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

Abstract

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

Description

[0001] BENZIMIDAZOLE COMPOUNDS AS CAMK2 INHIBITORS

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

[0003] 63 / 721,684, filed November 18, 2024; the content of which is herein incorporated by reference in its entirety.

[0004] FIELD OF THE INVENTION

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

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

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

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

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

[0010] SUMMARY OF THE INVENTION

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

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

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

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

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

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

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

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

[0019]

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

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

[0022] -(CRgRgl)o-3-(C3-8cycloalkyl substituted with 0 to 4 Re),

[0023] -(CRgRgl)o-2-(Cs-6 spirocycloalkyl or C5-6 bridged cycloalkyl substituted with 0 to 2 Re), -(CRgRgl)o-3-(phenyl substituted with 0 to 3 Rd), or

[0024] -(CRgRgl)o-3-(5- to 6-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 3 Rd);

[0025] R2is H, cyano, OH, SH, NH2, C1-4 alkylthio, C1-4 alkoxy, C1-8 alkyl substituted with 0 to 2 Ra, C2-6 alkenyl substituted with 0 to 1 Ra,

[0026] C2-6 alkynyl substituted with 0 to 1 Ra, C1-6 haloalkyl substituted with 0 to 1 Ra, -NH(C=O)C 1-4 alkyl, -(CRgRgl)o-3-(C3-8 cycloalkyl substituted with 0 to 4 Re), -(CRgRgl)o-2-(Cs-6 spirocycloalkyl or C5-6 bridged cycloalkyl substituted with 0 to 2 Re), -(CRgRgl)o-2-(4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re), -(CRgR^o-s- phenyl substituted with 0 to 3 Rd), or -(CRgRgl)o-3-(5- to 6-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 3 Rd);

[0027] R3is halogen, cyano, Ci-4 haloalkyl, Ci-4 haloalkoxy, -C(=O)O(Ci-4 alkyl), NH2, N(CI-4 alkyl)?, -C(=O)NH2, -C(=O)N(CI-4 alkyl)2, C2-6 alkenyl, C2-6 alkynyl, ORh, or C1-6 alkyl substituted with 0 to 2 Ra;

[0028] R4is H, halogen, cyano or C1-4 alkyl;

[0029] R5is H, halogen, cyano, -NO2, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl substituted with 0 to 2 Ra, -SO2R1, or

[0030] -(CH2)o-i-(phenyl substituted with 0 to 2 Rd);

[0031] R6is H, halogen, cyano, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -NH(Ci-4 alkyl), -SC>2(Ci-4 alkyl), or C1-4 alkyl substituted with 0 to 2 Ra;

[0032] R7is H, halogen, cyano, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -O(CH2)I-2O(CI-4alkyl), -OCH2CH2N(Ci-4alkyl)2, -NH(Ci-4 alkyl substituted with 0 to 1 Ra), C1-4 alkyl substituted with 0 to 2 Ra, -C(=O)ORn, -C(=O)NRnR12, or

[0033] -(CH2)O-I-NHC(=0)R10;

[0034] R8is H, halogen, cyano, C1-4 haloalkyl, C1-4 haloalkoxy, OR10, -C(=O)ORn, -(CH2)O-I-NR11R12, -(CH2)O-I-C(=0)NR11R12, -(CH2)O-I-NHC(=0)R10, CI-4alkylthio, -SC>2RC, -SChNR^R11, -NHSO2R10, C1-6 alkyl substituted with 0 to 2 Ra, or

[0035] C2-4 alkyl substituted with 0 to 1 Ra;

[0036] R9is H, halogen, C1-4 alkyl, or C1-4 haloalkyl;

[0037] R10is H, C1-4 alkyl substituted with 0 to 1 Ra, -(CH2)o-i-C3-6 cycloalkyl, or -(CH2)O-I -phenyl;

[0038] R11is H or C1-4 alkyl;

[0039] R12is H or R10;

[0040] Rais halogen, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 haloalkyl,

[0041] C1-4 haloalkoxy, NH2, NH(CI-4alkyl), N(CI-4alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;

[0042] Rbis H, C1-4 fluoroalkyl, -C(=O)(Ci-4 alkyl), -C(=O)O(Ci-4 alkyl) or C1-4 alkyl substituted with 0-1 OH;

[0043] Rcis halogen, OH, cyano, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl substituted with 0 to 2 Rf, or C1-4 alkoxy substituted with 0 to 1 Rf;

[0044] Rdis halogen, OH, cyano, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -O(C=O)H, -O(C=O)(C i-4 alkyl), -C(=O)O(Ci-4alkyl), NH2, N(CI-4alkyl)2, -C(=O)NH2, -C(=O)N(CI-4 alkyl)2, C2-6 alkenyl, C2-6 alkynyl, or Ci-6 alkyl substituted with 0 to 2 Rc;

[0045] Reis oxo or Rd;

[0046] Rfis halogen, OH, cyano, -CH20H, Ci-4 alkoxy, or N(Ci-4alkyl)2;

[0047] Rgis H, Ci-4 alkyl substituted with 0 to 1 Rf, Ci-4 alkoxy, or C3-6 cycloalkyl;

[0048] Rglis H or C1-4 alkyl;

[0049] Rhis H or C1-6 alkyl substituted with 0 to 1 Ra;

[0050] R1is C 1-4 alkyl substituted with 0 to 1 Rc;

[0051] n is 0, 1 or 2; and

[0052] p is 0, 1 or 2.

[0053] 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:

[0054] R1is H, C1-6 alkyl substituted with 0 to 2 Ra, C1-6 haloalkyl substituted with 0 to 1 Ra, a 4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re,

[0055] -(CH2)o-i-(CHRg))o-i-(CH2)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re),

[0056] -(CH2)o-i(CRgRgl)o-i-(Cs-6 spirocycloalkyl or C5-6 bridged cycloalkyl substituted with 0 to 2 Re), or -(CH2)o-i(CRgRgl)o-i(CH2)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 2 Rd);

[0057] R2is H, cyano, OH, SH, NH2, C1-4 alkylthio, C1-4 alkoxy, C2-4 alkynyl,

[0058] C1-8 alkyl substituted with 0 to 2 Ra, C2-4 alkenyl substituted with 0 to 1 Ra, C1-6 haloalkyl substituted with 0 to 1 Ra, -NH(C=0)C 1-4 alkyl,

[0059]

[0060] heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re), -(CH2)o-2- (CRgRgl)o-i-(phenyl substituted with 0 to 3 Rd), or -(CH2)o-i(CRgRgl)o-i(CH2)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 2 Rd);

[0061] R3is halogen, OH, Ci-4 haloalkyl, Ci-4 haloalkoxy, Ci-4 alkyl substituted with 0 to 1 Ra, or Ci-4 alkoxy substituted with 0 to 1 Ra;

[0062] R5is H, halogen, cyano, -NO2, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl substituted with 0 to 1 Ra, -SO2(C 1-4 alkyl substituted with 0 to 1 Rc), or -SO2(CH2)I-2O(CH2)I-2O(CI-4alkyl);

[0063] R6and R7are H, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or C1-4 haloalkoxy;

[0064] R8is H, halogen, cyano, C1-4 haloalkyl, C1-4 haloalkoxy, OR10,

[0065] C1-4 alkylthio, -SC>2(Ci-4 alkyl substituted with 0 to 1 Rc), -SO2NH2, -SChNR^R11, -NHSO2R10, C1-6 alkyl substituted with 0 to 1 Ra, or C2-4 alkyl substituted with 0 to 1 Ra; and

[0066] R10is H, Ci-4 alkyl substituted with 0 to 1 R , C3-6 cycloalkyl, or benzyl.

[0067] In a third aspect, the present invention provides a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of the first or second aspect and wherein, independently for each occurrence:

[0068] R1is H, C1-6 alkyl substituted with 0 to 2 Ra, C1-6 fluoroalkyl substituted with 0 to 1 Ra, a 4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re, -(CH2)o-i-(CHRg))o-i-(CH2)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re),

[0069] -(CH2)O-2-(CS-6 spirocycloalkyl or C5-6 bridged cycloalkyl substituted with 0 to 2 Re), or -(CH2)o-i(CRgRg)o-i(CH2)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 2 Rd);

[0070] R2is H, cyano, OH, SH, NH2, C1-4 alkylthio, C1-4 alkoxy, C1-6 alkyl substituted with 0 to 1 Ra, C2-4 alkenyl substituted with 0 to 1 Ra,

[0071] C1-6 fluoroalkyl substituted with 0 to 1 Ra, -NH(C=O)C 1-4 alkyl,

[0072] -(CH2)o-2-(CHRg))o-i-(C3-6 cycloalkyl substituted with 0-2 Re), -(CH2)O-2-(CS-6 spirocycloalkyl or C5-6 bridged cycloalkyl substituted with 0 to 2 Re), -(CH2)o-2-(4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re),

[0073] -(CH2)o-2-(CRgRgl)o-i-(phenyl substituted with 0 to 2 Rd), or

[0074] -(CH2)o-i(CRgRgl)o-i(CH2)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 2 Rd);

[0075] R3is halogen, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl, or

[0076] C1-4 fluoroalkoxy;

[0077] R5is H, halogen, C1-4 alkyl, C1-4 alkoxy, Ci-4haloalkyl, C 1-4 haloalkoxy, or -SO2(Ci-4 alkyl substituted with 0 to 1 Rc);

[0078] R8is H, halogen, OH, cyano, C1-4 alkyl, C1-4 alkoxy, Ci-4haloalkyl,

[0079] C1-4 haloalkoxy, or -CH2OH;

[0080] Rais halogen, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 fluoroalkyl,

[0081] C1-4 fluoroalkoxy, NH2, NH(Ci-4 alkyl), N(CI-4 alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;

[0082] Rbis H or C1-4 alkyl;

[0083] Rcis F, Cl, cyano, OH, C1-4 alkoxy, C1-4 fluoroalkyl, or C1-4 fluoroalkoxy;

[0084] Rdis halogen, cyano, OH, -CH2OH, C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, -O(C=O)H, -O(C=O)(Ci-4alkyl), or -C(=O)O(Ci-4alkyl);

[0085] Reis oxo or Rd;

[0086] Rgis H, C1-2 alkyl, -CH2OH, C1-2 alkoxy, or C3-4 cycloalkyl; and

[0087] Rglis H or C1-2 alkyl.

[0088] In a fourth aspect, the present invention provides a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of any of the first to third aspects and wherein, independently for each occurrence:

[0089] R1is H, C1-6 alkyl substituted with 0 to 2 Ra, C1-4 fluoroalkyl substituted with 0 to 1 Ra, -(CH2)o-i-(CHRg))o-i-(CH2)o-i-(C3-6 cycloalkyl substituted with 0-2 Re), a 4- to 6-membered heterocyclic ring including 1 ring heteroatom which is independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully

[0090] satuated, and is substituted with 0 to 2 Re,

[0091]

[0092] R2is H, cyano, SH, NH2, C 1-4 alkylthio, C1-6 alkyl substituted with 0 to 1 Ra, C2-4 alkenyl substituted with 0 to 1 Ra, C 1-4 fluoroalkyl substituted with 0 to 1 Ra, -NH(C=O)C 1-4 alkyl, -(CH2)o-2-(CHRg))o-i-(C3-6 cycloalkyl substituted with 0-2 Re), -(CH2)O-2-(4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re),

[0093] -(CH2)i-2-(CHRg))o-i-(phenyl substituted with 0 to 2 Rd),

[0094] -(CH2)o-i-(CRgRgl)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), or O, wherein the heteroaryl is substituted with 0 to 2 Rd),

[0095]

[0096] R4is H, F, Cl, cyano, or C1-2 alkyl;

[0097] R5is H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl, C 1-4 fluoroalkoxy, or - SO2(C 1-4 alkyl);

[0098] R6and R7are H, F, Cl, CF3, or C1-2 alkyl;

[0099] R8is H, halogen, OH, cyano, C1-4 alkyl, C1-4 alkoxy, Ci-4haloalkyl, or

[0100] C1-4 haloalkoxy;

[0101] R9is H, halogen, CF3, or C1-2 alkyl; and

[0102] Reis oxo, halogen, OH, -CH2OH, C1-4 alkyl, -O(C=O)H, or

[0103] -O(C=O)(Ci-4 alkyl).

[0104] In a fifth aspect, the present invention provides a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of any one of the first to fourth aspects and wherein, independently for each occurrence:

[0105] R3is F, Cl or C1-2 alkyl;

[0106] R4is H, F or Cl;

[0107] R6and R7are H or F;

[0108] R8is H, halogen, OH, cyano, C1-4 alkyl, C1-4 alkoxy, C 1-4 fluoroalkyl, or

[0109] C1-4 fluoroalkoxy; R9is H, F, Cl, CF3, or C1-2 alkyl; and

[0110] Rais F, Cl, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 fluoroalkyl, NH2,

[0111] N(Ci-4alkyl)2, -C(=O)OH, -C(=O)NH2, or -SO2NH2.

[0112] In a sixth aspect, the present invention provides a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of any one of the first to fifth aspects and wherein, independently for each occurrence:

[0113] R1is H, Ci-6 alkyl substituted with 0 to 2 Ra, C1-4 fluoroalkyl substituted with 0 to

[0114] 1 Ra, -(CHRg))o-i-(CH2)o-i-(C3-6 cycloalkyl substituted with 0-2 Re),

[0115]

[0116]

[0117] R2is H, cyano, NH2, C1-6 alkyl substituted with 0 to 1 Ra, C1-4 fluoroalkyl substituted with 0 to 1 Ra, -NH(C=O)C 1-4 alkyl, -CH=C(CH3)CF3,

[0118] -(CH2)O-I-(C3-6 cycloalkyl substituted with 0 to 2 Re), -(CH2)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), or O, wherein the heteroaryl is substituted with 0 to 2 Rd), -CH(cyclopropyl)CH2OH,

[0119]

[0120] R3is F;

[0121] R5is H, F, Cl, C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, or -SO2(Ci-2alkyl);

[0122] R9is H, F or Cl;

[0123] Rbis H or CH3;

[0124] Reis halogen, OH, -CH2OH, C1-4 alkyl, -O(C=O)H, or -O(C=O)Ci-4 alkyl;

[0125] Rgis H, CH3 -CH2OH, -CH2OCH3, or cyclopropyl; and n is 0 or 1.

[0126] In a seventh aspect, the present invention provides a compound of Formula (II):

[0127]

[0128] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:

[0129] R1is H, Ci-6 alkyl substituted with 0 to 2 Ra, Ci-4 fluoroalkyl,

[0130]

[0131] R2is H, cyano, NH2, C1-6 alkyl substituted with 0 to 1 Ra, C1-4 fluoroalkyl substituted with 0 to 1 Ra, -NH(C=O)C 1-4 alkyl, -CH=C(CH3)CF3,

[0132] -(CH2)O-I-(C3-6 cycloalkyl substituted with 0 to 2 Re), -CH(cyclopropyl)CH2OH,

[0133]

[0134] R4is H, F or Cl; R5is H, F, Cl, C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, or -SO2(Ci-2alkyl);

[0135] R6and R7are H or F;

[0136] R8is H, halogen, OH, cyano, C1-4 alkyl, C1-4 alkoxy, C 1-4 fluoroalkyl, or

[0137] C1-4 fluoroalkoxy;

[0138] R9is H, F or Cl;

[0139] Rais F, Cl, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 fluoroalkyl, NH2,

[0140] N(Ci-4alkyl)2, -C(=O)OH, -C(=O)NH2, or -SO2NH2;

[0141] Rbis H or CH3;

[0142] Reis halogen, OH, -CH2OH, C1-4 alkyl, -O(C=O)H, or -O(C=O)Ci-4 alkyl; and Rgis H, CH3-CH2OH, -CH2OCH3, or cyclopropyl.

[0143] 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:

[0144] R1is H, Ci-6 alkyl substituted with 0 to 2 Ra, C1-4 fluoroalkyl,

[0145] -(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re),

[0146]

[0147] , R2is H, cyano, NH2, C1-6 alkyl substituted with 0 to 1 Ra, C1-4 fluoroalkyl substituted with 0 to 1 Ra, -NH(C=O)C 1-4 alkyl, -CH=C(CH3)CF3,

[0148] -(CH2)O-I-(C3-6 cycloalkyl substituted with 0 to 2 Re), -CH(cyclopropyl)CH2OH,

[0149] -(CH2)i-2-phenyl, -CH2CH(CH3)-phenyl,

[0150]

[0151] R5is H, F, Cl, CH3, -OCH3, -OCHF2, or -SO2CH3.

[0152] In a ninth 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 or eighth aspect and wherein, independently for each occurrence:

[0153] R1is C1-4 alkyl substituted with 0 to 1 Ra, C1-4 fluoroalkyl, -CH(cyclopropyl)CH2OH, -CH(CH3)cyclopropyl, or C4-5 cycloalkyl;

[0154] R2is C1-6 alkyl substituted with 0 to 1 Raor C1-4 fluoroalkyl;

[0155] R4is H orF; R5is Cl or -SO2CH3;

[0156] R6is H orF;

[0157] R7is H;

[0158] R8is halogen, C1-4 alkoxy or C 1-4 fluoroalkoxy;

[0159] R9is H or F; and

[0160] Rais OH, NH2, or -C(=O)NH2.

