Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors

Abstract

Provided herein are compounds of the Formula I: (I) or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X1, X2, X3, X4, Ring D, E, Ra, Rb, n and m have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

Description

SUBSTITUTED PYRAZOLO[l,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial Nos. 62 / 566,030, filed September 29, 2017; 62 / 531,690, filed July 12, 2017; 62 / 491,180, filed April 27, 2017; 62 / 447,849, filed January 18, 2017; and 62 / 406,275, filed October 10, 2017, each of which is incorporated by reference in its entirety herein.BACKGROUND

[0002] The present disclosure relates to novel compounds which exhibit Rearranged during Transfection (RET) kinase inhibition, pharmaceutical compositions comprising the compounds, processes for making the compounds, and the use of the compounds in therapy. More particularly, it relates to substituted pyrazolo[l,5-a]pyridine compounds useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

[0003] RET is a single-pass transmembrane receptor belonging to the tyrosine kinase superfamily that is required for normal development, maturation and maintenance of several tissues and cell types (Mulligan, L. M., Nature Reviews Cancer, 2014, 14, 173-186). The extracellular portion of the RET kinase contains four calcium-dependent cadherin-like repeats involved in ligand binding and a juxtamembrane cysteine-rich region necessary for the correct folding of the RET extracellular domain, while the cytoplasmic portion of the receptor includes two tyrosine kinase subdomains.

[0004] RET signaling is mediated by the binding of a group of soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which also includes neurturin (NTRN), artemin (ARTN) and persephin (PSPN) (Arighi et al., Cytokine Growth Factor Rev., 2005, 16, 441-67). Unlike other receptor tyrosine kinases, RET does not directly bind to GFLs and requires an additional co-receptor: that is, one of four GDNF family receptor- ex (GFRa) family members, which are tethered to the cell surface by a glycosylphosphatidylinositol linkage. GFLs and GFRa family members form binary complexes that in turn bind to RET and recruit it into cholesterol -rich membrane subdomains,which are known as lipid rafts, where RET signaling occurs.

[0005] Upon binding of the ligand-co-receptor complex, RET dimerization and autophosphorylation on intracellular tyrosine residues recruits adaptor and signaling proteins to stimulate multiple downstream pathways. Adaptor protein binding to these docking sites leads to activation of Ras-MAPK and PI3K-Akt / mTOR signaling pathways or to recruitment of the CBL family of ubiquitin ligases that functions in RET downregulation of the RET- mediated functions.

[0006] Aberrant RET expression and / or activity have been demonstrated in different cancers and in gastrointestinal disorders such as irritable bowel syndrome (IBS).SUMMARY OF THE INVENTION

[0007] It has now been found that substituted pyrazolo[l,5-a]pyridine compounds are inhibitors of RET kinase, and are useful for treating diseases such as proliferative diseases such as cancers.

[0008] Accordingly, provided herein is a compound of the Formula I:

[0009] or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X1, X2, X3, X4, Ring D, E, Ra, Rb, n and m are as defined herein.

[0010] Also provided herein is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0011] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

[0012] Also provided herein is a method of treating a RET-associated disease or disorderin a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

[0013] Also provided herein is a method of treating cancer and / or inhibiting metastasis associated with a particular cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein.

[0014] Also provided herein is a method of treating irritable bowel syndrome (IBS) and / or pain associated with IBS in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein.

[0015] Also provided is a method of providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders, such as diarrhea, associated with treatment, including chemotherapeutic treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein.

[0016] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.

[0017] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer and / or inhibiting metastasis associated with a particular cancer.

[0018] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.

[0019] Also provided is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders, such as diarrhea, associated with treatment, including chemotherapeutic treatment.

[0020] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for use in the inhibition of RET kinase activity.

[0021] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a RET-associated disease or disorder.

[0022] Also provided herein is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer and / or inhibiting metastasis associated with a particular cancer.

[0023] Also provided herein is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.

[0024] Also provided herein is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders, such as diarrhea, associated with treatment, including chemotherapeutic treatment.

[0025] Also provided herein is a use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of RET kinase activity.

[0026] Also provided herein is the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a RET-associated disease or disorder.

[0027] Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining if the cancer is associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same (e.g., a RET- associated cancer); and (b) if the cancer is determined to be associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same (e.g., a RET- associated cancer), administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0028] Also provided herein is a pharmaceutical combination for treating cancer (e.g., aRET-associated cancer, such as a RET-associated cancer having one or more RET inhibitor resistance mutations) in a patient in need thereof, which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, wherein the compound of Formula I or the pharmaceutically acceptable salt or solvate thereof and the additional therapeutic are formulated as separate compositions or dosages for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and of the additional therapeutic agent are together effective in treating the cancer. Also provided herein is a pharmaceutical composition comprising such a combination. Also provided herein is the use of such a combination for the preparation of a medicament for the treatment of cancer. Also provided herein is a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer a patient in need thereof.

[0029] Also provided herein is a method for reversing or preventing acquired resistance to an anticancer drug, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, to a patient at risk for developing or having acquired resistance to an anticancer drug. In some embodiments, the patient is administered a dose of the anticancer drug (e.g., at substantially the same time as a dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered to the patient).

[0030] Also provided herein is a method of delaying and / or preventing development of cancer resistant to an anticancer drug in an individual, comprising administering to the individual an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of an effective amount of the anticancer drug.

[0031] Also provided herein is a method of treating an individual with cancer who has an increased likelihood of developing resistance to an anticancer drug, comprising administering to the individual (a) an effective amount of a compound of Formula I before, during, or after administration of (b) an effective amount of the anticancer drug.

[0032] Also provided are methods of treating an individual with a RET-associated cancerthat has one or more RET inhibitor resistance mutations that increase resistance of the cancer to a first RET inhibitor (e.g., a substitution at amino acid position 804, e.g., V804M, V804L, or V804E, and / or one or more RET inhibitor resistance mutations listed in Tables 3 and 4), that include administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of another anticancer drug (e.g., a second RET kinase inhibitor).

[0033] Also provided are methods of treating an individual with a RET- associated cancer that include administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of another anticancer drug (e.g., a first RET kinase inhibitor).

[0034] Also provided herein is a method for treating irritable bowel syndrome (IBS) in a patient in need thereof, the method comprising (a) determining if the IBS is associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same; and (b) if the IBS is determined to be associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0035] Also provided herein is a pharmaceutical combination for treating irritable bowel syndrome (IBS) in a patient in need thereof, which comprises administering (a) a compound of General Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use for the treatment of IBS, wherein the amounts of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and of the additional therapeutic agent are together effective in treating the IBS. Also provided herein is a pharmaceutical composition comprising such a combination. Also provided herein is the use of such a combination for the preparation of a medicament for the treatment of the IBS. Also provided herein is a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of the IBS a patient in need thereof.

[0036] Also provided herein is a process for preparing a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.

[0037] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof obtained by a process of preparing the compound as defined herein.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0039] Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.DETAILED DESCRIPTION OF THE INVENTIONProvided herein is a compound of Formula I:

[0041] and pharmaceutically acceptable salts and solvates thereof, wherein:

[0042] X1, X2, X3and X4are independently CH, CCH3, CF or N, wherein zero, one or two of X1, X2, X3and X4is N;

[0043] A is H, CN, CI, methyl, ethyl or cyclopropyl;

[0044] B is:

[0045] (a) hydrogen,

[0046] (b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

[0047] (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,

[0048] (d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionally substituted witha C3-C6 cycloalkylidene ring,

[0049] (e) (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,

[0050] (f) (R¾2N)C 1 -C6 alkyl- where R1and R2are independently selected from H, C 1 - C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-;

[0051] (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1- 3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents;

[0052] (h) (C3-C6 cycloalkyl)Cl-C3 alkyl-, wherein said cycloalkyl is optionally substituted with OH,

[0053] (i) (hetCyca)Cl-C3 alkyl-,

[0054] (j) hetCyc3,(k) (R1R2N)C(=0)C1-C6 alkyl-, where R1and R2are independently selected from H and C1-C6 alkyl;

[0055] (1) (R1R2N)C(=0)-, where R1and R2are independently selected from H and Cl- C6 alkyl, or

[0056] (m) hetCycaC(=0)C 1 -C6 alkyl-;

[0057] hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, halogen, (C1-C6 alkyl)C(O)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=0)-;

[0058] Ring D is (i) a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen, (ii) a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen, or (iii) a saturated 7-11 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen;

[0059] each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-;

[0060] Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) R¾jNC(=0)CH20CH2- where R and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted withhetCycb, hetAr3, C1-C6 alkoxy- or R'R"N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, (j) hetCycb(Cl-C3 alkyl)OCH2-, (k) hetCycbC(=0) H- or (1) hetAraC(=0) H-;

[0061] hetCycbis a 4-6 membered heterocyclic ring, a 7-8 membered bridged heterocyclic ring, or a 7-10 membered heterospirocyclic ring, each ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkoxy)C(=0)-, C1-C6 alkoxy, and R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl;

[0062] hetAr3is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S wherein hetAr3is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros),

[0063] Rcis hydrogen or C1-C6 alkyl;

[0064] Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2- wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl- C6 alkyl, (C1-C6 alkyl)S02-, R^- and (R^^Cl-Ce alkyl- where each Reand Rfis independently H or C1-C6 alkyl, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl;

[0065] n is 0, 1, 2, 3, 4, 5 or 6;

[0066] misOorl;

[0067] E is:

[0068] (a) hydrogen,

[0069] (b) hydroxy,

[0070] (c) C1-C6 alkyl optionally substituted with 1-3 fluoros,

[0071] (d)alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros,

[0072] (e) hetAr2Cl-C6 alkyl-,

[0073] (f) (Cl-C6alkoxy)Cl-C6alkoxy-,

[0074] (g) Ar'O-,

[0075] (h) hetAi^-O-,

[0076] (i) Ar1Rg- where Rgis H or C1-C6 alkyl,

[0077] (j) hetAr2Rg- where Rgis H or C1-C6 alkyl,

[0078] (k) R3C(=0) Rg- where R is H or C1-C6 alkyl;

[0079] (1) Ar1C(=0)NR- where R is H or C 1-C6 alkyl,

[0080] (m) hetAr2C(=0) R(CH2)P- where p is 0 or 1 and Rgis H or C 1 -C6 alkyl,

[0081] (n) R4R5NC(=0)-,

[0082] (o) A^NR^O)-, where R is H or C1-C6 alkyl,

[0083] (p) hetAr2RC(=0)-, where R is H or C1-C6 alkyl,

[0084] (q) Ar^Cl-Ce alkyl)C(=0)- wherein said alkyl portion is optionally substituted with OH, hydroxy(Cl-C6 alkyl), C1-C6 alkoxy or NH2,

[0085] (r) hetCyc5C(=0)-,

[0086] (s) R4R5NC(=0) R- where Rgis H or C 1 -C6 alkyl, or

[0087] (t) (Cl-C6alkyl)S02-;

[0088] (u) Ar^Cl-Ce alkyl)C(=0) R- where R is H or C1-C6 alkyl,

[0089] (v) hetAr4C(=0) R- where Rgis H or C 1 -C6 alkyl,

[0090] (w) hetAr2-S(=0)-,

[0091] (x) (C3-C6 cycloalkyl)CH2S02-,

[0092] (y) Ar1(Cl-C6alkyl)S02-,

[0093] (z) hetAr2S02-,

[0094] (aa) Ar1,

[0095] (bb) hetAr2,

[0096] (cc) hetCyc5,

[0097] (dd) Cl-C6 alkoxy,

[0098] (ee) Ar^Cl-Ce alkyl)-0-,

[0099] (ff) hetAr2(Cl-C6 alkyl)-0-,

[0100] (gg) hetA^-O-Cl-Ce alkyl-,

[0101] (hh) Ar^Cl-Ce alkyl) R - where Rgis H or C1-C6 alkyl,

[0102] (ii) hetAi^-S-,

[0103] Oj) Ar2S02Rg(CH2)P- where p is 0 or 1 and Rgis H or C1-C6 alkyl,

[0104] (kk) (Cl-C6 alkoxy)C(=0)-,

[0105] (11) (C1-C6 alkyl) R C(=0)0- where R is H or C1-C6 alkyl,

[0106] (mm) (C1-C6 alkyl) R S02- where R is H or C1-C6 alkyl,

[0107] (nn) hetCyc5C(=0) R - where R is H or C1-C6 alkyl,

[0108] (oo) Q- Rh(Cl-C3 alkyl)C(=0) R - where R and Rhare independently H or CI-C6 alkyl and Q i -C6 alkyl or (C1-C6 alkyl)OC(=0)-,

[0109] (pp)where R and Rhare independently H or CI -C6 alkyl, Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(=0)- and r is 1, 2, 3 or 4,

[0110] (qq) RhOwhere R and Rhare independently H or C1-C6 alkyl and Q is H, C1-C6 a -,

[0111] (rr)H or C1-C6 alkyl and Q is H, C1-C6 alkyl or(C1-C6 alkyl)OC(=0)-, or

[0112] (ss) RgRhN- where R and Rhare independently H or C 1 -C6 alkyl,

[0113] (tt) (C3-C6 cycloalkyl)C(=0) R - where the cycloalkyl is optionally and independently substituted with one or more halogens,

[0114] (uu) (C1-C6 alkyl)C(=0)NRgCH2- where Rgis H or C1-C6 alkyl, or

[0115] (vv) C1-C6 alkyl)S02NRg- where Rgis H or C1-C6 alkyl;

[0116] Ar1is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (Cl- C6 alkyl)S02-, R^- and (R^^Cl-Ce alkyl- where each Reand Rfis independently H or C1-C6 alkyl;

[0117] hetAr2is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr2is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros) and hydroxyCl-C6 alkoxy-;

[0118] hetCyc5is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and oxo;

[0119] R3is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C3-C6 cycloalkyl)0-, (C3-C6 cycloalkyl)CH20-, hetCyc70-, Ph-O-, or (C1-C6 alkoxy)Cl-C6 alkyl-; wherein each of said C3-C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH or R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl;

[0120] R4is H or Cl-C6 alkyl;

[0121] R5is Ar2, hetAr3, Ar2CH2-, hetCyc6-CH2-, hydroxyCl-C6 alkyl-, (C3-C6 cycloalkyl)CH2-, or C1-C6 alkyl optionally substituted with 1-3 fluoros;

[0122] Ar2is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R¾hN- where Rgand Rhare independently H or C1-C6 alkyl, or Ar2is phenyl fused to a 6 membered heterocyclicring having a ring nitrogen atom and optionally substituted with C1-C6 alkyl;

[0123] hetAr3is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros);

[0124] hetAr4is pyridin-4(lH)-onyl or pyridin-2(lH)-onyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen;

[0125] hetCyc6is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S; and

[0126] hetCyc7is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S.

[0127] For complex chemical names employed herein, a substituent group is typically named before the group to which it attaches. For example, methoxyethyl comprises an ethyl backbone with a methoxy substituent.

[0128] The term "halogen" means -F (sometimes referred to herein as "fluoro" or "fluoros"), -CI, -Br and -I.

[0129] The terms "C1-C3 alkyl", "C3-C6 alkyl", "C1-C6 alkyl", and "C2-C6 alkyl" as used herein refer to saturated linear or branched-chain monovalent hydrocarbon radicals of one to three, three to six, one to six, or two to six carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, isobutyl, sec-butyl, tert-butyl, 2- methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0130] The term "C1-C6 alkyl optionally substituted with 1-3 fluoros" as used herein refers to a C1-C6 alkyl radical as defined herein, wherein one to three hydrogen atoms is replaced with one to three fluoro atoms, respectively. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-and trifluoroethyl.

[0131] The term "C1-C6 alkoxy" as used herein refer to saturated linear or branched-chain monovalent alkoxy radicals of one to six carbon atoms, wherein the radical is on the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

[0132] The term "(C1-C6 alkoxy)Cl-C6 alkyl" as used herein refers to saturated linear orbranched-chain monovalent radicals of one to six carbon atoms, wherein one of the carbon atoms is substituted with a C1-C6 alkoxy group as defined herein. Examples include methoxymethyl (CH3OCH2-) and methoxyethyl (CH3OCH2CH2-).

[0133] The term "(C1-C6 alkoxy)Cl-C6 alkoxy" as used herein refers to a C1-C6 alkoxy radical as defined herein, wherein one of the carbon atoms is substituted with a C1 -C6 alkoxy group as defined herein. Examples include methoxymethoxy (CH3OCH2O-) and ethoxymethoxy (CH3CH2O-CH2O-).

[0134] The terms "hydroxyC l-C6 alkyl" and "hydroxyC2-C6 alkyl", as used herein refers to saturated linear or branched-chain monovalent alkyl radicals of one to six or two to six carbon atoms, respectively, wherein one of the carbon atoms is substituted with a hydroxy group.

[0135] The term "dihydroxyC3-C6 alkyl" as used herein refers to a C3-C6 alkyl radical as defined herein, wherein two hydrogen atoms are replaced with a hydroxy group, provided the hydroxy groups are not on the same carbon.

[0136] The term "(R^^Cl-Ce alkyl" as used herein refers to a C1 -C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a R¾2N- group, wherein R1and R2are as defined herein.

[0137] The term "hetA^C l-Ce alkyl" as used herein refers to a C1 -C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a hetAr1group, wherein hetAr1is as defined herein.

[0138] The term "C3-C6 cycloalkyl" as used herein refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0139] The term "C3-C6 cycloalkylidene ring" as used herein refers to a divalent C3-C6 cycloalkane ring derived from a saturated 3-6 membered hydrocarbon ring by removal of two hydrogen atoms from the same carbon atom, such as for example, cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene. It can be represented in illustrative fashion by the following structure in which n is 1, 2 or 3 :

[0140] The term "(C3-C6 cycloalkyl)Cl-C3 alkyl" as used herein refers to a C1-C3 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a C3-C6 cycloalkyl ring. An example is cyclobutylmethyl.

[0141] The term "(hetCyca)Cl-C3 alkyl" as used herein refers to a C1-C3 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a hetCyc3group, wherein hetCyc3is as defined herein.

[0142] The term " A^Cl-Ce alkyl" as used herein refers to a C1-C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with an Ar1group, wherein Ar1is as defined herein.

[0143] The terms "hetAr2Cl-C6 alkyl" as used herein refers to a C1-C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a hetAr2group, wherein hetAr2is as defined herein.

[0144] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom, i.e., =0. For example, in one embodiment when referring to hetCyc3, a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and substituted with an oxo may be, for example, a pyrrolidinyl ring substituted with oxo (e.g., a pyrrolidinonyl ring), which may be represented by the structure:

[0145] The term "spirocyclic ring" as used herein refers to a group having two rings joined by a spirocyclic linkage through a common single carbon atom, wherein each ring is a 4-7- membered ring (including the common carbon atom).

[0146] The term "heterospirocyclic" as used herein refers to a group having two rings joined by a spirocyclic linkage through a carbon atom, wherein each ring has 4 to 6 ring atoms (with one ring carbon atom being common to both rings), and wherein one of the ring atoms is a nitrogen atom.

[0147] The term "compound," as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include othertautomeric forms unless otherwise specified.

[0148] The term "tautomer" as used herein refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomer.

[0149] It will be appreciated that certain compounds provided herein may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.

[0150] In certain embodiments of Formula I, X1, X2, X3and X4are independently CH or CF. In certain embodiments, each of X1, X2, X3and X4is CH.

[0151] In certain embodiments of Formula I, X1, X2, X3and X4are independently CH, CF or N, wherein one of X1, X2, X3and X4is N and the remainder are independently CH or CF. In certain embodiments of Formula I, X1is N, and X2, X3and X4are independently CH or CF. In certain embodiments, X1is N, and X2, X3and X4are CH.

[0152] In certain embodiments of Formula I, X1, X2, X3and X4are independently CH, CF or N, wherein two of X1, X2, X3and X4are N. In certain embodiments of Formula I, X1and X3are N and X2and X4are independently CH or CF. In one embodiment, X1and X3are N and X2and X4are CH.

[0153] In certain embodiments of Formula I, A is H.

[0154] In certain embodiments of Formula I, A is CI.

[0155] In certain embodiments of Formula I, A is CN.

[0156] In certain embodiments of Formula I, A is methyl.

[0157] In certain embodiments of Formula I, A is ethyl.

[0158] In certain embodiments of Formula I, A is cyclopropyl.

[0159] In certain embodiments of Formula I, B is hydrogen.

[0160] In certain embodiments of Formula I, B is C1-C6 alkyl optionally substituted with 1-3 fluoros. Non-limiting examples include methyl, ethyl, propyl, isopropyl, isobutyl, sec- butyl, 2-ethylbutyl, neopentyl, difluorom ethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. In certain embodiments, B is methyl or ethyl.

[0161] In certain embodiments of Formula I, B is hydroxyC2-C6 alkyl wherein the alkylportion is optionally substituted with a C3-C6 cycloalkylidene ring. In certain embodiments, the alkyl portion is unsubstituted. Non-limiting examples include the structures:

[0162] In certain embodiments of Formula I, B is dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. A non-limiting example includes 2,3-dihydroxypropyl.

