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

SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS

[0001[

BACKGROUND

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

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

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

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[0005] Upon binding of the ligand-co-receptor complex, RET dimerization and autophosphorylation on intracellular tyrosine residues recruits adaptor and signaling proteins to stimulate multiple downstream pathways. Adaptor protein binding to these docking sites leads to activation of Ras-MAPK and PI3K-Akt/mTOR signaling pathways or to recruitment of the CBL family of ubiquitin ligases that functions in RET downregulation of the RET-mediated functions. [0006] Aberrant RET expression and/or activity have been demonstrated in different cancers and in gastrointestinal disorders such as irritable bowel syndrome (IBS).

SUMMARY OF THE INVENTION

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

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

<img file="CA3039760C_D0001.tif" />

( ^D ' ' ^χΝχΕ

I

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

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

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

[0012] Also provided herein is a method of treating a RET-associated disease or disorder

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PCT7US2017/055983 in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

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

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

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

[0016] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein for use in therapy. [0017] Also provided herein is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer and/or inhibiting metastasis associated with a particular cancer.

[0018] Also provided herein is a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of irritable bowel syndrome (IBS) or pain associated with IBS.

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

[0020] Also provided herein is a compound of Formula I or a pharmaceutically acceptable

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[0021] Also provided herein is a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a RET-associated disease or disorder.

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

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

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

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

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

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

[0028] Also provided herein is a pharmaceutical combination for treating cancer (e g., a RET-associated cancer, such as a RET-associated cancer having one or more RET inhibitor resistance mutations) in a patient in need thereof, which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and

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PCT/US2017/055983 (c) optionally at least one pharmaceutically acceptable carrier, wherein the compound of Formula 1 or the pharmaceutically acceptable salt or solvate thereof and the additional therapeutic are formulated as separate compositions or dosages for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and of the additional therapeutic agent are together effective in treating the cancer. Also provided herein is a pharmaceutical composition comprising such a combination. Also provided herein is the use of such a combination for the preparation of a medicament for the treatment of cancer. Also provided herein is a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer a patient in need thereof.

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

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

[0031] Also provided herein is a method of treating an individual with cancer who has an increased likelihood of developing resistance to an anticancer drug, comprising administering to the individual (a) an effective amount of a compound of Formula 1 before, during, or after administration of (b) an effective amount of the anticancer drug.

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

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

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

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

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

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

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention, other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting.

In case of conflict, the present specification, including definitions, will control.

(0039( Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION (0040( Provided herein is a compound of the Formula I:

<img file="CA3039760C_D0002.tif" />

I

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

[0042( X¹, X², X³ and X⁴ are independently CH, CF, CCHs or N, wherein zero, one or two ofX', X², X³ andX⁴ isN, (0043( A is H, CN, Cl, CH3-, CH3CH2-, cyclopropyl, -CH2CN or -CH(CN)CH3, (0044( B is

[0045( (a) hydrogen, (0046( (b) Cl-C6 alkyl optionally substituted with 1-3 fluoros,

[0047[ (c) hydroxyC2-C6 alkyl-, wherein the alkyl portion is optionally substituted with

1-3 fluoros or a C3-C6 cycloalkylidene ring,

[0048( (d) dihydroxyC3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a

C3-C6 cycloalkylidene ring, (0049( (e) (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,

[0050( (f) (R’R²N)C1-C6 alkyl- wherein said alkyl portion is optionally substituted with

OH and wherein R¹ and R² are independently H or C1-C6 alkyl (optionally substituted with 1-3

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[0051] (g) hetA^Cl-CJ 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;

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

[0053] (i) (hetCyc^a)Cl-C3 alkyl-,

[0054] (j) hetCyc^a-,

[0055] (k) C3-C6 cycloalkyl-, wherein said cycloalkyl is optionally substituted with OH,

[0056] (1) (C1-C4 alkyl)C(=O)O-C 1-C6 alkyl-, wherein each of the C1-C4 alkyl and C1 C6 alkyl portions is optionally and independently substituted with 1-3 fluoros, or

[0057] (m) (R¹R²N)C(=O)C1-C6 alkyl-, wherein R¹ and R² are independently H or ClC6 alkyl (optionally substituted with 1-3 fluoros);

[0058] hetCyc^a- is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(=O)-, (C1-C6 alkoxy)Cl-C6 alkyl-, and fluoro, or wherein hetCyc^a is substituted with oxo;

[0059] 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 ring heteroatom which is oxygen, (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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group;

[0060] Eis

[0061] (a) hydrogen,

[0062] (b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

[0063] (c) (C1-C6 alkoxy)C1-C6 alkyl-optionally substituted with 1-3 fluoros,

[0064] (d) (C1-C6 alkyl)C(=O)-, wherein said alkyl portion is optionally substituted with

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1-3 fluoros or with a RHl’TSI- substituent wherein R^e and R^h are independently H or C1-C6 alkyl, [0065] (e) (hydroxyC2-C6 alkyl)C(=O)- optionally substituted with 1-3 fluoros,

[0066] (f) (C1-C6 alkoxy )C(=O)-,

[0067] (g) (C3-C6 cycloalkyl)C(=O)-, wherein said cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy)Cl-C6 alkyl-, or said cycloalkyl is substituted with a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O,

[0068] (h) Ar'Cl-C6 alkyl-,

[0069] (i) Ar^Cl-Cô alkyl)C(=O)-, wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl-, C1-C6 alkoxy, R^mR“N- or R^mRⁿN-CH2-, wherein each R^m and R“ is independently H or C1-C6 alkyl,

[0070] (j) hetAi^C 1-C6 alkyl-, wherein said alkyl portion is optionally substituted with 1 3 fluoros,

[0071] (k) hetAr²(C 1-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl- or C1-C6 alkoxy,

[0072] (1) hetAr²C(=O)-,

[0073] (m) hetCyc¹C(=O)-,

[0074] (n) hetCy^Cl-Cô alkyl-,

[0075] (o) R³R⁴NC(=O)-,

[0076] (p) A?N(R³)C(=O)-,

[0077] (q) hetArN(R³)C(=O)-,

[0078] (r) (C1-C6 alkyl)SO2-, wherein the alkyl portion is optionally substituted with 1-3 fluoros,

[0079] (s) Ar^lSO2-,

[0080] (t) hetA?S02-,

[0081] (u) N-(C1-C6 alkyl)pyridinonyl,

[0082] (v) Ar¹C(=O)-;

[0083] (w) Ar¹O-C(=O)-,

[0084] (x) (C3-C6 cycloalkyl)(C 1-C6 alkyl)C(=O)-,

[0085] (y) (C3-C6 cycloalkyl)(Cl-C6 alkyl)SC>2-, wherein the alkyl portion is optionally substituted with 1-3 fluoros,

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[0086] (z) Ar*(Cl-C6 alkyOSCh-,

[0087] (aa) hetCyc¹-O-C(=O)-,

[0088] (bb) hetCyc¹CH₂C(=O)-,

[0089] (cc) hetAr², or

[0090] (dd) C3-C6 cycloalkyl;

[0091] Ar¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), R^eR^fN- wherein R^e and R^f are independently H, C1-C6 alkyl, (RPR^R^Cl-Cô alkoxy- wherein R^p and R^q are independently H or C1-C6 alkyl, and (hetAr^Cl-Cô alkyl- wherein hetAr³ is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar¹ is a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

[0092] hetAr² 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 hetAr² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), R^cR^fN- wherein R^c and R^f are independently H or C1-C6 alkyl, OH, (C1-C6 alkoxy)C1-C6 alkoxy- and C3-C6 cycloalkyl;

[0093] hetCyc¹ 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;

[0094] R³ is H or C1-C6 alkyl; and

[0095] R⁴ is Cl-C6 alkyl.

[0096] For complex chemical names employed herein, the substituent group is named before the group to which it attaches. For example, methoxyethyl comprises an ethyl backbone with a methoxy substituent.

[0097] The term ''halogen'¹ means -F (sometimes referred to herein as fluoro'' or fluoros), -Cl,-Brand -I.

[0098] The terms C 1-C3 alkyl, C 1-C6 alkyl, C2-C6 alkyl and C3-C6 alkyl as used herein refer to saturated linear or branched-chain monovalent hydrocarbon radicals of one to three,

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[0099] The term C1-C6 alkoxy as used herein refers to a saturated linear or branchedchain monovalent alkoxy radical of one to six carbon atoms, wherein the radical is on the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

[00100] The terms (C1-C6 alkoxy)Cl-C6 alkyl- and (C1-C6 alkoxy)C2-C6 alkyl- as used herein refers to saturated linear or branched-chain monovalent radicals of one to six carbon atoms or two to six carbon atoms, respectively, wherein one of the carbon atoms is substituted with a (C1-C6 alkoxy) group as defined herein. Examples include methoxymethyl (CH3OCH2-) and methoxy ethyl (CH3OCH2CH2-).

[00101] The terms hydroxyC 1-C6 alkyl- and hydroxyC2-C6 alkyl- as used herein refer to a saturated linear or branched-chain monovalent alkyl radicals of one to six or two to six carbon atoms, respectively, wherein one of the carbon atoms is substituted with a hydroxy group.

[00102] The term dihydroxyC3-C6 alkyl- as used herein refers to a saturated linear or branched-chain monovalent alkyl radical of three to six carbon atoms, wherein two of the carbon atoms are substituted with a hydroxy group.

[00103] The terms (R^lR²N)Cl-C6 alkyl- and (R^lR²N)C2-C6 alkyl- as used herein refers to a C1-C6 alkyl or C2-C6 radical, respectively, as defined herein, wherein one of the carbon atoms is substituted with a R¹R²N- group, wherein R¹ and R² are as defined herein.

[00104] The term hetAr^lCl-C6 alkyl- as used herein refers to a C1-C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a hetAr¹ group, wherein hetAr¹is as defined herein.

[00105] The term C3-C6 cycloalkyl as used herein refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[00106] The terms (C3-C6 cycloalkyl)C 1-C3 alkyl- and (C3-C6 cycloalkyl)C 1-C6 alkylas used herein refers to a C1-C3 alkyl radical or C1-C6 radical, respectively, as defined herein, wherein one of the carbon atoms is substituted with a C3-C6 cycloalkyl ring as defined herein.

[00107] The term C3-C6 cycloalkylidene ring as used herein refers to a divalent carbocyclic ring of three to six carbons. The suffix ylidine refers to bivalent radical derived from a saturated hydrocarbon by removal of two hydrogen atoms from the same carbon atom

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[00108] The term (hetCyc^a)Cl-C3 alkyl- as used herein refers to a C1-C3 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a hetCyc^a group, wherein hetCyc^a is as defined herein.

[00109] The term A^Cl-Cô alkyl- as used herein refers to a C1-C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with an Ar¹ group, wherein Ar¹ is as defined herein.

[00110] The terms hetArCl-C6 alkyl- as used herein refers to a C1-C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with an hetAr² group, wherein hetAr² is as defined herein.

[00111] The term hetCyc'Cl-Cô alkyl- as used herein refers to a C1-C6 alkyl radical as defined herein, wherein one of the carbon atoms is substituted with a hetCyc¹ group, wherein hetCyc¹ is as defined herein.

[00112] The term N-(C1-C6 alkyl)pyridinonyl as used herein refers to a pyridin-2(lH)-one ring wherein the ring nitrogen atom is substituted with a C1-C6 alkyl substituent, and wherein the radical may be on any of the ring carbon atoms other than the carbon bearing the oxo group. Examples include the structures:

(C1-C3 alkyl) (C1-C3 alkyl) (C1-C3 alkyl) (C1-C3 alkyl)

<img file="CA3039760C_D0003.tif" />

[00113] The term heterospirocyclic as used herein refers to a group having two rings joined by a spirocyclic linkage through a carbon atom, wherein each ring has 4 to 6 ring atoms (with one ring carbon atom being common to both rings), and wherein two of the ring atoms are nitrogen atoms.

[00114] The term oxo or oxo group as used herein means an oxygen that is double bonded to a carbon atom, i.e., =0. For example, in one embodiment when referring to Ring D, a saturated 6 membered heterocyclic ring having two ring nitrogen atoms may be, for example, a piperazinyl ring that is substituted with an oxo group (e g., a piperazinonyl ring), which may be represented by the structure:

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<img file="CA3039760C_D0004.tif" />

[00115] The term compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[00116] The term tautomer as used herein refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomer. Exemplary tautomerizations include, but are not limited to, keto-to-enol, amide-to-imide; lactam-to-lactim, enamine-to-imine; and enamine-to-(a different) enamine tautomerizations. A specific example of phenol-keto tautomerization is the interconversion of pyridin-2-ol and pyridin-2(lH)-one tautomers, for example;

o OH

<img file="CA3039760C_D0005.tif" />

[00117] It will be appreciated that certain compounds provided herein may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.

[00118] In certain embodiments of Formula I, X¹, X², X³ and X⁴ are independently CH, CF or CCH3. In certain embodiments, each of X¹, X², X³ and X⁴ is CH.

[00119] In certain embodiments of Formula I, X¹, X², X³ and X⁴ are independently CH, CF or CCHs or N, wherein one of X¹, X², X³ and X⁴ is N and the remainder are independently CH, CF or CCH3. In certain embodiments of Formula I, X¹ is N, and X², X³ and X⁴ are independently CH or CF. In certain embodiments, X¹ is N, and X², X³ and X⁴ are CH. In certain embodiments,

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X¹ is N, X² is CF, and X³ and X⁴ are CH.

[00120] In certain embodiments of Formula 1, X¹, X², X³ and X⁴ are independently CH, CF or CCHi or N, wherein two of X¹, X², X³ and X⁴ are N. In certain embodiments of Formula L, X¹and X³ are N and X² and X⁴ are independently CH, CF or CCH.3. In one embodiment, X¹ and X³are N and X² and X⁴ are CH. In certain embodiments of Formula I, X¹ and X² are N and X¹ and X⁴ are independently CH or CF. In certain embodiments of Formula Ï, X¹ and X² are N and X¹and X⁴ are CH.

[00121] In certain embodiments of Formula I, A is H.

[00122] In certain embodiments of Formula I, A is Cl.

[00123] In certain embodiments of Formula I, A is CN.

[00124] In certain embodiments of Formula I, A is CH3-.

[00125] In certain embodiments of Formula I, A is CH3CH2-.

[00126] In certain embodiments of Formula I, A is cyclopropyl.

[00127] In certain embodiments of Formula I, A is -CH2CN.

[00128] In certain embodiments of Formula I, A is -CH(CN)CH3.

[00129] In certain embodiments of Formula I, B is hydrogen.

[00130] In certain embodiments of Formula I, B is C1-C6 alkyl optionally substituted with

1-3 fluoros. Non-limiting examples include methyl, ethyl, propyl, isopropyl, isobutyl, 2methylbutyl, 2-ethylbutyl, 2,2-dimethylpropyl, difluoromethyl, 2,2-difluoroethyl, and 2,2,2trifluoroethyl.

[00131] In certain embodiments of Formula I, B is hydroxyC2-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros or a C3-C6 cycloalkylidene ring. In certain embodiments of Formula 1, B is hydroxyC2-C6 alkyl-, wherein the alkyl portion is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0006.tif" />

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[00132] In certain embodiments of Formula 1, B is dihydroxyC3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In certain embodiments of Formula I, B is dihydroxyC3-C6 alkyl-. A non-limiting example includes 2,3-dihydroxypropyl.

[00133] In certain embodiments of Formula I, B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros. In certain embodiments of Formula I, B is (C1-C6 alkoxy)C2-C6 alkyl- optionally substituted with 1-3 fluoros. Non-limiting examples include the structures:

<img file="CA3039760C_D0007.tif" />

<img file="CA3039760C_D0008.tif" />

<img file="CA3039760C_D0009.tif" />

F

[00134] In certain embodiments of Formula I, B is (R^NiCl-Cô alkyl-,wherein said alkyl portion is optionally substituted with OH and R¹ and R² are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros). In certain embodiments of Formula I, B is (R^NIClC6 alkyl-, wherein said alkyl portion is optionally substituted with OH and R¹ and R² are independently H or C2-C6 alkyl (optionally substituted with 1-3 fluoros). In certain embodiments of Formula I, B is (Β^²Ν)€1-Ο6 alkyl- wherein said alkyl portion is optionally substituted with OH and R^l and R² are independently selected from C1-C6 alkyl substituents. Non-limiting examples when B is (R¹R²N)C 1-C6 alkyl- include the structures

<img file="CA3039760C_D0010.tif" />

[00135] In certain embodiments of Formula I, B is hetAr'Cl-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. In certain embodiments, hetAr¹ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms

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PCT7US2017/055983 independently selected from N and 0 and is optionally substituted with C1-C6 alkyl. Non-limiting examples of hetA^Cl-CS alkyl- include the structures:

<img file="CA3039760C_D0011.tif" />

[00136] Tn certain embodiments of Formula I, B is (C3-C6 cycloalkyl)Cl -C3 alkyl- wherein said cycloalkyl is optionally substituted with OH Non-limiting examples include the structures:

<img file="CA3039760C_D0012.tif" />

[00137] In certain embodiments of Formula I, B is (hetCyc^a)C 1-C3 alkyl-, wherein hetCyc^ais a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, (ClC6 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl- and fluoro, or wherein hetCyc^a is substituted with oxo. Non-limiting examples include the structures:

<img file="CA3039760C_D0013.tif" />

<img file="CA3039760C_D0014.tif" />

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<img file="CA3039760C_D0015.tif" />

<img file="CA3039760C_D0016.tif" />

<img file="CA3039760C_D0017.tif" />

<img file="CA3039760C_D0018.tif" />

[00138] Tn certain embodiments of Formula I, B is hetCyc^a, 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 with one or more substituents independently selected from OH, ClC6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, (C1-C6

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PCT7US2017/055983 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl- and fluoro, or wherein hetCyc^a is substituted with oxo. In certain embodiments, hetCyc^a is optionally substituted with OH or C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

<img file="CA3039760C_D0019.tif" />

[00139] In certain embodiments of Formula I, B is C3-C6 cycloalkyl-, wherein said cycloalkyl is optionally substituted with OH. A non-limiting example is the structure: HCk _

[00140] In certain embodiments of Formula I, B is (C1-C4 alkyl)C(=O)O-Cl-C6 alkyloptionally substituted with 1-3 fluoros. A non-limiting example is the structure:

<img file="CA3039760C_D0020.tif" />

[00141] In certain embodiments of Formula I, B is (R'R²N)C(=O)C 1-C6 alkyl- wherein R¹and R² are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

<img file="CA3039760C_D0021.tif" />

<img file="CA3039760C_D0022.tif" />

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[00142] In one embodiment of Formula 1, Ring D is a (i) 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 ring heteroatom which is oxygen, (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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group.

[00143] As used herein, the phrase having two ring nitrogen atoms when referring to Ring D 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 the ring comprising X¹, X², X³ and X⁴, and the other ring nitrogen atom is bonded to the E group.

[00144] In one embodiment, Ring D is a (i) 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 ring heteroatom which is oxygen, (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 unsubstituted.

[00145] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. As used herein, the phrase having two ring nitrogen atoms when Ring D is a saturated monocyclic 4-7 membered heterocyclic ring means that said ring nitrogen atoms are the two nitrogen atoms shown in Ring D of Formula I, that is, Ring D may be represented by the structures:

N-*

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[00146] wherein the wavy line indicates the point of attachment to the ring comprising X¹, X², X³ and X⁴, 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, ClC3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment, Ring D is an unsubstituted saturated 6 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 wherein said ring is substituted with oxo. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms wherein said ring is substituted with a C3-C6 cycloalkylidene ring. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms wherein said ring is substituted with a C3-C6 cyclopropylidine ring. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms wherein said ring is substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms wherein said ring is substituted with C1-C3 alkyl which is optionally substituted with 1-3 fluoros. In one embodiment, Ring D is a saturated 7 membered heterocyclic ring having two ring nitrogen atoms, wherein said ring is unsubstituted.

[00147] In one embodiment when Ring D is a saturated 6-7 membered heterocyclic ring having two ring nitrogen atoms, Ring D and E portion of Formula I, that is,

<img file="CA3039760C_D0023.tif" />

[00149] wherein the wavy line indicates the point of attachment to the ring comprising X¹, X², X³ and X⁴, wherein Ring D is optionally substituted with (a) one to four groups independently

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PCT7US2017/055983 selected from halogen, OH, C1-C3 alkyl which is optionally substituted with 1-3 fluoros, or ClC3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment, Ring D is unsubstituted. In one embodiment, Ring D is substituted with oxo. In one embodiment, Ring D is substituted with a C3-C6 cyclopropylidine ring. In one embodiment, Ring D is substituted with oxo. In one embodiment, Ring D is substituted with one to four groups independently selected from halogen, OH, Cl -C3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 13 fluoros. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms wherein said ring is substituted with one to four C1-C3 alkyl groups which are optionally substituted with 1-3 fluoros. In one embodiment, Ring D is unsubstituted, or ring D is substituted with one to four independently selected C1-C3 alkyl groups (each of which is optionally substituted with 1- fluoros), or Ring D is substituted with a C3-C6 cyclopropylidine ring, or Ring D is substituted with oxo. In one embodiment, Ring D is a saturated 7 membered heterocyclic ring having two ring nitrogen atoms, wherein said ring is unsubstituted. Examples of saturated 6 and 7 membered heterocyclic D rings include the structures:

<img file="CA3039760C_D0024.tif" />

<img file="CA3039760C_D0025.tif" />

<img file="CA3039760C_D0026.tif" />

<img file="CA3039760C_D0027.tif" />

<img file="CA3039760C_D0028.tif" />

<img file="CA3039760C_D0029.tif" />

[00150] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene 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 heterocyclic ring having two ring nitrogen atoms. In one

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PCT7US2017/055983 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 oxo. In one embodiment, Ring D is substituted with a cyclopropylidine ring. In one embodiment, Ring D is substituted with one or two C1-C3 alkyl groups, for example one or two methyl groups.

[00151] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, andEis(a) hydrogen, (c) (C1-C6 alkoxy )C1-C6alkyloptionally substituted with 1-3 fluoros, (d) (C1-C6 alkyl)C(=O)- optionally substituted with 1-3 fluoros, (e) (hydroxy C2-C6 alkyl)C(=O)- optionally substituted with 1-3 fluoros, (f) (C1-C6 alkoxy)C(=O)-, (g) (C3-C6 cycloalkyl)C(=O)- wherein said cycloalkyl is optionally substituted with (C1-C6 alkoxy)Cl-C6 alkyl- or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O, (h) Ar'Cl-C6 alkyl-, (i) Ar^Cl-Cô alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl- or C1-C6 alkoxy, (j) hetAr²Cl-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros, (k) hetAr²(Cl-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl-or Cl-C6 alkoxy, (1) hetAr²C(=O)-, (m) hetCyc^(=0)-, (n) hetCy^ClC6 alkyl- (o) R³R⁴NC(=O)-, or (cc) hetAr², wherein Ar¹, hetAr², hetCyc¹, R³ and R⁴ are 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 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 oxo. In one embodiment, Ring D is substituted with a cyclopropylidine ring. In one embodiment, Ring D is substituted with one or two C1-C3 alkyd groups, for example one or two methyl groups.

