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

Abstract

The present application relates to substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors. Specifically, provided herein are compounds of formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, wherein A, B, X 1 , X 2 , X 3 , X 4 , ring D and E have the meanings given in the specification, which are inhibitors of RET kinase and are suitable for treating and preventing diseases treatable with RET kinase inhibitors, including RET-related diseases and disorders.

Description

[0001] This application is a divisional application of an invention patent application filed on October 10, 2017, with application number 201780076390.2 and entitled “Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. provisional application serial numbers: 62 / 566,093 filed September 29, 2017, 62 / 554,817 filed September 6, 2017, 62 / 491,164 filed April 27, 2017, 62 / 447,850 filed January 18, 2017, and 62 / 406,252 filed October 10, 2016, each of which is incorporated herein by reference in its entirety. Background Art

[0004] The present disclosure relates to novel compounds that exhibit rearrangement during repertoire transfection (RET) kinase inhibition, pharmaceutical compositions comprising the compounds, methods for preparing the compounds, and uses of the compounds in therapy. More specifically, it relates to substituted pyrazolo[1,5-a]pyridine compounds that are useful in treating and preventing diseases treatable with RET kinase inhibitors, including RET-related diseases and disorders.

[0005] RET is a single-pass transmembrane receptor belonging to the tyrosine kinase superfamily that is essential for the normal development, maturation, and maintenance of several tissues and cell types (Mulligan, LM, 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 required for normal folding of the RET extracellular domain, while the cytoplasmic portion of the receptor contains two tyrosine kinase subdomains.

[0006] RET signaling is mediated by binding to a group of soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs), which also include 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 bind directly to GFLs and requires an additional coreceptor: one of the four GDNF family receptor-α (GFRα) family members, which are tethered to the cell surface via glycosylphosphatidylinositol bonds. GFLs and GFRα family members form a binary complex that, in turn, binds to RET and recruits it to cholesterol-rich membrane subdomains known as lipid rafts, where RET signaling occurs.

[0007] Following ligand-coreceptor complex binding, RET dimerization and autophosphorylation on intracellular tyrosine residues recruit adaptor and signaling proteins to stimulate multiple downstream pathways. Adapter protein binding to these docking sites leads to activation of the Ras-MAPK and PI3K-Akt / mTOR signaling pathways or recruitment of the CBL family of ubiquitin ligases, which play a role in RET downregulation of RET-mediated functions.

[0008] Aberrant RET expression and / or activity has been demonstrated in various cancers and gastrointestinal disorders, such as irritable bowel syndrome (IBS). Summary of the Invention

[0009] It has now been discovered that substituted pyrazolo[1,5-a]pyridine compounds are inhibitors of RET kinase and are useful in treating diseases, such as proliferative diseases, including cancer.

[0010] Therefore, provided herein is a compound of formula I:

[0011]

[0012] or a pharmaceutically acceptable salt or solvate thereof, wherein A, B, X 1 、X 2 、X 3 、X 4 and Ring D are as defined herein.

[0013] 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.

[0014] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting the cell with an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0015] Also provided herein is a method of treating a RET-related disease or condition in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0016] Also provided herein is a method of treating cancer in a patient in need of such treatment and / or inhibiting metastasis associated with a particular cancer, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0017] 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, comprising administering to the patient a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0018] Also provided is a method of providing supportive care to a cancer patient comprising preventing or minimizing gastrointestinal disorders (such as diarrhea) associated with treatment (including chemotherapy), the method comprising administering to the patient a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0019] Also provided herein is a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in therapy.

[0020] Also provided herein is a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating cancer and / or inhibiting cancer metastasis associated with a specific cancer.

[0021] Also provided herein is a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating irritable bowel syndrome (IBS) or pain associated with IBS.

[0022] Also provided is a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in providing supportive care to cancer patients, including preventing or minimizing gastrointestinal disorders (such as diarrhea) associated with treatment (including chemotherapy).

[0023] Also provided herein is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for use in inhibiting RET kinase activity.

[0024] Also provided herein is a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating a RET-related disease or disorder.

[0025] Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating cancer and / or inhibiting metastasis associated with a particular cancer.

[0026] Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating irritable bowel syndrome (IBS) or pain associated with IBS.

[0027] Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for providing supportive care to cancer patients, including preventing or minimizing gastrointestinal disorders (such as diarrhea) associated with treatment (including chemotherapy).

[0028] Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for inhibiting RET kinase activity.

[0029] Also provided herein is the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating a RET-related disease or disorder.

[0030] Also provided herein is a method for treating cancer in a patient in need thereof, comprising: (a) determining whether the cancer is associated with dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any one thereof (e.g., RET-related cancer); and (b) if it is determined that the cancer is associated with dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any one thereof (e.g., RET-related 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.

[0031] Also provided herein is a pharmaceutical combination for treating cancer in a patient in need thereof (e.g., a RET-related cancer, such as a RET-related cancer with a mutation that confers resistance to one or more RET inhibitors), comprising: (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 a pharmaceutically acceptable salt or solvate thereof and the additional treatment are formulated into a separate composition or dosage for simultaneous, separate or sequential use in treating cancer, wherein the amount of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and the amount of the additional therapeutic agent together are effective to treat cancer. Also provided herein is a pharmaceutical composition comprising such a combination. Also provided herein is a use of such a combination for the preparation of a medicament for treating cancer. Also provided herein is a commercial package or product comprising such a combination, in the form of a combined preparation for simultaneous, separate or sequential use; and a method of treating cancer in a patient in need thereof.

[0032] Also provided herein is a method for reversing or preventing acquired resistance to an anticancer drug, comprising administering to a patient at risk of developing or having acquired resistance to an anticancer drug a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a dose of an anticancer drug is administered to the patient (e.g., substantially simultaneously with administering to the patient a dose of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof).

[0033] Also provided herein is a method of delaying and / or preventing the development of cancer resistance 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 administering an effective amount of the anticancer drug.

[0034] Also provided herein is a method of treating an individual having cancer with 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 administering (b) an effective amount of an anticancer drug.

[0035] Also provided are methods of treating an individual with a RET-related cancer who has one or more RET inhibitor resistance mutations (e.g., a substitution at amino acid position 804, such as V804M, V804L, or V804E, and / or one or more RET inhibitor resistance mutations listed in Tables 3 and 4) that increase the cancer's resistance to a first RET inhibitor, the methods comprising administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of another anti-cancer drug (e.g., a second RET kinase inhibitor).

[0036] Also provided are methods of treating an individual having a RET-related cancer comprising administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, before, during, or after administration of another anticancer drug (eg, a first RET kinase inhibitor).

[0037] Also provided herein is a method for treating irritable bowel syndrome (IBS) in a patient in need thereof, comprising: (a) determining whether the IBS is associated with dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any thereof; and (b) if it is determined that the IBS is associated with dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any thereof, 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.

[0038] Also provided herein is a pharmaceutical combination for treating irritable bowel syndrome (IBS) in a patient in need thereof, comprising administering (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, for simultaneous, separate, or sequential use to treat IBS, wherein the amount of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and the amount of the additional therapeutic agent together are effective to treat IBS. Also provided herein is a pharmaceutical composition comprising such a combination. Also provided herein is a use of such a combination for preparing a medicament for treating 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 a method of treating IBS in a patient in need thereof.

[0039] Also provided herein is a process for preparing a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.

[0040] Also provided herein is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof obtained by a process for preparing a compound as defined herein.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are 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 the event of a conflict, the present specification, including definitions, will prevail.

[0042] Other features and advantages of the invention will be apparent from the following detailed description and structural formula, and from the claims. DETAILED DESCRIPTION

[0043] Provided herein is a compound of formula I:

[0044]

[0045] and pharmaceutically acceptable salts and solvates thereof, wherein:

[0046] X 1 、X 2 、X 3 and X 4 are independently CH, CF, CCH3 or N, wherein X 1 、X 2 、X 3 and X 4 Zero, one, or two of them are N;

[0047] A is H, CN, Cl, CH3-, CH3CH2-, cyclopropyl, -CH2CN or -CH(CN)CH3;

[0048] B is

[0049] (a) hydrogen,

[0050] (b) a C1-C6 alkyl group optionally substituted by 1 to 3 fluorine groups,

[0051] (c) hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoro or C3-C6 cycloalkylene rings,

[0052] (d) dihydroxy C3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring,

[0053] (e) (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted by 1 to 3 fluorine groups,

[0054] (f)(R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with OH, and wherein R 1 and R 2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluorines);

[0055] (g)hetAr 1 C1-C3 alkyl-, wherein hetAr 1is 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;

[0056] (h) (C3-C6 cycloalkyl) C1-C3 alkyl-, wherein the cycloalkyl group is optionally substituted with OH,

[0057] (i)(hetCyc a ) C1-C3 alkyl-,

[0058] (j)hetCyc a -,

[0059] (k) C3-C6 cycloalkyl-, wherein the cycloalkyl group is optionally substituted by OH,

[0060] (1) (C1-C4 alkyl) C(=O)O-C1-C6 alkyl-, wherein each of the C1-C4 alkyl and C1-C6 alkyl moieties is optionally and independently substituted with 1 to 3 fluorines, or

[0061] (m)(R 1 R 2 N) C(=O) C1-C6 alkyl-, wherein R 1 and R 2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluorines);

[0062] hetCyc a - is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, and optionally substituted by one or more substituents independently selected from the group consisting of OH, C1-C6 alkyl (optionally substituted with 1-3 fluorine), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl- and fluorine, or wherein hetCyc a substituted with an oxo group;

[0063] Ring D is (i) a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, (ii) a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, (iii) a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein each of said rings is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluorines, or C1-C3 alkoxy optionally substituted with 1-3 fluorines, (b) a C3-C6 cycloalkylene ring, or (c) oxo;

[0064] E is

[0065] (a) hydrogen,

[0066] (b) a C1-C6 alkyl group optionally substituted by 1 to 3 fluorine groups,

[0067] (c) (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted by 1 to 3 fluorine groups,

[0068] (d) (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with 1-3 fluorine atoms or with R g R h N-substituted, where R g and R h are independently H or C1-C6 alkyl,

[0069] (e) (hydroxy C2-C6 alkyl) C(=O)- optionally substituted by 1 to 3 fluorine groups,

[0070] (f)(C1-C6 alkoxy)C(=O)-,

[0071] (g) (C3-C6 cycloalkyl) C(=O)-, wherein the cycloalkyl is optionally substituted by one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH and (C1-C6 alkoxy)C1-C6 alkyl-, or the cycloalkyl is substituted by a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O,

[0072] (h)Ar 1 Cl-C6 alkyl-,

[0073] (i)Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxy C1-C6 alkyl-, C1-C6 alkoxy, R m R n N- or R m R n N-CH2-substituted, wherein each R m and R n are independently H or C1-C6 alkyl,

[0074] (j)hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines,

[0075] (k)hetAr 2 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted by OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy,

[0076] (1)hetAr 2 C(=O)-,

[0077] (m)hetCyc 1 C(=O)-,

[0078] (n)hetCyc 1 C1-C6 alkyl-,

[0079] (o)R 3 R 4 NC(=O)-,

[0080] (p)Ar 1 N(R 3 )C(=O)-,

[0081] (q)hetAr 2 N(R 3 )C(=O)-,

[0082] (r)(C1-C6 alkyl)SO2-, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups,

[0083] (s)Ar 1 SO2-,

[0084] (t)hetAr 2 SO2-,

[0085] (u) N-(C1-C6 alkyl)pyridinone group,

[0086] (v)Ar 1 C(=O)-;

[0087] (w)Ar 1 OC(=O)-,

[0088] (x)(C3-C6 cycloalkyl)(C1-C6 alkyl)C(=O)-,

[0089] (y)(C3-C6 cycloalkyl)(C1-C6 alkyl)SO2-, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups,

[0090] (z)Ar 1 (C1-C6 alkyl)SO2-,

[0091] (aa)hetCyc 1 -OC(=O)-,

[0092] (bb)hetCyc 1 CH2C(=O)-,

[0093] (cc)hetAr2 ,or

[0094] (dd) C3-C6 cycloalkyl;

[0095] Ar 1 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of: halogen; CN; C1-C6 alkyl (optionally substituted by 1-3 fluorine); C1-C6 alkoxy (optionally substituted by 1-3 fluorine); R e R f N-, where R e and R f are independently H or C1-C6 alkyl; (R p R q N) C1-C6 alkoxy-, wherein R p and R q are independently H or C1-C6 alkyl; and (hetAr a )C1-C6 alkyl-, wherein hetAr a is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar 1 is a benzene ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

[0096] hetAr 2 is 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 ring having 1-3 ring nitrogen atoms, wherein hetAr 2 Optionally substituted with one or more substituents independently selected from the group consisting of: halogen; CN; C1-C6 alkyl (optionally substituted with 1-3 fluorine); C1-C6 alkoxy (optionally substituted with 1-3 fluorine); (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluorine); R e R f N-, where R e and R f are independently H or C1-C6 alkyl; OH; (C1-C6 alkoxy) C1-C6 alkoxy- and C3-C6 cycloalkyl;

[0097] hetCyc 1 is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and halogen;

[0098] R 3 is H or C1-C6 alkyl; and

[0099] R4 It is a C1-C6 alkyl group.

[0100] For complex chemical names used herein, the substituent is named before the group to which it is attached. For example, methoxyethyl includes an ethyl backbone with a methoxy substituent.

[0101] The term "halogen" refers to -F (sometimes referred to herein as "fluoro" or "fluoros"), -Cl, -Br, and -I.

[0102] As used herein, the terms "C1-C3 alkyl," "C1-C6 alkyl," "C2-C6 alkyl," and "C3-C6 alkyl" refer to saturated, straight-chain or branched, monovalent hydrocarbon radicals having one to three, one to six, two to six, or three 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.

[0103] As used herein, the term "C1-C6 alkoxy" refers to a saturated linear or branched monovalent alkoxy group having one to six carbon atoms, wherein the radical is on the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy.

[0104] As used herein, the terms "(C1-C6 alkoxy)C1-C6 alkyl-" and "(C1-C6 alkoxy)C2-C6 alkyl-" refer to a saturated straight or branched monovalent group having one to six carbon atoms or two to six carbon atoms, respectively, wherein one carbon atom is substituted with a (C1-C6 alkoxy) group as defined herein. Examples include methoxymethyl (CH3OCH2-) and methoxyethyl (CH3OCH2CH2-).

[0105] As used herein, the terms "hydroxy C1-C6 alkyl-" and "hydroxy C2-C6 alkyl-" refer to a saturated straight or branched monovalent alkyl group having one to six or two to six carbon atoms, respectively, wherein one carbon atom is substituted with a hydroxy group.

[0106] As used herein, the term "dihydroxy C3-C6 alkyl-" refers to a saturated straight-chain or branched monovalent alkyl group having three to six carbon atoms, two of which are substituted with hydroxy groups.

[0107] As used herein, the term "(R 1 R 2 N) C1-C6 alkyl-" and "(R 1 R 2N) C2-C6 alkyl-" refers to a C1-C6 alkyl group or a C2-C6 group as defined herein, wherein one of the carbon atoms is replaced by R 1 R 2 N-substituted groups, where R 1 and R 2 As defined herein.

[0108] As used herein, the term "hetAr 1 C1-C6 alkyl-" means a C1-C6 alkyl group as defined herein in which one of the carbon atoms is replaced by hetAr 1 Group substitution, where hetAr 1 As defined herein.

[0109] The term "C3-C6 cycloalkyl" as used herein refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0110] The terms "(C3-C6 cycloalkyl)C1-C3 alkyl-" and "(C3-C6 cycloalkyl)C1-C6 alkyl-" as used herein refer to a C1-C3 alkyl group or a C1-C6 group, respectively, as defined herein, in which one carbon atom is substituted by a C3-C6 cycloalkyl ring as defined herein.

[0111] As used herein, the term "C3-C6 cycloalkylene ring" refers to a divalent carbon ring having three to six carbon atoms. The suffix "ylidine" refers to a divalent group derived from a saturated hydrocarbon by removing two hydrogen atoms from the same carbon atom.

[0112] As used herein, the term "(hetCyc a )C1-C3 alkyl-" refers to a C1-C3 alkyl group as defined herein in which one of the carbon atoms is replaced by hetCyc a Group substitution, where hetCyc a As defined herein.

[0113] As used herein, the term "Ar 1 C1-C6 alkyl-" means a C1-C6 alkyl group as defined herein, wherein one of the carbon atoms is replaced by Ar 1 Group substituted, where Ar 1 As defined herein.

[0114] As used herein, the term "hetAr 2 C1-C6 alkyl-" means a C1-C6 alkyl group as defined herein in which one of the carbon atoms is replaced by hetAr 2 Group substitution, where hetAr 2 As defined herein.

[0115] As used herein, the term "hetCyc 1 C1-C6 alkyl-" means a C1-C6 alkyl group as defined herein, wherein one of the carbon atoms is replaced by hetCyc 1 Group substitution, where hetCyc 1 As defined herein.

[0116] As used herein, the term "N-(C1-C6 alkyl)pyridonyl" refers to a pyridin-2(1H)-one ring in which the ring nitrogen atom is substituted with a C1-C6 alkyl substituent, and in which the bond may be to any ring carbon atom except the carbon bearing the oxo group. Examples include the following structures:

[0117]

[0118] As used herein, the term "heterospirocyclic" refers to a group having two rings connected by a spiro linkage through a carbon atom, wherein each ring has 4 to 6 ring atoms (one ring carbon atom is common to both rings), and wherein two of the ring atoms are nitrogen atoms.

[0119] As used herein, the term "oxo" or "oxo group" means an oxygen double-bonded to a carbon atom, i.e., =0. For example, in one embodiment, when referring to ring D, a saturated 6-membered heterocyclic ring having two ring nitrogen atoms can be, for example, a piperazinyl ring (e.g., a piperazinonyl ring) substituted with an oxo group, which can be represented by the following structure:

[0120]

[0121] As used herein, the term "compound" is intended to encompass all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Unless otherwise specified, a compound identified herein as one particular tautomeric form by name or structure is intended to encompass the other tautomeric forms.

[0122] As used herein, the term "tautomer" refers to a compound whose structure differs significantly in the arrangement of atoms but exists in easy and rapid equilibrium, and it is understood that the compounds provided herein can be depicted as different tautomers, and when a compound has tautomeric forms, all tautomeric forms are within the scope of the present invention, and the naming of the compound does not exclude any tautomer. Exemplary tautomerizations include, but are not limited to, keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different) enamine tautomerizations. A specific example of phenol-keto tautomerization is the interconversion of pyridin-2-ol and pyridin-2(1H)-one tautomers, for example:

[0123]

[0124] It will be appreciated that certain compounds provided herein may contain one or more asymmetric centers and, therefore, can be prepared and isolated as mixtures of isomers (eg, racemic mixtures) or in enantiomerically pure form.

[0125] In certain embodiments of Formula I, X 1 、X 2 、X 3 and X 4 In certain embodiments, X 1 、X 2 、X 3 and X 4 Each of them is CH.

[0126] In certain embodiments of Formula I, X 1 、X 2 、X 3 and X 4 are independently CH, CF or CCH3 or N, wherein X 1 、X 2 、X 3 and X 4 One of the is N, and the remaining are independently CH, CF, or CCH3. In certain embodiments of Formula I, X 1 is N, and X 2 、X 3 and X 4 In certain embodiments, X 1 is N, and X 2 、X 3 and X 4 In certain embodiments, X 1 It is N, X 2 is CF, and X 3 and X 4 It is CH.

[0127] In certain embodiments of Formula I, X 1 、X 2 、X 3 and X 4 are independently CH, CF or CCH3 or N, wherein X 1 、X 2 、X 3 and X 4 In certain embodiments of Formula I, X 1 and X 3 is N, and X 2 and X 4 are independently CH, CF or CCH3. In one embodiment, X 1 and X 3 is N, and X2 and X 4 In certain embodiments of Formula I, X 1 and X 2 is N, and X 1 and X 4 is independently CH or CF. In certain embodiments of Formula I, X 1 and X 2 is N, and X 1 and X 4 It is CH.

[0128] In certain embodiments of Formula I, A is H.

[0129] In certain embodiments of Formula I, A is Cl.

[0130] In certain embodiments of Formula I, A is CN.

[0131] In certain embodiments of Formula I, A is CH3-.

[0132] In certain embodiments of Formula I, A is CH3CH2-.

[0133] In certain embodiments of Formula I, A is cyclopropyl.

[0134] In certain embodiments of Formula I, A is -CH2CN.

[0135] In certain embodiments of Formula I, A is -CH(CN)CH3.

[0136] In certain embodiments of Formula I, B is hydrogen.

[0137] In certain embodiments of Formula I, B is C1-C6 alkyl optionally substituted with 1-3 fluorine groups. Non-limiting examples include methyl, ethyl, propyl, isopropyl, isobutyl, 2-methylbutyl, 2-ethylbutyl, 2,2-dimethylpropyl, difluoromethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0138] In certain embodiments of Formula I, B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoro or C3-C6 cycloalkylene rings. In certain embodiments of Formula I, B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is unsubstituted. Non-limiting examples include the following structures:

[0139]

[0140] In certain embodiments of Formula I, B is a dihydroxy C3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring. In certain embodiments of Formula I, B is a dihydroxy C3-C6 alkyl-. Non-limiting examples include 2,3-dihydroxypropyl.

