H), 9.12 (s, 1H), 8.58-8.56 (m, 1H), 8.44 (d, J= 2.0 Hz, 1H), 8.39 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 5.40-5.28 (m, 1H), 4.08 N-(5-fluoro-4-(2-(2-hydroxy-2- (s, 3H), 3.58 (s, 3H), 3.37 (s, 2H), methylpropyl)- 1 -i sopropyl- 1 H- 1.83 (d, J = 7.2 Hz, 6H), 1.43 (s, benzo[d]imidazol-6-yl)pyridin-2-yl)-5- 6H). Protons missing due to (l-methyl-lH-l,2,4-triazol-3-yl)-3- solvent suppression or exchange

[1126]

[1127]

[1128] (methylsulfonyl)picolinamide or overlap with the NMR solvent. Method M, 1.68

[1129] 568.4

[1130] δ 8.51 (d, J=1.8 Hz, 1H), 8.49 (d, J=2.7 Hz, 1H), 8.41 (br d, J=5.8 Hz, 1H), 7.81 (d, J=2.7 Hz, 1H), 7.78 (s, 1H), 7.32 (s, 1H), 6.62 - 6.35 (m, 2H), 5.09 - 4.97 (m, 2H), 3.09 (s, 2H), 2.58 (s, 3H), 1.28 (s, N-(4-(l-(2,2-difluoroethyl)-4-fluoro-2- 6H). Protons missing due to (2-hydroxy-2-methylpropyl)- 1H- solvent suppression or exchange benzo[d]imidazol-6-yl)-5- or overlap with the NMR solvent. fluoropyridin-2-yl)-5- (difluoromethoxy)-2- methylnicotinamide

[1131] Method C, 1.75

[1132] 611.3

[1133] δ 9.12 (s, 1H), 8.52 (s, 1H), 8.30 (d, J=6.0 Hz, 1H), 7.83 (s, 1H), 7.34 (br d, J=11.3 Hz, 1H), 6.69 - 6.41 (m, 1H), 5.51 - 5.30 (m, 1H), 4.10 (s, 3H), 3.18 - 3.11 (m, 1H), 3.09 - 3.01 (m, 1H), 1.70 (br d, N-(4-(l -( 1, 1 -difluoropropan-2-yl)-4- J=7.1 Hz, 3H), 1.32 (s, 3H), 1.22 fluoro-2-(2 -hydroxy -2 -methylpropyl)- (s, 3H). Protons missing due to lH-benzo[d]imidazol-6-yl)-5- solvent suppression or exchange fluoropyridin-2-yl)-2-methoxy-5- or overlap with the NMR solvent. (methylsulfonyl)pyrimidine-4- carb oxami de

[1134] Method C, 1.74

[1135] 611.3

[1136] δ 9.12 (s, 1H), 8.52 (s, 1H), 8.30 (d, J=5.8 Hz, 1H), 7.82 (s, 1H), 7.34 (br d, J=10.9 Hz, 1H), 6.71 - 6.39 (m, 1H), 5.48 - 5.36 (m, 1H), 4.10 (s, 3H), 3.18 - 3.09 (m, 1H), 3.08 - 3.02 (m, 1H), 1.70 (d, N-(4-(1-(1,1-difluoropropan-2-yl)-4- J=7.0 Hz, 3H), 1.32 (s, 3H), 1.22 fluoro-2-(2 -hydroxy -2 -methylpropyl)- (s, 3H). Protons missing due to lH-benzo[d]imidazol-6-yl)-5- solvent suppression or exchange fluoropyridin-2-yl)-2-methoxy-5- or overlap with the NMR solvent. (methylsulfonyl)pyrimidine-4-

[1137]

[1138]

[1139] carb oxami de Method P, 1.385

[1140] 626

[1141] 1H NMR (400 MHz, Methanol- 6 / 4) δ 8.51 (d, J = 6.0 Hz, 1H), 8.49 (d, J= 8.4 Hz, 1H), 8.41 (d, J= 2.0 Hz, 1H), 8.19 (s, 1H), 7.85-7.84 (s, 2H), 7.72 (d, J= 10.8 Hz, 1H), 7.37 (d, J= 8.8 Hz, 1H), 5.40-5.27 (m, 1H), 3.46 (s, 6-(( 1 H-pyrazol-4-yl)oxy)-N-(5 -fluoro- 3H), 3.40 (s, 2H), 1.80 (d, J= 6.8 4-(4-fluoro-2-(2-hydroxy-2- Hz, 6H), 1.43 (s, 6H). Protons methylpropyl)- 1 -i sopropyl- 1 H- missing due to solvent benzo[d]imidazol-6-yl)pyridin-2-yl)-3- suppression or exchange or (methylsulfonyl)picolinamide overlap with the NMR solvent.

[1142] Method T, 0.724

[1143] 676

[1144] 1H NMR (400 MHz, Methanol- 6 / 4) δ 8.52 (d, J= 8.8 Hz, 1H), 8.50 (d, J= 6.4 Hz, 1H), 8.42 (d, J= 1.6 Hz, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 7.94 (s, 1H), 7.69 (d, J= 10.4 Hz, 1H), 7.46 (t, J= 59.6 Hz, 1H), 7.42 (d, J= 8.8 Hz, 1H), 5.37-5.25 (m, 1H), 3.46 (s, 3H), 6-(( 1 -(difluoromethyl)- 1 H-pyrazol-4- 3.37 (s, 2H), 1.79 (d, J= 6.8 Hz, yl)oxy)-N-(5-fluoro-4-(4-fluoro-2-(2- 6H), 1.42 (s, 6H). Protons hydroxy-2-methylpropyl)- 1 -isopropyl- missing due to solvent lH-benzo[d]imidazol-6-yl)pyridin-2- suppression or exchange or yl)-3-(methylsulfonyl)picolinamide overlap with the NMR solvent.

[1145] Method T, 1.38

[1146] 641

[1147] 1H NMR (400 MHz, Methanol- 6 / 4) δ 8.60 (d, J= 8.4 Hz, 1H), 8.47 (d, J= 6.0 Hz, 1H), 8.40 (d, J= 2.0 Hz, 1H), 8.38 (s, 1H), 8.14 (s, 1H), 7.68 (d, J= 11.2 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 5.38-5.24 (m, 1H), 3.95 (s, 3H), N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- 3.47 (s, 3H), 3.37 (s, 2H), 1.79 (d, 2-m ethylpropyl)- 1 -i sopropyl- 1 H- J= 7.2 Hz, 6H), 1.42 (s, 6H). benzo[d]imidazol-6-yl)pyridin-2-yl)-6- Protons missing due to solvent (( 1 -methyl- 1H- 1,2,4-triazol-3 -yl)oxy)- suppression or exchange or

[1148] 3-(methylsulfonyl)picolinamide

[1149]

[1150]

[1151] overlap with the NMR solvent. Method I, 0.691

[1152] 627

[1153] 1H NMR (400 MHz, Methanoldi δ 8.70 (s, 1H), 8.61 (d, J= 8.0 Hz, 1H), 8.49 (d, J= 4.0 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.10 (d, J= 4.0 Hz, 1H), 7.65-7.57 (m, 2H), 6.75 (d, J= 1.6 Hz, 1H), N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- 5.31-5.27 (m, 1H), 3.48 (s, 3H), 2-m ethylpropyl)- 1 -i sopropyl- 1 H- 3.33 (s, 2H), 1.79 (s, 6H), 1.42 (s, benzo[d]imidazol-6-yl)pyridin-2-yl)-6- 6H). Protons missing due to (isoxazol-3-yloxy)-3- solvent suppression or exchange (methylsulfonyl)picolinamide or overlap with the NMR solvent.