[0161] In another aspect, the present invention provides a compound of Formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of any of the seventh, eighth and ninth aspects and wherein, independently for each occurrence:

[0162] R1is C1-4 alkyl, CM fluoroalkyl, -CH(CH3)CH2OH, -CH(CH3)CH2NH2, -CH(cyclopropyl)CH2OH, -CH(CH3)cyclopropyl, or C4-5 cycloalkyl;

[0163] R2is C1-4 fluoroalkyl, -CH2C(CH3)2OH or -CH2C(CH3)2C(=O)NH2; and

[0164] R8is C alkoxy, or CM fluoroalkoxy.

[0165] In another aspect, the present invention provides a compound of Formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, within the scope of any of the seventh, eighth and ninth aspects and wherein, independently for each occurrence:

[0166] R1is -CH2CH3, -CH(CH3)2, -CH2CF2H, -CH(CH3)CH2OH, -CH(cyclopropyl)CH2OH, -CH(CH3)cyclopropyl, or cyclopentyl;

[0167] R2is -CH2CF3or -CH2C(CH3)2OH;

[0168] R4is F; and

[0169] R8is -OCH3, -OCF2H, or -OCH2CF2H.

[0170] In an embodiment, R1is independently -CH2CH3, -CH(CH3)2, or -CH2CF2H. In an embodiment, R1is independently -CH(CH3)CH2OH or -CH(cyclopropyl)CH2OH. In an embodiment, R1is independently -CH(CH3)cyclopropyl or cyclopentyl.

[0171] In an embodiment, R2is -CH2CF3. In an embodiment, R2is -CH2C(CH3)2OH.

[0172] In an embodiment, R5is -SO2CH3. In an embodiment, R5is Cl.

[0173] In an embodiment, R8is independently -OCH3, -OCHF2or -OCH2CHF2. In an embodiment, R8is -OCH3. In an embodiment, R8is -OCF2H or -OCH2CF2H.

[0174] In an embodiment, R9is H.

[0175] In an embodiment, Rais independently F, Cl, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 fluoroalkyl, NH2, N(CI-4 alkyl)2, -C(=O)OH, -C(=0)NH2, or -SO2NH2.

[0176] In an embodiment, Reis independently C1-2 alkyl, F, OH, -O(C=O)H, or -O(C=O)CH3.

[0177] In another aspect, the invention provides a compound selected from

[0178]

[0179]

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

[0181] 5 In another aspect, the invention provides a compound selected from

[0182]

[0183]

[0184] or a pharmaceutically acceptable salt thereof.

[0185] In another aspect, the invention provides a compound selected from

[0186]

[0187] or a stereoisomer or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides a compound selected from

[0188]

[0189] or a pharmaceutically acceptable salt thereof.

[0190] In a tenth aspect, the invention provides a compound selected from the exemplified Examples 1 to 338 or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0191] 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.

[0192] 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.

[0193] In another embodiment, the present invention provides a process for making a compound of the present invention. In another embodiment, the present invention provides an intermediate for making a compound of the present invention.

[0194] DEFINITIONS

[0195] 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.

[0196] 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.

[0197] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] “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.

[0202] 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".

[0203] 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.

[0204] Where a bonding attachment location is not specified, the bonding may be attached at any appropriate location as understood by practitioners in the art.

[0205] 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.

[0206] 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,

[0207] 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0208] 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.

[0209] The invention is intended to include all isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include13C and14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties. BIOLOGICAL METHODS

[0210] The inhibitory activity of compounds in the invention was tested in a CAMK2D activity assay in at least one of two formats.

[0211] CAMK2D HTRF Activity Assay (CAMK2D HTRF ACT)

[0212] The inhibitory activity of compounds was tested in the CAMK2D HTRF activity assays carried out in 20 mM Hepes (pH 7.5), 5 mM MgCh, 1 mM CaCh, 0.05 mg / mL BSA, 0.01 % 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%.

[0213] 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), 40 nM of the PLN peptide fragment (MEKVQYLTRSAIRRASTIEMPQQARQKLQN) were incubated with test compounds for 60 min. Following, the reactions were quenched with an EDTA solution (final concentration at 10 mM). pPLN K and pPLN D2 antibodies (diluted in detection buffer, Cis-Bio 63ADK074PEH) were added for a final 400-fold dilution from stock. This readout reaction was incubated for an additional 1.5 hours to 2 hours.

[0214] Endpoint data were collected on an Envision using TR-FRET (340 excitation, 665nm / 615nm ratiometric emission). 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.

[0215] CAMK2D ECHO MS Activity Assay

[0216] The inhibitory activity of compounds was tested in the CAMK2D ECHO MS activity assays carried out in 20 mM Hepes (pH 7.5), 10 mM MgCh, 1 mM CaCh, 50 ug / mL BSA, 0.015 % Brij-35 and 2 mM DTT. Compounds were solubilized at 10 mM in dimethylsulfoxide (DMSO) and serially diluted 3-fold for a total of eleven concentrations; final DMSO percentage in the reactions remained below 1%. 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.

[0217] Endpoint data was collected by determining the ratio of the m / z of product analyte using mass spectrometry, 731.7 — 712.3 divided by the m / z of internal standard analyte, 605.2 a 713.1.

[0218] 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.

[0219] 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.

[0220] Table 1

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230] Cellular Assay

[0231] 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 mis-expressed in 293T cells using the BacMam mammalian transduction system, again according to manufacturer’s protocols. In some cases, CAMK2D and PLN were stably co-transfected into HEK293T cells and a single clone was selected and expanded based on CAMK2D and PLN expression levels and assay performance. Cells were plated onto poly-D-lysine coated 96 well plates and grown to sub-confluence (24-48 hours). Test compounds were diluted in dimethyl sulfoxide to desired final concentrations. The growth medium was removed from the HEK 293 T cells, and was replaced with Opti-MEM without phenol red. Compounds were added directly to the wells; 96 or 384 well cell plates were shaken briefly by hand, and returned to the growth incubator to be incubated at 37 degrees Celsius under a humidified 5% CO2 atmosphere for 1 hour. Cells were then stimulated with 1 uM ionomycin final concentration for 15 minutes. Cell lysates were prepared and analyzed using the CisBio pPLN HTRF Assay Kit, following manufacturer’s protocols. Briefly, cell lysates were prepared by adding 50 uL supplemented cell lysis buffer and shaking at room temperature for 30 min. 16 uL of this lysate was transferred to a 384 well plate, and 4 uL of combined HTRF antibodies, and this was incubated overnight at room temperature in the dark. Plates were read for HTRF ratios 16-22 hours later on an Envision plate reader. Results were normalized as maximal inhibition observed in a staurosporin concentrationresponse 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.

[0232] Table 2. Assay in HEK293 cells measuring inhibition of PLN phosphorylation

[0233]

[0234]

[0235] < < <

[0236]

[0237] <

[0238]

[0239]

[0240] PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE

[0241] 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.

[0242] Unless otherwise specified, the following terms have the stated meanings. The term "subject" refers to any human or other mammalian species that could potentially benefit from treatment with a CAMK2D, CAMK2A, CAMK2B, CAMK2G inhibitor as understood by practitioners in this field. Some subjects include human beings of any age with risk factors for cardiovascular disease. Common risk factors include age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity arrthymia or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). The term "patient" means a person suitable for therapy as determined by practitioners in the field. As used herein, the term "patient" encompasses all mammalian species.

[0243] "Treating" or "treatment" cover the treatment of a patient or subject as understood by practitioners in this field. "Preventing" or "prevention" cover the preventive treatment ( / .< ., prophylaxis and / or risk reduction) of a subclinical disease-state in a patient or subject aimed at reducing the probability of the occurrence of a clinical disease-state as understood by practitioners in this field. Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. "Therapeutically effective amount" means an amount of a compound that is effective as understood by practitioners in this field.

[0244] 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. 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.

[0245] "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.

[0246] 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.

[0247] Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L.V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0248] 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.

[0249] 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.

[0250] 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.

[0251] Another aspect of the invention is a method for treating heart disease wherein the treatment is post myocardial infarction.

[0252] 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.

[0253] 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.

[0254] Another aspect of the invention is a method for treating heart disease wherein the treatment is given to a patient with chronic heart failure.

[0255] 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. The compounds of this invention can be administered by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0256] 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.

[0257] 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.

[0258] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition. A typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.

[0259] 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.

[0260] 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.

[0261] 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,

[0262] anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors (such as HMG CoA reductase inhibitors), LXR agonist, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (such as anion exchange resins, or quaternary amines (e.g., cholestyramine or colestipol)), low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin Bg, vitamin B 12, anti-oxidant vitamins, P-blockers, anti-diabetes agents, angiotensin II antagonists, angiotensin converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives.

[0263] 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.

[0264] The compounds of the invention may be used in combination with at least one of the following anti-diabetic agents depending on the desired target therapy. Studies indicate that diabetes and hyperlipidemia modulation can be further improved by the addition of a second agent to the therapeutic regimen. Examples of anti-diabetic agents include, but are not limited to, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone), and related insulin sensitizers, such as selective and non-selective activators of PPARa, PPARP and PPARg; dehydroepiandrosterone (also referred to as DHEA or its conjugated sulphate ester, DHEA-SO4); anti-glucocorticoids; TNFa inhibitors; dipeptidyl peptidase IV (DPP4) inhibitor (such as sitagliptin, saxagliptin), GLP-1 agonists or analogs (such as exenatide), a-glucosidase inhibitors (such as acarbose, miglitol, and voglibose), pramlintide (a synthetic analog of the human hormone amylin), other insulin secretagogues (such as repaglinide, gliquidone, and nateglinide), insulin, as well as the therapeutic agents discussed above for treating atherosclerosis.

[0265] 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,

[0266] P3 -adrenoreceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptins. Other agents used in treating obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, histamine H3 receptors, dopamine D2 receptor modulators, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA).

[0267] 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.

[0268] 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.

[0269] 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).

[0270] CHEMISTRY METHODS

[0271] Abbreviations as used herein, are defined as follows: "lx" for once, "2x" for twice, "3x" for thrice, " °C" for degrees Celsius, "aq" for aqueous, "Col" for column, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, "pL" for microliter or microliters, "N" for normal, "M" for molar, "nM" for nanomolar, "mol" for mole or moles, "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "RT" for retention time, "ON" for overnight, "atm" for atmosphere, "psi" for pounds per square inch, "cone." for concentrate, "aq" for "aqueous", "sat" or "sat'd " for saturated, "MW" for molecular weight, "mw" or "pwave" for microwave, "mp" for melting point, "Wt" for weight, "MS" or "Mass Spec" formass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid chromatography, "RP HPLC" for reverse phase HPLC, "TLC" or "tic" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser effect spectroscopy, "1H" for proton, "6 " for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" forbroad, "Hz" for hertz, and "a", "0", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art.

[0272] Ac Acetic

[0273] AcOH acetic acid

[0274] Acn (or MeCN) Acetonitrile

[0275] BBrs Boron tribromide

[0276] BINAP 2, 2'-bis(diphenylphosphino)- 1,1 '-binaphthyl

[0277] Bispin bis(pinacolato)diboron

[0278] Bn Benzyl

[0279] Boc / c / 7-butyl carbonyl

[0280] BOC2O di- / c77-butyl dicarbonate

[0281] BOP (Benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0282] BTFFH fluoro-N,N,N’,N’-bis(tetramethylene)formamidinium hexafluorophosphate

[0283] Bu Butyl

[0284] CDCI3 deutero-chloroform

[0285] CD3OD deutero-methanol Cs2CO3Cesium carbonate

[0286] dba as in (Pd2(dba)3) Dib enzy li deneacetone

[0287] DCM Dichloromethane

[0288] DEAD diethyl azodi carb oxy late

[0289] DIAD diisopropyl azodicarboxylate

[0290] DIEA or DIPEA Diisopropylethylamine

[0291] DMAP 4-dimethylaminopyridine

[0292] DME Dimethoxy ethane

[0293] DMF Dimethylformamide

[0294] DMSO dimethyl sulfoxide

[0295] DMSO-d6deutero-dimethyl sulfoxide

[0296] dppf 1,1 '-bis(diphenylphosphino)ferrocene

[0297] EDC 3-(Ethyliminomethyleamino)-N-N-dimethylpropan-l- amine

[0298] Et ethyl

[0299] EtOH Ethanol

[0300] EtOAc ethyl acetate

[0301] HATU 2-(7- Aza- IH-benzotri azole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluroni um hexafluorophosphate

[0302] HBTU 2-( 17 / -B enzotri azole- 1 -yl)- 1 , 1 ,3 , 3 -tetramethyluronium hexafluorophosphate

[0303] HC1 hydrochloric acid

[0304] HPLC high-performance liquid chromatography

[0305] z-Bu Isobutyl

[0306] z-Pr Isopropyl

[0307] K2HPO4 Dipotassium phosphate

[0308] LAH lithium aluminum hydride

[0309] LCMS liquid chromatography mass spectrometry

[0310] Me Methyl

[0311] MeOH Methanol

[0312] MgSO4magnesium sulfate NaCl sodium chloride

[0313] Na2CO3sodium carbonate

[0314] NaHCCh sodium bicarbonate

[0315] NaOH sodium hydroxide

[0316] Na2SO4sodium sulfate

[0317] NH4C1 ammonium chloride

[0318] NH4OAc ammonium acetate

[0319] NMM A-methylmorpholine

[0320] NCS N-Chlorosuccinimide

[0321] NBS A-Bromosuccinimide

[0322] NMP N-Methylpyrrolidone

[0323] Pd(OAc)2palladium(II) acetate

[0324] Pd(dppf)Cl2CH2C12[l,l'-Bis(diphenylphosphino)ferrocene]

[0325] dichloropalladium(II), complex with dichloromethane Pd(dba)2Bis(dibenzylideneacetone)palladium(0)

[0326] Ph Phenyl

[0327] PPh3Triphenylphosphine

[0328] Pr Propyl

[0329] t-Bu tert-butyl

[0330] TEA or Et3N Trimethylamine

[0331] TFA trifluoroacetic acid

[0332] THF Tetrahydrofuran

[0333] TMSC1 Trimethyl silyl chloride

[0334] T3P 1-Propanephosphonic anhydride solution

[0335] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0336] 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. 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).

[0337] Compounds having the general Formula (I) can be prepared by the following one or more of the synthetic schemes. Compounds of this invention can be prepared by the general route shown in Scheme 1, starting from 4-bromo-2-fluoro-l -nitrobenzene la. Miyaura borylation of la in presence of palladium catalysts such as [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)C12.CH2C12) under suitable solvents such as dioxane or dimethyl sulfoxide in presence of a base such as potassium acetate with conventional heating or microwave heating can provide 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane, intermediate lb. Additional methods for this transformation include other variations of Miyaura borylation using methods known to one skilled in the art for this type of coupling, (see for example Ishimaya & Miyaura, J. Org. Chem. 1995, 60, 7508).; Kurti, L. and Czako, B. Strategies and Applications of Named Reactions in Organic Synthesis, Elsevier (2005)).

[0338] Subsequent palladium-catalyzed coupling of lb to a suitably substituted iodide or bromide or chloride 1c, can provide intermediate Id. The coupling can be performed in presence of palladium catalysts such as l,r~bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (Pd(dppf)C12 CH2CI2) or 2nd gen XPhos precatalyst under suitable solvents such as dioxane and water in presence of a base such as potassium phosphate. Additional methods for this transformation include other variations of Suzuki -Miyaura cross coupling using methods known to one skilled in the art for this type of coupling, (see for example Miyaura & Suzuki, Chem. Rev. 1995, 95, 2457; Ashcroft & Wilford, Tett. Lett, 2013, 54, 4529).; Kurti, L. and Czako, B. Strategies and Applications of Named Reactions in Organic Synthesis, Elsevier (2005)). Nucleophilic aromatic substitution of Id with a suitably substituted amine in presence of a suitable solvent such as THF or DMF with or without Hunig’s base can provide intermediate le. Additional methods for this transformation include other variations of nucleophilic aromatic substitution using methods known to one skilled in the art. Subsequent nitro reduction of le in presence of a suitable reductant such as iron or zinc and a suitable acid such as HC1 or ammonium chloride in a suitable solvent such as ethanol under heating can provide intermediate If. This transformation can also be done in presence of sodium hydrosulfite and ammonia in THF at rt. Additional methods for this transformation include other variations of nitro reduction using methods known to one skilled in the art.