[00152] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6

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PCT7US2017/055983 cycloalkylidene 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. A non-limiting example is the structure:

<img file="CA3039760C_D0030.tif" />

[00153] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1 -3 fluoros. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. A non-limiting example is the structure:

<img file="CA3039760C_D0031.tif" />

[00154] 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 fluoros, or C1-C3 alkoxy which is optionally substituted w'ith 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (C1-C6 alkyl)C(=O)- optionally substituted with 1-3 fluoros. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having twO ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. A non-limiting example is the structure:

<img file="CA3039760C_D0032.tif" />

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[00155] 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 fluoros, or C1-C3 alkoxy which is optionally substituted w'ith 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (hydroxy C2-C6 alkyl)C(=O)- optionally substituted with 1 -3 fluoros. In one embodiment, Ring D is a saturated 6 membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. A non-limiting example is the structure:

<img file="CA3039760C_D0033.tif" />

[00156] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene 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. A non-limiting example is the structure:

<img file="CA3039760C_D0034.tif" />

[00157] 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 fluoros, or C1-C3 alkoxy which is optionally substituted w'ith 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (C3-C6 cycloalkyl)C(=O)- wherein said cycloalkyl is optionally substituted with (C1-C6 alkoxy)Cl-C6 alkyl- or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O, for example pyridinyl. 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

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PCT7US2017/055983 the structures:

<img file="CA3039760C_D0035.tif" />

<img file="CA3039760C_D0036.tif" />

[00158] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is Ar'C 1-C6 alkyl-, wherein Ar¹ is 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 oxo. In one embodiment, Ar¹ is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0037.tif" />

[00159] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is Ar'(Cl-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl, C1-C6 alkoxy, R^raRN- or R^mRNCH2-, wherein each R^m and R“ is independently H or C1-C6 alkyl, and Ar¹ is 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, Ar¹ is unsubstituted or substituted with one or more halogens. Non-limiting examples include the

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PCT7US2017/055983 structures:

<img file="CA3039760C_D0038.tif" />

<img file="CA3039760C_D0039.tif" />

<img file="CA3039760C_D0040.tif" />

<img file="CA3039760C_D0041.tif" />

<img file="CA3039760C_D0042.tif" />

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<img file="CA3039760C_D0043.tif" />

[00160] Tn 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAr²Cl-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros, and wherein hetAr² is 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 cyclopropylidine ring. In one embodiment, hetAr² is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. In one embodiment, hetAr² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy’ (optionally substituted with 1-3 fluoros) In one embodiment, hetAr² is a 6 membered heteroaryl 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 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). Non-limiting examples include the structures:

<img file="CA3039760C_D0044.tif" />

<img file="CA3039760C_D0045.tif" />

<img file="CA3039760C_D0046.tif" />

<img file="CA3039760C_D0047.tif" />

<img file="CA3039760C_D0048.tif" />

<img file="CA3039760C_D0049.tif" />

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<img file="CA3039760C_D0050.tif" />

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<img file="CA3039760C_D0051.tif" />

[00161] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAr(Cl-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl or C1-C6 alkoxy, and wherein hetAr² is as defined for Formula 1. 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, the alkyl portion of hetAr²(Cl-C6 alkyl)C(=O)- is unsubstituted. In one embodiment, hetAr² is a 5-6 membered heterocyclic ring having 1 -2 ring nitrogen atoms. In one embodiment, hetAr² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, hetAr² is a 6 membered ring having 1-2 ring nitrogen atoms and is optionally substituted with one or more halogens. A non-limiting example includes the structure:

<img file="CA3039760C_D0052.tif" />

[00162] In one embodiment, Ring D is a saturated 4-7 membered heterocyclic ring having

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PCT7US2017/055983 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAr²C(=O)- wherein hetAr² is 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, hetAr² is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. In one embodiment, hetAr² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, hetAr²is a 6 membered ring having 1-2 ring nitrogen atoms and is optionally substituted with C1-C6 alkoxy. Non-limiting examples includes the structures:

[00163] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetCyc¹C(=O)- wherein hetCyc¹ is 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 hetCyc¹is a 4-6 membered saturated heterocyclic ring having a ring nitrogen atom, wherein said heterocyclic ring is optionally substituted with one or more independently selected C1-C6 alkoxy substituents. A non-limiting example includes the structure:

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<img file="CA3039760C_D0053.tif" />

[00164] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetCy^Cl-Cô alkyl- wherein hetCyc¹ is 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 hetCyc¹ is a 4-6 membered saturated heterocyclic ring having a ring oxygen atom. In one embodiment, hetCyc¹ is unsubstituted. A non-limiting example includes the structure:

<img file="CA3039760C_D0054.tif" />

[00165] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is R³R⁴NC(=O)- wherein R³ and R⁴ are 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, said Ring D is unsubstituted. A non-limiting example includes the structure:

<img file="CA3039760C_D0055.tif" />

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[00166] 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAr², wherein hetAr² is 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, hetAr² is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. In one embodiment, hetAr² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, hetAr² is a 6 membered ring having 1-2 ring nitrogen atoms and is optionally substituted with C1-C6 alkoxy. A non-limiting example includes the structure:

<img file="CA3039760C_D0056.tif" />

[00167] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. As used herein, the phrase having two ring nitrogen atoms when Ring D is a saturated 7-8 membered bridged heterocyclic ring means that said ring nitrogen atoms are the two nitrogen atoms shown in Ring D of Formula I, wherein one of the ring nitrogen atoms is bonded the ring comprising X¹, X², X³ and X⁴, and the other ring nitrogen atom is bonded to the E group as shown in Formula I. Non-limiting examples when Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen include the following structures:

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<img file="CA3039760C_D0057.tif" />

<img file="CA3039760C_D0058.tif" />

<img file="CA3039760C_D0059.tif" />

<img file="CA3039760C_D0060.tif" />

[00168] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment, Ring D is unsubstituted.

[00169] 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, Ring D and E portion of Formula I, that is

<img file="CA3039760C_D0061.tif" />

[00170] may be represented by the non-limiting structures:

<img file="CA3039760C_D0062.tif" />

<img file="CA3039760C_D0063.tif" />

<img file="CA3039760C_D0064.tif" />

[00171] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E, wherein Ring

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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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment, Ring D is unsubstituted.

[00172] In one embodiment, Ring D is a saturated 7 membered bridged heterocyclic ring having two ring nitrogen atoms represented by the structure:

[00173] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X' and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment, Ring D is unsubstituted.

[00174] In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene 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.

[00175] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene 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)Cl-C6 alkyl-, (d) (C1-C6 alkyl)C(=O)-, (e) (hydroxyC2-C6 alkyl)C(=O)-, (f) (C1-C6 alkoxy)C(=O)-, (g) (C3-C6 cycloalkyl)C(=O)-, (h)

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Ar'Cl-Cô alkyl-, (i) Ar'(Cl-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl or C1-C6 alkoxy, (j) hetArCl-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros, (k) hetAr^Cl-Cô alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl- or C1-C6 alkoxy, (1) hetAr²C(=O)-, (m) hetCyc¹C(=O)-, (o) R³R⁴NC(=O)-, (p) Ar¹R³NC(=O)-, (q) hetAr²N(R³)C(=O), (r) (C1-C6 alkyl)SÛ2-, (t) hetArSO?- (u) N-(C1-C6 alkyl)pyridinonyl, (v) Ar'C(=O)-, (w) Ar¹0-0(=0)-, (x) (C3-C6 cycloalkyl)CH2C(=O)-, (y) (C3-C6 cycloalkyl)(Cl-C6 alkyl)S02-, (z) Ar'(Cl-C6 alkyl)S02-, (aa) hetCyc*-O-C(=O)-, (bb) hetCyc^l-CH2-C(=0)-, and (cc) hetAr², wherein Ar¹, hetAr², R³ and hetCyc¹ are as defined for Formula I. In one embodiment, Ring D is selected from the structures

<img file="CA3039760C_D0065.tif" />

<img file="CA3039760C_D0066.tif" />

[00176] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E.

[00177] In one embodiment. Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms represented by the structure:

<img file="CA3039760C_D0067.tif" />

[00178] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E, and E is selected from the group consisting of (a) hydrogen, (b) C1-C6 alkyl, (c) (C1-C6 alkoxy)Cl-C6 alkyl-, (d) (C1-C6 alkyl)C(=O)-, (e) (hydroxyC2-C6 alkyl)C(=O)-, (f) (C1-C6 alkoxy)C(=O)-, (g) (C3-C6 cycloalkyl)C(=O)-, (h) Ar^lCl-C6 alkyl-, (i) Ar *(01-06 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl or C1-C6 alkoxy, (j) hetAi^Cl-Cô

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PCT7US2017/055983 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros, (k) hetAr²(Cl-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl or C1-C6 alkoxy, (1) hetAr²C(=O)-, (m) hetCyc^lC(=O)-, (o) R³R⁴NC(=O)-, (p) Ar¹N(R³)C(=O)-, (q) hetAr² N(R')C (=0)-, (r) (C1-C6 alkyl)S02-, (t) hetAr²SO2-, (u) N-(C1-C6 alkyl)pyridinonyl, (v) Ar^lC(=O)-, (w) Ar*O-C(=O)-, (x) (C3-C6 cycloalkyl)CH2C(=O)-, (y) (C3-C6 cycloalkylXClC6 alkyl)SO₂-, (z) Ar*(C1-C6 alkyl)S02-, (aa) hetCyc¹-O-C(=O)-, (bb) hetCyc¹-CH2-C(=O)-, and (cc) hetAr², wherein Ar¹, hetAr², R³ and hetCyc* are as defined for Formula I. In one embodiment, said Ring D is unsubstituted.

[00179] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene 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 structure:

<img file="CA3039760C_D0068.tif" />

[00180] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0069.tif" />

<img file="CA3039760C_D0070.tif" />

[00181] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6

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PCT7US2017/055983 cycloalkylidene ring, or (c) an oxo group, and E is C1-C6 alkyl optionally substituted with 1-3 fluoros. 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 structure:

<img file="CA3039760C_D0071.tif" />

[00182] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0072.tif" />

<img file="CA3039760C_D0073.tif" />

[00183] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros. 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 structure:

<img file="CA3039760C_D0074.tif" />

[00184] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. A non-limiting example includes the structure:

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<img file="CA3039760C_D0075.tif" />

[00185] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (C1-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with 1-3 fluoros or with a R^^N- substituent wherein R^g and R^h are independently H or C1-C6 alkyl. 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 structure:

<img file="CA3039760C_D0076.tif" />

[00186] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0077.tif" />

<img file="CA3039760C_D0078.tif" />

O

<img file="CA3039760C_D0079.tif" />

<img file="CA3039760C_D0080.tif" />

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<img file="CA3039760C_D0081.tif" />

<img file="CA3039760C_D0082.tif" />

[00187] In one embodiment of Formula 1, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (hydroxyC2-C6 alkyl)C(=O)- optionally substituted with 1-3 fluoros. 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 structure:

<img file="CA3039760C_D0083.tif" />

[00188] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. A non-limiting example includes the structure:

<img file="CA3039760C_D0084.tif" />

[00189] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b a C3-C6

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PCT7US2017/055983 cycloalkylidene ring, or (c) an oxo group, 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 structures:

<img file="CA3039760C_D0085.tif" />

<img file="CA3039760C_D0086.tif" />

[00190] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0087.tif" />

<img file="CA3039760C_D0088.tif" />

[00191] In one embodiment of Formula 1, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is C3-C6 cycloalkyl)C(=O)- wherein said cycloalkyl is optionally substituted with one or more substituents independently selected from ClC6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy)Cl-C6 alkyl-, or said cycloalkyl is substituted with a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and 0. In one embodiment, E is C3-C6 cycloalkyl)C(=O)- wherein said cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy)Cl-C6 alkyl-. 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 structure:

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<img file="CA3039760C_D0089.tif" />

[00192] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0090.tif" />

[00193] 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 ring heteroatom which is oxygen, wherein said 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

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PCT7US2017/055983 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is A^Cl-Cô alkyl-, wherein Ar¹ is as defined for Formula I. In one embodiment, E is Ar'C 1-C6 alkyl- wherein Ar¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, ClC6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (R^pR^qN)Cl-C6 alkoxy- wherein R^p and R^q are independently H or C1-C6 alkyl, and (hetAf)Cl-C6 alkyl- wherein hetAf 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 structure:

<img file="CA3039760C_D0091.tif" />

[00194] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Nonlimiting examples include the structures:

F

<img file="CA3039760C_D0092.tif" />

<img file="CA3039760C_D0093.tif" />

F

<img file="CA3039760C_D0094.tif" />

<img file="CA3039760C_D0095.tif" />

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<img file="CA3039760C_D0096.tif" />

<img file="CA3039760C_D0097.tif" />

[00195] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is Ar^Cl-Cô alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl, C1-C6 alkoxy, R‘“R“N- or R*“R“NCH2-, wherein each R“ and R“ is independently H or C1-C6 alkyl, and Ar¹ is as defined for Formula I. In one embodiment, Ar¹ is phenyl which is unsubstituted or substituted with one or more halogens. 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 structure:

<img file="CA3039760C_D0098.tif" />

[00196] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

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<img file="CA3039760C_D0099.tif" />

<img file="CA3039760C_D0100.tif" />

<img file="CA3039760C_D0101.tif" />

<img file="CA3039760C_D0102.tif" />

[00197] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAr²C 1-C6 alkyl-, wherein said alkyl portion is optionally substituted with 1-3 fluoros and hetAr² is as defined for Formula I. In one embodiment, hetAr² 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 hetAr² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), OH, C3-C6 cycloalkyl, and R^eR^fN- wherein R^e and R^f are independently H or C1-C6 alkyl. 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 structures:

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<img file="CA3039760C_D0103.tif" />

[00198] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0104.tif" />

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<img file="CA3039760C_D0105.tif" />

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<img file="CA3039760C_D0106.tif" />

<img file="CA3039760C_D0107.tif" />

<img file="CA3039760C_D0108.tif" />

<img file="CA3039760C_D0109.tif" />

<img file="CA3039760C_D0110.tif" />

<img file="CA3039760C_D0111.tif" />

<img file="CA3039760C_D0112.tif" />

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<img file="CA3039760C_D0113.tif" />

<img file="CA3039760C_D0114.tif" />

[00199] In one embodiment of Formula I, Ring D is a saturated 7-9 membered bridged

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PCT7US2017/055983 heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAr²(Cl-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl- or C1-C6 alkoxy and hetAr² is as defined for Formula I. In one embodiment the alkyl portion is unsubstituted. In one embodiment hetAr² 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 structure:

<img file="CA3039760C_D0115.tif" />

[00200] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. A non-limiting example is the structure:

<img file="CA3039760C_D0116.tif" />

[00201] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAr²C(=O)- wherein hetAr² is as defined for Formula I. In one embodiment hetAr² is 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 fluoros) and (C1-C6 alkoxy)Cl-C6

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PCT7US2017/055983 alkoxy-. In one embodiment, Ring D is represented by the structures:

<img file="CA3039760C_D0117.tif" />

<img file="CA3039760C_D0118.tif" />

<img file="CA3039760C_D0119.tif" />

[00202] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0120.tif" />

<img file="CA3039760C_D0121.tif" />

O O

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<img file="CA3039760C_D0122.tif" />

<img file="CA3039760C_D0123.tif" />

<img file="CA3039760C_D0124.tif" />

<img file="CA3039760C_D0125.tif" />

<img file="CA3039760C_D0126.tif" />

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<img file="CA3039760C_D0127.tif" />

[00203] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetCyc¹ C(=O)-, wherein hetCyc¹ is as defined

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PCT7US2017/055983 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 represented by the structure:

<img file="CA3039760C_D0128.tif" />

[00204] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0129.tif" />

<img file="CA3039760C_D0130.tif" />

<img file="CA3039760C_D0131.tif" />

<img file="CA3039760C_D0132.tif" />

[00205] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is R³R⁴NC(=O)-, wherein R³ is H or C1-C6 alkyl and R⁴ is C1-C6 alkyl. 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 structure:

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<img file="CA3039760C_D0133.tif" />

[00206] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. A non-limiting example includes the structure:

<img file="CA3039760C_D0134.tif" />

[00207] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is Ar¹N(R³)C(=O)- wherein Ar¹ and R³ are as defined for Formula 1. In one embodiment, Ar¹ is unsubstituted or substituted with C1-C6 alkoxy (optionally substituted with 1-3 fluoros). 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 structure:

<img file="CA3039760C_D0135.tif" />

[00208] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

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<img file="CA3039760C_D0136.tif" />

<img file="CA3039760C_D0137.tif" />

[00209] Tn 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAr²N(R³)C(=O)-, wherein hetAr² and R³ are as defined for Formula I. In one embodiment, hetAr² is unsubstituted or substituted with C1-C6 alkoxy (optionally substituted with 1-3 fluoros). 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 structure:

<img file="CA3039760C_D0138.tif" />

[00210] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. A non-limiting example is the structure:

<img file="CA3039760C_D0139.tif" />

[00211] 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 ring heteroatom which is oxygen, wherein said 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

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PCT7US2017/055983 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (C1-C6 alkyl)S02- wherein the alkyl portion is optionally substituted with 1-3 fluoros. 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 structure:

<img file="CA3039760C_D0140.tif" />

[00212] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0141.tif" />

<img file="CA3039760C_D0142.tif" />

<img file="CA3039760C_D0143.tif" />

<img file="CA3039760C_D0144.tif" />

[00213] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAi^SCh- wherein hetAr² is as defined for Formula I. In one embodiment, hetAr² is unsubstituted or substituted with C1-C6 alkoxy (optionally substituted with 1-3 fluoros). 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 structure:

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<img file="CA3039760C_D0145.tif" />

[00214] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. A non-limiting example is the structure:

<img file="CA3039760C_D0146.tif" />

[00215] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is N-(C1-C6 alkyl)pyridinonyl. 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 structure:

<img file="CA3039760C_D0147.tif" />

[00216] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

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<img file="CA3039760C_D0148.tif" />

[00217] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is .4^0(=0)- wherein Ar¹ is as defined for Formula I. In one embodiment, Ar¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros), or Ar¹ is a phenyl 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 structure:

<img file="CA3039760C_D0149.tif" />

[00218] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0150.tif" />

<img file="CA3039760C_D0151.tif" />

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<img file="CA3039760C_D0152.tif" />

[00219] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is .4^0-6(=0)- wherein Ar¹ is as defined for Formula I. In one embodiment, Ar¹ is unsubstituted. 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 structure:

<img file="CA3039760C_D0153.tif" />

[00220] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. A nonlimiting example includes the structure:

<img file="CA3039760C_D0154.tif" />

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[00221] In one embodiment of Formula 1, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is C3-C6 cycloalkyl)CH2C(=O)-, wherein the alkyl portion is optionally substituted with 1-3 fluoros. 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 structure:

<img file="CA3039760C_D0155.tif" />

[00222] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. A non-limiting example includes the structure:

<img file="CA3039760C_D0156.tif" />

[00223] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (C3-C6 cycloalkyl)(Cl-C3 alkyl)S02-, wherein the alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one

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PCT7US2017/055983 embodiment, Ring D is represented by the structure:

<img file="CA3039760C_D0157.tif" />

[00224] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. A non-limiting example includes the structure:

<img file="CA3039760C_D0158.tif" />

[00225] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is Ar^Cl-Cô alkyl)S02- wherein Ar¹ is as defined for Formula 1. In one embodiment, Ar¹ 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 structure

<img file="CA3039760C_D0159.tif" />

[00226] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. A non-limiting example includes the structure:

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<img file="CA3039760C_D0160.tif" />

[00227] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetCy ^-0-(2(=0)-, wherein hetCyc¹ 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 represented by the structure:

<img file="CA3039760C_D0161.tif" />

[00228] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0162.tif" />

<img file="CA3039760C_D0163.tif" />

[00229] In one embodiment of Formula 1, Ring D is a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein said 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

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PCT7US2017/055983 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetCyc'-CHi-Cf^O)-, wherein hetCyc¹ 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 represented by the structure:

<img file="CA3039760C_D0164.tif" />

[00230] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. A non-limiting example includes the structure:

<img file="CA3039760C_D0165.tif" />

[00231] 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 ring heteroatom which is oxygen, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAr², wherein hetAr² is as defined for Formula I. In one embodiment, hetAr² is a 6 membered ring having 1-2 ring nitrogen atoms and is optionally substituted with C1-C6 alkoxy. 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 structures:

<img file="CA3039760C_D0166.tif" />

<img file="CA3039760C_D0167.tif" />

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[00232] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0168.tif" />

<img file="CA3039760C_D0169.tif" />

[00233] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. As used herein, the phrase having two ring nitrogen atoms when Ring D is a saturated 7-11 membered heterospirocyclic ring means that said ring nitrogen atoms are the two nitrogen atoms shown in Ring D of Formula I, wherein one of the ring nitrogen atoms is bonded the ring comprising X¹, X², X³ and X⁴, and the other ring nitrogen atom is bonded to the E group as shown in Formula I. Non-limiting examples when Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms include the structures:

<img file="CA3039760C_D0170.tif" />

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<img file="CA3039760C_D0171.tif" />

<img file="CA3039760C_D0172.tif" />

<img file="CA3039760C_D0173.tif" />

<img file="CA3039760C_D0174.tif" />

<img file="CA3039760C_D0175.tif" />

<img file="CA3039760C_D0176.tif" />

<img file="CA3039760C_D0177.tif" />

<img file="CA3039760C_D0178.tif" />

[00234] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment, Ring D is unsubstituted.

[00235] In one embodiment when Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, Ring D and E portion of Formula I, that is

<img file="CA3039760C_D0179.tif" />

[00236] may be represented by the non-limiting structures:

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<img file="CA3039760C_D0180.tif" />

[00237] wherein the wavy line indicates the point of attachment of Ring D to the ring containing X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is as defined for Formula I. In one embodiment, Ring D is unsubstituted.

[00238] In one embodiment, Ring D is represented by the structure:

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<img file="CA3039760C_D0181.tif" />

[00239] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E, wherein optionally substituted with (a) one to four groups independently selected from halogen, OH, ClC3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment, said Ring D is unsubstituted.

[00240] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene 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 fluoros, (d) (C1-C6 alkyl)C(=O)wherein said alkyl portion is optionally substituted with 1-3 fluoros or with a R^gR^1!N- substituent wherein R^g and R^h are independently H or C1-C6 alkyl, (f) (C1-C6 alkoxy)C(=O)-, (1) hetAr²C(=O)-, (o) R³R⁴NC(=O>, (s) Ar'SCh-, (t) hetAi^SCh-, (v) Ar¹C(=O)-, (cc) hetAr², and (dd) C3-C6 cycloalkyl, wherein hetAr², Ar¹, R³ and R⁴ are as defined for Formula I. In one embodiment, said Ring D is unsubstituted.