[1154] Method C, 1.18

[1155] 567.2

[1156] δ 8.49 (d, J=1.7 Hz, 1H), 8.40 (br d, J=5.8 Hz, 1H), 8.27 (d, J=2.8 Hz, 1H), 7.81 (s, 1H), 7.53 (d, J=2.7 Hz, 1H), 7.27 (br d, J=11.5 Hz, 1H), 5.07 (dt, J=13.8, 6.9 Hz, 1H), 4.17 (t, J=5.7 Hz, 2H), 3.07 5-(2-(dimethylamino)ethoxy)-N-(5- (s, 2H), 2.65 (t, J=5.5 Hz, 2H), fluoro-4-(4-fluoro-2-(2-hydroxy-2- 2.50 (s, 3H), 2.22 (s, 6H), 1.60 (d, methylpropyl)- 1 -i sopropyl- 1 H- J=6.9 Hz, 6H), 1.27 (s, 6H). benzo[d]imidazol-6-yl)pyridin-2-yl)-2- Protons missing due to solvent methylnicotinamide suppression or exchange or overlap with the NMR solvent.

[1157] Method i, 0.714

[1158] 580

[1159] 1H NMR (400 MHz, Methanolbi δ 8.93 (d, J= 4.8 Hz, 1H), 8.59 (d, J= 8.0 Hz, 1H), 8.53 (d, J= 6.0 Hz, 1H), 8.39 (s, 1H), 8.03 (s, 1H), 7.80 (dd, J= 8.0, 4.8 Hz, 1H), 7.56 (d, J = 10.8 Hz, 1H), 5.76-5.55 (m, 1H), 5.30-5.18 N-(4-(l-(l,3-difluoropropan-2-yl)-4- (m, 2H), 5.18-5.00 (m, 2H), 3.53 fluoro-2-(2 -hydroxy -2 -methylpropyl)- (s, 3H), 3.29 (s, 2H), 1.39 (s, 6H).

[1160] lH-benzo[d]imidazol-6-yl)-5- Protons missing due to solvent fluoropyri din-2 -yl)-3- suppression or exchange or (methylsulfonyl)picolinamide overlap with the NMR solvent.

[1161]

[1162]

[1163] Method L, 1.707

[1164] δ 11.52 (s, 1H), 9.10 (s, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.29 (d, J=6.0 Hz, 1H), 7.83 (s, 1H), 7.34 (d, J=11.2Hz, 1H), 6.75 - 6.36 (m, 1H), 5.52 - 5.27 (m, 1H), 4.89 (s, 1H), 4.11 (s, 3H), 3.55 - 3.47 (m, 2H), 3.19 - 3.11 (m, 1H), 3.09 - N-(4-(1-(1,1-difluoropropan-2-yl)-4- 3.01 (m, 1H), 1.70 (d, J=7.4 Hz, fluoro-2-(2 -hydroxy -2 -methylpropyl)- 3H), 1.33 (s, 3H), 1.23 - 1.22 (m, lH-benzo[d]imidazol-6-yl)-5- 3H), 1.22 - 1.18 (m, 3H). fluoropyridin-2-yl)-5-(ethylsulfonyl)-2- methoxypyrimidine-4-carboxamide

[1165] Method L, 1.652

[1166] 11.51 (s, 1H), 9.10 (s, 1H), 8.54 (d, J=1.9 Hz, 1H), 8.31 (d, J=6.0 Hz, 1H), 7.80 (s, 1H), 7.33 (d, J=11.4Hz, 1H), 6.63 - 6.34 (m, 1H), 5.09 - 4.98 (m, 2H), 4.92 (s, 1H), 4.11 (s, 3H), 3.50 (q, J=7.4 Hz, 2H), 3.09 (s, 2H), 1.28 (s, N-(4-(1-(2,2-difluoroethyl)-4-fluoro-2- 6H), 1.20 (t, J=7.4 Hz, 3H).

[1167] (2-hydroxy-2-methylpropyl)- 1H- benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-5-(ethylsulfonyl)-2- methoxypyrimidine-4-carboxamide

[1168] Method N, 1.74

[1169] δ 9.21 (s, 1H), 8.53 (br s, 1H), 8.38 - 8.22 (m, 1H), 7.79 (br s, 1H), 7.33 (br d, J=10.8 Hz, 1H), 6.63 - 6.32 (m, 1H), 5.11 - 4.91 (m, 2H), 3.65 - 3.43 (m, 1H), 3.09 (br s, 2H), 2.82 (s, 3H), 1.28 (s, 6H), 1.23 - 1.17 (m, 3H). Protons N-(4-(1-(2,2-difluoroethyl)-4-fluoro-2- missing due to solvent

[1170] (2-hydroxy-2-methylpropyl)- 1H- suppression or exchange or benzo[d]imidazol-6-yl)-5- overlap with the NMR solvent. fluoropyridin-2-yl)-5-(ethylsulfonyl)-2-

[1171]

[1172]

[1173] methylpyrimidine-4-carboxamide Method L, 1.694

[1174] δ 11.50 (s, 1H), 9.21 (s, 1H), 8.53 (d, J=1.9 Hz, 1H), 8.29 (d, J=6.0 Hz, 1H), 7.83 (s, 1H), 7.34 (d, J=11.2Hz, 1H), 6.70 - 6.42 (m, 1H), 5.49 - 5.34 (m, 1H), 4.89 (s, 1H), 3.54 (q, J=7.4 Hz, 2H), 3.18 - 3.11 (m, 1H), 3.08 - 3.03 (m, 1H), 2.83 (s, 3H), 1.70 (d, J=7.1 N-(4-(1-(1,1-difluoropropan-2-yl)-4- Hz, 3H), 1.33 (s, 3H), 1.24 - 1.22 fluoro-2-(2-hydroxy-2-methylpropyl)- (m, 3H), 1.20 (t, J=7.4 Hz, 3H). lH-benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-5-(ethylsulfonyl)-2- methylpyrimidine-4-carboxamide

[1175] Method C, 1.75

[1176] 609.1

[1177] δ 9.21 (s, 1H), 8.52 (s, 1H), 8.29 (br d, J=5.3 Hz, 1H), 7.83 (br s, 1H), 7.34 (br d, J=11.1 Hz, 1H), 6.68 - 6.40 (m, 1H), 5.48 - 5.35 (m, 1H), 3.61 - 3.49 (m, 1H), 3.19 - 3.10 (m, 1H), 3.09 - 3.01 (m, 1H), 2.82 (s, 3H), 1.70 (br d, N-(4-(l -( 1, 1 -difluoropropan-2-yl)-4- J=6.6 Hz, 3H), 1.32 (s, 3H), 1.22 fluoro-2-(2 -hydroxy -2 -methylpropyl)- (br s, 3H), 1.21 - 1.17 (m, 3H). lH-benzo[d]imidazol-6-yl)-5- Protons missing due to solvent fluoropyridin-2-yl)-5-(ethylsulfonyl)-2- suppression or exchange or methylpyrimidine-4-carboxamide overlap with the NMR solvent.