[0141] In certain embodiments of Formula I, B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluorine groups. In certain embodiments of Formula I, B is (C1-C6 alkoxy)C2-C6 alkyl- optionally substituted with 1-3 fluorine groups. Non-limiting examples include the following structures:

[0142]

[0143] In certain embodiments of Formula I, B is (R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with OH, and R 1 and R 2 is independently H or C1-C6 alkyl (optionally substituted with 1-3 fluorine). In certain embodiments of Formula I, B is (R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with OH, and R 1 and R 2 is independently H or C2-C6 alkyl (optionally substituted with 1-3 fluorine). In certain embodiments of Formula I, B is (R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with OH, and R 1 and R 2 are independently selected from C1-C6 alkyl substituents. 1 R 2 N) C1-C6 alkyl-, non-limiting examples include the following structures

[0144]

[0145] In certain embodiments of Formula I, B is hetAr 1 C1-C3 alkyl-, wherein hetAr 1 is 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, hetAr 1 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O, and is optionally substituted with C1-C6 alkyl. 1 Non-limiting examples of C1-C3 alkyl- include the following structures:

[0146]

[0147] In certain embodiments of Formula I, B is (C3-C6 cycloalkyl)C1-C3 alkyl-, wherein the cycloalkyl is optionally substituted with OH. Non-limiting examples include the following structures:

[0148]

[0149] In certain embodiments of Formula I, B is (hetCyc a )C1-C3 alkyl-, wherein hetCyc a is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, and is optionally substituted by one or more substituents independently selected from the group consisting of OH, C1-C6 alkyl (optionally substituted with 1-3 fluorine), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl- and fluorine, or wherein hetCyc a is substituted with an oxo group. Non-limiting examples include the following structures:

[0150]

[0151] In certain embodiments of Formula I, B is hetCyc a , where hetCyc a is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, and is optionally substituted by one or more substituents independently selected from the group consisting of OH, C1-C6 alkyl (optionally substituted with 1-3 fluorine), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl- and fluorine, or wherein hetCyc a In certain embodiments, hetCyc a Optionally substituted with OH or C1-C6 alkyl (optionally substituted with 1-3 fluorine). Non-limiting examples include the following structures:

[0152]

[0153] In certain embodiments of Formula I, B is C3-C6 cycloalkyl-, wherein the cycloalkyl is optionally substituted with OH. Non-limiting examples are the following structures:

[0154]

[0155] In certain embodiments of Formula I, B is (C1-C4 alkyl)C(=O)O-C1-C6 alkyl- optionally substituted with 1-3 fluorines. Non-limiting examples are the following structures:

[0156]

[0157] In certain embodiments of Formula I, B is (R 1 R 2 N) C(=O) C1-C6 alkyl-, wherein R 1 and R 2 is independently H or C1-C6 alkyl (optionally substituted with 1-3 fluorines). Non-limiting examples include the following structures:

[0158]

[0159] In one embodiment of Formula I, Ring D is: (i) a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, (ii) a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, (iii) a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein each of said rings is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines), or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) oxo.

[0160] As used herein, when referring to ring D, the phrase "having two ring nitrogen atoms" means that the two ring nitrogen atoms of ring D are the two ring nitrogen atoms shown in Formula I, wherein one of the ring nitrogen atoms is bonded to a ring nitrogen atom comprising X 1 、X 2 、X 3 and X 4 and another ring nitrogen atom is bonded to the E group.

[0161] In one embodiment, Ring D is: (i) a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, (ii) a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, (iii) a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein each of the rings is unsubstituted.

[0162] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group. As used herein, when ring D is a saturated monocyclic 4-7 membered heterocyclic ring, the phrase "having two ring nitrogen atoms" means that the ring nitrogen atoms are the two nitrogen atoms shown in ring D of Formula I, i.e., ring D can be represented by the following structure:

[0163]

[0164] The wavy lines indicate the 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of the E group, wherein the ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluorines, or C1-C3 alkoxy optionally substituted with 1-3 fluorines, (b) a C3-C6 cycloalkylene ring, or (c) an oxo group. In one embodiment, the ring D is an unsubstituted saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, the ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms, wherein the ring is substituted with an oxo group. In one embodiment, the ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms, wherein the ring is substituted with a C3-C6 cycloalkylene ring. In one embodiment, the ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms, wherein the ring is substituted with a C3-C6 cyclopropylidene ring. In one embodiment, ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms, wherein the ring is substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine groups), or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine groups). In one embodiment, ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms, wherein the ring is substituted with C1-C3 alkyl optionally substituted with 1-3 fluorine groups. In one embodiment, ring D is a saturated 7-membered heterocyclic ring having two ring nitrogen atoms, wherein the ring is unsubstituted.

[0165] In one embodiment, when ring D is a saturated 6-7 membered heterocyclic ring having two ring nitrogen atoms, the ring D and E moieties of formula I, namely

[0166]

[0167] It can be represented by the following structure:

[0168]

[0169] The wavy lines indicate the 1 、X 2 、X 3 and X 4 wherein Ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (optionally substituted with 1-3 fluorine groups), or C1-C3 alkoxy (optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group. In one embodiment, Ring D is unsubstituted. In one embodiment, Ring D is substituted with an oxo group. In one embodiment, Ring D is substituted with a C3-C6 cyclopropylene ring. In one embodiment, Ring D is substituted with an oxo group. In one embodiment, Ring D is substituted with one to four groups independently selected from halogen, OH, C1-C3 alkyl (optionally substituted with 1-3 fluorine groups), or C1-C3 alkoxy (optionally substituted with 1-3 fluorine groups). In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms, wherein the ring is substituted with one to four C1-C3 alkyl groups optionally substituted with 1-3 fluorine groups. In one embodiment, ring D is unsubstituted, or is substituted with one to four independently selected C1-C3 alkyl groups (each of which is optionally substituted with one fluorine group), or is substituted with a C3-C6 cyclopropylene ring, or is substituted with an oxo group. In one embodiment, ring D is a saturated 7-membered heterocyclic ring having two ring nitrogen atoms, wherein the ring is unsubstituted. Examples of saturated 6- and 7-membered heterocyclic rings D include the following structures:

[0170]

[0171] In one embodiment, ring D is a saturated 4-7 membered heterocycle having two ring nitrogen atoms, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is as defined for Formula I. In one embodiment, ring D is a saturated 6-7 membered heterocycle having two ring nitrogen atoms. In one embodiment, ring D is a saturated 6 membered heterocycle having two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is substituted with an oxo group. In one embodiment, ring D is substituted with a cyclopropylene ring. In one embodiment, ring D is substituted with one or two C1-C3 alkyl groups, such as one or two methyl groups.

[0172] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines); (b) a C3-C6 cycloalkylene ring; or (c) an oxo group, and E is (a) hydrogen; (c) (C1-C6 alkoxy)C1-C6 alkoxy optionally substituted with 1-3 fluorines; (d) (C1-C6 alkyl) C (= O) - optionally substituted by 1-3 fluorine atoms; (e) (hydroxy C2-C6 alkyl) C (= O) - optionally substituted by 1-3 fluorine atoms; (f) (C1-C6 alkoxy) C (= O) -; (g) (C3-C6 cycloalkyl) C (= O) -, wherein the cycloalkyl group is optionally substituted by (C1-C6 alkoxy) C1-C6 alkyl - or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O; (h) Ar 1 C1-C6 alkyl-; (i) Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy; (j) hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups; (k) hetAr 2 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted by OH, hydroxy C1-C6 alkyl- or C1-C6 alkoxy; (1) hetAr 2 C(=O)-;(m)hetCyc 1 C(=O)-;(n)hetCyc 1 C1-C6 alkyl-; (o)R 3 R 4 NC(=O)-;or (cc)hetAr 2 , where Ar 1 、hetAr 2 、hetCyc 1 、R 3 and R 4is as defined for Formula I. In one embodiment, Ring D is a saturated 6-7 membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is a saturated 7-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is a saturated 6-7 membered heterocyclic ring, wherein Ring D is unsubstituted. In one embodiment, Ring D is a saturated 6-membered ring. In one embodiment, Ring D is substituted with an oxo group. In one embodiment, Ring D is substituted with a cyclopropylene ring. In one embodiment, Ring D is substituted with one or two C1-C3 alkyl groups, such as one or two methyl groups.

[0173] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hydrogen. In one embodiment, ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. Non-limiting examples are the following structures:

[0174]

[0175] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluorine groups. In one embodiment, ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. Non-limiting examples are the following structures:

[0176]

[0177] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (C1-C6 alkyl)C(=O)- optionally substituted with 1-3 fluorine groups. In one embodiment, ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. Non-limiting examples are the following structures:

[0178]

[0179] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (hydroxy C2-C6 alkyl) C(=O)- optionally substituted with 1-3 fluorine groups. In one embodiment, ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. Non-limiting examples are the following structures:

[0180]

[0181] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (C1-C6 alkoxy)C(=O)-. In one embodiment, ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. Non-limiting examples are the following structures:

[0182]

[0183] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (C3-C6 cycloalkyl)C(=O)-, wherein the cycloalkyl group is optionally substituted with (C1-C6 alkoxy)C1-C6 alkyl- or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O (e.g., pyridyl). In one embodiment, ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0184]

[0185] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein Ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is Ar 1 C1-C6 alkyl-, wherein Ar 1 As defined for Formula I. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. In one embodiment, Ring D is substituted with an oxo group. In one embodiment, Ar 1 Non-limiting examples include the following structures:

[0186]

[0187] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein Ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxy C1-C6 alkyl, C1-C6 alkoxy, R m R n N- or R m R n N-CH2-substituted, wherein each R m and R n are independently H or C1-C6 alkyl, and Ar 1 As defined for Formula I. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. In one embodiment, Ar 1 Unsubstituted or substituted with one or more halogens. Non-limiting examples include the following structures:

[0188]

[0189]

[0190] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein Ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines, and wherein hetAr 2 As defined for Formula I. In one embodiment, Ring D is a saturated 6-7 membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. In one embodiment, Ring D is substituted with a cyclopropylene ring. In one embodiment, hetAr 2 is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). 2 Is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms, and is optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted by 1-3 fluorine) and C1-C6 alkoxy (optionally substituted by 1-3 fluorine). Non-limiting examples include the following structures:

[0191]

[0192]

[0193] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein Ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxy C1-C6 alkyl or C1-C6 alkoxy, and wherein hetAr 2 As defined for Formula I. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. In one embodiment, hetAr 2 The alkyl portion of (C1-C6 alkyl)C(=O)- is unsubstituted. 2is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). 2 Is a 6-membered ring having 1-2 ring nitrogen atoms, and is optionally substituted with one or more halogens. Non-limiting examples include the following structures:

[0194]

[0195] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein Ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 C(=O)-, wherein hetAr 2 As defined for Formula I. In one embodiment, Ring D is a saturated 6-7 membered heterocyclic ring having two ring nitrogen atoms, wherein Ring D is unsubstituted. In one embodiment, Ring D is a saturated 7 membered heterocyclic ring having two ring nitrogen atoms, wherein Ring D is unsubstituted. In one embodiment, hetAr 2 is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). 2 Is a 6-membered ring having 1-2 ring nitrogen atoms and is optionally substituted with a C1-C6 alkoxy group. Non-limiting examples include the following structures:

[0196]

[0197] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetCyc 1 C(=O)-, where hetCyc 1As defined for Formula I. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. In one embodiment, hetCyc 1 Is a 4-6 membered saturated heterocyclic ring having one ring nitrogen atom, wherein the heterocyclic ring is optionally substituted with one or more independently selected C1-C6 alkoxy substituents. Non-limiting examples include the following structures:

[0198]

[0199] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetCyc 1 C1-C6 alkyl-, wherein hetCyc 1 As defined for Formula I. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. In one embodiment, hetCyc 1 is a 4-6 membered saturated heterocyclic ring having one ring oxygen atom. In one embodiment, hetCyc 1 Non-limiting examples include the following structures:

[0200]

[0201] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein Ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is R 3 R 4 NC(=O)-, where R 3 and R 4 As defined for Formula I. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the following structures:

[0202]

[0203] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein Ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 , where hetAr 2 As defined for Formula I. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms, wherein Ring D is unsubstituted. In one embodiment, hetAr 2 is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). 2 Is a 6-membered ring having 1-2 ring nitrogen atoms and is optionally substituted with a C1-C6 alkoxy group. Non-limiting examples include the following structures:

[0204]

[0205] In one embodiment of Formula I, Ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group. As used herein, when Ring D is a saturated 7-8 membered bridged heterocycle, the phrase "having two ring nitrogen atoms" means that the ring nitrogen atoms are the two nitrogen atoms shown in Ring D of Formula I, wherein one of the ring nitrogen atoms is bonded to a group comprising X 1 、X 2 、X 3 and X 4 wherein the ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally a third oxygen ring heteroatom, and the other ring nitrogen atom is bonded to an E group as shown in Formula I. Non-limiting examples include the following structures:

[0206]

[0207] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4The asterisk indicates the point of attachment to the ring of E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group. In one embodiment, ring D is unsubstituted.

[0208] In one embodiment, when Ring D is a saturated 7-9 membered bridged heterocyclic ring having 2-3 ring heteroatoms independently selected from N and O, the Ring D and E moieties of Formula I, ie

[0209]

[0210] It can be represented by the following non-limiting structure:

[0211]

[0212]

[0213] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group. In one embodiment, ring D is unsubstituted.

[0214] In one embodiment, Ring D is a saturated 7-membered bridged heterocyclic ring having two ring nitrogen atoms, which is represented by the following structure:

[0215]

[0216] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group. In one embodiment, ring D is unsubstituted.

[0217] In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is as defined for Formula I. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is unsubstituted.

[0218] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is selected from the group consisting of: (a) hydrogen; (b) C1-C6 alkyl; (c) (C1-C6 alkoxy)C1-C6 alkyl-; (d) (C1-C6 alkyl)C(═O)-; (e) (hydroxy C2-C6 alkyl)C(═O)-; (f) (C1-C6 alkoxy)C(═O)-; (g) (C3-C6 cycloalkyl)C(═O)-; (h) Ar 1 C1-C6 alkyl-; (i) Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxy C1-C6 alkyl or C1-C6 alkoxy; (j) hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups; (k) hetAr 2 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted by OH, hydroxy C1-C6 alkyl- or C1-C6 alkoxy; (1) hetAr 2 C(=O)-;(m)hetCyc 1 C(=O)-;(o)R 3 R 4 NC(=O)-;(p)Ar 1 R 3 NC(=O)-;(q)hetAr 2 N(R 3 )C(=O)-;(r)(C1-C6 alkyl)SO2-;(t)hetAr 2 SO2-. (u) N-(C1-C6 alkyl)pyridone; (v) Ar 1C(=O)-;(w)Ar 1 OC(=O)-; (x)(C3-C6 cycloalkyl)CH2C(=O)-; (y)(C3-C6 cycloalkyl)(C1-C6 alkyl)SO2-; (z)Ar 1 (C1-C6 alkyl)SO2-; (aa)hetCyc 1 -OC(=O)-;(bb)hetCyc 1 -CH2-C(=O)-; and (cc)hetAr 2 , where Ar 1 、hetAr 2 、R 3 and hetCyc 1 As defined for Formula I. In one embodiment, Ring D is selected from the following structures

[0219]

[0220] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E.

[0221] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms, which is represented by the following structure:

[0222]

[0223] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring, and E is selected from the group consisting of: (a) hydrogen; (b) C1-C6 alkyl; (c) (C1-C6 alkoxy) C1-C6 alkyl-; (d) (C1-C6 alkyl) C(=O)-; (e) (hydroxy C2-C6 alkyl) C(=O)-; (f) (C1-C6 alkoxy) C(=O)-; (g) (C3-C6 cycloalkyl) C(=O)-; (h) Ar 1 Cl-C6 alkyl-; (i) Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxy C1-C6 alkyl or C1-C6 alkoxy; (j) hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups; (k) hetAr 2(C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted by OH, hydroxy C1-C6 alkyl- or C1-C6 alkoxy; (l) hetAr 2 C(=O)-;(m)hetCyc 1 C(=O)-;(o)R 3 R 4 NC(=O)-;(p)Ar 1 N(R 3 )C(=O)-;(q)hetAr 2 N(R 3 )C(=O)-;(r)(C1-C6 alkyl)SO2-;(t)hetAr 2 SO2-; (u) N-(C1-C6 alkyl)pyridone; (v) Ar 1 C(=O)-;(w)Ar 1 OC(=O)-; (x)(C3-C6 cycloalkyl)CH2C(=O)-; (y)(C3-C6 cycloalkyl)(C1-C6 alkyl)SO2-; (z)Ar 1 (C1-C6 alkyl)SO2-; (aa)hetCyc 1 -OC(=O)-;(bb)hetCyc 1 -CH2-C(=O)-; and (cc)hetAr 2 , where Ar 1 、hetAr 2 、R 3 and hetCyc 1 As defined for Formula I. In one embodiment, Ring D is unsubstituted.

[0224] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is H. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is represented by the following structure:

[0225]

[0226] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0227]

[0228] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is a C1-C6 alkyl group optionally substituted with 1-3 fluorine groups. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is represented by the following structure:

[0229]

[0230] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0231]

[0232] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine groups), (b) C3-C6 cycloalkylene ring, or (c) oxo, and E is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluorine groups. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is represented by the following structure:

[0233]

[0234] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0235]

[0236] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (C1-C6 alkyl)C(=O)-, wherein the alkyl portion is optionally substituted with 1-3 fluorines or with R g R h N-substituted, where R g and R h is independently H or C1-C6 alkyl. In one embodiment, ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0237]

[0238] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0239]

[0240]

[0241] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) C3-C6 cycloalkylene ring, or (c) oxo, and E is (hydroxy C2-C6 alkyl) C(=O)- optionally substituted with 1-3 fluorines. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is represented by the following structure:

[0242]

[0243] The wavy line indicates the ring D and includes X 1 、X2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0244]

[0245] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) C3-C6 cycloalkylene ring, or (c) oxo, and E is (C1-C6 alkoxy)C(=O)-. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is represented by the following structure:

[0246]

[0247] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0248]

[0249] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine), or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) oxo, and E is (C3-C6 cycloalkyl)C(═O)-, wherein the cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy)C1-C6 alkyl-, or the cycloalkyl is substituted with a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O. In one embodiment, E is (C3-C6 cycloalkyl) C(=O)-, wherein the cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy) C1-C6 alkyl-. In one embodiment, ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0250]

[0251] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0252]

[0253] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is Ar 1 C1-C6 alkyl-, wherein Ar 1 As defined for Formula I. In one embodiment, E is Ar 1 C1-C6 alkyl-, wherein Ar 1 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of: halogen; C1-C6 alkyl (optionally substituted by 1-3 fluorine); C1-C6 alkoxy (optionally substituted by 1-3 fluorine); (Rp R q N) C1-C6 alkoxy-, wherein R p and R q are independently H or C1-C6 alkyl; and (hetAr a )C1-C6 alkyl-, wherein hetAr a is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0254]

[0255] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0256]

[0257] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxy C1-C6 alkyl, C1-C6 alkoxy, R m R n N- or R m R n N-CH2-substituted, wherein each R m and R a are independently H or C1-C6 alkyl, and Ar 1 As defined for Formula I. In one embodiment, Ar 1 is a phenyl group that is unsubstituted or substituted with one or more halogens. In one embodiment, ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0258]

[0259] The wavy line indicates the ring D and includes X 1 、X2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0260]

[0261] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines, and hetAr 2 As defined for Formula I. In one embodiment, hetAr 2 is 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 ring having 1-3 ring nitrogen atoms, wherein hetAr 2 Optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluorine), C1-C6 alkoxy (optionally substituted with 1-3 fluorine), OH, C3-C6 cycloalkyl and R e R f N-, where R e and R f is independently H or C1-C6 alkyl. In one embodiment, ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0262]

[0263] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0264]

[0265]

[0266]

[0267]

[0268] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr2(C1-C6 alkyl)C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy, and hetAr2(C1-C6 alkyl)C(=O)- 2 As defined for Formula I. In one embodiment, the alkyl moiety is unsubstituted. In one embodiment, hetAr 2 is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, and is optionally substituted with one or more halogens. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0269]

[0270] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples are the following structures:

[0271]

[0272] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 C(=O)-, wherein hetAr 2 As defined for Formula I. In one embodiment, hetAr 2is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms, and is optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkoxy (optionally substituted with 1-3 fluorine atoms), and (C1-C6 alkoxy)C1-C6 alkoxy-. In one embodiment, ring D is represented by the following structure:

[0273]

[0274] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0275]

[0276]

[0277]

[0278] In one embodiment of Formula I, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetCyc 1 C(=O)-, where hetCyc 1 As defined for Formula I. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, Ring D is represented by the following structure:

[0279]

[0280] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0281]

[0282]

[0283] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is R 3 R 4 NC(=O)-, where R 3 is H or C1-C6 alkyl, and R 4 is a C1-C6 alkyl group. In one embodiment, ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0284]

[0285] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0286]

[0287] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is Ar 1 N(R 3 )C(=O)-, wherein Ar 1 and R 3 As defined for Formula I. In one embodiment, Ar 1 Unsubstituted or substituted with C1-C6 alkoxy (optionally substituted with 1-3 fluorine groups). In one embodiment, ring D is unsubstituted. In one embodiment, ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0288]

[0289] The wavy line indicates the ring D and includes X 1 、X 2 、X3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0290]

[0291] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 N(R 3 )C(=O)-, wherein hetAr 2 and R 3 As defined for Formula I. In one embodiment, hetAr 2 Unsubstituted or substituted with C1-C6 alkoxy (optionally substituted with 1-3 fluorine). In one embodiment, ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0292]

[0293] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples are the following structures:

[0294]

[0295] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (C1-C6 alkyl)SO2-, wherein the alkyl portion is optionally substituted with 1-3 fluorines. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. In one embodiment, Ring D is represented by the following structure:

[0296]

[0297] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0298]

[0299] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 SO2-, of which hetAr 2 As defined for Formula I. In one embodiment, hetAr 2 Unsubstituted or substituted with C1-C6 alkoxy (optionally substituted with 1-3 fluorine). In one embodiment, ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0300]

[0301] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples are the following structures:

[0302]

[0303] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo, and E is N-(C1-C6 alkyl)pyridonyl. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is represented by the following structure:

[0304]

[0305] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0306]

[0307] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is Ar 1 C(=O)-, wherein Ar 1 As defined for Formula I. In one embodiment, Ar 1 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted by 1-3 fluorine) and C1-C6 alkoxy (optionally substituted by 1-3 fluorine), or Ar 1 is a benzene ring fused to a 5-6 membered heterocyclic ring having two ring oxygen atoms. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0308]

[0309] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0310]

[0311] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is Ar 1 OC(=O)-, where Ar 1 As defined for Formula I. In one embodiment, Ar 1 Unsubstituted. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0312]

[0313] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E. Non-limiting examples include the following structures:

[0314]

[0315] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (C3-C6 cycloalkyl)CH2C(=O)-, wherein the alkyl portion is optionally substituted with 1-3 fluorines. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is represented by the following structure:

[0316]

[0317] The wavy line indicates the ring D and includes X 1 、X 2 、X3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0318]

[0319] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (C3-C6 cycloalkyl)(C1-C3 alkyl)SO2-, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is represented by the following structure:

[0320]

[0321] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0322]

[0323] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is Ar 1 (C1-C6 alkyl)SO2-, wherein Ar 1 As defined for Formula I. In one embodiment, Ar 1 In one embodiment, ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure

[0324]

[0325] The wavy line indicates the ring D and includes X1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0326]

[0327] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetCyc 1 -OC(=O)-, where hetCyc 1 As defined for Formula I. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, Ring D is represented by the following structure:

[0328]

[0329] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0330]

[0331] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetCyc 1 -CH2-C(=O)-, wherein hetCyc 1 As defined for Formula I. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, Ring D is represented by the following structure:

[0332]

[0333] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0334]

[0335] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third oxygen ring heteroatom, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 , where hetAr 2 As defined for Formula I. In one embodiment, hetAr 2 Is a 6-membered ring having 1-2 ring nitrogen atoms, and is optionally substituted by a C1-C6 alkoxy group. In one embodiment, ring D is a saturated 7-8 membered bridged heterocycle having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure:

[0336]

[0337] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures:

[0338]

[0339] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo. As used herein, when ring D is a saturated 7-11 membered heterospiro ring, the phrase "having two ring nitrogen atoms" means that the ring nitrogen atoms are the two nitrogen atoms shown in ring D of Formula I, wherein one of the ring nitrogen atoms is bonded to a ring comprising X 1 、X 2 、X 3and X 4 and the other ring nitrogen atom is bonded to the E group as shown in Formula I. When ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, non-limiting examples include the following structures:

[0340]

[0341]

[0342] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E, wherein each of the rings is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group. In one embodiment, ring D is unsubstituted.