[0339] Compounds of this invention can be obtained from subsequent amide bond coupling between If and a suitably substituted acid followed by cyclization of the resulting intermediate in presence of a suitable acid. The amide bond formation can be obtained with a suitable amide coupling reagent such as 1-propanephosphonic anhydride solution, 2-(7 -aza- IH-benzotri azole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate, (benzotri azol- 1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate and 2-(l JT-benzotri azole- 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). The resulting amide can be cyclized by condensation in presence of a suitable acid such as acetic acid or HC1 or p-toluenesulfonic acid in a suitable solvent such as dioxane under heating to obtain compounds of this invention. In certain cases R2can be replaced by methyl when acetic acid is used under prolonged heating. Additional methods for this transformation include other variations of amide condensation, using methods known to one skilled in the art. Alternatively, If can be converted directly to a compound of Formula (I) in the neat corresponding acid with conventional heating or microwave heating. Alternatively, If can be converted directly to a compound of Formula (I) with the presence of the corresponding aldehyde with catalytic amount of acetic acid at room temperature in a suitable solvent such as tetrahydrofuran.

[0340] Scheme 1

[0341]

[0342] Alternatively, as described in Scheme 2, compounds of this invention can be prepared starting with nucleophilic aromatic substitution of 4-bromo-2-fluoro-l-nitrobenzene la, with a suitably substituted amine using conditions similar to the transformation of Id to le in Scheme 1. Subsequent nitro reduction of 2a using conditions similar to the transformation of le to If in Scheme 1, can provide intermediate 2b. Amide coupling of 2b with a suitably substituted acid, followed by acid-catalyzed condensation using conditions similar to the transformation of If to a compound of Formula (I) in Scheme 1 can provide intermediate 2d. Subsequent Miyaura borylation of 2d using similar conditions to the transformation of la to lb in Scheme 1 can provide intermediate 2e. Compounds of Formula (I) can be prepared by palladium-catalyzed coupling of 2e to a suitably substituted iodide or bromide or chloride 1c using conditions similar to the transformation of lb to Id in Scheme 1.

[0343] Scheme 2

[0344]

[0345] Additionally, as shown in Scheme 3, compounds of this invention can be prepared starting from 2-chl oro-5 -fluoro-4-iodopyri dine 3a. Suzuki -Miyaura cross-coupling of 3a with a suitably substituted boronic ester 2e using conditions similar to the transformation of lb to Id in Scheme 1 can deliver intermediate 3b. The resulting biaryl intermediate 3b can be converted to intermediate 3c by Buchwald-Hartwig cross-coupling followed by acid-catalyzed deprotection. The palladium catalyzed cross-coupling can be performed in presence of a suitable palladium catalyst such bis(dibenzylidineacetone) palladium (0) in suitable solvents such as dioxane or dimethylacetamide and tert-butyl alcohol in presence of a base such as cesium carbonate or potassium carbonate and ligands such as (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and second generation BrettPhos precatalyst. Additional methods for this transformation include other variations of Buchwald-Hartwig cross-coupling using methods known to one skilled in the art for this type of coupling. (See for example. Hicks, J, D.; Buchwald, S. L. et al. J. Am. Chem. Soc.

[0346] 2009, 131, 16720.; B.P. Fors & Buchwald, S. L Tetrahedron. 2009, 65, 6576.; Yin, J. & Buchwald, S. L J. Am. Chem. Soc. 2002, 124, 6043). The resulting tert-butyl carbonyl protected amine can be deprotected with acid such as HC1 or trifluoroacetic acid in presence of a suitable solvent such as dioxane or methylene chloride to obtain intermediate 3c. Alternatively 3c can be prepared directly from 3d by Buchwald-Hartwig cross-coupling using methods known to one skilled in the art for this type of coupling.

[0347] Subsequent amide coupling of 3c with a suitably substituted acid intermediate 3e using a suitable amide coupling reagent such as 1-propanephosphonic anhydride solution, 2-chloro-l,3-dimethylimidazolinium chloride and fluoro-N,N,N’,N’-bis(tetramethylene)formamidinium hexafluorophosphate (BTFFH) in a suitable solvent such as dimethylformamide or dichloromethane in presence of a base such as pyridine and N,N-diisopropylethylamine or triethyl amine or 2,4,6-trimethylpyridine can provide compounds of this invention. Scheme 3

[0348]

[0349] 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 NHpOAc) and Solvent B (10% water, 90% MeOH, 10 mM NHpOAc) 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).

[0350] 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).

[0351] Representative Chiral Purification Methods by SFC and Chiral Columns

[0352] Separation of Example 145 and 146

[0353] Preparative Chromatographic Conditions: Column: Chiral AS 30 x 250 mm, 5 pm; mobile phase: 75% CO2 / 25% MeOH w / 0.1%DEA; flow Conditions: 100 mL / min, Detector Wavelength: 220 nm.

[0354] Analytical Chromatographic Conditions: Chiral AS 4.6 x 100 mm, 5 pm; mobile phase: 75% CO2 / 25% IPA w / 0.1%DEA; flow Conditions: 2 mL / min, Detector Wavelength: 220 nm.

[0355] Example 145 (enantiomer 1): retention time = 7.1 min, >95% ee;

[0356] Example 146 (enantiomer 2): retention time = 8.6 min, >95% ee.

[0357] Separation of Example 151 and 152

[0358] Preparative Chromatographic Conditions: Column: Luna Omega Polar C18 Column 5pm, 21.2 X 250mm; flow rate: 20 mL / min; mobile phase: A: 100 mM NH4OAC (pH:6.5); B: MeOH (%A=100-%B) 0 min 10 min 10.5 min %B = 53% 63% 95%; detector wavelength: 240 nm.

[0359] Analytical Chromatographic Conditions: Column: Luna Omega Polar C18 Column 1.6pm, 2.1 X 150mm; flow rate: 0.35 mL / min; mobile phase: A: 20mM NH4OAc (pH 6.5); B: MeOH(%A=100-%B) 0 min 15 min %B = 5% 100%.

[0360] Example 151 (isomer 1): retention time = 10.801 min, 99.8% purity;

[0361] Example 152 (isomer 2): retention time = 11.031 min, 99.9% purity. Separation of Example 165 and 166

[0362] Preparative Chromatographic Conditions: Column: Chiral IC, 21 x 250 mm. 5 micron; mobile phase: 70% CO2 / 30% IPA-ACN 50-50 w / 0.1%DEA; flow Conditions: 60 mL / min, Detector Wavelength: 220 nm.

[0363] Analytical Chromatographic Conditions: Chiral IC, 4.6 x 150 mm, 5 micron; mobile phase: 70% CO2 / 30% IPA-ACN 50-50 w / 0.1%DEA; flow Conditions: 2 mL / min, Detector Wavelength: 220 nm.

[0364] Example 165 (enantiomer 1): retention time = 9.1 min, >95% ee;

[0365] Example 166 (enantiomer 2): retention time = 10.8 min, >95% ee.

[0366] Separation of Example 171 and 172

[0367] Preparative Chromatographic Conditions: Column: Chiral IC, 21 x 250 mm. 5 micron; mobile phase: 50% CO2 / 50% MeOH w / 0.1%DEA; flow Conditions: 60 mL / min, Detector Wavelength: 220 nm.

[0368] Analytical Chromatographic Conditions: Chiral IC, 4.6 x 150 mm, 5 micron; mobile phase: 50% CO2 / 50% MeOH w / 0.1%DEA; flow Conditions: 2 mL / min, Detector Wavelength: 220 nm.

[0369] Example 171 (isomer 1): retention time = 2.55 min, >95% ee;

[0370] Example 172 (isomer 2): retention time = 3.17 min, >95% ee.

[0371] Separation of Example 191 and 192

[0372] Preparative Chromatographic Conditions: Column: Chiral OJ, 30 x 250 mm. 5 micron; mobile phase: 90% CO2 / 10% MeOH w / 0.1%DEA; flow Conditions: 100 mL / min, Detector Wavelength: 220 nm.

[0373] Analytical Chromatographic Conditions: Chiral OJ, 4.6 x 100 mm, 5 micron; mobile phase: 90% CO2 / 10% IPA w / 0.1%DEA; flow Conditions: 2 mL / min, Detector Wavelength: 220 nm.

[0374] Example 191 (enantiomer 1): retention time = 8.7 min, >95% ee;

[0375] Example 192 (enantiomer 2): retention time = 13.0 min, >95% ee.

[0376] Separation of Example 215 and 216 Preparative Chromatographic Conditions: Column: Chiral OJ, 30 x 250 mm. 5 micron; mobile phase: 90% CO2 / 10% MeOH w / 0.1%DEA; flow Conditions: 100 mL / min, Detector Wavelength: 220 nm.

[0377] Analytical Chromatographic Conditions: Chiral OJ, 4.6 x 100 mm, 5 micron; mobile phase: 90% CO2 / 10% IPA w / 0.1%DEA; flow Conditions: 2 mL / min, Detector Wavelength: 220 nm.

[0378] Example 215 (enantiomer 1): retention time = 4.6 min, >95% ee;

[0379] Example 216 (enantiomer 2): retention time = 6.3 min, >95% ee.

[0380] Analytical HPLC: Methods Employed in Characterization of Examples

[0381] Method A: Linear gradient of 0 to 100% B over 3 min, with 0.75 min hold time at 100% B; UV visualization at 220 nm; Column: Waters XBridge C18 2.1 x 50 mm; Flow rate: 1.0 mL / min; Solvent A: 0.1% TFA, 95% water, 5% Acn: Solvent B : 0.1% TFA, 5% water, 95% Acn

[0382] Method B: Linear gradient of 0 to 100% B over 3 min, with 0.75 min hold time at 100% B; UV visualization at 220 nm; Column: Waters XBridge Cl 8, 2.1 mm x 50 mm; Flow rate: 1.0 mL / min; Solvent A: 10 mM ammonium acetate, 95% water, 5% Acn

[0383] Method C: Sunfire C18, 3.5um x 3.0 xl50 mm, Solvent A: 95% water, 5% Acn, 0.05% TFA; Solvent B: 95% Acn, 5% water, 0.05% TFA; Gradient: 10-100% B over 12 minutes, then a 3 -minute hold at 100% B; Flow: 1 mL / min.

[0384] Method D: Xbridge C18, 3.5um x 4.6 x 150 mm, Solvent A: 95% water, 5% Acn, 0.05% TFA; Solvent B: 95% Acn, 5% water, 0.05% TFA; Gradient: 0-100% B over 12 minutes, then a 3 -minute hold at 100% B; Flow: 1 mL / min.

[0385] Method E: Linear gradient of 0 to 100% B over 3 min; UV visualization at 220 nm;

[0386] Column: Ascentis Express C182.7pm, 2.1 mm x 50 mm; Flow rate: 1.1 mL / min;

[0387] Solvent A: 10 mM ammonium acetate, 95% water, 5% Can; Solvent B: 10 mM ammonium acetate, 95% Acn, 5% water. Method F: Linear gradient of 0 to 100% B over 3 min; UV visualization at 220 nm;

[0388] Column: Waters XBridge BEH C18 XP 2.5pm, 2.1 mm x 50 mm; Flow rate: 1.1 mL / min; Solvent A: 10 mM ammonium acetate, 95% water, 5% Acn; Solvent B: 10 mM ammonium acetate, 95% Acn, 5% water.

[0389] Method G: Linear gradient of 0 to 100% B over 3 min, with 0.50 min hold time at 100% B; UV visualization at 220 nm; Column: Waters Acquity BEH C18 2.1 x 50 mm; Flow rate: 1.0 mL / min; Solvent A: 0.1% TFA, 95% water, 5% Acn: Solvent B: 0.1% TFA, 5% water, 95% Acn

[0390] Method H: Linear gradient of 5 to 55% B over 1.7 min; UV visualization at 254 nm; Column: HALO C183.0 x 30 mm; Flow rate: 1.5 mL / min; Solvent A: 0.05% TFA, water, Solvent B: 0.05% TFA, Acn.

[0391] Method I: Linear gradient of 5 to 95% B over 1.2 min; UV visualization at 254 nm; Column: HALO C18 3.0 x 30 mm; Flow rate: 1.5 mL / min; Solvent A: 0.05% TFA, water, Solvent B: 0.05% TFA, Acn.

[0392] NMR Employed in Characterization of Examples.1H NMR spectra were obtained with Bruker or JEOL® Fourier transform spectrometers operating at frequencies as follows: 1H NMR: 400 MHz (Bruker or JEOL®) or 500 MHz (Bruker or JEOL®). 13C NMR: 100 MHz (Bruker or JEOL®). Spectra data are reported in the format: chemical shift (multiplicity, coupling constants, and number of hydrogens). Chemical shifts are specified in ppm downfield of a tetramethylsilane internal standard (d units, tetramethylsilane = 0 ppm) and / or referenced to solvent peaks, which in1H NMR spectra appear at 2.49 ppm for (CDs^SO, 3.30 ppm for CD3OD, 1.94 for CD3CN, 7.24 ppm for CDCI3, and 8.03 ppm, 2.92 ppm and 2.75 ppm for C3D7NO and which in13C NMR spectra appear at 39.7 ppm for (CD3)2SO, 49.0 ppm for CD3OD, and 77.0 ppm for CDCI3. All13C NMR spectra were proton decoupled. In some cases, when solvents such as DMSO that required water suppression were used, exchangeable protons were not observed. The water suppression in DMSO-d6 was performed on the tallest peak in the rage 3-5 ppm. In some cases the methyl sulfone peak was obscured or diminished due to the water suppression.

[0393] Intermediate

[0394]

[0395] A solution of 4-bromo-2-fluoro-l -nitrobenzene (0.73 g, 3.3 mmol) in THF (5 mL) was added to cyclopentanamine (0.65 mL, 6.6 mmol) and the reaction was stirred at rt for 5 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was used in the next step without purification. LC / MS m / z 284.9, 286.9 (M+H, M+2+H)+.

[0396] Intermediate

[0397]

[0398] To a solution of 5-bromo-N-cyclopentyl-2-nitroaniline (460 mg, 1.6 mmol) in EtOH (5 mL) under N2 was added iron (360 mg, 6.4 mmol) and saturated NH4CI solution (~0.5 mL). The reaction mixture was stirred at 90 °C overnight. The reaction mixture was then cooled to rt, filtered through celite and rinsed with EtOAc. The filtrate was concentrated and the crude residue was purified by column chromatography (0-100%EtOAc / Hex) to obtain the title compound (0.37 g, 91%). LC / MS m / z 255.0, 257.0 M+H, M+2+H)+. Intermediate

[0399]

[0400] A mixture of HATU (830 mg, 2.2 mmol) and 5-bromo-Nl-cyclopentylbenzene- 1,2-diamine (370 mg, 1.5 mmol) was dissolved in DMF (5 mL). Then 3-hydroxy-3-methylbutanoic acid (0.18 mL, 1.5 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.51 mL, 2.9 mmol) were added. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% LiCl. The organic layer was concentrated and the crude residue was purified by column chromatography (EtOAc-Hexanes0-100%) to yield the title compound (470 mg, 1.3 mmol, 91 % yield).XH NMR (500 MHz, DMSO-de) 87.14 (d, J=8.9 Hz, 1H), 6.94 (d, J=8.9 Hz, 1H), 6.90 (s, 1H), 3.66 (m, 1H), 2.51 (s, 2H), 1.93 (m, 2H), 1.63 (m, 2H), 1.51 (m, 2H), 1.49 (m, 2H), 1.33 (s, 6H). LC / MS m / z 355.0, 357.0 (M+H, M+2+H)+.

[0401] Intermediate 4 : l-( 6-bromo-l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol

[0402]

[0403] A solution of N-(4-bromo-2-(cy cl opentylamino)phenyl)-3 -hydroxy-3 -methylbutanamide (450 mg, 1.3 mmol) in acetic acid (3 mL) was heated to 90 °C and stirred at this temperature overnight. The reaction mixture was allowed to cool to rt, diluted with ethyl acetate and washed with K2HPO4 solution. The organic layer was dried over Na2SC>4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc / Hexanes,0-100%) to yield the title compound (0.36 g, 1.1 mmol, 84 % yield). 'H NMR (400 MHz, CDCI3) 67.57 (d, J=8.6 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.34 (dd, J=8.5, 1.9 Hz, 1H), 4.78 (m, 1H), 2.99 (s, 2H), 2.22 - 2.09 (m, 4H), 1.88 - 1.76 (m, 2H), 1.57 - 1.47 (m, 2H), 1.35 (s, 6H). LC / MS m / z 336.9, 339.0 (M+H, 4M+2+H)+. Intermediate 5 : 1-(1 -cyclopentyl-6-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol

[0404] "

[0405]

[0406] A mixture of l-(6-bromo-l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (210 mg, 0.62 mmol), potassium acetate (180 mg, 1.9 mmol), Pd(dppf)C12 (51 mg, 0.062 mmol), bispin (240 mg, 0.93 mmol) was dissolved in dioxane (3 mL). The sealed reaction vessel was evacuated and backfilled with nitrogen 3x then heated to 85 °C and stirred for 16 h. The reaction mixture was cooled to rt, diluted with ethyl acetate andwashed with brine. The organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was used in the next step without further purification. LC / MS m / z 385.2 (M+H)+.