[1178] Method T, 0.751

[1179] 690

[1180] 1H NMR (400 MHz, Methanol- d4) δ 8.48 (s, 1H), 8.46 (d, J= 4.8 Hz, 1H), 8.40 (s, 1H), 8.37 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.60 (s, 1H), 7.45 (t, J= 59.6 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6-(( 1 -(difluoromethyl)- 1 H-pyrazol-4- 5.36-5.22 (m, 1H), 3.65 (q, J= yl)oxy)-3 -(ethyl sulfonyl)-N-(5 -fluoro- 7.6 Hz, 2H), 3.33 (s, 2H), 1.77 (d, 4-(4-fluoro-2-(2-hydroxy-2- J = 7.2 Hz, 6H), 1.41 (s, 6H), methylpropyl)- 1 -i sopropyl- 1 H- 1.33 (t, J= 7.6 Hz, 3H). Protons benzo[d]imidazol-6-yl)pyridin-2- missing due to solvent yl)picolinamide suppression or exchange or

[1181]

[1182]

[1183] overlap with the NMR solvent. Method M, 1.47

[1184] 589.2

[1185] 89.10 (s, 1H), 8.51 (s, 1H), 8.30 (d, J=6.0 Hz, 1H), 7.82 (s, 1H), 7.27 (d, J=11.6 Hz, 1H), 5.14 - 4.99 (m, 1H), 4.92 - 4.72 (m, 1H), 4.11 (s, 2H), 3.55 - 3.45 (m, 1H), 3.07 (s, 2H), 1.59 (d, J=6.9 Hz, 5-(ethylsulfonyl)-N-(5-fluoro-4-(4- 6H), 1.27 (s, 6H), 1.20 (t, J=7.4 fluoro-2-(2 -hydroxy -2 -methylpropyl)- Hz, 3H). Protons missing due to 1 -isopropyl- lH-benzo[d]imidazol-6- solvent suppression or exchange yl)pyridin-2-yl)-2-methoxypyrimidine- or overlap with the NMR solvent.

[1186] 4-carboxamide

[1187] Method C, 1.69

[1188] 580.2

[1189] δ 8.97 - 8.92 (m, 1H), 8.52 (s, 1H), 8.40 (d, J=8.1 Hz, 1H), 8.35 (d, J=6.0 Hz, 1H), 7.84 (dd, J=8.0, 4.8 Hz, 1H), 7.79 (s, 1H), 7.33 (br d, J=11.5 Hz, 1H), 6.65 - 6.29 (m, 1H), 5.12 - 4.90 (m, 2H), 3.56 (q, J=7.3 Hz, 1H), 3.09 (s, N-(4-(l-(2,2-difluoroethyl)-4-fluoro-2- (2-hydroxy-2-methylpropyl)- 1H- 2H), 1.28 (s, 6H), 1.17 (t, J=7.4 benzo[d]imidazol-6-yl)-5- Hz, 3H). Protons missing due to fluoropyridin-2-yl)-3 solvent suppression or exchange or overlap with the NMR solvent. Method C, 1.76

[1190] 594.3

[1191] δ 8.95 (br d, J=4.7 Hz, 1H), 8.51 (s, 1H), 8.40 (br d, J=8.1 Hz, 1H), 8.34 (br d, J=6.0 Hz, 1H), 7.90 - 7.80 (m, 2H), 7.34 (br d, J=10.9 Hz, 1H), 6.73 - 6.35 (m, 1H), 5.49 - 5.28 (m, 1H), 3.62 - 3.52 (m, 1H), 3.20 - 3.11 (m, 1H), 3.09 - 3.01 (m, 1H), 1.71 (br d, J=6.9 N-(4-(l -( 1, 1 -difluoropropan-2-yl)-4- Hz, 3H), 1.33 (s, 3H), 1.23 (s, fluoro-2-(2 -hydroxy -2 -methylpropyl)- 3H), 1.18 (br t, J=7.4 Hz, 3H). lH-benzo[d]imidazol-6-yl)-5- Protons missing due to solvent fluoropyri din-2 -yl)-3- suppression or exchange or (ethylsulfonyl)picolinamide overlap with the NMR solvent.

[1192]

[1193]

[1194] Method C, 1.75

[1195] 594.2

[1196] δ 8.95 (br d, J=4.5 Hz, 1H), 8.51 (s, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.34 (d, J=6.0 Hz, 1H), 7.89 - 7.79 (m, 2H), 7.34 (br d, J=11.6 Hz, 1H), 6.74 - 6.38 (m, 1H), 5.50 - 5.29 (m, 1H), 3.56 (q, J=7.1 Hz, 1H), 3.18 - 3.11 (m, N-(4-(l -( 1, 1 -difluoropropan-2-yl)-4- 1H), 3.08 - 3.03 (m, 1H), 1.71 (br fluoro-2-(2 -hydroxy -2 -methylpropyl)- d, J=7.0 Hz, 3H), 1.33 (s, 3H), lH-benzo[d]imidazol-6-yl)-5- 1.22 (s, 3H), 1.18 (t, J=7.3 Hz, fluoropyri din-2 -yl)-3- 3H). Protons missing due to (ethylsulfonyl)picolinamide solvent suppression or exchange or overlap with the NMR solvent.

[1197] Method M, 1.38

[1198] 586.2

[1199] δ 8.98 - 8.90 (m, 1H), 8.51 (s, 1H), 8.44 - 8.36 (m, 2H), 7.91 (s, 1H), 7.88 - 7.79 (m, 1H), 7.34 (br d, J=11.3 Hz, 1H), 5.69 - 5.46 (m, 1H), 4.39 - 4.27 (m, 1H), 4.10 (br d, J=10.4 Hz, 1H), 3.93 (brt, J=8.9 Hz, 1H), 3.76 - 3.65 (m, 1H), 3.58 (br d, J=7.0 Hz, 1H), (R)-3-(ethylsulfonyl)-N-(5-fluoro-4-(4- 3.21 - 3.14 (m, 1H), 3.14 - 3.06 fluoro-2-(2 -hydroxy -2 -methylpropyl)- (m, 1H), 2.25 - 2.13 (m, 1H), 1.28 1 -(tetrahydrofuran-3 -yl)- 1H- (s, 3H), 1.23 (s, 3H), 1.21 - 1.15 benzo[d]imidazol-6-yl)pyridin-2- (m, 3H). Protons missing due to yl)picolinamide solvent suppression or exchange or overlap with the NMR solvent.