[00241] In one embodiment, Ring D is a saturated 9 membered heterospirocyclic ring having two ring nitrogen atoms represented by the structure:

*

[00242] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is

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PCT7US2017/055983 selected from the group consisting of (a) hydrogen, (d) (C1-C6 alkoxy)C(=O)- and (o) R³R⁴NC(=O)-. In one embodiment, said Ring D is unsubstituted

[00243] In one embodiment, In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hydrogen. In one embodiment, said Ring D is represented by the structures:

<img file="CA3039760C_D0182.tif" />

[00244] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, said Ring D is unsubstituted. Non-limiting examples includes the structures:

<img file="CA3039760C_D0183.tif" />

[00245] Tn one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (b) C1-C6 alkyl optionally substituted with 13 fluoros. In one embodiment, said Ring D is represented by the structure:

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[00246] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, said Ring D is unsubstituted. Non-limiting examples includes the structures:

<img file="CA3039760C_D0184.tif" />

<img file="CA3039760C_D0185.tif" />

<img file="CA3039760C_D0186.tif" />

[00247] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (Cl -C6 alkyl)C(=O)-, wherein said alkyl portion is optionally substituted with 1-3 fluoros or with a R^'TM- substituent wherein R^g and R^h are independently H or C1-C6 alkyl. In one embodiment, said Ring D is represented by the structures:

<img file="CA3039760C_D0187.tif" />

<img file="CA3039760C_D0188.tif" />

[00248] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, said Ring D is unsubstituted. Non-limiting examples includes the structures:

<img file="CA3039760C_D0189.tif" />

<img file="CA3039760C_D0190.tif" />

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[00249] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (C1-C6 alkoxy)C(=O)-. In one embodiment, said Ring D is represented by the structures:

<img file="CA3039760C_D0191.tif" />

<img file="CA3039760C_D0192.tif" />

[00250] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, said Ring D is unsubstituted. Non-limiting examples include the structures:

<img file="CA3039760C_D0193.tif" />

<img file="CA3039760C_D0194.tif" />

[00251] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAr²C(=O)-, wherein hetAr² is as defined for Formula I In one embodiment, hetAr² is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. In one embodiment, hetAr² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1 -3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, hetAr² is a 6 membered ring having 1-2 ring nitrogen atoms and is optionally substituted with ClC6 alkoxy. In one embodiment, Ring D is unsubstituted. In one embodiment, Ring D is represented by the structure:

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<img file="CA3039760C_D0195.tif" />

[00252] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. A nonlimiting example includes the structure:

<img file="CA3039760C_D0196.tif" />

[00253] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, Cl -C3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is R³R⁴NC(=O)- wherein R' and R⁴ are as defined for Formula I. In one embodiment, R³ is H and R⁴ is C1-C6 alkyl. In one embodiment, said Ring

D is represented by the structure:

<img file="CA3039760C_D0197.tif" />

[00254] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, said Ring D is unsubstituted. A non-limiting example includes the structure:

<img file="CA3039760C_D0198.tif" />

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[00255] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is Ar¹ SO:-, wherein Ar¹ is as defined for Formula I. In one embodiment, Ar¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, said Ring D is unsubstituted. In one embodiment, said Ring D is represented by the structure

<img file="CA3039760C_D0199.tif" />

[00256] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. Non-limiting examples include the structures:

<img file="CA3039760C_D0200.tif" />

<img file="CA3039760C_D0201.tif" />

<img file="CA3039760C_D0202.tif" />

<img file="CA3039760C_D0203.tif" />

[00257] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6

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PCT7US2017/055983 cycloalkylidene ring, or (c) an oxo group, and E is hetAr²SCh-, wherein hetAr² is as defined for Formula 1. In one embodiment, hetAr² is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. In one embodiment, hetAr² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1 -3 fluoros), and C1-C6 alkoxy (optionally substituted with 1 -3 fluoros). In one embodiment, hetAi^is a 6 membered ring having 1-2 ring nitrogen atoms and is optionally substituted with ClC6 alkoxy. In one embodiment, said Ring D is unsubstituted. In one embodiment, said Ring D is represented by the structure:

<img file="CA3039760C_D0204.tif" />

[00258] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. A nonlimiting example includes the structure:

<img file="CA3039760C_D0205.tif" />

[00259] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is Ar¹C(=O)-, wherein Ar¹ is as defined for Formula I. In one embodiment, Ar¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1 -3 fluoros), and C1-C6 alkoxy (optionally substituted with 1 -3 fluoros). In one embodiment, said Ring D is unsubstituted. In one embodiment, said Ring D is represented by the structure:

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<img file="CA3039760C_D0206.tif" />

[00260] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. Non-limiting examples include the structures:

<img file="CA3039760C_D0207.tif" />

[00261] In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, Cl -C3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hetAr², wherein hetAr² is as defined for Formula I. In one embodiment, hetAr² is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. In one embodiment, hetAr² is optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, hetAr²is a 6 membered ring having 1-2 ring nitrogen atoms and is optionally substituted with C1-C6 alkoxy. In one embodiment, said Ring D is unsubstituted. In one embodiment, said Ring D is represented by the structure:

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[00262] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. A nonlimiting example includes the structure:

-&lt;~^o/

[00263]

In one embodiment, Ring D is a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is C3-C6 cycloalkyl. In one embodiment, said Ring D is unsubstituted. In one embodiment, said Ring D is represented by the structure:

N—*

[00264] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. A nonlimiting example includes the structure:

[00265] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein said ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally

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PCT7US2017/055983 substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. As used herein, the phrase having two ring nitrogen atoms when Ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring means that said ring nitrogen atoms are the two nitrogen atoms shown in Ring D of Formula I, wherein one of the ring nitrogen atoms is bonded the ring comprising X¹, X², X³ and X⁴, and the other ring nitrogen atom is bonded to the E group as shown in Formula T. Fused ring include 5,5, 5,6,6,5 and 6,6 fused ring systems. In one embodiment, said Ring D is represented by the structure:

<img file="CA3039760C_D0208.tif" />

[00266] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment, said Ring D is unsubstituted.

[00267] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is as defined for Formula 1.

[00268] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1 -3 fluoros, (b) a C3-C6 cycloalkylidene 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 structure:

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[00269] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted.

[00270] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is hydrogen. In one embodiment, Ring D is represented by the structure: « s I

[00271] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, Ring D is unsubstituted. A nonlimiting example is the structure:

H j /

[00272] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein said 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, and E is (C1-C6 alkoxy)C(=O)-. In one embodiment, Ring D is represented by the structure:

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[00273] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E. In one embodiment, said Ring D is unsubstituted. A nonlimiting example is the structure:

[00274] In one embodiment, Formula I includes compounds of Formula I-A, wherein: [00275] X¹, X², X³ and X⁴ are independently CH, CF or N, wherein zero, one or two of X¹,

X², X³ andX⁴isN;

[00276] A is H, CN, Cl, CKb-, CH3CH2-, cyclopropyl, -CH2CN or -CH(CN)CH₃;

[00277] B is

[00278] (a) hydrogen,

[00279] (b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

[00280] (c) hydroxyC2-C6 alkyl-, wherein the alkyl portion is optionally substituted with

1-3 fluoros or a C3-C6 cycloalkylidene ring,

[00281] (d) dihydroxyC3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,

[00282] (e) (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,

[00283] (f) (R^bOCl-Cô alkyl- wherein said alkyl portion is optionally substituted with

OH and wherein R¹ and R² are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros);

[00284] (g) hetAr¹Cl-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;

[00285] (h) (C3-C6 cycloalkyl)Cl-C3 alkyl-, wherein said cycloalkyl is optionally

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[00286] (i) (hetCyc^a)Cl-C3 alkyl-,

[00287] (j) hetCyc%

[00288] (k) C3-C6 cycloalkyl-, wherein said cycloalkyl is optionally substituted with OH,

[00289] (1) (C1-C4 alkyl)C(=O)O-Cl-C6 alkyl-, wherein each of the C1-C4 alkyl and ClC6 alkyl portions is optionally and independently substituted with 1-3 fluoros, or

[00290] (m) (R'R²N)C(=O)C1-C6 alkyl-, wherein R¹ and R² are independently H or ClC6 alkyl (optionally substituted with 1-3 fluoros);

[00291] hetCyc^a- is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(=O)-, (C1-C6 alkoxy)Cl-C6 alkyl-, and fluoro, or wherein hetCyc^a is substituted with oxo,

[00292] Ring D is

<img file="CA3039760C_D0209.tif" />

[00293] wherein the wavy line indicates the point of attachment to the ring comprising X¹, X², X³ and X⁴, 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, ClC3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group;

[00294] Eis

[00295] (a) hydrogen,

[00296] (c) (C1-C6 alkoxy)C1-C6 alkyl-optionally substituted with 1-3 fluoros,

[00297] (d) (C1-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with

1-3 fluoros or with a R^eR^hN- substituent wherein R^g and R^h are independently H or C1-C6 alkyl, [00298] (e) (hydroxy C2-C6 alkyl)C(=O)- optionally substituted with 1-3 fluoros,

[00299] (f) (C1-C6 alkoxy)C(=O)-,

[00300] (g) (C3-C6 cycloalkyl)C(=O)- wherein said cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH, and

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PCT7US2017/055983 (C 1-C6 alkoxy )C 1-C6 alkyl-, or said cycloalkyl is substituted with a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O,

[00301] (h) A?C1-C6 alkyd-,

[00302] (i) Ar^Cl-Cô alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl-, C1-C6 alkoxy, R^mRⁿN- or R^mRN-CH2-, wherein each R^m and R“ is independently H or Cl -C6 alkyl,

[00303] (j) hetAHCl-Cô alkyl- wherein said alkyl portion is optionally substituted with 13 fluoros,

[00304] (k) hetAPfCl-Cô alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl or C1-C6 alkoxy,

[00305] (1) hetAr²C(=O)-.

[00306] (m) hetCyc¹C(=O)-,

[00307] (n) hetCy^Cl-Cô alkyl-,

[00308] (o) R³R⁴NC(=O)-, or

[00309] (cc) hetAr²;

[00310] Ar¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), R®R^- wherein R^c and R^f are independently H or C1-C6 alkyl, (R^pR^qN)Cl-C6 alkoxy- wherein R^p and R^q are independently H or C1-C6 alkyl, and (hetAr^a)C 1-C6 alkyl- wherein hetAr³ is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar¹ is a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

[00311] hetAr² 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 hetAr² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), R^eR^fN- wherein R^e and R^f are independently H or C1-C6 alkyl, OH, (C1-C6 alkoxy)Cl-C6 alkoxy- and C3-C6 cycloalkyl;

[00312] hetCyc¹ 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

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PCT7US2017/055983 with one or more substituents independently selected from C1-C6 alkoxy and halogen; and [00313] R⁴ is Cl-C6 alkyl.

[00314] In one embodiment of Formula I-A, Ring D is unsubstituted.

[00315] In one embodiment of Formula I-A, X¹ is N; X², X³ and X⁴ are CH.

[00316] In one embodiment of Formula I-A, A is CN.

[00317] Tn one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X³ and

X⁴ are CH; and A is CN

[00318] In one embodiment of Formula I-A, B is C1-C6 alkyl optionally substituted with 1-3 fluoros.

[00319] In one embodiment of Formula I-A, B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.

[00320] In one embodiment of Formula I-A, B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros. In one embodiment of Formula I-A, B is (C1-C6 alkoxy )C2-C6 alkyloptionally substituted with 1-3 fluoros.

[00321] In one embodiment of Formula I-A, B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, the alkyl portion is unsubstituted.

[00322] In one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X³ and X⁴ are CH; A is CN; and B is (C 1-C6 alkoxy)C 1-C6 alkyl- optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.

[00323] In one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X³ and X⁴ are CH; A is CN; and B is (C1-C6 alkoxy )C1-C6 alkyl- optionally substituted with 1-3 fluoros. In one embodiment, B is (C1-C6 alkoxy )C2-C6 alkyl- optionally substituted with 1-3 fluoros.

[00324] In one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X³ and X⁴ are CH; A is CN; and B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, the alkyl portion of the B group is unsubstituted.

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[00325] In one embodiment of Formula I-A, E is Ar'Cl-C6 alkyl-, hetAr²Cl-C6 alkylwherein the alkyl portion is optionally substituted with 1-3 fluoros, or Ar^l(Cl-C6 alkyl)C(=O)-, wherein Ar¹ and hetAr² are as defined for Formula I-A.

[00326] In one embodiment of Formula I-A, E is A^Cl-Cô alkyl-, hetAr²Cl-C6 alkylwherein the alkyl portion is optionally substituted with 1-3 fluoros, or Ar^l(Cl-C6 alkyl)C(=O)-, wherein Ar¹ is an unsubstituted phenyl and hetAr² is a 5-6 membered heterocyclic ring having 12 ring nitrogen atoms and is optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1-3 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment of Formula I-A, hetAr² is a 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 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros).

[00327] In one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X³ and X⁴ are CH; A is CN; B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and E is A^Cl-Cô alkyl-, hetAr²Cl-C6 alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or Ar^l(Cl-C6 alkyl)C(=O)-, wherein Ar¹ and hetAr² are as defined for Formula I-A.

[00328] In one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X³ and X⁴ are CH; A is CN; B is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros; and E is Ar^lCl-C6 alkyl-, hetAr²Cl-C6 alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or Ar^Cl-Cô alkyl)C(=O)-, wherein Ar¹ and hetAr² are as defined for Formula I-A.

[00329] In one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X³ and X⁴ are CH; A is CN; B is (C1-C6 alkoxy )C1-C6 alkyl- optionally substituted with 1-3 fluoros; and E is Ar*Cl-C6 alkyl- wherein Ar¹ is as defined for Formula I-A.

[00330] In one embodiment of Formula T-A, Ring D is unsubstituted; X¹ is N; X², X³ and X⁴ are CH; A is CN; B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros; and E is hetAr²Cl-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros and hetAr² is as defined for Formula I-A.

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[00331] In one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X³ and X⁴ are CH; A is CN; B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros; or E is Ar'(Cl-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl- or C1-C6 alkoxy and Ar¹ is as defined for Formula I-A.

[00332] In one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X³ and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and E is Ar’Cl-C6 alkyl-, hetAr²Cl-C6 alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or Ar'(Cl-C6 alkyl)C(=O)-, wherein Ar¹and hetAr² are as defined for Formula I-A. In one embodiment, the alkyl portion of the B group is unsubstituted.

[00333] In one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X’ and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, and E is Ar'Cl-C6 alkyl- wherein Ar¹ is as defined for Formula I-A. In one embodiment, the alkyl portion of the B group is unsubstituted.

[00334] In one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X³ and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and E is hetAr²Cl-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros and hetAr² is as defined for Formula I-A. In one embodiment, the alkyl portion of the B group is unsubstituted.

[00335] In one embodiment of Formula I-A, Ring D is unsubstituted; X¹ is N; X², X³ and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and E is Ar^l(Cl-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl- or C1-C6 alkoxy and Ar¹ is as defined for Formula I-A. In one embodiment, Ar¹ is an unsubstituted phenyl. In one embodiment, B is hydroxyC2-C6 alkyl- wherein the alkyl portion is unsubstituted.

[00336] In one embodiment of Formula I-A, Ring D is unsubstituted; X² is N; X¹, X³ and X⁴ are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, (C1-C6 alkoxy)C1C6 alkyl- optionally substituted with 1-3 fluoros, or (hetCyc^a)Cl-C3 alkyl-; and E is Ar^lCl-C6 alkyl- or Ar'(Cl-C6 alkyl)C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl- or C1-C6 alkoxy and hetCyc^a and Ar¹ are as defined for Formula I-A.

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[00337] In one embodiment of Formula I-A, Ring D is unsubstituted; X² is N; X¹, X³ and X⁴ are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and E is Ar^l(Cl-C6 alkyl)C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkylor C1-C6 alkoxy and Ar¹ is as defined for Formula I-A.

[00338] In one embodiment of Formula I-A, Ring D is unsubstituted; X² is N; X¹, X³ and X⁴ are CH; A is CN; B is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros; and E is Ar'Cl-C6 alkyl- and Ar¹ is as defined for Formula I-A.

[00339] In one embodiment of Formula I-A, Ring D is unsubstituted; X² is N; X¹, X³ and X⁴ are CH; A is CN; B is (hetCyc^a)Cl-C3 alkyl-; and E is Ar*01-06 alkyl- and hetCyc^a and Ar¹are as defined for Formula I-A.

[00340] In one embodiment, Formula I includes compounds of Formula I-B, wherein: [00341] X¹, X², X³ and X⁴ are independently CH, CF or N, wherein zero, one or two of X¹,

X², X³ and X⁴ is N;

[00342] A is H, CN, Cl, CH3-, CH3CH2-, cyclopropyl, -CH2CN or -CH(CN)CH₃;

[00343] B is

[00344] (a) hydrogen,

[00345] (b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

[00346] (c) hydroxyC2-C6 alkyl-, wherein the alkyl portion is optionally substituted with

1-3 fluoros or a C3-C6 cycloalkylidene ring,

[00347] (d) dihydroxyC3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a

C3-C6 cycloalkylidene ring,

[00348] (e) (C 1-C6 alkoxy)C1-C6 alkyl-optionally substituted with 1-3 fluoros,

[00349] (f) (R¹R²N)C1-C6 alkyl- wherein said alkyl portion is optionally substituted with

OH and wherein R¹ and R² are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros);

[00350] (g) hetAr¹Cl-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;

[00351] (h) (C3-C6 cycloalkyl)Cl-C3 alkyl-, wherein said cycloalkyl is optionally substituted with OH,

[00352] (i) (hetCyc^a)Cl-C3 alkyl-,

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[00353] (j) hetCyc^a-,

[00354] (k) C3-C6 cycloalkyl-, wherein said cycloalkyl is optionally substituted with OH,

[00355] (1) (C1-C4 alkyl)C(=O)O-Cl-C6 alkyl-, wherein each of the C1-C4 alkyl and ClC6 alkyl portions is optionally and independently substituted with 1-3 fluoros, or

[00356] (m) (R¹R²N)C(=O)C1-C6 alkyl-, wherein R¹ and R² are independently H or ClC6 alkyl (optionally substituted with 1-3 fluoros);

[00357] hetCyc^a- is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyCl-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl-, and fluoro, or wherein hetCyc³ is substituted with oxo,

[00358] Ring D is

<img file="CA3039760C_D0210.tif" />

<img file="CA3039760C_D0211.tif" />

<img file="CA3039760C_D0212.tif" />

or

<img file="CA3039760C_D0213.tif" />

[00359] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group;

[00360] Eis

[00361] (a) hydrogen,

[00362] (b)Cl-C6 alkyl,

[00363] (c) (C 1-C6 alkoxy)C 1-C6 alkyl-,

[00364] (d) (C1-C6 alkyl)C(=O>,

[00365] (e) (hydroxyC2-C6 alkyl)C(=O)-,

[00366] (f) (C 1-C6 alkoxy)C(=O)-,

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<td> [00367]</td><td> (g) (C3-C6 cycloalkyl)C(=O)-,</td>

<td> [00368] [00369]</td><td> OOAr’Cl-Cô alkyl-, (i) Ar^Cl-Cô alkyl)C(=O)- wherein said alkyl portion is optionally substituted</td>

with OH, hydroxyCl-C6 alkyl-, C1-C6 alkoxy, R^mR“N- or R^mRN-CH2-, wherein each R“ and R“ is independently H or C1-C6 alkyl,

<td> [00370] 3 fluoros,</td><td> (j) hetAr^Cl-Cô alkyl- wherein said alkyl portion is optionally substituted with 1-</td>

<td> [00371]</td><td> (k) hetAr(Cl-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted</td>

with OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy,

<td> [00372] [00373] [00374] [00375] [00376]</td><td> (1) hetAr²C(=O)-, (m) hetCyc‘C(=O)-, (o) R³R⁴NC(=O)-, (p) Ar*R³NC(=O)-, (q) hetAr²N(R³)C(=O)-,</td>

<td> [00377] fluoros,</td><td> (r) (C1-C6 alkyl)SO2- wherein the alkyl portion is optionally substituted with 1-3</td>

<td> [00378] [00379] [00380] [00381] [00382]</td><td> (t) hetAr²SO₂-, (u) N-(C1-C6 alkyl)pyridinonyl, (v) Ar*C(=O)-, (w) Ar¹O-C(=O)-, (x) (C3-C6 cycloalkyl)CH2C(=O)-,</td>

<td> [00383] [00384] [00385] [00386] [00387] [00388]</td><td> (y) (C3-C6 cycloalkyl)(Cl-C6 alkyl)SO2-, (z) Ar^Cl-Cô alkyl)SO₂-, (aa) hetCy^-O-C^O)-, (bb) hetCyc¹-CH₂-C(=O)-, or (cc) hetAr²; Ar¹ is phenyl optionally substituted with one or more substituents independently</td>

selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), R^^- wherein R^e and R^f are independently H or C1-C6 alkyl, (R^pR^qN)Cl-C6 alkoxy- wherein R^p and R^q are independently H or C1-C6 alkyl, and (hetAr')C 1-C6 alkyl- wherein hetAr³ is a 5-6 membered heteroaryl ring having

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1-2 ring nitrogen atoms, or Ar¹ is a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

[00389] hetAr² 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 hetAr² is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)Cl-C6 alkyl- (optionally substituted with 1-3 fluoros), R^eR^fN- wherein R^e and R^f are independently H or C1-C6 alkyl, OH, (C 1-C6 alkoxy)Cl-C6 alkoxy- and C3-C6 cycloalkyl;

[00390] hetCyc¹ 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;

[00391] R³ is H or C1-C6 alkyl, and

[00392] R⁴ is C1-C6 alkyl.

[00393] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH.

[00394] In one embodiment of Formula I-B, X¹ and X³ are N; and X² and X⁴ are CH.

[00395] In one embodiment of Formula I-B, A is CN.

[00396] In one embodiment of Formula I-B, Ring D is

<img file="CA3039760C_D0214.tif" />

[00397] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group.

[00398] In one embodiment of Formula I-B, Ring Dis

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[00399] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E, wherein Ring D is unsubstituted.

[00400] In one embodiment of Formula I-B, B is C1-C6 alkyl optionally substituted with 1-3 fluoros; (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros; hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; hetAr¹ C1-C3 alkyl-; or (hetCyc^a)Cl-C3 alkyl-; wherein hetAr¹ and hetCyc” are as defined for Formula I-B.

[00401] In one embodiment of Formula I-B, B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment of Formula I-B, B is C1-C6 alkyl.

[00402] In one embodiment of Formula I-B, B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.

[00403] In one embodiment of Formula I-B, B is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros. In one embodiment ofFormula I-B, Bis (Cl-C6 alkoxy )C2-C6alkyloptionally substituted with 1-3 fluoros.

[00404] In one embodiment of Formula I-B, B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, the alkyl portion of the B group is unsubstituted.

[00405] In one embodiment ofFormula I-B, B is hetAr*Cl-C3 alkyl-, wherein hetAr¹ is as defined for Formula I-B.