[0343] In one embodiment, when ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, the ring D and E moieties of formula I, namely

[0344]

[0345] It can be represented by the following non-limiting structure:

[0346]

[0347]

[0348] The wavy line indicates the ring D and the ring containing X 1 、X 2 、X 3 and X 4 wherein each of the rings is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is as defined for Formula I. In one embodiment, ring D is unsubstituted.

[0349] In one embodiment, ring D is represented by the following structure:

[0350]

[0351] The wavy line indicates the ring D and includes X 1 、X2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E, wherein D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo. In one embodiment, the ring D is unsubstituted.

[0352] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is selected from the group consisting of: (a) hydrogen; (b) C1-C6 alkyl optionally substituted with 1-3 fluorines; (d) (C1-C6 alkyl)C(=O)-, wherein the alkyl portion is optionally substituted with 1-3 fluorines or with R g R h N-substituted, where R g and R h are independently H or C1-C6 alkyl; (f)(C1-C6 alkoxy)C(=O)-; (1)hetAr 2 C(=O)-;(o)R 3 R 4 NC(=O)-;(s)Ar 1 SO2-;(t)hetAr 2 SO2-;(v)Ar 1 C(=O)-;(cc)hetAr 2 ; and (dd) C3-C6 cycloalkyl, wherein hetAr 2 、Ar 1 、R 3 and R 4 As defined for Formula I. In one embodiment, Ring D is unsubstituted.

[0353] In one embodiment, ring D is a saturated 9-membered heterospiro ring having two ring nitrogen atoms, which is represented by the following structure:

[0354]

[0355] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is selected from the group consisting of: (a) hydrogen, (d) (C1-C6 alkoxy)C(═O)-, and (o) R 3 R 4 NC(=O)-. In one embodiment, the ring D is unsubstituted

[0356] In one embodiment, in one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo, and E is hydrogen. In one embodiment, the ring D is represented by the following structure:

[0357]

[0358] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, the ring D is unsubstituted. Non-limiting examples include the following structures:

[0359]

[0360] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (b) a C1-C6 alkyl group optionally substituted with 1-3 fluorine groups. In one embodiment, ring D is represented by the following structure:

[0361]

[0362] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4The asterisk indicates the point of attachment to the ring of E. In one embodiment, the ring D is unsubstituted. Non-limiting examples include the following structures:

[0363]

[0364] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (C1-C6 alkyl)C(=O)-, wherein the alkyl portion is optionally substituted with 1-3 fluorine or with R g R h N-substituted, where R g and R h is independently H or C1-C6 alkyl. In one embodiment, the ring D is represented by the following structure:

[0365]

[0366] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, the ring D is unsubstituted. Non-limiting examples include the following structures:

[0367]

[0368] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is (C1-C6 alkoxy)C(=O)-. In one embodiment, ring D is represented by the following structure:

[0369]

[0370] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, the ring D is unsubstituted. Non-limiting examples include the following structures:

[0371]

[0372] In one embodiment, Ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 C(=O)-, wherein hetAr 2 As defined for Formula I. In one embodiment, hetAr 2 is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). 2 Is a 6-membered ring having 1-2 ring nitrogen atoms and is optionally substituted with a C1-C6 alkoxy group. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is represented by the following structure:

[0373]

[0374] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E. Non-limiting examples include the following structures:

[0375]

[0376] In one embodiment, Ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is R 3 R 4 NC(=O)-, where R 3 and R 4 As defined for Formula I. In one embodiment, R 3 is H, and R 4In one embodiment, the ring D is represented by the following structure:

[0377]

[0378] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, the ring D is unsubstituted. Non-limiting examples include the following structures:

[0379]

[0380] In one embodiment, Ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is Ar 1 SO2-, of which Ar 1 As defined for Formula I. In one embodiment, Ar 1 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted by 1-3 fluorine) and C1-C6 alkoxy (optionally substituted by 1-3 fluorine). In one embodiment, the ring D is unsubstituted. In one embodiment, the ring D is represented by the following structure

[0381]

[0382] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E. Non-limiting examples include the following structures:

[0383]

[0384] In one embodiment, Ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 SO2-, of which hetAr2 As defined for Formula I. In one embodiment, hetAr 2 is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). 2 Is a 6-membered ring having 1-2 ring nitrogen atoms, and is optionally substituted with a C1-C6 alkoxy group. In one embodiment, the ring D is unsubstituted. In one embodiment, the ring D is represented by the following structure:

[0385]

[0386] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E. Non-limiting examples include the following structures:

[0387]

[0388] In one embodiment, Ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is Ar 1 C(=O)-, wherein Ar 1 As defined for Formula I. In one embodiment, Ar 1 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted by 1-3 fluorine) and C1-C6 alkoxy (optionally substituted by 1-3 fluorine). In one embodiment, the ring D is unsubstituted. In one embodiment, the ring D is represented by the following structure:

[0389]

[0390] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E. Non-limiting examples include the following structures:

[0391]

[0392] In one embodiment, Ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hetAr 2 , where hetAr 2 As defined for Formula I. In one embodiment, hetAr 2 is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). 2 Is a 6-membered ring having 1-2 ring nitrogen atoms, and is optionally substituted with a C1-C6 alkoxy group. In one embodiment, the ring D is unsubstituted. In one embodiment, the ring D is represented by the following structure:

[0393]

[0394] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E. Non-limiting examples include the following structures:

[0395]

[0396] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine groups) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine groups), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is a C3-C6 cycloalkyl group. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is represented by the following structure:

[0397]

[0398] The wavy line indicates the ring D and includes X 1 、X 2 、X3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E. Non-limiting examples include the following structures:

[0399]

[0400] In one embodiment, ring D is a saturated 9-10 membered bicyclic fused heterocycle having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group. As used herein, when ring D is a saturated 9-10 membered bicyclic fused heterocycle, the phrase "having two ring nitrogen atoms" means that the ring nitrogen atoms are the two nitrogen atoms shown in ring D of Formula I, wherein one of the ring nitrogen atoms is bonded to a group comprising X 1 、X 2 、X 3 and X 4 The ring D is a ring having a ring nitrogen atom bonded to an E group as shown in Formula I. The fused ring includes 5,5,5,6,6,5 and 6,6 fused ring systems. In one embodiment, the ring D is represented by the following structure:

[0401]

[0402] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E, wherein the ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluorines, or C1-C3 alkoxy optionally substituted with 1-3 fluorines, (b) C3-C6 cycloalkylene ring, or (c) oxo. In one embodiment, the ring D is unsubstituted.

[0403] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused heterocycle having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluorine groups, or C1-C3 alkoxy optionally substituted with 1-3 fluorine groups, (b) a C3-C6 cycloalkylene ring, or (c) oxo, and E is as defined for Formula I.

[0404] In one embodiment, ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluorine groups, or C1-C3 alkoxy optionally substituted with 1-3 fluorine groups, (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hydrogen or (C1-C6 alkoxy)C(=O)-. In one embodiment, ring D is represented by the following structure:

[0405]

[0406] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted.

[0407] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluorine groups, or C1-C3 alkoxy optionally substituted with 1-3 fluorine groups, (b) a C3-C6 cycloalkylene ring, or (c) an oxo group, and E is hydrogen. In one embodiment, Ring D is represented by the following structure:

[0408]

[0409] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, ring D is unsubstituted. Non-limiting examples are the following structures:

[0410]

[0411] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein the ring is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluorine groups, or C1-C3 alkoxy optionally substituted with 1-3 fluorine groups, (b) a C3-C6 cycloalkylene ring, or (c) oxo, and E is (C1-C6 alkoxy)C(═O)—.

[0412] In one embodiment, ring D is represented by the following structure:

[0413]

[0414] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E. In one embodiment, the ring D is unsubstituted. Non-limiting examples are the following structures:

[0415]

[0416] In one embodiment, Formula I comprises a compound of Formula IA, wherein:

[0417] X 1 、X 2 、X 3 and X 4 are independently CH, CF or N, wherein X 1 、X 2 、X 3 and X 4 Zero, one, or two of them are N;

[0418] A is H, CN, Cl, CH3-, CH3CH2-, cyclopropyl, -CH2CN or -CH(CN)CH3;

[0419] B is

[0420] (a) hydrogen,

[0421] (b) a C1-C6 alkyl group optionally substituted by 1 to 3 fluorine groups,

[0422] (c) hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoro or C3-C6 cycloalkylene rings,

[0423] (d) dihydroxy C3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring,

[0424] (e) (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted by 1 to 3 fluorine groups,

[0425] (f)(R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with OH, and wherein R 1 and R 2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluorines);

[0426] (g)hetAr 1 C1-C3 alkyl-, wherein hetAr1 is 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;

[0427] (h) (C3-C6 cycloalkyl) C1-C3 alkyl-, wherein the cycloalkyl group is optionally substituted with OH,

[0428] (i)(hetCyc a ) C1-C3 alkyl-,

[0429] (j)hetCyc a -,

[0430] (k) C3-C6 cycloalkyl-, wherein the cycloalkyl group is optionally substituted by OH,

[0431] (l) (C1-C4 alkyl) C(=O)O-C1-C6 alkyl-, wherein each of the C1-C4 alkyl and C1-C6 alkyl moieties is optionally and independently substituted with 1 to 3 fluorines, or

[0432] (m)(R 1 R 2 N) C(=O) C1-C6 alkyl-, wherein R 1 and R 2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluorines);

[0433] hetCyc a - is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, and optionally substituted by one or more substituents independently selected from the group consisting of OH, C1-C6 alkyl (optionally substituted with 1-3 fluorine), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl- and fluorine, or wherein hetCyc a substituted with an oxo group;

[0434] Ring D is

[0435]

[0436] The wavy lines indicate the 1 、X 2 、X 3 and X 4The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to the E group, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluorines, or C1-C3 alkoxy optionally substituted with 1-3 fluorines, (b) a C3-C6 cycloalkylene ring, or (c) an oxo group;

[0437] E is

[0438] (a) hydrogen,

[0439] (c) (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted by 1 to 3 fluorine groups,

[0440] (d) (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with 1-3 fluorine atoms or with R g R h N-substituted, where R g and R h are independently H or C1-C6 alkyl,

[0441] (e) (hydroxy C2-C6 alkyl) C(=O)- optionally substituted by 1 to 3 fluorine groups,

[0442] (f)(C1-C6 alkoxy)C(=O)-,

[0443] (g) (C3-C6 cycloalkyl) C(=O)-, wherein the cycloalkyl is optionally substituted by one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH and (C1-C6 alkoxy)C1-C6 alkyl-, or the cycloalkyl is substituted by a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O,

[0444] (h)Ar 1 C1-C6 alkyl-,

[0445] (i)Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxy C1-C6 alkyl-, C1-C6 alkoxy, R m R n N- or R m R n N-CH2-substituted, wherein each R m and R n are independently H or C1-C6 alkyl,

[0446] (j)hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines,

[0447] (k)hetAr 2 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted by OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy,

[0448] (l)hetAr 2 C(=O)-,

[0449] (m)hetCyc 1 C(=O)-,

[0450] (n)hetCyc 1 C1-C6 alkyl-,

[0451] (o)R 3 R 4 NC(=O)-, or

[0452] (cc)hetAr 2 ;

[0453] Ar 1 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of: halogen; CN; C1-C6 alkyl (optionally substituted by 1-3 fluorine); C1-C6 alkoxy (optionally substituted by 1-3 fluorine); R e R f N-, where R e and R f are independently H or C1-C6 alkyl; (R p R q N) C1-C6 alkoxy-, wherein R p and R q are independently H or C1-C6 alkyl; and (hetAr a )C1-C6 alkyl-, wherein hetAr a is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar 1 is a benzene ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

[0454] hetAr 2 is 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 ring having 1-3 ring nitrogen atoms, wherein hetAr 2 Optionally substituted with one or more substituents independently selected from the group consisting of: halogen; CN; C1-C6 alkyl (optionally substituted with 1-3 fluorine); C1-C6 alkoxy (optionally substituted with 1-3 fluorine); (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluorine); Re R f N-, where R e and R f are independently H or C1-C6 alkyl; OH; (C1-C6 alkoxy) C1-C6 alkoxy- and C3-C6 cycloalkyl;

[0455] hetCyc 1 is 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 halogen; and

[0456] R 4 It is a C1-C6 alkyl group.

[0457] In one embodiment of Formula IA, Ring D is unsubstituted.

[0458] In one embodiment of Formula IA, X 1 It is N; X 2 、X 3 and X 4 It is CH.

[0459] In one embodiment of Formula IA, A is CN.

[0460] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 is CH; and A is CN.

[0461] In one embodiment of Formula IA, B is C1-C6 alkyl optionally substituted with 1-3 fluorine groups.

[0462] In one embodiment of Formula IA, B is (C1-C6 alkoxy)C1-C6 alkyl-, optionally substituted with 1-3 fluorines, or hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring.

[0463] In one embodiment of Formula IA, B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluorines. In one embodiment of Formula IA, B is (C1-C6 alkoxy)C2-C6 alkyl- optionally substituted with 1-3 fluorines.

[0464] In one embodiment of Formula IA, B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring. In one embodiment, the alkyl portion is unsubstituted.

[0465] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 is CH; A is CN; and B is (C1-C6 alkoxy)C1-C6 alkyl-, optionally substituted by 1-3 fluorines, or hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted by a C3-C6 cycloalkylene ring.

[0466] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 A is CN; and B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted by 1-3 fluorines. In one embodiment, B is (C1-C6 alkoxy) C2-C6 alkyl- optionally substituted by 1-3 fluorines.

[0467] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 A is CN; and B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring. In one embodiment, the alkyl portion of the B group is unsubstituted.

[0468] In one embodiment of Formula IA, E is Ar 1 C1-C6 alkyl-; hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines; or Ar 1 (C1-C6 alkyl) C(=O)-, wherein Ar 1 and hetAr 2 As defined for Formula IA.

[0469] In one embodiment of Formula IA, E is Ar 1 C1-C6 alkyl-; hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines; or Ar 1 (C1-C6 alkyl) C(=O)-, wherein Ar 1 is an unsubstituted phenyl group, and hetAr 2is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms 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 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). In one embodiment of Formula IA, hetAr 2 is a 6-membered heterocyclic ring having 1-2 ring nitrogen atoms, and is optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted by 1-3 fluorine) and C1-C6 alkoxy (optionally substituted by 1-3 fluorine).

[0470] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl-, or hydroxy C2-C6 alkyl-, optionally substituted with 1-3 fluorine atoms, wherein the alkyl moiety is optionally substituted with a C3-C6 cycloalkylene ring; and E is Ar 1 C1-C6 alkyl-, hetAr 2 C1-C6 alkyl- (wherein the alkyl portion is optionally substituted with 1-3 fluorine) or Ar 1 (C1-C6 alkyl)C(=O)-(wherein Ar 1 and hetAr 2 As defined for Formula IA).

[0471] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine atoms; and E is Ar 1 C1-C6 alkyl-, hetAr 2 C1-C6 alkyl- (wherein the alkyl portion is optionally substituted with 1-3 fluorine) or Ar 1 (C1-C6 alkyl)C(=O)-(wherein Ar 1 and hetAr 2 As defined for Formula IA).

[0472] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine atoms; and E is Ar1 C1-C6 alkyl-, wherein Ar 1 As defined for Formula IA.

[0473] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine atoms; and E is hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines, and hetAr 2 As defined for Formula IA.

[0474] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine atoms; or E is Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted by OH, hydroxy C1-C6 alkyl- or C1-C6 alkoxy, and Ar 1 As defined for Formula IA.

[0475] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; and E is Ar 1 C1-C6 alkyl-, hetAr 2 C1-C6 alkyl- (wherein the alkyl portion is optionally substituted with 1-3 fluorine) or Ar 1 (C1-C6 alkyl)C(=O)-(wherein Ar 1 and hetAr 2 As defined for Formula IA). In one embodiment, the alkyl portion of the B group is unsubstituted.

[0476] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; and E is Ar 1 C1-C6 alkyl-, wherein Ar 1 As defined for Formula IA. In one embodiment, the alkyl portion of the B group is unsubstituted.

[0477] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; and E is hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines, and hetAr 2 As defined for Formula IA. In one embodiment, the alkyl portion of the B group is unsubstituted.

[0478] In one embodiment of Formula IA, Ring D is unsubstituted; X 1 It is N; X 2 、X 3 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; and E is Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted by OH, hydroxy C1-C6 alkyl- or C1-C6 alkoxy, and Ar 1 As defined for Formula IA. In one embodiment, Ar 1 In one embodiment, B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is unsubstituted.

[0479] In one embodiment of Formula IA, Ring D is unsubstituted; X 2 It is N; X 1 、X 3 and X 4 is CH; A is CN; B is C1-C6 alkyl optionally substituted by 1-3 fluorine, (C1-C6 alkoxy) C1-C6 alkyl optionally substituted by 1-3 fluorine-or (hetCyc a ) C1-C3 alkyl-; and E is Ar 1 C1-C6 alkyl- or Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted by OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy, and hetCyc a and Ar1 As defined for Formula IA.

[0480] In one embodiment of Formula IA, Ring D is unsubstituted; X 2 It is N; X 1 、X 3 and X 4 is CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluorines; and E is Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted by OH, hydroxy C1-C6 alkyl- or C1-C6 alkoxy, and Ar 1 As defined for Formula IA.

[0481] In one embodiment of Formula IA, Ring D is unsubstituted; X 2 It is N; X 1 、X 3 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine atoms; and E is Ar 1 C1-C6 alkyl-, wherein Ar 1 As defined for Formula IA.

[0482] In one embodiment of Formula IA, Ring D is unsubstituted; X 2 It is N; X 1 、X 3 and X 4 is CH; A is CN; B is (hetCyc a ) C1-C3 alkyl-; and E is Ar 1 C1-C6 alkyl-, and hetCyc a and Ar 1 As defined for Formula IA.

[0483] In one embodiment, Formula I comprises a compound of Formula IB, wherein:

[0484] X 1 、X 2 、X 3 and X 4 are independently CH, CF or N, wherein X 1 、X 2 、X 3 and X 4 Zero, one, or two of them are N;

[0485] A is H, CN, Cl, CH3-, CH3CH2-, cyclopropyl, -CH2CN or -CH(CN)CH3;

[0486] B is

[0487] (a) hydrogen,

[0488] (b) a C1-C6 alkyl group optionally substituted by 1 to 3 fluorine groups,

[0489] (c) hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoro or C3-C6 cycloalkylene rings,

[0490] (d) dihydroxy C3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring,

[0491] (e) (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted by 1 to 3 fluorine groups,

[0492] (f)(R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with OH, and wherein R 1 and R 2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluorines);

[0493] (g)hetAr 1 C1-C3 alkyl-, wherein hetAr 1 is 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;

[0494] (h) (C3-C6 cycloalkyl) C1-C3 alkyl-, wherein the cycloalkyl group is optionally substituted with OH,

[0495] (i)(hetCyc a ) C1-C3 alkyl-,

[0496] (j)hetCyc a -,

[0497] (k) C3-C6 cycloalkyl-, wherein the cycloalkyl group is optionally substituted by OH,

[0498] (l) (C1-C4 alkyl) C(=O)O-C1-C6 alkyl-, wherein each of the C1-C4 alkyl and C1-C6 alkyl moieties is optionally and independently substituted with 1 to 3 fluorines, or

[0499] (m)(R 1 R 2 N) C(=O) C1-C6 alkyl-, wherein R 1 and R 2are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluorines);

[0500] hetCyc a - is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, and optionally substituted by one or more substituents independently selected from the group consisting of OH, C1-C6 alkyl (optionally substituted with 1-3 fluorine), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl- and fluorine, or wherein hetCyc a substituted with an oxo group;

[0501] Ring D is

[0502]

[0503] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group;

[0504] E is

[0505] (a) hydrogen,

[0506] (b) a C1-C6 alkyl group,

[0507] (c) (C1-C6 alkoxy) C1-C6 alkyl-,

[0508] (d) (C1-C6 alkyl) C(=O)-,

[0509] (e) (hydroxy C2-C6 alkyl) C(=O)-,

[0510] (f)(C1-C6 alkoxy)C(=O)-,

[0511] (g)(C3-C6 cycloalkyl)C(=O)-,

[0512] (h)Ar 1 C1-C6 alkyl-,

[0513] (i)Ar 1 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxy C1-C6 alkyl-, C1-C6 alkoxy, Rm R n N- or R m R n N-CH2-substituted, wherein each R m and R n are independently H or C1-C6 alkyl,

[0514] (j)hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines,

[0515] (k)hetAr 2 (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted by OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy,

[0516] (1)hetAr 2 C(=O)-,

[0517] (m)hetCyc 1 C(=O)-,

[0518] (o)R 3 R 4 NC(=O)-,

[0519] (p)Ar 1 R 3 NC(=O)-,

[0520] (q)hetAr 2 N(R 3 )C(=O)-,

[0521] (r)(C1-C6 alkyl)SO2-, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups,

[0522] (t)hetAr 2 SO2-,

[0523] (u) N-(C1-C6 alkyl)pyridinone group,

[0524] (v)Ar 1 C(=O)-,

[0525] (w)Ar 1 OC(=O)-,

[0526] (x)(C3-C6 cycloalkyl)CH2C(=O)-,

[0527] (y)(C3-C6 cycloalkyl)(C1-C6 alkyl)SO2-,

[0528] (z)Ar1 (C1-C6 alkyl)SO2-,

[0529] (aa)hetCyc 1 -OC(=O)-,

[0530] (bb)hetCyc 1 -CH2-C(=O)-, or

[0531] (cc)hetAr 2 ;

[0532] Ar 1 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of: halogen; CN; C1-C6 alkyl (optionally substituted by 1-3 fluorine); C1-C6 alkoxy (optionally substituted by 1-3 fluorine); R e R f N-, where R e and R f are independently H or C1-C6 alkyl; (R p R q N) C1-C6 alkoxy-, wherein R p and R q are independently H or C1-C6 alkyl; and (hetAr a )C1-C6 alkyl-, wherein hetAr a is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar 1 is a benzene ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

[0533] hetAr 2 is 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 ring having 1-3 ring nitrogen atoms, wherein hetAr 2 Optionally substituted with one or more substituents independently selected from the group consisting of: halogen; CN; C1-C6 alkyl (optionally substituted with 1-3 fluorine); C1-C6 alkoxy (optionally substituted with 1-3 fluorine); (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluorine); R e R f N-, where R e and R f are independently H or C1-C6 alkyl; OH; (C1-C6 alkoxy) C1-C6 alkoxy- and C3-C6 cycloalkyl;

[0534] hetCyc 1is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and halogen;

[0535] R 3 is H or C1-C6 alkyl; and

[0536] R 4 It is a C1-C6 alkyl group.