[1200] Method T, 0.516

[1201] 523

[1202] 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.40 (d, J = 6.0 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.93 (s, 1H), 7.42 (d, J = 11.6 Hz, 1H), 5.14-5.02 (m, 1H), 2.62 (s, N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- 3H), 1.80 (s, 6H), 1.66 (d, J = 6.8 2-m ethylpropyl)- 1 -i sopropyl- 1 H- Hz, 6H), 1.50 (s, 6H). benzo[d]imidazol-6-yl)pyridin-2-yl)-5- (2-hydroxypropan-2-yl)-2-

[1203]

[1204]

[1205] mi Method T, 0.714

[1206] 580

[1207] 1H NMR (400 MHz, Methanol- 6 / 4) δ 8.93 (d, J = 4.8 Hz, 1H), 8.59 (d, J= 8.0 Hz, 1H), 8.53 (d, J= 6.0 Hz, 1H), 8.39 (s, 1H), 8.03 (s, 1H), 7.80 (dd, J= 8.0, 4.8 Hz, 1H), 7.56 (d, J = 10.8 Hz, 1H), 5.76-5.55 (m, 1H), 5.30-5.18 N-(4-(l-(l,3-difluoropropan-2-yl)-4- (m, 2H), 5.18-5.00 (m, 2H), 3.53 fluoro-2-(2 -hydroxy -2 -methylpropyl)- (s, 3H), 3.29 (s, 2H), 1.39 (s, 6H). lH-benzo[d]imidazol-6-yl)-5- fluoropyri din-2 -yl)-3- mi

[1208] Method T, 1.28

[1209] 586

[1210] 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.94 (dd, J = 4.8, 1.6 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.44 (dd, J = 8.0, 1.6 Hz, 1H), 8.35 (d, J = 6.0 Hz, 1H), 8.00 (s, 1H), 7.85 (dd, J = 8.0, 4.8 Hz, 1H), 7.34 (d, J = 11.2 Hz, 1H), 4.91-4.78 (m, 1H), 4.14-3.84 (S)-N-(5-fluoro-4-(4-fluoro-2-(2- (m, 2H), 3.90-3.88 (m, 1H), 3.65- hydroxy-2-methylpropyl)- 1 - 3.53 (m, 1H), 3.43 (s, 3H), 3.16 (tetrahy dro-2H-pyran-3 -yl)- 1 H- (d, J = 14.8 Hz, 1H), 3.11 (d, J = benzo[d]imidazol-6-yl)pyridin-2-yl)-3- 14.8 Hz, 1H), 2.49-2.39 (m, 1H), (methylsulfonyl)picolinamide

[1211] 2.10-2.08 (m, 1H), 1.90-1.78 (m, 2H), 1.28 (s, 3 H), 1.27 (s, 3H). Method T, 0.687

[1212] 617

[1213] 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 9.13 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 6.0 Hz, 1H), 7.96 (s, 1H), 7.28 (d, J = 11.2 Hz, 1H), 4.90-4.76 (m, 2H), 4.11 (s, 3H), 4.07-3.94 (m, (S)-N-(5-fluoro-4-(4-fluoro-2-(2- 2H), 3.92-3.82 (m, 1H), 3.64-3.53 hydroxy-2-methylpropyl)- 1 - (m, 1H), 3.41 (s, 3H), 3.16-3.03 (tetrahy dro-2H-pyran-3 -yl)- 1 H- (m, 2H), 2.52-2.38 (m, 1H), 2.10- benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 2.00 (m, 1H), 1.90-1.74 (m, 2H), methoxy-5- 1.27 (s, 6H). (methylsulfonyl)pyrimidine-4-

[1214]

[1215]

[1216] carb oxami de Method V, 0.994

[1217] 577

[1218] 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 9.13 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 6.0 Hz, 1H), 7.96 (s, 1H), 7.28 (d, J = 11.2 Hz, 1H), 4.90-4.76 (m, 2H), 4.11 (s, 3H), 4.07-3.94 (m, 5-(2-(dimethylamino)ethoxy)-N-(5- 2H), 3.92-3.82 (m, 1H), 3.64-3.53 fluoro-4-(4-fluoro- 1 -isopropyl-2- (m, 1H), 3.41 (s, 3H), 3.16-3.03 (2, 2, 2-tri fluoroethyl)- 1H- (m, 2H), 2.52-2.38 (m, 1H), 2.10- benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 2.00 (m, 1H), 1.90-1.74 (m, 2H), methylnicotinamide 1.27 (s, 6H), _

[1219] Method T, 0.555

[1220] 644

[1221] 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 9.66 (s, 1H), 8.50 (s, 1H), 8.34 (d, J= 6.0 Hz, 1H), 7.83 (s, 1H), 7.74 (d, J= 8.4 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.44 (dd, J= 8.4, 2.4 Hz, 1H), 4-(2-(dimethylamino)ethoxy)-2- 7.30-7.26 (m, 1H), 5.13-5.05 (m, (ethylsulfonyl)-N-(5-fluoro-4-(4- 1H), 4.49 (t, J = 4.0 Hz, 2H), fluoro-2-(2 -hydroxy -2 -methylpropyl)- 3.63-3.50 (m, 4H), 3.09 (s, 2H), 1 -isopropyl- lH-benzo[d]imidazol-6- 2.91-2.90 (m, 6H), 1.60 (d, J= yl)pyridin-2-yl)benzamide 6.8 Hz, 6H), 1.27 (s, 6H), 1.18 (t,

[1222] J= 7.6 Hz, 3H), Method T, 0.554

[1223] 644

[1224] 1H NMR (400 MHz, Methanol- d4) δ 8.45 (d, J= 6.0 Hz, 1H), 8.32 (d, J= 2.4 Hz, 1H), 7.99 (d, J= 8.8 Hz, 1H), 7.88 (s, 1H), 7.37- 7.26 (m, 3H), 5.20-5.08 (m, 1H), 4.38 (t, J= 5.2 Hz, 2H), 3.56-3.46 (m, 2H), 3.17 (s, 2H), 3.12 (t, J = 5-(2-(dimethylamino)ethoxy)-2- 5.2 Hz, 2H), 2.59 (s, 6H), 1.71 (d, (ethylsulfonyl)-N-(5-fluoro-4-(4- J= 7.2 Hz, 6H), 1.38 (s, 6H), fluoro-2-(2 -hydroxy -2 -methylpropyl)- 1.28 (t, J = 7.6 Hz, 3H).

[1225] 1 -isopropyl- lH-benzo[d]imidazol-6-

[1226]

[1227]

[1228] in-2- Method T, 0.583

[1229] 603

[1230] 1H NMR (400 MHz, Methanol- d4) δ 8.50 (d, J= 6.0 Hz, 1H), 8.37 (t, J= 2.8 Hz, 1H), 8.29 (dd, J= 2.8, 1.2 Hz, 1H), 7.88 (s, 1H), 7.63 (dd, J = 2.8, 1.2 Hz, 1H), 7.39 (dd, J= 11.2, 1.6 Hz, 1H), 6.39 (td, J= 55.2, 3.2 Hz, 1H), N-(4-(l -( 1, 1 -difluoropropan-2-yl)-4- 5.48-5.40 (m, 1H), 4.25 (t, J = 5.2 fluoro-2-(2 -hydroxy -2 -methylpropyl)- Hz, 2H), 3.25 (d, J= 14.8 Hz, lH-benzo[d]imidazol-6-yl)-5- 1H), 3.13 (d, J= 14.8 Hz, 1H), fluoropyridin-2-yl)-5-(2- 2.84 (t, J = 5.2 Hz, 2H), 2.62 (s, (dimethylamino)ethoxy)-2- 3H), 2.39 (s, 6H), 1.83 (d, J = 7.2 methylnicotinamide Hz, 3H), 1.42 (s, 3H), 1.34 (s,

[1231] 3H). _ _____ _ Method M, 1.45

[1232] 589.2

[1233] δ 9.10 (s, 1H), 8.51 (s, 1H), 8.30 (d, J=6.0 Hz, 1H), 7.82 (s, 1H), 7.27 (d, J=11.6 Hz, 1H), 5.14 - 4.99 (m, 1H), 4.92 - 4.72 (m, 1H), 4.11 (s, 2H), 3.55 - 3.45 (m, 1H), 3.07 (s, 2H), 1.59 (d, J=6.9 Hz, 6H), 1.27 (s, 6H), 1.20 (t, J=7.4 5-(ethylsulfonyl)-N-(5-fluoro-4-(4- Hz, 3H). Protons missing due to fluoro-2-(2 -hydroxy -2 -methylpropyl)- 1 -isopropyl- lH-benzo[d]imidazol-6- solvent suppression or exchange yl)pyridin-2-yl)-2-methoxypyrimidine- or overlap with the NMR solvent.