[00406] In one embodiment ofFormula I-B, B is (hetCyc^a)Cl-C3 alkyl-; wherein hetCyc^ais as defined for Formula I-B.

[00407] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; and B is C1-C6 alkyl optionally substituted with 1-3 fluoros. In one embodiment ofFormula I-B, B is C1-C6 alkyl.

[00408] In one embodiment ofFormula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³areN; and X² and X⁴ are CH; A is CN; and B is (Cl -C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, X¹ is N; X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N, and X² and X⁴ are CH.

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[00409] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; and B is (C1-C6 alkoxy)C 1-C6 alkyl- optionally substituted with 1-3 fluoros. In one embodiment, X¹ is N; X², X³ and X⁴ are CH. In one embodiment, X¹and X³ are N; and X² and X⁴ are CH.

[00410] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; and B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, the alkyl portion of the B group is unsubstituted. In one embodiment, X¹ is N; X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00411] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N, and X² and X⁴ are CH; A is CN, and B is hetAr^lCl-C3 alkyl-, wherein hetAr¹ is as defined for Formula I-B. In one embodiment, X¹ is N; X², X³ and X⁴ are CH. In one embodiment, X¹and X³ are N, and X² and X⁴ are CH

[00412] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; and B is (hetCyc^a)Cl-C3 alkyl-; wherein hetCyc^a is as defined for Foimula I-B. In one embodiment, X¹ is N; X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00413] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; and Ring Dis

<img file="CA3039760C_D0215.tif" />

[00414] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment of Formula I-B, said Ring D is unsubstituted. In one embodiment, X¹ is N; X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

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[00415] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; B is (C1-C6 alkoxy )C1-C6 alkyl- optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a

C3-C6 cycloalkylidene ring; and Ring D is

<img file="CA3039760C_D0216.tif" />

[00416] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment of Formula I-B, said Ring D is unsubstituted. In one embodiment, X¹ is N; X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00417] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and Ring D is

<img file="CA3039760C_D0217.tif" />

[00418] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E, wherein Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00419] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hetAr'Cl-C3 alkyl-, wherein hetAr¹ is as defined for Formula I-B; and Ring D is

<img file="CA3039760C_D0218.tif" />

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[00420] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment of Formula T-B, Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00421] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is (hetCyc^a)Cl-C3 alkyl-; wherein hetCyc^a is as defined for Formula I-B, and Ring D is

<img file="CA3039760C_D0219.tif" />

*

[00422] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment of Formula I-B, Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00423] In one embodiment of Formula I-B, E is hetAr²Cl-C6 alkyl wherein the alkyl portion is optionally substituted with 1-3 fluoros, hetAr²C(=O)-, Ar*R³NC(=O)-, or (C1-C6 alkyl)SOz-, wherein hetAr², Ar¹, and R³ are as defined for Formula I-B. In one embodiment, hetAr² 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 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros).

[00424] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is

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<img file="CA3039760C_D0220.tif" />

[00425] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAr²Cl-C6 alkyl wherein the alkyl portion is optionally substituted with 1-3 fluoros, hetAr²C(=O)-, Ar¹R³NC(=O)- or (C1-C6 alkyl)SO2- wherein hetAr², Ar¹ and R³ are as defined for Formula I-B. In one embodiment of Formula I-B, said Ring D is unsubstituted. In one embodiment, X¹ is N; X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N, and X² and X⁴ are CH

[00426] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros, Ring D is

<img file="CA3039760C_D0221.tif" />

[00427] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAi^Cl-Cô alkyl wherein the alkyl portion is optionally substituted with 1-3 fluoros. In one embodiment of Formula I-B, said Ring D is unsubstituted. In one embodiment, X¹ is N; X², X³and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00428] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros; Ring D is

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<img file="CA3039760C_D0222.tif" />

[00429] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAr²C(=O)-, wherein hetAr² is as defined for Formula I-B. In one embodiment of Formula I-B, said Ring D is unsubstituted. In one embodiment, X¹ is N; X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00430] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros;

Ring D is

<img file="CA3039760C_D0223.tif" />

[00431] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is Ar^lR³NC(=O)- wherein Ar¹ is as defined for Formula I-B. In one embodiment of Formula IB, said Ring D is unsubstituted. In one embodiment, X¹ is N; X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00432] In one embodiment of Formula I-B, X¹ is N; X², X³ and X⁴ are CH, or X¹ and X³are N; and X² and X⁴ are CH; A is CN; B is C1-C6 alkyl optionally substituted with 1-3 fluoros;

Ring D is

<img file="CA3039760C_D0224.tif" />

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[00433] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1 -3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and Eis(Cl-C6alkyl)SÛ2-. In one embodiment of Formula I-B, said Ring Dis unsubstituted. In one embodiment, X¹ is N; X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH

[00434] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ areN, and X² and X⁴ are CH; A is CN; B is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

[00435] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAr²Cl-C6 alkyl wherein the alkyl portion is optionally substituted with 1-3 fluoros, hetAr²C(=O)-, Ar^lR³NC(=O)- or (C1-C6 alkyl )SO2- wherein hetAr², Ar¹ and R³ are as defined for Formula I-B. In one embodiment, Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00436] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ areN, and X² and X⁴ are CH; A is CN; B is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros; Ring D is

[00437] wherein the wavy line indicates the point of attachment of Ring D to the ring

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PCT7US2017/055983 comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAr²Cl-C6 alkyl wherein the alkyl portion is optionally substituted with 1-3 fluoros, hetAi^C^O)-, Ar¹R³NC(=O)- or (Cl -C6 alkyl)SÛ2- wherein hetAr², Ar¹ and R³ and are as defined for Formula I-B. In one embodiment said Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00438] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

<img file="CA3039760C_D0225.tif" />

[00439] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAr²Cl-C6 alkyl wherein the alkyl portion is optionally substituted with 1-3 fluoros, hetAr²C(=O)-, Ar'R³NC(=O)- or (C 1-C6 alkyl)S02- wherein hetAr², Ar¹ and R³ and are as defined for Formula I-B. In one embodiment said Ring D is unsubstituted. In one embodiment, X¹ is N, and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00440] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hetAr'Cl-C3 alkyl-, wherein hetAr¹ is as defined for Formula I-B; Ring D is

<img file="CA3039760C_D0226.tif" />

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[00441] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAi^Cl-Cô alkyl wherein the alkyl portion is optionally substituted with 1-3 fluoros, hetAr²C(=O)-, Ar'R³NC(=0)- or (C 1-C6 alkyl)S02- wherein hetAr², Ar¹ and R³ and are as defined for Formula I-B. In one embodiment said Ring D is unsubstituted. In one embodiment, X¹ is N, and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00442] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is (hetCyc^a)Cl-C3 alkyl-, wherein hetCyc³ is as defined for Formula I-B; Ring D is

<img file="CA3039760C_D0227.tif" />

[00443] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAPCl-Cô alkyl wherein the alkyl portion is optionally substituted with 1-3 fluoros, hetAr²C(=O)-, Αγ^³ΝΟ(=Ο)- or (C1-C6 alkyl)SO2- wherein hetAr², Ar¹ and R³ and are as defined for Formula I-B. In one embodiment said Ring D is unsubstituted. In one embodiment, X¹ is N, and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00444] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

<img file="CA3039760C_D0228.tif" />

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[00445] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAi^Cl-Cô alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluoros and hetAr²is as defined for Formula I-B. In one embodiment said Ring D is unsubstituted. In one embodiment, hetAr² 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 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00446] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

<img file="CA3039760C_D0229.tif" />

[00447] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy’ which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAr²C(=O)-, wherein hetAr² is as defined for Formula I-B. In one embodiment said Ring D is unsubstituted. In one embodiment, hetAr² 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 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X²and X⁴ are CH.

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[00448] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

[00449] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or Cl -C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is Ar'R³NC(=O)- wherein Ar’ and R³ are as defined for Formula I-B. In one embodiment, Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹and X³ are N, and X² and X⁴ are CH.

[00450] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is xLn

[00451] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is (ClC6 alkyl)SO2-. In one embodiment said Ring D is unsubstituted. In one embodiment, X¹ is N, and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00452] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ areN, and X² and X⁴ are CH; A is CN; B is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros; Ring D is

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[00453] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAi^Cl-Cô alkyl wherein the alkyl portion is optionally substituted with 1-3 fluoros, hetAr²C(=O)-, Ar¹R³NC(=O)- or (C 1-C6 alkyl)SO2- wherein hetAr², Ar¹ and R³ are as defined for Formula I-B. In one embodiment said Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00454] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ areN, and X² and X⁴ are CH; A is CN, B is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros; Ring D is

[00455] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAr²Cl-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluoros and hetAr²is as defined for Formula I-B. In one embodiment said Ring D is unsubstituted. In one embodiment, hetAr² 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 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

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[00456] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is (C1-C6 alkoxy )C1-C6 alkyl- optionally substituted with 1-3 fluoros; Ring D is

<img file="CA3039760C_D0230.tif" />

[00457] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or Cl -C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAr²C(=O)-, wherein hetAr² is as defined for Formula I-B. In one embodiment said Ring D is unsubstituted. In one embodiment, hetAr² 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 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X²and X⁴ are CH.

[00458] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ areN, and X² and X⁴ are CH; A is CN; B is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros; Ring D is

<img file="CA3039760C_D0231.tif" />

[00459] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is Ar¹R³NC(=O)- wherein Ar¹ and R³ are as defined for Formula I-B. In one embodiment, Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹

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PCT7US2017/055983 and X³ are N; and X² and X⁴ are CH.

[00460] In one embodiment of Formula 1-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros; Ring D is

<img file="CA3039760C_D0232.tif" />

[00461] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is (ClC6 alkyl)SO2-. In one embodiment Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00462] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl-; Ring D is

<img file="CA3039760C_D0233.tif" />

[00463] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E; and E is hetArCl-Cô alkyl wherein the alkyl portion is optionally substituted with 1-3 fluoros, or hetAr²C(=O), wherein hetAr² 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 fluoros) and hetAr² is as defined for Formula I-B. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00464] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl-; Ring D is

<img file="CA3039760C_D0234.tif" />

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[00465] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E; and E is hetAi^Cl-Cô alkyl wherein the alkyl portion is optionally substituted with 1-3 fluoros, wherein hetAr² is optionally substituted with one or more substituents independently selected from the group consisting of halogen and Cl -C6 alkoxy (optionally substituted with 1-3 fluoros) and hetAr²is as defined for Formula I-B. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00466] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl-; Ring D is

<img file="CA3039760C_D0235.tif" />

[00467] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E; and E is hetAr²C(=O), wherein hetAr² 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 fluoros) and hetAr² is as defined for Formula I-B. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00468] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

<img file="CA3039760C_D0236.tif" />

[00469] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E; and E is Ar¹N(R³)C(=O) and Ar¹ and R³ are as defined for Formula I-B. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00470] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

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<img file="CA3039760C_D0237.tif" />

[00471] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E; and E is hetAr²Cl-C6 alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or hetAr²C(=O)-, and hetAr² is as defined for Formula I-B. In one embodiment, X¹ is N; and X², X³and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00472] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

<img file="CA3039760C_D0238.tif" />

[00473] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E; and E is hetAr²Cl-C6 alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros and hetAr²is as defined for Formula I-B. In one embodiment, X¹ is N, and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00474] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³are N, and X² and X⁴ are CH; A is CN, B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

<img file="CA3039760C_D0239.tif" />

[00475] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E; and E is hetAr²C(=O)- and hetAr² is as defined for Formula I-B. In one embodiment, X¹ is N; and X², X³and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00476] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is

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<img file="CA3039760C_D0240.tif" />

[00477] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E; and E is hetAi^Cl-Cô alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros and hetAr²is as defined for Formula I-B. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00478] In one embodiment of Formula T-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and

X³ are N, and X² and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; Ring D is

<img file="CA3039760C_D0241.tif" />

[00479] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E; and E is hetAr²Cl-C6 alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros and hetAr²is as defined for Formula I-B. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00480] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hetAr'Cl-C3 alkyl-, wherein hetAr¹ is as defined for Formula I-B; Ring D is

<img file="CA3039760C_D0242.tif" />

[00481] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy’ which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is

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PCT7US2017/055983 hetAPCl-Cô alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluoros and hetAr²is as defined for Formula I-B. In one embodiment, Ring D is unsubstituted. In one embodiment, hetAr² 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 fluoros), and C1-C6 alkoxy (optionally substituted with 1 -3 fluoros). In one embodiment, X¹ is N; and X², X³ and X⁴are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00482] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hetAr'C 1-C3 alkyl-, wherein hetAr¹ is as defined for Formula I-B; Ring D is

<img file="CA3039760C_D0243.tif" />

[00483] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAr²C(=O)-, wherein hetAr² is as defined for Formula I-B. In one embodiment, Ring D is unsubstituted. In one embodiment, hetAr² 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 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X²and X⁴ are CH.

[00484] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is hetAr'C 1-C3 alkyl-, wherein hetAr¹ is as defined for Formula I-B; Ring D is

<img file="CA3039760C_D0244.tif" />

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[00485] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is Αγ^³Ν0(=Ο)- wherein Ar¹ and R³ are as defined for Formula I-B. In one embodiment, Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N, and X² and X⁴ are CH.

[00486] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN, B is hetAr'C 1-C3 alkyl-, wherein hetAr¹ is as defined for Formula I-B, Ring D is

<img file="CA3039760C_D0245.tif" />

[00487] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is (C1 C6 alkyl)S02-. In one embodiment, Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00488] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is (hetCyc^a)Cl-C3 alkyl-, wherein hetCyc^a is as defined for Formula I-B; Ring D is

<img file="CA3039760C_D0246.tif" />

[00489] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally

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PCT7US2017/055983 substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAr²Cl-C6 alkyl, wherein the alkyl portion is optionally substituted with 1-3 fluoros and hetAr²is as defined for Formula I-B. In one embodiment, Ring D is unsubstituted. In one embodiment, hetAr² 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 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, X¹ is N; and X², X’ and X⁴are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00490] In one embodiment ofFormula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is (hetCyc^a)Cl-C3 alkyl-, wherein hetCyc^a is as defined for Formula I-B; Ring D is

<img file="CA3039760C_D0247.tif" />

*

[00491] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is hetAr²C(=O)-, wherein hetAr² is as defined for Formula I-B. In one embodiment, Ring D is unsubstituted. In one embodiment, hetAr² 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 fluoros), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros). In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X²and X⁴ are CH.

[00492] In one embodiment ofFormula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and X³ are N, and X² and X⁴ are CH; A is CN; B is (hetCyc^a)Cl-C3 alkyl-, wherein hetCyc^a is as defined for Formula I-B; Ring D is

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<img file="CA3039760C_D0248.tif" />

[00493] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is Ar'R³NC(=O)- wherein Ar¹ and R³ are as defined for Formula I-B. In one embodiment, Ring D is unsubstituted In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00494] In one embodiment of Formula I-B, X¹ is N, and X², X³ and X⁴ are CH; or X¹ and

X³ are N, and X² and X⁴ are CH; A is CN; B is (hetCyc^a)Cl-C3 alkyl-, wherein hetCyc^a is as defined for Formula I-B; Ring D is

<img file="CA3039760C_D0249.tif" />

[00495] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, 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 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; and E is (ClC6 alkyl)S02-. In one embodiment, Ring D is unsubstituted. In one embodiment, X¹ is N; and X², X³ and X⁴ are CH. In one embodiment, X¹ and X³ are N; and X² and X⁴ are CH.

[00496] In one embodiment, Formula I includes compounds of Formula I-C wherein: [00497] X¹, X², X³ and X⁴ are independently CH, CF or N, wherein zero, one or two of X¹,

X², X³ and X⁴ is N;

[00498] A is H, CN, Cl, CH3-, CH3CH2-, cyclopropyl, -CH2CN or -CH(CN)CH₃;

[00499] B is

[00500] (a) hydrogen,

[00501] (b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

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[00502] (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a

C3-C6 cycloalkylidene ring,

[00503] (d) dihydroxyC3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a

C3-C6 cycloalkylidene ring,

[00504] (e) (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros,

[00505] (f) (R¹R²N)C1-C6 alkyl- wherein R¹ and R² are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros);

[00506] (g) hetAr’Cl-C3 alkyl-, wherein hetAr’ 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;

[00507] (h) (C3-C6 cycloalkyl)Cl-C3 alkyl-,

[00508] (i) (hetCyc^a)Cl-C3 alkyl-, or

[00509] (j) hetCyc^a;

[00510] hetCyc^a is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and is optionally substituted with OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyCl-C6 alkyl-;

[00511] Ring Dis

<img file="CA3039760C_D0250.tif" />

<img file="CA3039760C_D0251.tif" />

<img file="CA3039760C_D0252.tif" />

[00512] wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X¹, X², X³ and X⁴, and the asterisk indicates the point of attachment to E;

[00513] Eis

[00514] (a) hydrogen,

[00515] (b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

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[00516] (d) (C1-C6 alkyl)C(=O)- wherein said alkyl portion is optionally substituted with

1-3 fluoros or with a R^gR^hN- substituent wherein R^g and R^h are independently H or C1-C6 alkyl, [00517] (f) (C 1-C6 alkoxy)C(=O),

[00518] (1) hetAr2C(=O)-,

[00519] (o) R³R⁴NC(=O)-,

[00520] (s) Ar^lSO₂-,

[00521] (t) hetAr²SO2-,

[00522] (v) Ar’C(=O)-,

[00523] (cc) hetAr², or

[00524] (dd) C3-C6 cycloalkyl;

[00525] R³ is H or C1-C6 alkyl, and

[00526] R⁴ is Cl-C6 alkyl.

[00527] In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH.

[00528] In one embodiment of Formula I-C, A is CN.

[00529] In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; and A is CN.

[00530] In one embodiment of Formula I-C, B is (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.

[00531] In one embodiment of Formula I-C, B is (C1-C6 alkoxy )C1-C6 alkyl- optionally substituted with 1-3 fluoros. In one embodiment ofFormula I-C, Bis (Cl-C6 alkoxy )C2-C6alkyloptionally substituted with 1-3 fluoros.

[00532] In one embodiment of Formula I-C, B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In one embodiment, the alkyl portion of the B group is unsubstituted.

[00533] In one embodiment of Formula I-C, X¹ is N; X², X³ and X⁴ are CH; A is CN; and B is (C1-C6 alkoxy)Cl-C6 alkyl optionally substituted with 1-3 fluoros.

[00534] In one embodiment ofFormula I-C, X² is N; X¹, X³ and X⁴ are CH; A is CN; B is hydroxyC2-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; and E is (C1-C6 alkoxy)C(=O)-.

[00535] In one embodiment ofFormula I-C, X¹ is N; X², X³ and X⁴ are CH; A is CN; and B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6

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PCT7US2017/055983 cycloalkylidene ring. In one embodiment, the alkyl portion of the B group is unsubstituted.

[00536] The compounds of Formula I include pharmaceutically acceptable salts thereof. In addition, the compounds of Formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating enantiomers of compounds of Formula I Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include monohydrochloride, dihydrochloride, trifluoroacetic acid, and di-trifluoroacetic acid salts. In one embodiment, compounds of Formula I include trifluoroacetic acid and dihydrochloride salts.

[00537] It will further be appreciated that the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention. For example, compounds of Formula I and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[00538] In one embodiment, the compounds of Formula I include the compounds of Examples 1-561 and stereoisomers and pharmaceutically acceptable salts and solvates thereof. In one embodiment, the compounds of Examples 1-561 are in the free base form. In one embodiment, the compounds of Examples 1-561 are dihydrochloride, and trifluoroacetic acid salts.

[00539] The term pharmaceutically acceptable indicates that the compound, or salt or composition thereof is compatible chemically and/or toxicologically with the other ingredients comprising a formulation and/or the patient being treated therewith.

[00540] Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula I, comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to ³Η, ²H, ³H or mixtures thereof; when carbon is mentioned, it is understood to refer to ^llC, ¹²C, ¹³C, ^l4C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to¹³N, ¹⁴N,¹⁵N or mixtures thereof; when oxygen is mentioned, it is understood to refer to ¹⁴O, ^I5O, ^l6O, ¹⁷O, ¹⁸O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to ¹⁸F, ¹⁹F or mixtures thereof. The compounds provided herein therefore also

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PCT7US2017/055983 comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[00541] For illustrative purposes, Schemes 1-6 show general methods for preparing the compounds provided herein as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

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<img file="CA3039760C_D0253.tif" />

<img file="CA3039760C_D0254.tif" />

SCHEME 1

[00542] Scheme 1 shows a general scheme for the synthesis of compound 12 wherein A is CN, and B, X¹, X², X³, X⁴, Ring D and E are as defined for Formula I.

[00543] Compound 2 is obtained by treating 3-bromo-5-methoxypyridine (compound 1), which is commercially available, with O-(mesitylsulfonyl)hydroxylamine. The Omesitylsulfonylhydroxylamine may be prepared as described in Mendiola, J., et al., Org. Process Res. Dev. 2009, 13(2), 263-267. Compound 2 may be reacted with ethyl propiolate to provide a mixture of compounds 3A and 3B, which typically are obtained in a ratio of approximately 2:1 to

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9:1, respectively. The mixture of compounds 3A and 3B may be treated with 48% HBr at elevated temperatures, followed by recrystallization or chromatography purifications, to isolate compound 4A as the minor isomer and compound 4B as the major isomer. After isolation, compound 4A may be treated with POCh to provide compound 5. The formyl group may be converted to an oxime group using NH2OH to provide compound 6. The oxime group may be converted to a nitrile group using acetic anhydride to provide compound 7. The methoxy group of compound 7 may be converted to a hydroxy group by treating compound 7 with aluminum trichloride to provide compound 8.

[00544] To prepare compound 12 wherein B is hydrogen, compound 12 may be prepared by coupling compound 8 with the corresponding boronic ester compound 10 (wherein Ring D, X¹, X², X³ and X⁴ are as defined for Formula I; P^l is an amino protecting group; Z is -B(0R^x)(0R^y) and R^z and R^y are H or (l-6C)alkyl, or R^x and R^y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) to provide compound Ila using appropriate palladium-catalyzed cross-coupling reaction conditions, e g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and NazCCh in dioxane at elevated temperatures). The protecting group P¹ on Ring D of compound Ila may be removed under standard conditions (for example, a Boc group may be removed by treating compound Ila to acidic conditions, e g., HC1) to provide compound 12 wherein B is hydrogen and E is hydrogen. Alternatively, the deprotected Ring D may be functionalized (i.e., reacted or treated with an appropriate reagent) to introduce the E group under standard conditions such as described below to provide compound 12 wherein B is hydrogen and E is as defined for Formula I except that E is not hydrogen.