[0163] In certain embodiments of Formula I, B is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros. In certain embodiments of Formula I, B is (C1-C6 alkoxy)C2-C6 alkyl- optionally substituted with 1-3 fluoros. Non-limiting examples include the structures:

[0164] In certain embodiments of Formula I, B is (R^R^Cl-Ce alkyl-, where R1and R2are independently H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl- C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-. Non-limiting examples of (R^N^l-Ce alkyl- include the structures:

[0165] In certain embodiments of Formula I, B is hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents. In certain embodiments, hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O and is optionally substituted with Cl- C6 alkyl. Non-limiting examples of hetA^Cl-CS alkyl- include the structures:

[0166] In certain embodiments of Formula I, B is (C3-C6 cycloalkyl)Cl-C3 alkyl- wherein said cycloalkyl is optionally substituted with OH. A non-limiting example is cyclobutylmethyl .

[0167] In certain embodiments of Formula I, B is (hetCyca)Cl-C3 alkyl-, where hetCyc3is as defined for Formula I. In certain embodiments of Formula I, B is (hetCyca)Cl-C3 alkyl- , where hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, halogen, (C1-C6 alkyl)C(=0)-, C1-C6 alkoxy, oxo and (Cl- C6 alkoxy)C(=0)-. Non-limiting examples include the structures:

[0168] In certain embodiments of Formula I, B is hetCyc3, where hetCyc2is as defined for Formula I. In certain embodiments, hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl-. Non-limiting examples include the structures:

[0169] In certain embodiments of Formula I, B is (Κ¾2Ν)0(=0)01-06 alkyl- where R1and R2are independently selected from H and C1-C6 alkyl. Non-limiting examples include the structures:

[0170] In certain embodiments of Formula I, B is (R1R2N)C(=0)-, where R1and R2are independently selected from H and C1-C6 alkyl. Non-limiting examples include the structure:

[0171] In certain embodiments of Formula I, B is hetCycaC(=0)Cl-C6 alkyl- where hetCyc3is as defined for Formula I. A non-limiting example includes the structure:

[0172] In certain embodiments of Formula I, B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In certain embodiments of Formula I, B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (c) hydroxyC2-C6 alkyl-.

[0173] Referring now to Ring D of Formula I,IRing D is (i) a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen, (ii) a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen, or (iii) a saturated 7-11 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen, wherein the E group may be bonded to any ring carbon atom of Ring D, each Ramay be bonded to any ring carbon atom of Ring D, and Rbmay be bonded to any ring carbon of Ring D, provided that the ring carbon atom bonded to the E group is optionally substituted with only one of Raor Rb.

[0174] In one embodiment, Ring D is a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen. The phrase "having one ring heteroatomwhich is nitrogen" when Ring D is a saturated monocyclic 4-7 membered heterocyclic ring means that said ring nitrogen atom is the nitrogen atom shown in Ring D of Formula I. Nonlimiting examples include the structures:

[0175] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I. In one embodiment, n is 0, 1, 2, 3 or 4. In one embodiment, n is 0, 1 or 2. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, n is 0 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0.

[0176] In one embodiment of Formula I, Ring D is a saturated monocyclic 4-6 membered heterocyclic ring having one ring heteroatom which is nitrogen selected from the structures

[0177] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I. In one embodiment, n is 0, 1, 2, 3 or 4. In one embodiment, n is 0, 1 or 2. In one embodiment, n is zero. In one embodiment, n is one. In one embodiment, n is two. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1.

[0178] In certain embodiments of Formula I, Ring D is a saturated monocyclic 5-6membered heterocyclic ring having one ring heteroatom which is nitrogen having the structure:

[0179] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I. In one embodiment, each Rais independently selected from C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-. In one embodiment, n is 0, 1, 2, 3 or 4. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2- (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, (j) hetCycb(Cl-C3 alkyl)OCH2-, (k) hetCycbC(=0)NH- or (1) hetAraC(=0)NH-; Rcis hydrogen or C1-C6 alkyl; hetCycbis as defined for Formula I; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, ( ¾·Ν)01-06 alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, Ring D is a saturated monocyclic 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, Ring D is a saturated monocyclic 5 membered heterocyclic ring having onering heteroatom which is nitrogen

[0180] In certain embodiments of Formula I, Ring D is a saturated monocyclic 4-6 membered heterocyclic ring having one ring heteroatom which is nitrogen selected from the structures:

[0181] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I. In one embodiment, each Rais independently selected from C1-C6 alkyl (optionally substituted with 1-3 fluoros) or (C1-C6 alkoxy)Cl-C6 alkyl-. In one embodiment, n is 0, 1, 2, 3 or 4. In one embodiment, n is 0, 1 or 2. In one embodiment, n is 0. In one embodiment, n is one. In one embodiment, Rbis (a) hydroxy, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and R are independently H or C1-C6 alkyl, (e) R^N-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or RR'N-, or said alkyl portion is optionally substituted with two substituents independently selected from RR'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, (j) hetCycb(Cl-C3 alkyl)OCH2-, (k) hetCycbC(=0)NH- or (1) hetAraC(=0)NH-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, n is 0 or 1 and m is 0 or 1. Non-limiting examples when Ring D is an optionallysubstituted saturated 4-7 membered heterocyclic ring include the structures:30

[0182] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, and asterisk indicates the point of attachment to the E group.

[0183] In one embodiment, Ring D is a saturated monocyclic 6 membered heterocyclic ring having one ring heteroatom which is nitrogen which may be represented by the structure:ere n and m are zero, that is, Ring D may be represented by the structure:

[0185] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, and the asterisk indicates the point of attachment to the E group.

[0186] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; E is (a) hydrogen, (b) hydroxy, (c) C1-C6 alkyl optionally substituted with 1-3 fluoros, (d) A^Cl-Ce alkyl wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl, (f) (C1-C6 alkoxy)Cl-C6 alkoxy-, (g) A^O-, (h) hetAr20-, (i) Ar1^- where R is H or C1-C6 alkyl, (j) hetAr2R - where Rgis H or C1-C6 alkyl, (k) R3C(=0) R - where R is H or C1-C6 alkyl, (1) Ar1C(=0)NR - where R is H or C1-C6 alkyl, (m) hetAr2C(=0)NR (CH2)P- where p is 0 or 1, (n) R4R5NC(=0)-, (o) A^ R^O)-, where R is H or C1-C6 alkyl, (p) hetAr2R C(=0)-, where Rgis H or C1-C6 alkyl, (r) hetCyc5C(=0)-, (s) R4R5NC(=0) Rg- where Rgis H or Cl- C6 alkyl, (t) C1-C6 alkyl)S02-, (u) Ar^Cl-Ce alkyl)C(=0) R - where R is H or C1-C6 alkyl, (v) hetAr4C(=0) R - where R is H or C1-C6 alkyl, (w) hetAr2-S(=0)-, (x) (C3-C6 cycloalkyl)CH2S02-, (y) Ar^Cl-Ce alkyl)S02-, (z) hetAr2S02-, (aa) Ar1, (bb) hetAr2, (cc) hetCyc5, (dd) C1-C6 alkoxy, (ee) Ar^Cl-Ce alkyl)-0-, (ff) hetAr2(Cl-C6 alkyl)-0-, (gg) hetAr2-0-Cl-C6 alkyl-, (hh) Ar^Cl-Ce alkyl) R - where R is H or C1-C6 alkyl, (ii) hetAr2- S-, Gj) Ar2S02R (CH2)P- where p is 0 or 1 and R is H or C1-C6 alkyl, (kk) (C1-C6 alkoxy)C(=0)-, (11) (C1-C6 alkyl) R C(=0)0- where R is H or C1-C6 alkyl, (mm) (C1-C6 alkyl) R S02- where R is H or C1-C6 alkyl, (nn) hetCyc5C(=0) R -, (oo) Q- Rh(Cl-C3 alkyl)C(=0)NR - where R and Rhare independently H or C1-C6 alkyl and Q is H, C1-C6Q-NIalkyl or (C1-C6 alkyl)OC(=0)-, (pp) RhO where R and Rhare independentlyH or C1-C6 alk l, Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(=0)- and r is 1, 2, 3 or 4, (qq)Rgand Rhare independently H or CI -C6 alkyl and Q is H, CI -C6alkyl or (C 1 -C6 alkyl)OC(=0)-, (rr)Rgis H or C1-C6 alkyl and Q isH, C1-C6 alkyl or (C1-C6 alkyl)OC(=0)-, (ss) RgRhN- where R and Rhare independently H or C1-C6 alkyl, (tt) (C3-C6 cycloalkyl)C(=0) R - where the cycloalkyl is optionally and independently substituted with one or more halogens, (uu) (C1-C6 alkyl)C(=0)NRgCH2- where R is H or C1-C6 alkyls, or (vv) C1-C6 alkyl)S02R - where R is H or C1-C6 alkyl; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl- C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2- , (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) R^N- , (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, (j) hetCycb(Cl-C3 alkyl)OCH2-, (k) hetCycbC(=0)NH- or (1) hetAraC(=0)NH-; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and Ar1, hetAr2, hetAr3, hetCycb,hetCyc5, Rg, R3, R4, and R5are as defined for Formula I. In one embodiment, each Rais independently selected from a C1-C6 substituent (optionally substituted with 1-3 fluoros). In one embodiment, Rbis (a) hydroxy, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) R^N- f) RcRdNCH2-, (h) (C1-C4 alkyl)- C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, or (k) hetCycbC(=0)NH-; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, Cl- C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyc0where hetCyc0is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; hetCycband hetAr3are as defined for Formula I, n is 0, 1 or 2; and m is 0 or 1. In one embodiment, Rbis (a) OH, (c) hetCycbCH2- wherein hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), (e) RcRdN- or (f) RcRdNCH2-; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros).

[0187] In one embodiment, Ring D is a saturated monocyclic 6-membered heterocyclic ring having one ring heteroatom which is nitrogen which may be represented by the structure:

[0188] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, and the asterisk indicates the point of attachment to the E group, and Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (Cl- C6 alkoxy)Cl-C6 alkyl-. In one embodiment, Rais C1-C6 alkyl.

[0189] In one embodiment, Ring D is a saturated monocyclic 6-membered heterocyclicring having one ring heteroatom which is nitrogen which may be represented by the structures:

[0190] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, and the asterisk indicates the point of attachment to the E group, and Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) R^N-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, (j) hetCycb(Cl-C3 alkyl)OCH2-, (k) hetCycbC(=0)NH- or (1) hetAraC(=0)NH-; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R¾1N)C1-C6 alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl. In one embodiment, Rbis (a) OH, (c) hetCycbCH2- , (e) R^N- or (f) RcRdNCH2-; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros); and hetCycbis as defined for Formula I. In one embodiment, Rbis (c) hetCycbCH2- , (e) RcRdN- or (f) RcRdNCH2-; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros); and hetCycbis as defined for Formula I.

[0191] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (k) R3C(=0)NR where Rgis H or C1-C6 alkyl, (1) Ar1C(=0)NRg- where R is H or C1-C6 alkyl,(m) hetAr2C(=0) Rg(CH2)P- where p is 0 or 1, or (n) R4R5NC(=0)- where n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and Ar1, hetAr2, Rg, R3, R4, and R5are as defined for Formula I. In one embodiment, each Rais independently selected from a C1-C6 substituent, Rbis OH or RcRdN- where Rcis hydrogen or C1-C6 alkyl and Rdis hydrogen, C1-C6 alkyl or (C1-C6 alkoxy)C(=0)-; n is 0, 1 or 2; and m is 0 or 1.

[0192] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; E is hydrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, (d) ^^ΝΟ(=0)ΟΗ2ΟΟΗ2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or RR'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or 0) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or Cl- C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R¾1N)C1-C6 alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; and m is 0 or 1. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom. In one embodiment, Ring D is a saturated 5 membered heterocyclic ring having one ring heteroatom. In one embodiment, Rbis OH or RcRdN- where Rcis hydrogen or C1-C6 alkyl and Rdis hydrogen, C1-C6 alkyl, (C1-C6 alkoxy)C(=0)- or PhCH2-. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0 or 1. Non-limiting examples include the structures:

[0193] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl-C6 alkoxy- or R'R"N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C 1 -C6 alkyl, PhCH2-, (C 1 -C6 alkoxy)C 1 - C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hydroxy. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, Rbis RcRdN- where Rcis hydrogen or Cl- C6 alkyl and Rdis hydrogen, C1-C6 alkyl or (C1-C6 alkoxy)C(=0)-. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0 or 1. A non-limiting example includes the structure:

[0194] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) ^^ΝΟ(=0)ΟΗ2ΟΟΗ2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogenor C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, Rbis OH or R°RdN- where Rcis hydrogen or C1-C6 alkyl and Rdis hydrogen, C1-C6 alkyl or (C1-C6 alkoxy)C(=0)-. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0 or 1. Non-limiting examples include the structures:

[0195] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen, Ra, Rb, n, and m are as defined for Formula I, and E isalkyl wherein said alkyl portion is optionally substituted with 1-3 fluoros and where Ar1is as defined for Formula I. In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently Cl- C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl- C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) ^ΝΟ(=0)ΟΗ2ΟΟΗ2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, (j) hetCycb(Cl-C3 alkyl)OCH2- or (k) hetCycbC(=0)NH-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)- , hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)- , (C1-C6 alkyl)C(=0)-, (R¾1N)C1-C6 alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Α^Ο-Οό alkyl, wherein said alkyl portion is optionally substituted with 1-3 fluoros and where Ar1is as defined for Formula I. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, Rbis OH. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0 or 1. Non-limiting examples include the structures:4142

[0196] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, (j) hetCycb(Cl-C3 alkyl)OCH2-, (k) hetCycbC(=0)NH- or (1) hetAraC(=0)NH-; hetAr3and hetCycbare as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and Oand optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2Cl-C6 alkyl, where hetAr1is as defined for Formula I. In one embodiment, hetAr2is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 0. In one embodiment, n is 0 and m is 1. In one embodiment, Rbis (a) hydroxy, (e) RcRdN-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (k) hetCycbC(=0)NH- or (1) hetAraC(=0)NH-. Non-limiting examples include the structures:

[0197] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (^R^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is (C1-C6 alkoxy)Cl-C6 alkoxy-. In one embodiment, n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 0. In one embodiment, n is 0 and m is 1. In one embodiment, Rbis RcRdN-. Non-limiting examples include the structures:

[0198] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (^R^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is A^O-, where Ar1is as defined for Formula I. In one embodiment, Ar1is unsubstituted or substituted with one or more substituents independently selected from halogen, CN and C1-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, Ring D is a saturated 4 or 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0. Non-limiting examples include the structures:

[0199] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr20-, where hetAr2is as defined for Formula I. In one embodiment, hetAr2is a 5-6-membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkoxy (optionally substituted with 1-3 fluoros), C1-C6 alkyl (optionally substituted with 1-3 fluoros) and hydroxyCl-C6 alkoxy. In one embodiment, Ring D is a saturated 4-6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, Ring D is a saturated 5-6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 0. In one embodiment, n is 0 and m is 1. In one embodiment, Rais C1-C6 alkyl. In one embodiment, Rbis RcRdN-. Non-limiting examples include the structures:5153

[0200] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRNC(=0)CH2OCH2- where R1and R areindependently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar1NRg-, where Ar1is as defined for Formula I and Rgis H or C1-C6 alkyl. In one embodiment, Ar1is optionally substituted with one or more halogens. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0. A non-limiting example includes the structure:

[0201] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) ^ΝΟ(=0)ΟΗ2ΟΟΗ2- where R1and R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" areindependently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2Rg- where hetAr2is a defined for Formula I and Rgis H or C1-C6 alkyl. In one embodiment, hetAr2is a pyridyl ring optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, Rais C1-C6 alkyl. In one embodiment, n is 0 and m is 0. Non-limiting examples include the structures:

[0202] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-,(R¾1N)C1-C6 alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is R3C(=0) Rg- where R3and Rgare as defined for Formula I. In one embodiment, Rgis hydrogen. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, m is 1 and n is 0. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, Rbis hydroxy, hetCycbCH2-, RcRdN-, RcRdNCH2-, C1-C6 alkoxy, (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or hetCycb(Cl-C3 alkyl)OCH2-, where hetCycb, Rcand Rdare as defined for Formula I. In one embodiment, Rbis hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and RR'N- where R and R" are independently hydrogen or C1-C6 alkyl. In one embodiment, Rbis RcRdN- or RcRdNCH2- where Rcis hydrogen or C1-C6 alkyl and Rdis hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:6062

[0203] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogenor C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is ΑΓ^(=0)Μ^- where Ar1is as defined for Formula I. In one embodiment, Ar1is unsubstituted or substituted with one or more substituents independently selected from halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (Cl- C6 alkyl)S02-, and (R^^Cl-Ce alkyl- where each Reand Rfis independently H or C1-C6 alkyl. In one embodiment, Ring D is a saturated 5-6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, n is i and m is 0. In one embodiment, n is 0 and m is 1. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl. In one embodiment, Rbis C1-C6 alkoxy, hetCycbCH2- or RcRdNCH2-, where hetCycb, Rcand Rdare as defined for Formula I. In one embodiment, Rbis hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros) and (C1-C6 alkoxy)Cl-C6 alkyl-. In one embodiment, Rbis RcRdNCH2- where Rcis H or C1-C6 alkyl and Rdis C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, Rbis hydroxyl. Non-limiting examples include the structures:66

[0204] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2C(=0)NR (CH2)P- where p is 0 or 1, and hetAr2and Rgare as defined for Formula I. In one embodiment, hetAr2is a 5-6-membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros) and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl. In one embodiment, Rbis hydroxy, hetCycbCH2-, RcRdNCH2-, C1-C6 alkoxy, or hetCycb(Cl-C3 alkyl)OCH2-, where hetCycb, Rcand Rdare as defined for Formula I. In one embodiment, Rbis hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from C1-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, Rbis RcRdNCH2- where Rcis H or C1-C6 alkyl and Rdis C1-C6 alkyl (optionally substituted with -3 fluoros). Non-limiting examples include the structures:7274757677

[0205] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is R4R5NC(=0)- where R4and R5are as defined for Formula I. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl. In one embodiment, Rbis hetCycbCH2- , RcRdNCH2-, or hetCycb(Cl-C3 alkyl)OCH2-, where hetCycb, Rcand Rdare as defined for Formula I. In one embodiment, Rbis hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring, a 7-8 membered bridged heterocyclic ring, or a 7-10 membered heterospirocyclic ring, each ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, (C1-C6 alkoxy)C(=0)-, and R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl. In one embodiment, Rbis RcRdNCH2- where Rcis H or C1-C6 alkyl and Rdis C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples includes the structures:8182

[0206] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis asdefined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar1RgC(=0)- where Ar1and Rgare as defined for Formula I. In one embodiment, Ar1is unsubstituted or substituted with one or more halogens. In one embodiment, m is 0. In one embodiment n is 0 or 1. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

[0207] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R"N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2RgC(=0)- where hetAr2and Rgare as defined for Formula I. In one embodiment, hetAr1is a 5-6 membered heteroaryl having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from C1-C6 alkyl (optionally substituted with 1-3 fluoros) and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, m is 0. In one embodiment n is 0 or 1. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

[0208] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetCyc5C(=0)- where hetCyc5is as defined for Formula I. In one embodiment, m is 0. In one embodiment n is 0 or 1. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). A non-limiting example is the structure:

[0209] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d)where R1and R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R"N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is R4R5NC(=0)NR - where R4, R5and R are as defined for Formula I. In one embodiment, R4and R5are independently hydrogen or C1-C6 alkyl. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, n is 0 and m is 1. In one embodiment, Rbis hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, Rbis RcRdNCH2- where Rcis H or C1-C6 alkyl and Rdis C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

[0210] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionallysubstituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R¾1N)C1-C6 alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is (C1-C6 alkyl)S02-. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

[0211] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^N^l-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ringheteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar^Cl-Ce alkyl)C(=0) R - where Ar1and Rgare as defined for Formula I. In one embodiment, Ar1is unsubstituted or substituted with one or more halogens. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

[0212] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (^R^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr4C(=0) Rg- where hetAr4and Rgare as defined for Formula I. In one embodiment, n is 0 or 1 and m is 0. In one embodiment, Rais C1-C6 alkyl. Non-limiting examples include the structures:

[0213] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2-S(=0)- where hetAr2is as defined for Formula I. In one embodiment, hetAr2is a 5-6-membered heteroaryl ring. In one embodiment, hetAr2is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0. A non-limiting example includes the structure:

[0214] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a)hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is (C3-C6 cycloalkyl)CH2S02-. In one embodiment, n is 0. In one embodiment, m is 0. A non-limiting example includes the structure:

[0215] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) ^^ΝΟ(=0)ΟΗ2ΟΟΗ2- where R1and R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" areindependently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar^Cl-Ce alkyl)S02- where Ar1is as defined for Formula I. In one embodiment, Ar1is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0. A non-limiting example includes the structure:

[0216] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2S02- where hetAr2is as defined for Formula I. In one embodiment, hetAr2is a 5-6-membered heteroaryl ring. In one embodiment, hetAr2is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0. A non-limiting example includes the structure:

[0217] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar1where Ar1is as defined for Formula I. In one embodiment,Ar1is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0 or 1. In one embodiment, Rbis OH. A non-limiting example includes the structure:

[0218] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2- (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2where hetAr2is as defined for Formula I. In one embodiment, hetAr2is unsubstituted or substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, n is 0. In one embodiment, m is 0 or 1. In one embodiment, Rbis OH. Non-limiting examples include the structures:

[0219] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyc0where hetCyc0is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetCyc5where hetCyc5is as defined for Formula I. In one embodiment, m is 0. In one embodiment, n is 0 or 1. In one embodiment, Rais C1-C6 alkyl(optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

[0220] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^N^l-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is C1-C6 alkoxy. In one embodiment, n is 0. In one embodiment, m is 0 or 1. In one embodiment, Rbis RcRdN- where Rcis H and Rdis H. Non-limiting examples include the structures:

[0221] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar^Cl-Ce alkyl)-0- where Ar1is as defined for Formula I. In one embodiment, Ar1is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0. Non-limiting examples include the structures:

[0222] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; (d) RiRNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, or (f) RcRdNCH2-; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2(Cl-C6 alkyl)-0- where hetAr2is as defined for Formula I. In one embodiment, hetAr2is a 5-6-membered heteroaryl ring. In one embodiment, hetAr2is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0. Non-limiting examples include the structures:

[0223] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a)hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2-0-Cl-C6 alkyl- where hetAr2is as defined for Formula I. In one embodiment, hetAr2is a 5-6-membered heteroaryl ring. In one embodiment, hetAr2is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0. Non-limiting examples include the structures:

[0224] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d)where R1and R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituentsindependently selected from R'R"N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar^Cl-Ce alkyl) Rg- where Ar1and Rgare as defined for Formula I. In one embodiment, Ar1is unsubstituted or substituted with one or more halogens. In one embodiment, m is 0. In one embodiment, n is 0 or 1. In one embodiment, R1is C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

[0225] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) ^ΝΟ(=0)ΟΗ2ΟΟΗ2- where R1and R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or RR'N-, or said alkyl portion is optionally substituted with two substituents independently selected from RR'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionallysubstituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (^R^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2-S- where hetAr2is as defined for Formula I. In one embodiment, hetAr2is a 5-6-membered heteroaryl ring. In one embodiment, hetAr2is unsubstituted. In one embodiment, n is 0. In one embodiment, m is 0. A non-limiting example is the structure:

[0226] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ringheteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar2S02 R (CH2)P- where p is 0 or 1, R is H or C1-C6 alkyl, and Ar2is as defined for Formula I. In one embodiment, p is 0. In one embodiment, p is 1. In one embodiment, Ar2is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and RgRhN- where Rgand Rhare independently H or C1-C6 alkyl. In one embodiment, Ar2is phenyl optionally substituted with one or more independently selected C1-C6 alkyl (optionally substituted with 1-3 fluoros) substituents. In one embodiment, m is 0 or 1. In one embodiment, n is 0. Non-limiting examples include the structures:

[0227] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjareindependently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is (C1-C6 alkoxy)C(=0)-. In one embodiment, m is 0. In one embodiment, n is 0 or 1. In one embodiment, Rais hydroxyCl-C6 alkyl. Non-limiting examples include the structures:

[0228] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) ^^ΝΟ(=0)ΟΗ2ΟΟΗ2- where R1and R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" areindependently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is (C1-C6 alkyl)NRgC(=0)0- where Rgis H or C1-C6 alkyl. In one embodiment, m is 0. In one embodiment, n is 0 or 1. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

[0229] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^N^l-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is (C1-C6 alkyl)NR S02- where Rgis H or C1-C6 alkyl. In one embodiment, m is 0. In one embodiment, n is 0. A non-limiting example is the structure:

[0230] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetCyc5C(=0)NRg- where R is H or C1-C6 alkyl and hetCyc5is as defined for Formula I. In one embodiment, hetCyc5is a 5-6 membered heterocyclic ring having a ring nitrogen atom. In one embodiment, m is 0 or 1. In one embodiment, n is 0. In one embodiment, Rbis RcRdNCH2- where Rcand Rdare as defined for Formula I. In oneembodiment, Rcand Rdare hydrogen or C1-C6 alkyl. Non-liming examples include the structures:

[0231] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^N^l-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Q-NRh(Cl-C3 alkyl)C(=0)NR - where Rgand Rhare independently H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(=0)-. In one embodiment, m is 0. In one embodiment, n is 0 or 1. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

[0232] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3,4, 5 or 6; m is 0 or 1; and E is (pp)where Rgand Rhare independently H or C1-C6 alkyl, Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(=0)- and r is 1, 2, 3 or 4. In one embodiment, m is 0. In one embodiment, n is 0 or 1. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

[0233] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis asdefined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and o tionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3,4, 5 or 6; m is 0 or 1; and E iswhere Rgand Rhare independently H or Cl- C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(=0)-. In one embodiment, m is 0. In one embodiment, n is 0 or 1. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

[0234] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl-C6 alkoxy- or R'R"N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3,4, 5 or 6; m is 0 or 1; and E is0where Rgis H or C1-C6 alkyl and Q is H, Cl-C6 alkyl or (C1-C6 alkyl)OC(=0)-. In one embodiment, m is 0. In one embodiment, n is 0 or 1. In one embodiment, Rais C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non- limiting examples include the structures:

[0235] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a)hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is R^ 'TST- where Rgand Rhare independently H or C1-C6 alkyl. In one embodiment, n is 0 or 1. In one embodiment, m is 0 or 1. In one embodiment, Rbis hydroxy, C1-C6 alkoxy- or hetCycb(Cl-C3 alkyl)OCH2-, where hetCycbis as defined for Formula I. In one embodiment, hetCycbis a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O. Non-limiting examples include the structures:

[0236] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is (C3-C6 cycloalkyl)C(=0)NRg- where the cycloalkyl is optionally and independently substituted with one or more halogens. A non-limiting example includes the structure:

[0237] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is (C1-C6 alkyl)C(=0)NR CH2- where Rgis H or C1-C6 alkyl. A non-limiting example includes the structure:

[0238] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d)where R1and R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, Cl- C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituentsindependently selected from R'R"N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2-; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is C1-C6 alkyl)S02R - where Rgis H or C1-C6 alkyl. A non- limiting example includes the structure:

[0239] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen. The phrase "having one ring heteroatom which is nitrogen" when Ring D is a saturated 7-8 membered bridged heterocyclic ring means that the one ring nitrogen atom is the nitrogen atom shown in Ring D of Formula I. Non-limiting exam les include rings such as

[0240] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I. In one embodiment, n is 0 or 1. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, n is 0 and m is 0 or 1.

[0241] In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ring havin one ring heteroatom which is nitrogen. Non-limiting examples include structures:

[0242] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I. In one embodiment, n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 0 or 1. In one embodiment, Rbis RcRdN- where Rcis H or C1-C6 alkyl and Rdis H or C1-C6 alkyl. In one embodiment, Rbis R°RdN- where Rcand Rdare H.

[0243] In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ringhaving one ring heteroatom which is nitrogen having the structure

[0244] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Rband m are as defined for Formula I. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, Rbis RcRdN- where Rcis H or C1-C6 alkyl and Rdis H or CI -C6 alkyl. In one embodiment, Rbis RcRdN- where Rcand Rdare H. Non-limiting examples include the structures:

[0245] where the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment to the E group.

[0246] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen, and E is selected from (a) hydrogen, (b) hydroxy, (f) (C1-C6 alkoxy)Cl-C6 alkoxy, (h) hetAr20-, (j) hetAr2NR - where Rgis H or Cl- C6 alkyl, (n) R4R5NC(=0)-, (o) A^NR^O)-, where Rgis H or C1-C6 alkyl, and (p) hetAr2NRgC(=0)-, where R is H or C1-C6 alkyl, where Ar1, hetAr2, R4and R5are as defined for Formula I.

[0247] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen, each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) R^N-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with twosubstituents independently selected from R'R"N- and OH, where each R' and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1 2, 3, 4, 5 or 6; m is 0 or 1; and E is hydrogen. In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0 or 1. In one embodiment, Rbis R°RdN- where Rcis hydrogen or C1-C6 alkyl and Rdis hydrogen, C1-C6 alkyl or (C1-C6 alkoxy)C(=0)-. A non-limiting example includes the structure:

[0248] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) ^ΝΟ(=0)ΟΗ2ΟΟΗ2- where R and R are independently H or C1-C6 alkyl, (e) R^N-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl(optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1 ; and E is hydroxy. In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0. A non-limiting example includes the structure:

[0249] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) R^N-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is (C1-C6 alkoxy)Cl-C6 alkoxy. In one embodiment, Ring D isa saturated 7 membered bridged heterocyclic ring having one ring heteroatom which nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and is 0. A non-limiting example includes the structure:

[0250] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr20- where hetAr2is as defined for Formula I. In one embodiment hetAr2is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and halogen. In one embodiment, hetAr2is unsubstituted. In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1and m is 0. In one embodiment, n is 0 and m is 0. Non-limiting examples include the structures:

[0251] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) R^N-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0)NH- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2NH- where hetAr2is as defined for Formula I. In one embodiment hetAr2is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from C1-C6 alkoxy, halogen and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0. Non-limiting examples include the structures:

[0252] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) R^N-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ringheteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is R3C(=0) Rg- where R3and Rgare as defined for Formula I. In one embodiment, n is 0 and m is 0. A non-limiting example includes the structure:

[0253] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) R^N-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar1C(=0)NH- where Ar1is as defined for Formula I. In one embodiment, Ar1is unsubstituted. In one embodiment, n is 0 and m is 0. A non-limiting example includes the structure:

[0254] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2C(=0)NR- where hetAr2and R' are as defined for Formula I. In one embodiment, hetAr2is unsubstituted. In one embodiment, n is 0 and m is 0. A non- limiting example includes the structure:

[0255] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC l-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) R^N-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C 1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1 -3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyC l-C6 alkyl (optionally substituted with 1 -3 fluoros), (hydroxyCl -C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)C l- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C 1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is R4R5NC(=0)- where R4and R5are as defined for Formula I. In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0. Non-limiting examples includes the structures:

[0256] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC l-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RRNC(=0)CH2OCH2- where Riand R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is Ar1NRgC(=0)-, where Ar1and Rgareas defined for Formula I. In one embodiment, Ar1is substituted with one or more substituents independently selected from halogen, CN and C1-C6 alkyl (optionally substituted with 1-3 fluoros). In one embodiment, Ar1is unsubstituted. In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0. A non-limiting example includes the structure:

[0257] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d)where R and R are independently H or C1-C6 alkyl, (e) R^N-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-,(h) (C 1 -C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R"N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R"N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hetAr2RgC(=0)- where hetAr2and Rgare as defined for Formula I. In one embodiment hetAr2is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from halogen and C1-C6 alkoxy. In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 and m is 0. A non-limiting example includes the structure:

[0258] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) ^^ΝΟ(=0)ΟΗ2ΟΟΗ2- where R1and R are independently H or C1-C6 alkyl, (e) R^N-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb,hetAr3, C1-C6 alkoxy- or R'R"N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1. The phrase "having one ring heteroatom which is nitrogen" when Ring D is a saturated 7-11 membered heterospirocyclic ring system means that said one ring nitrogen is the ring nitrogen atom shown in Ring D of Formula I. In one embodiment, Ring D is a saturated 9 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen. In one embodiment, Ring D is a 7-azaspiro[3.5]nonanyl ring, e.g., a 7- azaspiro[3.5]nonan-2-yl ring. Nonlimiting examples include the structures:

[0259] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to theE group, and Ra, n, Rband m are as defined for Formula I. In one embodiment, n is 0, 1 or 2 and m is 0 or 1. In one embodiment, n is 0 or 1. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, n is 0 and m is 0.

[0260] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen; each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl - ; Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, (h) (C 1 -C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, or (j) hetCycb(Cl-C3 alkyl)OCH2- ; hetCycbis as defined for Formula I; Rcis hydrogen or C1-C6 alkyl; Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyc0where hetCyc0is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0 or 1; and E is hydrogen. In one embodiment, Ring D is a 7- azaspiro[3.5]nonanyl ring, e.g., a 7-azaspiro[3.5]nonan-2-yl ring. In one embodiment, n is 0 and m is 0 or 1. In one embodiment, Rbis RcRdN- where Rcis hydrogen or C1-C6 alkyl and Rdis hydrogen, C1-C6 alkyl or (C1-C6 alkoxy)C(=0)-. Non-limiting examples include the structures:

[0261] In one embodiment, Formula I includes compounds of Formula I- A, wherein:

[0262] X1, X2, X3and X4are independently CH, CF or N, wherein zero, one or two of X1,X2, X3and X4is N;

[0263] A is H, CN, CI, methyl, ethyl or cyclopropyl;

[0264] B is

[0265] (a) hydrogen,

[0266] (b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

[0267] (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,

[0268] (d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,

[0269] (e) (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,

[0270] (f) (R¾2N)C 1 -C6 alkyl- where R1and R2are independently selected from H, C 1 - C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-;

[0271] (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1- 3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl groups;

[0272] (h) (C3-C6 cycloalkyl)Cl-C3 alkyl-,

[0273] (i) (hetCyca)Cl-C3 alkyl-,

[0274] (j) hetCyc3,

[0275] (k) (R1R2N)C(=0)C1-C6 alkyl- where R1and R2are independently selected from H and C1-C6 alkyl,

[0276] (1) (R1R2N)C(=0)-, where R1and R2are independently selected from H and Cl- C6 alkyl, or

[0277] (m) hetCycaC(=0)C 1 -C6 alkyl-;

[0278] hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, halogen, (C1-C6 alkyl)C(O)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=0)-;

[0279] Ring D is a saturated 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen;

[0280] each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-;

[0281] Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) ^ΝΟ(=0)ΟΗ2ΟΟΗ2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R"N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (RR"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, (j) hetCycb(Cl-C3 alkyl)OCH2-, (k) hetCycbC(=0) H- or (1) hetAraC(=0) H-;

[0282] hetCycbis a 4-6 membered heterocyclic ring, a 7-8 membered bridged heterocyclic ring, or a 7-10 membered heterospirocyclic ring, each ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkoxy)C(=0)-, C1-C6 alkoxy, and R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl;

[0283] hetAr3is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S herein hetAr3is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros);

[0284] Rcis hydrogen or C1-C6 alkyl;

[0285] Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with CI -C6 alkyl;

[0286] n is 0, 1, 2, 3, 4, 5 or 6;

[0287] m is O or l;

[0288] E is

[0289] (a) hydrogen,

[0290] (b) hydroxy,

[0291] (c) C1-C6 alkyl optionally substituted with 1-3 fluoros,

[0292] (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros,

[0293] (e) hetAr2C 1 -C6 alkyl-,

[0294] (f) (C 1 -C6 alkoxy)C 1 -C6 alkoxy-,

[0295] (g) A^O-,

[0296] (h) hetAr20-,

[0297] (i) ArxR - where Rgis H or C1-C6 alkyl,

[0298] (j) hetAi^ RS- where Rgis H or C1-C6 alkyl,

[0299] (k) R3C(=0) Rg- where Rgis H or C 1 -C6 alkyl,

[0300] (1) Ar1C(=0)NRg- where R is H or C 1 -C6 alkyl,

[0301] (m) hetAr2C(=0) R (CH2)P- where p is 0 or 1 and R is H or C 1-C6 alkyl,

[0302] (n) R4R5NC(=0)-,

[0303] (o) Ar1R8C(=0)-, where R is H or C1-C6 alkyl,

[0304] (p) hetAr2R C(=0)-, where Rgis H or C 1 -C6 alkyl,

[0305] (r) hetCyc5C(=0)-,

[0306] (s) R4R5NC(=0)NR - where R is H or C1-C6 alkyl,

[0307] (t) (C1-C6 alkyl)S02-;

[0308] (u) Ar^C 1 -C6 alkyl)C(=0)NRg- where R is H or C 1 -C6 alkyl,

[0309] (v) hetAr4C(=0) Rg- where R is H or C1-C6 alkyl,

[0310] (w) hetAr2-S(=0)-,

[0311] (x) (C3-C6 cycloalkyl)CH2S02-,

[0312] (y) Ar1(Cl-C6 alkyl)S02-,

[0313] (z) hetAr2S02-,

[0314] (aa) Ar1,

[0315] (bb) hetAr2,

[0316] (cc) hetCyc5,

[0317] (dd) Cl-C6alkoxy,

[0318] (ee) Ατ^ΟΙ-Οό alkyl)-0-,

[0319] (ff) hetAr2(Cl-C6 alkyl)-0-,

[0320] (gg) hetAr2-0-Cl-C6 alkyl-,

[0321] (hh) Ar^Cl-Ce alkyl) R- where Rgis H or C1-C6 alkyl, or

[0322] (ii) hetAr2-S-,

[0323] (jj) Ar2S02R(CH2)P- where p is 0 or 1 and Rgis H or C1-C6 alkyl,

[0324] (kk) (Cl-C6alkoxy)C(=0)-,

[0325] (11) (C1-C6 alkyl) RgC(=0)0- where R is H or C1-C6 alkyl,

[0326] (mm) (C1-C6 alkyl) R S02- where R is H or C1-C6 alkyl,

[0327] (nn) hetCyc5C(=0) R- where R is H or C1-C6 alkyl,

[0328] (oo) Q- Rh(C 1 -C3 alkyl)C(=0) R- where R and Rhare independently H or C 1 -C6 alkyl and Q i -C6 alkyl or (C1-C6 alkyl)OC(=0)-,

[0329] (pp)where R and Rhare independently H or CI -C6 alkyl, Q is H, C1-C6 alkyl or C1-C6 alkyl)OC(=0)- and r is 1, 2, 3 or 4,

[0330] (qq) and Rhare independently H or C1-C6 alkyl and Q is H, C1-C6 a -,

[0331] (rr)H or C1-C6 alkyl and Q is H, C1-C6 alkyl or(C1-C6 alkyl)OC(=0)-, or

[0332] (ss) R¾hN- where R and Rhare independently H or C 1 -C6 alkyl,

[0333] (tt) (C3-C6 cycloalkyl)C(=0)NR - where the cycloalkyl is optionally and independently substituted with one or more halogens,

[0334] (uu) (C 1 -C6 alkyl)C(=0)NRgCH2- where Rgis H or C 1 -C6 alkyl, or

[0335] (vv) C1-C6 alkyl)S02NRg- where Rgis H or C1-C6 alkyl;

[0336] Ar1is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (Cl- C6 alkyl)S02-, ^R^- and (R^^Cl-Ce alkyl- where each Reand Rfis independently H or C1-C6 alkyl;

[0337] hetAr2is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr2is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros) and hydroxyCl-C6 alkoxy-;

[0338] hetCyc5is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and oxo;

[0339] R3is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C3-C6 cycloalkyl)0-, (C3-C6 cycloalkyl)CH20-, hetCyc70-, Ph-O-, or (C1-C6 alkoxy)Cl-C6 alkyl-; wherein each of said C3-C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH or R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl;

[0340] R4is H or Cl-C6 alkyl;

[0341] R5is Ar2, hetAr3, Ar2CH2-, hetCyc6-CH2-, hydroxyCl-C6 alkyl-, (C3-C6 cycloalkyl)CH2-, or C1-C6 alkyl optionally substituted with 1-3 fluoros;

[0342] Ar2is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and RSR^N- where RgandRhare independently H or C1-C6 alkyl, or Ar2is phenyl fused to a 6 membered heterocyclic ring having a ring nitrogen atom and optionally substituted with C1-C6 alkyl;

[0343] hetAr3is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl(optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros);

[0344] hetAr4is pyridin-4(lH)-onyl or pyridin-2(lH)-onyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen;

[0345] hetCyc6is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S; and

[0346] hetCyc7is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S.

[0347] In one embodiment of Formula I- A, X1is N; X2, X3and X4are CH.

[0348] In one embodiment of Formula I- A, A is CN.

[0349] In one embodiment of Formula I- A, X1is N; X2, X3and X4are CH; and A is CN.

[0350] In one embodiment of Formula I- A, B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I- A, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.

[0351] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.

[0352] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.

[0353] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; and B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is hydroxyC2-C6 alkyl-.

[0354] In one embodiment of Formula I-A, Ring D is:

[0355] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A. In one embodiment, n is 0, 1, 2, 3 or 4. In one embodiment, n is 0. In one embodiment, n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 1. In one embodiment, Rbis hydroxy, or R°RdN- where Rcis hydrogen or C1-C6 alkyl and Rdis hydrogen or C1-C6 alkyl.

[0356] In one embodiment of Formula I-A, Ring D is:

[0357] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A. In one embodiment, n is 0, 1, 2, 3 or 4. In one embodiment, n is 0. In one embodiment, n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 1. In one embodiment, Rbis hydroxy, or R°RdN- where Rcis hydrogen or C1-C6 alkyl and Rdis hydrogen or C1-C6 alkyl.

[0358] In one embodiment of Formula I-A, Ring D is:

[0359] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A. In one embodiment, n is 0, 1, 2, 3 or 4. In one embodiment, n is 0. In one embodiment, n is 0 or 1 and m is 0 or 1. In oneembodiment, n is 0 and m is 1. In one embodiment, Rbis hydroxy, or RcRdN- where Rcis hydrogen or C1-C6 alkyl and Rdis hydrogen or C1-C6 alkyl.