[1234] 4-carboxamide

[1235] Method M, 1.33

[1236] 581.5

[1237] δ 10.61 (s, 1H), 8.50 - 8.37 (m, 2H), 8.27 (br s, 1H), 7.82 (br s, 1H), 7.44 (br s, 1H), 7.28 (br s, 1H), 5.16 - 4.99 (m, 1H), 4.24 (br s, 2H), 3.26 (br d, J=6.7 Hz, 2H), 5-(3-(dimethylamino)propoxy)-N-(5- 3.07 (br s, 2H), 2.83 (br s, 6H), fluoro-4-(4-fluoro-2-(2-hydroxy-2- 2.69 (s, 3H), 2.16 (br s, 2H), 1.59 methylpropyl)- 1 -i sopropyl- 1 H- (br d, J=6.6 Hz, 6H), 1.26 (s, 6H). benzo[d]imidazol-6-yl)pyridin-2-yl)-3-

[1238]

[1239]

[1240] mi Method M, 1.25

[1241] \(F621.5

[1242] t J \\ A 6 8.51 - 8.46 (m, 1H), 8.40 (br d,

[1243] J=6.2 Hz, 1H), 8.27 (d, J=2.7 Hz, 00jjJ / 1H), 7.81 (s, 1H), 7.52 (d, J=2.7

[1244] Hz, 1H), 7.31 - 7.24 (m, 1H), 1J" 5.08 (dt, J=13.9, 6.8 Hz, 1H), 5-(((ls,4s)-4- 4.64 (br s, 1H), 3.08 (s, 2H), 2.19 (dimethylamino)cyclohexyl)oxy)-N-(5- (s, 6H), 1.99 - 1.92 (m, 2H), 1.74 fluoro-4-(4-fluoro-2-(2-hydroxy-2- (br s, 2H), 1.60 (br d, J=7.0 Hz, methylpropyl)- 1 -i sopropyl- 1 H- 10H), 1.28 (s, 6H). benzo[d]imidazol-6-yl)pyridin-2-yl)-2- methylnicotinamide

[1245] F Method M, 1.21

[1246] F581.2

[1247] \\ A 68.47 (s, 1H), 8.38 (d, J=6.0 Hz, I << Z ''N

[1248] N / / / 1H), 8.34 (s, 1H), 7.81 (s, 1H),

[1249] 7.27 (d, J=11.5 Hz, 1H), 6.75 (s, 1H), 5.13 - 4.98 (m, 1H), 4.32 (t, J=6.6 Hz, 2H), 3.07 (s, 2H), 2.40 6-(3-(dimethylamino)propoxy)-N-(5- (s, 3H), 2.35 (t, J=7.1 Hz, 2H), fluoro-4-(4-fluoro-2-(2-hydroxy-2- 2.15 (s, 6H), 1.91 - 1.80 (m, 2H), methylpropyl)- 1 -i sopropyl- 1 H- 1.59 (d, J=6.9 Hz, 6H), 1.27 (s, benzo[d]imidazol-6-yl)pyridin-2-yl)-4- 6H).

[1250] methylnicotinamide

[1251] Method N, 1.75

[1252] F

[1253] N564.2

[1254] ^Af F

[1255] δ 11.30 (s, 1H), 8.52 (d, J=1.4 Hz,\ A 1H), 8.49 (d, J=2.7 Hz, 1H), 8.41 I

[1256] (br d, J=5.3 Hz, 1H), 8.13 (s, 1H), HF2CO^ Z^Z^° \|J / /

[1257] 7.94 (d, J=8.5 Hz, 1H), 7.81 (d,F^ OH J=2.7 Hz, 1H), 7.68 (d, J=8.5 Hz,

[1258] 1H), 7.48 - 7.16 (m, 1H), 6.79 - 6.45 (m, 1H), 5.58 - 5.43 (m, 1H), (R)-5-(difluoromethoxy)-N-(4-( 1-(1,1- 3.35 - 3.28 (m, 1H), 3.25 - 3.19 difluoropropan-2-yl)-4-fluoro-2-(2- (m, 1H), 2.57 (s, 3H), 1.76 (d, hydroxy-2-methylpropyl)- 1H- J=7.1 Hz, 3H), 1.33 (s, 3H), 1.25 benzo[d]imidazol-6-yl)-5- fluoropyridin-2-yl)-2- (s, 3H). Protons missing due to solvent suppression or exchange methylnicotinamide

[1259]

[1260] or overlap with the NMR solvent. Method M, 1.48

[1261] 579

[1262] δ 11.30 (s, 1H), 8.52 (d, J=1.4 Hz, 1H), 8.49 (d, J=2.7 Hz, 1H), 8.41 (br d, J=5.3 Hz, 1H), 8.13 (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.81 (d, J=2.7 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.48 - 7.16 (m, 1H), 6.79 - 6.45 (m, 1H), 5.58 - 5.43 (m, 1H), l-(2,2-difluoroethyl)-4-(ethylsulfonyl)- 3.35 - 3.28 (m, 1H), 3.25 - 3.19 N-(5-fluoro-4-(2-(2-hydroxy-2- (m, 1H), 2.57 (s, 3H), 1.76 (d, methylpropyl)- 1 -i sopropyl- 1 H- J=7.1 Hz, 3H), 1.33 (s, 3H), 1.25 benzo[d]imidazol-6-yl)pyridin-2-yl)- (s, 3H). Protons missing due to lH-pyrazole-3-carboxamide solvent suppression or exchange or overlap with the NMR solvent.

[1263] Method M, 1.45

[1264] 543

[1265] 10.47 (s, 1H), 8.51 (s, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.29 (d, J=6.0 Hz, 1H), 7.97 (s, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 5.10 - 5.00 (m, 1H), 4.95 (s, 1H), 4.01 (s, 3H), 3.57 (q, J=7.3 4-(ethylsulfonyl)-N-(5-fluoro-4-(2-(2- Hz, 2H), 3.05 (s, 2H), 1.59 (d, hydroxy-2-methylpropyl)- 1 -isopropyl- J=6.9 Hz, 6H), 1.26 (s, 6H), 1.16 lH-benzo[d]imidazol-6-yl)pyridin-2- (t, J=7.4 Hz, 3H).