[00545] Alternatively, to prepare compound 12 wherein B is as defined for Formula 1 other than hydrogen, compound Ila may be reacted with a reagent such as C1-C6 alkyl-OH optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-OH, dihydroxyC3-C6 alkyl-OH, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R^lR²N)Cl-C6 alkyl-OH wherein R¹ and R² are as defined for Formula I, hetAr'Cl-C3 alkyl-OH, (C3-C6 cycloalkyl)Cl-C3 alkylOH, (hetCyc^a)Cl-C3alkyl-OH, or hetCyc^a-OH, wherein hetAr¹ and hetCyc* are defined for Formula I, and wherein each of said reagents ins optionally substituted with a protecting group, under Mitsunobu reaction conditions (e.g., PPI13 and diisopropyl azodicarboxylate) to provide

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PCT7US2017/055983 compound 11. Compound 12 may then be prepared from compound 11 as described above, followed by removal of the protecting group on B if present.

[00546] As an alternative process for preparing compound 12 wherein B is as defined for Formula I other than hydrogen, compound 9 may be prepared by reacting compound 8 with reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X, dihydroxyC3-C6 alkyl-X, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 1-3 fluoros, (R'R²N)C1-C6 alkyl-X wherein R¹ and R² are as defined for Formula I, hetAr'Cl-C3 alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyc^a)Cl-C3 alkyl-X, or hetCyc^a-X, wherein hetAr’ and hetCyc^a are defined for Formula I and X is a leaving atom or group (such as a halide or triflate), in the presence of a suitable base (e g., a metal alkali carbonate, such as potassium carbonate), wherein each of said reagents is optionally substituted with a protecting group (eg., a tbutyldimethylsilyl group if the B group has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound 9 may be prepared by reacting compound 8 with C1-C6 alkyl-X wherein said alkyl is optionally substituted with 1-3 fluoros and X is a halogen such as Br or Cl, or a leaving group such as triflate. Compound 11 may then be prepared by coupling compound 9 with the corresponding boronic ester compound 10 using appropriate palladium-catalyzed cross-coupling reaction conditions, e g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh₃)4 and Na₂CO₃ in dioxane at elevated temperatures). Compound 12 may then be prepared from compound 11 as described above, followed by removal of the protecting group on B if present.

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<img file="CA3039760C_D0255.tif" />

<img file="CA3039760C_D0256.tif" />

<img file="CA3039760C_D0257.tif" />

<img file="CA3039760C_D0258.tif" />

1. Deprotect

2. Optionally functionalize

<img file="CA3039760C_D0259.tif" />

SCHEME 2

[00547] Scheme 2 shows another general scheme for the synthesis of compound 12 wherein A is CN, and B, X¹, X², X³, X⁴, Ring D and E are as defined for Formula I.

[00548] Compound 9 (prepared, e g., as described in Scheme 1) in which B is as defined for Formula I, may be coupled with the corresponding boronic ester 13 (wherein X¹, X², X³ and X⁴are as defined for Formula I; L² is a leaving group such as a inflate or halide); Z is -B(OR^x)(OR^y) and R^£ and R^y are H or (l-6C)alkyl, or R^x and R^y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)), using appropriate palladium-catalyzed cross-coupling reaction conditions, e g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and NazCCh in dioxane at elevated temperatures) to provide compound 14. Compound 16 may be prepared by coupling compound 14 with compound 15 wherein Ring D is as defined for Formula I and P¹ is an amino protecting group, under appropriate SnAt conditions (for example, optionally in the presence of a base such as KzCOî and at elevated temperature).

[00549] The protecting group P¹ on Ring D ring of compound 16 may be removed under standard conditions (for example, a Boc group may be removed by treating compound 1 to acidic conditions, e.g., HC1) to provide compound 12 wherein E is H. Alternatively, the deprotected Ring D may be functionalized (i.e., reacted or treated with an appropriate reagent) to introduce the E

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PCT7US2017/055983 group under standard conditions such as described below to provide compound 12 wherein E is as defined for Formula 1 except that E is not H.

<img file="CA3039760C_D0260.tif" />

<img file="CA3039760C_D0261.tif" />

<img file="CA3039760C_D0262.tif" />

SCHEME 3

[00550] Scheme 3 shows a general scheme for the synthesis of Compound 21 wherein A is H, and B, X¹, X², X³, X⁴, Ring D and E are as defined for Formula 1.

[00551] Compound 18 may be prepared by coupling compound 4A (prepared e g,, as described in Scheme 1) with the corresponding boronic ester compound 10 (wherein Ring D, X¹, X², X³ and X⁴ are as defined for Formula I; P^l is an amino protecting group; Z is -B(OR^x)(OR^y) and R^z and R^y are H or (l-6C)alkyl, or R^x and R^y together with the atoms to which they are

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PCT7US2017/055983 connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPhs)4 and Na2CCh in dioxane at elevated temperatures. Compound 19 may be prepared by treating compound 18 with aluminum trichloride. [00552] To prepare compound 21 wherein B is as defined for Formula I other than hydrogen, compound 20 may be prepared by reacting compound 19 with reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X, dihydroxyC3-C6 alkyl-X, (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 1-3 fluoros, (R^lR²N)Cl-C6 alkyl-X wherein R¹ and R² are as defined for Formula I, hetAr’Cl-Cj alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyc^a)Cl-C3alkyl-X or hetCyc^a-X, wherein hetAr¹ and hetCyc^a are as defined for Formula I and X is a leaving atom or group (such as a halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if the B group has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 19 with a C1-C6 alkyl-X wherein said alkyl is optionally substituted with 1-3 fluoros and X is a halogen such as Br or Cl, or a leaving group such as triflate. The protecting group P¹ on Ring D ring of compound 20 may be removed under standard conditions (for example, a Boc group may be removed by treating compound 20 to acidic conditions, e.g., HC1) to provide compound 21 wherein E is H. Alternatively, the deprotected Ring D of compound 21 may be functionalized (i.e., reacted or treated with an appropriate reagent) to introduce the E group under standard conditions such as described below to provide compound 21 wherein E is as defined for Formula I except that E is not H.

[00553] Alternatively, to prepare compound 21 wherein B is as defined for Formula 1 other than hydrogen, compound 19 may be reacted with a reagent such as C1-C6 alkyl-OH optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-OH, dihydroxyC3-C6 alkyl-OH, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R^lR²N)Cl-C6 alkyl-OH wherein R¹ and R² are as defined for Formula I, hetAr’Cl-CS alkyl-OH, (C3-C6 cycloalkyl)Cl-C3 alkylOH, (hetCyc^a)C 1-C3alkyl-OH, or hetCyc^a-OH, wherein hetAr¹ and hetCyc^a are defined for Formula I, wherein each of said reagents is optionally substituted with a protecting group, under Mitsunobu reaction conditions (e.g., PPh? and diisopropyl azodicarboxylate) to provide compound

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20. Compound 21 may then be prepared from compound 20 as described above, followed by removal of the protecting group on B if present.

[00554] When group B is hydrogen, compound 21 may be prepared from compound 19 according to the deprotection and optional functionalization steps described herein.

<img file="CA3039760C_D0263.tif" />

<img file="CA3039760C_D0264.tif" />

<img file="CA3039760C_D0265.tif" />

<img file="CA3039760C_D0266.tif" />

<img file="CA3039760C_D0267.tif" />

SCHEME4

[00555] Scheme 4 shows an alternative general scheme for the synthesis of Compound 21 wherein A is H, and B, X¹, X², X³, X⁴, Ring D and E are as defined for Formula I.

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[00556] Compound 22 may be prepared by treating compound 4A (prepared e.g., as described in Scheme 1) with aluminum trichloride.

[00557] To prepare compound 21 wherein B is hydrogen, compound 19 may be prepared by coupling compound 22 with the corresponding boronic ester compound 10 (wherein Ring D, X¹, X², X³ and X⁴ are as defined for Formula I; P^l is an amino protecting group; Z is -B(OR^x)(OR^y) and R^z and R^y are H or (l-6C)alkyl, or R^x and R^y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and NaîCOs in dioxane at elevated temperatures). Compound 21 may be prepared from compound 19 according to the process described for Scheme 3.

[00558] Alternatively, to prepare compound 21 wherein B is as defined for Formula I other than hydrogen, compound 23 may be prepared by reacting compound 22 with reagent such as ClC6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X, dihydroxyC3-C6 alkyl-X, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R^lR²N)Cl-C6 alkyl-X wherein R¹ and R² are as defined for Formula I, hetAi^Cl-CS alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyc^a)Cl-C3 alkyl-X or hetCyc^a-X, wherein hetAr¹ and hetCyc⁸are defined for Formula I and X is a leaving atom or group (such as a halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e g., a t-butyldimethylsilyl group if the B group has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound 23 may be prepared by reacting compound 22 with a C1-C6 alkyl-X wherein said alkyl is optionally substituted with 1-3 fluoros and X is a halogen such as Br or Cl, or a leaving group such as triflate. Compound 20 may be prepared by coupling compound 23 with compound 10 as described in Scheme 3. Compound 21 may be prepared from compound 20 according to the process described for Scheme 3.

[00559] Alternatively, to prepare compound 21 wherein B is as defined for Formula I other than hydrogen, compound 19 may be reacted with a reagent such as C1-C6 alkyl-OH optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-OH, dihydroxyC3-C6 alkyl-OH, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R'R²N)C1-C6 alkyl-OH wherein R¹ and R² are as defined for Formula I, hetAr'Cl-C3 alkyl-OH, (C3-C6 cycloalkyl)Cl-C3 alkyl120

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OH, (hetCyc^a)Cl-C3alkyl-0H, or hetCyc^a-OH, wherein hetAr¹ and hetCyc^a are defined for Formula I, wherein each of said reagents is optionally substituted with a protecting group, under Mitsunobu reaction conditions (e.g., PPhi and diisopropyl azodicarboxylate) to provide compound 20. Compound 21 may then be prepared from compound 20 as described for Scheme 3, followed by removal of the protecting group on B if present.

<img file="CA3039760C_D0268.tif" />

SCHEMES

[00560] Scheme 5 shows an alternative general scheme for the synthesis of Compound 21 wherein A is H, and B, X¹, X², X³, X⁴, Ring D and E are as defined for Formula I.

[00561] Compound 22 may be prepared by treating compound 4A (prepared e g., as described in Scheme 1) with aluminum trichloride.

[00562] To prepare compound 21 wherein B is as defined for Formula I other than hydrogen, compound 23 may be prepared by reacting compound 22 with reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X, dihydroxyC3-C6 alkyl-X, (C1-C6

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PCT7US2017/055983 alkoxy )C 1-C6 alkyl-X optionally substituted with 1-3 fluoros, (R'R²N)C 1-C6 alkyl-X wherein R¹and R² are as defined for Formula 1, hetAr'C 1-C3 alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X , (hetCyc^a)Cl-C3 alkyl-X or hetCyc^a-X, wherein hetAr¹ and hetCyc^a are defined for Formula 1 and X is a leaving atom or group (such as a halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (eg., a t-butyldimethylsilyl group if the B group has one or two additional hydroxy groups). For example, when B is Cl -C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 22 with a C1-C6 alkyl-X wherein said alkyl is optionally substituted with 1-3 fluoros and X is a halogen such as Br or Cl, or a leaving group such as triflate.

[00563] Compound 24 may be prepared by reacting compound 23 with the boronic ester 13 (wherein X¹, X², X³ and X⁴ are as defined for Formula I; L² is a leaving group such as a triflate or halide); Z is -B(OR^xXOR^y) and R^z and R^y are H or (l-6C)alkyl, or R^x and R^y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium-catalyzed cross-coupling reaction conditions, e g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and NazCCh in dioxane at elevated temperatures).

[00564] To prepare compound 21 wherein B is hydrogen, compound 24 may be prepared by reacting compound 22 directly with compound 13 as described above.

[00565] Compound 20 may be prepared by coupling compound 24 with compound 15 wherein P¹ is an amino protecting group under appropriate SwAr conditions (for example, optionally in the presence of a base such as K2CO3 and at elevated temperature).

[00566] Compound 21 may be prepared from compound 20 according to the process described for Scheme 3.

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<img file="CA3039760C_D0269.tif" />

SCHEMES

[00567] Scheme 6 shows a general scheme for the synthesis of Compound 31 wherein A is Cl, and B, X¹, X², X³, X⁴, Ring D and E are as defined for Formula I.

[0056S] Compound 25 may be prepared by treating compound 4A (prepared e g., as described in Scheme 1) with aluminum trichloride.

[00569] Compound 26 may be prepared by treating compound 25 with aluminum trichloride.

[00570] To prepare compound 31 wherein B is as defined for Formula I other than hydrogen, compound 27 may be prepared by reacting compound 26 with reagent such as C1-C6 alkyl-X optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl-X, dihydroxyC3-C6 alkyl-X, (C1-C6 alkoxy)C 1-C6 alkyl-X optionally substituted with 1 -3 fluoros, (R*R²N)C 1-C6 alkyl-X wherein R¹

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PCT7US2017/055983 and R² are as defined for Formula I, hetAr’Cl-CS alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyc^a)Cl-C3 alkyl-X or hetCyc^a-X, wherein hetAr¹ and hetCyc^a are defined for Formula 1 and X is a leaving atom or group (such as a halide or triflate), wherein each of said reagents is optionally substituted with a protecting group (e.g., a t-butyldimethylsilyl group if the B group has one or two additional hydroxy groups). For example, when B is C1-C6 alkyl optionally substituted with 1-3 fluoros, compound may be prepared by reacting compound 26 with a C1-C6 alkyl-X wherein said alkyl is optionally substituted with 1-3 fluoros and X is a halogen such as Br or Cl, or a leaving group such as triflate.

[00571] Compounds 28 (wherein group B is methyl), 29 (wherein group B is hydrogen) and 30 (wherein group B is other than hydrogen) may be prepared by coupling compounds 25,26 and 27, respectively, with the corresponding boronic ester compound 10 (wherein Ring D, X¹, X², X³and X⁴ are as defined for Formula I; P¹ is an amino protecting group; Z is -B(OR^x)(OR^y) and R^zand R^y are H or (l-6C)alkyl, or R^x and R^y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium-catalyzed cross-coupling reaction conditions, e g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPhs)4 and NaiCCh in dioxane at elevated temperatures).

[00572] The protecting group P¹ on Ring D of compound 29 or 30 may be removed under standard conditions (for example, a Boc group may be removed by treating compound 29 or 30 to acidic conditions, e.g., HC1) to provide compound 31 wherein E is H. Alternatively, the deprotected Ring D may be functionalized (i.e., reacted or treated with an appropriate reagent) to include the E group under standard conditions such as described below to provide compound 31 wherein E is as defined for Formula 1 except that E is not H.

[00573] Ring D of compounds 12, 21 and 31 described in Schemes 1-6 may be functionalized (i.e., reacted or treated with an appropriate reagent) to include an E group, wherein E is any of the E groups defined for Formula I with the exception of hydrogen, using standard chemistry well known to persons skilled in the art As used herein, the term functionalized refers to a process step in which a compound of Formula 12,21 or 31 wherein E is hydrogen is reacted or treated with an appropriate reagent to provide a compound of Formula 12,21 or 31 wherein E is as defined for Formula I other than hydrogen.

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[00574] For example, a compound of Formula I wherein E is (C1-C6 alkyl)C(=O)optionally substituted with one to three fluoros; (hydroxy C2-C6 alkyl)C(=O)- optionally substituted with one to three fluoros; (C1-C6 alkoxy )C(=O)-; (C3-C6 cycloalkyl)C(=O)- (wherein said cycloalkyl is optionally substituted with (C1-C6 alkoxy)Cl-C6 alkyl or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O); Ar^l(Cl-C6 alkyl)C(=O)- (wherein the alkyl portion is optionally substituted with OH, hydroxyCi -C6 alkyl-, or C1-C6 alkoxy); hetAr²(Cl-C6 alkyl)C(=O)- (wherein the alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl, or C1-C6 alkoxy); or hetCyc’(Cl-C6 alkyl)C(=O)-, may be obtained by treating compound 12 having a deprotected Ring D (i.e., compound 12 wherein E is hydrogen) with a corresponding carboxylic acid using conventional amide bond formation conditions, for example by treating the corresponding carboxylic acid with an activating agent (e.g., HATU), followed by addition of the compound 12 having a deprotected Ring D (i.e., wherein E is H) in the presence of a base (e.g., an amine base such as DŒA) in an appropriate solvent (such as DMA) to provide a functionalized compound 12 (i.e., in this instance compound 12 wherein E is (C1-C6 alkyl)C(=O)- optionally substituted with one to three fluoros; (hydroxy C2-C6 alkyl)C(=O)- optionally substituted with one to three fluoros; (C1-C6 alkoxy)C(=O)-; (C3-C6 cycloalkyl)C(=O)- (wherein said 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'(C 1-C6 alkyl)C(=O)- (wherein the alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy); hetAr^Cl-Cô alkyl)C(=O)- (wherein the alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyd-, or C1-C6 alkoxy); or hetCyc^l(Cl-C6 alkyl)C(=O)-). The same chemistry may be utilized with compounds 21 and 31 to prepare functionalized compounds 21 and 31 (i.e., in this instance compounds 21 and 31, respectively, wherein E is (C1-C6 alkyl)C(=O)- optionally substituted with one to three fluoros; (hydroxy C2C6 alkyl)C(=O)- optionally substituted with one to three fluoros; (C1-C6 alkoxy)C(=O)·; (C3-C6 cycloalkyl)C(=O)- (wherein said cycloalkyl is optionally substituted with (C1-C6 alkoxy)Cl-C6 alkyl- or a 5-6 membered heteroaryl ring having 1 -3 ring heteroatoms independently selected from N and O); Ar'(C 1-C6 alkyl)C(=O)- (wherein the alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl-, or C1-C6 alkoxy); hetAr²(Cl-C6 alkyl)C(=O)- (wherein the alkyl portion is optionally substituted with OH, hydroxyCl-C6 alkyl-, or (Cl-C6)alkoxy); or hetCyc*(Cl-C6 alkyl)C(=O)-).

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[00575] As another example, a compound of Formula I wherein E is hetCy^C^O)- or R³R⁴NC(=O)- may be prepared by first activating the deprotected ring nitrogen in Ring D of compound 12 (i.e., wherein E is H) with triphosgene in the presence of DIEA and in a solvent such as DCM, followed by addition of an amine reagent having the formula hetCyc¹-H or R³R⁴NH (wherein hetCyc^l-H is a saturated 4-6 membered heterocycle having 1-2 ring heteroatoms independently selected from N, O and S wherein the ring has at least one ring N atom and the H indicates that the hydrogen is on the ring nitrogen atom, wherein said heterocycle is optionally substituted with one or more independently selected C1-C6 alkoxy substituents) to provide a functionalized compound 12 (i.e., in this instance compound 12 wherein E is hetCyc¹C(=O)- or R³R⁴NC(=O)-). The same chemistry may be utilized with compounds 21 and 31 to prepare functionalized compounds 21 and 31 (i.e., in this instance compound 21 and 31, respectively, wherein E is hetCyc¹C(=O)- or R³R⁴NC(=O)-).

[00576] As another example, a compound of Formula I wherein E is C1-C6 alkyl optionally substituted with one to three fluoros, (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 13 fluoros, Ar*Cl-C6 alkyl-, hetArCl-Cô alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or hetCyc'Cl-Cô alkyl-, may be prepared by treating deprotected compound 12 (i.e., wherein E is H) with a corresponding reagent having the formula C1-C6 alkyl-X optionally substituted with one to three fluoros, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, A^Cl-Cô alkyl-X, hetA^Cl-Cô alkyl-X, or hetCyc^lCl-C6 alkyl-X wherein X is Br or Cl, in the presence of a base such as DIEA in a solvent at ambient or elevated temperatures) to provide a functionalized compound 12 (i.e., in this instance compound 12 wherein E is C1-C6 alkyl optionally substituted with one to three fluoros, (C1-C6 alkoxy)C1-C6 alkyl optionally substituted with 1-3 fluoros, Ar*Cl-C6 alkyl-, hetAi^Cl-Cô alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or hetCy^Cl-Cô alkyl-). The same chemistry may be utilized with compounds 21 and 31 to prepare functionalized compounds 21 and 31 (i.e., in this instance in this instance compound 21 and 31, respectively, wherein E is C1-C6 alkyl optionally substituted with one to three fluoros, (C 1-C6 alkoxy)C 1-C6 alkyl- optionally substituted with 1 -3 fluoros, Ar*Cl-C6 alkyl-, hetArCl-Cô alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or hetCyc’Cl-C6 alkyl-).

[00577] As another example, a compound of Formula I wherein E is C1-C6 alkyl optionally substituted with one to three fluoros, (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3

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PCT7US2017/055983 fluoros; Ar'Cl-Cô alkyl-, hetAr²Cl-C6 alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or hetCyc^1-06 alkyl-), may be prepared by treating deprotected compound 12 (i.e., wherein E is H), with corresponding aldehyde, e.g., (C1-C5 alkyl(C=O)H optionally substituted with one to three fluoros; (C1-C6 alkoxy )(C 1-C 5 alkyl)C(=O)H optionally substituted with one to three fluoros; Ar^l(Cl-C5 alkyl)C(=O)H; hetAr²(Cl-C5 alkyl)C(=O)H; or hetCyc*(C1-C5 alkyl)-C(=O)H, in the presence of a reducing agent, e g, NaBH(AcO)j to provide a functionalized compound 12 (i.e., in this instance compound 12 wherein E is C1-C6 alkyl optionally substituted with one to three fluoros; (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros; Arid-C6 alkyl-, hetAr²Cl-C6 alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or hetCyc'Cl-Cô alkyl-). The same chemistry may be utilized with compounds 21 and 31 to prepare functionalized compounds 21 and 31 (i.e., in this instance in this instance compounds 21 and 31, respectively, wherein E is C1-C6 alkyl optionally substituted with one to three fluoros; (C1-C6 alkoxy)Cl-C6 alkyl- optionally substituted with 1-3 fluoros; Ar'Cl-C6 alkyl-, hetAr²Cl-C6 alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or hetCyc'Cl-C6 alkyl-).