[0537] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 It is CH.

[0538] In one embodiment of Formula IB, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0539] In one embodiment of Formula IB, A is CN.

[0540] In one embodiment of Formula IB, Ring D is

[0541]

[0542] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) a C3-C6 cycloalkylene ring, or (c) oxo.

[0543] In one embodiment of Formula IB, Ring D is

[0544]

[0545] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E, wherein ring D is unsubstituted.

[0546] In one embodiment of Formula IB, B is: C1-C6 alkyl optionally substituted with 1-3 fluorines; (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluorines; hydroxy C2-C6 alkyl, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; hetAr 1 C1-C3 alkyl-; or (hetCyc a )C1-C3 alkyl-; wherein hetAr 1 and hetCyc a As defined for Formula IB.

[0547] In one embodiment of Formula IB, B is C1-C6 alkyl optionally substituted with 1-3 fluorine. In one embodiment of Formula IB, B is C1-C6 alkyl.

[0548] In one embodiment of Formula IB, B is (C1-C6 alkoxy)C1-C6 alkyl-, optionally substituted with 1-3 fluorines, or hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring.

[0549] In one embodiment of Formula IB, B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluorines. In one embodiment of Formula IB, B is (C1-C6 alkoxy)C2-C6 alkyl- optionally substituted with 1-3 fluorines.

[0550] In one embodiment of Formula IB, B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring. In one embodiment, the alkyl portion of the B group is unsubstituted.

[0551] In one embodiment of Formula IB, B is hetAr 1 C1-C3 alkyl-, wherein hetAr 1 As defined for Formula IB.

[0552] In one embodiment of Formula IB, B is (hetCyc a )C1-C3 alkyl-; wherein hetCyc a As defined for Formula IB.

[0553] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4is CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluorine. In one embodiment of Formula IB, B is C1-C6 alkyl.

[0554] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; and B is (C1-C6 alkoxy) C1-C6 alkyl-, or hydroxy C2-C6 alkyl-, optionally substituted with 1-3 fluorine atoms, wherein the alkyl moiety is optionally substituted with a C3-C6 cycloalkylene ring. In one embodiment, X 1 It is N; X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0555] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; and B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine atoms. In one embodiment, X 1 It is N; X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0556] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4is CH; A is CN; and B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring. In one embodiment, the alkyl portion of the B group is unsubstituted. In one embodiment, X 1 It is N; X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0557] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; and B is hetAr 1 C1-C3 alkyl-, wherein hetAr 1 As defined for Formula IB. In one embodiment, X 1 It is N; X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH

[0558] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; and B is (hetCyc a )C1-C3 alkyl-; wherein hetCyc a As defined for Formula IB. In one embodiment, X 1 It is N; X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0559] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluorine groups; and ring D is

[0560]

[0561] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo. In one embodiment of Formula IB, ring D is unsubstituted. In one embodiment, X 1 It is N; X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0562] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; and B is (C1-C6 alkoxy) C1-C6 alkyl-, or hydroxy C2-C6 alkyl-, optionally substituted with 1-3 fluorine atoms, wherein the alkyl moiety is optionally substituted with a C3-C6 cycloalkylene ring; and ring D is

[0563]

[0564] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4The asterisk indicates the point of attachment to the ring of E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo. In one embodiment of Formula IB, ring D is unsubstituted. In one embodiment, X 1 It is N; X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0565] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; B is hydroxyC2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; and ring D is

[0566]

[0567] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0568] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4is CH; A is CN; B is hetAr 1 C1-C3 alkyl-, wherein hetAr 1 As defined for Formula IB; and Ring D is

[0569]

[0570] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo. In one embodiment of Formula IB, ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0571] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is (hetCyc a )C1-C3 alkyl-; wherein hetCyc a As defined for Formula IB; and Ring D is

[0572]

[0573] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4The asterisk indicates the point of attachment to the ring of E, wherein ring D is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo. In one embodiment of Formula IB, ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0574] In one embodiment of Formula IB, E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups, hetAr 2 C(=O)-,Ar 1 R 3 NC(=O)-, or (C1-C6 alkyl)SO2-, wherein hetAr 2 、Ar 1 and R 3 As defined for Formula IB. In one embodiment, hetAr 2 is a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O, and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine).

[0575] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluorine groups; Ring D is

[0576] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups, hetAr 2 C(=O)-,Ar 1 R 3 NC(=O)- or (C1-C6 alkyl)SO2-, wherein hetAr 2 、Ar 1 and R 3 As defined for Formula IB. In one embodiment of Formula IB, Ring D is unsubstituted. In one embodiment, X 1 It is N; X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0577] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluorine groups; Ring D is

[0578] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorine. In one embodiment of Formula IB, the ring D is unsubstituted. In one embodiment, X 1It is N; X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0579] In one embodiment of Formula IB, X1 is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluorine groups; Ring D is

[0580] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C(=O)-, wherein hetAr 2 As defined for Formula IB. In one embodiment of Formula IB, Ring D is unsubstituted. In one embodiment, X 1 It is N; X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0581] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluorine groups; Ring D is

[0582] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is Ar 1 R 3 NC(=O)-, where Ar 1 As defined for Formula IB. In one embodiment of Formula IB, Ring D is unsubstituted. In one embodiment, X 1 It is N; X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0583] In one embodiment of Formula IB, X 1 It is N; X 2 、X 3 and X 4 is CH, or X 1 and X 3 is N; and X 2 and X 4 is CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluorine groups; Ring D is

[0584] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo; and E is (C1-C6 alkyl)SO2-. In one embodiment of Formula IB, the ring D is unsubstituted. In one embodiment, X 1 It is N; X 2 、X 3 and X 4 In one embodiment, X1 and X 3 is N; and X 2 and X 4 It is CH.

[0585] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl-, or hydroxy C2-C6 alkyl-, optionally substituted by 1-3 fluorine groups, wherein the alkyl portion is optionally substituted by a C3-C6 cycloalkylene ring; Ring D is

[0586]

[0587] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups, hetAr 2 C(=O)-,Ar 1 R 3 NC(=O)- or (C1-C6 alkyl)SO2-, wherein hetAr 2 、Ar 1 and R 3 As defined for Formula IB. In one embodiment, Ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0588] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine groups; Ring D is

[0589]

[0590] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups, hetAr 2 C(=O)-,Ar 1 R 3 NC(=O)- or (C1-C6 alkyl)SO2-, wherein hetAr 2 、Ar 1 and R 3 As defined for Formula IB. In one embodiment, the ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0591] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; Ring D is

[0592]

[0593] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups, hetAr 2 C(=O)-,Ar 1 R 3 NC(=O)- or (C1-C6 alkyl)SO2-, wherein hetAr 2 、Ar 1 and R 3 As defined for Formula IB. In one embodiment, the ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0594] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hetAr 1 C1-C3 alkyl-, wherein hetAr 1 As defined for Formula IB; Ring D is

[0595]

[0596] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups, hetAr 2 C(=O)-,Ar 1 R 3 NC(=O)- or (C1-C6 alkyl)SO2-, wherein hetAr 2 、Ar 1 and R 3 As defined for Formula IB. In one embodiment, the ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0597] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is (hetCyc a )C1-C3 alkyl-, wherein hetCyc a As defined for Formula IB; Ring D is

[0598]

[0599] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups, hetAr 2 C(=O)-,Ar 1 R 3 NC(=O)- or (C1-C6 alkyl)SO2-, wherein hetAr 2 、Ar 1 and R 3 As defined for Formula IB. In one embodiment, the ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0600] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; Ring D is

[0601]

[0602] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorines, and hetAr 2 As defined for Formula IB. In one embodiment, the ring D is unsubstituted. In one embodiment, hetAr 2is 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 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0603] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; Ring D is

[0604]

[0605] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C(=O)-, wherein hetAr 2 As defined for Formula IB. In one embodiment, the ring D is unsubstituted. In one embodiment, hetAr 2 is 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 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). In one embodiment, X 1 is N; and X 2 、X 3 and X 4In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0606] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; Ring D is

[0607]

[0608] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is Ar 1 R 3 NC(=O)-, where Ar 1 and R 3 As defined for Formula IB. In one embodiment, Ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0609] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; Ring D is

[0610]

[0611] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo; and E is (C1-C6 alkyl)SO2-. In one embodiment, the ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0612] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine groups; Ring D is

[0613]

[0614] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorine groups, hetAr 2 C(=O)-,Ar 1 R 3 NC(=O)- or (C1-C6 alkyl)SO2-, wherein hetAr 2 、Ar 1 and R 3 As defined for Formula IB. In one embodiment, the ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0615] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine groups; Ring D is

[0616]

[0617] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorines, and hetAr 2 As defined for Formula IB. In one embodiment, the ring D is unsubstituted. In one embodiment, hetAr 2is 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 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0618] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine groups; Ring D is

[0619]

[0620] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C(=O)-, wherein hetAr 2 As defined for Formula IB. In one embodiment, the ring D is unsubstituted. In one embodiment, hetAr 2 is 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 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). In one embodiment, X 1 is N; and X 2 、X 3 and X 4In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0621] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine groups; Ring D is

[0622]

[0623] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is Ar 1 R 3 NC(=O)-, where Ar 1 and R 3 As defined for Formula IB. In one embodiment, Ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0624] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4is CH; A is CN; B is (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted with 1-3 fluorine groups; Ring D is

[0625]

[0626] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo; and E is (C1-C6 alkyl)SO2-. In one embodiment, ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0627] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-; ring D is

[0628]

[0629] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 and the asterisk indicates the point of attachment to E; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorines; or hetAr 2 C(=O), wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen and C1-C6 alkoxy (optionally substituted with 1-3 fluorine), and hetAr 2As defined for Formula IB. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0630] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-; ring D is

[0631]

[0632] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 and the asterisk indicates the point of attachment to E; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorine, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen and C1-C6 alkoxy (optionally substituted with 1-3 fluorine), and hetAr 2 As defined for Formula IB. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0633] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-; ring D is

[0634]

[0635] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 and the asterisk indicates the point of attachment to E; and E is hetAr 2 C(=O), wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen and C1-C6 alkoxy (optionally substituted with 1-3 fluorine), and hetAr 2 As defined for Formula IB. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0636] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; Ring D is

[0637]

[0638] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 and the asterisk indicates the point of attachment to E; and E is Ar 1 N(R 3 )C(=O), and Ar 1 and R 3 As defined for Formula IB. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X2 and X 4 It is CH.

[0639] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; Ring D is

[0640]

[0641] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 and the asterisk indicates the point of attachment to E; and E is hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines; or hetAr 2 C(=O)-, and hetAr 2 As defined for Formula IB. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0642] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; Ring D is

[0643]

[0644] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X4 and the asterisk indicates the point of attachment to E; and E is hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines, and hetAr 2 As defined for Formula IB. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0645] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; Ring D is

[0646]

[0647] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 and the asterisk indicates the point of attachment to E; and E is hetAr 2 C(=O)-, and hetAr 2 As defined for Formula IB. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0648] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; Ring D is

[0649]

[0650] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 and the asterisk indicates the point of attachment to E; and E is hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines, and hetAr 2 As defined for Formula IB. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0651] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; Ring D is

[0652]

[0653] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 and the asterisk indicates the point of attachment to E; and E is hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines, and hetAr 2 As defined for Formula IB. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X2 and X 4 It is CH.

[0654] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hetAr 1 C1-C3 alkyl-, wherein hetAr 1 As defined for Formula IB; Ring D is

[0655]

[0656] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorines, and hetAr 2 As defined for Formula IB. In one embodiment, Ring D is unsubstituted. In one embodiment, hetAr 2 is 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 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0657] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hetAr 1 C1-C3 alkyl-, wherein hetAr 1 As defined for Formula IB; Ring D is

[0658]

[0659] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C(=O)-, wherein hetAr 2 As defined for Formula IB. In one embodiment, Ring D is unsubstituted. In one embodiment, hetAr 2 is 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 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0660] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hetAr 1 C1-C3 alkyl-, wherein hetAr 1 As defined for Formula IB; Ring D is

[0661]

[0662] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is Ar 1 R 3 NC(=O)-, where Ar 1 and R 3 As defined for Formula IB. In one embodiment, Ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0663] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is hetAr 1 C1-C3 alkyl-, wherein hetAr 1 As defined for Formula IB; Ring D is

[0664]

[0665] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo; and E is (C1-C6 alkyl)SO2-. In one embodiment, ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0666] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is (hetCyc a )C1-C3 alkyl-, wherein hetCyc a As defined for Formula IB; Ring D is

[0667]

[0668] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluorines, and hetAr 2 As defined for Formula IB. In one embodiment, Ring D is unsubstituted. In one embodiment, hetAr 2is 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 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0669] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is (hetCyc a )C1-C3 alkyl-, wherein hetCyc a As defined for Formula IB; Ring D is

[0670]

[0671] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is hetAr 2 C(=O)-, wherein hetAr 2 As defined for Formula IB. In one embodiment, Ring D is unsubstituted. In one embodiment, hetAr 2 is 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 fluorine) and C1-C6 alkoxy (optionally substituted with 1-3 fluorine). In one embodiment, X 1 is N; and X 2 、X3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0672] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X 2 and X 4 is CH; A is CN; B is (hetCyc a )C1-C3 alkyl-, wherein hetCyc a As defined for Formula IB; Ring D is

[0673]

[0674] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 wherein the asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorines) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorines), (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; and E is Ar 1 R 3 NC(=O)-, where Ar 1 and R 3 As defined for Formula IB. In one embodiment, Ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0675] In one embodiment of Formula IB, X 1 is N, and X 2 、X 3 and X 4 is CH; or X 1 and X 3 is N, and X2 and X 4 is CH; A is CN; B is (hetCyc a )C1-C3 alkyl-, wherein hetCyc a As defined for Formula IB; Ring D is

[0676]

[0677] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E, wherein ring D is optionally substituted with: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl (which is optionally substituted with 1-3 fluorine) or C1-C3 alkoxy (which is optionally substituted with 1-3 fluorine), (b) C3-C6 cycloalkylene ring, or (c) oxo; and E is (C1-C6 alkyl)SO2-. In one embodiment, ring D is unsubstituted. In one embodiment, X 1 is N; and X 2 、X 3 and X 4 In one embodiment, X 1 and X 3 is N; and X 2 and X 4 It is CH.

[0678] In one embodiment, Formula I comprises a compound of Formula IC, wherein:

[0679] X 1 、X 2 、X 3 and X 4 are independently CH, CF or N, wherein X 1 、X 2 、X 3 and zero, one, or two of X4 are N;

[0680] A is H, CN, Cl, CH3-, CH3CH2-, cyclopropyl, -CH2CN or -CH(CN)CH3;

[0681] B is

[0682] (a) hydrogen,

[0683] (b) a C1-C6 alkyl group optionally substituted by 1 to 3 fluorine groups,

[0684] (c) hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring,

[0685] (d) dihydroxy C3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring,

[0686] (e) (C1-C6 alkoxy) C1-C6 alkyl- optionally substituted by 1 to 3 fluorine groups,

[0687] (f)(R 1 R 2 N) C1-C6 alkyl-, wherein R 1 and R 2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluorines);

[0688] (g)hetAr 1 C1-C3 alkyl-, wherein hetAr 1 is 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;

[0689] (h)(C3-C6 cycloalkyl)C1-C3 alkyl-,

[0690] (i)(hetCyc a ) C1-C3 alkyl-, or

[0691] (j)hetCyc a ;

[0692] hetCyc a is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, and is optionally substituted by OH, C1-C6 alkyl (optionally substituted with 1-3 fluorine) or hydroxyC1-C6 alkyl-;

[0693] Ring D is

[0694]

[0695] The wavy line indicates the ring D and includes X 1 、X 2 、X 3 and X 4 The asterisk indicates the point of attachment to the ring of E;

[0696] E is

[0697] (a) hydrogen,

[0698] (b) a C1-C6 alkyl group optionally substituted by 1 to 3 fluorine groups,

[0699] (d) (C1-C6 alkyl) C(=O)-, wherein the alkyl portion is optionally substituted with 1-3 fluorine atoms or with R g R h N-substituted, where R g and R h are independently H or C1-C6 alkyl,

[0700] (f)(C1-C6 alkoxy)C(=O),

[0701] (l)hetAr 2 C(=O)-,

[0702] (o)R 3 R 4 NC(=O)-,

[0703] (s)Ar 1 SO2-,

[0704] (t)hetAr 2 SO2-,

[0705] (v)Ar 1 C(=O)-,

[0706] (cc)hetAr 2 ,or

[0707] (dd) C3-C6 cycloalkyl;

[0708] R 3 is H or C1-C6 alkyl; and

[0709] R 4 It is a C1-C6 alkyl group.

[0710] In one embodiment of Formula 1C, X 1 It is N; X 2 、X 3 and X 4 It is CH.

[0711] In one embodiment of Formula IC, A is CN.

[0712] In one embodiment of Formula 1C, X 1 It is N; X 2 、X 3 and X 4 is CH; and A is CN.

[0713] In one embodiment of Formula IC, B is (C1-C6 alkoxy)C1-C6 alkyl-, optionally substituted with 1-3 fluorines, or hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring.

[0714] In one embodiment of Formula IC, B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluorines. In one embodiment of Formula IC, B is (C1-C6 alkoxy)C2-C6 alkyl- optionally substituted with 1-3 fluorines.

[0715] In one embodiment of Formula IC, B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring. In one embodiment, the alkyl portion of the B group is unsubstituted.

[0716] In one embodiment of Formula 1C, X 1 It is N; X 2 、X 3 and X 4 is CH; A is CN; and B is (C1-C6 alkoxy)C1-C6 alkyl optionally substituted with 1-3 fluorines.

[0717] In one embodiment of Formula 1C, X 2 It is N; X 1 、X 3 and X 4 is CH; A is CN; B is hydroxyC2-C6alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; and E is (C1-C6alkoxy)C(=O)-.

[0718] In one embodiment of Formula 1C, X 1 It is N; X 2 、X 3 and X 4 A is CN; and B is hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring. In one embodiment, the alkyl portion of the B group is unsubstituted.

[0719] 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 can be used as intermediates for preparing and / or purifying the compounds of formula I and / or for separating the enantiomers of the compounds of formula I. Non-limiting examples of pharmaceutically acceptable salts of the compounds of formula I include monohydrochloride, dihydrochloride, trifluoroacetate, and ditrifluoroacetate. In one embodiment, the compounds of formula I include trifluoroacetate and dihydrochloride.

[0720] It should also be understood that the compounds of formula I or their salts can be isolated in the form of solvates, and therefore any such solvates are included within the scope of the present invention. For example, the compounds of formula I and their salts can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.).

[0721] In one embodiment, the compound of formula I comprises the compounds of Examples 1-561 and their stereoisomers and pharmaceutically acceptable salts and solvates. In one embodiment, the compounds of Examples 1-561 are in free base form. In one embodiment, the compounds of Examples 1-561 are dihydrochloride and trifluoroacetate.

[0722] The term "pharmaceutically acceptable" indicates that the compound or salt thereof or composition is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the patient being treated therewith.

[0723] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more atoms comprising such compounds. That is, particularly when referring to compounds according to Formula I, atoms include all isotopes and isotopic mixtures of such atoms occurring in nature or produced synthetically, in natural abundance or isotopically enriched form. For example, reference to hydrogen is understood to refer to 1 H. 2 H. 3 H or mixtures thereof; when carbon is mentioned, it is understood to mean 11 C. 12 C. 13 C. 14 C or mixtures thereof; when nitrogen is mentioned, it is understood to mean 13 N. 14 N. 15 N or mixtures thereof; when oxygen is mentioned, it is understood to mean 14 O. 15 O. 16 O. 17 O. 18 O or mixtures thereof; and when fluorine is mentioned, it is understood to mean 18 F. 19 F or mixtures thereof. Thus, the compounds provided herein also include compounds and mixtures thereof having one or more isotopes of one or more atoms, including radioactive compounds in which one or more non-radioactive atoms have been replaced by one of their radioactively enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, such as cancer therapeutics, research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variants of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0724] For illustrative purposes, schemes 1-6 show general methods and key intermediates for preparing compounds provided herein. For a more detailed description of individual reaction steps, see the following example sections. Those skilled in the art will appreciate that other synthetic pathways can be used to synthesize the compounds of this invention. Although specific starting materials and reagents are described in the scheme and discussed below, other starting materials and reagents can be easily replaced to obtain various derivatives and / or reaction conditions. In addition, many compounds prepared by the methods described below can be further modified according to the present disclosure using conventional chemical reactions known to those skilled in the art.

[0725]

[0726] Scheme 1 shows a general scheme for the synthesis of compound 12, wherein A is CN, and B, X 1 、X 2 、X 3 、X 4 , Ring D and E are as defined for Formula I.

[0727] Compound 2 is obtained by treating commercially available 3-bromo-5-methoxypyridine (Compound 1) with O-(mesitylenesulfonyl)hydroxylamine. O-mesitylenesulfonylhydroxylamine can be prepared as described in Mendiola, J. et al., Org. Process Res. Dev. 2009, 13(2), 263-267. Compound 2 can be reacted with ethyl propiolate to give a mixture of compounds 3A and 3B, which are typically obtained in a ratio of about 2:1 to 9:1, respectively. The mixture of compounds 3A and 3B can be treated with 48% HBr at elevated temperature, followed by recrystallization or chromatography, to separate compound 4A as the minor isomer and compound 4B as the major isomer. After separation, compound 4A can be treated with POCl to give compound 5. The formyl group can be converted to an oxime group using NH2OH to give compound 6. The oxime group can be converted to a nitrile group using acetic anhydride to give compound 7. The methoxy group of compound 7 can be converted to a hydroxyl group by treating compound 7 with aluminum trichloride to give compound 8.