[1266] yl)- 1 -methyl- 1 H-pyrazole-3 - carboxamide

[1267] Method M, 1.41

[1268] 522.1

[1269] δ 11.19 - 11.08 (m, 1H), 8.46 (s, 1H), 8.40 - 8.33 (m, 2H), 7.81 (s, 1H), 7.71 (s, 1H), 7.33 - 7.16 (m, 1H), 5.06 (s, 1H), 3.17 (d, J=5.1 Hz, 2H), 3.06 (s, 2H), 2.69 (s, N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- 2H), 2.55 (s, 3H), 1.59 (br d, 2-m ethylpropyl)- 1 -i sopropyl- 1 H- J=6.6 Hz, 6H), 1.26 (s, 6H), 1.14 benzo[d]imidazol-6-yl)pyridin-2-yl)-5- - 1.03 (m, 6H).

[1270] (2-hydroxy-2-methylpropyl)-2-

[1271]

[1272] mi I Method M, 1.30

[1273] MN\£F635.2

[1274] J HN^^M \ δ 11.45 (s, 1H), 8.53 - 8.46 (m, 2H), 8.35 (br d, J=6.1 Hz, 1H), A M^

[1275] yM° / 7.94 (s, 1H), 7.86 (s, 1H), 7.80 - 7.74 (m, 1H), 7.33 (d, J=11.4 Hz, < N^CF3— \ 6H 1H), 5.10 (dt, J=14.2, 7.1 Hz, 5-(3-(dimethylamino)propoxy)-N-(5- 1H), 4.28 (br t, J=5.9 Hz, 2H), fluoro-4-(4-fluoro-2-(2-hydroxy-2- 3.24 (br d, J=3.1 Hz, 2H), 3.12 (s, methylpropyl)- 1 -i sopropyl- 1 H- 2H), 2.83 (br s, 6H), 2.23 - 2.12 benzo[d]imidazol-6-yl)pyridin-2-yl)-2- (m, 2H), 1.60 (d, J=6.9 Hz, 6H), (trifluoromethyl)nicotinamide 1.27 (s, 6H).

[1276] Method M, 1.30

[1277] M 1N F582.2

[1278] J HN^^M \ δ 8.28 (s, 1H), 8.20 (s, 2H), 7.61 (s, 1H), 7.06 (br d, J=11.4 Hz, 1H), 4.91 - 4.77 (m, 1H), 4.23 (br 1 X -A Mr t, J=6.3 Hz, 2H), 2.84 (s, 2H), \ OH 2.47 (s, 3H), 2.15 (t, J=7.1 Hz,

[1279] 2H), 1.92 (s, 6H), 1.70 (brt, 6-(3-(dimethylamino)propoxy)-N-(5- fluoro-4-(4-fluoro-2-(2-hydroxy-2- J=6.7 Hz, 2H), 1.37 (d, J=6.8 Hz, methylpropyl)- 1 -i sopropyl- 1 H- 6H), 1.04 (s, 6H). benzo[d]imidazol-6-yl)pyridin-2-yl)-3- methylpyrazine-2-carboxamide

[1280] F Method N, 1.47

[1281] NMfF647.3

[1282] 11.18 - 11.10 (m, 1H), 8 \\ A.48 (dd, L A'NJ=14.6, 2.0 Hz, 2H), 8.41 (br d, I ° NA / J=6.0 Hz, 1H), 7.84 - 7.73 (m, X -x Mr 2H), 7.31 - 7.23 (m, 1H), 5.14 - \ OH

[1283] 5.01 (m, 1H), 3.91 (br dd, J=10.8, N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- 3.7 Hz, 2H), 3.30 (s, 6H), 3.07 (s, 2-methylpropyl)- 1 -i sopropyl- 1 H- 4H), 2.66 - 2.57 (m, 1H), 2.56 (s, benzo[d]imidazol-6-yl)pyridin-2-yl)-2- 3H), 1.88 - 1.65 (m, 6H), 1.63 - methyl-5-(l-(tetrahydro-2H-pyran-4- 1.57 (m, 6H), 1.54 - 1.40 (m, 2H), yl)piperidin-4-yl)nicotinamide

[1284] 1.27 (s, 6H).

[1285] F Method N, 1.72

[1286] 701.7NMff

[1287] tkk \\ A δ 11.49 (s, 1H), 8.78 (s, 1H), 8.50

[1288] (s, 1H), 8.39 - 8.30 (m, 1H), 8.12 \ MA° NA /

[1289] - 8.02 (m, 1H), 7.84 (s, 1H), 7.35 ^Mi M -x Mr < NCF3 \ OH - 7.27 (m, 1H), 5.14 - 5.01 (m, N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- 1H), 4.15 - 3.86 (m, 2H), 3.73 - 2-methylpropyl)- 1 -i sopropyl- 1 H- 3.56 (m, 1H), 3.44 - 3.29 (m, 2H), benzo[d]imidazol-6-yl)pyridin-2-yl)-5- 3.10 (s, 5H), 2.25 - 2.12 (m, 2H), (1 -(tetrahydro-2H-pyran-4- 2.12 - 1.89 (m, 5H), 1.76 - 1.65 yl)piperidin-4-yl)-2- (m, 2H), 1.60 (d, J=6.9 Hz, 6H), (trifluoromethyl)nicotinamide 1.35 - 1.23 (m, 7H).

[1290]

[1291] Method M, 1.5

[1292] 597.1

[1293] δ 9.05 (s, 1H), 8.52 (s, 1H), 8.25 (br d, J=5.6 Hz, 1H), 8.08 - 7.84 (m, 1H), 7.83 (s, 1H), 7.28 (br d, J=11.6Hz, 1H), 5.15 - 4.98 (m, 1H), 4.84 (s, 1H), 3.66 - 3.55 (m, 1H), 3.07 (s, 2H), 1.60 (br d, l-(difluoromethyl)-4-(ethylsulfonyl)- J=6.8 Hz, 6H), 1.27 (s, 6H), 1.20 N-(5-fluoro-4-(4-fluoro-2-(2-hydroxy- (brt, J=7.3 Hz, 3H). Protons 2-m ethylpropyl)- 1 -i sopropyl- 1 H- missing due to solvent benzo[d]imidazol-6-yl)pyridin-2-yl)- suppression or exchange or lH-pyrazole-3-carboxamide overlap with the NMR solvent.

[1294] Method N, 1.63

[1295] 683.2

[1296] 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 9.60 - 9.31 (m, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.45 - 8.37 (m, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 2-(difluoromethyl)-N-(5-fluoro-4-(4- 7.31 (d, J=11.4 Hz, 1H), 5.10 (s, fluoro-2-(2 -hydroxy -2 -methylpropyl)- 1H), 4.05 - 3.96 (m, 2H), 3.71 - 1 -isopropyl- lH-benzo[d]imidazol-6- 3.60 (m, 2H), 3.56 - 3.44 (m, 1H), yl)pyridin-2-yl)-5-(l-(tetrahydro-2H- 3.35 (s, 2H), 3.22 - 3.03 (m, 6H), pyran-4-yl)piperidin-4-yl)nicotinamide 2.24 - 2.15 (m, 2H), 2.08 - 1.94 (m, 4H), 1.79 - 1.65 (m, 2H), 1.61 (d, J=6.9 Hz, 6H), 1.28 (s, 6H). Method N, 1.75