[0360] In one embodiment of Formula I-A, E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) A^NR^ where R is H or C1-C6 alkyl, (1) Ar1C(=0)NRg- where Rgis H or Cl- C6 alkyl, or (m) hetAr2C(=0)NR (CH2)P-, where p is 0 or 1 and Ar1, hetAr2and R are as defined for Formula I-A.

[0361] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is:

[0362] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A.

[0363] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is:

[0364] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A.

[0365] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionallysubstituted cloalkylidene ring; and Ring D is:

[0366] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A.

[0367] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ring D is

[0368] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A.

[0369] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ring D is

[0370] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A.

[0371] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ring D is

[0372] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A.

[0373] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is a piperidin-4-yl ring having the structure:

[0374] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A.

[0375] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is a piperidin-4-yl ring having the structure:

[0376] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A.

[0377] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D isa piped din- -yl ring having the structure:

[0378] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A.

[0379] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is a piperidin-4-yl ring having the structure:

[0380] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A; and E is (d) A^Cl-Ce alkyl - wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAi^O-, (1) Ar1C(=0)NR - where Rgis H or C1-C6 alkyl, or (m)where p is 0 or 1 and Ar1, hetAr2and Rgare as defined for Formula I-A.

[0381] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is a piperidin-4-yl ring having the structure:

[0382] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A; and E is (d) A^Cl-Ce alkyl - wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAi^O-, (1) Ar1C(=0) R - where Rgis H or C1-C6 alkyl, or (m)where p is 0 or 1 and Ar1, hetAr2and Rgare as defined for Formula I-A.

[0383] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is a piperidin-4-yl ring having the structure:

[0384] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A; and E is (d) A^Cl-Ce alkyl - wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAi^O-, (1) Ar1C(=0)NR - where R is H or C1-C6 alkyl, or (m)where p is 0 or 1 and Ar1, hetAr2and Rgare as defined for Formula I-A.

[0385] In one embodiment of Formula I-A, E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (1)where p is 0 or 1 and Ar1, hetAr2and Rgare as defined for Formula I-A.

[0386] In one embodiment of Formula I- A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is

[0387] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A; and E is (d) A^Cl-Ce alkyl - wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) A^NR8- where R is H or C1-C6 alkyl, (1) Ar1C(=0)NRg- where RSis H or C1-C6 alkyl, or (m) hetAr2C(=0)NR (CH2)P-, where p is 0 or 1 and Ar1, hetAr2and Rgare as defined for Formula I-A.

[0388] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is

[0389] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A; and E is (d) A^Cl-Ce alkyl - wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAi^O-, (1) Ar1C(=0)NR - where R is H or C1-C6 alkyl, or (m)where p is 0 or 1 and Ar1, hetAr2and Rgare as defined for Formula I-A

[0390] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is

[0391] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A; and E is (d) A^Cl-Ce alkyl - wherein said alkyl portion is optionally substituted with 1 -3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) ΑΐιΟ-, (h) hetAr20-, (1) Ar1C(=0) R - where R is H or C1-C6 alkyl, or (m)where p is 0 or 1 and Ar1, hetAr2and Rgare as defined for Formula I-A

[0392] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

[0393] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A; and E is (d) A^Cl-Ce alkyl - wherein said alkyl portion is optionally substituted with 1 -3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAi^O-, (1) Ar1C(=0)NR - where R is H or C1-C6 alkyl, or (m)where p is 0 or 1 and Ar1, hetAr2and Rgare as defined for Formula I-A

[0394] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

[0395] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A; and E is (d) A^Cl-Ce alkyl - wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) Α^Ο-, (h) hetAi^O-, (1) Ar1C(=0) R - where Rgis H or C1-C6 alkyl, or (m)where p is 0 or 1 and Ar1, hetAr2and Rgare as defined for Formula I-A

[0396] In one embodiment of Formula I-A, X1is N; X2, X3and X4are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

[0397] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A; and E is (d) A^Cl-Ce alkyl - wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) Α^Ο-, (h) hetAr20-, (1) Ar1C(=0)NR - where R is H or C1-C6 alkyl, or (m)where p is 0 or 1 and Ar1, hetAr2and Rgare as defined for Formula I-A

[0398] In one embodiment, Formula I includes compounds of Formula I-B, wherein:

[0399] X1, X2, X3and X4are independently CH, CF or N, wherein zero, one or two of X1,X2, X3and X4is N;

[0400] A is H, CN, CI, methyl, ethyl or cyclopropyl;

[0401] B is

[0402] (a) hydrogen,

[0403] (b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

[0404] (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,

[0405] (d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,

[0406] (e) (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,

[0407] (f) (R¾2N)C 1 -C6 alkyl- where R1and R2are independently selected from H, C 1 - C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- and (C1-C6 alkoxy)C(=0)-;

[0408] (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1- 3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl groups;

[0409] (h) (C3-C6 cycloalkyl)Cl-C3 alkyl-,

[0410] (i) (hetCyca)Cl-C3 alkyl-, or

[0411] (j) hetCyc3;

[0412] hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and hydroxyCl-C6 alkyl;

[0413] Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen;

[0414] each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl;

[0415] Rbis hydroxy, cyclopropyl, or RcRdN- where Rcis hydrogen or C1-C6 alkyl and Rdis hydrogen, C1-C6 alkyl or (C1-C6 alkoxy)C(=0)-;

[0416] n is 0, 1, 2, 3, 4, 5 or 6;

[0417] m is O or l;

[0418] E is

[0419] (a) hydrogen,

[0420] (b) hydroxy,

[0421] (f) (C1-C6 alkoxy)Cl-C6 alkoxy,

[0422] (h) hetAr20-,

[0423] (j) hetAr2R - where Rgis H or C1-C6 alkyl,

[0424] (n) R4R5NC(=0)-,

[0425] (o) A^ ^C^O)-, where Rgis H or C1-C6 alkyl, or

[0426] (p) hetAr2RgC(=0)-, where R is H or C1-C6 alkyl;

[0427] Ar1is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R^R^ f- where Reand Rfare independently H or C1-C6 alkyl;

[0428] hetAr2is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr2is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and (Cl- C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros);

[0429] R4is H or Cl-C6 alkyl;

[0430] R5is Ar2, hetAr3or C1-C6 alkyl optionally substituted with 1-3 fluoros;

[0431] Ar2is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R¾hN- where Rgand Rhare independently H or C1-C6 alkyl; and

[0432] hetAr3is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros).

[0433] In one embodiment of Formula I-B, X1is N; X2, X3and X4are CH.

[0434] In one embodiment of Formula I-B, A is CN.

[0435] In one embodiment of Formula I-B, X1is N; X2, X3and X4are CH; and A is CN.

[0436] In one embodiment of Formula I-B, B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I-B, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.

[0437] In one embodiment of Formula I-B, X1is N; X2, X3and X4are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.

[0438] In one embodiment of Formula I-B, X1is N; X2, X3and X4are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.

[0439] In one embodiment of Formula I-B, X1is N; X2, X3and X4are CH; A is CN; and hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is hydroxyC2-C6 alkyl-.one embodiment of Formula I-B, Ring D is

[0441] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Rband m are as defined for Formula I-B. In one embodiment, n is 0, 1, 2, 3 or 4. In one embodiment, n is 0. In one embodiment, n is 0 or 1 and m is 0 or 1. In one embodiment, n is 0 and m is 1. In one embodiment, Rbis RcRdN- where Rcis H or C1-C6 alkyl and Rdis H or C1-C6 alkyl. In one embodiment, Rbis RcRdN- where Rcand Rdare H.

[0442] In one embodiment of Formula I-B, E is R4R5NC(=0)-, where R4and R5are as defined for Formula I-B.

[0443] In one embodiment of Formula I-B, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is

[0444] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Rband m are as defined for Formula I-B. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, Rbis RcRdN- where Rcis H or C1-C6 alkyl and Rdis H or C1-C6 alkyl. In one embodiment, Rbis RcRdN- where Rcand Rdare H.

[0445] In one embodiment of Formula I-B, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

[0446] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group, and Ra, n, Rband m are as defined for Formula I-A; and E is (n) R4R5NC(=0)-, where R4and R5are as defined for Formula I-B.

[0447] In one embodiment of Formula I-B, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

[0448] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group; E is (h) hetAr20-, (j) hetAi^NR8- where R is H or C1-C6 alkyl, (o) ΑΓ^¾(=0)-, where Rgis H or C1-C6 alkyl, or (p) hetAr2NRgC(=0)-, where Rgis H or C1-C6 alkyl; and Rband m are as defined for Formula I-B. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, Rbis RcRdN- where Rcis H or C1-C6 alkyl and Rdis H or C1-C6alkyl. In one embodiment, Rbis RcRdN- where Rcand Rdare H.

[0449] In one embodiment of Formula I-B, X1is N; X2, X3and X4are CH; A is CN; B -C6 alkyl optionally substituted with 1-3 fluoros; Ring D is

[0450] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group; E is (h) hetAr20-, (j) hetAr2R - where Rgis H or C1-C6 alkyl, (o) A^NRSC^O)-, where Rgis H or C1-C6 alkyl, or (p) hetAr2RgC(=0)-, where Rgis H or C1-C6 alkyl; and Rband m are as defined for Formula I-B. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, Rbis RcRdN- where Rcis H or C1-C6 alkyl and Rdis H or C1-C6 alkyl. In one embodiment, Rbis RcRdN- where Rcand Rdare H.

[0451] In one embodiment of Formula I-B, X1is N; X2, X3and X4are CH; A is CN; B hydroxyCl-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is

[0452] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group; E is (h) hetAr20-, (j) hetAi^NRS- where Rgis H or C1-C6 alkyl, (o) A^NRSC^O)-, where Rgis H or C1-C6 alkyl, or (p) hetAr2NRgC(=0)-, where Rgis H or C1-C6 alkyl; and Rband m are as defined for Formula I-B. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, Rbis RcRdN- where Rcis H or C1-C6 alkyl and Rdis H or C1-C6 alkyl. In one embodiment, Rbis R°RdN- where Rcand Rdare H.

[0453] In one embodiment, Formula I includes compounds of Formula I-C,

[0454] wherein:

[0455] X1, X2, X3and X4are independently CH, CF or N, wherein zero, one or two of X1,X2, X3and X4is N;

[0456] A is H, CN, CI, methyl, ethyl or cyclopropyl;

[0457] B is

[0458] (a) hydrogen,

[0459] (b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

[0460] (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,

[0461] (d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,

[0462] (e) (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,

[0463] (f) (R¾2N)C 1 -C6 alkyl- where R1and R2are independently selected from H, C 1 - C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-;

[0464] (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1- 3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl groups;

[0465] (h) (C3-C6 cycloalkyl)Cl-C3 alkyl-,

[0466] (i) (hetCyca)Cl-C3 alkyl-,

[0467] (j) hetCyc3,

[0468] (k) (R1R2N)C(=0)C1-C6 alkyl- where R1and R2are independently selected from H and C1-C6 alkyl, or

[0469] (1) (R1R2N)C(=0)-, where R1and R2are independently selected from H and Cl- C6 alkyl;

[0470] hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, halogen, (C1-C6 alkyl)C(O)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=0)-;

[0471] Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) Κ¾ΝΟ(=0)ΟΗ2ΟΟΗ2- where R1and Rjare independently H or C1-C6 alkyl, (e) RcRdN-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-,(h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, (j) hetCycb(Cl-C3 alkyl)OCH2-, (k) hetCycbC(=0)NH- or (1) hetAraC(=0)NH-;

[0472] hetCycbis a 4-6 membered heterocyclic ring, a 7-8 membered bridged heterocyclic ring, or a 7-10 membered heterospirocyclic ring, each ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkoxy)C(=0)-, C1-C6 alkoxy, and R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl;

[0473] hetAr3is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S herein hetAr3is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros);

[0474] Rcis hydrogen or C1-C6 alkyl;

[0475] Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^N^l-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C I -C6 alkyl;

[0476] E is

[0477] (a) hydrogen,

[0478] (b) hydroxy,

[0479] (c) C1-C6 alkyl optionally substituted with 1 -3 fluoros,

[0480] (d) A^C l-Ce alkyl- wherein said alkyl portion is optionally substituted with 1 -3 fluoros,

[0481] (e) hetAr2Cl-C6 alkyl-,

[0482] (f) (C 1 -C6 alkoxy)C 1 -C6 alkoxy-,

[0483] (g) A^O-,

[0484] (h) hetAr20-,

[0485] (i) A^ R6- where Rgis H or C 1-C6 alkyl,

[0486] (j) hetAi^ RS- where Rgis H or C1-C6 alkyl,

[0487] (k) R3C(=0) Rg- where R is H or C1-C6 alkyl,

[0488] (1) Ar1C(=0) R - where R is H or C 1 -C6 alkyl,

[0489] (m) hetAr2C(=0)NRg(CH2)P- where p is 0 or 1 and R is H or C1-C6 alkyl,

[0490] (n) R4R5NC(=0)-,

[0491] (o) Ar1RgC(=0)-, where R is H or C 1 -C6 alkyl,

[0492] (p) hetAr2RgC(=0)-, where R is H or C 1 -C6 alkyl,

[0493] (r) hetCyc5C(=0)-,

[0494] (s) R4R5NC(=0) R - where Rgis H or C 1 -C6 alkyl,

[0495] (t) (C1-C6 alkyl)S02-;

[0496] (u) Ατ^ϋ ΐ-ϋό alkyl)C(=0) R - where R is H or C 1-C6 alkyl,

[0497] (v) hetAr4C(=0)NR - where R is H or C 1-C6 alkyl,

[0498] (w) hetAr2-S(=0)-,

[0499] (x) (C3-C6 cycloalkyl)CH2S02-,

[0500] (y) Ar1(C l-C6 alkyl)S02-,

[0501] (z) hetAr2S02-,

[0502] (aa) Ar1,

[0503] (bb) hetAr2,

[0504] (cc) hetCyc5,

[0505] (dd) C1-C6 alkoxy,

[0506] (ee) Ar^Cl-Ce alkyl)-0-,

[0507] (ff) hetAr2(Cl-C6 alkyl)-0-,

[0508] (gg) hetAr2-0-Cl-C6 alkyl-,

[0509] (hh) Ar^Cl-Ce alkyl) R - where Rgis H or C1-C6 alkyl-,

[0510] (ii) hetAi^-S-,

[0511] Oj) Ar2S02 Rg(CH2)p- where p is 0 or 1 and Rgis H or C1-C6 alkyl,

[0512] (kk) (Cl-C6 alkoxy)C(=0)-,

[0513] (11) (C1-C6 alkyl) RgC(=0)0- where Rgis H or C1-C6 alkyl,

[0514] (mm) (C1-C6 alkyl) RgS02- where Rgis H or C1-C6 alkyl,

[0515] (oo) Q- Rh(Cl-C3 alkyl)C(=0)NR - where Rgand Rhare independently H or CI-C6 alkyl and Q i -C6 alkyl or (C1-C6 alkyl)OC(=0)-,

[0516] (pp)where Rgand Rhare independently H or CI -C6 alkyl, Q is H, C1-C6 alkyl r (C1-C6 alkyl)OC(=0)- and r is 1, 2, 3 or 4,

[0517] (qq where R and Rhare independently H or C1-C6 alkyl and Q is H, C1-C6 l)OC(=0)-,

[0518] (rr)where R is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or(C1-C6 alkyl)OC(=0)-, or

[0519] (ss) R¾hN- where R and Rhare independently H or C 1 -C6 alkyl;

[0520] Ar1is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (Cl-C6 alkyl)S02-, R¾¾- and (R^^Cl-Ce alkyl- where each Reand Rfis independently H or C1-C6 alkyl;

[0521] hetAr2is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr2is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros) and hydroxyCl-C6 alkoxy-;

[0522] hetCyc5is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and oxo;

[0523] R3is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C3-C6 cycloalkyl)0-, (C3-C6 cycloalkyl)CH20-, hetCyc70-, Ph-O-, or (C1-C6 alkoxy)Cl-C6 alkyl-; wherein each of said C3-C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH or R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl;

[0524] R4is H or Cl-C6 alkyl;

[0525] R5is Ar2, hetAr3, Ar2CH2-, hetCyc6-CH2-, hydroxyCl-C6 alkyl-, (C3-C6 cycloalkyl)CH2-, or C1-C6 alkyl optionally substituted with 1-3 fluoros;

[0526] Ar2is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R¾hN- where Rgand Rhare independently H or C1-C6 alkyl, or Ar2is phenyl fused to a 6 membered heterocyclic ring having a ring nitrogen atom and optionally substituted with C1-C6 alkyl;

[0527] hetAr3is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros);

[0528] hetAr4is pyridin-4(lH)-onyl or pyridin-2(lH)-onyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen;

[0529] hetCyc6is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S; and

[0530] hetCyc7is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S.

[0531] In one embodiment of Formula I-C, X1is N; and X2, X3and X4are CH.

[0532] In one embodiment of Formula I-C, A is CN.

[0533] In one embodiment of Formula I-C, X1is N; X2, X3and X4are CH; and A is CN.

[0534] In one embodiment of Formula I-C, B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I-C, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.

[0535] In one embodiment of Formula I-C, X1is N; X2, X3and X4are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-.

[0536] In one embodiment of Formula I-C, X1is N; X2, X3and X4are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.

[0537] In one embodiment of Formula I-C, X1is N; X2, X3and X4are CH; A is CN; and B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is hydroxyC2-C6 alkyl-.

[0538] In one embodiment of Formula I-C, E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) A^NR^- where R is H or C1-C6 alkyl, (k) R3C(=0)NRg- where Rgis H or Cl- C6 alkyl, (1) ΑΓ^(=0)ΝΕΙ§- where Rgis H or C1-C6 alkyl, or (m) hetAr2C(=0)NRg(CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C.

[0539] In one embodiment of Formula I-C, A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) A^NR^- where R is H or C1-C6 alkyl, (k) R3C(=0)NR - where R is H or C1-C6 alkyl, (1)Αι¾(=0)ΝΚ§- where Rgis H or C1-C6 alkyl, or (m) hetAr2C(=0) Rg(CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C.

[0540] In one embodiment of Formula I-C, A is CN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; and E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) Ar1Rg- where R is H or C1-C6 alkyl, (k) R3C(=0) R - where R is H or Cl- C6 alkyl, (1) Ar1C(=0) R - where R is H or C1-C6 alkyl, or (m) hetAr2C(=0) R (CH2)P-, where p is 0 or 1 and Ar1, hetAr2and Rgare as defined for Formula I-C.

[0541] In one embodiment of Formula I-C, Rbis (c) hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl- C6 alkyl- (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl-, (e) RcRdN-, or (f) RcRdNCH2-; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl.

[0542] In one embodiment of Formula I-C, Rbis hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl- C6 alkyl- (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl-.

[0543] In one embodiment of Formula I-C, Rbis RcRdN-; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 memberedheterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with CI -C6 alkyl.

[0544] In one embodiment of Formula I-C, Rbis RcRdNCH2-; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with CI -C6 alkyl.

[0545] In one embodiment of Formula I-C, A is CN, B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) Ar1Rg- where Rgis H or C1-C6 alkyl, (k) R3C(=0) Rg- where R is H or Cl- C6 alkyl, (1) Ar1C(=0) R - where R is H or C1-C6 alkyl, or (m) hetAr2C(=0) R (CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C; and Rbis (c) hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl-.

[0546] In one embodiment of Formula I-C, A is CN, B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) Ar*NRg- where R is H or C1-C6 alkyl, (k) R3C(=0)NR - where R is H or Cl- C6 alkyl, (1) Ar1C(=0)NRg- where Rgis H or C1-C6 alkyl, or (m) hetAr2C(=0)NRg(CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C; Rbis (e) RcRdN-; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnareindependently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl.

[0547] In one embodiment of Formula I-C, A is CN, B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) Ar1Rg- where Rgis H or C1-C6 alkyl, (k) R3C(=0) Rg- where R is H or Cl- C6 alkyl, (1) Ar1C(=0) R - where R is H or C1-C6 alkyl, or (m) hetAr2C(=0) R (CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C; Rbis (f) RcRdNCH2- ; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, ( ¾·Ν)01-06 alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl.

[0548] In one embodiment of Formula I-C, A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) Ai^NR8- where R is H or C1-C6 alkyl, (k) R3C(=0)NR - where R is H or C1-C6 alkyl, (1) Ar1C(=0)NR - where R is H or C1-C6 alkyl, or (m) hetAr2C(=0)NR (CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C; and Rbis (c) hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl-.

[0549] In one embodiment of Formula I-C, A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) A^NR^ where R is H or C1-C6 alkyl, (k) R3C(=0)NR - where R is H or C1-C6 alkyl, (1)Αι¾(=0)ΝΚ§- where Rgis H or C1-C6 alkyl, or (m) hetAr2C(=0) Rg(CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C; Rbis (e) R^N-; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (Cl- C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl.

[0550] In one embodiment of Formula I-C, A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) Ar1Rg- where R is H or C1-C6 alkyl, (k) R3C(=0) R - where R is H or C1-C6 alkyl, (1) Ar1C(=0)NR - where R is H or C1-C6 alkyl, or (m) hetAr2C(=0) R (CH2)P-, where p is 0 or 1 and R3, R , Ar1and hetAr2are as defined for Formula I-C; Rbis (f) RcRdNCH2-; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl.