[00578] Accordingly, also provided herein is a process for preparing of a compound of Formula I or a pharmaceutically acceptable salt thereof as defined herein which comprises: [00579] (a) for a compound of Formula I wherein E is H, A is CN, -CFbCN or CH(CN)CFh and B, X¹, X², X³, X⁴, and Ring D are as defined for Formula I, coupling a corresponding compound 9 having the formula

[00580] wherein B is as defined for Formula I, with a corresponding boronic ester of the formula 10

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[00581] wherein P¹ is an amino protecting group, Z is -B(OR^x)(OR^y) wherein R^x and R^yare H or C1-C6 alkyl, or R^x and R^y together with the atoms to which they are connected form a 56 membered ring optionally substituted with 1-4 substituents selected from C1-C3 alkyl, and X¹, X², X³ and X⁴ are as defined for Formula I, in the presence of a palladium catalyst and optionally a ligand and in the presence of a base, followed by removal of the protecting group; or

[00582] (b) for a compound ofFormula I wherein A, B, X¹, X², X³, X⁴, Ring D and E are as defined for Formula I with the exception that E is not hydrogen, functionalizing a corresponding compound of the formula

[00583] wherein A, Ring D, B, X¹, X², X³ and X⁴ are as defined for Formula 1 and E^l is hydrogen; or

[00584] (c) for a compound ofFormula I wherein A is CN, and Ring D, B, X¹, X², X³, X⁴ and E are as defined for Formula I, reacting a corresponding compound of the formula 14

[00585] wherein B, X¹, X², X³ and X⁴ are as defined for Formula I and L² is a leaving group or atom, with a compound of the formula 15

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[00586] wherein P¹ is an amino protecting group, followed by removing the protecting group P^l and optionally functionalizing Ring D; or

[00587] (d) for a compound of Formula 1 wherein E is H, A is CN, and B, X¹, X², X³, X⁴, and Ring D are as defined for Formula I, coupling a compound of formula 14

<img file="CA3039760C_D0270.tif" />

[00588] wherein L² is a leaving group or atom and B, X¹, X², X³, and X⁴ are as defined for

Formula I, with a compound of formula 15

<img file="CA3039760C_D0271.tif" />

[00589] wherein P¹ is an amino protecting group, followed by removing the protecting group P^l; or

[00590] (e) for a compound of Formula I wherein A is H, B is H, and X¹, X², X³, X⁴, Ring

D and E are as defined for Formula I, treating a compound of formula 18

<img file="CA3039760C_D0272.tif" />

[00591] wherein P¹ is an amino protecting group and X¹, X², X³, X⁴, Ring D are as defined for Formula I, with aluminum trichloride to provide compound 19

<img file="CA3039760C_D0273.tif" />

P¹

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[00592] wherein Ring D, X¹, X², X³, and X⁴ are as defined for Formula I and P¹ is an amino protecting group;

[00593] followed by removal of the protecting group P¹ and optionally functionalizing Ring D; or

[00594] (f) for a compound of Formula I wherein A is H, B is C1-C6 alkyl optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl, dihydroxyC3-C6 alkyl, (C1-C6 alkoxy)Cl-C6 alkyl optionally substituted with 1-3 fluoros, (R^fR²N)Cl-C6 alkyl, (hetAr*)Cl-C3 alkyl, (C3-C6 cycloalkyl)Cl-C3 alkyl, (hetCyc^a)Cl-C3 alkyl, or hetCyc^a, wherein R¹, R², hetAr¹, hetCyc^a, X¹, X², X³, X⁴, Ring D and E are as defined for Formula I,

[00595] (i) treating a compound of formula 18

<img file="CA3039760C_D0274.tif" />

[00596] wherein P¹ is an amino protecting group and X¹, X², X³, X⁴ and Ring D are as defined for Formula I, with aluminum trichloride to provide compound 19

<img file="CA3039760C_D0275.tif" />

[00597] wherein Ring D is as defined for Formula I, P¹ is an amino protecting group, and X¹, X², X³, and X⁴ are as defined for Formula I;

[00598] (ii) reacting compound 19 with C1-C6 alkyl-X optionally substituted with

1-3 fluoros, hydroxyC2-C6 alkyl-X wherein the alkyl portion is optionally substituted with a C3C6 cycloalkylidene ring, dihydroxyC3-C6 alkyl-X, (C1-C6 alkoxy)Cl-C6 alkyl-X optionally substituted with 1-3 fluoros, (R^NJCl-Cô alkyl-X, (hetAr^Cl-CS alkyl-X, (C3-C6 cycloalkyl)Cl-C3 alkyl-X, (hetCyc^a)Cl-C3 alkyl-X, or hetCyc^a-X, wherein R¹, R², hetAr¹ and

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PCT7US2017/055983 hetCyc^a are as defined for Formula I and X is a leaving atom or group such as a halide or a triflate, in the presence of a base, to provide compound 20

<img file="CA3039760C_D0276.tif" />

[00599] wherein Ring D is as defined for D ofFormula I, P¹ is an amino protecting group, X¹, X², X³, and X⁴ are as defined for Formula I and B is C1-C6 alkyl optionally substituted with 1-3 fluoros, hydroxyC2-C6 alkyl, dihydroxyC3-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl optionally substituted with 1-3 fluoros, (R^btyCl-Cô alkyl, (hetAr^Cl-CS alkyl, (C3-C6 cycloalkyl)ClC3 alkyl, (hetCyc^a)Cl-C3 alkyl, or hetCyc^a, wherein R¹, R², hetAr¹, hetCyc^a are as defined for Formula I, followed by removal of the protecting group P¹ and optionally functionalizing Ring D, or

[00600] (g) for a compound ofFormula I wherein A is H or Cl, B is H, and X¹, X², X³, X⁴,

Ring D and E are as defined for Formula I, treating a compound of formula

N=\

HCr^^Br

[00601] wherein A is H or Cl with a corresponding boronic ester of formula 10

<img file="CA3039760C_D0277.tif" />

[00602] wherein Ring D, X¹, X², X³ and X⁴ are as defined for Formula I; P¹ is an amino protecting group; Z is -B(OR^x)(OR^y) and R^z and R^y are H or (l-6C)alkyl, or R^x and R^y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from C1-C3 alkyl, to provide a compound of formula 19

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<img file="CA3039760C_D0278.tif" />

[00603] wherein Ring D, X¹, X², X³, and X⁴ are as defined for Formula I, P¹ is an amino protecting group and A is H or Cl, followed by removal of the protecting group P¹ and optionally functionalizing Ring D; or

[00604] (h) for a compound of Formula I wherein A is H or Cl, and B, X¹, X², X³, X⁴, Ring

D and E are as defined for Formula I, coupling a compound of the formula

N=\ sAA

O^^Br

[00605] wherein A is H or Cl, and B is as defined for Formula I, with a corresponding boronic ester of formula 10

<img file="CA3039760C_D0279.tif" />

[00606] wherein Ring D, X¹, X², X³ and X⁴ are as defined for Formula I; P¹ is an amino protecting group, and Z is -B(OR^X)(OR') and R^z and R^y are H or (l-6C)alkyl, or R^x and R^y together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from C1-C3 alkyl, in the presence of a palladium catalyst and optionally a ligand and in the presence of a base, to provide a compound of the formula

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<img file="CA3039760C_D0280.tif" />

[00607] wherein Ring D, X¹, X², X³, X⁴ and B are as defined for Formula I; A is H or Cl; and P¹ is an amino protecting group, followed by removal of the protecting group P¹ and optionally functionalizing Ring D;

[00608] (i) for a compound of Formula I wherein A is H, and B, X¹, X², X³, X⁴, Ring D and

E are as defined for Formula I, coupling a compound of formula 24

<img file="CA3039760C_D0281.tif" />

[00609] wherein L² is a leaving group and B, X¹, X², X³, and X⁴ are as defined for Formula

I, with a compound of formula 15

<img file="CA3039760C_D0282.tif" />

P¹

[00610] wherein P^l is an amino protecting group and Ring D is as defined for Formula I, to provide a compound of formula 20

<img file="CA3039760C_D0283.tif" />

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[00611] wherein P¹ is an amino protecting group, and Ring D, X¹, X², X³, X⁴, and B are as defined for Formula I, followed by removal of the protecting group P¹ and optionally functionalizing Ring D; and

[00612] removing any additional protecting groups if present and optionally forming a pharmaceutically acceptable salt thereof.

[00613] The term amino protecting group as used herein refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound. Examples of suitable protecting groups for use in any of the processes described herein include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group. Non-limiting examples of amino protecting groups are acetyl, trifluoroacetyl, tbutyloxycarbonyl (“Boe”), benzyloxycarbonyl (“CBz”) and 9-fluorenylmethyleneoxycarbonyl (“Fmoc”). Further examples of these groups, and other protecting groups, are found in T. W. Greene, et al., Greene’s Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.

[00614] Hydroxy groups may be protected with any convenient hydroxy protecting group, for example as described in T. W. Greene, et al., Greene’s Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006. Examples include benzyl, trityl, silyl ethers, and the like.

[00615] Nitrogen atoms in compounds described in any of the above methods may be protected with any convenient nitrogen protecting group, for example as described in Greene &amp; Wuts, eds., “Protecting Groups in Organic Synthesis”, 2^nd ed. New York; John Wiley &amp; Sons, Inc., 1991. Examples of nitrogen protecting groups include acyl and alkoxycarbonyl groups, such as tbutoxycarbonyl (BOC), phenoxycarbonyl, and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[00616] The ability of test compounds to act as RET inhibitors may be demonstrated by the assay described in Example A. ICso values are shown in Table 5.

[00617] In some embodiments, the compounds provided herein exhibit potent and selective RET inhibition. For example, the compounds provided herein exhibit nanomolar potency against wild type RET and select RET mutants, including the KIF5B-RET fusion and V804M gatekeeper mutation, w'ith minimal activity against related kinases.

[00618] In some embodiments, the compounds of Formula I or a pharmaceutically acceptable salt or solvate thereof, selectively target a RET kinase. For example, a compound of

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Formula I or a pharmaceutically acceptable salt or solvate thereof, can selectively target a RET kinase over another kinase or non-kinase target.

[00619J In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, exhibits at least a 30-fold selectivity for a RET kinase over another kinase. For example, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, exhibits at least a 40-fold selectivity; at least a 50-fold selectivity; at least a 60-fold selectivity; at least a 70-fold selectivity; at least a 80-fold selectivity; at least a 90-fold selectivity; at least 100fold selectivity; at least 200-fold selectivity; at least 300-fold selectivity; at least 400-fold selectivity; at least 500-fold selectivity; at least 600-fold selectivity; at least 700-fold selectivity, at least 800-fold selectivity; at least 900-fold selectivity; or at least 1000-fold selectivity for a RET kinase over another kinase. In some embodiments, selectivity for a RET kinase over another kinase is measured in a cellular assay (e.g., a cellular assay as provided herein).

[00620] In some embodiments, the compounds provided herein can exhibit selectivity for a RET kinase over a KDR kinase (e.g., VEGFR2). In some embodiments, the selectivity for a RET kinase over a KDR kinase is observed without loss of gatekeeper mutant potency. In some embodiments, the selectivity over a KDR kinase is at least 10-fold (e.g., at least a 40-fold selectivity; at least a 50-fold selectivity; at least a 60-fold selectivity; at least a 70-fold selectivity, at least a 80-fold selectivity; at least a 90-fold selectivity; at least 100-fold selectivity; at least 150fold selectivity; at least 200-fold selectivity; at least 250-fold selectivity’; at least 300-fold selectivity; at least 350-fold selectivity; or at least 400-fold selectivity) as compared to the inhibition of KIF5B-RET (i.e. the compounds were more potent against KIF5B-RET than KDR). In some embodiments, the selectivity for a RET kinase over a KDR kinase is about 30-fold. In some embodiments, the selectivity for a RET kinase over a KDR kinase is at least 100-fold. In some embodiments, the selectivity for a RET kinase over a KDR kinase is at least 150-fold. In some embodiments, the selectivity for a RET kinase over a KDR kinase is at least 400-fold. Without being bound by any theory, potent KDR kinase inhibition is believed to be a common feature among multikinase inhibitors (MKIs) that target RET and may be the source of the doselimiting toxicities observed with such compounds

[00621] In some embodiments, inhibition of V804M was similar to that observed for wildtype RET. For example, inhibition of V804M was within about 2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) of inhibition of wild-type RET (i.e. the compounds were similarly potent

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PCT7US2017/055983 against wild-type RET and V804M). In some embodiments, selectivity for a wildtype or V804M RET kinase over another kinase is measured in an enzyme assay (e.g., an enzyme assay as provided herein). In some embodiments, the compounds provided herein exhibit selective cytotoxicity to RET-mutant cells.

[00622] In some embodiments, the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood brain barrier and inhibiting a RET kinase in the brain and/or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount. For example, treatment of a patient with cancer (e.g., a RET-associated cancer such as a RET-associated brain or CNS cancer) can include administration (e g., oral administration) of the compound to the patient. In some such embodiments, the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor.

[00623] In some embodiments, the compounds of Formula I or a pharmaceutically acceptable salt or solvate thereof, exhibit one or more of high GI absorption, low clearance, and low potential for drug-drug interactions.

[00624] Compounds of Formula I are useful for treating diseases and disorders which can be treated with a RET kinase inhibitor, such as RET-associated diseases and disorders, e g., proliferative disorders such as cancers, including hematological cancers and solid tumors, and gastrointestinal disorders such as IBS.

[00625] As used herein, terms treat or treatment refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.

[00626] As used herein, the terms subject, individual, or patient, are used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the

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PCT7US2017/055983 subject has been identified or diagnosed as having a cancer with a dysrégulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (a RET-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g, FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a dysrégulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (e.g, as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumorfs) that is positive for a dysrégulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysrégulation of a RET gene, a RET protein, or expression or activity, or a level of the same (e g., where the tumor is identified as such using a regulatory' agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a RET-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysrégulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the patient is a pediatric patient.

[00627J The term “pediatric patient” as used herein refers to a patient under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. 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 &amp; Wilkins; 1994. In some embodiments, a pediatric patient is from birth through the first 28 days of life, from 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 through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric patient is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age

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PCT7US2017/055983 to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

[00628] In certain embodiments, compounds ofFormula I are useful for preventing diseases and disorders as defined herein (for example, autoimmune diseases, inflammatory diseases, and cancer). The term preventing” as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.

[00629] The term RET-associated disease or disorder as used herein refers to diseases or disorders associated with or having a dysrégulation of a RET gene, a RET kinase (also called herein RET kinase protein), or the expression or activity or level of any (e.g., one or more) of the same (e g., any of the types of dysrégulation of a RET gene, a RET kinase, a RET kinase domain, or the expression or activity or level of any of the same described herein). Non-limiting examples of a RET-associated disease or disorder include, for example, cancer and gastrointestinal disorders such as irritable bowel syndrome (IBS).

[00630] The term “RET-associated cancer” as used herein refers to cancers associated with or having a dysrégulation of a RET gene, a RET kinase (also called herein RET kinase protein), or expression or activity, or level of any of the same. Non-limiting examples of a RET-associated cancer are described herein.

[00631] The phrase “dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a RET gene translocation that results in the expression of a fusion protein, a deletion in a RET gene that results in the expression of a RET protein that includes a deletion of at least one amino acid as compared to the wild-type RET protein, a mutation in a RET gene that results in the expression of a RET protein with one or more point mutations, or an alternative spliced version of a RET mRNA that results in a RET protein having a deletion of at least one amino acid in the RET protein as compared to the wild-type RET protein) or a RET gene amplification that results in overexpression of a RET protein or an autocrine activity resulting from the overexpression of a RET gene in a cell that results in a pathogenic increase in the activity of a kinase domain of a RET protein (e g., a constitutively active kinase domain of a RET protein) in a cell. As another example, a dysrégulation of a RET gene, a RET protein, or expression or activity, or level of any of the same,

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PCT7US2017/055983 can be a mutation in a RET gene that encodes a RET protein that is constitutively active or has increased activity as compared to a protein encoded by a RET gene that does not include the mutation. For example, a dysrégulation of a RET gene, a RET protein, or expression or activity, or level of any of the same, can be the result of a gene or chromosome translocation which results in the expression of a fusion protein that contains a first portion of RET that includes a functional kinase domain, and a second portion of a partner protein (i .e., that is not RET). In some examples, dysrégulation of a RET gene, a RET protein, or expression or activity or level of any of the same can be a result of a gene translocation of one 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. Additional examples of RET kinase protein mutations (e.g., point mutations) are RET inhibitor resistance mutations. Non-limiting examples of RET inhibitor resistance mutations are described in Tables 3 and 4.

[00632] The term wildtype or wild-type describes a nucleic acid (e.g., a RET gene or a RET mRNA) or protein (e.g., a RET protein) that is found in a subject that does not have a RETassociated disease, e g., a RET-associated cancer (and optionally also does not have an increased risk of developing a RET-associated disease and/or is not suspected of having a RET-associated disease), or is found in a cell or tissue from a subject that does not have a RET-associated disease, e g., a RET-associated cancer (and optionally also does not have an increased risk of developing a RET-associated disease and/or is not suspected of having a RET-associated disease).

[00633] The term regulatory agency refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory' agency is the U.S. Food and Drug Administration (FDA).

[00634] Provided herein is a method of treating cancer (e g., a RET-associated 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 are methods for treating a RET-associated cancer in a patient in need of such treatment, the method comprising a) detecting a dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same 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, the dysrégulation of a RET gene, a RET kinase, or the expression

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PCT7US2017/055983 or activity or level of any of the same includes 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 K1F5B-RET. In some embodiments, the dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same includes 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 mutations/insertions/deletions are selected from the group consisting of M918T, M918V, C634W, V804L, and V804M. In some embodiments, a compound of Formula I is selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 6180; v) Example No. 81-100, vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200, xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360, xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt or solvate thereof.

[00635] In some embodiments of any of the methods or uses described herein, the cancer (e g., RET-associated cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e g., RET-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET-associated cancer) is lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid ademona, endocrine gland neoplasms, lung adenocarcinoma, bronchioles lung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, mammary neoplasm, colorectal cancer (eg., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, inflammatory myofibroblastic tumor, or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (e g., RET-associated cancer) is selected from the group of: acute lymphoblastic leukemia (ALL), acute

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PCT7US2017/055983 myeloid leukemia (AML), cancer in adolescents, 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, unknown primary carcinoma, cardiac tumors, cervical cancer, childhood cancers, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, neoplasms by site, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, bile duct cancer, ductal carcinoma in situ, embryonal tumors, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic neoplasms, head and neck neoplasms, CNS tumor, primary CNS tumor, heart cancer, hepatocellular cancer, histiocytosis, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinémie, malignant fibrous histiocytoma of bone, osteocarcinoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, neoplasms by site, neoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin’s lymphoma, nonsmall cell lung cancer, lung neoplasm, pulmonary cancer, pulmonary neoplasms, respiratoiy tract neoplasms, bronchogenic carcinoma, bronchial neoplasms, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromosytoma, 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, colonic neoplasms, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome,

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PCT7US2017/055983 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, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, unknown primary carcinoma, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms’ tumor.

[00636] Tn some embodiments, a hematological cancer (e g., hematological cancers that are RET-associated cancers) is selected from the group consisting of leukemias, lymphomas (nonHodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, for instance, 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), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM). Additional examples of hematological cancers include myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF/IPF/PMF). In one embodiment, the hematological cancer (e g., the hematological cancer that is a RET-associated cancer) is AML or CMML.

[00637] In some embodiments, the cancer (e.g., the RET-associated cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are RET-associated cancers) include, for example, thyroid cancer (e g., papillary thyroid carcinoma, medullary thyroid carcinoma), lung cancer (e.g., lung adenocarcinoma, small-cell lung carcinoma), 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.

[00638] Tn 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, ganglioneuromatosis of the gastroenteric

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PCT7US2017/055983 mucosa, and cervical cancer.

[00639] In some embodiments, the patient is a human.

[00640] Compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are also useful for treating a RET-associated cancer.

[00641] Accordingly, also provided herein is a method for treating a patient diagnosed with or identified as having a RET-associated cancer, e g., any of the exemplary RET-associated cancers disclosed herein, comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

[00642] Dysrégulation of a RET kinase, a RET gene, or the expression or activity or level of any (e.g., one or more) of the same can contribute to tumorigenesis. For example, a dysrégulation of a RET kinase, a RET gene, or expression or activity or level of any of the same can be a translocation, overexpression, activation, amplification, or mutation of a RET kinase, a RET gene, or a RET kinase domain. Translocation can include translocations involving the RET kinase domain, mutations can include mutations involving the RET ligand-binding site, and amplification can be of a RET gene. Other dysregulations can include RET mRNA splice variants and RET autocrine/paracrine signaling, which can also contribute to tumorigenesis.

[00643] In some embodiments, the dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, includes overexpression of wild-type RET kinase (e g., leading to autocrine activation). In some embodiments, the dysrégulation of a RET gene, a RET kinase protein, or expression or activity or level of any of the same, includes overexpression, activation, amplification, or mutation in a chromosomal segment comprising the RET gene or a portion thereof, including, for example, the kinase domain portion, or a portion capable of exhibiting kinase activity.

[00644] In some embodiments, the dysrégulation of a RET gene, a RET kinase protein, or expression or activity or level of any of the same, includes one or more chromosome translocations or inversions resulting in a RET gene fusion In some embodiments, the dysrégulation of a RET gene, a RET kinase protein, or expression or activity or level of any of the same, is a result of genetic translocations in which the expressed protein is a fusion protein containing residues from a non-RET partner protein, and includes a minimum of a functional RET kinase domain.

[00645] Non-limiting examples of RET fusion proteins are shown in Table 1.