[1297] 692.3

[1298] δ 11.51 - 11.42 (m, 1H), 8.86 - 8.74 (m, 1H), 8.49 (s, 1H), 8.39 (br d, J=6.0 Hz, 1H), 8.11 - 8.00 (m, 2H), 7.90 - 7.83 (m, 1H), 7.53 - 7.43 (m, 1H), 5.03 (s, 1H), 4.10 N-(4-(2-(2-cyano-2-methylpropyl)-4- - 3.90 (m, 2H), 3.82 - 3.46 (m, fluoro- 1 -i sopropyl - 1 H- 4H), 3.43 - 3.28 (m, 2H), 3.23 - benzo[d]imidazol-6-yl)-5- 3.02 (m, 3H), 2.26 - 2.12 (m, 2H), fluoropyridin-2-yl)-5-(l-(tetrahydro- 2.00 (br d, J=12.3 Hz, 4H), 1.76 - 2H-pyran-4-yl)piperidin-4-yl)-2- 1.67 (m, 2H), 1.67 - 1.62 (m, 6H), (trifluoromethyl)nicotinamide 1.56 (s, 6H), 1 proton presumed

[1299]

[1300]

[1301] supressed along with water. Method N, 1.85

[1302] 693.2

[1303] 8.77 - 8.71 (m, 1H), 8.49 - 8.43 (m, 1H), 8.39 - 8.31 (m, 1H), 8.08 - 7.98 (m, 2H), 7.89 - 7.80 (m, 1H), 7.52 - 7.40 (m, 1H), 5.01 - 4.84 (m, 1H), 4.30 - 4.17 (m, 2H), N-(5-fluoro-4-(4-fluoro- 1 -isopropyl-2- 3.92 - 3.83 (m, 2H), 3.35 - 3.23 (2, 2, 2-tri fluoroethyl)- 1H- (m, 2H), 3.08 - 2.93 (m, 2H), 2.84 benzo[d]imidazol-6-yl)pyridin-2-yl)-5- - 2.72 (m, 1H), 2.48 - 2.40 (m, ( 1 -(tetrahy dro-2H-pyran-4- 1H), 2.33 - 2.18 (m, 2H), 1.87 - yl)piperidin-4-yl)-2- 1.80 (m, 2H), 1.79 - 1.67 (m, 4H), (trifluoromethyl)nicotinamide 1.61 (d, J=6.8 Hz, 6H), 1.50 - 1.35 (m, 2H), _

[1304] Method M, 1.57

[1305] 561.1

[1306] 68.51 - 8.46 (m, 2H), 8.26 (d, J=5.9 Hz, 1H), 7.82 (s, 1H), 7.27 (d, J=11.3 Hz, 1H), 5.14 - 5.01 (m, 1H), 4.84 (s, 1H), 4.01 (s, 3H), 3.60 - 3.54 (m, 1H), 3.06 (s, 2H), 1.59 (d, J=6.9 Hz, 6H), 1.26 4-(ethylsulfonyl)-N-(5-fluoro-4-(4- (s, 6H), 1.16 (t, J=7.4 Hz, 3H). fluoro-2-(2 -hydroxy -2 -methylpropyl)- 1 -isopropyl- lH-benzo[d]imidazol-6- yl)pyridin-2-yl)-l-methyl-lH-pyrazole- 3 -carboxamide

[1307] Method N, 1.74 min

[1308] 749.2

[1309] 1H NMR (400 MHz, DMSO-d6) 6 = 11.42 (s, 1H), 8.76 (d, J = 1.5 Hz, 1H), 8.50 (s, 1H), 8.35 (d, J = 5.8 Hz, 1H), 8.07 (s, 1H), 7.80 (s, 1H), 7.32 (d, J = 11.3 Hz, 1H), 6.55 (dt, J = 4.8, 54.5 Hz, 1H), 5-( 1 -(2-oxaspiro[3.3 ]heptan-6- 5.41 (br dd, J = 3.4, 7.6 Hz, 1H), yl)piperidin-4-yl)-N-(4-( 1-(1,1- 4.91 (s, 1H), 4.59 (s, 2H), 4.45 (s, difluoropropan-2-yl)-4-fluoro-2-(2- 2H), 3.20 - 3.10 (m, 1H), 3.09 - hydroxy-2-methylpropyl)- 1H- 3.01 (m, 1H), 2.91 (br d, J = 9.0 benzo[d]imidazol-6-yl)-5- Hz, 2H), 2.81 - 2.70 (m, 1H), fluoropyridin-2-yl)-2- 2.55 (s, 1H), 2.41 - 2.28 (m, 2H), (trifluoromethyl)nicotinamide Isomer 1 2.00 - 1.89 (m, 2H), 1.87 - 1.75 (m, 4H), 1.70 (d, J = 7.0 Hz, 5H),

[1310]

[1311]

[1312] 1.32 (s, 3H), 1.22 (s, 3H). Method N, 1.74 min

[1313] 749.2

[1314] 1H NMR (400 MHz, DMSO-d6) 8 = 11.42 (s, 1H), 8.76 (d, J = 1.5 Hz, 1H), 8.50 (s, 1H), 8.35 (d, J = 5.8 Hz, 1H), 8.07 (s, 1H), 7.80 (s, 1H), 7.32 (d, J = 11.3 Hz, 1H), 6.55 (dt, J = 4.8, 54.5 Hz, 1H), 5-( 1 -(2-oxaspiro[3.3 ]heptan-6- 150 5.41 (br dd, J = 3.4, 7.6 Hz, 1H), yl)piperidin-4-yl)-N-(4-( 1 -( 1, 1 - 4.91 (s, 1H), 4.59 (s, 2H), 4.45 (s, difluoropropan-2-yl)-4-fluoro-2-(2- 2H), 3.20 - 3.10 (m, 1H), 3.09 - hydroxy-2-methylpropyl)- 1H- 3.01 (m, 1H), 2.91 (br d, J = 9.0 benzo[d]imidazol-6-yl)-5- Hz, 2H), 2.81 - 2.70 (m, 1H), fluoropyridin-2-yl)-2- 2.55 (s, 1H), 2.41 - 2.28 (m, 2H), (trifluoromethyl)nicotinamide

[1315] 2.00 - 1.89 (m, 2H), 1.87 - 1.75 Isomer 2

[1316] (m, 4H), 1.70 (d, J = 7.0 Hz, 5H),

[1317]

[1318] 1.32 (s, 3H), 1.22 (s, 3H).