[0728] To prepare compound 12 wherein B is hydrogen, compound 12 can be prepared by reacting compound 8 with the corresponding boronate compound 10 (wherein ring D, X) using appropriate palladium-catalyzed cross-coupling reaction conditions, such as Suzuki coupling reaction conditions (e.g., a palladium catalyst and optionally a ligand in the presence of an inorganic base, such as Pd(PPh3)4 and Na2CO3 in dioxane at elevated temperature). 1 、X 2 、X 3 and X 4As defined for Formula I; P 1 is an amino protecting group; Z is -B(OR x )(OR y ), and R z and R y is H or (1-6C) alkyl, or R x and R y The protective group P on the ring D of compound 11a is formed by coupling with the atoms to which it is attached to form a 5-6 membered ring optionally substituted by 1-4 substituents selected from (C1-C3 alkyl) to give compound 11a. 1 The Boc group can be removed under standard conditions (e.g., the Boc group can be removed by treating compound 11a with acidic conditions, such as HCl) to provide compound 12, wherein B is hydrogen and E is hydrogen. Alternatively, the deprotected ring D can be functionalized (i.e., reacted with or treated with an appropriate reagent) to introduce the E group under standard conditions described below to provide compound 12, wherein B is hydrogen and E is as defined for Formula I (except that E is not hydrogen).

[0729] Alternatively, to prepare compound 12 wherein B is as defined for formula I (except hydrogen), compound 11a can be reacted under Mitsunobu reaction conditions (e.g., PPh3 and diisopropyl azodicarboxylate) with reagents such as: C1-C6 alkyl-OH optionally substituted with 1-3 fluorines; hydroxy C2-C6 alkyl-OH; dihydroxy C3-C6 alkyl-OH; (C1-C6 alkoxy) C1-C6 alkyl-X optionally substituted with 1-3 fluorines; (R 1 R 2 N) C1-C6 alkyl-OH, wherein R 1 and R 2 As defined for Formula I; hetAr 1 C1-C3 alkyl-OH; (C3-C6 cycloalkyl) C1-C3 alkyl-OH; (hetCyc a )C1-C3 alkyl-OH; or hetCyc a -OH, where hetAr 1 and hetCyc a Compound 12 can then be prepared from compound 11 as described above, followed by removal of the protecting group on B, if present, as defined for formula I, and wherein each of the reagents is optionally substituted with a protecting group.

[0730] As an alternative method for preparing compound 12 wherein B is as defined for formula I (except hydrogen), compound 9 can be prepared by reacting compound 8 with a reagent such as: C1-C6 alkyl-X optionally substituted with 1-3 fluorines; hydroxy C2-C6 alkyl-X; dihydroxy C3-C6 alkyl-X; (C1-C6 alkoxy) C1-C6 alkyl-X optionally substituted with 1-3 fluorines; (R 1 R 2 N) C1-C6 alkyl-X, wherein R 1 and R 2 As defined for Formula I; hetAr 1 C1-C3 alkyl-X; (C3-C6 cycloalkyl) C1-C3 alkyl-X; (hetCyc a )C1-C3 alkyl-X; or hetCyc a -X, where hetAr 1 and hetCyc a As defined for formula I and X is a leaving atom or leaving group (such as halogen or triflate), wherein each of the reagents is optionally substituted with a protecting group (e.g., tert-butyldimethylsilyl if the B group has one or two additional hydroxy groups). For example, when B is a C1-C6 alkyl group optionally substituted with 1-3 fluorines, compound 9 can be prepared by reacting compound 8 with C1-C6 alkyl-X, wherein the alkyl group is optionally substituted with 1-3 fluorines and X is a halogen (such as Br or Cl) or a leaving group (such as triflate). Compound 11 can then be prepared by coupling compound 9 with the corresponding boronate compound 10 using appropriate palladium-catalyzed cross-coupling reaction conditions, such as Suzuki coupling reaction conditions (e.g., a palladium catalyst and an optional ligand in the presence of an inorganic base, such as dioxane containing Pd(PPh3)4 and Na2CO3 at elevated temperature). Compound 12 can then be prepared from compound 11 as described above, followed by removal of the protecting group on B, if present.

[0731]

[0732] Scheme 2 shows another general scheme for the synthesis of compound 12, wherein A is CN, B, X 1 、X 2 、X 3 、X 4 , Ring D and E are as defined for Formula I.

[0733] Compound 9 (e.g., prepared as described in Scheme 1) (wherein B is as defined for Formula I) can be reacted with the corresponding boronate ester 13 (wherein X is 1 or 2) using appropriate palladium-catalyzed cross-coupling reaction conditions, such as Suzuki coupling reaction conditions (e.g., a palladium catalyst and optionally a ligand in the presence of an inorganic base, such as Pd(PPh3)4 and Na2CO3 in dioxane at elevated temperature). 1 、X 2 、X 3 and X 4 As defined for Formula I; L 2 is a leaving group, such as triflate or halogen; Z is -B(OR x )(OR y ), and R z and R y is H or (1-6C) alkyl, or R x and R y and the atoms to which they are attached form a 5-6 membered ring optionally substituted by 1-4 substituents selected from (C1-C3 alkyl)) to give compound 14. Compound 16 can be prepared by the following: in the presence of an appropriate S N Ar conditions (e.g., optionally in the presence of a base such as K2CO3 and at elevated temperature), compound 14 is coupled with compound 15, wherein ring D is as defined for formula I, and P 1 It is an amino protecting group.

[0734] The protecting group P on the ring D of compound 16 1 The Boc group can be removed under standard conditions (e.g., the Boc group can be removed by treating compound 1 with acidic conditions, such as HCl) to provide compound 12, wherein E is H. Alternatively, the deprotected ring D can be functionalized (i.e., reacted with or treated with an appropriate reagent) to introduce the E group under standard conditions as described below to provide compound 12, wherein E is as defined for Formula I, except that E is not H.

[0735]

[0736] Scheme 3 shows a general scheme for the synthesis of compound 21, wherein A is H, and B, X 1 、X 2 、X 3 、X 4 , Ring D and E are as defined for Formula I.

[0737] Compound 18 can be prepared by reacting compound 4A (e.g., prepared as described in Scheme 1) with the corresponding boronate compound 10 (wherein ring D, X) using appropriate palladium-catalyzed cross-coupling reaction conditions, such as Suzuki coupling reaction conditions (e.g., a palladium catalyst and optionally a ligand in the presence of an inorganic base, such as Pd(PPh3)4 and Na2CO3 in dioxane at elevated temperature). 1 、X 2 、X 3 and X 4 As defined for Formula I; P 1 is an amino protecting group; Z is -B(OR x )(OR y ), and R z and R y is H or (1-6C) alkyl, or R x and R y and the atoms to which they are attached together to form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl). Compound 19 can be prepared by treating compound 18 with aluminum chloride.

[0738] To prepare compound 21 (wherein B is as defined for formula I (except hydrogen)), compound 20 can be prepared by reacting compound 19 with a reagent such as: C1-C6 alkyl-X optionally substituted with 1-3 fluorines; hydroxy C2-C6 alkyl-X; dihydroxy C3-C6 alkyl-X; (C1-C6 alkoxy) C1-C6 alkyl-X optionally substituted with 1-3 fluorines; (R 1 R 2 N) C1-C6 alkyl-X, wherein R 1 and R 2 As defined for Formula I; hetAr 1 C1-C3 alkyl-X; (C3-C6 cycloalkyl) C1-C3 alkyl-X; (hetCyc a )C1-C3 alkyl-X or hetCyc a -X, where hetAr 1 and hetCyc aAs defined for formula I and X is a leaving atom or leaving group (such as halogen or triflate), wherein each of the reagents is optionally substituted with a protecting group (e.g., tert-butyldimethylsilyl if the B group has one or two additional hydroxy groups). For example, when B is a C1-C6 alkyl group optionally substituted with 1-3 fluorines, the compound can be prepared by reacting compound 19 with a C1-C6 alkyl-X group, wherein the alkyl group is optionally substituted with 1-3 fluorines and X is a halogen (such as Br or Cl) or a leaving group (such as triflate). The protecting group P on the ring D of compound 20 1 The Boc group can be removed under standard conditions (e.g., the Boc group can be removed by treating compound 20 with acidic conditions, such as HCl) to provide compound 21, wherein E is H. Alternatively, the deprotected ring D of compound 21 can be functionalized (i.e., reacted with or treated with an appropriate reagent) to introduce the E group under standard conditions as described below to provide compound 21, wherein E is as defined for Formula I, except that E is not H.

[0739] Alternatively, to prepare compound 21 wherein B is as defined for formula I (except hydrogen), compound 19 can be reacted under Mitsunobu reaction conditions (e.g., PPh3 and diisopropyl azodicarboxylate) with reagents such as: C1-C6 alkyl-OH optionally substituted with 1-3 fluorines; hydroxy C2-C6 alkyl-OH; dihydroxy C3-C6 alkyl-OH; (C1-C6 alkoxy) C1-C6 alkyl-X optionally substituted with 1-3 fluorines; (R 1 R 2 N) C1-C6 alkyl-OH, wherein R 1 and R 2 As defined for Formula I; hetAr 1 C1-C3 alkyl-OH; (C3-C6 cycloalkyl) C1-C3 alkyl-OH; (hetCyc a )C1-C3 alkyl-OH; or hetCyc a -OH, where hetAr 1 and hetCyc a As defined for formula I, wherein each of the reagents is optionally substituted with a protecting group. Compound 21 can then be prepared from compound 20 as described above, followed by removal of the protecting group on B, if present.

[0740] When group B is hydrogen, compound 21 can be prepared from compound 19 according to the deprotection and optional functionalization procedures described herein.

[0741]

[0742] Scheme 4 shows an alternative general scheme for the synthesis of compound 21, wherein A is H, and B, X 1 、X 2 、X 3 、X 4 , Ring D and E are as defined for Formula I.

[0743] Compound 22 can be prepared by treating compound 4A (prepared, for example, as described in Scheme 1) with aluminum trichloride.

[0744] To prepare compound 21 (wherein B is hydrogen), compound 19 can be prepared by reacting compound 22 with the corresponding boronate compound 10 (wherein ring D, X) using appropriate palladium-catalyzed cross-coupling reaction conditions, such as Suzuki coupling reaction conditions (e.g., a palladium catalyst and optionally a ligand in the presence of an inorganic base, such as Pd(PPh3)4 and Na2CO3 in dioxane at elevated temperature). 1 、X 2 、X 3 and X 4 As defined for Formula I; P 1 is an amino protecting group; Z is -B(OR x )(OR y ), and R z and R y is H or (1-6C) alkyl, or R x and R y Compound 21 can be prepared from compound 19 according to the method described in Scheme 3.

[0745] Alternatively, to prepare compound 21 (wherein B is as defined for formula I (except hydrogen)), compound 23 can be prepared by reacting compound 22 with a reagent such as: C1-C6 alkyl-X optionally substituted with 1-3 fluorines; hydroxy C2-C6 alkyl-X; dihydroxy C3-C6 alkyl-X; (C1-C6 alkoxy) C1-C6 alkyl-X optionally substituted with 1-3 fluorines; (R 1 R 2 N) C1-C6 alkyl-X, wherein R 1 and R 2 As defined for Formula I; hetAr 1 C1-C3 alkyl-X; (C3-C6 cycloalkyl) C1-C3 alkyl-X; (hetCyc a )C1-C3 alkyl-X or hetCyc a -X, where hetAr 1 and hetCyc aAs defined for formula 1 and X is a leaving atom or leaving group (such as halogen or trifluoromethanesulfonate), each of which is optionally substituted by a protecting group (such as tert-butyldimethylsilyl if the B group has one or two additional hydroxyls). For example, when B is a C1-C6 alkyl optionally substituted by 1-3 fluorine, compound 23 can be prepared by reacting compound 22 with C1-C6 alkyl-X, wherein the alkyl is optionally substituted by 1-3 fluorine and X is halogen (such as Br or Cl) or a leaving group (such as trifluoromethanesulfonate). Compound 20 can be prepared by coupling compound 23 with the compound 10 as described in scheme 3. Compound 21 can be prepared by compound 20 according to the method described in scheme 3.

[0746] Alternatively, to prepare compound 21 wherein B is as defined for formula I (except hydrogen), compound 19 can be reacted under Mitsunobu reaction conditions (e.g., PPh3 and diisopropyl azodicarboxylate) with reagents such as: C1-C6 alkyl-OH optionally substituted with 1-3 fluorines; hydroxy C2-C6 alkyl-OH; dihydroxy C3-C6 alkyl-OH; (C1-C6 alkoxy) C1-C6 alkyl-X optionally substituted with 1-3 fluorines; (R 1 R 2 N) C1-C6 alkyl-OH, wherein R 1 and R 2 As defined for Formula I; hetAr 1 C1-C3 alkyl-OH; (C3-C6 cycloalkyl) C1-C3 alkyl-OH; (hetCyc a )C1-C3 alkyl-OH; or hetCyc a -OH, where hetAr 1 and hetCyc a As defined for Formula I, wherein each of the reagents is optionally substituted with a protecting group. Compound 21 can then be prepared from compound 20 as described in Scheme 3, followed by removal of the protecting group on B, if present.

[0747]

[0748] Scheme 5 shows an alternative general scheme for the synthesis of compound 21, wherein A is H, and B, X 1 、X 2 、X 3 、X 4 , Ring D and E are as defined for Formula I.

[0749] Compound 22 can be prepared by treating compound 4A (eg, prepared as described in Scheme 1) with aluminum trichloride.

[0750] To prepare compound 21 (wherein B is as defined for formula I (except hydrogen)), compound 23 can be prepared by reacting compound 22 with a reagent such as: C1-C6 alkyl-X optionally substituted with 1-3 fluorines; hydroxy C2-C6 alkyl-X; dihydroxy C3-C6 alkyl-X; (C1-C6 alkoxy) C1-C6 alkyl-X optionally substituted with 1-3 fluorines; (R 1 R 2 N) C1-C6 alkyl-X, wherein R 1 and R 2 As defined for Formula I; hetAr 1 C1-C3 alkyl-X; (C3-C6 cycloalkyl) C1-C3 alkyl-X; (hetCyc a )C1-C3 alkyl-X or hetCyc a -X, where hetAr 1 and hetCyc a As defined for Formula I and X is a leaving atom or leaving group (such as halogen or triflate), wherein each of the reagents is optionally substituted with a protecting group (e.g., tert-butyldimethylsilyl if the B group has one or two additional hydroxyl groups). For example, when B is a C1-C6 alkyl group optionally substituted with 1-3 fluorine groups, the compound can be prepared by reacting compound 22 with C1-C6 alkyl-X, wherein the alkyl group is optionally substituted with 1-3 fluorine groups and X is a halogen (such as Br or Cl) or a leaving group (such as triflate).

[0751] Compound 24 can be prepared by reacting compound 23 with boronate ester 13 (wherein X is 1 or 2) using appropriate palladium-catalyzed cross-coupling reaction conditions, such as Suzuki coupling reaction conditions (e.g., a palladium catalyst and optionally a ligand in the presence of an inorganic base, such as Pd(PPh3)4 and Na2CO3 in dioxane at elevated temperature). 1 、X 2 、X 3 and X 4 As defined for Formula I; L 2 is a leaving group, such as triflate or halogen; Z is -B(OR x )(OR y ), and R z and R y is H or (1-6C) alkyl, or R x and R y and the atoms to which they are attached to form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)).

[0752] To prepare compound 21 (wherein B is hydrogen), compound 24 can be prepared by reacting compound 22 directly with compound 13 as described above.

[0753] Compound 20 can be prepared by the following steps: N Ar conditions (eg, optionally in the presence of a base such as K2CO3 and at elevated temperature) are used to react compound 24 with compound 15 (wherein P 1 is an amino protecting group) coupling.

[0754] Compound 21 can be prepared from compound 20 according to the method described in Scheme 3.

[0755]

[0756] Scheme 6 shows a general scheme for the synthesis of compound 31, wherein A is Cl, and B, X 1 、X 2 、X 3 、X 4 , Ring D and E are as defined for Formula I.

[0757] Compound 25 can be prepared by treating compound 4A (eg, prepared as described in Scheme 1) with aluminum trichloride.

[0758] Compound 26 can be prepared by treating compound 25 with aluminum trichloride.

[0759] To prepare compound 31 (wherein B is as defined for formula I (except hydrogen)), compound 27 can be prepared by reacting compound 26 with a reagent such as: C1-C6 alkyl-X optionally substituted with 1-3 fluorines; hydroxy C2-C6 alkyl-X; dihydroxy C3-C6 alkyl-X; (C1-C6 alkoxy) C1-C6 alkyl-X optionally substituted with 1-3 fluorines; (R 1 R 2 N) C1-C6 alkyl-X, wherein R 1 and R 2 As defined for Formula I; hetAr 1 C1-C3 alkyl-X; (C3-C6 cycloalkyl) C1-C3 alkyl-X; (hetCyc a )C1-C3 alkyl-X or hetCyc a -X, where hetAr 1 and hetCyc aAs defined for Formula I and X is a leaving atom or leaving group (such as halogen or triflate), wherein each of the reagents is optionally substituted with a protecting group (e.g., tert-butyldimethylsilyl if the B group has one or two additional hydroxyl groups). For example, when B is a C1-C6 alkyl group optionally substituted with 1-3 fluorine groups, the compound can be prepared by reacting compound 26 with C1-C6 alkyl-X, wherein the alkyl group is optionally substituted with 1-3 fluorine groups and X is a halogen (such as Br or Cl) or a leaving group (such as triflate).

[0760] Compounds 28 (wherein group B is methyl), 29 (wherein group B is hydrogen) and 30 (wherein group B is not hydrogen) can be prepared by reacting compounds 25, 26 and 27 with the corresponding boronate compound 10 (wherein ring D, X) using appropriate palladium-catalyzed cross-coupling reaction conditions, such as Suzuki coupling reaction conditions (e.g., a palladium catalyst and optionally a ligand in the presence of an inorganic base, such as Pd(PPh3)4 and Na2CO3 in dioxane at elevated temperature). 1 、X 2 、X 3 and X 4 As defined for Formula I; P 1 is an amino protecting group; Z is -B(OR x )(OR y ), and R z and R y is H or (1-6C) alkyl, or R x and R y and the atoms to which they are attached form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)).

[0761] The protecting group P on the ring D of compound 29 or 30 1 The Boc group can be removed under standard conditions (e.g., the Boc group can be removed by subjecting compound 29 or 30 to acidic conditions, such as HCl) to provide compound 31, wherein E is hydrogen. Alternatively, the deprotected ring D can be functionalized (i.e., reacted with or treated with an appropriate reagent) to incorporate the E group under standard conditions as described below to provide compound 31, wherein E is as defined for Formula I, except that E is not H.

[0762] Using standard chemical methods well known to those skilled in the art, Ring D of compounds 12, 21, and 31 described in Schemes 1-6 can be functionalized (i.e., reacted with or treated with an appropriate reagent) to incorporate an E group, wherein E is any of the E groups defined for Formula I, except hydrogen. As used herein, the term "functionalization" refers to a process step wherein a compound of Formula 12, 21, or 31 (wherein E is hydrogen) is reacted with or treated with an appropriate reagent to provide a compound of Formula 12, 21, or 31 (wherein E is as defined for Formula I, except hydrogen).

[0763] For example, a compound of formula I (wherein E is: (C1-C6 alkyl) C(=O)- optionally substituted with one to three fluorines; (hydroxy C2-C6 alkyl) C(=O)- optionally substituted with one to three fluorines; (C1-C6 alkoxy) C(=O)-; (C3-C6 cycloalkyl) C(=O)- (wherein the cycloalkyl is optionally substituted with (C1-C6 alkoxy) C1-C6 alkyl or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O); Ar 1 (C1-C6 alkyl) C(=O)- (wherein the alkyl portion is optionally substituted by OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy); hetAr 2 (C1-C6 alkyl) C(=O)- (wherein the alkyl portion is optionally substituted with OH, hydroxyC1-C6 alkyl or C1-C6 alkoxy); or hetCyc 1 (C1-C6 alkyl) C(=O)-), can be obtained by treating compound 12 having a deprotected ring D (i.e., compound 12 wherein E is hydrogen) with the corresponding carboxylic acid using conventional amide bond forming conditions, for example, treating the corresponding carboxylic acid with an activating agent (e.g., HATU), followed by adding compound 12 having a deprotected ring D (i.e., compound 12 wherein E is H) in the presence of a base (e.g., an amine base such as DIEA) in an appropriate solvent such as DMA to give functionalized compound 12 (i.e., In this case, compound 12 wherein E is: (C1-C6 alkyl)C(=O)- optionally substituted by one to three fluorines; (hydroxy C2-C6 alkyl)C(=O)- optionally substituted by one to three fluorines; (C1-C6 alkoxy)C(=O)-; (C3-C6 cycloalkyl)C(=O)- (wherein the cycloalkyl is optionally substituted by (C1-C6 alkoxy)C1-C6 alkyl- or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O); Ar 1 (C1-C6 alkyl) C(=O)- (wherein the alkyl portion is optionally substituted by OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy); hetAr 2(C1-C6 alkyl) C(=O)- (wherein the alkyl portion is optionally substituted by OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy); or hetCyc 1 The same chemical methods can be used on compounds 21 and 31 to prepare functionalized compounds 21 and 31 (i.e., in this case, compounds 21 and 31, respectively, wherein E is (C1-C6 alkyl)C(=O)- optionally substituted with one to three fluorines; (hydroxyC2-C6 alkyl)C(=O)- optionally substituted with one to three fluorines; (C1-C6 alkoxy)C(=O)-; (C3-C6 cycloalkyl)C(=O)- (wherein the cycloalkyl is optionally substituted with (C1-C6 alkoxy)C1-C6 alkyl- or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O); Ar 1 (C1-C6 alkyl) C(=O)- (wherein the alkyl portion is optionally substituted by OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy); hetAr 2 (C1-C6 alkyl)C(=O)- (wherein the alkyl portion is optionally substituted by OH, hydroxyC1-C6 alkyl- or (C1-C6) alkoxy); or hetCyc 1 (C1-C6 alkyl)C(=O)-).

[0764] As another example, a compound of formula I (wherein E is hetCyc 1 C(=O)- or R 3 R 4 NC(=O)-) can be prepared by first activating the deprotected ring nitrogen of ring D of compound 12 (i.e., wherein E is H) with triphosgene in the presence of DIEA in a solvent such as DCM, followed by the addition of a cyclopentane having the formula hetCyc 1 -H or R 3 R 4 NH (where hetCyc 1 -H is a saturated 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S, wherein the ring has at least one ring N atom and "-H" indicates that the hydrogen is on the ring nitrogen atom, wherein the heterocyclic ring is optionally substituted with one or more independently selected C1-C6 alkoxy substituents) to provide functionalized compounds 12 (i.e., in this case, wherein E is hetCyc 1 C(=O)- or R 3 R 4 Compound 12 is NC(=O)-). The same chemical approach can be used for compounds 21 and 31 to prepare functionalized compounds 21 and 31 (ie, in this case, wherein E is hetCyc 1C(=O)- or R 3 R 4 Compounds 21 and 31 containing NC(=O)-.