[0407] Intermediate 6 : 2-(3-fluoro-4-nitrophenyl)-4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane

[0408]

[0409] A mixture of bispin (1.7 g, 6.8 mmol), 4-bromo-2-fluoro-l -nitrobenzene (1.0 g, 4.6 mmol), potassium acetate (0.89 g, 9.1 mmol) and Pd(dppf)C12.CH2C12 (0.17 g, 0.23 mmol) was suspended in dioxane (20 mL) and the reaction mixture degassed 3X and backfilled with nitrogen. The reaction mixture was then heated to 90 °C and allowed to stir at this temperature for 2 h. LCMS analysis showed trace starting material present. The reaction mixture was stirred for additional 1 h. then cooled to rt. The reaction mixture was filtered through celite and the volatiles were removed under reduced pressure. The crude residue was purified by column chromatography (EtOAc / Hexanes 0-100%) to yield the title compound (1.3 g, 4.8 mmol, 99 % yield). 'H NMR (400 MHz, DMSO-de) 88.16 (dd, J=8.0, 7.4 Hz, 1H), 7.71 - 7.64 (m, 2H), 1.33 (s, 12H). Intermediate 7 : N-(5-fluoro-4-(3-fluoro-4-nitrophenyl)pyridm-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide

[0410]

[0411] A mixture of potassium phosphate (1.6 g, 7.4 mmol), pd(dppf)C12.CH2C12 (0.243 g, 0.30 mmol), N-(5-fluoro-4-iodopyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide (1.3 g, 3.0 mmol) and 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.84 g, 3.1 mmol) was suspended in dioxane (15 mL) and water (1.5 mL). The reaction mixture was heated to 85 °C and allowed to stir at this temperature for 3 h. The reaction mixture was allowed to cool to rt. Celite was added to the reaction mixture and the solvent removed under reduced pressure. The crude material on celite was purified by column chromatography (DCM / EtOAc, 0-100%) to deliver the desired compound (1.2 g, 2.5 mmol, 84 % yield). 'H NMR (500 MHz, DMSO-d6) 6 11.44 (s, 1H), 8.59 (s, 1H), 8.46 - 8.25 (m, 2H), 8.00 - 7.89 (m, 2H), 7.72 (m, 1H), 7.35 - 7.16 (m, 2H), 3.92 (s, 3H), 3.30 (s, 3H). LC / MS m / z 464.3 (M+H)+.

[0412] Intermediate 8 : 4-(5-fluoro-2-(5-methoxy-2-(methylsulfonyl)benzamido)pyridin-4-yl)-2-(methylamino)phenyl nitrate

[0413]

[0414] A solution N-(5-fluoro-4-(3-fluoro-4-nitrophenyl)pyri din-2 -yl)-5-methoxy-2-(methylsulfonyl)benzamide (1.0 g, 2.2 mmol) in methanamine (5.5 ml, 11 mmol, 2M in THF) was stirred at rt for 2 h. Celite was added and the mixture was concentrated and purified by column chromatography (DCM / EtOAc, 0-70%) to yield the title compound (0.49 g, 47 % yield). 'HNMR (500 MHz, CDC13) 88.55 (d, J=l.l Hz, 1H), 8.49 (d, . / =4,7 Hz, 1H), 8.32 (d, . / =8,8 Hz, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.18 -7.08 (m, 3H), 6.93 (d, J=8.8 Hz, 1H), 3.96 (s, 3H), 3.34 (s, 3H), 3.12 (d, J=5.0 Hz, 3H). LC / MS m / z 475.4 (M+H)+.

[0415] Intermediate 9: N-(4-(4-amino-3-(ethylamino)phenyl)-5-fluoropyridm-2-yl)-5-methoxy-2- (methylsulfonyl)benzamide

[0416]

[0417] N-(4-(3-(ethylamino)-4-nitrophenyl)-5-fluoropyri din-2 -yl)-5-methoxy-2-(methylsulfonyl)benzamide (490 mg, 1.0 mmol) (prepared in a similar procedure as intermediate 8, using ethyl amine)was suspended in ethanol (10 mL) then iron (280 mg, 5.0 mmol) and HC1 (aq, 10 mL, 10 mmol) were added. The reaction mixture was then heated to 100 °C and stirred at this temperature for 1 h. The reaction mixture was allowed to cool to rt and diluted with ethyl acetate. The layers were then separated. Water was added to the organic layer followed by potassium phosphate solution to neutral pH. The organic layer was washed with water 3X and concentrated under reduced pressure. The crude residue was dissolved in methylene chloride purified by column chromatography (EtOAc / DCM, 0-100%) to deliver the title compound (280 mg, 0.62 mmol, 62 % yield). LC / MS m / z 459.2 (M+H)+.

[0418] Intermediate 10 : l-( 6-(2-chloro-5-fluoropyridin-4-yl)-l-( tetrahydrofuran-3-yl)-lH-

[0419]

[0420] A stirred suspension of l-(6-bromo-l-(tetrahydrofuran-3-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (15 g, 41 mmol) (prepared from a similar procedure as intermediate 4) was added 2-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (12 g, 45 mmol) and potassium phosphate tribasic anhydrous (26 g, 120 mmol). The reaction mixture was degassed under Argon for 5 min, then 1,1'-bi s(diphenylphosphino)

[0421] ferrocenepalladium (II) di chloride (3.0 g, 4.1 mmol) was added and the reaction mixture was stirred for 2 h at 85 °C. The reaction mixture was cooled to rt, filtered through celite and the celite bed was washed with EtOAc. The collected filtrate was washed with water and the water layer was back extracted with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulphate and concentrated. The crude residue was purified by column chromatography (EtOAc / petroleum ether, 80-100% EtOAc) to deliver the title compound (11 g, 23 mmol, 56 % yield). LC / MS m / z 390.41 (M+H)+.!H NMR (400 MHz, DMSO-d6) 88.55 (d, . / =2,5 Hz, 1H), 7.98 (s, 1H), 7.82 (d, J=5.5 Hz, 1H), 7.74 (d, . / =8,5 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 5.63 - 5.52 (m, 1H), 4.30 (m, 1H), 4.13 - 4.07 (m, 1H), 3.93 (m, 1H), 3.74 - 3.65 (m, 1H), 3.10 (m, 2H), 2.22 (m, 1H), 1.24 (s, 3H), 1.22 (s, 3H). One CH was obscured by solvent peak.

[0422] Intermediate 11 : tert-butyl (5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-

[0423] >

[0424]

[0425] A stirred suspension of l-(6-(2-chloro-5-fluoropyridin-4-yl)-l-(tetrahydrofuran-3-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (11 g, 28 mmol), tert-butyl carbamate (6.6 g, 56 mmol), potassium phosphate (12 g, 56 mmol) and X-Phos (2.7 g, 5.6 mmol) in 1,4-di oxane (110 mL) was degassed with Argon for 15 min.

[0426] Bis(dibenzylideneacetone)palladium(0) (1.6 g, 2.8 mmol) was added and the reaction mixture was stirred for 2 h at 100 °C. The reaction mixture was cooled to rt, filtered through celite and the celite bed was washed with EtOAc. The collected filtrate was washed with water and the water layer was back extracted with EtOAc. The combined organic layers were washed with brine, then dried over sodium sulphate and concentrated. The crude residue was purified by column chromatography (EtOAc / petroleum ether, 80- 100%) to deliver the title compound (11 g, 19 mmol, 66 % yield) as a pale brown solid. LC / MS m / z 471.46 (M+H)+, RT = 1.53 min. 'HNMR (400 MHz, DMSO-d6) 69.93 (s, 1H), 8.33 (d, .7=2.5 Hz, 1H), 8.04 - 7.96 (m, 2H), 7.75 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 5.64 - 5.53 (m, 1H), 4.30 (m, 1H), 4.11 - 4.04 (m, 1H), 3.96 - 3.87 (m, 1H), 3.76 - 3.63 (m, 1H), 3.10 (d, J=15.6 Hz, 2H), 2.26 - 2.12 (m, 1H), 1.49 (s, 9H), 1.24 (s, 3H), 1.22 (s, 3H). One CH was obscured by solvent peak.

[0427] Intermediate 12: l-(6-(2-amino-5-fluoropyridm-4-yl)-l-(tetrahydrofuran-3-yl)-lH-

[0428]

[0429] Trifluoroacetic acid (14 mL) was added to a stirred solution of tert-butyl (5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-(tetrahydrofuran-3-yl)-lH-benzo[d]imidazol-6-yl)pyridin-2-yl)carbamate (11 g, 19 mmol) at 0 °C and stirred for 5 h at rt. The reaction mixture was concentrated and the crude residue was diluted with DCM and washed with 10% aqueous NaHCOs solution and brine. The organic layer was concentrated and the crude residue was purified by column chromatography (methanol / DCM, 0-20%).

[0430] Trituration with EtOAc / MTBE delivered the title compound l-(6-(2-amino-5-fluoropyridin-4-yl)-l-(tetrahydrofuran-3-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (5.0 g, 13 mmol, 70 % yield) as an off white solid. 'H NMR (400 MHz, DMSO-de) 8 8.01 - 7.91 (m, 1H), 7.89 - 7.81 (m, 1H), 7.75 - 7.61 (m, 1H), 7.42 - 7.18 (m, 1H), 6.72 - 6.50 (m, 1H), 5.98 - 5.83 (m, 2H), 5.67 - 5.39 (m, 1H), 4.80 (s, 1H), 4.39 - 4.24 (m, 1H), 4.17 - 3.99 (m, 1H), 3.97 - 3.84 (m, 1H), 3.79 - 3.60 (m, 1H), 3.19 - 2.99 (m, 2H), 2.27 - 2.09 (m, 1H), 1.34 - 1.14 (m, 6H).

[0431] Intermediate 13 : l-(6-(2-amino-5-fluoropyridm-4-yl)-l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol

[0432]

[0433] A mixture of potassium phosphate tribasic (0.69 g, 3.3 mmol), 5-fluoro-4-iodopyridin-2-amine (0.31 g, 1.3 mmol), l-(l-cyclopentyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (0.50 g, 1.3 mmol) in dioxane (10 ml) and water (1.0 ml) were degassed and then Pd(dppf)C12 (0.11 g, 0.13 mmol) was added. The mixture stirred under nitrogen and heated at 85 °C for 3 h. The reaction mixture was filtered through celite. The filtrate was diluted with EtOAc and water and extracted with EtOAc (3x). The combined extracts were dried and concentrated in vacuo. The crude product was purified by silica column chromatography (0-20% MeOH / DCM) to give l-(6-(2-amino-5-fluoropyridin-4-yl)-l -cyclopentyl- 1H-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (0.39 g, 1.1 mmol, 81 % yield) as a light brown solid. LC / MS m / z 369.5 (M+H)+.

[0434] Intermediate 14. methyl 2-bromo-5-(difhioromethoxy)benzoate

[0435]

[0436] To a flask containing methyl 2-bromo-5-hydroxybenzoate (5.0 g, 21 mmol), sodium 2-chloro-2,2-difluoroacetate (8.3 g, 54.1 mmol), and CS2CO3 (8.5 g, 26 mmol) was added DMF (44 mL) and water (4.4 mL). The reaction mixture was heated at 100 °C for 3 h, then cooled to rt. The reaction was diluted with water and extracted with EtOAc. The organic extracts were washed with 1 : 1 sat’d aq NaCl and water, dried over MgSCh, filtered and evaporated to dryness in vacuo. The crude product was dissolved in CHCI3 and loaded onto a 120 g silica column pre-conditioned with 5% EtOAc in hexanes. The product was eluted with EtOAc in hexanes to provide Methyl 2-bromo-5-(difluoromethoxy)benzoate (2.5 g, 41% yield).XH NMR (400 MHz, CDCI387.66 (d, J = 8.8 Hz, 1H), 7.58 (d, J= 3.1 Hz, 1H), 7.14 (dd, J= 8.7, 3.0 Hz, 1H), 6.53 (t, J= 72.8 Hz, 1H), 3.95 (s, 3H). Intermediate 15. 5-(difluoromethoxy)-2-(methylsulfonyl)benzoic acid

[0437]

[0438] To a solution of intermediate 14 (2.5 g, 8.9 mmol) in anhydrous DMSO (18 mL) was added L-proline (0.41 g, 3.5 mmol), NaOH (0.142 g, 3.54 mmol), copper (I) iodide (0.34 g, 1.8 mmol) and sodium methyl sulfinate (1.8 g, 18 mmol). The reaction was heated to 130 °C under nitrogen for 24 h. The reaction mixture was poured into 150 mL of water and 1 N aq NaOH was added to adjust the pH to 11-12. Celite was added to the solution and the celite was filtered and washed with EtOAc. The aqueous layer was acidified with cone. HC1 to pH 1-2 and extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered and evaporated to dryness in vacuo. 5-(Difluoromethoxy)-2-(methylsulfonyl)benzoic acid was obtained by trituration of the solids with DCM (0.98 g, 37% yield). 'HNMR (400 MHz, DMSO-d6) 8 14.01 (s, 1H), 8.07 - 8.02 (m, 1H), 7.54 - 7.52 (m, 1H), 7.51 (s, 1H), 7.48 (t, J= 73 Hz, 1H), 3.37 (s, 3H).

[0439] Intermediate 16. methyl 2-bromo-5-(2,2-difluoroethoxy)benzoate

[0440]

[0441] To a suspension of methyl 2-bromo-5-hydroxybenzoate (4.9 g, 21 mmol) and CS2CO3 (10 g, 32 mmol) in DMF (42 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (3.4 mL, 26 mmol). The reaction mixture was stirred at rt for 36 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 1 : 1 sat’d aq NaCl and water, dried over MgSO4, filtered and evaporated to dryness to provide methyl 2-bromo-5-(2,2-difluoroethoxyjbenzoate (5.4 g, 87% yield).1H NMR (400 MHz, CDCI3) 67.58 (d, J = 8.8 Hz, 1H), 7.36 (d, J= 3.1 Hz, 1H), 6.94 (dd, J= 8.8, 3.1 Hz, 1H), 6.06 (tt, J= 54.8, 4.2 Hz, 1H), 4.20 (td, J= 12.9, 4.1 Hz, 2H), 3.94 (s, 3H). Intermediate 17.

[0442]

[0443] By application of the same method used for Intermediate 15, methyl 2-bromo-5-(2,2-difluoroethoxy)benzoate (5.46 g, 18.5 mmol) was converted to Intermediate 17 (2.8 g, 49% yield). ' H NMR (400 MHz, CD3OD) 88.04 (d, J=9.0 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.28 (dd, J=8.9, 2.8 Hz, 1H), 6.22 (dt, J=54.7, 3.7 Hz, 1H), 4.40 (td, J= 13.6, 3.7 Hz, 2H), 3.34 (s, 3H).

[0444] Intermediate 18.

[0445]

[0446] 5-Chloro-2-fluorobenzaldehyde (2.0 g, 13 mmol) and sodium methanesulfmate (1.4 g, 13 mmol) were dissolved in dry DMSO (20 mL) and then heated at 130 °C for 45 min. The reaction mixture was allowed to cool to rt then diluted with EtOAc and washed with water 2x, brine lx, and dried over sodium sulfate. The solvent was removed in vacuo. The product was used in subsequent reaciton without further purifications.1H NMR (500 MHz, CDCI3) 6 10.76 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.78 (dd, J=8.5, 2.2 Hz, 1H), 3.28 (s, 3H).

[0447] Intermediate 19. 5-chloro-2-(methylsulfonyl)benzoic acid

[0448]

[0449] To a rapidly stirred mixture of intermediate 18 (2.8 g, 12 mmol) and sulfamic acid (1.8 g, 19 mmol) in THF (30 mL) and water (30 mL) at 0 °C was added sodium chlorite (2.1 g, 19 mmol) solution in water (5 mL) dropwise. The reaction mixture was stirred at 0 °C for 10 min and then allowed to warm to rt and stirred for 1 h. The mixture was partitioned between EtOAc and water. The aq. layer was back-extracted with with EtOAc 2x. The combined organic layers were washed with brine, dried with sodium sulfate, filtered, concentrated onto celite and purified by reverse phase chromatography to deliver 5-chloro-2-(methylsulfonyl)benzoic acid (1.3 g, 5.7 mmol, 45 % yield). 'H NMR (500 MHz, DMSO-de) 8 14.06 (s, 1H), 8.01 (d, J=9.1 Hz, 1H), 7.87 - 7.83 (m, 2H), 3.40 (s, 3H).

[0450] Intermediate 20. 5-methoxy-2-(methylsulfonyl)benzoic acid

[0451]

[0452] Methyl 2-bromo-5-methoxybenzoate (6.6 mL, 41 mmol) in DMSO (100 mL) was added L-proline (1.9 g, 16 mmol), NaOH (0.65 g, 16 mmol), sodium methanesulfmate (8.3 g, 82 mmol) and copper(I) iodide (1.6 g, 8.2 mmol) at rt. The mixture was stirred in a sealed tube The reaction mixture was poured into ice cold water (500 mL), then filtered through celite and the collected filtrate was extracted with EtOAc (3 x300 mL).

[0453] Remaining aqueous layer was acidified with cone HC1 to pH 2, extracted with EtOAc (6 x300 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product as a brown liquid. The crude material was taken into 30 mL of water and stirred for 10 min. Solid precipitates formed and were filtered, and dried ON to obtain 5-methoxy-2-(methylsulfonyl)benzoic acid (7.0 g, 29 mmol, 70 % yield). 'HNMR (400MHZ, DMSO-d6) 6 13.75 (s, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.36 - 7.09 (m, 2H), 3.90 (s, 3H), 3.32 (s, 3H).