[0551] In one embodiment of Formula I-C, X1is N; X2, X3and X4are CH; A is CN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; E is (d) Ar^l- C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAi^Cl- C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) A^NRS- where R is H or C1-C6 alkyl, (k) R3C(=0)NR - where R is H or C1-C6 alkyl, (1) Ar1C(=0)NR - where R is H or C1-C6 alkyl, or (m) hetAr2C(=0)NRg(CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C; and Rbis (c) hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, fluoro,C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl-.

[0552] In one embodiment of Formula I-C, X1is N; X2, X3and X4are CH; A is CN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; E is (d) Ar^l- C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl- C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) Ar1Rg- where Rgis H or C1-C6 alkyl, (k) R3C(=0) Rg- where R is H or C1-C6 alkyl, (1) Ar1C(=0) R - where R is H or C1-C6 alkyl, or (m) hetAr2C(=0) Rg(CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C; Rbis (e) RcRdN-; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)- , (RkR^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl- C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl- C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl.

[0553] In one embodiment of Formula I-C, X1is N; X2, X3and X4are CH; A is CN; B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring; E is (d) Ar^l- C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAi^Cl- C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) Ai^NR8- where R is H or C1-C6 alkyl, (k) R3C(=0)NR - where R is H or C1-C6 alkyl, (1) Ar1C(=0)NR - where R is H or C1-C6 alkyl, or (m) hetAr2C(=0)NRg(CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C; Rbis (f) RcRdNCH2-; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen, Cl- C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl.

[0554] In one embodiment of Formula I-C, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h)hetAr20-, (i) A^NRS- where R is H or C1-C6 alkyl, (k) R3C(=0)NR - where Rgis H or Cl- C6 alkyl, (1) Ar1C(=0) R - where R is H or C1-C6 alkyl, or (m) hetAr2C(=0) R (CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C; and Rbis (c) hetCycbCH2- where hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl-.

[0555] In one embodiment of Formula I-C, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) Ar1Rg- where R is H or C1-C6 alkyl, (k) R3C(=0) R - where R is H or Cl- C6 alkyl, (1) Ar1C(=0) Rg- where Rgis H or C1-C6 alkyl, or (m) hetAr2C(=0) Rg(CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C; Rbis (e) RcRdN-; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, ( ¾·Ν)01-06 alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl.

[0556] In one embodiment of Formula I-C, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (i) Ar*NRg- where R is H or C1-C6 alkyl, (k) R3C(=0)NR - where R is H or Cl- C6 alkyl, (1) Ar1C(=0)NRg- where Rgis H or C1-C6 alkyl, or (m) hetAr2C(=0)NRg(CH2)P-, where p is 0 or 1 and R3, Rg, Ar1and hetAr2are as defined for Formula I-C; Rbis (f) RcRdNCH2- ; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C(=0)-, hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros), (hydroxyCl-C6 alkyl)C(=0)-, (C1-C6 alkyl)C(=0)-, (R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl, RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnareindependently H or C1-C6 alkyl, PhCH2-, (C1-C6 alkoxy)Cl-C6 alkyl-, or hetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl.

[0557] In one embodiment, Formula I includes compounds of Formula I-D, wherein:

[0558] X1and X3are N, and X2and X4are CH or CF; and A, B, E, Ra, Rb, m and n are as defined for Formula I.

[0559] In one embodiment of Formula I-D, A is CN.

[0560] In one embodiment of Formula I-D, B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R1R2N)C1-C6 alkyl- where R1and R2are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-, (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyca)Cl-C3 alkyl-; and hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, halogen, (C1-C6 alkyl)C(=0)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=0)-.

[0561] In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R^lNOCl-Ce alkyl- where R1and R2are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-, (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyca)Cl-C3 alkyl-; and hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, halogen, (C1-C6 alkyl)C(=0)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=0)-.

[0562] In one embodiment of Formula I-D, E is (1) ΑΓ^(=0) ¾§- where R is H or Cl- C6 alkyl, or (m) hetAr2C(=0) Rg(CH2)P- where p is 0 or 1 and Rgis H or C1-C6 alkyl.

[0563] In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl - wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R^lNOCl-Ce alkyl- where R1and R2are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-, (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyca)Cl-C3 alkyl-; hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, halogen, (C1-C6 alkyl)C(=0)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=0)-; and E is (1) Ar1C(=0) Rg- where Rgis H or C1-C6 alkyl, or (m)where p is 0 or 1 and Rgis H or C1-C6 alkyl.

[0564] In one embodiment of Formula I-D, m is 1; and n is 0 or 1.

[0565] In one embodiment of Formula I-D, m is 1; and n is 0.

[0566] In one embodiment of Formula I-D, m is 1; n is 0; and Rbis hydroxy.

[0567] In one embodiment of Formula I-D, m is 0; and n is 0 or 1.

[0568] In one embodiment of Formula I-D, m is 0; n is 0 or 1; and Rais C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0569] In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) ^¾2Ν)01-06 alkyl- where R1and R2are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-, (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyca)Cl-C3 alkyl-; hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3fluoros), hydroxyCl-C6 alkyl, halogen, (C1-C6 alkyl)C(=0)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=0)-; E is (1) Αι¾(=0) ^- where R is H or C1-C6 alkyl, or (m) hetAr2C(=0)NRg(CH2)P- where p is 0 or 1 and Rgis H or C1-C6 alkyl; m is 0 or 1; n is 0 or 1; Rais C1-C6 alkyl optionally substituted with 1-3 fluoros; and Rbis hydroxy. In one embodiment, m is 1, n is 0, and Rbis hydroxy. In one embodiment, m is 0, n is 1, and Rbis C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0570] In one embodiment of Formula I-D, Ring D is

[0571] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group.

[0572] In one embodiment of Formula I-D, A is CN; B is (c) hydroxyC2-C6 alkyl - wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) ^¾2Ν)01-06 alkyl- where R1and R2are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-, (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyca)Cl-C3 alkyl-; hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, halogen, (C1-C6 alkyl)C(=0)-, C1-C6 alkoxy, oxo and (C1-C6 alkoxy)C(=0)-; E is (1) Ar1C(=0) R - where R is H or C1-C6 alkyl, or (m) hetAr2C(=0)NR (CH2)P- where p is 0 or 1 and R is H or C1-C6 alkyl; m is 0 or 1; n is 0 or 1; Rais C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ring D is

[0574] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, the asterisk indicates the point of attachment of Ring D to the E group. In one embodiment, m is 1, n is 0, and Rbis hydroxy. In one embodiment, m is 0, n is 1, and Rbis C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0575] In one embodiment, compounds of Formula I include compounds of Formula I-E:B-I-E

[0576] where E is (k) R3C(=0) R - where Rgis H or C 1 -C6 alkyl; Rbis (c) hetCycbCH2- ; and R3, A, B, X1, X2, X3and X4are as defined for Formula I.

[0577] In one embodiment of Formula I-E, X1is N; and X2, X3and X4are CH.

[0578] In one embodiment of Formula I-E, A is CN.

[0579] In one embodiment of Formula I-E, X1is N; X2, X3and X4are CH; and A is CN.

[0580] In one embodiment of Formula I-E, B is C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0581] In one embodiment of Formula I-E, X1is N; X2, X3and X4are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0582] In one embodiment, compounds of Formula I include compounds of Formula I-FI-F

[0583] where E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substitutedwith 1-3 fluoros or (e) hetAr2Cl-C6 alkyl-; Rbis (a) hydroxy, (d) RiRjNC(=0)CH2OCH2- where R1and Rjare independently H or C1-C6 alkyl, or (e) RcRdN-; and X1, X1, X3, X4, A, B, Ar1, hetAr2, Rcand Rdare as defined for Formula I.

[0584] In one embodiment of Formula I-F, X1is N; and X2, X3and X4are CH. In one embodiment, E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr2Cl-C6 alkyl-.

[0585] In one embodiment of Formula I-F, A is CN. In one embodiment, E is (d) ArlCl- C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr2Cl-C6 alkyl-.

[0586] In one embodiment of Formula I-F, B is C1-C6 alkyl optionally substituted with 1- 3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I-F, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-. In one embodiment, E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr2Cl-C6 alkyl-.

[0587] In one embodiment of Formula I-F, X1is N; X2, X3and X4are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is C1-C6 alkyl or hydroxyC2-C6 alkyl-. In one embodiment, E is (d) ΑΓ^1 6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr2Cl-C6 alkyl-.

[0588] In one embodiment of Formula I-F, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and Rbis (a) hydroxy. In one embodiment, E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr2Cl-C6 alkyl-.

[0589] In one embodiment of Formula I-F, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and Rbis (d) RiRjNC(=0)CH2OCH2- where R[and Rjare independently H or C1-C6 alkyl. In one embodiment, E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr2Cl-C6 alkyl-.

[0590] In one embodiment of Formula I-F, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and Rbis (e) RcRdN- where Rcand Rdare as defined for Formula I. In one embodiment, E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr2Cl-C6 alkyl-.

[0591] In one embodiment of Formula I-F, X1is N; X2, X3and X4are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and Rbis (e) RcRdN- where Rcand Rdare as defined for Formula I. In one embodiment, E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, E is (e) hetAr2Cl-C6 alkyl-.

[0592] In one embodiment, compounds of Formula I include compounds of Formula I-GB-I-G

[0593] where E is (1) Ar1C(=0)NR - where Rgis H or C1-C6 alkyl or (m)where p is 0 or 1 and Rgis H or C1-C6 alkyl; Rais C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ar1, hetAr2, X1, X1, X3, X4, A and B are as defined for Formula I.

[0594] In one embodiment of Formula I-G, X1is N; and X2, X3and X4are CH.

[0595] In one embodiment of Formula I-G, A is CN.

[0596] In one embodiment of Formula I-G, B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) ^¾2Ν)Ο 6 alkyl- where R1and R2are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-, (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or moreindependently selected C1-C6 alkyl substituents, or (i) (hetCyca)Cl-C3 alkyl-, where hetCyc3is as defined for Formula I.

[0597] In one embodiment of Formula I-G, X1is N; X2, X3and X4are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.

[0598] In one embodiment of Formula I-G, X1is N; X2, X3and X4are CH; A is CN; and B is hydroxyC2-C6 alkyl- optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, B is hydroxyC2-C6 alkyl-.

[0599] In one embodiment of Formula I-G, X1is N; X2, X3and X4are CH; A is CN; and B is (R^NJCI-Ce alkyl- where R1and R2are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (C1-C6 alkyl)C(=0)- and (C1-C6 alkoxy)C(=0)-.

[0600] In one embodiment of Formula I-G, X1is N; X2, X3and X4are CH; A is CN; and B is hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents.

[0601] In one embodiment of Formula I-G, X1is N; X2, X3and X4are CH; A is CN; andB is (hetCyca)Cl-C3 alkyl-, where hetCyc3is as defined for Formula I.

[0602] In one embodiment, compounds of Formula I include compounds of Formula I-HB-I-H

[0603] where E is (1) Ar1C(=0)NR - where Rgis H or C1-C6 alkyl or (m)where p is 0 or 1 and Rgis H or C1-C6 alkyl; Rbis (a) hydroxy, (c) hetCycbCH2-, (f) RcRdNCH2-, (g) C1-C6 alkoxy-, or (j) hetCycb(Cl-C3 alkyl)OCH2-; and AT1, hetAr2, X1, X1, X3, X4, A, B, hetCycb, Rcand Rdare as defined for Formula I.

[0604] In one embodiment of Formula I-H, X1is N; and X2, X3and X4are CH.

[0605] In one embodiment of Formula I-H, A is CN.

[0606] In one embodiment of Formula I-H, B is (b) C1-C6 alkyl optionally substitutedwith 1-3 fluoros. In one embodiment, B is C1 -C6 alkyl.

[0607] In one embodiment of Formula I-H, X1is N; X2, X3and X4are CH; A is CN; andB is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.

[0608] In one embodiment of Formula I-H, X1is N; X2, X3and X4are CH; A is CN; B isC1-C6 alkyl optionally substituted with 1-3 fluoros; and Rbis (a) hydroxy.

[0609] In one embodiment of Formula I-H, X1is N; X2, X3and X4are CH; A is CN; B isC1-C6 alkyl optionally substituted with 1-3 fluoros; and Rbis (c) hetCycbCH2-.

[0610] In one embodiment of Formula I-H, X1is N; X2, X3and X4are CH; A is CN; B isC1-C6 alkyl optionally substituted with 1-3 fluoros; and Rbis (f) RcRdNCH2-.

[0611] In one embodiment of Formula I-H, X1is N; X2, X3and X4are CH; A is CN; B isC1-C6 alkyl optionally substituted with 1-3 fluoros; and Rbis (g) C 1-C6 alkoxy-.

[0612] In one embodiment of Formula I-H, X1is N; X2, X3and X4are CH; A is CN; B isC1-C6 alkyl optionally substituted with 1-3 fluoros; and Rbis (j) hetCycb(Cl-C3 alkyl)OCH2-

[0613] In one embodiment, compounds of Formula I include compounds of Formula I-II-I

[0614] where E is (n) R4R5NC(=0)-; Rbis (c) hetCycbCH2-, (f) RcRdNCH2- or (j) hetCycb(Cl-C3 alkyl)OCH2-; and X1, X1, X3, X4, A, B, hetCycb, Rc, Rd, R4and R5are as defined for Formula I.

[0615] In one embodiment of Formula I-I, X1is N; and X2, X3and X4are CH.

[0616] In one embodiment of Formula I-I, A is CN.

[0617] In one embodiment of Formula I-I, B is (b) C 1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C 1-C6 alkyl.

[0618] In one embodiment of Formula I-I, X1is N; X2, X3and X4are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is C1-C6 alkyl.

[0619] In one embodiment of Formula I-H, X1is N; X2, X3and X4are CH; A is CN; B isC1-C6 alkyl optionally substituted with 1-3 fluoros; and Rbis (c) hetCycbCH2-.

[0620] In one embodiment of Formula I-H, X1is N; X2, X3and X4are CH; A is CN; B isC1-C6 alkyl optionally substituted with 1-3 fluoros; and Rbis (f) RcRdNCH2-.

[0621] In one embodiment of Formula I-H, X1is N; X2, X3and X4are CH; A is CN; B isC1-C6 alkyl optionally substituted with 1-3 fluoros; and Rbis (j) hetCycb(Cl-C3 alkyl)OCH2-

[0622] In one embodiment, compounds of Formula I include compounds of Formula I-II-I

[0623] where E is (n) R4R5NC(=0)-; Rbis (c) hetCycbCH2-, (f) RcRdNCH2-, or (j) hetCycb(Cl-C3 alkyl)OCH2-; and X1, X1, X3, X4, A, B, R4, R5, hetCycb, Rcand Rdare as defined for Formula I.

[0624] In one embodiment of Formula I-I, X1is N; and X2, X3and X4are CH.

[0625] In one embodiment of Formula I-I, A is CN.

[0626] In one embodiment of Formula I-I, B is (b) CI -C6 alkyl optionally substituted with 1-3 fluoros or (i) (hetCyca)Cl-C3 alkyl-.

[0627] In one embodiment of Formula I-I, X1is N; X2, X3and X4are CH; A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0628] In one embodiment of Formula I-I, X1is N; X2, X3and X4are CH; A is CN; and B is (i) (hetCyca)Cl-C3 alkyl-.

[0629] In one embodiment of Formula I-I, X1is N; X2, X3and X4are CH; A is CN; B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (i) (hetCyca)Cl-C3 alkyl-; and Rbis (c) hetCycbCH2-.

[0630] In one embodiment of Formula I-I, X1is N; X2, X3and X4are CH; A is CN; B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (i) (hetCyca)Cl-C3 alkyl-; and Rbis (f) RcRdNCH2-.

[0631] In one embodiment of Formula I-I, X1is N; X2, X3and X4are CH; A is CN; B is(b) C1-C6 alkyl optionally substituted with 1-3 fluoros or (i) (hetCyca)Cl-C3 alkyl-; and Rbis Q) hetCycb(Cl-C3 alkyl)OCH2-.

[0632] In one embodiment, compounds of Formula I include compounds of Formula I-JI-J

[0633] where E is (n) R4R5NC(=0)-; Rais C1-C6 alkyl optionally substituted with 1-3 fluoros; and X1, X1, X3, X4, A, B, R4and R5are as defined for Formula I.

[0634] In one embodiment of Formula I-J, X1is N; and X2, X3and X4are CH.

[0635] In one embodiment of Formula I-J, A is CN.

[0636] In one embodiment of Formula I-J, X1is N; X2, X3and X4are CH; and A is CN.

[0637] In one embodiment of Formula I-J, B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is (b) C1-C6 alkyl.

[0638] In one embodiment of Formula I-J, B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I-J, B is (c) hydroxyC2-C6 alkyl-

[0639] In one embodiment of Formula I-J, X1is N; X2, X3and X4are CH; A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is (b) C1-C6 alkyl.

[0640] In one embodiment of Formula I-J, X1is N; X2, X3and X4are CH; A is CN; and B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment of Formula I-J, B is (c) hydroxyC2-C6 alkyl-.

[0641] In one embodiment, compounds of Formula I include compounds of Formula I-K where E is (1) Ar1C(=0)NR - where Rgis H or C1-C6 alkyl or (m) hetAr2C(=0)NRg(CH2)P- where p is 0 or 1 and Rgis H or C1-C6 alkyl; Ring D is

[0642] where the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4; Rais C1-C6 alkyl optionally substituted with 1-3 fluoros; and X1, X1, X3, X4, A, B, Ar1and hetAr2are as defined for Formula I.

[0643] In one embodiment of Formula I-K, X1is N; and X2, X3and X4are CH.

[0644] In one embodiment of Formula I-K, A is CN.

[0645] In one embodiment of Formula I-K, X1is N; X2, X3and X4are CH; and A is CN.

[0646] In one embodiment of Formula I-K, B is (a) hydrogen, (b) C1-C6 alkyl optionally substituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R1R2N)C1-C6 alkyl- where R1and R2are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- and (C1-C6 alkoxy)C(=0)-, (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents, or (i) (hetCyca)Cl-C3 alkyl-, where hetCyc3is as defined for Formula I.

[0647] In one embodiment of Formula I-K, X1is N; X2, X3and X4are CH; A is CN; and B is (a) hydrogen.

[0648] In one embodiment of Formula I-K, X1is N; X2, X3and X4are CH; A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0649] In one embodiment of Formula I-K, X1is N; X2, X3and X4are CH; A is CN; and B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3- C6 cycloalkylidene ring.

[0650] In one embodiment of Formula I-K, X1is N; X2, X3and X4are CH; A is CN; and B is (f) (R^tfN Cl-Ce alkyl- where R1and R2are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- and (C1-C6 alkoxy)C(=0)-.

[0651] In one embodiment of Formula I-K, X1is N; X2, X3and X4are CH; A is CN; and B is (g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents.

[0652] In one embodiment of Formula I-K, X1is N; X2, X3and X4are CH; A is CN; and B is (i) (hetCyca)Cl-C3 alkyl-, where hetCyc3is as defined for Formula I.

[0653] In one embodiment, compounds of Formula I include compounds of Formula I-L where E is A^O- or (h) hetAr2-0-; Ring D is

[0654] where the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4; and X1, X1, X3, X4, A, B, Ar1and hetAr2are as defined for Formula I.

[0655] In one embodiment of Formula I-L, X1is N; and X2, X3and X4are CH.

[0656] In one embodiment of Formula I-L, A is CN.

[0657] In one embodiment of Formula I-L, X1is N; X2, X3and X4are CH; and A is CN.

[0658] In one embodiment of Formula I-L, B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (i) (hetCyca)Cl-C3 alkyl- or (k) (R1R2N)C(=0)C1-C6 alkyl- where R1and R2are independently selected from H and C1-C6 alkyl.

[0659] In one embodiment of Formula I-L, X1is N; X2, X3X4are CH; and A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros.

[0660] In one embodiment of Formula I-L, X1is N; X2, X3X4are CH; and A is CN; and B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.

[0661] In one embodiment of Formula I-L, X1is N; X2, X3X4are CH; and A is CN; and B is (i) (hetCyca)Cl-C3 alkyl- or (k) (R1R2N)C(=0)C1-C6 alkyl- where R1and R2are independently selected from H and C1-C6 alkyl.

[0662] In one embodiment, compounds of Formula I include compounds of Formula I-MI-Mwhere E is (k) R3C(=0)NR where Rgis H or C1-C6 alkyl; Rbis (a) hydroxy; and X3, X4, R3, A and B, are as defined for Formula I.

[0664] In one embodiment of Formula I-M, X1is N; and X2, X3and X4are CH.

[0665] In one embodiment of Formula I-M, A is CN.

[0666] In one embodiment of Formula I-M, X1is N; X2, X3and X4are CH; and A is CN.

[0667] In one embodiment of Formula I-M, B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is (b) C1-C6 alkyl.

[0668] In one embodiment of Formula I-M, X1is N; X2, X3and X4are CH; A is CN; and B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment, B is (b) C1-C6 alkyl.

[0669] In one embodiment of Formula I-M, R3is C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH, or R'R"N- where R and R" are independently hydrogen or C1-C6 alkyl.