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[00646]

Table 1. Exemplary RET Fusion Partners and Cancers

<td> Fusion Partner</td><td> Non-limiting Exemplary RETAssociated Cancer(s)</td>

<td> BCR</td><td> Chronic Myelomonocytic Leukemia (CMML)</td>

<td> CLIP1</td><td> Adenocarcinoma</td>

<td> KIF5B</td><td> NSCLC, Ovarian Cancer, Spitzoid Neoplasms; Lung Adenocarcinoma³·⁴’^l4,28; Adenosquamous Carcinomas¹³</td>

<td> CCDC6 (also called PTCI, DI OS 170, orH4)</td><td> NSCLC, Colon Cancer, Papillary Thyroid Cancer; Adenocarcinomas; Lung Adenocarcinoma; Metastatic Colorectal Cancer⁵; Adenosquamous Carcinomas¹⁵, Breast Cancer³⁰</td>

<td> PTClex9 (a novel CCDC6 rearrangement)</td><td> Metastatic papillary thyroid cancer²</td>

<td> NCOA4 (also called PTC3, ELEl.andRFG)</td><td> Papillary Thyroid Cancer²¹, NSCLC, Colon Cancer, Salivary Gland Cancer, Metastatic Colorectal Cancer⁵; Lung Adenocarcinoma¹³, Adenosquamous Carcinomas¹⁵ Diffuse Sclerosing Variant of Papillary Thyroid Cancer¹⁶, Breast Cancer³⁰, Acinic Cell Carcinoma³², Mammary Analog Secretory Carcinoma³³</td>

<td> TRIM33 (also called PTC7 and RFG7)</td><td> NSCLC, Papillary Thyroid Cancer</td>

<td> ERC1 (also called ELKS)</td><td> Papillary Thyroid Cancer, Breast Cancer</td>

<td> FGFR1OP</td><td> CMML, Primary Myelofibrosis with</td>

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<td> Fusion Partner</td><td> Non-limiting Exemplary RETAssociated Cancer(s)</td>

<td></td><td> secondary Acute Myeloid Leukemia</td>

<td> MBDl(also known asPCMl)</td><td> Papillary Thyroid Cancer</td>

<td> RAB61P2</td><td> Papillary Thyroid Cancer</td>

<td> PRKAR1A (also called PTC2)</td><td> Papillary Thyroid Cancer</td>

<td> TRIM24 (also called PTC6)</td><td> Papillary Thyroid Cancer</td>

<td> KTN1 (also called PTC8)</td><td> Papillary Thyroid Cancer</td>

<td> GOLGA5 (also called PTC5)</td><td> Papillary Thyroid Cancer, Spitzoid Neoplasms</td>

<td> HOOK3</td><td> Papillary Thyroid Cancer</td>

<td> KIAA1468 (also called PTC9 and RFG9)</td><td> Papillary Thyroid Cancer, Lung Adenocarcinoma^8,12</td>

<td> TRIM27 (also called RFP)</td><td> Papillary Thyroid Cancer</td>

<td> AKAP13</td><td> Papillary Thyroid Cancer</td>

<td> FKBP15</td><td> Papillary Thyroid Cancer</td>

<td> SPECC1L</td><td> Papillary Thyroid Cancer; Thyroid Gland Carcinoma</td>

<td> TBL1XR1</td><td> Papillary Thyroid Cancer; Thyroid Gland Carcinoma</td>

<td> CEP55</td><td> Diffuse Gastric Cancer⁷</td>

<td> CUX1</td><td> Lung Adenocarcinoma</td>

<td> ACBD5</td><td> Papillary Thyroid Carcinoma</td>

<td> MYH13</td><td> Medullary Thyroid Carcinoma¹</td>

<td> Uncharacterized</td><td> Inflammatory Myofibroblastic Tumor⁶</td>

<td> PIBF1</td><td> Bronchiolus Lung Cell Carcinoma⁹</td>

<td> KIAA1217 (also called SKT)</td><td> Papillary Thyroid Cancer^10,13 Lung Adenocarcinoma¹⁴ NSCLC¹⁴</td>

<td> MPRIP</td><td> NSCLC¹¹</td>

<td> HRH4-RET</td><td> Thyroid cancer and/or paillary thyroid carcinoma¹⁷</td>

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<td> Fusion Partner</td><td> Non-limiting Exemplary RETAssociated Cancer(s)</td>

<td> Ria-RET</td><td> Thyroid cancer and/or papillary thyroid carcinoma¹⁷</td>

<td> RFG8</td><td> Papillary thyroid * 1R carcinoma</td>

<td> FOXP4</td><td> Lung adenocarcinoma¹⁹</td>

<td> MYH10</td><td> Infantile myofibromatosis²⁰</td>

<td> HTIF1</td><td> Various²²</td>

<td> TIF1G</td><td> Various²²</td>

<td> H4L</td><td> Various²²</td>

<td> PTC4 (a novel NCO4/ELE1 rearrangement)</td><td> Papillary thyroid cancer²³</td>

<td> FRMD4A</td><td> NSCLC²⁴</td>

<td> SQSTM1</td><td> Papillary thyroid carcinoma²⁵</td>

<td> AFAP1L2</td><td> Papillary thyroid carcinoma²⁵</td>

<td> AFAP1</td><td> NSCLC³¹</td>

<td> PPFIBP2</td><td> Papillary thyroid carcinoma²⁵</td>

<td> EML4</td><td> Papillary thyroid cancer²⁶</td>

<td> PARD3</td><td> NSCLC²⁷</td>

<td> UVELD</td><td> Papillary thyroid cancer²⁹</td>

<td> RASGEF1A</td><td> Breast cancer³⁰</td>

<td> TEL</td><td> In vitro™</td>

<td> RUFY1</td><td> Colorectal Cancer³⁵</td>

<td> OLFM4</td><td> Small-Bowel Cancer³⁶</td>

<td> UEVLD</td><td> Papillary Thyroid Carcinoma³⁷</td>

<td> DLG5</td><td> Non-Anaplastic Thyroid (NAT) Cancer³⁸</td>

<td> RRBP1</td><td> Colon Cancer³⁹</td>

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

² Halkova et al., Human Pathology 46:1962-1969, 2015.

’’U.S. Patent No. 9,297,011 ⁴ U.S. Patent No. 9,216,172 ⁵ Le Rolle et al., Oncotarget. 6(30):28929-37, 2015.

⁶ Antonescu et al., Am J Surg Pathol. 39(7):957-67, 2015.

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PCT7US2017/055983 ⁷ U.S. Patent Application Publication No. 2015/0177246.

⁸ U.S. Patent Application Publication No. 2015/0057335.

⁹ Japanese Patent Application Publication No. 2015/109806A.

¹⁰ Chinese Patent Application Publication No. 105255927A.

¹¹ Fang, et al. Journal of Thoracic Oncology 11.2 (2016): S21-S22.

¹² European Patent Application Publication No. EP3037547A1 ¹⁵ Lee et al ., Oncotarget. DOI: 10.18632/oncotarget.9137, e-published ahead of printing, 2016.

¹⁴ Saito et al., Cancer Science 107:713-720, 2016.

¹⁵ Pirker et al., Transi. Lung Cancer Res. 4(6):797-800, 2015.

¹⁶ Joung et al., Histopathology 69(1):45-53, 2016.

¹⁷ PCT Patent Application Publication No. WO 2016/141169.

¹⁸ Klugbauer et al., Cancer Res., 60(24):7028-32,2000.

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²⁰ Rosenzweig et al., Pediatr Blood Cancer, doi:10.1002/pbc.26377,2016.

²¹ Su et al., PLoS One, 11(111): e0165596, 2016.

²² U.S. Patent No. 9,487,491.

²³ Fugazzola et al., Oncogene, 13(5): 1093-7,1996.

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²⁶ Demeure et al., World J Surg.. 38(6):1296-305. doi: 10.1007/s00268-014-2485-3, 2014.

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[00647] In some embodiments, the dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, includes one or more deletions (e g., deletion of an amino acid at position 4), insertions, or point mutation(s) in a RET kinase. In some embodiments, the dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, includes a deletion of one or more residues from the RET kinase, resulting in constitutive activity of the RET kinase domain.

[00648] In some embodiments, the dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, includes at least one point mutation in a RET gene that results in the production of a RET kinase that has one or more amino acid substitutions, insertions, or deletions as compared to the wild-type RET kinase (see, for example, the point mutations listed in Table 2).

[00649] Table 2. Activating RET Kinase Protein Point Mutations/Insertions/Deletions

Exemplary RET Point Mutations

Amino acid position 2____________

Amino acid position 3____________

Amino acid position 4____________

Amino acid position 5____________

Amino acid position 6

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Amino acid position 7_____________________________

Amino acid position 8_____________________________

Amino acid position 11_____________________________

Amino acid position 12____________________________

Amino acid position 13____________________________

Amino acid position 20____________________________

Amino acid position 32 (e.g., S32L)_________________

Amino acid position 34 (e.g., D34S)_________________

Amino acid position 40 (e g., L40P)_________________

Amino acid position 56 (e.g., L56M)³⁰______________

Amino acid position 64 (e.g., P64L)_________________

Amino acid position 67 (e.g., R67H)________________

Amino acid position 114 (e.g., RI 14H)_______________

Amino acid position 136 (e.g., glutamic acid to stop codon)________________________________________

Amino acid position 145 (e.g., V145G)______________

Amino acid position 180 (e g., arginine to stop codon)

Amino acid position 200___________________________

Amino acid position 292 (e g., V292M)_____________

Amino acid position 294___________________________

Amino acid position 321 (e.g., G321R)______________

Amino acid position 330 (e.g., R330Q)______________

Amino acid position 338 (e.g., T338I)________________

Amino acid position 360 (e.g., R360W)_____________

Amino acid position 373 (e.g., alanine to frameshift)

Amino acid position 393 (e.g., F393L)_______________

Amino acid position 423 (e.g., G423R)²⁷_____________

Amino acid position 432___________________________

Amino acid position 446 (e.g., G446R)²⁸____________

Δ Amino acid residues 505-506 (6-Base Pair In-Frame

Germline Deletion in Exon 7)³_____________________

Amino acid position 510 (e.g., A510V)______________

Amino acid position 511 (e.g., E51 IK)_______________

Amino acid position 513 (e.g., G513D)⁷*_____________

Amino acid position 515 (e.g., C515S, C515W⁴)

Amino acid position 525 (e.g., R525W)'*____________

Amino acid position 531 (e.g., C531R, or 9 base pair duplication²)________________________________________

Amino acid position 532 (e.g., duplication)²___________

Amino acid position 533 (e g., G533C, G533S)______

Amino acid position 550 (e.g., G55OE)______________

Amino acid position 591 (e.g., V591I)_______________

Amino acid position 593 (e.g., G593E)______________

Amino acid position 595 (e.g., E595D and E595A)¹⁸

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Amino acid position 600 (e.g., R600Q)______________

Amino acid position 602 (e.g., 1602V)⁶_______________

Amino acid position 603 (e.g., K603Q, K603E²)______

Amino acid position 606 (e g., Y606C)______________

Amino acid position 609 (e.g., C609Y, C609S, C609G, C609R, C609F, C609W, C609C³²)________________

Amino acid position 611 (e.g., C61 IR, C61 IS, C611G, C611Y, C611F, C611W) ___________________

Amino acid position 616 (e g., E616Q)²³_____________

Amino acid position 618 (e.g., C618S, C618Y, C618R, C618Y, C618G, C618F, C618W)_________________

Amino acid position 619 (e.g., F619F)________________

Amino acid position 620 (e.g., C620S, C620W, C620R, C620G, C620L, C620Y, C620F)___________

Amino acid position 623 (e.g., E623K)_______________

Amino acid position 624 (e.g., D624N)______________

Amino acid position 630 (e.g., C630A, C630R, C630S, C630Y, C630F, C630W) ___________________

Amino acid position 631 (e.g., D631N, D631Y, D631A, D631G, D631V, D631E, )________________

Amino acid position 632 (e.g., E632K, E632G^{5, n}) Δ Amino acid residues 632-633 (6-Base Pair In-Frame Germline Deletion in Exon 11)⁹_____________________

Amino acid position 633 (e g., 9 base pair duplication²) Amino acid position 634 (e.g., C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, or C634T, or an insertion ELCR², or a 12 base pair duplication²) (e.g., causing MTC)____________________

Amino acid position 635 (e.g., R635G)______________

Amino acid position 636 (e g., T636P², T636M⁴)______

Amino acid position 640 (e.g., A640G)______________

Amino acid position 641 (e.g., A641S, A641T⁸)______

Amino acid position 648 (e.g., V648I)________________

Amino acid position 649 (e.g., S649L)²⁸______________

Amino acid position 664 (e.g., A664D)______________

Amino acid position 665 (e.g., H665Q)______________

Amino acid position 666 (e.g., K666E, K666M, K666N, K666R)___________________________

Amino acid position 675 (T675T, silent nucleotide change)¹⁸___________________________________________

Amino acid position 686 (e.g., S686N)_______________

Amino acid position 689 (e.g., S689T)¹⁸______________

Amino acid position 691 (e.g., G691S)_______________

Amino acid position 694 (e.g., R694Q)

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Amino acid position 700 (e.g., M700L)_____________

Amino acid position 706 (e.g., V706M, V706A)

Amino acid position 713 splice variant (e.g., E713K)⁶

Amino acid position 732 (e g., E732K)²⁰____________

Amino acid position 736 (e.g., G736R)⁶____________

Amino acid position 748 (e.g., G748C)_____________

Amino acid position 750 (e.g., A750P)_____________

Amino acid position 765 (e.g., S765P)______________

Amino acid position 766 (e g., P766S, P766M⁶)

Amino acid position 768 (e.g., E768Q, E768D)______

Amino acid position 769 (e.g., L769L)_____________

Amino acid position 770 (e.g., R770Q)_____________

Amino acid position 771 (e.g., D771N)_____________

Amino acid position 777 (e.g., N777S)_____________

Amino acid position 778 (e.g., V778I)_______________

Amino acid position 781 (e.g., Q781R)_____________

Amino acid position 788 (e.g., I788I³²)_______________

Amino acid position 790 (e.g., L790F)______________

Amino acid position 791 (e.g., Y791F, Y791N²⁴)

Amino acid position 802__________________________

Amino acid position 804 (e.g., V804L^15,16, V804M¹⁵¹⁶, V804E¹²) (e.g., causing MTC)___________________

Amino acid position 805 (e.g., E805K)_____________

Amino acid position 804/805 (e.g., V804M/E805K)¹⁷

Amino acid position 806 (e.g., Y806F, Y806S¹², Y806G, Y806C^2,12’¹⁴, Y806E¹⁴, Y806H¹², Y806N¹², Y806Y³²)__________________

Amino acid position 810 (e.g., G810R¹², G810S¹²,

G810A¹³)____________

Amino acid position 818 (e.g., E818K)_____________

Amino acid position 819 (e.g., S819I)_______________

Amino acid position 823 (e.g., G823E)_____________

Amino acid position 826 (e.g., Y826M, Y826S)¹⁰

Amino acid position 833 (e g., R833C)_____________

Amino acid position 836 (e.g., S836S)¹⁹____________

Amino acid position 841 (e.g., P841L, P841P)______

Amino acid position 843 (e.g., E843D)_____________

Amino acid position 844 (e.g., R844W, R844Q,

R844L)__________________________________

Amino acid position 848 (e.g., M848T)____________

Amino acid position 852 (e.g., I852M)_____________

Amino acid position 865 (e.g., L865V)¹²____________

Amino acid position 870 (e.g., L870F)¹²

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Exemplary RET Point Mutations_______________

Amino acid position 873 (e.g., R873W)______________

Amino acid position 876 (eg., A876V)______________

Amino acid position 881 (e.g., L881V)_______________

Amino acid position 882___________________________

Amino acid position 883 (e.g., A883F, A883S, A883T)

Amino acid position 884 (e.g., E884K)_______________

Amino acid position 886 (e.g., R886W)______________

Amino acid position 891 (e.g., S891A, S891S³²)______

Amino acid position 897 (e g., R897Q)______________

Amino acid position 898 (e.g., D898V)______________

Amino acid position 900 (e.g., Y900F)²²______________

Amino acid position 901 (e.g., E901K)_______________

Amino acid position 904 (e g., S904F, S904S, S904C²)

Amino acid position 905 (e.g., Y905F)²²______________

Amino acid position 907 (e.g., K907E, K907M)______

Amino acid position 908 (e.g., R908K)______________

Amino acid position 911 (e.g., G91 ID)_______________

Amino acid position 912 (e.g., R912P, R912Q)_______

Amino acid position 918 (e.g., M918T², M918V,

M918L⁶) (e.g., causing MTC)______________________

Amino acid position 919 (e g., A919V)______________

Amino acid position 921 (e.g., E921K)_______________

Amino acid position 922 (e g., S922P, S922Y)

Amino acid position 930 (e.g., T930M)_________

Amino acid position 961 (e.g., F961L)__________

Amino acid position 972 (e.g., R972G)_________

Amino acid position 981 (e.g., Y981F)²²_________

Amino acid position 982 (e.g., R982C)__________

Amino acid position 1009 (e.g., Ml009V)_______

Amino acid position 1015 (e.g., Y1015F)²²______

Amino acid position 1017 (e.g., D1017N)_______

Amino acid position 1041 (e.g., V1041G)_______

Amino acid position 1064 (e.g., M1064T)_______

Amino acid position 1096 (e.g., Y1096F)²¹______

RET+3¹_______________________________ (In-Frame Deletion in Exons 6 and 11)²⁵_________ (3bp In-Frame Deletion in Exon 15)²⁶___________

Nucleotide position 2136+2 (e.g., 2136+2T>G)²⁹(de!632-636 ins6)³¹______________________________

Amino acid positions 791 and 852 (e.g., Y791F +

I852M)³¹____________________________________

Amino acid positions 634 and 852 (e.g., C634R + I852M)³¹

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⁶ Jovanovic, et al., Prilozi 36(1):93-107, 2015.

Qi, et al., Oncotarget. 6(32):33993-4003, 2015. *R525W and G513D appear to act in combination with S891A to enchance oncogenic activity.

⁸ Kim, et al. ACTA ENDOCRINOLOGICA-BUCHAREST 11.2, 189-194, 2015.

⁹ Cecchirini, et al. Oncogene, 14, 2609-2612, 1997.

¹⁰ Karrasch, et al. Eur. Thyroid J., 5(1):73-7,2016.

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

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

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

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

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

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²⁴ De Almeida et al., Endocrine Reviews, 2016, Vol. 37, No. 2, Supp. Supplement 1. Abstract Number: SUN-068; 98^th Annual Meeting and Expo of the Endocrine Society, ENDO 2016. Boston, MA, US. 01 Apr 2016-04 Apr 2016.

²⁵ Vanden et al., Annals of Oncology, 2016, Vol. 27, Supp. Supplement 6. Abstract Number: 427PD, 41^s* European Society for Medical Oncology Congress, ESMP 2016. Copenhagen,

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²⁶ Romei et al., European Thyroid Journal (August 2016) Vol. 5, Supp. Supplement 1, pp. 75; 39^thAnnual Meeting of the European Thyroid Association, ETA 2016. Copenhagen, Denmark. 03 Sep 2016-06 Sep 2016.

²⁷ Lee et al., Oncotarget, 8(4): 6579-6588, doi: 10.18632/oncotarget.l4172, 2017.

²⁸ Zhang et al., Laboratory Investigation, (February 2017) Vol. 97, Supp. 1, pp. 209A. Abstract Number: 840, Meeting Info: 106th Annual Meeting of the United States and Canadian Academy of Pathology, USCAP 2017. San Antonio, TX, United States.

²⁹ Borecka et al., European Journal of Cancer, (July 2016) Vol. 61, No. 1, pp. S26, Abstract Number: 162, Meeting Info: 24th Biennial Congress of the European Association for Cancer Research, EACR 2016. Manchester, United Kingdom.

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³¹ Gazizova et al., Endocrine Reviews, (JUN 2014) Vol. 35, No. 3, Suppl. S, pp. SAT-0304, Meeting Info.: 96th Annual Meeting and Expo of the Endocrine-Society, Chicago, IL, USA, June 21-24, 2014.

³² Sromek et al., Endocr Pathol., doi: 10.1007/s 12022-017-9487-2,2017.

[00650] In some embodiments, the dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, includes at least one point mutation in a RET gene that results in the production of a RET kinase that has one or more amino acid substitutions, insertions, or deletions as compared to the wild-type RET kinase (see, for example, the point mutations listed in Table 2a).

[00651] Table 2a Exemplary activating RET Kinase Protein Point Mutations/Insertions/Deletions

Exemplary RET Point Mutations________________

Amino acid position 20_____________________________

Amino acid position 32 (e.g,, S32L)___________________

Amino acid position 34 (e.g., D34S)___________________

Amino acid position 40 (e g., L40P)__________________

Amino acid position 64 (e.g., P64L)___________________

Amino acid position 67 (e g., R67H)

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Exemplary RET Point Mutations_______________

Amino acid position 114 (e.g., RI 14H)_______________

Amino acid position 145 (e.g., V145G)______________

Amino acid position 200___________________________

Amino acid position 292 (e.g., V292M)______________

Amino acid position 294___________________________

Amino acid position 321 (e.g., G321R)______________

Amino acid position 330 (e.g., R330Q)______________

Amino acid position 338 (e.g., T338I)________________

Amino acid position 360 (e g., R360W)______________

Amino acid position 393 (e.g., F393L)________________

Amino acid position 432___________________________

Δ Amino acid residues 505-506 (6-Base Pair In-Frame

Germline Deletion in Exon 7)_______________________

Amino acid position 510 (e.g., A510V)______________

Amino acid position 511 (e g., E51 IK)_______________

Amino acid position 513 (e.g., G513D)______________

Amino acid position 515 (e g., C515S, C515W⁴)______

Amino acid position 525 (e.g., R525W)______________

Amino acid position 531 (eg., C531R, or 9 base pair duplication)__________________________________________

Amino acid position 532 (e.g., duplication)____________

Amino acid position 533 (e.g., G533C, G533S)_______

Amino acid position 550 (e.g., G550E)_______________

Amino acid position 591 (e.g., V591I)________________

Amino acid position 593 (e.g., G593E)_______________

Amino acid position 595 (e.g., E595D and E595A)

Amino acid position 600 (e.g., R600Q)______________

Amino acid position 602 (e.g., 1602V)________________

Amino acid position 603 (e.g., K603Q, K603E)_______

Amino acid position 606 (e.g., Y606C)______________

Amino acid position 609 (e.g., C609Y, C609S, C609G,

C609R, C609F, C609W) ___________________

Amino acid position 611 (e.g., C61 IR, C61 IS, C611G,

C611 Y, C61 IF, C611W) _____________________

Amino acid position 616 (e.g., E616Q)_______________

Amino acid position 618 (e.g., C618S, C618Y, C618R,

C618G, C618F, C618W) ___________________

Amino acid position 620 (e.g., C620S, C620W, C620R, C620G, C620L, C620Y, C620F)___________

Amino acid position 623 (e.g., E623K)_______________

Amino acid position 624 (e.g., D624N)______________

Amino acid position 630 (e.g., C630A, C630R, C630S, C630Y, C630F, C630W)

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Exemplary RET Point Mutations_______________

Amino acid position 631 (e.g., D631N, D631Y, D631A, D631G, D631V, D631E, )_______________

Amino acid position 632 (e.g., E632K, E632G)______

Δ Amino acid residues 632-633 (6-Base Pair In-Frame Germline Deletion in Exon 11)_____________________

Amino acid position 633 (e g., 9 base pair duplication) Amino acid position 634 (e g., C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, or C634T, or an insertion ELCR, or a 12 base pair duplication) (e.g., causing MTC)____________________

Amino acid position 635 (e.g., R635G)______________

Amino acid position 636 (e.g., T636P, T636M)______

Amino acid position 640 (e.g., A640G)______________

Amino acid position 641 (e g., A641S, A641T)_______

Amino acid position 648 (e.g., V648I)_______________

Amino acid position 649 (e g., S649L)______________

Amino acid position 664 (e.g., A664D)______________

Amino acid position 665 (e g., H665Q)______________

Amino acid position 666 (e.g., K666E, K666M, K666N, K666R)______

Amino acid position 686 (e.g., S686N)______________

Amino acid position 689 (e.g., S689T)_______________

Amino acid position 691 (e.g., G691S)_______________

Amino acid position 694 (e.g., R694Q)______________

Amino acid position 700 (e.g., M700L)______________

Amino acid position 706 (e.g., V706M, V706A)_____

Amino acid position 713 splice variant (e.g., E713K)

Amino acid position 732 (e.g., E732K)______________

Amino acid position 736 (e.g., G736R)______________

Amino acid position 748 (e.g., G748C)______________

Amino acid position 750 (e.g., A750P)______________

Amino acid position 765 (e.g., S765P)_______________

Amino acid position 766 (e.g., P766S, P766M)_______

Amino acid position 768 (e.g., E768Q, E768D)______

Amino acid position 769 (e g., L769L)______________

Amino acid position 770 (e.g., R770Q)______________

Amino acid position 771 (e.g., D771N)______________

Amino acid position 777 (e.g., N777S)______________

Amino acid position 778 (e.g., V778I)_______________

Amino acid position 781 (e.g., Q781R)______________

Amino acid position 790 (e.g., L790F)_______________

Amino acid position 791 (e.g., Y791F, Y791N)______

Amino acid position 802

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Exemplary RET Point Mutations_______________

Amino acid position 804 (e.g., V804L, V804M,

V804E) (e.g., causing MTC)_______________________

Amino acid position 805 (e.g., E805K)_______________

Amino acid position 804/805 (e g., V804M/E805K)

Amino acid position 806 (e.g., Y806F, Y806S, Y806G,

Y806C, Y806E, Y806H, Y806N)_________________

Amino acid position 810 (e g., G810R, G810S,

G810A)___________________________________

Amino acid position 818 (e g., E818K)_______________

Amino acid position 819 (e.g., S819I)________________

Amino acid position 823 (e.g., G823E)_______________

Amino acid position 826 (e.g., Y826M, Y826S)_______

Amino acid position 833 (e.g., R833C)_______________

Amino acid position 836 (e.g., S836S)________________

Amino acid position 841 (e.g., P841L, P841P)________

Amino acid position 843 (e.g., E843D)_______________

Amino acid position 844 (e.g., R844W, R844Q,

R844L)___________________________________

Amino acid position 848 (e.g., M848T)______________

Amino acid position 852 (e.g., I852M)_______________

Amino acid position 865 (e.g., L865V)_______________

Amino acid position 870 (e.g., L870F)_______________

Amino acid position 873 (e.g., R873W)______________

Amino acid position 876 (e.g., A876V)______________

Amino acid position 881 (e.g., L881V)_______________

Amino acid position 882___________________________

Amino acid position 883 (e.g., A883F, A883S, A883T)

Amino acid position 884 (e.g., E884K)_______________

Amino acid position 886 (e.g., R886W)______________

Amino acid position 891 (e.g., S891 A)_______________

Amino acid position 897 (e.g., R897Q)______________

Amino acid position 898 (e.g., D898V)______________

Amino acid position 900 (e.g., Y900F)_______________

Amino acid position 901 (e.g., E901K)_______________

Amino acid position 904 (e g., S904F, S904S, S904C)

Amino acid position 907 (e.g., K907E, K.907M)______

Amino acid position 908 (e.g., R908K)______________

Amino acid position 911 (e.g., G91 ID)_______________

Amino acid position 912 (e.g., R912P, R912Q)_______

Amino acid position 918 (e.g., M918T, M918V,

M918L) (e.g., causing MTC)______________________

Amino acid position 919 (e.g., A919V)______________

Amino acid position 921 (e.g., E921K)_______________

Amino acid position 922 (e.g., S922P, S922Y)

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Exemplary RET Point Mutations________________

Amino acid position 930 (e.g., T930M)_______________

Amino acid position 961 (e.g., F961L)_________________

Amino acid position 972 (e.g., R972G)_______________

Amino acid position 982 (e g., R982C)_______________

Amino acid position 1009 (e.g., M1009V)_____________

Amino acid position 1015 (e.g., Y1015F)_____________

Amino acid position 1017 (e.g., D1017N)_____________

Amino acid position 1041 (e.g., V1041G)_____________

Amino acid position 1064 (e g., M1064T)_____________

Amino acid position 1096 (e.g., Y1096F)_____________

RET+3__________________________________ (In-Frame Deletion in Exons 6 and 11)________________ (3bp In-Frame Deletion in Exon 15)

[00652] In some embodiments, the dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, includes a splice variation in a RET mRNA which results in an expressed protein that is an alternatively spliced variant of RET having at least one residue deleted (as compared to the wild-type RET kinase) resulting in a constitutive activity of a RET kinase domain.