[0454] Intermediate 25. N-(5-fluoro-4-iodopyridin-2-yl)-5-methoxy-2- (methylsulfonyl)benzamide

[0455]

[0456] In two separate pressure release vials a mixture of Intermediate 20 (1.9 g, 8.4 mmol) and l-(fluoro(pyrrolidin-l-yl)methylene)pyrrolidin-l-ium hexafluorophosphate(V) (2.9 g, 9.2 mmol) were suspended in dry DCM (28 mL), and then pyridine (0.8 mL, 9 mmol) was added. The reaction mixture was stirred at rt for 1 h. 5-Fluoro-4-iodopyridin-2-amine (2.0 g, 8.4 mmol) was added followed by addition of DIEA (2.2 mL, 13 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was allowed to cool to rt, then diluted with EtOAc and washed with brine. The organic layer was concentrated and loaded onto a 80 g silica column and eluted with an EtOAc / hexanes gradient (0-100%) to deliver the title compound (3.0 g, 6.73 mmol, 80 % yield).!H NMR (500 MHz, DMSO-d6) 6 11.34 (s, 1H), 8.66 (d, J=4.7 Hz, 1H), 8.34 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.27 - 7.22 (m, 2H), 3.91 (s, 3H), 3.31 (s, 3H). LC / MS m / z 451.1 (M+H)+, RT = 0.81 min.

[0457] Intermediate 26. N-(4-bromopyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide

[0458]

[0459] To a suspension of 4-bromopyridin-2-amine hydrochloride (1.0 g, 4.8 mmol) in DMF (5 mL) was added Intermediate 20 (1.2 g, 5.0 mmol), TEA (2.0 mL, 14 mmol) and T3P (4.3 mL, 7.2 mmol). The mixture was stirred at R overnight. The reaction was diluted with water and extracted with EtOAc (3x). The combined organics were dried over Na2SC>4 and concentrated. The crude produce was purified by column chromatography (EtOAc / hexanes 0-100%) to deliver the title compound (1.6 g, 89 % yield). LC / MS m / z 386.7 (M+2+H)+, RT = 0.82 min.

[0460] Intermediate 28. (5-fluoro-2-(5-methoxy-2-(methylsulfonyl)benzamido)pyridin-4-yl)boronic acid

[0461]

[0462] A mixture of Pd(dppf)Ch.CH2C12 (0.073 g, 0.089 mmol), potassium acetate (0.52 g, 5.3 mmol), bis(pinacolato)diboron (0.68 g, 2.7 mmol) and intermediate 25 (0.80 g, 1.8 mmol) was dissolved in DMSO (3.6 mL). The reaction mixture was degassed and backfilled with N2 (3x) and heated at 85 °C overnight. The reaction mixture was diluted with EtOAc, neutralized with ammonium chloride solution and washed with 10% LiCl solution, and the organic layer was concentrated in vacuo. The crude material was loaded onto a 80 g silica column and eluted with EtOAc / hexanes (0-100%) to recover the unreacted starting material. The column was then eluted with a gradient of DCM / MeOH (0-20%) to deliver the title compound (0.59 g, 1.6 mmol, 90 % yield). 'H NMR (500 MHz, CDCI3) 89.56 (s, 1H), 8.52 - 8.20 (m, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.14 - 7.08 (m, 1H), 7.05 (dd, J=8.8, 1.9 Hz, 1H), 3.89 (s, 3H), 3.31 (s, 3H). LC / MS m / z 369.0 (M+H)+, RT = 0.62 min.

[0463] Intermediate 29.

[0464]

[0465] To a solution of 3-fluoro-5-methoxybenzoic acid (1.25 g, 7.35 mmol) in DMF (10 mL) was added NBS (2.62 g, 14.7 mmol). The reaction mixture was stirred at rt for 45 min. IM NaOH (14.7 mL, 14.7 mmol) was added, and the reaction mixture was stirred at rt for 3 days. The reaction mixture was quenched with 5% sodium bisulfite, then acidified with cone. HC1, extracted with EtOAc (2x10 mL), washed with water and brine, dried over Na2SO4, and concentrated to give 2-bromo-3-fluoro-5-methoxybenzoic acid as a white solid, which was used directly without purification.1H NMR (400 MHz, CDCI3) 6 7.39 (d, . / 2.5 Hz, 1H), 6.91 (dd, J=11.0, 2.5 Hz, 1H), 3.84 (s, 3H). LC / MS m / z 248.9 (M+H)+, 250.9 (M+2+H)+. Intermediate 30. 2-bromo-N-(4-(l -cyclopentyl-2-(2-hydroxy-2-methylpropyl)-lH-

[0466]

[0467] To a suspension of 2-bromo-3-fluoro-5-methoxybenzoic acid (56.8 mg, 0.228 mmol) and BTFFH (72.1 mg, 0.228 mmol) in DCE (1.5 ml) was added pyridine (25 pl, 0.30 mmol). The mixture was stirred at rt for 1 h, then intermediate 29 (56 mg, 0.15 mmol) and DIPEA (40 pl, 0.23 mmol) were added. The reaction was heated at 80 °C overnight. The reaction was diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude residue was purified by silica gel chromatography (EtOAc / Hex 0-100%) to obtain the title compound (40 mg, 0.067 mmol, 44 % yield). LC / MS m / z 599.2 (M+H)+, 601.1 (M+2+H)+.

[0468] Intermediate 31.

[0469]

[0470] To a solution of methyl 5-bromo-2-(methylthio)benzoate (720 mg, 2.76 mmol) in methanol (25 mL) at ice bath temp was added a solution of oxone(R), monopersulfate compound (5.09 mg, 8.27 mmol) in water (25 mL). The ice bath was removed and the mixture stirred for 20 h. The mixture was evaporated under reduced pressure to remove most of the MeOH then poured into water and extracted with EtOAc (3x). The extracts were dried over Na2SO4, filtered and concentrated to give the title compound (0.80 g, 2.7 mmol, 99 % yield) as a white solid. 'H NMR (500 MHz, CDC13) 88.01 (d, J=8.3 Hz, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.83 (dd, J=8.4, 1.8 Hz, 1H), 4.01 (s, 3H), 3.37 (s, 3H).

[0471] Intermediate 32. 5-bromo-2-(methylsulfonyl)benzoic acid

[0472]

[0473] To a solution of methyl 5-bromo-2-(methylsulfonyl)benzoate (1.51 g, 5.15 mmol) in THF (25.8 ml) was added IM LiOH (10.3 ml, 10.3 mmol) and the mixture stirred at 45 °C for 45 min. The mixture was evaporated to remove most of the THF then the mixture acidified with IN HC1 and extracted with EtOAc (3x). The extracts were dried (Na2SO4) filt and concentrated to give the title compound (1.33 g, 4.77 mmol, 93 % yield) as a white solid. ' H NMR (500 MHz, DMSO-d6) 8 14.09 (br s, 1H), 8.00 - 7.96 (m, 1H), 7.95 (s, 1H), 7.93 - 7.89 (m, 1H), 3.40 (s, 3H).

[0474] Intermediate 33. 5-bromo-N-(4-(l -cyclopentyl-2-(2-hydroxy-2-methylpropyl)-lH-

[0475]

[0476] l-(6-(2-amino-5-fluoropyridin-4-yl)-l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (250 mg, 0.679 mmol), 5-bromo-2-(methylsulfonyl)benzoic acid (208 mg, 0.746 mmol), 2-chloro-l,3-dimethylimidazolinium chloride (149 mg, 0.882 mmol) were dissolved in pyridine (0.5 mL). The reaction mixture was stirred to 100 °C for 1 h. The mixture was evaporated and satd NH4CI added and extracted with EtOAc (3x) the extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel chromatography (EtOAc / Hex 0-100%) to obtain the title compound (0.36 g, 0.57 mmol, 84% yield) as a white solid. LC / MS m / z 629.2 (M+H)+, 631.1 (M+2+H)+.

[0477] Intermediate 34. 5-bromo-2-chloro-N-(4-(l-cyclopentyl-2-(2-hydroxy-2-methylpropyl)~ lH-benzo[ d]imidazol-6-yl)-5-fluoropyridin-2-yl) benzamide

[0478]

[0479] By application of the same method used for Intermediate 33, 5-bromo-2-chlorobenzoic acid (105 mg, 0.448 mmol) was converted to Intermediate 34 (188 mg, 78.7% yield). LC / MS m / z 585.2 (M+H)+, 587.2 (M+2+H)+.

[0480] Example 1. 5-chloro-N-(4-(l-cyclopentyl-2-(2-hydroxy-2-methylpropyl)-lH-

[0481]

[0482] A mixture of K3PO4 (48 mg, 0.23 mmol), intermediate 5 (35 mg, 0.091 mmol), 5-chloro-N-(5-fluoro-4-iodopyridin-2-yl)-2-(methylsulfonyl)benzamide (prepared from a similar procedure as Intermediate 25 from Intermediate 19, 41 mg, 0.091 mmol), and 2nd gen XPhos precat (7.2 mg, 9.1 pmol) was suspended in dioxane (1 mL) and water (0.1 mL). The reaction mixture was then degassed 3X and backfilled with nitrogen then heated to 80 °C and allowed to stir at this temperature for 2 h. The reaction mixture was diluted with water and extracted with EtOAcs. The organic layers were concentrated and the crude residue was purified by reverse phase chromatography to deliver the title compound (12 mg, 22% yield). 'H NMR (500 MHz, DMSO-d6-ws) 6 11.42 (s, 1H), 8.49 (s, 1H), 8.42 (d, J=6.1 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.90 (s, 1H), 7.86 (dd, J=8.5, 1.8 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.49 (d, J=8.2 Hz, 1H), 5.19 (quin, J=8.9 Hz, 1H), 3.09 (s, 3H), 2.15 (d, . / =6,7 Hz, 4H), 2.01 (s, 2H), 1.85 - 1.69 (m, 2H), 1.26 (s, 6H). m / z = 585.3(M+H)+, RT = 1.6 min (Method A). Example 2. N-(4-(l-ethyl-2-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide

[0483]

[0484] A mixture of N-(4-(4-amino-3-(ethylamino)phenyl)-5-fluoropyri din-2 -yl)-5-methoxy-2-(methylsulfonyl)benzamide (Intermediate 9, 20 mg, 0.044 mmol), 3-hydroxy-3 -methylbutanoic acid (6.7 mg, 0.057 mmol) and Hunig's base (0.015 mL, 0.087 mmol) were dissolved in DMF (1 mL). HATU (18 mg, 0.048 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and the resulting residue was dissolved in 2 mL of acetic acid and stirred at 90 °C for 2 h. The reaction mixture was concentrated and purified by reverse phase chromatography to deliver the title compound (10 mg, 0.018 mmol, 40 % yield).XH NMR (500 MHz, DMSO-d6) 6 11.30 (s, 1H), 8.46 (s, 1H), 8.35 (d, J=5.6 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.82 (s, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.28 - 7.22 (m, 2H), 4.40 (d, .7=7.0 Hz, 2H), 3.91 (s, 3H), 3.28 (s, 3H), 3.03 (s, 2H), 1.33 (t, J=7.1 Hz, 3H), 1.26 (s, 6H). m / z 541.2 (M+H)+, RT = 1.58 min (Method B).

[0485] Example 3. 2-chloro-N-(5-fluoro-4-(2-(2-hydroxy-2-methylpropyl)-l-(tetrahydrofuran-3-

[0486]

[0487] To a solution of l-(6-(2-amino-5-fluoropyridin-4-yl)-l-(tetrahydrofuran-3-yl)-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (Intermediate 12, 20 mg, 0.054 mmol) in pyridine (0.5 mL) was added 2-chloro-5-methylbenzoic acid (0.011g, 0.065 mmol), 2,4,6-trimethylpyridine (6.5 mg, 0.054 mmol) and 2-chloro-l,3-dimethylimidazolinium chloride (12 mg, 0.070 mmol). The reaction mixture was stirred at 100 °C for 1 h. The crude material was purified by reverse phase chromatography to deliver the title compound, m / z 523.3 (M+H)+, RT = 1.80 min (Method E). 'H NMR (400 MHz, DMSO-d6-ws) 6 11.12 (s, 1H), 8.48 - 8.44 (m, 1H), 8.44 - 8.40 (m, 1H), 8.06 - 8.01 (m, 1H), 7.81 - 7.74 (m, 1H), 7.51 - 7.45 (m, 1H), 7.45 - 7.39 (m, 2H), 7.33 - 7.28 (m, 1H), 5.66 - 5.51 (m, 1H), 4.37 - 4.28 (m, 1H), 4.14 - 4.04 (m, 1H), 3.96 - 3.90 (m, 1H), 3.76 - 3.65 (m, 1H), 2.39 - 2.29 (m, 3H), 2.24 - 2.12 (m, 1H), 1.30 - 1.25 (s, 3H), 1.22 (s, 3H).

[0488] Example 4. N-[4-(2-ethyl-l -methyl- 1H-1, 3-benzodiazol-6-yl)-5-fluoropyri din-2-yl]-2-methanesulfonyl-5-methoxybenzamide

[0489]

[0490] To a 2 dram pressure release vial, 6-bromo-2-ethyl-l -methyl- 1H-benzo[d]imidazole (prepared by using similar procedure as described in Intermediate 4, 19 mg, 0.081 mmol), potassium phosphate (17 mg, 0.081 mmol), Pd(dppf)C12 (67 mg, 0.081 mmol) and (5-fluoro-2-(5-methoxy-2-(methylsulfonyl)benzamido)pyridin-4-yl)boronic acid (Intermediate 28, 30 mg, 0.081 mmol) were added. The solids were suspended in dioxane (1 mL) and water (0.1 mL) and the reaction mixture degassed 3X and backfilled with nitrogen. The reaction mixture was to stirred at 85 °C for 3 h. The reaction mixture was allowed to cool to rt then diluted with EtOAc and washed with brine. The organic layer was concentrated under reduced pressure and the crude material was purified by reverse phase chromatography to deliver the title compound (9.9 mg, 0.020 mmol, 25% yield). 'HNMR (500 MHz, DMSO-d6) 8 11.27 (s, 1H), 8.43 (s, 1H), 8.29 (d, J=5.8 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.82 (s, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.25 - 7.16 (m, 2H), 3.87 (s, 3H), 3.23 (s, 3H), 3.04 (d, J=7.6 Hz, 2H), 2.53 (s, 3H), 1.35 (t, J=7.0 Hz, 3H). LC / MS m / z 483.0 (M+H)+, RT = 1.46 min (Method B).

[0491] Example 5. N-{4-[l-ethyl-2-(l-hydroxy-Method A,2-dimethylpropyl)-lH-l,3-benzodiazol-6-yl]-5-fluoropyridin-2-yl}-2-methanesulfonyl-5-methoxybenzamide

[0492]

[0493] N-(4-(4-amino-3-(ethylamino)phenyl)-5-fluoropyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide (Intermediate 9, 25 mg, 0.055 mmol), potassium 3,3-dimethyl-2-oxobutanoate (10 mg, 0.060 mmol) and Hunig's base (0.038 mL, 0.22 mmol) were dissolved in DMF (1 mL). HATU (62 mg, 0.16 mmol) was added and the reaction mixture was allowed to stir at rt overnight. The reaction was diluted with EtOAc, washed with 1.5M dipotassium phosphate 2x, 10% citric acid 2x, brine lx, dried with sodium sulfate, filtered and concentrated. The residue was dissolved in AcOH and stirred at 90 °C for Ih. LCMS analysis showed presence of the desired product N-(4-(l -ethyl-2-pival oyl-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide. The product was brought forward without further purification.. LCMS [M+l] = 553.2.

[0494] N-(4-(l-ethyl-2-pivaloyl-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide (30 mg, 0.054 mmol) was dissolved MeOH (2 mL). Sodium borohydride (31 mg, 0.81 mmol) was added and the reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was quenched with saturated ammonium chloride and diluted with EtOAc. The organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by reverse phase chromatography to deliver the titled compound (4.3 mg, 7.5 pmol, 14% yield). 'HNMR (500 MHz, DMSO-d6) 8 11.32 (s, IH), 8.52 - 8.46 (m, IH), 8.38 (s, IH), 7.93 (d, J=9.4 Hz, IH), 7.84 (s, IH), 7.80 (d, J=8.4 Hz, IH), 7.44 (d, J=8.5 Hz, IH), 7.30 - 7.21 (m, 2H), 4.65 (d, J=5.5 Hz, IH), 4.57 (dd, J=14.3, 7.4 Hz, IH), 4.39 (dd, J=14.1, 7.2 Hz, IH), 3.92 (s, 3H), 3.00 (s, 3H), 1.37 (t, J=7.1 Hz, 3H), 1.05 (s, 9H). LC / MS m / z 555.3 (M+H)+, RT = 1.72 min (Method B).