[0670] The compounds of Formula I include pharmaceutically acceptable salts thereof. In addition, the compounds of Formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and / or purifying compounds of Formula I and / or for separating enantiomers of compounds of Formula I. Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include monohydrochloride, dihydrochloride, trifluoroacetic acid, and di-trifluoroacetic acid salts. In one embodiment, compounds of Formula I include trifluoroacetic acid and dihydrochloride salts.

[0671] It will further be appreciated that the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention. For example, compounds of Formula I and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0672] In one embodiment, the compounds of Formula I include the compounds of Examples 1-819 and stereoisomers and pharmaceutically acceptable salts and solvates thereof. In one embodiment, the compounds of Examples 1-819 are in the free base form. In one embodiment, the compounds of Examples 1-819 are dihydrochloride or trifluoroacetic acid salts.

[0673] The term "pharmaceutically acceptable" indicates that the compound, or salt or composition thereof is compatible chemically and / or toxicologically with the other ingredients comprising a formulation and / or the patient being treated therewith.

[0674] Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula I, comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to ¾,2H,3H or mixtures thereof; when carbon is mentioned, it is understood to refer toUC,12C,13C,14C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to13N,14N,15N or mixtures thereof; when oxygen is mentioned, it is understood to refer to140,150,160,170,180 or mixtures thereof; and when fluoro is mentioned, it is understood to refer to18F,19F or mixtures thereof. The compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0675] For illustrative purposes, Schemes 1-6 show general methods for preparing the compounds provided herein as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0676] Scheme 1 shows a general scheme for the synthesis of compound X where A is CN, and B, X1, X2, X3, X4, Ring D, Ra, Rb, n, m and E are as defined for Formula I.

[0677] Compound 2 is obtained by treating 3-bromo-5-methoxypyridine (compound 1), which is commercially available, with 0-(mesitylsulfonyl)hydroxylamine. The O- mesitylsulfonylhydroxylamine may be prepared as described in Mendiola, J., et al., Org. Process Res. Dev. 2009, 13(2), 263-267. Compound 2 may be reacted with ethyl propiolate to provide a mixture of compounds 3A and 3B, which typically are obtained in a ratio ofapproximately 2: 1 to 9: 1, respectively. The mixture of compounds 3A and 3B may be treated with 48% HBr at elevated temperatures, followed by recrystallization or chromatography purifications, to isolate compound 4A as the minor isomer and compound 4B as the major isomer. After isolation, compound 4A may be treated with POCb to provide compound 5. The formyl group may be converted to an oxime group using H2OH to provide compound 6. The oxime group may be converted to a nitrile group using acetic anhydride to provide compound 7. The methoxy group of compound 7 may be converted to a hydroxy group by treating compound 7 with aluminum trichloride to provide compound 8.

[0678] When group B is hydrogen, compound 12 may be prepared by coupling compound 8 with the corresponding boronic ester compound 10 (where Ring D, E, X1, X2, X3and X4are as defined for Formula I; Z is -B(ORx)(ORy) and Rzand Ryare H or (l-6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) to provide compound 11a using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and Na2C03in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group prior to coupling. The amino protecting group if present on a substituent of Ring D of compound 11a may be removed under standard conditions (for example, a Boc group may be removed by treating compound 11a to acidic conditions, e.g., HC1) to provide compound 12 where B is hydrogen. Alternatively, the E group may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions such as described below to provide compound 12 where B is hydrogen and E is as defined for Formula I except that E is not hydrogen.

[0679] Alternatively, when group B is as defined for Formula I other than hydrogen, Compound 11a may be reacted with a reagent such as C1-C6 alkyl -OH, (C1-C6 alkoxy)Cl- C6 alkyl-OH optionally substituted with 1-3 fluoros, hetA^Cl-CS alkyl-OH, (C3-C6 cycloalkyl)Cl-C3 alkyl-OH, (hetCyca)Cl-C3 alkyl-OH, hetCycOH or hetCycaC(=0)Cl-C6 alkyl-OH, where hetAr1and hetCyc3are as defined for Formula I, under Mitsunobu reaction conditions (PPh3and diisopropyl azodicarboxylate) to provide compound 11. Compound 12may then be prepared from compound 11 as described above.

[0680] Alternatively, when group B is as defined for Formula I other than hydrogen, compound 9 may be prepared by reacting compound 8 with a reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R^R^Cl-Ce alkyl-X, hetA^Cl-CS alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyca)Cl-C3 alkyl-X, hetCyc3- X, or hetCycaC(=0)Cl-C6 alkyl-X, where R1, R2, hetAr1, and hetCyc3are as defined for Formula I and X is a leaving atom or group (such as a halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if the B group has one or two additional hydroxy groups), in the presence of a base (for example, an alkali metal carbonate, such as potassium carbonate). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 8 with a C1-C6 alkyl-X, where X is a halogen such as Br or CI, or a leaving group such as triflate. Compound 11 may then be prepared by coupling compound 9 with the corresponding boronic ester compound 10 using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and Na2C03in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group prior to coupling. Compound 12 may then be prepared from compound 11 as described above.SCHEME 2

[0681] Scheme 2 shows another general scheme for the synthesis of compound 17 where A is CN, and B, X1, X2, X3, X4, Ring D, Ra, Rb, n, m and E are as defined for Formula I.

[0682] Compound 9 (prepared, e.g., as described in Scheme 1) in which B is as defined for Formula I, may be coupled with compound 13 (where X1, X2, X3and X4are as defined for Formula I; L2is a leaving group such as a triflate or halide); Z is -B(ORx)(ORy) and Rzand Ryare H or (l-6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)), using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and Na2C03in dioxane at elevated temperatures) to provide compound 14. Compound 16 may be prepared by coupling compound14 with compound 15 under appropriate SNAr conditions (for example, optionally in the presence of a base such as K2C03and at elevated temperature), wherein if Ring D of compound15 is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group prior to coupling. The amino protecting group if present may then be removed under standard conditions (for example, a Boc group may be removed by treating compound 1 to acidic conditions, e.g., HC1) to provide compound 17 where E is H.

[0683] Alternatively, the E group may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions such as described below to provide compound 17 where E is as defined for Formula I except that E is not H.SCHEME 3

[0684] Scheme 3 shows a general scheme for the synthesis of Compound 21 where A is H, and B, X1, X2, X3, X4, Ring D, Ra, Rb, n, m and E are as defined for Formula I.

[0685] Compound 18 may be prepared by coupling compound 4A (prepared e.g., as described in Scheme 1) with the corresponding boronic ester compound 10 (where Ring D, X1, X2, X3and X4are as defined for Formula I; Z is -B(ORx)(ORy) and Rzand Ryare H or (1- 6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) usingappropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and Na2C03in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substituted with an Rbsubstituent that is R^N- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group prior to coupling. Compound 19 may be prepared by treating compound 18 with aluminum trichloride.

[0686] When B is as defined for Formula I other than hydrogen, compound 20 may be prepared by reacting compound 19 with a reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R^^Cl-Ce alkyl-X, hetA^Cl-CS alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyca)Cl-C3 alkyl-X, hetCyca-X or hetCycaC(=0)Cl-C6 alkyl- X, where R1, R2, hetAr1, and hetCyc3are as defined for Formula I and X is a leaving atom or group (such as a halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if B has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 19 with C1-C6 alkyl-X, where X is a halogen such as Br or CI, or a leaving group such as triflate. Compound 21 may then be prepared from compound 20. If Ring D comprises a substituent having an amino protecting group, the amino protecting group may be removed under standard conditions (for example, a Boc group may be removed by treating compound 20 to acidic conditions, e.g., HC1) to provide compound 21 where E is H.

[0687] Alternatively, the E group of compound 20 may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions such as described below to provide compound 21 where E is as defined for Formula I except that E is not H.

[0688] Alternatively, when group B is hydrogen, compound 21 may be prepared from compound 19 according to the deprotection and optional functionalization steps described herein.

[0689] Scheme 4 shows an alternative general scheme for the synthesis of Compound 21 where A is H, and B, X1, X2, X3, X4, Ring D, Ra, Rb, n, m and E are as defined for Formula I.

[0690] Compound 22 may be prepared by treating compound 4A (prepared e.g., as described in Scheme 1) with aluminum trichloride.

[0691] When group B is hydrogen, compound 19 may be prepared by coupling compound 22 with the corresponding boronic ester compound 10 (where Ring D, X1, X2, X3and X4are as defined for Formula I; Z is -B(ORx)(ORy) and Rzand Ryare H or (l-6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium- catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and Na2C03in dioxane at elevated temperatures), wherein if Ring D of compound 10 is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group prior to coupling. Compound 21 may be prepared from compound 19 according to the process described for Scheme 3.

[0692] Alternatively, when group B is as defined for Formula I other than hydrogen, compound 23 may be prepared by reacting compound 22 with a reagent such as C1-C6 alkyl- X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (RAR^Cl-Ce alkyl-X, hetA^Cl-CS alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyca)Cl-C3 alkyl-X, hetCyc3- X or hetCycaC(=0)Cl-C6 alkyl-X, where R1, R2, hetAr1, and hetCyc3are as defined for Formula I and X is a leaving atom or group (such as a halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if B has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 22 with Cl- C6 alkyl-X, where X is a halogen such as Br or CI, or a leaving group such as triflate. Compound 20 may be prepared by coupling compound 23 with compound 10 as described inScheme 3. Compound 21 may be prepared from compound 20 according to the process described for Scheme 3.

[0693] Alternatively, when group B is as defined for Formula I other than hydrogen, compound 20 may be prepared by reacting compound 19 with a group such as (C1-C6 alkyl)OH, an appropriately substituted (C1-C3 alkyl)OH, an appropriately substituted (C1-C6 alkyl)OH, or hetCycaOH (i.e., where hetCyc3a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl) under Mitsunobu reaction conditions (PPh3and diisopropyl azodicarboxylate). Compound 21 may be prepared from compound 20 according to the process described for Scheme 3.SCHEME 5

[0694] Scheme 5 shows an alternative general scheme for the synthesis of Compound 21 where A is H, and B, X1, X2, X3, X4, Ring D, Ra, Rb, n, m and E are as defined for Formula I.

[0695] Compound 22 may be prepared by treating compound 4A (prepared e.g., as described in Scheme 1) with aluminum trichloride.

[0696] When group B is as defined for Formula I other than hydrogen, compound 23 may be prepared by reacting compound 22 with a reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R^R^Cl-Ce alkyl-X, hetA^Cl-CS alkyl -X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyca)Cl-C3 alkyl-X, hetCyca-X or hetCycaC(=0)Cl-C6 alkyl-X, where R1, R2, hetAr1, and hetCyc3are as defined for Formula I and X is a leaving atom or group (such as a halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if B has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 22 with C1-C6 alkyl-X, where X is a halogen such as Br or CI, or a leaving group such as triflate.

[0697] Compound 24 may be prepared by reacting compound 23 with compound 13 (whereXI, X2, X3and X4are as defined for Formula I; L2is a leaving group such as a triflate or halide); Z is -B(ORx)(ORy) and Rzand Ryare H or (l-6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium-catalyzed cross- coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and Na2C03in dioxane at elevated temperatures).

[0698] When group B is hydrogen, compound 24 may be prepared by reacting compound 22 directly with compound 13 as described above.

[0699] Compound 20 may be prepared by coupling compound 24 with compound 15 where Ring D and E are as defined for Formula I under appropriate SNAr conditions (for example, optionally in the presence of a base such as K2C03and at elevated temperature). If Ring D of compound 15 comprises a substituent having a primary or secondary ring nitrogen atom, the nitrogen atom is protected with an appropriate amino protecting group prior tocoupling, and then the amino protecting group may be removed subsequent to coupling as described above.

[0700] Compound 21 may be prepared from compound 20 according to the process described for Scheme 3.SCHEME 6

[0701] Scheme 6 shows a general scheme for the synthesis of Compound 31 where A is CI, and B, X1, X2, X3, X4, Ring D, Ra, Rb, n, m and E are as defined for Formula I.

[0702] Compound 25 may be prepared by treating compound 4A (prepared e.g., as described in Scheme 1) with aluminum trichloride.

[0703] Compound 26 may be prepared by treating compound 25 with aluminum trichloride.

[0704] When group B is as defined for Formula I other than hydrogen, compound 27 may be prepared by reacting compound 26 with a reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R^R^Cl-Ce alkyl-X, hetA^Cl-CS alkyl - X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyca)Cl-C3 alkyl-X, hetCyca-X or hetCycaC(=0)Cl-C6 alkyl-X, where R1, R2, hetAr1, and hetCyc3are as defined for Formula I and X is a leaving atom or group (such as a halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if B has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 26 with C1-C6 alkyl-X, where X is a halogen such as Br or CI, or a leaving group such as triflate.

[0705] Compounds 28 (when group B is methyl), 29 (when group B is hydrogen) and 30 (when group B is other than hydrogen) may be prepared by coupling compounds 25, 26 and 27, respectively, with the corresponding boronic ester compound 10 (where Ring D, E, X1, X2, X3and X4are as defined for Formula I; Z is -B(ORx)(ORy) and Rzand Ryare H or (1- 6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and Na2C03in dioxane at elevated temperatures), wherein if Ring D of is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group prior to coupling. The amino protecting group if present on a substituent of Ring D of compound 29 or 30 may be removed under standard conditions (for example, a Boc group may be removed by treating compound 1 to acidic conditions, e.g., HC1) to provide compound 31 where E is H.

[0706] Alternatively, the E group may be functionalized (i.e., reacted or treated with an appropriate reagent) under standard conditions such as described below to provide compound 31 where E is as defined for Formula I except that E is not H.

[0707] The E group of compounds 11, 11a, 16, 19, 20, 29 and 30 described in Schemes 1- 6 may be functionalized (i.e., reacted or treated with an appropriate reagent) to introduce an E group, where E is any of the E groups defined for Formula I with the exception of hydrogen, using standard chemistry well known to persons skilled in the art. As used herein, the term "functionalized" refers to a process step in the E group of a compound of general Formula I is reacted or treated with an appropriate reagent to provide a compound of Formula I where E is as defined for Formula I except that E is other than hydrogen.

[0708] For example, an amide derivative (e.g., where E is ΑΓ^(=0)Νίε-, hetAr2C(=0)NR (CH2)P- p is 0 or 1 , or R4R5NC(=0) R -, may be obtained by reacting compound 11 wherein E is - H2with an carboxylic acid derivative such as an acid chloride using conventional amide bond formation conditions, for example in the presence of a base (e.g., an amine base such as DIEA) in an appropriate solvent (such as DCM) to provide a functionalized compound 12. Alternative, compound 11 wherein E is - H2may be reacted with an carboxylic acid using conventional amide bond formation conditions, for example by treating the carboxylic acid with an activating agent (e.g., HATU) followed by addition of compound 11 in the presence of a base ( (e.g., an amine base such as DIEA) in an appropriate solvent (such as DMA) to provide a functionalized compound 12. The same chemistry may be utilized with compounds 11a, 16, 19, 20, 29 and 30 to prepare functionalized compounds 12, 17, 21 and 31.

[0709] As another example, a urea derivative, (e.g., where E is R4R5HC(=0) Rg-) may be prepared reacting a compound 11 where E is - H2with a compound having the formula R4R5N=C(=0) where R4and R5are as defined for Formula I in the presence of an appropriate base (e.g., DIEA) to provide a functionalized compound 12. The same chemistry may be utilized with compounds 11a, 16, 19, 20, 29 and 30 to prepare functionalized compounds 12, 17, 21 and 31.

[0710] As another example, an alkoxy, aryloxy or heteroaryloxy derivative (e.g., where E is (C1 -C6 alkoxy)C l-C6 alkoxy, ΑΓΧΟ- or hetAr20-), may be prepared by reacting a compound 11 where E is hydroxy with a compound having the formula (C 1-C6 alkoxy)Cl-C6 alkyl-X, Arx-X or hetAr2-X, where X is a halogen, in the presence of an inorganic base (e.g., an alkali metal hydride, such as sodium hydride or potassium hydride) in an appropriatesolvent (e.g., an aprotic solvent such as DMA). The same chemistry may be utilized with compounds 11a, 16, 19, 20, 29 and 30 to prepare functionalized compounds 12, 17, 21 and 31.

[0711] The term "amino protecting group" as used herein refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound. Examples of suitable protecting groups for use in any of the processes described herein include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group. Non-limiting examples of amino protecting groups are acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc"), benzyloxycarbonyl ("CBz") and 9- fluorenylmethyleneoxycarbonyl ("Fmoc"). Further examples of these groups, and other protecting groups, are found in T. W. Greene, et al. Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.

[0712] Accordingly, further provided herein is a process for preparing of a compound of Formula I or a pharmaceutically acceptable salt thereof as defined herein which comprises:

[0713] (a) for a compound of Formula I where E is H, A is CN, and B, X1, X2, X3, X4, Ring D, Ra, Rb, m and n are as defined for Formula I, coupling a corresponding compound 9 having the formula9

[0714] where B is as defined for Formula I, with a corresponding boronate ester having the formula 1010

[0715] where Z is -B(ORx)(ORy) and Rxand Ryare H or (l-6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl), and Ring D, E, X1, X2, X3, X4, Ra, Rb, mand n are as defined for Formula I, wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an amino protecting group prior to coupling, in the presence of a palladium catalyst and optionally a ligand and in the presence of a base, optionally followed by removal of the amino protecting group if present; or

[0716] (b) for a compound of Formula I where A, B, X1, X2, X3, X4, Ring D,Ra, Rb, m, n, and E are as defined for Formula I with the exception that E is not hydrogen, functionalizing a correspondin compound of the formula

[0717] wherein Ring D, B, X1, X2, X3,X4, Ra, Rb, m and n are as defined for Formula I

[0718] (c) for a compound of Formula I where A is CN and B, X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined for Formula I, reacting a corresponding compound of the formula1414

[0719] wherein Ring D, B, X1, X2, X3, and X4are as defined for Formula I and L2is a leaving group such as a halogen or triflate with a compound of the formula 1515

[0720] wherein Ring D, Ra, Rb, m, n, and E are as defined for Formula I and wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group prior to coupling, in the presence of a base, optionally followed by removal of the amino protecting group if present; or

[0721] (d) for a compound of Formula I where E is H, A is CN, and B, X1, X2, X3, X4, and Ring D are as defined for Formula I coupling a corresponding compound of formula 1414

[0722] where L2is a leaving group and B, X1, X2, X3, and X4are as defined for Formula I, with a compound of formula 1515

[0723] where Ring D, Ra, Rb, m and n are as defined for Formula I and E is hydrogen, wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group prior to coupling, in the presence of a base, optionally followed by removal of the amino protecting group if present; or

[0724] (e) for a compound of Formula I where A is H, B is H, and X1, X2, X3, X4, Ring D and E are as defined for Formula I treating a corresponding compound of formula 18

[0725] where A is H, B is H, and X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined for Formula I wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an amino protecting group, with aluminum trichloride to rovide compound 19

[0726] optionally followed by removal of the amino protecting group if present; or

[0727] (f) for a compound of Formula I where A is H, and B, X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined for Formula I,

[0728] (i) treatin a corresponding compound of formula 18

[0729] where A is H, and X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined for Formula I, wherein if Ring D is substituted with an Rbsubstituent that is R^N- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group, with aluminum trichloride to provide compound 19

[0730] (ii) reacting compound 19 with C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3- C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R^^Cl-Ce alkyl-X, hetA^Cl-CS alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyca)Cl-C3 alkyl-X, hetCyca-X or hetCycaC(=0)Cl-C6 alkyl- X, where R1, R2, hetAr1, and hetCyc3are as defined for Formula I and X is a leaving atom or group, optionally followed by removal of the amino protecting group if present; or

[0731] (g) for a compound of Formula I where A is H or CI, B is H, and X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined for Formula I, coupling a compound of formula

[0732] where A is H or CI with a boronate ester having formula 1010

[0733] where Z is -B(ORx)(ORy) and Rxand Ryare H or (l-6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl), and Ring D, E, X1, X2, X3, X4, Ra, Rb, m and n are as defined for Formula I, wherein if Ring D is substituted with an Rbsubstituent thatis RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an amino protecting group prior to said coupling, in the presence of a palladium catalyst and optionally a ligand and in the presence of a base, optionally followed by removal of the amino protecting group if present; or

[0734] (h) for a compound of Formula I where A is H or CI, and B, X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined for Formula I coupling a compound of the formula

[0735] where A is H or CI, with a corres onding boronate ester compound of formula 1010

[0736] where Z is -B(ORx)(ORy) and Rxand Ryare H or (l-6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl), and Ring D, E, X1, X2, X3, X4, Ra, Rb, m and n are as defined for Formula I, wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an amino protecting group prior to said coupling, in the presence of a palladium catalyst and optionally a ligand and in the presence of a base, and optionally followed by removal of the amino protecting group if present; or

[0737] (i) for a compound of Formula I where A is H, and B, X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined for Formula I coupling a compound of formula 24

[0738] where B, X1, X2, X3and X4, are as defined for Formula I and L2is a leaving group or atom, with a corresponding compound of formula 1515

[0739] where Ring D, Ra, Rb, m, n, and E are as defined for Formula I wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an amino protecting group, optionally followed by removal of the amino protecting group if present; and

[0740] removing any additional protecting groups if present and optionally forming a pharmaceutically acceptable salt thereof.