[0765] As another example, the compound of formula I (wherein E is: C1-C6 alkyl optionally substituted with one to three fluorines; (C1-C6 alkoxy) C1-C6 alkyl optionally substituted with 1-3 fluorines; Ar 1 C1-C6 alkyl-; hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines; or hetCyc 1 C1-C6 alkyl-) can be prepared by treating the deprotected compound 12 (i.e., wherein E is H) with the corresponding reagent having the formula C1-C6 alkyl-X optionally substituted with one to three fluorines, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 1-3 fluorines, Ar 1 C1-C6 alkyl-X, hetAr 2 C1-C6 alkyl-X or hetCyc 1 C1-C6 alkyl-X (wherein X is Br or Cl) to provide functionalized compound 12 (i.e., in this case, compound 12 wherein E is: C1-C6 alkyl optionally substituted with one to three fluorines; (C1-C6 alkoxy) C1-C6 alkyl optionally substituted with 1-3 fluorines; Ar 1 C1-C6 alkyl-; hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines; or hetCyc 1 C1-C6 alkyl-). The same chemical methods can be used on compounds 21 and 31 to prepare functionalized compounds 21 and 31 (i.e., in this case, in this case, compounds 21 and 31, respectively, wherein E is: C1-C6 alkyl optionally substituted with one to three fluorine groups; (C1-C6 alkoxy) C1-C6 alkyl optionally substituted with 1-3 fluorine groups; Ar 1 C1-C6 alkyl-; hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines; or hetCyc 1 C1-C6 alkyl-).

[0766] As another example, the compound of formula I (wherein E is: C1-C6 alkyl optionally substituted with one to three fluorines; (C1-C6 alkoxy) C1-C6 alkyl optionally substituted with 1-3 fluorines; Ar 1 C1-C6 alkyl-; hetAr 2C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines; or hetCyc 1 C1-C6 alkyl-) can be prepared by treating the deprotected compound 12 (i.e., wherein E is H) with the corresponding aldehyde, such as (C1-C5 alkyl(C=O)H optionally substituted with one to three fluorines; (C1-C6 alkoxy)(C1-C5 alkyl)C(=O)H optionally substituted with one to three fluorines; Ar 1 (C1-C5 alkyl)C(=O)H; hetAr 2 (C1-C5 alkyl)C(=O)H; or hetCyc 1 (C1-C5 alkyl)-C(=O)H, to provide functionalized compound 12 (i.e., in this case, compound 12 wherein E is: C1-C6 alkyl optionally substituted with one to three fluorines; (C1-C6 alkoxy)C1-C6 alkyl optionally substituted with 1-3 fluorines; Ar 1 C1-C6 alkyl-; hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines; or hetCyc 1 C1-C6 alkyl-). The same chemical methods can be used on compounds 21 and 31 to prepare functionalized compounds 21 and 31 (i.e., in this case, in this case, compounds 21 and 31, respectively, wherein E is: C1-C6 alkyl optionally substituted with one to three fluorine groups; (C1-C6 alkoxy) C1-C6 alkyl optionally substituted with 1-3 fluorine groups; Ar 1 C1-C6 alkyl-; hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines; or hetCyc 1 C1-C6 alkyl-).

[0767] Therefore, the present invention also provides a process for preparing a compound of formula I as defined herein or a pharmaceutically acceptable salt thereof, comprising:

[0768] (a) For compounds of formula I, wherein E is H, A is CN, -CH2CN or -CH(CN)CH3, and B, X 1 、X 2 、X 3 、X 4 and ring D are as defined for formula I, in the presence of a palladium catalyst and optionally a ligand, and in the presence of a base, the corresponding compound 9 having the formula

[0769]

[0770] wherein B is as defined for formula I, coupled with the corresponding boronate ester of formula 10 below

[0771]

[0772] Among them, P 1 is an amino protecting group, Z is -B(OR x )(OR y ), where R x and R y is H or C1-C6 alkyl, or R x and R y Together with the atoms to which they are attached, they form a 5-6 membered ring optionally substituted with 1-4 substituents selected from C1-C3 alkyl, and X 1 、X 2 、X 3 and X 4 The protecting groups are subsequently removed as defined for formula I; or

[0773] (b) For compounds of formula I, wherein A, B, X 1 、X 2 、X 3 、X 4 , ring D and E are as defined for formula I, except that E is not hydrogen, and the corresponding compound of the formula is functionalized

[0774]

[0775] Among them A, ring D, B, X 1 、X 2 、X 3 and X 4 As defined for formula I, and E1 is hydrogen; or

[0776] (c) For compounds of formula I, wherein A is CN, and rings D, B, X 1 、X 2 、X 3 、X 4 and E are as defined for formula I, so that the corresponding compound of formula 14

[0777]

[0778] Among them, B, X 1 、X 2 、X 3 and X 4 As defined for Formula I, and L 2 is a leaving group or atom, reacting with the compound of formula 15 below

[0779]

[0780] Among them, P 1 is an amino protecting group, followed by removal of the protecting group P 1 and optionally functionalizing ring D; or

[0781] (d) For compounds of formula I, wherein E is H, A is CN, and B, X 1 、X 2 、X 3 , X4 and ring D are as defined for formula I, and the compound of formula 14

[0782]

[0783] Among them L 2 is a leaving group or atom, and B, X 1 、X 2 、X 3 and X 4 As defined for formula I, coupled with a compound of formula 15

[0784]

[0785] Among them, P 1 is an amino protecting group, followed by removal of the protecting group P 1 ;or

[0786] (e) For compounds of formula I, wherein A is H, B is H, and X 1 、X 2 、X 3 、X 4 , Ring D and E are as defined for Formula I, and the compound of Formula 18 is treated with aluminum trichloride

[0787]

[0788] Among them, P 1 is an amino protecting group, and X 1 、X 2 、X 3 、X 4 , Ring D is as defined for Formula I, to give Compound 19

[0789]

[0790] Among them, ring D, X 1 、X 2 、X 3 and X 4 As defined for Formula I, and P 1 is an amino protecting group;

[0791] The protecting group P is then removed 1 and optionally functionalizing Ring D; or

[0792] (f) For compounds of formula I, wherein A is H, B is C1-C6 alkyl optionally substituted with 1-3 fluorine groups, hydroxy C2-C6 alkyl, dihydroxy C3-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl optionally substituted with 1-3 fluorine groups, (R 1 R 2 N) C1-C6 alkyl, (hetAr 1 )C1-C3 alkyl, (C3-C6 cycloalkyl)C1-C3 alkyl, (hetCyc a )C1-C3 alkyl or hetCyc a , where R 1 、R 2 、hetAr 1 、hetCyc a 、X 1 、X 2 、X 3 、X 4 , Ring D and E are as defined for Formula I,

[0793] (i) treating the compound of formula 18 with aluminum chloride

[0794]

[0795] Among them, P 1 is an amino protecting group, and X 1 、X 2 、X 3 、X 4 and ring D are as defined for formula I, to give compound 19

[0796]

[0797] wherein Ring D is as defined for Formula I, P 1 is an amino protecting group, and X 1 、X 2 、X 3 and X 4 As defined for formula I;

[0798] (ii) in the presence of a base, reacting compound 19 with: C1-C6 alkyl-X, which is optionally substituted with 1-3 fluorines; hydroxy C2-C6 alkyl-X, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring; dihydroxy C3-C6 alkyl-X; (C1-C6 alkoxy) C1-C6 alkyl-X, which is optionally substituted with 1-3 fluorines; (R 1 R 2 N) C1-C6 alkyl-X; (hetAr 1 )C1-C3 alkyl-X; (C3-C6 cycloalkyl)C1-C3 alkyl-X; (hetCyca )C1-C3 alkyl-X; or hetCyc a -X, where R 1 、R 2 、hetAr 1 and hetCyc a As defined for formula I, and X is a leaving atom or group, such as halogen or triflate, to give compound 20

[0799]

[0800] wherein ring D is as defined for D of formula I, P 1 is an amino protecting group, X 1 、X 2 、X 3 and X 4 As defined for formula I, and B is C1-C6 alkyl optionally substituted by 1-3 fluorines, hydroxy C2-C6 alkyl, dihydroxy C3-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl optionally substituted by 1-3 fluorines, (R 1 R 2 N) C1-C6 alkyl, (hetAr 1 )C1-C3 alkyl, (C3-C6 cycloalkyl)C1-C3 alkyl, (hetCyc a )C1-C3 alkyl or hetCyc a , where R 1 、R 2 、hetAr 1 、hetCyc a The protecting group P is subsequently removed as defined for formula I. 1 and optionally functionalizing Ring D; or

[0801] (g) For compounds of formula I, wherein A is H or Cl, B is H, and X 1 、X 2 、X 3 、X 4 , ring D and E are as defined for formula I, and the compound of formula 10 is treated with the corresponding boronate ester

[0802]

[0803] Where A is H or Cl,

[0804]

[0805] Among them, ring D, X 1 、X 2 、X 3 and X 4 As defined for Formula I; P1 is an amino protecting group; Z is -B(OR x )(OR y ), and R z and R y is H or (1-6C) alkyl, or R x and R y Together with the atoms to which it is attached, it forms a 5-6 membered ring optionally substituted with 1-4 substituents selected from C1-C3 alkyl, to give a compound of formula 19

[0806]

[0807] Among them, ring D, X 1 、X 2 、X 3 and X 4 As defined for Formula I, P 1 is an amino protecting group, and A is H or Cl, followed by removal of the protecting group P 1 and optionally functionalizing Ring D; or

[0808] (h) For compounds of formula I, wherein A is H or Cl, and B, X 1 、X 2 、X 3 、X 4 , ring D and E are as defined for formula I, in the presence of a palladium catalyst and optionally a ligand, and in the presence of a base, a compound of the formula

[0809]

[0810] wherein A is H or Cl, and B is as defined for formula I, coupled with the corresponding boronate of formula 10

[0811]

[0812] Among them, ring D, X 1 、X 2 、X 3 and X 4 As defined for Formula I; P 1 is an amino protecting group; Z is -B(OR x )(OR y ), and R z and R y is H or (1-6C) alkyl, or R x and R y Together with the atoms to which it is attached, it forms a 5-6 membered ring optionally substituted with 1-4 substituents selected from C1-C3 alkyl, giving a compound of the formula

[0813]

[0814] Among them, ring D, X 1 、X 2 、X 3 、X 4 and B are as defined for Formula I; A is H or Cl; and P 1 is an amino protecting group, followed by removal of the protecting group P 1 and optionally functionalizing ring D;

[0815] (i) For compounds of formula I, wherein A is H, and B, X 1 、X 2 、X 3 、X 4 , Ring D and E are as defined for Formula I, and the compound of Formula 24

[0816]

[0817] Among them L 2 is a leaving group, and B, X 1 、X 2 、X 3 and X 4 As defined for formula I, coupled with a compound of formula 15

[0818]

[0819] Among them, P 1 is an amino protecting group, and ring D is as defined for formula I, to give a compound of formula 20

[0820]

[0821] Among them, P 1 is an amino protecting group, and ring D, X 1 、X 2 、X 3 、X 4 and B are as defined for formula I, followed by removal of the protecting group P 1 and optionally functionalizing Ring D; and

[0822] Any additional protecting groups, if present, are removed, and a pharmaceutically acceptable salt thereof is optionally formed.

[0823] As used herein, the term "amino protecting group" refers to a derivative of a group that is typically used to block or protect an amino group and to react with other functional groups on a compound. Examples of suitable protecting groups for use in any of the methods described herein include carbamates, amides, alkyl and aryl groups, imines, and many N-heteroatom derivatives, which can be removed to regenerate the desired amine group. Non-limiting examples of amino protecting groups are acetyl, trifluoroacetyl, tert-butyloxycarbonyl ("Boc"), benzyloxycarbonyl ("CBz"), and 9-fluorenylmethyleneoxycarbonyl ("Fmoc"). Other examples of these groups and other protecting groups are found in: TW Greene et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.

[0824] The hydroxy group can be protected with any suitable hydroxy protecting group, such as those described in TW Greene et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006. Examples include benzyl, trityl, silyl ether, and the like.

[0825] The nitrogen atom in the compound described in any of the above methods may be protected with a suitable nitrogen protecting group, for example, as described in Greene and Wuts, eds., "Protecting Groups in Organic Synthesis," 2nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of nitrogen protecting groups include acyl and alkoxycarbonyl groups, such as tert-butoxycarbonyl (BOC), phenoxycarbonyl, and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0826] The ability of a test compound to act as a RET inhibitor can be shown by the assay described in Example A. 50 The values ​​are shown in Table 5.

[0827] In some embodiments, the compounds provided herein exhibit potent and selective inhibition of RET. For example, the compounds provided herein exhibit nanomolar potency against wild-type RET and select RET mutants, including the KIF5B-RET fusion and the V804M gatekeeper mutant, with minimal activity against related kinases.

[0828] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, selectively targets RET kinase. For example, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, can selectively target RET kinase over another kinase or non-kinase target.

[0829] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, exhibits at least 30-fold selectivity for RET kinase over another kinase. For example, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, exhibits at least 40-fold selectivity, at least 50-fold selectivity, at least 60-fold selectivity, at least 70-fold selectivity, at least 80-fold selectivity, at least 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 RET kinase over another kinase. In some embodiments, the selectivity for RET kinase over another kinase is measured in a cell assay (e.g., a cell assay as provided herein).

[0830] In some embodiments, provided herein are compounds that may exhibit selectivity for RET kinases that is superior to KDR kinases (e.g., VEGFR2). In some embodiments, selectivity for RET kinases that is superior to KDR kinases is observed without losing gatekeeper mutant potency. In some embodiments, compared to inhibiting KIF5B-RET, the selectivity of KDR kinases is at least 10 times higher (e.g., at least 40 times the selectivity, at least 50 times the selectivity, at least 60 times the selectivity, at least 70 times the selectivity, at least 80 times the selectivity, at least 90 times the selectivity, at least 100 times the selectivity, at least 150 times the selectivity, at least 200 times the selectivity, at least 250 times the selectivity, at least 300 times the selectivity, at least 350 times the selectivity, or at least 400 times the selectivity) (i.e., the compound is more potent than KDR for KIF5B-RET). In some embodiments, the selectivity for RET kinases is about 30 times higher than that of KDR kinases. In some embodiments, the selectivity for RET kinases is at least 100 times higher than that of KDR kinases. In some embodiments, the selectivity for RET kinases is at least 150 times higher than that of KDR kinases. In some embodiments, the selectivity for RET kinase is at least 400-fold greater than that for KDR kinase. Without being bound by any theory, potent KDR kinase inhibition is believed to be a common feature among multikinase inhibitors (MKIs) targeting RET and may be the root cause of the dose-limiting toxicity observed for this class of compounds.

[0831] In some embodiments, the inhibition of V804M is similar to that observed for wild-type RET. For example, the inhibition of V804M is within about 2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) of the inhibition of wild-type RET (i.e., the compound has similar potency to wild-type RET and V804M). In some embodiments, the selectivity for wild-type 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.

[0832] In some embodiments, provided herein are compounds that exhibit brain and / or central nervous system (CNS) permeability. Such compounds are capable of crossing the blood-brain barrier and inhibiting RET kinases in the brain and / or other CNS structures. In some embodiments, provided herein are compounds that are capable of crossing the blood-brain barrier in a therapeutically effective amount. For example, treating a patient with cancer (e.g., a RET-related cancer, such as a RET-related brain cancer or CNS cancer) may comprise administering (e.g., orally administering) a compound to the patient. In some such embodiments, provided herein are compounds suitable for treating primary brain tumors or metastatic brain tumors.

[0833] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, exhibits one or more of: high GI absorption, low clearance, and low drug-drug interaction potential.

[0834] The compounds of Formula I are useful for treating diseases and disorders treatable with RET kinase inhibitors, such as RET-related diseases and disorders, for example, proliferative disorders (such as cancer, including hematological cancers and solid tumors) and gastrointestinal disorders (such as IBS).

[0835] As used herein, the term "treat" or "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, complete or partial relief of symptoms associated with a disease, disorder, or condition, lessening of the extent of the disease, stabilization (i.e., non-worsening) of the disease state, delay or slowing of disease progression, improvement or alleviation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also refer to an extension of survival compared to expected survival if not receiving treatment.

[0836] As used herein, the terms "subject" or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the individual has experienced and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the individual has been identified or diagnosed as having a cancer (RET-related cancer) in which the expression or activity or level of the RET gene, RET protein, or any one thereof is abnormally regulated (e.g., as determined using an assay or kit approved by an administrative agency, such as an FDA-approved assay). In some embodiments, the individual has a tumor that is positive for abnormal expression or activity or level of the RET gene, RET protein, or any one thereof (e.g., as determined using an assay or kit approved by an administrative agency). The individual can be an individual with a tumor that is positive for abnormal expression or activity or level of the RET gene, RET protein, or any one thereof (e.g., identified as positive using an assay or kit approved by an administrative agency, such as an FDA-approved assay). The individual may be an individual whose tumor has a RET gene, RET protein, or any one thereof with abnormal expression or activity or level regulation (e.g., wherein the tumor is also identified using a regulatory agency approved, e.g., FDA-approved kit or assay). In some embodiments, the individual is suspected of having a RET-related cancer. In some embodiments, the individual has a clinical record indicating that the individual has a tumor with abnormal expression or activity or level regulation of the RET gene, RET protein, or any one thereof (and optionally the clinical record indicates that the individual should be treated with any one of the compositions provided herein). In some embodiments, the patient is a pediatric patient.

[0837] As used herein, the term "pediatric patient" refers to a patient under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (two to 12 years); and adolescents (12 to 21 years (up to but not including the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics, 21st ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric patient is from birth to the first 28 days of life, 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age to 21 years of age (up to but not including the twenty-second birthday). In some embodiments, the pediatric patient is from birth to the first 28 days of life, 29 days of age to less than one year of age, one month of age to less than four months of age, three months of age to less than seven months of age, six months of age to less than one year of age, one year of age to less than two years of age, two years of age to less than three years of age, two years of age to less than seven years of age, three years of age to less than five years of age, five years of age to less than 10 years of age, six years of age to less than 13 years of age, 10 years of age to less than 15 years of age, or 15 years of age to less than 22 years of age.

[0838] In certain embodiments, compounds of Formula I are useful for preventing diseases and conditions as defined herein (e.g., autoimmune diseases, inflammatory diseases, and cancer). As used herein, the term "prevent" or "prevent" means to prevent, in whole or in part, the onset, recurrence, or spread of a disease or condition, or its symptoms, as described herein.

[0839] As used herein, the term "RET-related disease or disorder" refers to a disease or disorder associated with or having dysregulation of the expression, activity, or level of a RET gene, RET kinase (also referred to herein as a RET kinase protein), or any one (e.g., one or more) thereof (e.g., any type of dysregulation of the expression, activity, or level of a RET gene, RET kinase, RET kinase domain, or any one thereof described herein). Non-limiting examples of RET-related diseases or disorders include, for example, cancer and gastrointestinal disorders such as irritable bowel syndrome (IBS).

[0840] As used herein, the term "RET-related cancer" refers to a cancer that is associated with or has dysregulation of the expression, activity, or level of the RET gene, RET kinase (also referred to herein as RET kinase protein), or any one thereof. Non-limiting examples of RET-related cancers are described herein.

[0841] The phrase "dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any thereof" refers to a gene mutation (e.g., a RET gene translocation that results in the expression of a fusion protein, a deletion in the RET gene that results in the expression of a RET protein comprising a deletion of at least one amino acid compared to the wild-type RET protein, a mutation in the RET gene that results in the expression of a RET protein having one or more point mutations, or an alternatively spliced ​​version of RET mRNA that results in a deletion of at least one amino acid in the RET protein compared to the wild-type RET protein), or amplification of the RET gene that results in overexpression of the RET gene in a cell (which results in a pathogenic increase in the activity of the kinase domain of the RET protein (e.g., the constitutively active kinase domain of the RET protein) in the cell). As another example, dysregulation of the expression, activity, or level of the RET gene, RET protein, or any thereof may be a mutation in the RET gene encoding the RET protein that encodes a RET protein that is constitutively active or has increased activity compared to a protein encoded by a RET gene that does not contain the mutation. For example, abnormal regulation of the expression, activity, or level of the RET gene, RET protein, or any one thereof may be the result of a gene or chromosomal translocation that results in the expression of a fusion protein containing a first portion RET comprising a functional kinase domain and a second portion chaperone (ie, not RET). In some examples, abnormal regulation of the expression, activity, or level of the RET gene, RET protein, or any one thereof may be the result of a gene translocation of a RET gene with another non-RET gene. Non-limiting examples of fusion proteins are described in Table 1. Non-limiting examples of RET kinase protein point mutations / insertions / deletions are described in Table 2. Other examples of RET kinase protein mutations (eg, point mutations) are RET inhibitor resistance mutations. Non-limiting examples of RET inhibitor resistance mutations are described in Tables 3 and 4.

[0842] The term "wildtype" or "wild-type" describes a nucleic acid (e.g., a RET gene or RET mRNA) or protein (e.g., a RET protein) found in an individual who does not have a RET-related disease (e.g., a RET-related cancer) (and optionally, does not have an increased risk of developing a RET-related disease and / or is not suspected of having a RET-related disease), or a nucleic acid or protein found in cells or tissues from an individual who does not have a RET-related disease (e.g., a RET-related cancer) (and optionally, does not have an increased risk of developing a RET-related disease and / or is not suspected of having a RET-related disease).