[0495] Example 6. 3-{ l-ethyl-6-[5-fluoro-2-(2-methanesulfonyl-5-methoxybenzamido) pyridin-4-yl]- 1H- 1 ,3 -benzodiazol -2 -yl } -2,2-dimethylpropanoic acid

[0496]

[0497] Example 7. N-{4-[2-(2-carbamoyl-2,2-dimethylethyl)-l-ethyl-lH-l,3-benzodiazol-6-yl]-5-fluoropyridin-2-yl}-2-methanesulfonyl-5-methoxybenzamide

[0498]

[0499] In a 2 dram pressure release vial, N-(4-(4-(3-cyano-3-methylbutanamido)-3-(ethylamino)phenyl)-5-fluoropyri din-2 -yl)-5-methoxy-2-(methylsulfonyl) benzamide (prepared by using similar procedure as described in Example 2, 61 mg, 0.11 mmol) was dissolved in acetic acid (1 mL) and the reaction mixture heated to 90 °C and allowed to stir at this temperature for 1 h. The reaction mixture was heated at 90 °C for additional 2 h. The reaction mixture was allowed to cool to rt then diluted with EtOAc and washed with water. The organic layer was concentrated and the crude material was purified by reverse phase chromatography to deliver Examples 6 and 7. Example 6 (28 mg, 0.048 mmol, 45 % yield). LC / MS m / z 569.0 (M+H)+, RT = 1.36 min (Method B).!H NMR (500 MHz, DMSO-d6-ws) 8 11.29 (s, 1H), 8.47 (s, 1H), 8.37 (d, J=6.1 Hz, 1H), 7.93 (d, J=9.5 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.26 (d, J=7.0 Hz, 2H), 4.34 (q, J=6.7 Hz, 2H), 3.92 (s, 3H), 3.15 (s, 2H), 1.37-1.30 (m, 9H). Example 7 (1.9 mg, 3.4 pmol, 3.1 % yield). LC / MS m / z 568.3 (M+H)+, RT = 1.39 min (Method B).XH NMR (500 MHz, DMSO-d6-ws) 6 11.33 (s, 1H), 8.51 (s, 1H), 8.37 (d, J=5.8 Hz, 1H), 8.00 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.25 (d, J=1.8 Hz, 2H), 4.48 (q, J=6.4 Hz, 2H), 3.96-3.89 (m, 3H), 3.22 (s, 1H), 1.38 (t, J=7.2 Hz, 3H), 1.33 (s, 6H). Example 8. N-{ 5-fluoro-4-[2-(2 -hydroxy -2-methylpropyl)-l -(2 -m ethylpropyl)-lH- 1,3-benzodiazol-6-yl]pyridin-2-yl}-2-methanesulfonyl-5-methoxybenzamide

[0500]

[0501] In a 2 dram pressure release vial, N-(5-fluoro-4-(4-(3 -hydroxy-3 -methylbutanamido)-3-(isobutylamino)phenyl)pyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide (prepared by using similar procedure as described in Example 2, 36 mg, 0.061 mmol) was dissolved in ethanol (1 mL) then 4-methylbenzenesulfonic acid (21.1 mg, 0.123 mmol) was added and the reaction mixture was stirred at 78 °C overnight. The reaction mixture was allowed to cool to rt then diluted with EtOAc and washed with brine. The organic layer was concentrated and crude material was purified by reverse phase chromatography to deliver the titled compound (11 mg, 0.019 mmol, 30 % yield). LC / MS m / z 569.3 (M+H)+, RT = 1.86 min (Method B). 'HNMR (500 MHz, DMSO-d6-ws) 6 11.31 (s, 1H), 8.47 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.84 (s, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.28 - 7.23 (m, 2H), 4.20 (d, J=7.2 Hz, 2H), 3.92 (s, 3H), 3.30 (s, 3H), 3.04 (s, 2H), 2.20 - 2.10 (m, 1H), 1.26 (s, 6H), 0.90 (d, J=6.5 Hz, 6H).

[0502] Example 9. N-{5-fluoro-4-[l-(3-hydroxycyclopentyl)-2-methyl-lH-l,3-benzodiazol-6-yl]pyridin-2-yl}-2-methanesulfonyl-5-methoxybenzamide

[0503]

[0504] Example 10. 3-{6-[5-fluoro-2-(2-methanesulfonyl-5-methoxybenzamido)pyridin-4-yl]-2-m ethyl - 1 H- 1 , 3 -b enzodi azol - 1 -y 1 } cy cl openty 1 acetate

[0505]

[0506] In a 2 dram pressure release vial, N-(5-fluoro-4-(3 -((3 -hydroxy cyclopentyl) amino)-4-(3,3,3-trifluoropropanamido)phenyl)pyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide (prepared by using similar procedure as described in Example 2, 40 mg, 0.064 mmol) was dissolved in acetic acid (1 mL) and the reaction mixture was stirred at 90 °C overnight. The crude material was purified by reverse phase chromatography to deliver Example 9 (3.0 mg, 8.3%) and Example 10 (5.6 mg, 15%). Example 9: LC / MS m / z 539.3 (M+H)+, RT = 1.49 min (Method B). 'H NMR (500 MHz, DMSO-d6) 8 11.28 (s, 1H), 8.46 (s, 1H), 8.35 (d, J=5.8 Hz, 1H), 8.32 (s, 1H), 7.93 (d, J=9.2 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.30 - 7.23 (m, 2H), 5.00 -4.86 (m, 1H), 4.30 (d, J=2.7 Hz, 1H), 3.92 (s, 3H), 3.30 (s, 3H), 2.63 (s, 3H), 2.48 - 2.34 (m, 2H), 2.11 - 1.98 (m, 2H), 1.90 - 1.78 (m, 2H). Example 10: LC / MS m / z 581.1 (M+H)+, RT = 1.62 min (Method B). 'HNMR (500 MHz, DMSO-d6) 6 11.31 (s, 1H), 8.47 (s, 1H), 8.38 (d, J=6.1 Hz, 1H), 8.01 (s, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.9, 2.7 Hz, 1H), 7.23 (s, 1H), 5.24 (d, J=2.1 Hz, 1H), 5.12 - 4.98 (m, 1H), 3.92 (s, 3H), 3.29 (s, 3H), 2.90 (s, 3H), 2.73 - 2.65 (m, 1H), 2.39 (m, 1H), 2.22 - 2.09 (m, 2H), 2.02 - 1.96 (m, 2H), 1.95 (s, 3H).

[0507] Example 11. N-[4-(l -{bicyclofl. l.l]pentan-l-yl J-1H-1, 3-benzodiazol-6-yl)-5-fluoropyridin-2-yl]-2-methanesulfonyl-5-methoxybenzamide

[0508]

[0509] N-(4-(3 -(bicyclofl .1. l]pentan-l-ylamino)-4-nitrophenyl)-5-fluoropyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide (prepared by using similar procedure as described in Intermediate 9, 28 mg, 0.053 mmol) and iron (15 mg, 0.27 mmol) were suspended in ethanol (2 ml) then HC1 (0.53 ml, 0.53 mmol) was added. The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was allowed to cool to rt and formic acid (0.10 mL, 2.7 mmol) was added to the reaction mixture which was then allowed to stir at 100 °C for 1 h. The reaction mixture as basified with 1.5M dipotassium phosphate then extracted with EtOAc 2x. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. The product was purified by reverse phase chromatography to give the title compound (0.6 mg, 2% yield). LC / MS m / z 507.0 (M+H)+, RT = 1.43 min (Method A).1H NMR (500 MHz, DMSO-d6-ws) 6 11.31 (s, 1H), 8.52 - 8.42 (m, 1H), 8.41 - 8.31 (m, 2H), 7.95 (s, 1H), 7.92 (d, J=9.4 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.31 - 7.19 (m, 2H), 3.92 (s, 3H), 3.29 (s, 1H), 2.75 (s, 1H), 2.48 (s, 6H).

[0510] Example 12. N-{5-fluoro-4-[l-(2-hydroxycyclopentyl)-lH-l,3-benzodiazol-6-yl]pyridin-2-yl}-2-methanesulfonyl-5-methoxybenzamide

[0511]

[0512] A solution ofN-(4-(4-amino-3-((2-hydroxycyclopentyl)amino)phenyl)-5-fluoropyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide (prepared by using similar procedure as described in Intermediate 9, 11 mg, 0.021 mmol) in formic acid (1 mL) was stirred at 100°C for 3 h. The reaction was cooled to rt and purified by reverse phase chromatography to give 2-(6-(5-fluoro-2-(5-methoxy-2-(methylsulfonyl)benzamido)pyridin-4-yl)-lH-benzo[d]imidazol-l-yl)cyclopentyl formate (6.7 mg, 54%). LC / MS m / z 553.2 (M+H)+, RT = 1.73 min (Method B).

[0513] A mixture of 2-(6-(5-fluoro-2-(5-methoxy-2-(methylsulfonyl)benzamido) pyridin-4-yl)-lH-benzo[d]imidazol-l-yl)cyclopentyl formate (4.0 mg, 7.2 pmol) in MeOH (0.5 mL) and ammonium hydroxide (10 pl, 0.072 mmol) was stirred at rt for 1 h. The reaction mixture was purified by reverse phase chromatography to give the titled compound (3.7 mg, 97%). LC / MS m / z 524.9 (M+H)+, RT = 1.27 min (Method B). 'H NMR (500 MHz, DMSO-d6) 68.47 (d, J=6.2 Hz, 2H), 8.39 - 8.33 (m, 1H), 7.97 - 7.90 (m, 2H), 7.85 (d, J=8.5 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.30 - 7.22 (m, 2H), 4.67 - 4.57 (m, 1H), 4.40 - 4.30 (m, 1H), 3.91 (s, 3H), 3.29 (s, 3H), 2.35 - 2.27 (m, 1H), 2.12 - 1.97 (m, 2H), 1.90 - 1.85 (m, 2H), 1.69 - 1.59 (m, 1H).

[0514] Example 13. N-{4-[l-(azetidin-3-yl)-2-(2,2,2-trifluoroethyl)-lH-l,3-benzodiazol-6-yl]-5-fluoropyridin-2-yl}-2-methanesulfonyl-5-methoxybenzamide

[0515]

[0516] In a 2 dram pressure release vial, tert-butyl 3-((5-(5-fluoro-2-(5-methoxy-2-(methylsulfonyl)benzamido)pyridin-4-yl)-2-(3,3,3-trifluoropropanamido)phenyl) amino)azetidine-l -carboxylate (prepared by using similar procedure as described in Example 2, 33 mg, 0.047 mmol) was dissolved in acetic acid (1 mL) and the reaction mixture stirred at 80 °C temperature for 1 h. The reaction mixture was concentrated. The crude product was added TFA / DCM (1 / 1, 1 mL) and the solution was stirred for 1 h at rt. The reaction mixture was concentrated and purified by reverse phase chromatography to give the title compound (8.6 mg, 31%). LC / MS m / z 578.3 (M+H)+, RT = 1.41 min (Method B). 'HNMR (500 MHz, DMSO-d6) 5 11.33 (s, 1H), 8.50 (s, 1H), 8.33 (d, J=4.1 Hz, 1H), 8.29 (s, 1H), 7.92 (dd, J=8.5, 4.9 Hz, 2H), 7.50 (d, J=8.0 Hz, 1H), 7.26 (dd, J=8.9, 2.4 Hz, 1H), 7.21 (s, 1H), 5.85 - 5.74 (m, 1H), 4.80 (s, 2H), 4.38 (m, 2H), 4.33 -4.20 (m, 2H), 3.91 (s, 3H), 3.27 (s, 3H).

[0517] Example 14. N-{4-[l-(2,2-difluoroethyl)-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-1H-1, 3-benzodiazol-6-yl]-5-fluoropyri din-2 -yl}-2-methanesulfonyl-5-m ethoxybenzamide

[0518]

[0519] Example 15. N-{4-[l-(2,2-difluoroethyl)-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-1H-1, 3-benzodiazol-6-yl]-5-fluoropyri din-2 -yl}-2-methanesulfonyl-5-m ethoxybenzamide

[0520]

[0521] A solution ofN-(4-(3-((2,2-difluoroethyl)amino)-4-(4,4,4-trifluoro-3-hydroxy-3-methylbutanamido)phenyl)-5-fluoropyridin-2-yl)-5-methoxy-2-(methylsulfonyl) benzamide (prepared by using similar procedure as described in Example 2, 65 mg, 0.10 mmol) in acetic acid (1 mL) was stirred at 90 °C for 1 h. The reaction mixture was allowed to cool to rt then diluted with EtOAc and washed with potassium phosphate solution. The organic layer was concentrated under reduced pressure and the residue was purified by reverse phase chromatography to give N-(4-(l-(2,2-difluoroethyl)-2-(3,3,3-tri fluoro-2-hydroxy-2-methylpropyl)-lEI-benzo[d]imidazol-6-yl)-5-fluoropyri din-2 -yl)-5-m ethoxy -2-(m ethyl sulfonyl)

[0522] benzamide (11 mg, 0.018 mmol, 18 % yield) and (Z)-N-(4-(l-(2,2-difluoroethyl)-2-(3,3,3-trifluoro-2-methylprop-l-en-l-yl)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-5-methoxy-2-(methylsulfonyl)benzamide (21 mg, 0.033 mmol, 33 % yield). Example 14: LC / MS m / z 631.3 (M+H)+, RT = 1.74 min (Method B).1H NMR (500 MHz, CDC13) 8 8.76 (s, 1H), 8.53 (s, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.73 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.17 (s, 1H), 7.12 (dd, J=8.8, 2.8 Hz, 1H), 6.30 - 6.04 (m, 1H), 4.75 - 4.57 (m, 2H), 3.99 - 3.90 (m, 3H), 3.44 (d, J=16.0 Hz, 1H), 3.34 (s, 3H), 3.26 (d, J=15.7 Hz, 1H), 1.58 (s, 3H). Example 15: LC / MS m / z 613.2 (M+H)+, RT = 2.04 min (Method B).1H NMR (500 MHz, DMSO-d6-ws) 6 11.32 (s, 1H), 8.53 - 8.47 (m, 1H), 8.38 (d, J=6.1 Hz, 1H), 8.02 (s, 1H), 7.94 (dd, J=8.5, 5.5 Hz, 2H), 7.58 - 7.53 (m, 1H), 7.29 (s, 1H), 7.28 - 7.24 (m, 2H), 6.65 - 6.35 (m, 1H), 5.11 (t, J=16.5 Hz, 2H), 3.92 (s, 3H), 3.30 (s, 1H).

[0523] Example 160: N-(4-(2-acetamido-l-ethyl-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-5-(2,2-difluoroethoxy)-2-(methylsulfonyl)benzamide

[0524] <

[0525]

[0526] To a solution of N-(4-(2-amino-l-ethyl-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-5-(2,2-difluoroethoxy)-2-(methylsulfonyl)benzamide (10 mg, 0.019 mmol) dissolved in DCM (0.02 mL) was added pyridine (0.02 mL) and cooled in an ice water bath. Acetyl chloride (0.002 mL, 0.02 mmol) was added dropwise as a dilute solution dissolved in DCM and the reaction mixture was stirred for 30 min. The mixture was concentrated and purified by reverse phase chromatography to furnish the title compound (4.6 mg, 0.0077 mmol, 41% yield). LC / MS m / z 576.0 (M+H)+, RT = 1.56 min (Method B). 'H NMR (500 MHz, DMSO-d6-ws) 8 11.29 (s, 1H), 8.48 (s, 1H), 8.36 (br d, J=3.1 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.83 (br s, 1H), 7.79 - 7.68 (m, 1H), 7.45 (br d, J=7.9 Hz, 1H), 7.39 -7.27 (m, 2H), 6.60 - 6.31 (m, 1H), 4.61 - 4.44 (m, 2H), 4.26 - 4.14 (m, 2H), 3.31 (s, 3H), 2.19 (br s, 3H), 1.40 - 1.25 (m, 3H). one exchangeable proton under solvent.

[0527] Example 241. 5-(2,2-difluoroethoxy)-N-[4-(l-ethyl-2-sulfanyl-lH-l,3-benzodiazol-6-yl)- 5-fluoropyridin-2-yl]-2-methanesulfonylbenzamide

[0528]

[0529] A mixture of N-(4-(4-amino-3-(ethylamino)phenyl)-5-fluoropyridin-2-yl)-5-(2,2-difluoroethoxy)-2-(methylsulfonyl)benzamide (173 mg, 0.340 mmol, prepared in a similar procedure as intermediate 9, using cyclopentyl amine) and 1,1'- thiocarbonyldiimidazole (81 mg, 0.45 mmol) in acetonitrile (5 mL) was stirred at 80 °C for 1 h. LCMS showed the reaction was completed. The solvents were evaporated to give the title compound (187 mg, 100%). Ten mgs of this crude was purified by reverse phase chromatography to give 4.9 mg of the title compound and the rest was used directly in the next step. LC / MS m / z 551.3 (M+H)+, RT = 1.75 min (Method A). 'H NMR (500 MHz, DMSO-d6-ws) 6 13.00 - 12.94 (m, 1H), 11.36 - 11.28 (m, 1H), 8.53 - 8.46 (m, 1H), 8.38 -8.31 (m, 1H), 7.99 - 7.92 (m, 1H), 7.72 - 7.66 (m, 1H), 7.49 - 7.43 (m, 1H), 7.43 - 7.33 (m, 3H), 6.61 - 6.34 (m, 1H), 4.61 - 4.48 (m, 2H), 4.40 - 4.28 (m, 2H), 1.29 (br t, J=7.0 Hz, 3H).