[0741] The term "amino protecting group" as used herein refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound. Examples of suitable protecting groups for use in any of the processes described herein include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group. Non-limiting examples of amino protecting groups are acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc"), benzyloxycarbonyl ("CBz") and 9- fluorenylmethyleneoxycarbonyl ("Fmoc"). Further examples of these groups, and other protecting groups, are found in T. W. Greene, et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.

[0742] Hydroxy groups may be protected with any convenient hydroxy protecting group, for example as described in T. W. Greene, et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006. Examples include benzyl, trityl, silyl ethers, and the like.

[0743] Nitrogen atoms in compounds described in any of the above methods may be protected with any convenient nitrogen protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2nded. New York; John Wiley & Sons, Inc., 1991. Examples of nitrogen protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC), phenoxycarbonyl, and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0744] The ability of test compounds to act as RET inhibitors may be demonstrated by the assay described in Example A. IC50 values are shown in Table 5.

[0745] In some embodiments, the compounds provided herein exhibit potent and selective RET inhibition. For example, the compounds provided herein exhibit nanomolar potency against wild type RET and select RET mutants, including the KIF5B-RET fusion and V804M gatekeeper mutation, with minimal activity against related kinases.

[0746] In some embodiments, the compounds of Formula I or a pharmaceutically acceptable salt or solvate thereof, selectively target a RET kinase. For example, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, can selectively target a RET kinase over another kinase or non-kinase target.

[0747] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, exhibits at least a 30-fold selectivity for a RET kinase over another kinase. For example, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, exhibits at least a 40-fold selectivity; at least a 50-fold selectivity; at least a 60-fold selectivity; at least a 70-fold selectivity; at least a 80-fold selectivity; at least a 90-fold selectivity; at least 100-fold selectivity; at least 200-fold selectivity; at least 300-fold selectivity; at least 400-fold selectivity; at least 500-fold selectivity; at least 600-fold selectivity; at least 700-fold selectivity; at least 800-fold selectivity; at least 900-fold selectivity; or at least 1000-fold selectivity for a RET kinase over another kinase. In some embodiments, selectivity for a RET kinase over another kinase is measured in a cellular assay (e.g., a cellular assay as provided herein).

[0748] In some embodiments, the compounds provided herein can exhibit selectivity for a RET kinase over a KDR kinase (e.g., VEGFR2). In some embodiments, the selectivity for a RET kinase over a KDR kinase is observed without loss of gatekeeper mutant potency. In some embodiments, the selectivity over a KDR kinase is at least 10-fold (e.g., at least a 40-fold selectivity; at least a 50-fold selectivity; at least a 60-fold selectivity; at least a 70-fold selectivity; at least a 80-fold selectivity; at least a 90-fold selectivity; at least 100-fold selectivity; at least 150-fold selectivity; at least 200-fold selectivity; at least 250-fold selectivity; at least 300-fold selectivity; at least 350-fold selectivity; or at least 400-fold selectivity) as compared to the inhibition of KIF5B-RET (i.e. the compounds were more potentagainst KIF5B-RET than KDR). In some embodiments, the selectivity for a RET kinase over a KDR kinase is about 30-fold. In some embodiments, the selectivity for a RET kinase over a KDR kinase is at least 100-fold. In some embodiments, the selectivity for a RET kinase over a KDR kinase is at least 150-fold. In some embodiments, the selectivity for a RET kinase over a KDR kinase is at least 400-fold. Without being bound by any theory, potent KDR kinase inhibition is believed to be a common feature among multikinase inhibitors (MKIs) that target RET and may be the source of the dose-limiting toxicities observed with such compounds.

[0749] In some embodiments, inhibition of V804M was similar to that observed for wild- type RET. For example, inhibition of V804M was within about 2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) of inhibition of wild-type RET (i.e. the compounds were similarly potent against wild-type RET and V804M). In some embodiments, selectivity for a wildtype or V804M RET kinase over another kinase is measured in an enzyme assay (e.g., an enzyme assay as provided herein). In some embodiments, the compounds provided herein exhibit selective cytotoxicity to RET-mutant cells.

[0750] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood brain barrier and inhibiting a RET kinase in the brain and / or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount. For example, treatment of a patient with cancer (e.g., a RET-associated cancer such as a RET-associated brain or CNS cancer) can include administration (e.g., oral administration) of the compound to the patient. In some such embodiments, the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor.

[0751] In some embodiments, the compounds of Formula I or a pharmaceutically acceptable salt or solvate thereof, exhibit one or more of high GI absorption, low clearance, and low potential for drug-drug interactions.

[0752] Compounds of Formula I are useful for treating diseases and disorders which can be treated with a RET kinase inhibitor, such as RET-associated diseases and disorders, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors, and gastrointestinal disorders such as IBS.

[0753] As used herein, terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0754] As used herein, the terms "subject," "individual," or "patient," are used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (a RET-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency -approved assay or kit). The subject can be a subject with a tumor(s) that is positive for a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a RET gene, a RET protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency- approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a RET-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (and opt...

Claims

What is claimed is:

1. A compound of the Formula I:and pharmaceutically acceptable salts and solvates thereof, wherein:X1, X2, X3and X4are independently CH, CCH3, CF or N, wherein zero, one or two of X1, X2, X3and X4is N;A is H, CN, CI, methyl, ethyl or cyclopropyl;B is:(a) hydrogen,(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,(c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,(d) dihydroxyC3-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3- C6 cycloalkylidene ring,(e) (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,(f) (R^ N Cl-Ce alkyl- where R1and R2are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- and (C1-C6 alkoxy)C(=0)-(g) hetA^Cl-CS alkyl-, where hetAr1is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents;(h) (C3-C6 cycloalkyl)Cl-C3 alkyl-,(i) (hetCyca)Cl-C3 alkyl-,G) hetCyc3,(k) (R1R2N)C(=0)C1-C6 alkyl- where R1and R2are independently selected from H and C1-C6 alkyl,(1) (R1R2N)C(=0)-, where R1and R2are independently selected from H and C1-C6 alkyl, or(m) hetCycaC(=0)Cl-C6 alkyl-;hetCyc3is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl, halogen, (C1-C6 alkyl)C(=0)-, C1-C6 alkoxy, oxo, and (C1-C6 alkoxy)C(=0)-;Ring D is(i) a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen,(ii) a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen, or(iii) a saturated 7-11 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen;each Rais independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl- C6 alkyl or (C1-C6 alkoxy)Cl-C6 alkyl-;Rbis (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2-, (d) RiRjNC(=0)CH2OCH2- where R and R are independently H or C1-C6 alkyl, (e) RcRdN-, (f) R^NCifc-, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(=0) H- wherein said alkyl portion is optionally substituted with hetCycb, hetAr3, C1-C6 alkoxy- or R'R'N-, or said alkyl portion is optionally substituted with two substituents independently selected from R'R'N- and OH, where each R and R" is independently hydrogen or C1-C6 alkyl, (i) (R'R"N)C1-C6 alkoxy(CH2)n- where n is 0 or 1 and R and R" are independently hydrogen or C1-C6 alkyl, (j) hetCycb(Cl-C3 alkyl)OCH2-, (k) hetCycbC(=0)NH- or (1) hetAraC(=0)NH-;hetCycbis a 4-6 membered heterocyclic ring, a 7-8 membered bridged heterocyclic ring, or a 7-10 membered heterospirocyclic ring, each ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCycbis optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros),hydroxyCl-C6 alkyl- (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl-, (Cl- C6 alkoxy)C(=0)-, C1-C6 alkoxy, and R'R"N- where R' and R" are independently hydrogen or C1-C6 alkyl;hetAr3is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S herein hetAr3is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros);Rcis hydrogen or C1-C6 alkyl;Rdishydrogen,C1-C6 alkyl (optionally substituted with 1-3 fluoros),(C1-C6 alkoxy)C(=0)-,hydroxyCl-C6 alkyl (optionally substituted with 1-3 fluoros),(hydroxyCl-C6 alkyl)C(=0)-,(C1-C6 alkyl)C(=0)-,(R^^Cl-Ce alkyl- where Rkand R1are independently H or C1-C6 alkyl,RmRnNC(=0)Cl-C6 alkyl- where Rmand Rnare independently H or C1-C6 alkyl, PhCH2- wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (C1-C6 alkyl)S02-, R^- and (R^^Cl-Ce alkyl- where each Reand Rfis independently H or C1-C6 alkyl,(C1-C6 alkoxy)Cl-C6 alkyl-, orhetCyccwhere hetCyccis a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl;n is 0, 1, 2, 3, 4, 5 or 6;m is 0 or 1;E is:(a) hydrogen,(b) hydroxy,(c) C1-C6 alkyl optionally substituted with 1-3 fluoros,(d) alkyl- wherein said alkyl portion is optionally substituted with 1 -3 fluoros,(e) hetAr2Cl-C6 alkyl-,(f) (C 1 -C6 alkoxy)C 1 -C6 alkoxy-,(g) A^O-,(h) hetAr2-0-,(i) Ar1Rg- where Rgis H or C1-C6 alkyl,(j) where Rgis H or C1-C6 alkyl,(k) R3C(=0) Rg- where R is H or C1-C6 alkyl;(1) Ar1C(=0) Rg- where Rgis H or C1-C6 alkyl,(m) hetAr2C(=0)NR (CH2)P- where p is 0 or 1 and R is H or C 1-C6 alkyl,(n) R4R5NC(=0)-,(o) A^ R^O)-, where R is H or C1-C6 alkyl,(p) hetAr2RgC(=0)-, where Rgis H or C1-C6 alkyl,(q) Ar^Cl-Ce alkyl)C(=0)- wherein said alkyl portion is optionally substituted with OH, hydroxy(C l-C6 alkyl), C1-C6 alkoxy or NH2,(r) hetCyc5C(=0)-,(s) R4R5NC(=0)NRg- where Rgis H or C1-C6 alkyl,(t) (Cl-C6 alkyl)S02-,(u) Ar^Cl-Ce alkyl)C(=0) R - where R is H or C1-C6 alkyl,(v) hetAr4C(=0)NR - where R is H or C1-C6 alkyl,(w) hetAr2-S(=0)-,(x) (C3-C6 cycloalkyl)CH2S02-,(y) Ar1(Cl-C6 alkyl)S02-,(z) hetAr2S02-,(aa) Ar1,(bb) hetAr2,(cc) hetCyc5,(dd) C1-C6 alkoxy,(ee) Ar^Cl-Ce alkyl)-0-,(ff) hetAr2(Cl-C6 alkyl)-0-,(gg) hetA^-O-Cl-Ce alkyl-,(hh) Ar^Cl-Ce alkyl)NR - where R is H or C1-C6 alkyl,(ii) hetAi^-S-,Oj) Ar2S02NR (CH2)P- where p is 0 or 1 and Rgis H or C1-C6 alkyl,(kk) (Cl-C6 alkoxy)C(=0)-,(11) (C1-C6 alkyl) RgC(=0)0- where Rgis H or C1-C6 alkyl,(mm) (C1-C6 alkyl) R S02- where R is H or C1-C6 alkyl,(nn) hetCyc5C(=0) R - where R is H or C1-C6 alkyl,(oo) Q- Rh(C 1 -C3 alkyl)C(=0)NR - where R and Rhare independently H or C 1 -C6 alkyl and Q is H, -C6 alkyl or (C1-C6 alkyl)OC(=0)-,(pp)where R and Rhare independently H or C1-C6 alkyl, Q is H, C1-C6 alkyl or (C1-C6 alk l)OC(=0)- and r is 1, 2, 3 or 4,(qq)where Rgand Rhare independently H or CI -C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(=0)-, / Q(rr) O where R is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(=0)-,(ss) R¾hN- where R and Rhare independently H or C1-C6 alkyl,(tt) (C3-C6 cycloalkyl)C(=0) Rg- where the cycloalkyl is optionally and independently substituted with one or more halogens,(uu) (C1-C6 alkyl)C(=0) R CH2- where R is H or C1-C6 alkyl, or(vv) C1-C6 alkyl)S02Rg- where Rgis H or C1-C6 alkyl;Ar1is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyCl-C6 alkyl, (C1-C6 alkyl)S02-, R^-and (R^^Cl-Ce alkyl- where each Reand Rfis independently H or C1-C6 alkyl; hetAr2is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr2is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), Cl- C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros) and hydroxyCl-C6 alkoxy-;hetCyc5is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and oxo;R3is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C3-C6 cycloalkyl)0-, (C3-C6 cycloalkyl)CH20-, hetCyc70-, Ph-O-, or (C1-C6 alkoxy)Cl-C6 alkyl-; wherein each of said C3- C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH, or R'R'N- where R and R" are independently hydrogen or C1-C6 alkyl;R4is H or Cl-C6 alkyl;R5is Ar2, hetAr3, Αι¾Η2-, hetCyc6-CH2-, hydroxyCl-C6 alkyl-, (C3-C6 cycloalkyl)CH2- , or C1-C6 alkyl optionally substituted with 1-3 fluoros;Ar2is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, and R¾hN- where Rgand Rhare independently H or C1-C6 alkyl, or Ar2is phenyl fused to a 6 membered heterocyclic ring having a ring nitrogen atom and optionally substituted with C1-C6 alkyl;hetAr3is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), and (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros);hetAr4is pyridin-4(lH)-onyl or pyridin-2(lH)-onyl optionally substituted with one or moresubstituents independently selected from C1-C6 alkyl and halogen;hetCyc6is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S; andhetCyc7is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S.

2. A compound according to claim 1, wherein D is a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen.

3. A compound according to claim 2, wherein D iswherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, and the asterisk indicates the point of attachment of Ring D to the E group.

4. A com ound according to claim 3, wherein D iswherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, and the asterisk indicates the point of attachment of Ring D to the E group.

5. A compound according to claim 4, wherein D iswherein the wavy line indicates the point of attachment of Ring D to the ring comprising X3and X4, and the asterisk indicates the point of attachment of Ring D to the E group.

6. A compound according to any one of claims 2-5, wherein each Rais an independently selected C1-C6 alkyl group. ound according to claim 6, wherein D iswherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, and the asterisk indicates the point of attachment of Ring D to the E group.

8. A compound according to any one of claims 2-5, wherein Rbis (a) hydroxy, (c) hetCycbCH2- wherein hetCycbis a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and wherein hetCycbis optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), (e) RcRdN- or (f) RcRdNCH2-; Rcis hydrogen or C1-C6 alkyl; and Rdis hydrogen or C1-C6 alkyl (optionally substituted with 1-3 fluoros).ound according to claim 8, wherein D iswherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, and the asterisk indicates the point of attachment to the E group.

10. A compound according to any one of claims 2-5, wherein n is 0 or 1 and m is 0 or 1.

11. A compound according to any one of claims 2-10, wherein E is (a) hydrogen, (b) hydroxy, (c) C1-C6 alkyl optionally substituted with 1-3 fluoros, (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20-, (k) R3C(=0) R - where Rgis H or C1-C6 alkyl, (1) ΑΓ^(=0) ^- where Rgis H or C1-C6 alkyl, (m) hetAr2C(=0) Rg(CH2)P- where p is 0 or 1, (n) R4R5NC(=0)-, or (s)R4R5NC(=0) R - where R is H or C1-C6 alkyl.

12. A compound according to claim 11, wherein E is (d) A^Cl-Ce alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, (e) hetAr2Cl-C6 alkyl-, (g) A^O-, (h) hetAr20- , (1) Ar1C(=0) R - where R is H or C1-C6 alkyl, or (m) hetAr2C(=0) R (CH2)P- where p is 0 or 1.

13. A compound according to claim 1, wherein D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen.

14. A com ound according to claim 13, wherein D iswherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, and the asterisk indicates the point of attachment of Ring D to the E group.

15. A compound according to claim 14, wherein D iswherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, and the asterisk indicates the point of attachment of Ring D to the E group. nd according to claim 15, wherein D iswherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3and X4, and the asterisk indicates the point of attachment of Ring D to the E group.

17. A compound according to any one of claims 13-16, wherein E is (a) hydrogen, (b) hydroxy, (f) (C1-C6 alkoxy)Cl-C6 alkoxy-, (h) hetAr20-, (j) hetAr2R - where R is H or C1-C6 alkyl, (n) R4R5NC(=0)-, (o) A^NRSCC ))-, where Rgis H or C1-C6 alkyl, or (p) hetAr2RgC(=0)-, where Rgis H or Cl-C6 alkyl.

18. A compound according to claim 17, wherein E is (h) hetAr20-, (j) hetAr2Rg- where Rgis H or C1-C6 alkyl, (o) A^ R^O)-, where R is H or C1-C6 alkyl, or (p) hetAr2R C(=0)-, where R is H or C1-C6 alkyl.

19. A compound according to claim 1, wherein D is a saturated 7-11 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen.

20. A compound according to any one of claims 1-19, wherein B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.

21. A compound according to claim 20, wherein B is C1-C6 alkyl optionally substituted with 1-3 fluoros.

22. A compound according to claim 20, wherein B is hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.

23. A compound according to any one of claims 1-22, wherein X1is N, and X2, X3and X4are independently CH or CF.

24. A compound according to claim 23, wherein X1is N, and X2, X3and X4are CH.

25. A compound according to any one of claims 1-22, wherein X1and X3are N and X2and X4are independently CH or CF.

26. A compound according to claim 25, wherein X1and X3are N and X2and X4are CH.

27. A compound according to any one of claims 1-26, wherein A is CN.

28. A compound according to claim 1, wherein the compound of Formula I is selected from the compounds of Examples 1-819 or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition, comprising a compound according to any one of claims 1- 28, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

30. A method for treating cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29.

31. A method for treating cancer in a patient in need thereof, the method comprising (a) determining if the cancer is associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same; and (b) if the cancer is determined to be associated with a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, administering to the patient a therapeutically effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29.

32. A method of treating a RET-associated cancer in a patient, the method comprising administering to a patient identified or diagnosed as having a RET-associated cancer a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29.

33. A method of treating a RET-associated cancer in a patient, the method comprising:determining if the cancer in the patient is a RET-associated cancer; andadministering to a patient determined to have a RET-associated cancer a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29.

34. A method of treating a patient, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29, to a patient having a clinical record that indicates that the patient has a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same.

35. A method of selecting a treatment for a patient, the method comprising selecting a treatment comprising administration of a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29, for a patient identified or diagnosed as having a RET- associated cancer.

36. A method of selecting a treatment for a patient having a cancer, the method comprising: determining if the cancer in the patient is a RET-associated cancer; andselecting a treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29, for a patient determined to have a RET- associated cancer.

37. A method of selecting a patient for treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29, the method comprising:identifying a patient having a RET-associated cancer; andselecting the patient for treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29.

38. A method of selecting a patient having cancer for treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29, the method comprising:determining if the cancer in the patient is a RET-associated cancer; andselecting a patient determined to have a RET-associated cancer for treatment including administration of a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29.

39. The method of any one of claims 33, 36, and 38, wherein the step of determining if the cancer in the patient is a RET-associated cancer includes performing an assay to detect dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same in a sample from the patient.

40. The method of claim 39, further comprising:obtaining a sample from the patient.

41. The method of claim 40, wherein the sample is a biopsy sample.

42. The method of any one of claims 39-41, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

43. The method of claim 42, wherein the FISH is break apart FISH analysis.

44. The method of claim 42, wherein the sequencing is pyrosequencing or next generation sequencing.

45. The method of any one of claims 39-44, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutations in the RET gene.

46. The method of claim 45, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 423, 432, 446, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781,788, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1062, 1064, and 1096.

47. The method of claim 46, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1064, and 1096.

48. The method of claim 47, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions: S32L, D34S, L40P, L56M, P64L, R67H, R114H, V145G, V292M, G321R, R330Q,T338I, R360W, F393L, G423R, G446R, A510V, E511K, G513D, C515S, C515W, R525W, C531R, G533C, G533S, G550E, V591I, G593E, E595D, E595A, R600Q, I602V, K603Q, K603E, Y606C, C609C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611 S, C611G, C611Y, C611F, C611W, E616Q, C618S, C618Y, C618R, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641 S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, T675T S686N, S689T, G691 S, R694Q, M700L, V706M, V706A, E713K, E732K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, I788I, L790F, Y791F, Y791N, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, Y806Y, G810R, G810S, G810A, E818K, S819I, G823E, Y826M, Y826S, R833C, S836S, P841L, P841P, E843D,R844W, R844Q, R844L, M848T, I852M, L865V, L870F, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, S891 S, R897Q, D898V, Y900F, E901K, S904F, S904S, S904C, Y905F, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, Y981F, R982C, M1009V, Y1015F, D1017N, V1041G, M1064T, and Y1096F.