[1319] 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 2 nitrogen atoms, 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-4alkyl)2, -NH(CI-4haloalkyl), -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, 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, C 1-4 haloalkoxy substituted with 0-2 Rc, -NHC(=O)O(C 1-4 alkyl), -NHC(=O)O(CI-4alkyl),-(O)0-1-(CH2)0-1-(C3-6cycloalkyl 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 a monocycle, bridged cycle or spiro cycle, is partially satuated or fully satuated, and is substituted with 0 to 3 Re; or -(O)0-1-(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,CM haloalkoxy, NH2, NH(CI-4alkyl), N(CI-4alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;Rbis H, C1-4 haloalkyl, -C(=O)(Ci-4alkyl), -C(=O)O(Ci-4alkyl), C alkyl substituted with 0-1 Rf, or a 4- to 8-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;Rcis halogen, cyano, OH, C haloalkyl, CM haloalkoxy, N(Ci-4alkyl)2, CM alkyl substituted with 0 to 2 Rf, or CM alkoxy substituted with 0 to 1 Rf;Rdis halogen, cyano, OH, CM alkoxy, CM haloalkyl, CM haloalkoxy, -O(C=O)H, -O(C=O)(C 1-4 alkyl), -C(=0)0(CM alkyl), NH2, N(CM alkyl)2, -C(=O)NH2, -C(=O)N(CI-4 alkyl)2, C2-6 alkenyl, C2-6 alkynyl, or C1-6 alkyl substituted with 0 to 2 Rc;Reis oxo or Rd;Rfis halogen, OH, cyano, -CH2OH, CM alkoxy, or N(Ci-4alkyl)2;Rgis H, CM alkyl substituted with 0 to 1 Rf, CM alkoxy, or C3-6 cycloalkyl; Rglis H or CM 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:Het is a 6-membered heteroaryl containing 1 to 2 nitrogen atoms, wherein the heteroaryl is substituted with 1 R5and 0 to 3 R6;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;R2is H, Ci-4 alkoxy, Ci-6 alkyl substituted with 0 to 1 Ra, Ci-6 haloalkyl substituted with 0 to 1 Ra, or -NHC(=0)( Ci-4 alkyl);R3is halogen, -OH, cyano, Ci-6 alkyl, Ci-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, C 1-4 haloalkyl, C 1-4 haloalkoxy, or -SO2(Ci-4 alkyl substituted with 0 to 1 Rc);Rais halogen, cyano, -OH, -CH2OH, C1-4 alkoxy, C1-4 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, orC1-4 haloalkoxy, -NH2, -NH(CI-4 alkyl) or -N(CI-4 alkyl)2; andRdis halogen, cyano, OH, C1-4 alkyl substituted with 0-1 OH,C1-4 alkoxy, C1-4 haloalkyl, or C1-4 haloalkoxy.

3. A compound of Formula (II):or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:Het is a 6-membered heteroaryl containing 1 to 2 nitrogen atoms, 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 ring heteroatom which is N, N(Rb), O, or S(O)P, and wherein said heterocycle is partially satuated or fully satuated, and is substituted with 0 to 2 Re;R2is CM fluoroalkyl or Ci-6 alkyl substituted with 0 to 1 Ra, or -NHC(=O)( C i-4 alkyl);R3ais H orR3;R3is F, Cl, cyano, Ci-4 alkyl, or Ci-4 fluoroalkyl;R4is H, F or Cl;R5is halogen, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 fluoroalkyl, Ci-4 fluoroalkoxy, or -SO2(Ci-4alkyl);R6is halogen, cyano, Ci-6 alkyl substituted with 0-2 Rc, C2-6 alkynyl substituted with 0-1 Rc, Ci-4haloalkyl substituted with 0-1 Rc, C1-4 alkoxy substituted with 0-1 Rc, C1-4 haloalkoxy substituted with 0-1 Rc,-NHC(=O)O(Ci-4 alkyl), C3-6 cycloalkyl, a 5- to 6-membered heteroaryl including 1 to 4 ring heteroatom which are N, N(Rb), O, or S(O)P, and is substituted with 0 to 2 Rd; or a 5 - to 6-membered heterocycle including 1 to 4 ring heteroatom which are N, N(Rb), O, or S(O)P, and wherein the heterocycle is partially satuated or fully satuated, and is substituted with 0 to 2 Re;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, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy,-NH2, -NH(CI-4alkyl) or -N(CI-4alkyl)2;Rdis F, cyano, Ci-4 alkyl substituted with 0-1 OH, Ci-4 fluoroalkyl or Ci-4 alkoxy;Reis oxo, F, Cl, OH, Ci-4 alkyl, or Ci-4 fluoroalkyl;Rgis H or Ci-2alkyl or -CH20H; andp is 0, 1 or 2.

4. The compound of claim 3, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R5VS Y"'(R6)o-1,Or (r6)°-1;R1is Ci-4 alkyl, C1-4 fluoroalkyl, -CH(Ci-2alkyl)-cyclopropyl, cyclopentyl, xC alkyl)(C1-2alkyl)0-2cyclohexyl substituted with 0 to 1 -N(C1-4alkyl)2?,1-2, orxRb.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;R3ais H orR3;R3is F or Cl;R4is H, F or Cl;R5is halogen, C1-4 alkyl, C 1-4 fluoroalkyl, -SO2(Ci-4 alkyl), or -SO2CH2(C3-4 cycloalkyl);R6is Ci-6 alkyl substituted with 0-2 Rc, C2-6 alkynyl substituted with 0-1 Rc, Ci-4haloalkyl substituted with 0-1 Rc, C1-4 alkoxy substituted with 0-1 Rc,C1-4 haloalkoxy substituted with 0-1 Rc, -NHC(=O)O(CI-4 alkyl), C3-4 cycloalkyl,lH-l,2,3-triazol-l-yl, lH-l,2,3,4-tetrazol-l-yl,R6ais H or cyano;Rais cyano or OH;Rbis H, C1-4 alkyl or C1-4 fluoroalkyl; andRcis -OH, -NH2, -NH(CI-4alkyl) or -N(CI-4alkyl)2.

5. The compound of claim 3 or claim 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is C1-4 alkyl, C1-4 fluoroalkyl, -CH(Ci-2alkyl)-cyclopropyl, cyclopentyl, orR2is C1-4 fluoroalkyl or C1-6 alkyl substituted with 0 to 1 Ra, or-NHC(=O)( C 1-4 alkyl); andR5is halogen, C1-4 alkyl, or SO2(Ci-4alkyl).

6. The compound of any one of claims 3 to 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R5(R6)o-17. The compound of any one of claims 3 to 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is Ci-4 alkyl, cyclopentyl or cyclohexyl substituted with -N(C1-4 alkyl)2; R2is Ci-4 fluoroalkyl or Ci-6 alkyl substituted with OH;R3ais H orF;R4is F;R5is Cl, Ci-2 alkyl, or -SO2(C1-2 alkyl); 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 7, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is C1-4 alkyl or cyclopentyl;R2is C1-6 alkyl substituted with OH; andR6is C alkyl, C3-5 alkynyl substituted with -NH(CI-2 alkyl), CM alkoxy, or 1 H- 1, 2, 3, 4 -tetr azol - 1 -y 1.

9. A compound of F ormul a (III):R3aor a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:R1is Ci-4 alkyl, Ci-4 fluoroalkyl, -CH(Ci-2alkyl)-cyclopropyl, cyclopentyl, or1-2R2is C1-4 fluoroalkyl, C alkyl substituted with 0 to 1 RaorR3ais H orR3;R3is F or Cl;R4is F;R5is Ci-2alkyl, -SO2(C1-2alkyl) or -SO2CH2(cyclopropyl);R6bis H or R6;R6is C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkoxy, cyclopropyl, orNalkyl1'4; andRais cyano or -OH.

10. The compound of claim 9, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:R1is -CH2CH3, -CH(CH3)2, -CH2CHF2, -CH(CH3)CHF2,-CH(CH3)-cyclopropyl, cyclopentyl,or;R2is -CH2CF3, -CH2C(CH3)2OH, -CH2C(CH3)2CN, orF. R3ais H, F or Cl; R5is -CH3, -SO2CH3, -SO2CH2CH3, or -SO2CH2(cyclopropyl); andR6bis H, -CH3, -OCH3, -OCH2CHF2, cyclopropyl, orz'Pr.

11. The compound according to claim 1, which is selected from any one of the Examples 1 to 150 as described in the specification, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

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

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

14. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, or a composition according to claim 12 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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