[0530] Example 242. 5-(2,2-difluoroethoxy)-N-{4-[l-ethyl-2-(methylsulfanyl)-lH-l,3-benzodiazol-6-yl]-5-fluoropyridin-2-yl}-2-methanesulfonylbenzamide

[0531] >

[0532]

[0533] To a solution of 5-(2,2-difluoroethoxy)-N-(4-(l-ethyl-2-mercapto-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-2-(methylsulfonyl)benzamide (177 mg, 0.321 mmol) and naoh (0.129 mL, 0.643 mmol) in MeOH (2 mL) was added Mel (0.020 mL, 0.32 mmol). The reaction was stirred at rt for 15 min. LCMS showed the reaction was completed. The reaction was diluted with EtOAc, washed with 10% citric acid then brine. The organics were dried over Na2SC>4 and concentrated to give the title compound (182 mg, 100%). Ten mgs of this crude was purified by reverse phase chromatography to give 8.1 mg of the title compound and the rest was used directly in the next step. LC / MS m / z 565 (M+H)+, RT = 1.58 min (Method A). 'HNMR (500 MHz, DMSO-d6-ws) 8 11.34 - 11.25 (m, 1H), 8.52 - 8.45 (m, 1H), 8.39 - 8.34 (m, 1H), 7.99 - 7.93 (m, 1H), 7.84 - 7.78 (m, 1H), 7.76 - 7.71 (m, 1H), 7.46 - 7.40 (m, 1H), 7.39 - 7.32 (m, 2H), 6.61 - 6.33 (m, 1H), 4.60 - 4.48 (m, 2H), 4.31 - 4.19 (m, 2H), 2.83 - 2.77 (m, 3H), 1.38 - 1.31 (m, 3H). Example 244. N-(4-(2-cyano-l -ethyl- lH-benzo[d]imidazol-6-yl)-5-fluoropyri din-2-yl)-5-(2,2-difluoroethoxy)-2-(methylsulfonyl)benzamide

[0534] >

[0535]

[0536] To a solution of 5-(2,2-difluoroethoxy)-N-(4-(l-ethyl-2-(methylthio)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-2-(methylsulfonyl)benzamide (172 mg, 0.305 mmol) in ethyl acetate (1 mL) and DCM (1 mL) was added m-CPBA (137 mg, 0.609 mmol). The reaction was stirred at rt for 3 h. LCMS showed DP and sulfoxide product. Another m-CPBA (137 mg, 0.609 mmol) was added. And the reaction was stirred at rt for 2 h. The reaction was diluted with sat1NaHCO3 solution, extracted with EtOAc (3x). Combined extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated. The crude was purified by silica gel chromatography (EtOAc / Hex 0-100%) to give 5-(2,2-difluoroethoxy)-N-(4-(l-ethyl-2-(methylsulfonyl)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-2-(methylsulfonyl)benzamide (63 mg, 0.11 mmol, 35 % yield). LC / MS m / z 597.3 (M+H)+To 5-(2,2-difluoroethoxy)-N-(4-(l-ethyl-2-(methylsulfonyl)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-2-(methylsulfonyl)benzamide (63 mg, 0.11 mmol) in DMSO (1 mL) was added KCN (20.6 mg, 0.317 mmol). The reaction was stirred for 20 min. LCMS showed the reaction was completed. Reaction mixture was diluted with water and extracted 3x with EtOAc. Combined extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by reverse phase chromatography to give the title compound (35 mg, 59%). LC / MS m / z 544.4 (M+H)+, RT = 1.88 min (Method B). 'H NMR (500 MHz, DMSO-d6-ws) 611.40 - 11.32 (m, 1H), 8.56 - 8.52 (m, 1H), 8.40 - 8.36 (m, 1H), 8.17 -8.12 (m, 1H), 8.05 - 8.00 (m, 1H), 7.97 - 7.92 (m, 1H), 7.67 - 7.62 (m, 1H), 7.40 - 7.33 (m, 2H), 6.59 - 6.34 (m, 1H), 4.61 - 4.56 (m, 2H), 4.56 - 4.48 (m, 2H), 1.51 - 1.46 (m, 3H). Example 246. N-[4-(2-amino-l-cyclopentyl-lH-l,3-benzodiazol-6-yl)-5-fluoropyridin-2-yl]-5-(difluoromethoxy)-2-methanesulfonylbenzamide

[0537]

[0538] A mixture of N-(4-(4-amino-3-(cyclopentylamino)phenyl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)-2-(methylsulfonyl)benzamide (56 mg, 0.11 mmol, prepared in a similar procedure as intermediate 9, using cyclopentyl amine) and cyanic bromide (22 mg, 0.21 mmol) in MeOH (1 mL) was stirred at rt for 1 h. Reaction mixture was diluted with water and extracted 3X with EtOAc. Combined extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by reverse phase chromatography to give the title compound (23 mg, 39%). LC / MS m / z 560.2 (M+H)+, RT = 1.68 min (Method B). 'H NMR (500 MHz, DMSO-d6-ws) 8 11.40 - 11.35 (m, 1H), 8.47 - 8.43 (m, 1H), 8.40 (br d, J=6.1 Hz, 1H), 8.11 - 8.06 (m, 1H), 7.60 - 7.57 (m, 1H), 7.57 - 7.53 (m, 2H), 7.37 (s, 2H), 7.66 - 7.35 (m, 1H), 7.06 -6.95 (m, 1H), 4.91 - 4.82 (m, 1H), 2.15 - 2.05 (m, 4H), 2.03 - 1.96 (m, 2H), 1.78 - 1.68 (m, 2H).

[0539] Example 257. N-{4-[l-cyclopentyl-2-(2-hydroxy-2-methylpropyl)-lH-l,3-benzodiazol-6-yl]-5-fluoropyridin-2-yl}-3-fluoro-2-methanesulfonyl-5-methoxybenzamide

[0540]

[0541] A suspension of sodium methanesulfmate (27.2 mg, 0.267 mmol), intermediate 30 (40 mg, 0.067 mmol), copper(I) iodide (50.8 mg, 0.267 mmol) in DMSO (2 mL) and sodium hydroxide (0.016 mL, 0.080 mmol) was heated at 120 °C for 2 h in microwave. The reaction was completed. The reaction was diluted with water, extracted with EtOAc (x3), dried over Na2SC>4, and concentrated. The residue was purified by reverse phase chromatography to give the title compound (5.0 mg, 12%). LC / MS m / z 599.2 (M+H)+, RT = 1.48 min (Method A). 'HNMR (500 MHz, DMSO-d6-ws) 6 11.28 (s, 1H), 8.56 -8.48 (m, 1H), 8.42 - 8.36 (m, 1H), 8.10 - 8.04 (m, 1H), 8.04 - 7.99 (m, 1H), 7.81 - 7.75 (m, 1H), 7.26 - 7.21 (m, 1H), 7.06 - 7.01 (m, 1H), 5.39 - 5.26 (m, 1H), 3.93 (s, 3H), 3.31 (s, 2H), 2.28 - 2.13 (m, 4H), 2.09 - 2.00 (m, 2H), 1.85 - 1.72 (m, 2H), 1.31 (s, 6H).

[0542] Example 263. N-(4-{l-[(lS)-l-carbamoylethyl]-2-(2,2,2-trifluoroethyl)-lH-l,3-benzodiazol-6-yl}-5-fluoropyridin-2-yl)-5-(difluoromethoxy)-2-methanesulfonylbenzamide

[0543]

[0544] In a 40 dram pressure release vial, 5-(difluoromethoxy)-N-(5-fluoro-4-(3-fluoro-4-nitrophenyl)pyridin-2-yl)-2-(methylsulfonyl)benzamide (prepared in a similar procedure as intermediate 7, 0.60 g, 1.2 mmol) was dissolved in THF (5 mL) then tert-butyl L-alaninate, HC1 (0.327 g, 1.80 mmol) and hunig's base (0.630 mL, 3.60 mmol) were added and the reaction mixture was stirred at 60 °C for ON. Reaction mixture was cooled down to rt and diluted with water and extracted 3X with EtOAc. Combined extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (0-100% EtOAc / Hex) on silica gel column to give tert-butyl (5-(2-(5-(difluoromethoxy)-2-(methylsulfonyl)benzamido)-5-fluoropyridin-4-yl)-2-nitrophenyl)-L-alaninate (0.748 g, 1.20 mmol, 100 % yield). LC / MS m / z 625.0 (M+H)+.

[0545] To tert-butyl (5-(2-(5-(difluoromethoxy)-2-(methylsulfonyl)benzamido)-5-fluoropyridin-4-yl)-2-nitrophenyl)-L-alaninate (748 mg, 1.20 mmol) in THF (10 mL). sodium hydrosulfite (2085 mg, 11.98 mmol) and ammonia solution (28% NH3 in water, 1.62 mL, 24.0 mmol) were added and the reaction was stirred at rt for ON. EtOAc and IM NaOH (5 mL each) were added to the reaction and stirred for 10 min, before separated. The aqueous was extracted with EtOAc (x2). Combined extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (0-100%EtOAc / Hex) to give tert-butyl (2-amino-5-(2-(5-(difluoromethoxy)-2-(methylsulfonyl)benzamido)-5-fluoropyridin-4-yl)phenyl)-L-alaninate (337 mg, 0.567 mmol, 47.3 % yield). LC / MS m / z 595.1 (M+H)+To tert-butyl (2-amino-5-(2-(5-(difluoromethoxy)-2-(methylsulfonyl) benzamido)-5-fluoropyridin-4-yl)phenyl)-L-alaninate (75 mg, 0.13 mmol) in THF (2 mL), 3,3,3-trifluoropropanal (42.4 mg, 0.378 mmol) was added followed by several drops of acetic acid. The reaction mixture was allowed to stir at RT overnight. The reaction was concentrated and dissolved in TFA and heated at 85 °C for 1 h. The reaction mixture was concentrated and purified by flash chromatography (0-100% EtOAc / Hex) to give (S)-2-(6-(2-(5-(difluoromethoxy)-2-(methylsulfonyl)benzamido)-5-fluoropyridin-4-yl)-2-(2,2,2-trifluoroethyl)-lH-benzo[d]imidazol-l-yl)propanoic acid (40 mg, 0.063 mmol, 50 % yield). LC / MS m / z 631.0 (M+H)+

[0546] To a solution of (S)-2-(6-(2-(5-(difluoromethoxy)-2-(methylsulfonyl) benzamido)-5-fluoropyridin-4-yl)-2-(2,2,2-trifluoroethyl)-lH-benzo[d]imidazol-l-yl)propanoic acid (15 mg, 0.024 mmol) and T3P (45.4 mg, 0.071 mmol) (50% solution in EtOAc) in THF (0.5 mL) was added ammonia solution (28% NH3 in water, 0.066 mL, 0.48 mmol). The reaction was stirred at rt for 15 min. Reaction mixture was diluted with water and extracted 3X with EtOAc. Combined extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated. The crude was purified by reversed phase chromatography to give Example 263 (5.8 mg, 39% yield). LC / MS m / z 630.0 (M+H)+, RT = 1.57 min (Method A). 'HNMR (500 MHz, DMSO-d6) 8 8.50 - 8.43 (m, 1H), 8.35 - 8.29 (m, 1H), 8.09 - 8.03 (m, 1H), 7.88 - 7.83 (m, 1H), 7.82 -7.76 (m, 1H), 7.67 - 7.61 (m, 1H), 7.56 - 7.53 (m, 1H), 7.53 - 7.51 (m, 1H), 7.51 - 7.47 (m, 1H), 7.40 - 7.36 (m, 1H), 7.58 - 7.29 (m, 1H), 5.46 - 5.38 (m, 1H), 4.38 - 4.25 (m, 1H), 4.24 - 4.11 (m, 1H), 3.33 (s, 3H), 1.66 (br d, J=7.0 Hz, 3H).

[0547] Example 280. N-(4-(2-(3 -amino-2,2-dimethyl-3 -oxopropyl)- 1 -cyclopentyl- 1H-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)-2-(methylsulfonyl)benzamide

[0548]

[0549] N-(4-(4-amino-3-(cyclopentylamino)phenyl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)-2-(methylsulfonyl)benzamide (65 mg, 0.12 mmol) was dissolved in THF (5 mL). 2,2-Dimethyl-4-oxobutanenitrile (40.5 mg, 0.365 mmol) was added and the reaction mixture was allowed to stir at RT for 2h. LCMS analysis after stirring for 2h showed the desired product as the major component of the mixture. The reaciton mixture was concentrated to yield N-(4-(2-(2-cyano-2-methylpropyl)-l-cyclopentyl-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)-2-(methylsulfonyl)benzamide (76.0 mg, 100%). Product was brought forward without further purification. LC / MS m / z 626.4 (M+H)+.

[0550] N-(4-(2-(2-cyano-2-methylpropyl)-l -cyclopentyl- lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)-5-(difluoromethoxy)-2-(methylsulfonyl)benzamide (36 mg, 0.058 mmol) was suspended in 2: 1 : 1 35% hydrogen peroxide / saturated K2CO3 / EtOH (4 mL). DMSO (3 mL) was added to aid solubility and the reaction mixture was allowed to stir at RT ON. Another same scale reaction was carried out at exactly same way. These two reaction mixtures were combined and quenched with 10% sodium diothionite and extracted with EtOAc 2x. The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by reversed phase chromatography to give Example 280 (9.7 mg, 13% yield). LC / MS m / z 644.2 (M+H)+, RT = 1.54 min (Method A). 'HNMR (500 MHz, DMSO-d6-ws) 8 11.41 (s, 1H), 8.53 -8.44 (m, 1H), 8.40 (br d, J=5.8 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.79 (br s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.56 (br s, 1H), 7.54 (br d, J=8.9 Hz, 1H), 7.62 - 7.33 (m, 1H), 7.24 - 7.17 (m, 1H), 6.90 (br s, 1H), 5.09 (quin, J=8.9 Hz, 1H), 3.36 (s, 1H), 3.15 (s, 1H), 2.13 (br d, J=6.1 Hz, 4H), 2.05 - 1.95 (m, 2H), 1.82 - 1.70 (m, 2H), 1.26 (s, 6H).

[0551] Example 302: 2-chloro-4-cyano-N-(4-(l-cyclopentyl-2-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazol-6-yl)-5-fluoropyridin-2-yl)benzamide

[0552]

[0553] POCI3 (5.1 pl, 0.054 mmol) was added to a solution of 2-chloro-4-cyanobenzoic acid (10 mg, 0.054 mmol), l-(6-(2-amino-5-fluoropyridin-4-yl)-l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-2-methylpropan-2-ol (20 mg, 0.054 mmol), and pyridine (0.088 mL, 1.1 mmol) in DCM (1.5 mL) at 0° C. The reaction mixture was stirred for 1 h and evaporated in vacuo. The residue was purified by reversed phase chromatography to give Example 302 (9.7 mg, 32% yield). LC / MS m / z 532.2 (M+H)+, RT = 1.94 min (Method B). 1H NMR (500 MHz, DMSO-d6-ws) 88.47 - 8.40 (m, 2H), 8.07 (s, 1H), 8.00 (br s, 1H), 7.96 (br d, J=8.3 Hz, 1H), 7.88 (br d, J=7.6 Hz, 1H), 7.75 (br dd, J=16.5, 8.4 Hz, 2H), 5.33 - 5.25 (m, 1H), 3.34 - 3.28 (m, 2H), 2.23 - 2.15 (m, 4H), 2.04 - 1.98 (m, 2H), 1.81 - 1.74 (m, 2H), 1.28 (s, 6H).

[0554] The following Examples in Table 3 were made by using the similar procedures as shown above in Intermediates 1-34 and Examples 1-15, 160, 241, 242, 244, 246, 257, 263, 280, and 302 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.