49. The method of claim 45, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.

50. The method of any one of claims 39-44, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.

51. The method of claim 50, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIPl-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRFM33-RET, ERC1- RET, FGFR1 OP-RET, RET-MBDl, RET-RAB61P2, RET-PRKARIA, RET-TRIM24, RET- GOLGA5, HOOK3-RET, KTNl-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET,SPECCIL-RET, TBLIXRI / RET, CEP 55 -RET, CUXl-RET, KIAA1468-RET, RFG8 / RET, ACBD5-RET, PTClex9-RET, MYH13-RET, PIBFl-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, Ria-RET, RET-PTC4, FRMD4A-RET, SQSTMl-RET, AFAP1L2-RET, PPFIBP2- RET, EML4-RET, PARD3-RET, MYHIO-RET, HTIFl / RET, AF API-RET, RASGEFIA-RET, TEL-RET, RUFYl-RET, UEVLD-RET, DLG5-RET, FOXP4-RET, TIFIG-RET, H4L-RET, OFLM4-RET, and RRBPl-RET.

52. The method of any one of claims 32, 33, and 36-51, wherein the RET-associated cancer is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.

53. The method of claim 52, wherein the lung cancer is RET fusion lung cancer or the canceris medullary thyroid cancer.

54. The method of claim 52, wherein the lung cancer is small cell lung carcinoma, non-small cell lung cancer, bronchioles lung cell carcinoma, or lung adenocarcinoma.

55. The method of any one of claims 30-54, wherein the compound of Formula I or apharmaceutically acceptable salt or solvate thereof is orally administered.

56. The method of any one of claims 30-55, further comprising administering an additional therapy or therapeutic agent to the patient.

57. The method according to claim 56, wherein said additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase targeted-therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies and angiogene sis-targeted therapies.

58. The method according to claim 57, wherein said additional therapeutic agent is selected from one or more kinase targeted therapeutics.

59. The method according to any one of claims 56-58, wherein the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29, and the additional therapeutic agent are administered simultaneously as separate dosages.

60. The method according to any one of claims 56-58, wherein the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29, and the additional therapeutic agent are administered as separate dosages sequentially in any order.

61. Use of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a RET-associated cancer in apatient.

62. The use of claim 61, wherein the RET-associated cancer is a cancer having adysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same.

63. The use of claim 62, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutations in the RET gene.

64. The use of claim 63, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 423, 432, 446, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1062, 1064, and 1096.

65. The use of claim 64, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1064, and 1096.

66. The use of claim 65, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions:S32L, D34S, L40P, L56M, P64L, R67H, R114H, V145G, V292M, G321R, R330Q,T338I, R360W, F393L, G423R, G446R, A510V, E511K, G513D, C515S, C515W, R525W, C531R, G533C, G533S, G550E, V591I, G593E, E595D, E595A, R600Q, I602V, K603Q, K603E, Y606C, C609C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611 S, C611G, C611Y, C611F, C611W, E616Q, C618S, C618Y, C618R, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641 S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, T675T S686N, S689T, G691 S, R694Q, M700L, V706M, V706A, E713K, E732K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, I788I, L790F, Y791F, Y791N, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, Y806Y, G810R, G810S, G810A, E818K, S819I, G823E, Y826M, Y826S, R833C, S836S, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, L865V, L870F, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, S891 S, R897Q, D898V, Y900F, E901K, S904F, S904S, S904C, Y905F, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, Y981F, R982C, M1009V, Y1015F, D1017N, V1041G, M1064T, and Y1096F.

67. The use of claim 63, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.

68. The use of claim 62, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.

69. The use of claim 68, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIPl-RET, KXF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERCl-RET, FGFRIOP-RET, RET-MBD1, RET-RAB61P2, RET-PRK AR 1 A, RET-TRFM24, RET-GOLGA5, HOOK3-RET, KTNl-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1 / RET, CEP 55 -RET, CUXl-RET, KIAA1468-RET, RFG8 / RET, ACBD5-RET, PTClex9-RET, MYH13-RET, PIBFl-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, Ria-RET, RET-PTC4, FRMD4A-RET, SQSTMl-RET, AFAP1L2-RET, PPFIBP2- RET, EML4-RET, PARD3-RET, MYHIO-RET, HTIFl / RET, AF API-RET, RASGEFIA-RET, TEL-RET, RUFY1-RET, UEVLD-RET, DLG5-RET, F0XP4-RET, TIFIG-RET, H4L-RET, 0FLM4-RET, and RRBPl-RET.

70. The use of any one of claims 61-69, wherein the RET-associated cancer is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer,differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively),pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.

71. The use of claim 70, wherein the lung cancer is RET fusion lung cancer or the cancer is medullary thyroid cancer.

72. The use of claim 70, wherein the lung cancer is small cell lung carcinoma, non-small cell lung cancer, bronchioles lung cell carcinoma, or lung adenocarcinoma.

73. The use of any one of claims 61-72, wherein the medicament is formulated for oral administration.

74. A compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition according to claim 29 for use in treating a patient identified or diagnosed as having a RET-associated cancer.

75. The compound of claim 74, wherein the RET-associated cancer is a cancer having a dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same.

76. The compound of claim 75, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutations in the RET gene.

77. The compound of claim 76, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 423, 432, 446, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1062, 1064, and 1096.

78. The compound of claim 77, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1064, and 1096.

79. The compound of claim 78, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions: S32L, D34S, L40P, L56M, P64L, R67H, R114H, V145G, V292M, G321R, R330Q,T338I, R360W, F393L, G423R, G446R, A510V, E511K, G513D, C515S, C515W, R525W,C531R, G533C, G533S, G550E, V591I, G593E, E595D, E595A, R600Q, I602V, K603Q, K603E, Y606C, C609C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611 S, C611G, C611Y, C611F, C611W, E616Q, C618S, C618Y, C618R, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641 S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, T675T S686N, S689T, G691 S, R694Q, M700L, V706M, V706A, E713K, E732K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, I788I, L790F, Y791F, Y791N, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, Y806Y, G810R, G810S, G810A, E818K, S819I, G823E, Y826M, Y826S, R833C, S836S, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, L865V, L870F, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, S891 S, R897Q, D898V, Y900F, E901K, S904F, S904S, S904C, Y905F, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, Y981F, R982C, M1009V, Y1015F, D1017N, V1041G, M1064T, and Y1096F.

80. The compound of claim 76, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.

81. The compound of claim 75, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.

82. The compound of claim 81, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIPl-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33- RET, ERC1-RET, FGFRIOP-RET, RET-MBD1, RET-RAB61P2, RET-PRKARIA, RET- TRIM24, RET-GOLGA5, HOOK3-RET, KTNl-RET, TRIM27-RET, AKAP13-RET, FKBP15- RET, SPECC1L-RET, TBL1XR1 / RET, CEP55-RET, CUX1-RET, KIAA1468-RET,RFG8 / RET, ACBD5-RET, PTClex9-RET, MYH13-RET, PIBF1-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, Ria-RET, RET-PTC4, FRMD4A-RET, SQSTMl-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, MYH10-RET, HTIF1 / RET, AF API-RET, RASGEF1A-RET, TEL-RET, RUFY1-RET, UEVLD-RET, DLG5-RET, F0XP4-RET, TIF1G- RET, H4L-RET, 0FLM4-RET, and RRBPl-RET.

83. The compound of any one of claims 74-82, wherein the RET-associated cancer is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively),pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.

84. The compound of claim 83, wherein the lung cancer is RET fusion lung cancer or the cancer is medullary thyroid cancer.

85. The compound of claim 83, wherein the lung cancer is small cell lung carcinoma, non-small cell lung cancer, bronciolus lung cell carcinoma, or lung adenocarcinoma.

86. A method for inhibiting RET kinase activity in a mammalian cell, the method comprising contacting the mammalian cell with a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof.

87. The method of claim 86, wherein the contacting occurs in vivo.

88. The method of claim 86, wherein the contacting occurs in vitro.

89. The method of any one of claims 86-88, wherein the mammalian cell is a mammalian cancer cell.

90. The method of claim 89, wherein the mammalian cancer cell is a mammalian RET-associated cancer cell.

91. The method of any one of claims 86-90, wherein the cell has a dysregulation of a RET gene, a RET kinase protein, or expression or activity or level of any of the same.

92. The method of claim 91, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutations in the RET gene.

93. The method of claim 92, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32, 34, 40, 56, 64, 67, 114, 136, 145, 180, 200, 292, 294, 321, 330, 338, 360, 373, 393, 423, 432, 446, 505, 506, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 633, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 802, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 882, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1062, 1064, and 109694. The method of claim 93, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more amino acid substitutions at one or more of the following amino acid positions: 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1064, and 1096.

95. The method of claim 94, wherein the one or more point mutations in a RET gene results in the translation of a RET protein having one or more of the following amino acid substitutions:S32L, D34S, L40P, L56M, P64L, R67H, R114H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, G423R, G446R, A510V, E511K, G513D, C515S, C515W, R525W, C531R, G533C, G533S, G550E, V591I, G593E, E595D, E595A, R600Q, I602V, K603Q, K603E, Y606C, C609C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611 S, C611G, C611Y, C611F, C611W, E616Q, C618S, C618Y, C618R, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641 S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, T675T S686N, S689T, G691 S, R694Q, M700L, V706M, V706A, E713K, E732K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, I788I, L790F, Y791F, Y791N, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, Y806Y, G810R, G810S, G810A, E818K, S819I, G823E, Y826M, Y826S, R833C, S836S, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, L865V, L870F, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, S891 S, R897Q, D898V, Y900F, E901K, S904F, S904S, S904C, Y905F, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, Y981F, R982C, M1009V, Y1015F, D1017N, V1041G, M1064T, and Y1096F.

96. The method of claim 92, wherein the one or more point mutations in a RET gene occur in one or more of exons 10, 11, 13, 14, 15, and 16 of a human RET gene.

97. The method of claim 91, wherein the dysregulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is a RET gene fusion.

98. The method of claim 97, wherein the RET gene fusion is selected from the group consisting of: BCR-RET, CLIPl-RET, KXF5B-RET, CCDC6-RET, NCOA4-RET, TRFM33-RET, ERC1- RET, FGFR1 OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKARIA, RET-TRIM24, RET- GOLGA5, HOOK3-RET, KTN1-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET,SPECC1L-RET, TBL1XR1 / RET, CEP 55 -RET, CUX1-RET, KIAA1468-RET, RFG8 / RET,ACBD5-RET, PTClex9-RET, MYH13-RET, PIBF1-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, Ria-RET, RET-PTC4, FRMD4A-RET, SQSTMl-RET, AFAP1L2-RET, PPFIBP2- RET, EML4-RET, PARD3-RET, MYHIO-RET, HTIFl / RET, AF API-RET, RASGEFIA-RET, TEL-RET, RUFY1-RET, UEVLD-RET, DLG5-RET, F0XP4-RET, TIFIG-RET, H4L-RET, 0FLM4-RET, and RRBPl-RET.

99. A method of treating irritable bowel syndrome in a patient, the method comprising administering to a patient identified or diagnosed as having irritable bowel syndrome a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29.

100. A method for reducing pain associated with irritable bowel syndrome in a patient in need thereof, the method comprising administering to a patient identified or diagnosed as having irritable bowel syndrome a therapeutically effective amount of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 29.

101. A method for inhibiting metastasis of a cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition according to claim 29.

102. The method of claim 101, wherein the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof is used in combination with another chemotherapeutic agent.

103. A method of treating a subject having a cancer, wherein the method comprises:(a) administering one or more doses of a first RET inhibitor to the subject for a period of time;(b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); and(c) administering a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); or(d) administering additional doses of the first RET inhibitor of step (a) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a).

104. The method of claim 103, wherein the anticancer agent in step (c) is a second RET inhibitor, an immunotherapy, or a combination thereof.

105. The method of claim 103, wherein the anticancer agent in step (c) is the first RET inhibitor administered in step (a).

106. The method of claim 103, wherein the subject is administered additional doses of the first RET inhibitor of step (a), and the method further comprises (e) administering another anticancer agent to the subject.

107. The method of claim 106, wherein the anticancer agent of step (e) is a second RET inhibitor, an immunotherapy, or a combination thereof.

108. The method of claim 107, wherein the anticancer agent of step (e) is a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof.

109. A method of treating a subject having a cancer, wherein the method comprises:(a) administering one or more doses of a first RET inhibitor to the subject for a period of time;(b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); and(c) administering a second RET inhibitor as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); or(d) administering additional doses of the first RET inhibitor of step (a) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor of step (a); wherein the mutation is a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.

110. The method of claim 109, wherein the anticancer agent of step (c) is the first RET inhibitor administered in step (a).

111. The method of claim 109, wherein the subject is administered additional doses of the first RET inhibitor of step (a), and the method further comprises (e) administering another anticancer agent.

112. The method of claim 111, wherein the anticancer agent of step (e) is a second RET inhibitor, an immunotherapy, or a combination thereof.

113. The method of claim 111, wherein the anticancer agent of step (e) is a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof.

114. A method of treating a subject having a cancer, wherein the method comprises:(a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject; and(b) administering a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject; or(c) administering additional doses of the first RET inhibitor to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor previously administered to the subject.

115. The method of claim 114, wherein the anticancer agent of step (b) is a second RET inhibitor, an immunotherapy, or a combination thereof.

116. The method of claim 114, wherein the anticancer agent of step (b) is the first RET inhibitor previously administered to the subject.

117. The method of claim 116, wherein the subject is administered additional doses of the first RET inhibitor previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject.

118. The method of claim 117, wherein the anticancer agent of step (d) is a second RET inhibitor, an immunotherapy, or a combination thereof.

119. The method of claim 117, wherein the anticancer agent of step (d) is a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof.

120. A method of treating a subject having a cancer, wherein the method comprises:(a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor previously administered to the subject; and(b) administering a second RET inhibitor to the subject as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject; or(c) administering additional doses of the first RET inhibitor that was previously administered to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor that was previously administered to the subject.

121. The method of claim 120, wherein the anticancer agent of step (b) is the first RET inhibitor previously administered to the subject.

122. The method of claim 120, wherein the subject is administered additional doses of the first RET inhibitor previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject.

123. The method of claim 122, wherein the anticancer agent of step (d) is a second RET inhibitor, an immunotherapy, or a combination thereof.

124. The method of claim 122, wherein the anticancer agent of step (d) is a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof.

125. A method of treating a subject having a cancer, wherein the method comprises:(a) administering one or more doses of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof for a period of time;(b) after (a), determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof of step (a); and(c) administering a second RET inhibitor or a second compound of any one of claims 1-28or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to a subject determined to have one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof of step (a); or(d) administering additional doses of the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof of step (a) to a subject having a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof of step (a).

126. The method of claim 125, wherein the second RET inhibitor is administered in step (c).

127. The method of claim 125, wherein the second compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof is administered in step (c).

128. The method of claim 125, wherein the anticancer agent of step (c) is a first RET inhibitor, an immunotherapy, or a combination thereof.

129. The method of claim 125, wherein the anticancer agent of step (c) is a second compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof that is different from that administered in step (a).

130. The method of claim 125, wherein the anticancer agent of step (c) is the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof administered in step (a).

131. The method of claim 125, wherein the subject is administered additional doses of the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof of step (a), and the method further comprises (e) administering another anticancer agent to the subj ect.

132. The method of claim 131, wherein the anticancer agent of step (e) is a second RET inhibitor,an immunotherapy, or a combination thereof.

133. The method of claim 131, wherein the anticancer agent of step (e) is a second compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof that is different from the compound of step (a).

134. A method of treating a subject having a cancer, wherein the method comprises:(a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof that was previously administered to the subject; and(b) administering a second RET inhibitor or a second compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to a subject determined to have a cancer cell that has one or more RET inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof that was previously administered to the subject; or(c) administering additional doses of the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof previously administered to the subject having a cancer cell that does not have a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof that was previously administered to the subject.

135. The method of claim 134, wherein the second RET inhibitor is administered in step (b).

136. The method of claim 134, wherein the second compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof is administered in step (b).

137. The method of claim 134, wherein the anticancer agent of step (b) is a second RET inhibitor, an immunotherapy, or a combination thereof.

138. The method of claim 134, wherein the anticancer agent of step (b) is a second compound of any one of claims 1 -28 or a pharmaceutically acceptable salt or solvate thereof.

139. The method of claim 134, wherein the anticancer agent of step (b) is the compound of any one of claims 1-28 or a pharmaceutically acceptable salt or solvate thereof that was previously administered to the subject.

140. The method of claim 134, wherein the subject is administered additional doses of the compound of any one of claims 1 -28 or a pharmaceutically acceptable salt or solvate thereof that was previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject.

141. The method of claim 140, wherein the anticancer agent of step (d) is a second RET inhibitor, an immunotherapy, or a combination thereof.

142. The method of claim 141, wherein the anticancer agent of step (d) is a second compound of any one of claims 1 -28 or a pharmaceutically acceptable salt or solvate thereof.

143. A process for preparing of a compound of claim 1 or a pharmaceutically acceptable salt thereof, comprising:(a) for a compound of claim 1 where E is H, A is CN, and B, X1, X2, X3, X4, Ring D, Ra, Rb, m and n are as defined in claim 1, cou ling a corresponding compound 9 having the formula9where B is as defined in claim 1, with a corresponding boronate ester having the formula 1010where Z is -B(ORx)(ORy) and Rxand Ryare H or (l-6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl), and Ring D, E, X1, X2, X3, X4, Ra, Rb, m and n are as defined in claim 1, wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an amino protecting group prior to coupling, in the presence of a palladium catalyst and optionally a ligand and in the presence of a base, optionally followed by removal of the amino protecting group if present; or(b) for a compound of claim 1 where A, B, X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined in claim 1 with the exception that E is not hydrogen, functionalizing a corresponding compound of the formulawherein Ring D, B, X1, X2, X3,X4, Ra, Rb, m and n are as defined in claim 1 and E1is - H2 or OH; or(c) for a compound of claim 1 where A is CN and B, X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined in claim 1, reactin a corresponding compound of the formula 1414wherein Ring D, B, X1, X2, X3, and X4are as defined in claim 1 and L2is a leaving group such as a halogen or triflate, with a compound of the formula 1515wherein Ring D, Ra, Rb, m, n, and E are as defined in claim 1 and wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group prior to coupling, in the presence of a base, optionally followed by removal of the amino protecting group if present; or(d) for a compound of claim 1 where E is H, A is CN, and B, X1, X2, X3, X4, and Ring D are as defined in claim 1, coupling a corres onding compound of formula 1414where L2is a leaving group and B, X1, X2, X3, and X4are as defined in claim 1, with a compound of formula 1515where Ring D, Ra, Rb, m and n are as defined in claim 1 and E is hydrogen, wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group prior to coupling, in the presence of a base, optionally followed by removal of the amino protecting group if present; or(e) for a compound of claim 1 where A is H, B is H, and X1, X2, X3, X4, Ring D and E are as defined in claim 1, treating a corresponding compound of formula 18where A is H, B is H, and X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined in claim 1 wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an amino protecting group, with aluminum trichloride to provide compound 19optionally followed by removal of the amino protecting group if present; or(f) for a compound of claim 1 where A is H, and B, X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined in claim 1,(i) treating a corresponding compound of formula 18where A is H, and X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined in claim 1, wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdishydrogen, the nitrogen atom of Rbmay be protected with an appropriate amino protecting group, with aluminum trichloride to rovide compound 19(ii) reacting compound 19 with C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R^tfN Cl-Ce alkyl-X, hetA^Cl-CS alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyca)Cl-C3 alkyl-X, hetCyca-X or hetCycaC(=0)Cl-C6 alkyl-X, where R1, R2, hetAr1, and hetCyc3are as defined in claim 1 and X is a leaving atom or group, optionally followed by removal of the amino protecting group if present; or(g) for a compound of claim 1 where A is H or CI, B is H, and X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined in claim 1, cou ling a compound of formulawhere A is H or CI with a boronate ester havin formula 1010where Z is -B(ORx)(ORy) and Rxand Ryare H or (l-6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituentsselected from (C1-C3 alkyl), and Ring D, E, X1, X2, X3, X4, Ra, Rb, m and n are as defined in claim 1, wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an amino protecting group prior to said coupling, in the presence of a palladium catalyst and optionally a ligand and in the presence of a base, optionally followed by removal of the amino protecting group if present; or(h) for a compound of claim 1 where A is H or CI, and B, X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined in claim 1, cou ling a compound of the formulawhere A is H or CI, with a correspondin boronate ester compound of formula 1010 where Z is -B(ORx)(ORy) and Rxand Ryare H or (l-6C)alkyl, or Rxand Rytogether with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl), and Ring D, E, X1, X2, X3, X4, Ra, Rb, m and n are as defined in claim 1, wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an amino protecting group prior to said coupling, in the presence of a palladium catalyst and optionally a ligand and in the presence of a base, and optionally followed by removal of the amino protecting group if present; or(i) for a compound of claim lwhere A is H, and B, X1, X2, X3, X4, Ring D, Ra, Rb, m, n, and E are as defined in claim 1, coupling a compound of formula 24where B, X1, X2, X3and X4, are as defined in claim 1 and L2is a leaving group or atom, with a corresponding compound of formula 1515where Ring D, Ra, Rb, m, n, and E are as defined in claim 1 wherein if Ring D is substituted with an Rbsubstituent that is RcRdN- wherein one or both of Rcand Rdis hydrogen, the nitrogen atom of Rbmay be protected with an amino protecting group, optionally followed by removal of the amino protecting group if present; andremoving any additional protecting groups if present and optionally forming a pharmaceutically acceptable salt thereof.