[0843] The term "regulatory agency" refers to a national agency that approves the medical use of national pharmaceutical agents. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0844] Provided herein is a method for treating a cancer (e.g., a RET-related 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. For example, provided herein is a method for treating a RET-related cancer in a patient in need of such treatment, the method comprising: a) detecting abnormal regulation of the expression or activity or level of the RET gene, RET protein, or any one thereof in a sample from the patient; and b) administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, abnormal regulation of the expression or activity or level of the RET gene, RET protein, or any one thereof comprises one or more fusion proteins. Non-limiting examples of RET gene fusion proteins are described in Table 1. In some embodiments, the fusion protein is KIF5B-RET. In some embodiments, abnormal regulation of the expression or activity or level of the RET gene, RET kinase, or any one thereof comprises one or more RET kinase protein point mutations / insertions. Non-limiting examples of RET kinase protein point mutations / insertions / deletions are described in Table 2. In some embodiments, the RET kinase protein point mutation / insertion / deletion is selected from the group consisting of: M918T, M918V, C634W, V804L and V804M. In some embodiments, the compound of Formula I is selected from: i) Example Nos. 1-20; ii) Example Nos. 21-40; iii) Example Nos. 41-60; iv) Example Nos. 61-80; v) Example Nos. 81-100; vi) Example Nos. 101-120; vii) Example Nos. 121-140; viii) Example Nos. 141-160; ix) Example Nos. 161-180; x) Example Nos. 181-200; xi) Example Nos. 201-220; xii) Example Nos. 221-240; xiii) Example Nos. 241-260; xiv) Example Nos. 261-280; xv) Example Nos. 281-300; xvi) Example Nos. 301-320; xvii) Example Nos. 321-340; xviii) Example Nos. 341-360; xix) Example Nos. 361-380; xx) Example Nos. 381-400; xxi) Example Nos. 401-420; xxii) Example Nos. 421-440; xxiii) Example Nos. 441-460; xxiii) Example Nos. 461-480; xxiv) Example Nos. 481-500; xxv) Example Nos. 501-520; xxvi) Example Nos. 521-540; or xxvii) Example Nos. 541-561, or a pharmaceutically acceptable salt or solvate thereof.

[0845] In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is a blood cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is a lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland tumor, lung adenocarcinoma, bronchiolar lung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, breast neoplasm, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma, inflammatory myofibroblastoma, or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-related cancer) is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), juvenile cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, heart tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, neoplasms by site), tumors, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, bile duct cancer, ductal carcinoma in situ, embryonal tumors, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors;GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic neoplasm, head and neck neoplasm, CNS tumor, primary CNS tumor, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma carcinoma, mesothelioma, metastatic squamous cell carcinoma, cervical cancer, midline cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, localized neoplasm, neoplasm, myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, lung neoplasm, lung cancer, pulmonary neoplasms, respiratory tract cancer, bronchial cancer, bronchial neoplasm, oral cancer, oral cavity cancer cancer), lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasm, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colon neoplasm, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, stomach cancer, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, cancer of unknown primary, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0846] In some embodiments, the blood cancer (e.g., a blood cancer that is a RET-associated cancer) is selected from the group consisting of: leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin's lymphoma), and myeloma, e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), and myeloma. leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorder (MPD), and multiple myeloma (MM). Other examples of hematologic cancers include myeloproliferative disorders (MPDs), such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF / IPF / PMF). In one embodiment, the hematologic cancer (e.g., a hematologic cancer that is a RET-associated cancer) is AML or CMML.

[0847] In some embodiments, the cancer (e.g., a RET-related cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are RET-related cancers) include, for example, thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer), lung cancer (e.g., lung adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic ductal carcinoma, breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell carcinoma, head and neck tumors, neuroblastoma, and melanoma. See, for example, Nature Reviews Cancer, 2014, 14, 173-186.

[0848] In some embodiments, the 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, gastrointestinal ganglioneuroma, and cervical cancer.

[0849] In some embodiments, the patient is a human.

[0850] The compounds of formula I and pharmaceutically acceptable salts and solvates thereof are also suitable for treating RET-related cancers.

[0851] Thus, also provided herein is a method for treating a patient diagnosed with or identified as having a RET-related cancer (e.g., any exemplary RET-related cancer disclosed herein), comprising administering to the patient a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0852] Abnormal regulation of the expression or activity or level of RET kinase, RET gene, or any one thereof (e.g., one or more) can promote tumorigenesis. For example, abnormal regulation of the expression or activity or level of RET kinase, RET gene, or any one thereof can be a translocation, overexpression, activation, amplification, or mutation of RET kinase, RET gene, or RET kinase domain. Translocation can include a translocation involving a RET kinase domain, a mutation can include a mutation involving a RET ligand binding site, and amplification can be an amplification of a RET gene. Other abnormalities can include RET mRNA splice variants and RET autocrine / paracrine signaling, which can also promote tumorigenesis.

[0853] In some embodiments, the expression or activity or level of the RET gene, RET kinase, or any one thereof is abnormally regulated, comprising overexpression of wild-type RET kinase (e.g., resulting in autocrine activation). In some embodiments, the expression or activity or level of the RET gene, RET kinase protein, or any one thereof is abnormally regulated, comprising overexpression, activation, amplification, or mutation of a chromosomal segment comprising the RET gene or a portion thereof, comprising, for example, a kinase domain portion, or a portion capable of exhibiting kinase activity.

[0854] In some embodiments, the dysregulation of expression, activity, or levels of the RET gene, RET kinase protein, or any thereof comprises one or more chromosomal translocations or inversions resulting in RET gene fusions. In some embodiments, the dysregulation of expression, activity, or levels of the RET gene, RET kinase protein, or any thereof is the result of a gene translocation, wherein the expressed protein is a fusion protein containing residues from a non-RET partner protein and comprises at least one functional RET kinase domain.

[0855] Non-limiting examples of RET fusion proteins are shown in Table 1.

[0856] Table 1. Exemplary RET fusion partners and cancers

[0857]

[0858]

[0859] 1 Grubbs et al., J. Clin. Endocrinol. Metab. 100: 788-793, 2015.

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[0898] In some embodiments, the expression or activity or level of the RET gene, RET kinase, or any thereof is dysregulated, comprising one or more deletions (e.g., a deletion of an amino acid at position 4), insertions, or point mutations in the RET kinase. In some embodiments, the expression or activity or level of the RET gene, RET kinase, or any thereof is dysregulated, comprising deletion of one or more residues from the RET kinase, resulting in constitutive activity of the RET kinase domain.

[0899] In some embodiments, the expression or activity or level of the RET gene, RET kinase, or any thereof is dysregulated, comprising at least one point mutation in the RET gene that results in a RET kinase having one or more amino acid substitutions, insertions, or deletions compared to wild-type RET kinase (see, e.g., the point mutations listed in Table 2).

[0900] Table 2. Activating RET kinase protein point mutations / insertions / deletions

[0901]

[0902]

[0903]

[0904]

[0905]

[0906] 1 U.S. Patent Application Publication No. 2014 / 0272951.

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[0917] 12 PCT Patent Application Publication No. WO 2016 / 127074.

[0918] 13 Huang et al. Mol. Cancer Ther., 2016, Aug. 5. pii:molcanther.0258.2016. [Epub ahead of print].

[0919] 14 Carlomagno et al., Endocr. Rel. Cancer 16(1): 233-41, 2009.

[0920] 15 Yoon et al., J. Med. Chem. 59(1): 358-73, 2016.

[0921] 16 U.S. Patent No. 8,629,135.

[0922] 17 Cranston et al., Cancer Res. 66(20): 10179-87, 2006.

[0923] 18 Kheiroddin et al., Clin. Lab. 62(5):871-6, 2016.

[0924] 19 Ceolin et al., PLoS One. 11(2): e0147840, doi: 10.1371 / journal.pone.0147840, 2016.

[0925] 20Nadezda et al., Summer Undergraduate Research Programs (SURP) Student Abstracts, University of Oklahoma Health Sciences Center, 2016.

[0926] 21 Liu et al., J. Biol. Chem., 271(10): 5309-12, 1995.

[0927] 22 Kato et al., Cancer Res., 62: 2414-22, 2002.

[0928] 23 Grey et al., Endocrine Pathology, doi:10.1007 / s12022-016-9451-6, 2016.

[0929] 24 De Almeida et al., Endocrine Reviews, 2016, Volume 37, Issue 2, Supplement 1. Abstract number: SUN-068; Presented at the 98th Annual Meeting and Exhibition of the Endocrine Society, ENDO 2016. Boston, MA, USA. April 1–4, 2016.

[0930] 25 Vanden et al., Annals of Oncology, 2016, Volume 27, Supplement 6. Abstract number: 427PD; 41st European Society for Medical Oncology Congress, ESMP 2016. Copenhagen, Denmark. October 7–11, 2016.

[0931] 26 Romei et al., European Thyroid Journal (August 2016), Volume 5, Supplement 1, p. 75; 39th Annual Meeting of the European Thyroid Association, ETA 2016. Copenhagen, Denmark. September 3–6, 2016.

[0932] 27 Lee et al., Oncotarget, 8(4): 6579-6588, doi: 10.18632 / oncotarget.14172, 2017.

[0933] 28 Zhang et al., Laboratory Investigation, Vol. 97, Suppl. 1, p. 209A (February 2017). Abstract ID: 840. Conference information: 106th Annual Meeting of the American and Canadian Academy of Pathology, USCAP 2017. San Antonio, TX, USA.

[0934] 29 Borecka et al., European Journal of Cancer, (July 2016), Vol. 61, No. 1, p. S26, Abstract No. 162, Conference Information: 24th European Association for Cancer Research Biennial Congress, EACR 2016. Manchester, UK.

[0935] 30 Corsello et al., Endocrine Reviews, Vol. 35, No. 3, Suppl. S, p. SUN-0322 (June 2014), Conference Information: 96th Annual Meeting and Exhibition of the Endocrine Society, Chicago, IL, USA, June 21–24, 2014.

[0936] 31 Gazizova et al., Endocrine Reviews, Vol. 35, No. 3, Suppl. S, p. SAT-0304 (June 2014), Conference Information: 96th Annual Meeting and Exhibition of the Endocrine Society, Chicago, IL, USA, June 21–24, 2014.

[0937] 32 Sromek et al., Endocr Pathol., doi: 10.1007 / s12022-017-9487-2, 2017.

[0938] In some embodiments, the expression or activity or level of the RET gene, RET kinase, or any thereof is dysregulated, comprising at least one point mutation in the RET gene that results in a RET kinase having one or more amino acid substitutions, insertions, or deletions compared to wild-type RET kinase (see, e.g., the point mutations listed in Table 2a).

[0939] Table 2a Exemplary activating RET kinase protein point mutations / insertions / deletions

[0940]

[0941]

[0942]

[0943]

[0944] In some embodiments, the dysregulation of expression or activity or levels of the RET gene, RET kinase, or any thereof comprises a splice variation in RET mRNA that results in expression of a protein that is an alternative splice variant of RET lacking at least one residue compared to wild-type RET kinase, resulting in constitutive activity of the RET kinase domain.

[0945] As defined herein, a "RET kinase inhibitor" comprises any compound that exhibits RET inhibitory activity. In some embodiments, the RET kinase inhibitor is selective for RET kinase. Exemplary RET kinase inhibitors may exhibit inhibitory activity (IC) against RET kinase. 50 ), the inhibitory activity is less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM as measured by an assay described herein. In some embodiments, a RET kinase inhibitor may exhibit inhibitory activity (IC) against RET kinase. 50 ), the inhibitory activity is less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as measured by the assays provided herein.

[0946] As used herein, a "first RET kinase inhibitor" or "first RET inhibitor" is a RET kinase inhibitor as defined herein, but does not include a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof. As used herein, a "second RET kinase inhibitor" or "second RET inhibitor" is a RET kinase inhibitor as defined herein, but does not include a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof. When both a first and a second RET inhibitor are present in the methods provided herein, the first and second RET kinase inhibitors are different.

[0947] In some embodiments, the expression or activity or level of the RET gene, RET kinase, or any of them is abnormally regulated, comprising at least one point mutation in the RET gene, which results in the production of a RET kinase having one or more amino acid substitutions or insertions or deletions in the RET gene (which results in the production of a RET kinase having one or more amino acids inserted or removed compared to the wild-type RET kinase). In some cases, the resulting RET kinase is more resistant to inhibition of its phosphotransferase activity by one or more first RET kinase inhibitors than the wild-type RET kinase or a RET kinase that does not comprise the same mutation. Optionally, such mutations do not reduce the sensitivity of cancer cells or tumors having the RET kinase to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., compared to cancer cells or tumors that do not comprise a specific RET inhibitor resistance mutation). In such embodiments, when in the presence of a first RET kinase inhibitor, the RET inhibitor resistance mutation may result in a RET kinase having an increased V compared to a wild-type RET kinase or a RET kinase that does not comprise the same mutation in the presence of the same first RET kinase inhibitor. max , K for ATP reduction m and increased K for the first RET kinase inhibitor D .

[0948] In other embodiments, the expression or activity or level of the RET gene, RET kinase, or any thereof is dysregulated, comprising at least one point mutation in the RET gene that results in a RET kinase having one or more amino acid substitutions compared to wild-type RET kinase and increased resistance to a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, compared to a wild-type RET kinase or RET kinase that does not comprise the same mutation. In such embodiments, the RET inhibitor resistance mutation may result in a RET kinase having one or more of the following in the presence of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof: an increased V max , reduced K m and reduced K D .

[0949] Examples of RET inhibitor-resistance mutations include, for example, point mutations, insertions, or deletions within and near the ATP binding site in the tertiary structure of RET kinase, including, but not limited to, gatekeeper residues, P-loop residues, residues within or near the DFG motif, and amino acid residues at the solvent front of the ATP cleft. Other examples of these types of mutations include changes in residues that may affect enzyme activity and / or drug binding, including, but not limited to, residues within the activation loop, residues near or interacting with the activation loop, and residues that contribute to active or inactive enzyme conformations. Changes include mutations, deletions, and insertions within the C-helix and loops within the C-helix. Specific residues or residue regions that can be altered (and are RET inhibitor-resistance mutations) include, but are not limited to, those listed in Table 3 based on the human wild-type RET protein sequence (e.g., SEQ ID NO: 1). Additional examples of RET inhibitor-resistance mutation positions are shown in Table 4. Changes in these residues can include single or multiple amino acid changes, insertions within or flanking the sequence, and deletions within or flanking the sequence.

[0950] Exemplary sequence of mature human RET protein (SEQ ID NO: 1)

[0951]

[0952]

[0953] In some embodiments, compounds of Formula I and pharmaceutically acceptable salts and solvates are indicated for treating patients with cancer that has a RET inhibitor resistance mutation (e.g., that confers increased resistance to a first RET inhibitor, such as a substitution at amino acid position 804, such as V804M, V804L, or V804E, and / or one or more RET inhibitor resistance mutations listed in Tables 3 and 4), by administration in combination with an existing drug therapy (e.g., another RET kinase inhibitor; such as a first and / or second RET kinase inhibitor) or as a follow-up therapy to an existing drug therapy. Exemplary first and second RET kinase inhibitors are described herein. In some embodiments, the first or second RET kinase inhibitor may be selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864.

[0954] In some embodiments, the compounds of Formula I, or pharmaceutically acceptable salts and solvates thereof, are useful for treating cancers that have been identified as having one or more RET inhibitor resistance mutations that confer increased resistance to a first or second RET inhibitor, e.g., substitutions at amino acid position 804, e.g., V804M, V804L, or V804E. Non-limiting examples of RET inhibitor resistance mutations are listed in Tables 3 and 4.

[0955] Table 3. RET inhibitor resistance mutations

[0956] Exemplary RET resistance mutations <![CDATA[Amino acid position 732 (e.g., E732K) 7 > <![CDATA[Amino acid position 788 (e.g., I788N) 8 > <![CDATA[Amino acid position 804 (e.g., V804M 1，2 , V804L 1，2 , V804E 6 )]]> <![CDATA[Amino acid positions 804 / 805 (e.g., V804M / E805K) 3 > <![CDATA[Amino acid position 806 (e.g., Y806C 4，6 , Y806E 4 , Y806S 6 , Y806H 6 , Y806N 6 )]]> <![CDATA[Amino acid position 810 (e.g., G810A 5 , G810R 6 , G810S 6 )]]> <![CDATA[Amino acid position 865 (e.g., L865V 6 )]]> <![CDATA[Amino acid position 870 (e.g., L870F 6 )]]>

[0957] 1 Yoon et al., J. Med. Chem. 59(1): 358-73, 2016.

[0958] 2 U.S. Patent No. 8,629,135.

[0959] 3 Cranston et al., Cancer Res. 66(20): 10179-87, 2006.

[0960] 4 Carlomagno et al., Endocr Rel. Cancer 16(1): 233-41, 2009.

[0961] 5 Huang et al. Mol. Cancer Ther., 2016, Aug 5. pii:molcanther.0258.2016. [Epub ahead of print].

[0962] 6 PCT Patent Application Publication No. WO 2016 / 127074.

[0963] 7 Nadezda et al., Summer Undergraduate Research Programs (SURP) Student Abstracts, University of Oklahoma Health Sciences Center, 2016.

[0964] 8 Plenker et al., Sci. Transl. Med., 9(394), doi: 10.1126 / scitranslmed.aah6144, 2017.

[0965] Table 4. Additional exemplary amino acid positions of RET inhibitor resistance mutations

[0966]

[0967]

[0968] The oncogenic role of RET was first described in papillary thyroid carcinoma (PTC) (Grieco et al., Cell, 1990, 60, 557-63), which originates from follicular thyroid cells and is the most common thyroid malignancy. Approximately 20-30% of PTCs harbor somatic chromosomal rearrangements (translocations or inversions) that link the promoter and the 5′ portion of a constitutively expressed unrelated gene to the RET tyrosine kinase domain (Greco et al., QJ Nucl. Med. Mol. Imaging, 2009, 53, 440-54), thereby driving its ectopic expression in thyroid cells. Fusion proteins generated by such rearrangements are termed "RET / PTC" proteins. For example, RET / PTC 1 is a fusion between CCDD6 and RET that is commonly found in papillary thyroid carcinoma. Similarly, RET / PTC3 and RET / PTC4 are both fusions of ELE1 and RET that are commonly found in papillary thyroid carcinoma, although the fusion events that produce RET / PTC3 and RET / PTC4 produce different proteins with different molecular weights (see, e.g., Fugazzola et al., Oncogene, 13(5):1093-7, 1996). Some RET fusions associated with PTC are not referred to as "RET / PTC" but are instead referred to as the fusion protein itself. For example, fusions between RET and both ELKS and PCM1 are found in PTC, but the fusion proteins are referred to as ELKS-RET and PCM1-RET (see, e.g., Romei and Elisei, Front. Endocrinol. (Lausanne), 3:54, doi:10.3389 / fendo.2012.00054, 2012). The role of the RET-PTC rearrangement in the pathogenesis of PTC has been confirmed in transgenic mice (Santoro et al., Oncogene, 1996, 12, 1821-6). To date, a variety of fusion partners from PTC and other cancer types have been identified, all of which provide protein / protein interaction domains that induce ligand-independent RET dimerization and constitutive kinase activity (see, for example, Table 1).In recent years, a 10.6 Mb pericentric inversion in chromosome 10 (where the RET gene is mapped) has been identified in approximately 2% of lung adenocarcinoma patients, resulting in different variants of the chimeric gene KIF5B-RET (Ju et al., Genome Res., 2012, 22, 436-45; Kohno et al., 2012, Nature Med., 18, 375-7; Takeuchi et al., Nature Med., 2012, 18, 378-81; Lipson et al., 2012, Nature Med., 18, 382-4). The fusion transcripts are highly expressed, and all the resulting chimeric proteins contain the N-terminal portion of the coiled-coil region of KIF5B, which mediates homodimerization, and the entire RET kinase domain. None of the RET-positive patients had other known oncogenic alterations (e.g., EGFR or K-Ras mutations, ALK translocations), supporting the possibility that the KIF5B-RET fusion may be a driver mutation in lung adenocarcinoma. The oncogenic potential of KIF5B-RET has been confirmed by transfection of the fusion gene into cultured cell lines: similar to that observed with the RET-PTC fusion protein, KIF5B-RET is constitutively phosphorylated and induces transformation of NIH-3T3 and growth of IL-3-independent BA-F3 cells. However, other RET fusion proteins have been identified in patients with lung adenocarcinoma, such as the CCDC6-RET fusion protein, which has been found to play a key role in the proliferation of the human lung adenocarcinoma cell line LC-2 / ad (Journal of Thoracic Oncology, 2012, 7(12):1872-1876). RET inhibitors have been shown to be useful in treating lung cancers involving RET rearrangements (Drilon, AE et al. J Clin Oncol 33, 2015 (Suppl; Abstract 8007). RET fusion proteins have also been identified in patients with colorectal cancer (Song Eun-Kee et al. International Journal of Cancer, 2015, 136:1967-1975).

[0969] In addition to rearrangements of the RET sequence, the acquisition of functional point mutations in the RET proto-oncogene also drives carcinogenesis, as shown in medullary thyroid carcinoma (MTC), which originates from parafollicular calcitonin-producing cells (de Groot et al., Endocrine Rev., 2006, 27, 535-60; Wells and Santoro, Clin. Cancer Res., 2009, 15, 7119-7122). Approximately 25% of MTCs are associated with multiple endocrine neoplasia type 2 (MEN2), a group of hereditary cancer syndromes affecting neuroendocrine organs caused by germline activating point mutations in RET. Within the MEN2 subtypes (MEN2A, MEN2B, and familial MTC / FMTC), RET gene mutations have strong phenotype-genotype correlations, defining the different MTC aggressiveness and clinical manifestations of the disease. In MEN2A syndrome, mutations involve one of the six cysteine ​​residues (primarily C634) located in the cysteine-rich extracellular region, leading to ligand-independent homodimerization and constitutive RET activation. Patients develop MTC at a young age (onset between 5 and 25 years) and may also develop pheochromocytomas (50%) and hyperparathyroidism. MEN2B is primarily caused by the M918T mutation, which is located in the kinase domain. This mutation constitutively activates RET in its monomeric state and alters substrate recognition by the kinase. The MEN2B syndrome is characterized by early-onset (<1 year) and extremely aggressive MTC, pheochromocytomas (50% of patients), and ganglioneuromas. In FMTC, the only disease manifestation is MTC, which usually occurs in adulthood. Many different mutations have been detected across the entire RET gene. The remaining 75% of MTC cases are sporadic, and approximately 50% of these have somatic mutations in RET: the most common mutation is M918T, which, as in MEN2B, is associated with the most aggressive phenotype. Somatic point mutations in RET have also been described in other tumors, such as colorectal cancer (Wood et al., Science, 2007, 318, 1108-13) and small cell lung cancer (Jpn. J. Cancer Res., 1995, 86, 1127-30).

[0970] RET signaling components have been found to be expressed in primary breast tumors and to functionally interact with the estrogen receptor-cc pathway in breast tumor cell lines (Boulay et al., Cancer Res. 2008, 68, 3743-51; Plaza-Menacho et al., Oncogene, 2010, 29, 4648-57), and RET expression and activation through GDNF family ligands may play an important role in perineural invasion of different types of cancer cells (Ito et al., Surgery, 2005, 138, 788-94; Gil et al., J. Natl. Cancer Inst., 2010, 102, 107-18; Iwahashi et al., Cancer, 2002, 94, 167-74).