[0555] Table 3

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[0835] It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

1. WE CLAIM:

1. A compound of Formula (I):

4. 6.or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:7.R1is H, Ci-6 alkyl substituted with 0 to 3 Ra, Ci-6 haloalkyl substituted with 0 to 2 Ra, a 4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re, -(CRgRgl)o-3-(C3-8 cycloalkyl substituted with 0 to 4 Re),8.-(CRgRgl)o-2-(Cs-6 spirocycloalkyl or C5-6 bridged cycloalkyl substituted with 0 to 2 Re), -(CRgRgl)o-3-(phenyl substituted with 0 to 3 Rd), or9.-(CRgRgl)o-3-(5- to 6-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 3 Rd);10.R2is H, cyano, OH, SH, NH2, C1-4 alkylthio, C1-4 alkoxy, C1-8 alkyl substituted with 0 to 2 Ra, C2-6 alkenyl substituted with 0 to 1 Ra,11.C2-6 alkynyl substituted with 0 to 1 Ra, C1-6 haloalkyl substituted with 0 to 1 Ra, -NH(C=O)C 1-4 alkyl, -(CRgRgl)o-3-(C3-8 cycloalkyl substituted with 0 to 4 Re), -(CRgRgl)o-2-(Cs-6 spirocycloalkyl or C5-6 bridged cycloalkyl substituted with 0 to 2 Re), -(CRgRgl)o-2-(4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re), -(CRgRgl)o-3-(phenyl substituted with 0 to 3 Rd), or -(CRgRgl)o-3-(5- to 6- membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 3 Rd);12.R3is halogen, cyano, Ci-4 haloalkyl, Ci-4 haloalkoxy,13.-C(=O)O(Ci-4alkyl), NH2, N(CI-4alkyl)2, -C(=O)NH2, -C(=O)N(CI-4alkyl)2, C2-6 alkenyl, C2-6 alkynyl, ORh, or Ci-6 alkyl substituted with 0 to 2 Ra;14.R4is H, halogen, cyano or Ci-4 alkyl;15.R5is H, halogen, cyano, -NO2, Ci-4 alkoxy, Ci-4 haloalkyl,16.Ci-4 haloalkoxy, Ci-4 alkylthio, Ci-4 alkyl substituted with 0 to 2 Ra, -SO2R‘, or -(CH2)o-i-(phenyl substituted with 0 to 2 Rd);17.R6is H, halogen, cyano, Ci-4 alkoxy, Ci-4 haloalkyl, Ci-4 haloalkoxy, -NH(Ci-4 alkyl), -SO2(Ci-4 alkyl), or Ci-4 alkyl substituted with 0 to 2 Ra;18.R7is H, halogen, cyano, Ci-4 alkoxy, Ci-4 haloalkyl, Ci-4 haloalkoxy, -O(CH2)i-2O(Ci-4 alkyl), -OCH2CH2N(Ci-4 alkyl)2, -NH(Ci-4 alkyl substituted with 0 to 1 Ra), Ci-4 alkyl substituted with 0 to 2 Ra, -C(=O)ORn,19.-C(=O)NRnR12, or -(CH2)0-I-NHC(=O)R10;20.R8is H, halogen, cyano, Ci-4 haloalkyl, Ci-4 haloalkoxy, OR10, -C(=O)ORn, -(CH2)o-i-NRnR12, -(CH2)o-i-C(=0)NRnR12,21.-(CH2)O-I-NHC(=0)R10, Ci-4 alkylthio, -SO2RC, -SO2NR10Rn, -NHSO2R10, Ci-6 alkyl substituted with 0 to 2 Ra, or C2-4 alkyl substituted with 0 to 1 Ra;22.R9is H, halogen, Ci-4 alkyl, or Ci-4 haloalkyl;23.R10is H, Ci-4 alkyl substituted with 0 to 1 Ra, -(CH2)o-i-C3-6 cycloalkyl, or -(CH2)O-I -phenyl;24.R11is H or Ci-4 alkyl;25.R12is H or R10;26.Rais halogen, cyano, OH, -CH2OH, Ci-4 alkoxy, Ci-4 haloalkyl,27.Ci-4 haloalkoxy, NH2, NH(CI-4alkyl), N(CI-4alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;28.Rbis H, C1-4 fluoroalkyl, -C(=O)(Ci-4alkyl), -C(=O)O(Ci-4alkyl) or C1-4 alkyl substituted with 0-1 OH;29.Rcis halogen, OH, cyano, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl substituted with 0 to 2 Rf, or C 1-4 alkoxy substituted with 0 to 1 Rf;30.Rdis halogen, OH, cyano, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, -O(C=O)H, -O(C=O)(C i-4 alkyl), -C(=O)O(Ci-4alkyl), NH2, N(CI-4alkyl)2, -C(=O)NH2, -C(=O)N(CI-4 alkyl)2, C2-6 alkenyl, C2-6 alkynyl, or Ci-6 alkyl substituted with 0 to 2 Rc;31.Reis oxo or Rd;32.Rfis halogen, OH, cyano, -CH20H, Ci-4 alkoxy, or N(Ci-4alkyl)2;33.Rgis H, Ci-4 alkyl substituted with 0 to 1 Rf, Ci-4 alkoxy, or34.C3-6 cycloalkyl;35.Rglis H or C1-4 alkyl;36.Rhis H or C1-6 alkyl substituted with 0 to 1 Ra;37.R1is C1-4 alkyl substituted with 0 to 1 Rc;38.n is 0, 1 or 2; and39.p is 0, 1 or 2.

2. The compound of claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:41.R1is H, C1-6 alkyl substituted with 0 to 2 Ra, C1-6 haloalkyl substituted with 0 to 1 Ra, a 4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re, -(CH2)O-I-(CHRg))o-i-(CH2)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re), -(CH2)o-i(CRgRgl)o-i-(C5-6 spirocycloalkyl or C5-6 bridged cycloalkyl substituted with 0 to 2 Re), or -(CH2)o-i(CRgRgl)o-i(CH2)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 2 Rd);42.R2is H, cyano, OH, SH, NH2, C1-4 alkylthio, C1-4 alkoxy, C2-4 alkynyl, C1-8 alkyl substituted with 0 to 2 Ra, C2-4 alkenyl substituted with 0 to 1 Ra,43.C1-6 haloalkyl substituted with 0 to 1 Ra, -NH(C=0)C 1-4 alkyl,44.-(CH2)o-2-(CRgRgl)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re),45.-(CH2)o-i(CRgRgl)o-i-(Cs-6 spirocycloalkyl or C5-6 bridged cycloalkyl substituted with 0 to 2 Re), -(CH2)o-i(CRgRgl)o-i-(4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re), -(CH2)o-2-(CRgRgl)o-i -(phenyl substituted with 0 to 3 Rd), or -(CH2)o-i(CRgRgl)o-i(CH2)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 2 Rd);46.R3is halogen, OH, Ci-4 haloalkyl, Ci-4 haloalkoxy, Ci-4 alkyl substituted with 0 to 1 Ra, or Ci-4 alkoxy substituted with 0 to 1 Ra;47.R5is H, halogen, cyano, -NO2, C1-4 alkoxy, C1-4 haloalkyl,48.C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl substituted with 0 to 1 Ra, -SO2(Ci-4 alkyl substituted with 0 to 1 Rc), or -SO2(CH2)i-2O(CH2)i-2O(Ci-4 alkyl);49.R6and R7are H, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or C1-4 haloalkoxy;50.R8is H, halogen, cyano, C1-4 haloalkyl, C1-4 haloalkoxy, OR10,51.C1-4 alkylthio, -SC>2(Ci-4 alkyl substituted with 0 to 1 Rc), -SO2NH2, -SO2NR10Rn, -NHSO2R10, C1-6 alkyl substituted with 0 to 1 Ra, or C2-4 alkyl substituted with 0 to 1 Ra; and52.R10is H, Ci-4 alkyl substituted with 0 to 1 R , C3-6 cycloalkyl, or benzyl.

3. The compound of claim 1 or claim 2, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:54.R1is H, C1-6 alkyl substituted with 0 to 2 Ra, C1-6 fluoroalkyl substituted with 0 to 1 Ra, a 4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re, -(CH2)O-I-(CHRg))o-i-(CH2)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re), -(CH2)o-2-(Cs-6 spirocycloalkyl or C5-6 bridged cycloalkyl substituted with 0 to 2 Re), or -(CH2)o-i(CRgRg)o-i(CH2)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 2 Rd);55.R2is H, cyano, OH, SH, NH2, C1-4 alkylthio, C1-4 alkoxy, C1-6 alkyl substituted with 0 to 1 Ra, C2-4 alkenyl substituted with 0 to 1 Ra,56.C1-6 fluoroalkyl substituted with 0 to 1 Ra, -NH(C=O)C 1-4 alkyl,57.-(CH2)o-2-(CHRg))o-i-(C3-6 cycloalkyl substituted with 0-2 Re),58.-(CH2)O-2-(CS-6 spirocycloalkyl or C5-6 bridged cycloalkyl substituted with 0 to 2 Re), -(CH2)O-2-(4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re), -(CH2)o-2-(CRgRgl)o-i-(phenyl substituted with 0 to 2 Rd), or59.-(CH2)o-i(CRgRgl)o-i(CH2)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), O, or S, wherein the heteroaryl is substituted with 0 to 2 Rd);60.R3is halogen, OH, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 fluoroalkyl, or61.Ci-4 fluoroalkoxy;62.R5is H, halogen, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 haloalkyl, C 1-4 haloalkoxy, or -SO2(Ci-4 alkyl substituted with 0 to 1 Rc);63.R8is H, halogen, OH, cyano, C1-4 alkyl, C1-4 alkoxy, C 1-4 haloalkyl,64.C1-4 haloalkoxy, or -CH2OH;65.Rais halogen, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 fluoroalkyl,66.C1-4 fluoroalkoxy, NH2, NH(Ci-4 alkyl), N(CI-4 alkyl)2, -C(=O)OH, -C(=O)NH2, -SO2NH2, C3-6 cycloalkyl or phenyl;67.Rbis H or C1-4 alkyl;68.Rcis F, Cl, cyano, OH, C1-4 alkoxy, C1-4 fluoroalkyl, or69.C1-4 fluoroalkoxy;70.Rdis halogen, cyano, OH, -CH2OH, C1-4 alkyl, C1-4 alkoxy,71.C1-4 fluoroalkyl, C1-4 fluoroalkoxy, -O(C=O)H, -O(C=O)(Ci-4 alkyl), or -C(=O)O(Ci-4alkyl);72.Reis oxo or Rd;73.Rgis H, C1-2 alkyl, -CH2OH, C1-2 alkoxy, or C3-4 cycloalkyl; and74.Rglis H or C1-2 alkyl.

4. The compound of any one of claims 1 to 3, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:76.R1is H, C1-6 alkyl substituted with 0 to 2 Ra, C1-4 fluoroalkyl substituted with 0 to 1 Ra, -(CH2)o-i-(CHRg))o-i-(CH2)o-i-(C3-6 cycloalkyl substituted with 0-2 Re), a 4-to 6-membered heterocyclic ring including 1 ring heteroatom which is independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully77.satuated, and is substituted with 0 to 2 Re,78.

79. R2is H, cyano, SH, NH2, C 1-4 alkylthio, C1-6 alkyl substituted with 0 to 1 Ra, C2-4 alkenyl substituted with 0 to 1 Ra, C1-4 fluoroalkyl substituted with 0 to 1 Ra, -NH(C=0)CI-4 alkyl, -(CH2)o-2-(CHRg))o-i-(C3-6 cycloalkyl substituted with 0-2 Re), -(CH2)o-2-(4- to 6-membered heterocyclic ring including 1 to 2 ring heteroatoms which are independently N, N(Rb), O, or S(O)P, and wherein the heterocyclic ring is partially satuated or fully satuated, and is substituted with 0 to 2 Re), -(CH2)I-2-(CHRg))o-i-(phenyl substituted with 0 to 2 Rd),80.-(CH2)o-i-(CRgRgl)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), or O, wherein the heteroaryl is substituted with 0 to 282.

83. or C1-2 alkyl;84.R5is H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl,85.C1-4 fluoroalkoxy, or -SC>2(Ci-4 alkyl);86.R6and R7are H, F, Cl, CF3, or C1-2 alkyl;87.R8is H, halogen, OH, cyano, C1-4 alkyl, C1-4 alkoxy, Ci-4haloalkyl, or C1-4 haloalkoxy;88.R9is H, halogen, CF3, or C1-2 alkyl; and89.Reis oxo, halogen, OH, -CH2OH, C1-4 alkyl, -O(C=O)H, or90.-O(C=O)(Ci-4 alkyl).

5. The compound of any one of claims 1 to 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:92.R3is F, Cl or C1-2 alkyl;93.R4is H, F or Cl;94.R6and R7are H or F;95.R8is H, halogen, OH, cyano, C1-4 alkyl, C1-4 alkoxy, C 1-4 fluoroalkyl, or C1-4 fluoroalkoxy; R9is H, F, Cl, CF3, or C1-2 alkyl; and96.Rais F, Cl, cyano, OH, -CH2OH, C1-4 alkoxy, C1-4 fluoroalkyl, NH2, N(Ci-4alkyl)2, -C(=O)OH, -C(=O)NH2, or -SO2NH2.

6. The compound of any one of claims 1 to 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:98.R1is H, Ci-6 alkyl substituted with 0 to 2 Ra, Ci-4 fluoroalkyl substituted with99.0 to 1 Ra, -(CHRg))o-i-(CH2)o-i-(C3-6 cycloalkyl substituted with 0-2 Re),100.

103.

104. R2is H, cyano, NH2, C1-6 alkyl substituted with 0 to 1 Ra, C1-4 fluoroalkyl substituted with 0 to 1 Ra, -NH(C=O)C 1-4 alkyl, -CH=C(CH3)CF3,105.-(CH2)O-I-(C3-6 cycloalkyl substituted with 0 to 2 Re), -(CH2)o-i-(5-membered heteroaryl wherein from 1 to 4 ring atoms are each independently N, N(Rb), or O, wherein the heteroaryl is substituted with 0 to 2 Rd),108.

109. R3is F;110.R5is H, F, Cl, C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, or - SO2(C 1-2 alkyl);111.R9is H, F or Cl; Rbis H or CH3;112.Reis halogen, OH, -CH2OH, CM alkyl, -O(C=O)H, or113.-O(C=O)Ci-4 alkyl;114.Rgis H, CH3 -CH2OH, -CH2OCH3, or cyclopropyl; and115.n is 0 or 1.

7. A compound of F ormul a (II) :

118. 120.or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:121.R1is H, Ci-6 alkyl substituted with 0 to 2122.-(CHRg))o-i-(CH2)o-i-(C3-6 cycloalkyl substituted123.

126.

127. R2is H, cyano, NH2, C1-6 alkyl substituted with 0 to 1 Ra, C1-4 fluoroalkyl substituted with 0 to 1 Ra, -NH(C=O)C 1-4 alkyl, -CH=C(CH3)CF3,128.-(CH2)o-i-(C3-6 cycloalkyl substituted with 0 to 2 Re), -CH(cyclopropyl)CH2OH,129.

130. R4is H, F or Cl;131.R5is H, F, Cl, Ci-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl, C1-4 fluoroalkoxy, or - SO2(C i-2 alkyl);132.R6and R7are H or F;133.R8is H, halogen, OH, cyano, C1-4 alkyl, C alkoxy, C 1-4 fluoroalkyl, or CM fluoroalkoxy;134.R9is H, F or Cl;135.Rais F, Cl, cyano, OH, -CH2OH, C alkoxy, CM fluoroalkyl, NH2, N(Ci-4alkyl)2, -C(=O)OH, -C(=O)NH2, or -SO2NH2;136.Rbis H or CH3;137.Reis halogen, OH, -CH2OH, CM alkyl, -O(C=O)H, or138.-O(C=O)Ci-4 alkyl; and139.Rgis H, CH3-CH2OH, -CH2OCH3, or cyclopropyl.

8. The compound of claim 7, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:141.R1is H, C1-6 alkyl substituted with 0 to 2 Ra, CM fluoroalkyl,142.-(CHRg)o-i-(C3-6 cycloalkyl substituted with 0 to 2 R ),143.

144. R2is H, cyano, NH2, C1-6 alkyl substituted with 0 to 1 Ra, CM fluoroalkyl substituted with 0 to 1 Ra, -NH(C=O)C 1-4 alkyl, -CH=C(CH3)CF3, -(CH2)O-I-(C3-6 cycloalkyl substituted with 0 to 2 Re), -CH(cyclopropyl)CH2OH,145.-(CH2)i-2-phenyl, -CH2CH(CH3)-phenyl,146. 148.R5is H, F, Cl, CH3, -OCH3, -OCHF2, or -SO2CH3.

9. The compound of claim 7 or claim 8, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein independently for each occurrence:150.R1is C1-4 alkyl substituted with 0 to 1 Ra, C1-4 fluoroalkyl, -CH(cyclopropyl)CH2OH, -CH(CH3)cyclopropyl, or C4-5 cycloalkyl;151.R2is C1-6 alkyl substituted with 0 to 1 Raor C1-4 fluoroalkyl;152.R4is H or F;153.R5is Cl or -SO2CH3;154.R6is H orF;155.R7is H;156.R8is halogen, C1-4 alkoxy or C 1-4 fluoroalkoxy;157.R9is H or F; and158.Rais OH, NH2, or -C(=O)NH2.

10. The compound according to claim 1, which is selected from any one of the Examples 1 to 338 as described in the specification, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

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

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

13. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, or a composition according to claim 11 for use in treating one or more diseases or disorders selected heart failure, fibrosis, cardiomyopathies, atrialfibrillation, catecholaminergic polymeric ventricular tachycardia, heart block, cardiac arrhythmias, contraception, anxiety, post-traumatic stress disorder, hypertension, tachycardia, diabetes, allergy, and asthma.

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