[0971] RET is also expressed in 30-70% of invasive breast cancers, with expression being relatively more frequent in estrogen receptor-positive tumors (Plaza-Menacho, I. et al., Oncogene, 2010, 29, 4648-4657; Esseghir, S. et al., Cancer Res., 2007, 67, 11732-11741; Morandi, A. et al., Cancer Res., 2013, 73, 3783-3795; Gattelli, A., EMBO Mol. Med., 2013, 5, 1335-1350).

[0972] The identification of RET rearrangements has been reported in a subset of PDXs (patient-derived xenografts) established from colorectal cancer. Although the frequency of such events in colorectal cancer patients remains to be determined, these data suggest that RET plays a targetable role in this indication (Gozgit et al., AACR Annual Meeting 2014). Studies have shown that the RET promoter is frequently methylated in colorectal cancer, and heterozygous missense mutations predicted to reduce RET expression are identified in 5-10% of cases, suggesting that RET may have some characteristics of a tumor suppressor in sporadic colon cancer (Luo, Y et al., Oncogene, 2013, 32, 2037-2047; Sjoblom, T. et al., Science, 2006, 268-274; Cancer Genome Atlas Network, Nature, 2012, 487, 330-337).

[0973] An increasing number of tumor types are now shown to express substantial levels of wild-type RET kinase, which may have an impact on tumor progression and spread. RET is expressed in 50-65% of pancreatic ductal carcinomas and is more frequently expressed in metastatic and higher-grade tumors (Ito, Y. et al., Surgery, 2005, 138, 788-794; Zeng, Q. et al., Int. Med. Res. 2008, 36, 656-664).

[0974] Among neoplasms of the hematopoietic lineage, RET is expressed in acute myeloid leukemia (AML) with monocytic differentiation and in CMML (Gattei, V. et al., Blood, 1997, 89, 2925-2937; Gattei, V. et al., Ann. Hematol, 1998, 77, 207-210; Camos, M., Cancer Res. 2006, 66, 6947-6954). Recent studies have identified rare chromosomal rearrangements involving RET in patients with chronic myelomonocytic leukemia (CMML). CMML is often associated with the rearrangement of several tyrosine kinases, which leads to the expression of chimeric cytoplasmic tumor proteins that lead to activation of the RAS pathway (Kohlmann, A. et al., J. Clin. Oncol. 2010, 28, 2858-2865). In the case of RET, gene fusions linking RET to BCR (BCR-RET) or to the fibroblast growth factor receptor 1 oncogene partner (FGFR10P-RET) transform early hematopoietic progenitor cells and, possibly by initiating RET-mediated RAS signaling, can divert these cells toward the monocytic pathway of maturation (Ballerini, P et al., Leukemia, 2012, 26, 2384-2389).

[0975] RET expression has also been shown to occur in several other tumor types, including prostate cancer, small cell lung cancer, melanoma, renal cell carcinoma, and head and neck tumors (Narita, N. et al., Oncogene, 2009, 28, 3058-3068; Mulligan, L., M. et al., Genes Chromosomes Cancer, 1998, 21, 326-332; Flavin, R. et al., Urol. Oncol., 2012, 30, 900-905; Dawson, DM, J Natl Cancer Inst, 1998, 90, 519-523).

[0976] In neuroblastoma, RET expression and activation through GFL play a role in tumor cell differentiation, possibly cooperating with other neurotrophic factor receptors to downregulate N-Myc, whose expression is a marker of poor prognosis (Hofstra, RM, W. et al., Hum. Genet. 1996, 97, 362-364; Petersen, S. and Bogenmann, E., Oncogene, 2004, 23, 213-225; Brodeur, GM, Nature Ref. Cancer, 2003, 3, 203-216).

[0977] Multi-target inhibitors are known to cross-react with RET (Borrello, MG et al., Expert Opin. Ther. Targets, 2013, 17(4), 403-419; International Patent Application Nos. WO 2014 / 141187, WO 2014 / 184069, and WO 2015 / 079251).

[0978] Thus, provided herein are methods for treating a patient diagnosed with (or identified as having) cancer, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. Also provided herein are methods for treating a patient identified or diagnosed as having RET-related cancer, 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. In some embodiments, a patient is identified or diagnosed with RET-related cancer by using a test or assay approved by a regulatory agency, such as an FDA-approved test for confirming abnormal expression or activity or level regulation of a RET gene, RET kinase, or any one thereof in a biopsy sample from a patient, or by performing any non-limiting example of an assay described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a RET-related cancer. For example, a RET-related cancer can be a cancer comprising one or more RET inhibitor resistance mutations.

[0979] Also provided are methods for treating cancer in patients in need thereof, the methods comprising: (a) determining whether the patient's cancer is a RET-related cancer; and (b) if the cancer is determined to be a RET-related 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. Some embodiments of these methods further comprise administering another anticancer agent (e.g., a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy) to the individual. In some embodiments, the individual was previously treated with a first RET inhibitor or was previously treated with another anticancer treatment (e.g., tumor resection or radiotherapy). In some embodiments, the patient is determined to have a RET-related cancer by using a test or assay approved by a regulatory agency, such as an FDA-approved test for confirming abnormal expression or activity or level regulation of a RET gene, RET kinase, or any one thereof in a biopsy sample from a patient, or by performing any non-limiting example of an assay described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a RET-related cancer. For example, a RET-related cancer can be a cancer comprising one or more RET inhibitor resistance mutations.

[0980] Also provided are methods for treating patients, comprising assaying a sample obtained from the patient to determine whether the patient has a RET gene, RET kinase, or any one thereof, expression or activity or level abnormality, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof to a patient assayed for a RET gene, RET kinase, or any one thereof, expression or activity or level abnormality. Some embodiments of these methods further comprise administering another anticancer agent (e.g., a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy) to the individual. In some embodiments of these methods, the individual was previously treated with a first RET inhibitor or was previously treated with another anticancer treatment (e.g., tumor resection or radiotherapy). In some embodiments, the patient is a patient suspected of having a RET-related cancer, a patient suffering from one or more symptoms of a RET-related cancer, or a patient at high risk of developing a RET-related cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or split FISH analysis. In some embodiments, the assay is an assay approved by a regulatory agency, such as an FDA-approved kit. Other non-limiting assays that can be used in these methods are described herein. Other assays are also known in the art.In some embodiments, the expression or activity or level of the RET gene, RET kinase, or any thereof is dysregulated, comprising one or more RET inhibitor resistance mutations.

[0981] Also provided is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating a RET-related cancer in a patient identified or diagnosed as having a RET-related cancer by performing an assay (e.g., an in vitro assay) on a sample obtained from the patient to determine whether the patient has dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any of them, wherein the presence of dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any of them determines that the patient has a RET-related cancer. Also provided is the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for treating a RET-related cancer in a patient identified or diagnosed as having a RET-related cancer by performing an assay on a sample obtained from the patient to determine whether the patient has dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any of them, wherein the presence of dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any of them determines that the patient has a RET-related cancer. Some embodiments of any of the methods or uses described herein further comprise recording in the patient's clinical record (e.g., computer-readable media) that the patient is determined to have abnormal regulation of expression or activity or level of the RET gene, RET kinase, or any one thereof by performing an assay, and should be administered a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or split FISH analysis. In some embodiments, the assay is an assay approved by a regulatory agency, such as an FDA-approved kit. In some embodiments, the expression or activity or level of the RET gene, RET kinase, or any one thereof is abnormally regulated, comprising one or more RET inhibitor resistance mutations.

[0982] Also provided is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for treating a patient in need or a patient identified or diagnosed as having a RET-related cancer. Also provided is the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a cancer in a patient identified or diagnosed as having a RET-related cancer. In some embodiments, the cancer is a RET-related cancer, for example, a RET-related cancer with one or more RET inhibitor resistance mutations. In some embodiments, the patient is identified or diagnosed as having a RET-related cancer by using an approved by a regulatory agency, such as an FDA-approved method for confirming abnormal expression or activity or level of a RET gene, RET kinase, or any one thereof in a biopsy sample from a patient or from a sample. As provided herein, RET-related cancers include those described herein and known in the art.

[0983] In some embodiments of any of the methods or uses described herein, the patient has been identified or diagnosed as having a cancer with a RET gene, RET kinase, or any one thereof having an abnormal expression or activity or level of RET. In some embodiments of any of the methods or uses described herein, the patient has a tumor that is positive for a RET gene, RET kinase, or any one thereof having an abnormal expression or activity or level of RET. In some embodiments of any of the methods or uses described herein, the patient may be a patient with a tumor that is positive for a RET gene, RET kinase, or any one thereof having an abnormal expression or activity or level of RET. In some embodiments of any of the methods or uses described herein, the patient may be a patient whose tumor has an abnormal expression or activity or level of RET gene, RET kinase, or any one thereof. In some embodiments of any of the methods or uses described herein, the patient is suspected of having a RET-related cancer (e.g., a cancer with one or more RET inhibitor resistance mutations). In some embodiments, provided herein are methods for treating RET-related cancers in patients in need of such treatment, comprising: a) detecting dysregulation of expression, activity, or levels of a RET gene, RET kinase, or any thereof in a sample from the patient; and b) administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, dysregulation of expression, activity, or levels of a RET gene, RET protein, or any thereof comprises one or more fusion proteins. Non-limiting examples of RET gene fusion proteins are described in Table 1. In some embodiments, the fusion protein is KIF5B-RET. In some embodiments, dysregulation of expression, activity, or levels of a RET gene, RET kinase, or any thereof comprises one or more RET kinase protein point mutations / insertions / deletions. Non-limiting examples of RET kinase protein point mutations / insertions / deletions are described in Table 2. In some embodiments, the RET kinase protein point mutation / insertion / deletion is selected from the group consisting of: M918T, M918V, C634W, V804L, and V804M. In some embodiments, the expression or activity or level of the RET gene, RET kinase, or any one thereof is abnormally regulated, comprising one or more RET inhibitor resistance mutations. Non-limiting examples of RET inhibitor resistance mutations are described in Tables 3 and 4. In some embodiments, the RET inhibitor resistance mutation is V804M. In some embodiments, a cancer having abnormal expression or activity or level of the RET gene, RET kinase, or any one thereof is determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit. In some embodiments, a tumor positive for abnormal expression or activity or level of the RET gene, RET kinase, or any one thereof is a tumor positive for one or more RET inhibitor resistance mutations.In some embodiments, a tumor having dysregulated expression or activity or levels of a RET gene, RET kinase, or either thereof is determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit.

[0984] In some embodiments of any of the methods or uses described herein, the patient has a clinical record indicating that the patient has a tumor with abnormal expression or activity or level regulation of the RET gene, RET kinase, or any one thereof (e.g., a tumor with one or more RET inhibitor resistance mutations). In some embodiments, the clinical record indicates that the patient should be treated with one or more of the compounds of Formula I provided herein, or a pharmaceutically acceptable salt or solvate thereof, or a composition thereof. In some embodiments, a cancer with abnormal expression or activity or level regulation of the RET gene, RET kinase, or any one thereof is a cancer with one or more RET inhibitor resistance mutations. In some embodiments, an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit, is used to determine a cancer with abnormal expression or activity or level regulation of the RET gene, RET kinase, or any one thereof. In some embodiments, a tumor positive for abnormal expression or activity or level regulation of the RET gene, RET kinase, or any one thereof is a tumor positive for one or more RET inhibitor resistance mutations. In some embodiments, an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit, is used to determine a tumor with abnormal expression or activity or level regulation of the RET gene, RET kinase, or any one thereof.

[0985] Also provided is a method for treating a patient, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof to a patient, the patient having a clinical record indicating that the patient has abnormal regulation of expression or activity or level of the RET gene, RET kinase, or any one thereof. Also provided is the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for treating a patient's RET-related cancer, the patient having a clinical record indicating that the patient has abnormal regulation of expression or activity or level of the RET gene, RET kinase, or any one thereof. Some embodiments of these methods and uses may further comprise: performing an assay step on a sample obtained from a patient to determine whether the patient has abnormal regulation of expression or activity or level of the RET gene, RET kinase, or any one thereof, and recording the information in the patient's clinical file (e.g., a computer-readable medium), the patient having been identified as having abnormal regulation of expression or activity or level of the RET gene, RET kinase, or any one thereof. In some embodiments, the assay is an in vitro assay. For example, an assay utilizing next-generation sequencing, immunohistochemistry, or split FISH analysis. In some embodiments, the assay is an agency-approved, such as an FDA-approved kit. In some embodiments, the expression or activity or level of the RET gene, RET kinase, or any thereof is dysregulated, comprising one or more RET inhibitor resistance mutations.

[0986] Also provided herein is a method for treating an individual. The method includes measuring a sample obtained from an individual to determine whether the individual has an expression or activity or level abnormality of the RET gene, RET protein, or any one thereof. The method also includes administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to an individual who is determined to have an expression or activity or level abnormality of the RET gene, RET protein, or any one thereof. In some embodiments, the expression or activity or level abnormality of the RET gene, RET protein, or any one thereof is a gene or chromosomal translocation that results in the expression of a RET fusion protein (e.g., any one of the RET fusion proteins described herein). In some embodiments, the RET fusion may be selected from a KIF5B-RET fusion and a CCDC6-RET fusion. In some embodiments, the expression or activity or level abnormality of the RET gene, RET kinase protein, or any one thereof is one or more point mutations in the RET gene (e.g., any one of one or more of the RET point mutations described herein). One or more point mutations in the RET gene can result in, for example, translation of a RET protein having one or more of the following amino acid substitutions: M918T, M918V, C634W, V804L, and V804M. In some embodiments, the abnormal regulation of expression, activity, or level of the RET gene, RET kinase protein, or any of them is one or more RET inhibitor resistance mutations (e.g., any combination of one or more RET inhibitor resistance mutations described herein). Some embodiments of these methods further comprise administering another anticancer agent (e.g., a second RET inhibitor, a second compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy) to the individual.

[0987] In some embodiments, provided herein are compounds that exhibit brain and / or central nervous system (CNS) permeability. Such compounds are capable of crossing the blood-brain barrier and inhibiting RET kinases in the brain and / or other CNS structures. In some embodiments, provided herein are compounds that are capable of crossing the blood-brain barrier in a therapeutically effective amount. For example, treating a patient with cancer (e.g., a RET-related cancer, such as a RET-related brain or CNS cancer) may comprise administering (e.g., orally administering) a compound to the patient. In some such embodiments, provided herein are compounds suitable for treating primary brain tumors or metastatic brain tumors. For example, the compounds can be used to treat one or more of the following: gliomas, such as glioblastomas (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas; meningiomas; medulloblastomas; gangliogliomas; schwannomas / neurilemmomas, and craniopharyngiomas (see, e.g., DN et al., Acta Neuropathol 131(6), 803-820 (June 2016) for a list of tumors). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the patient has previously been treated with another anticancer agent, e.g., another RET inhibitor (e.g., a compound that is not a compound of Formula I) or a multikinase inhibitor. In some embodiments, the brain tumor is a metastatic brain tumor. In some embodiments, the patient has previously been treated with another anticancer agent, e.g., another RET inhibitor (e.g., a compound that is not a compound of Formula I) or a multikinase inhibitor.

[0988] Also provided are methods for selecting a treatment for a patient identified or diagnosed as having a RET-related cancer (e.g., an in vitro method). Some embodiments may further comprise administering the selected treatment to a patient identified or diagnosed as having a RET-related cancer. For example, the selected treatment may comprise administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Some embodiments may further comprise the steps of assaying a sample obtained from the patient to determine whether the patient has abnormal regulation of expression, activity, or level of the RET gene, RET kinase, or any one thereof, and identifying and diagnosing the patient as having a RET-related cancer. In some embodiments, the cancer is a RET-related cancer with one or more RET inhibitor resistance mutations. In some embodiments, the patient is identified or diagnosed as having a RET-related cancer by using an assay approved by a regulatory agency, such as an FDA-approved assay for confirming abnormal regulation of expression, activity, or level of the RET gene, RET kinase, or any one thereof in a patient or a biopsy sample from the patient. In some embodiments, the RET-related cancer is a cancer described herein or known in the art. In some embodiments, the assay is an in vitro assay. For example, an assay utilizing next generation sequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency approved, such as an FDA approved kit.

[0989] Also provided herein is a method for selecting a treatment for a patient, wherein the method comprises the following steps: performing an assay on a sample obtained from the patient to determine whether the patient has a RET gene, RET kinase, or any one thereof, expression or activity or level abnormality (e.g., one or more RET inhibitor resistance mutations), and identifying or diagnosing a patient with a RET gene, RET kinase, or any one thereof, expression or activity or level abnormality as having a RET-related cancer. Some embodiments further comprise administering the selected treatment to a patient identified or diagnosed as having a RET-related cancer. For example, the selected treatment may comprise administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, to a patient identified or diagnosed as having a RET-related cancer. In some embodiments, the assay is an in vitro assay. For example, an assay utilizing next-generation sequencing, immunohistochemistry, or split FISH analysis. In some embodiments, the assay is an approved test kit by a regulatory agency, such as an FDA-approved test kit.

[0990] Also provided are methods for selecting a patient for treatment, wherein the method comprises selecting, identifying, or diagnosing a patient with a RET-related cancer, and selecting the patient for treatment comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, identifying or diagnosing a patient as having a RET-related cancer m...

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating RET-related cancers: in: X 1 is N, and X 2 , X 3 and X 4 It is CH; A is CN; B is (b) a C1-C6 alkyl group optionally substituted by 1 to 3 fluorine groups, (c) hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorine or C3-C6 cycloalkylene rings, (e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted by 1 to 3 fluorine groups, Ring D is The wavy line indicates the ring D and includes X 1 , X 2 , X 3 and X 4 The asterisk indicates the point of attachment to the ring of E, and wherein the ring is optionally substituted by: (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluorines, or C1-C3 alkoxy optionally substituted with 1-3 fluorines, (b) a C3-C6 cycloalkylene ring, or (c) an oxo group; E is (h)Ar 1 C1-C6 alkyl-, (j)hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluorines, or (l)hetAr 2 C(=O)-, Ar 1 is phenyl optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of: halogen; CN; C1-C6 alkyl optionally substituted by 1-3 fluorines; C1-C6 alkoxy optionally substituted by 1-3 fluorines; R e R f N-, where R e and R f are independently H or C1-C6 alkyl; (R p R q N) C1-C6 alkoxy-, wherein R p and R q are independently H or C1-C6 alkyl; and (hetAr a )C1-C6 alkyl-, wherein hetAr a is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar 1 is a benzene ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O; and he 2 is 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 ring having 1-3 ring nitrogen atoms, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen; CN; C1-C6 alkyl optionally substituted by 1-3 fluorine groups; C1-C6 alkoxy optionally substituted by 1-3 fluorine groups; (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted by 1-3 fluorine groups; R e R f N-, where R e and R f are independently H or C1-C6 alkyl; OH; (C1-C6 alkoxy)C1-C6 alkoxy- and C3-C6 cycloalkyl; Wherein the cancer is selected from the group consisting of: Breast cancer, cervical cancer, colon cancer, prostate cancer, head and neck cancer, pancreatic cancer, colorectal cancer, gastrointestinal ganglioneuroma, gastric cancer, gastrointestinal stromal tumor, glioma, leukemia, lung cancer, lymphoma, multiple endocrine neoplasia type 2A or 2B, multiple myeloma, non-Hodgkin lymphoma, ovarian cancer, papillary renal cell carcinoma, paraganglioma, parathyroid hyperplasia, pheochromocytoma, thyroid cancer, neuroblastoma and melanoma.

2. The use according to claim 1, wherein ring D is The wavy line indicates the ring D and includes X 1 , X 2 , X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E.

3. The use according to claim 2, wherein E is: (h)Ar 1 C1-C6 alkyl-, or (j)hetAr 2 C1-C6 alkyl - wherein the alkyl portion is optionally substituted with 1-3 fluorines.

4. The use according to claim 1, wherein ring D is The wavy line indicates the ring D and includes X 1 , X 2 , X 3 and X 4 The asterisk indicates the point of attachment to the ring of , and the asterisk indicates the point of attachment to E.

5. The use according to claim 4, wherein E is: (j)hetAr 2 C1-C6 alkyl - wherein the alkyl portion is optionally substituted by 1-3 fluorines, or (l)hetAr 2 C(=O)-.

6. The use of claim 3, wherein B is (c) hydroxy C2-C6 alkyl - wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylene ring, or (e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted by 1 to 3 fluorine groups.

7. The use of claim 5, wherein B is (b) a C1-C6 alkyl group optionally substituted by 1 to 3 fluorine groups, (c) hydroxy C2-C6 alkyl-, wherein the alkyl portion is optionally substituted by a C3-C6 cycloalkylene ring, (f)(R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with OH, and wherein R 1 and R 2 is independently H or C1-C6 alkyl optionally substituted by 1-3 fluorines; or (g)hetAr 1 C1-C3 alkyl-, wherein hetAr 1 is 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.

8. The use according to claim 1, wherein the compound of formula I is selected from: 4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-methoxyethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-((l-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

9. The use of claim 1, wherein the compound of formula I is 4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile or a pharmaceutically acceptable salt thereof.

10. The use of claim 1, wherein the compound of formula I is 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile or a pharmaceutically acceptable salt thereof.

11. The use of claim 1, wherein the compound of formula I is (R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile or a pharmaceutically acceptable salt thereof.

12. The use of claim 1, wherein the compound of formula I is 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile or a pharmaceutically acceptable salt thereof.

13. The use of claim 1, wherein the compound of formula I is 6-(2-methoxyethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile or a pharmaceutically acceptable salt thereof.

14. The use of claim 1, wherein the compound of formula I is 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile or a pharmaceutically acceptable salt thereof.

15. The use of claim 1, wherein the compound of formula I is 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile or a pharmaceutically acceptable salt thereof.

16. The use of claim 1, wherein the compound of formula I is 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile or a pharmaceutically acceptable salt thereof.

17. The use of claim 1, wherein the compound of formula I is 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-((l-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile or a pharmaceutically acceptable salt thereof.

18. The use of claim 1, wherein the compound of formula I is 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile or a pharmaceutically acceptable salt thereof.

19. The use of claim 1, wherein the cancer is leukemia, lung cancer or thyroid cancer.

20. The use of claim 1, wherein the thyroid cancer is papillary thyroid cancer or medullary thyroid cancer.

21. The use of claim 1, wherein the lung cancer is lung adenocarcinoma, non-small cell lung cancer or small cell lung cancer; wherein the pancreatic cancer is pancreatic ductal carcinoma; wherein the leukemia is acute lymphoblastic leukemia or acute myeloid leukemia.

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