[00653] A “RET kinase inhibitor” as defined herein includes any compound exhibiting RET inhibition activity. In some embodiments, a RET kinase inhibitor is selective for a RET kinase Exemplary RET kinase inhibitors can exhibit inhibition activity (ICso) against a RET kinase of 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 in an assay as described herein. In some embodiments, a RET kinase inhibitors can exhibit inhibition activity (ICso) against a RET kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein.

[00654] As used herein, a “first RET kinase inhibitor” or “first RET inhibitor” is a RET kinase inhibitor as defined herein, but which does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as defined herein. As used herein, a “second RET kinase inhibitor” or a “second RET inhibitor” is a RET kinase inhibitor as defined herein, but which does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as defined herein. When both a first and a second RET inhibitor are present in a method provided herein, the first and second RET kinase inhibitor are different.

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[00655] In some embodiments, the dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, includes at least one point mutation in a RET gene that results in the production of a RET kinase that has one or more amino acid substitutions or insertions or deletions in a RET gene that results in the production of a RET kinase that has one or more amino acids inserted or removed, as 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 inhibitor(s), as compared to a wildtype RET kinase or a RET kinase not including the same mutation. Such mutations, optionally, do not decrease the sensitivity of the cancer cell or tumor having the RET kinase to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (e g., as compared to a cancer cell or a tumor that does not include the particular RET inhibitor resistance mutation). In such embodiments, a RET inhibitor resistance mutation can result in a RET kinase that has one or more of an increased Vmax, a decreased Km for ATP, and an increased Kd for a first RET kinase inhibitor, when in the presence of a first RET kinase inhibitor, as compared to a wildtype RET kinase or a RET kinase not having the same mutation in the presence of the same first RET kinase inhibitor.

[00656] In other embodiments, the dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, includes at least one point mutation in a RET gene that results in the production of a RET kinase that has one or more amino acid substitutions as compared to the wild-type RET kinase, and which has increased resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as compared to a wildtype RET kinase or a RET kinase not including the same mutation. In such embodiments, a RET inhibitor resistance mutation can result in a RET kinase that has one or more of an increased Vmax, a decreased Km, and a decreased Kd in the presence of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as compared to a wildtype RET kinase or a RET kinase not having the same mutation in the presence of the same compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.

[00657] Examples of RET inhibitor resistance mutations can, e.g., include point mutations, insertions, or deletions in and near the ATP binding site in the tertiary structure of RET kinase, including but not limited to the gatekeeper residue, P-loop residues, residues in or near the DFG motif, and ATP cleft solvent front amino acid residues. Additional examples of these types of mutations include changes in residues that may affect enzyme activity and/or drug binding

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PCT7US2017/055983 including but are not limited to residues in the activation loop, residues near or interacting with the activation loop, residues contributing to active or inactive enzyme conformations, changes including mutations, deletions, and insertions in the loop proceeding the C-helix and in the Chelix. Specific residues or residue regions that may be changed (and are RET inhibitor resistance mutations) include but are not limited to those listed in Table 3 based on the human wildtype RET protein sequence (eg., SEQ ID NO: 1 ). Additional examples of RET inhibitor resistance mutation positions are shown in Table 4. Changes to these residues may include single or multiple amino acid changes, insertions within or flanking the sequences, and deletions within or flanking the sequences.

[00658] Exemplary Sequence of Mature Human RET Protein (SEQ ID NO: 1)

MAKATSGAAG LRLLLLLLLP LLGKVALGLY FSRDAYWEKL YVDQAAGTPL LYVHALRDAP EEVPSFRLGQ

HLYGTYRTRL HENNWICIQE DTGLLYLNRS LDHSSWEKLS VRNRGFPLLT VYLKVFLSPT SLREGECQWP

GCARVYFSFF NTSFPACSSL KPRELCFPET RPSFRIRENR PPGTFHQFRL LPVQFLCPNI SVAYRLLEGE

GLPFRCAPDS LEVSTRWALD REQREKYELV AVCTVHAGAR EEWMVPFPV TVYDEDDSAP TFPAGVDTAS

AWEFKRKED TWATLRVFD ADWPASGEL VRRYTSTLLP GDTWAQQTFR VEHWPNETSV QANGSFVRAT

VHDYRLVLNR NLSISENRTM QLAVLVNDSD FQGPGAGVLL LHFNVSVLPV SLHLPSTYSL SVSRRARRFA

QIGKVCVENC QAFSGINVQY KLHSSGANCS TLGWTSAED TSGILFVNDT KALRRPKCAE LHYMWATDQ

QTSRQAQAQL LVTVEGSYVA EEAGCPLSCA VSKRRLECEE CGGLGSPTGR CEWRQGDGKG ITRNFSTCSP

STKTCPDGHC DWETQDINI CPQDCLRGSI VGGHEPGEPR GIKAGYGTCN CFPEEEKCFC EPEDIQDPLC

DELCRTVIAA AVLFSFIVSV LLSAFCIHCY HKFAHKPPIS SAEMTFRRPA QAFPVSYSSS GARRPSLDSM

ENQVSVDAFK ILEDPKWEFP RKNLVLGKTL GSGEFGKWK ATAFHLKGRA GYTTVAVKML KENASPSELR

DLLSEFNVLK QVNHPHVIKL YGACSQDGPL LLIVEYAKYG SLRGFLRESR KVGPGYLGSG GSRNSSSLDH

PDERALTMGD LISFAWQISQ GMQYLAEMKL VHRDLAARNI LVAEGRKMKI SDFGLSRDVY EEDSYVKRSQ

GRIPVKWMAI ESLFDHIYTT QSDVWSFGVL LWEIVTLGGN PYPGIPPERL FNLLKTGHRM ERPDNCSEEM

YRLMLQCWKQ EPDKRPVFAD ISKDLEKMMV KRRDYLDLAA STPSDSLIYD DGLSEEETPL VDCNNAPLPR

ALPSTWIENK LYGMSDPNWP GESPVPLTRA DGTNTGFPRY PNDSVYANWM LSPSAAKLMD TFDS [00659] In some embodiments, compounds of Formula I and pharmaceutically acceptable salts and solvates are useful in treating patients that develop cancers with RET inhibitor resistance mutations (e g., that result in an increased resistance to a first RET inhibitor, e g., a substitution at amino acid position 804, e.g., V804M, V804L, or V804E, and/or one or more RET inhibitor resistance mutations listed in Tables 3 and 4) by either dosing in combination or as a follow-up therapy to existing drug treatments (e.g., other RET kinase inhibitors; e.g., first and/or second RET kinase inhibitors). Exemplary first and second RET kinase inhibitors are described herein. In some embodiments, a first or second RET kinase inhibitor can be selected from the group consisting of

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PCT7US2017/055983 cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864.

[00660] In some embodiments, compounds of Formula I or pharmaceutically acceptable salts and solvates thereof are useful for treating a cancer that has been identified as having one or more RET inhibitor resistance mutations (that result in an increased resistance to a first or second RET inhibitor, e g., a substitution at amino acid position 804, e.g, V804M, V804L, or V804E). Nonlimiting examples of RET inhibitor resistance mutations are listed in Tables 3 and 4.

Table 3. RET Inhibitor Resistance Mutations

Exemplary RET Resistance Mutations________________________________________

Amino acid position 732 (e.g., E732K)'_______________________________________________

Amino acid position 788 (e.g, I788N)^g_______________________________________________

Amino acid position 804 (e.g, V804M¹·², V804L¹·², V804E⁶)___________________________

Amino acid position 804/805 (e.g., V804MÆ805K)³__________________________________

Amino acid position 806 (e.g., Y806C^{4 6}, Y806E⁴, Y806S⁶, Y806H⁶, Y806N⁶)___________

Amino acid position 810 (e g., G810A⁵, G810R⁶, G810S⁶)______________________________

Amino acid position 865 (e.g., L865V⁶)_________________________________________________

Amino acid position 870 (e.g, L870F⁶) ¹ Yoon et al., J. Med. Chem. 59(1):358-73, 2016.

² U.S. Patent No. 8,629,135.

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

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

⁵ Huang et al., Mol. Cancer Ther., 2016 Aug 5. pii: molcanther.0258.2016. [Epub ahead of print], ⁶ PCT Patent Application Publication No. WO 2016/127074.

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

⁸ Plenker et al., Sci. Transi. Med., 9(394), doi: 10.1126/scitranslmed.aah6144, 2017.

Table 4. Additional Exemplary Amino Acid Positions of RET Inhibitor Resistance Mutations

<td> RET Amino Acid and Position</td><td> Exemplary Mutation</td><td> Mechanistic Resistance Rationale</td>

<td> L730</td><td> P</td><td> Steric hindrance and/or active conformational effect</td>

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<td> G731</td><td> V</td><td> Steric hindrance and/or active conformational effect</td>

<td> E732</td><td> K</td><td> Steric hindrance and/or active conformational effect</td>

<td> G733</td><td> V</td><td> Steric hindrance and/or active conformational effect</td>

<td> E734</td><td> K</td><td> Steric hindrance and/or active conformational effect</td>

<td> L760</td><td> M</td><td> Active conformational effect</td>

<td> K761</td><td> E</td><td> Active confoimational effect</td>

<td> E762</td><td> K</td><td> Active conformational effect</td>

<td> N763</td><td> D</td><td> Active conformational effect</td>

<td> A764</td><td> V</td><td> Active conformational effect</td>

<td> S765</td><td> N</td><td> Active confoimational effect</td>

<td> P766</td><td> A</td><td> Active confoimational effect</td>

<td> S767</td><td> C</td><td> Active conformational effect</td>

<td> E768</td><td> K</td><td> Active confoimational effect</td>

<td> L779</td><td> M</td><td> Steric hindrance and/or active conformational effect</td>

<td> 1788</td><td> M</td><td> Steric hindrance and/or active conformational effect</td>

<td> M868</td><td> R</td><td> Steric hindrance and/or active conformational effect</td>

<td> K869</td><td> E</td><td> Steric hindrance and/or active conformational effect</td>

<td> L870</td><td> Q</td><td> Steric hindrance and/or active conformational effect</td>

<td> V871</td><td> M</td><td> Steric hindrance and/or active conformational effect</td>

<td> H872</td><td> R</td><td> Steric hindrance and/or active conformational effect</td>

<td> R873</td><td> P</td><td> Steric hindrance and/or active conformational effect</td>

<td> D874</td><td> Y</td><td> Steric hindrance and/or active conformational effect</td>

<td> L881</td><td> R</td><td> Steric hindrance and/or active conformational effect</td>

<td> L895</td><td> M</td><td> Active conformational effect</td>

<td> S896</td><td> N</td><td> Active confoimational effect</td>

<td> R897</td><td> C</td><td> Active confoimational effect</td>

<td> D898</td><td> Y</td><td> Active confoimational effect</td>

<td> V899</td><td> G</td><td> Active conformational effect</td>

<td> Y900</td><td> D</td><td> Active conformational effect</td>

<td> E901</td><td> K</td><td> Active confoimational effect</td>

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<td> E902</td><td> K</td><td> Active confonmational effect</td>

<td> D903</td><td> Y</td><td> Active confonmational effect</td>

<td> S904</td><td> C</td><td> Active conformational effect</td>

<td> Y905</td><td> D</td><td> Active conformational effect</td>

<td> V906</td><td> M</td><td> Active conformational effect</td>

<td> K907</td><td> E</td><td> Active confonmational effect</td>

<td> R908</td><td> P</td><td> Active conformational effect</td>

<td> S909</td><td> C</td><td> Active confonmational effect</td>

<td> Q910</td><td> R</td><td> Active conformational effect</td>

<td> G911</td><td> C</td><td> Active confonmational effect</td>

<td> R912</td><td> P</td><td> Active confonmational effect</td>

[00661] The oncogenic role of RET was firstly described in papillary thyroid carcinoma (PTC) (Grieco et al., Cell, 1990, 60, 557-63), which arises from follicular thyroid cells and is the most common thyroid malignancy. Approximately 20-30% of PTC harbor somatic chromosomal rearrangements (translocations or inversions) linking the promoter and the 5' portions of constitutively expressed, unrelated genes to the RET tyrosine kinase domain (Greco et al., Q. J. Nucl. Med. Mol. Imaging, 2009, 53, 440-54), therefore 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 carcinomas. Similarly, both RET/PTC3 and RET/PTC4 are fusions of ELEI and RET that are commonly found in papillary thyroid carcinomas, although the fusion events resulting RET/PTC3 and RET/PTC4 lead to 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 instead are referred to as the the fusion protein inself. For example, fusion between RET and both ELKS and PCM1 are found in PTCs, 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 RET-PTC rearrangements 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 have been identified, from PTC and other cancer types, all providing a protein/protein interaction domain that induces ligand-independent RET

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PCT/US2017/055983 dimerization and constitutive kinase activity (see, e.g., Table 1). Recently, a 10.6 Mb pericentric inversion in chromosome 10, where RET gene maps, has been identified in about 2% of lung adenocarcinoma patients, generating different variants of the chimeric gene K1F5B-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 RET positive patients harbor other known oncogenic alterations (such as EGFR or K-Ras mutation, ALK translocation), supporting the possibility that KIF5B-RET fusion could be a driver mutation of lung adenocarcinoma. The oncogenic potential of KIF5B-RET has been confirmed by transfecting the fusion gene into cultured cell lines: similarly to what has been observed with RET-PTC fusion proteins, KIF5B-RET is constitutively phosphorylated and induces NIH-3T3 transformation and IL-3 independent growth of BA-F3 cells. However, other RET fusion proteins have been identified in lung adenocarcinoma patients, such as the CCDC6RET 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, A.E. et d . J Clin Oncol 33,2015 (suppl; abstr 8007)). RET fusion proteins have also been identified in patients having colorectal cancer (Song Eun-Kee, et al. International Journal of Cancer, 2015, 136: 1967-1975).

[00662] Besides rearrangements of the RET sequence, gain of function point mutations of RET proto-oncogene are also driving oncogenic events, as shown in medullary thyroid carcinoma (MTC), which arises 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). Around 25% of MTC are associated with multiple endocrine neoplasia type 2 (MEN2), a group of inherited cancer syndromes affecting neuroendocrine organs caused by germline activating point mutations of RET. In MEN2 subtypes (MEN2A, MEN2B and Familial MTC/FMTC) RET gene mutations have a strong phenotype-genotype correlation defining different MTC aggressiveness and clinical manifestations of the disease. In MEN2A syndrome mutations involve one of the six cysteine residues (mainly C634) located in the cysteine-rich extracellular region, leading to ligandindependent homodimerization and constitutive RET activation. Patients develop MTC at a young

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PCT7US2017/055983 age (onset at 5-25 years) and may also develop pheochromocytoma (50%) and hyperparathyroidism. MEN2B is mainly caused by 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. MEN2B syndrome is characterized by an early onset (&lt; 1 year) and very aggressive form of MTC, pheochromocytoma (50% of patients) and ganglioneuromas. In FMTC the only disease manifestation is MTC, usually occurring at an adult age. Many different mutations have been detected, spanning the entire RET gene. The remaining 75% of MTC cases are sporadic and about 50% of them harbor RET somatic mutations: the most frequent mutation is M918T that, as in MEN2B, is associated with the most aggressive phenotype. Somatic point mutations of RET have also been described in other tumors such as colorectal cancer (Wood et al., Science, 2007, 318, 1108-13) and small cell lung carcinoma (Jpn. J. Cancer Res., 1995, 86, 1127-30).

[00663] RET signaling components have been found to be expressed in primary breast tumors and to functionally interact with 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, 464857), while RET expression and activation by GDNF family ligands could play an important role in perineural invasion by 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).

[00664] 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., EMBOMol. Med, 2013, 5, 1335-1350).

[00665] The identification of RET rearrangements has been reported in a subset of (patientderived xenograft) PDX established from colorectal cancer. Although the frequency of such events in colorectal cancer patients remains to be defined, these data suggest a role of RET as a target in this indication (Gozgit et al., AACR Annual Meeting 2014). Studies have shown that the RET promoter is frequently methylated in colorectal cancers, and heterozygous missense mutations, which are predicted to reduce RET expression, are identified in 5-10% of cases, which suggests that RET might have some features of a tumor suppressor in sporadic colon cancers (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).

[00666] An increasing number of tumor types are now being shown to express substantial

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PCT7US2017/055983 levels of wild-type RET kinase that could have implications for tumor progression and spread. RET is expressed in 50-65% of pancreatic ductal carcinomas, and expression is more frequent in metastatic and higher grade tumors (Ito, Y, et al., Surgery, 2005, 138, 788-794; Zeng, Q., et al., J. hit. Med. Res. 2008, 36, 656-664).

[00667] In neoplasms of hematopoietic lineages, RET is expressed in acute myeloid leukemia (AML) with monocytic differentiation, as well as 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 that involve RET in patients with chronic myelomonocytic leukemia (CMML). CMML is frequently associated with rearrangements of several tyrosine kinases, which result in the expression of chimeric cytosolic oncoproteins that lead to activation of RAS pathways (Kohlmann, A., et al., J. Clin. Oncol. 2010, 28, 2858-2865). In the case of RET, gene fusions that link RET with BCR (BCR-RET) or with fibroblast growth factor receptor 1 oncogene partner (FGFR1OP-RET) were transforming in early hematopoietic progenitor cells and could shift maturation of these cells towards monocytic paths, probably through the initiation of RET-mediated RAS signaling (Ballerini, P., et al., Leukemia, 2012, 26, 2384-2389).

[00668] RET expression has also been shown to occur in several other tumor types, including prostate cancer, small-cell lung carcinoma, 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, D. M., J Natl Cancer Inst, 1998, 90, 519-523).

[00669] In neuroblastoma, RET expression and activation by GFLs has roles in tumor cell differentiation, potentially collaborating with other neurotrophic factor receptors to down regulate N-Myc, the expression of which is a marker of poor prognosis (Hofstra, R. M., W., et al., Hum. Genet. 1996, 97, 362-364; Petersen, S. and Bogenmann, E., Oncogene, 2004, 23, 213-225, Brodeur, G. M, Nature Ref. Cancer, 2003, 3, 203-216).

[00670] Multitargeted inhibitors which cross react with RET are known (Borrello, M.G., 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).

[00671] Accordingly, provided herein are methods for treating a patient diagnosed with (or identified as having) a cancer that include administering to the patient a therapeutically effective

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PCT7US2017/055983 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 a RETassociated cancer that include 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, the patient that has been identified or diagnosed as having a RET-associated cancer through the use of a regulatory agency-approved, e g., FDA-approved test or assay for identifying dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, in a patient or a biopsy sample from the patient or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a RETassociated cancer. For example, the RET-associated cancer can be a cancer that includes one or more RET inhibitor resistance mutations.

[00672] Also provided are methods for treating cancer in a patient in need thereof, the method comprising: (a) determining if the cancer in the patient is a RET-associated cancer; and (b) if the cancer is determined to be a RET-associated cancer, administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject 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). In some embodiments, the subject was previously treated with a first RET inhibitor or previously treated with another anticancer treatment, e.g., resection of the tumor or radiation therapy. In some embodiments, the patient is determined to have a RET-associated cancer through the use of a regulatory agency-approved, e g., FDA-approved test or assay for identifying dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, in a patient or a biopsy sample from the patient or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a RET-associated cancer. For example, the RET-associated cancer can be a cancer that includes one or more RET inhibitor resistance mutations.

[00673] Also provided are methods of treating a patient that include performing an assay on a sample obtained from the patient to determine whether the patient has a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, and administering (e.g.,

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PCT7US2017/055983 specifically or selectively administering) a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof to the patient determined to have a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. Some embodiments of these methods further include administering to the subject another anti cancer agent (eg., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments of these methods, the subject was previously treated with a first RET inhibitor or previously treated with another anticancer treatment, eg., resection of a tumor or radiation therapy. In some embodiments, the patient is a patient suspected of having a RET-associated cancer, a patient presenting with one or more symptoms of a RET-associated cancer, or a patient having an elevated risk of developing a RET-associated cancer. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. Additional, non-limiting assays that may be used in these methods are described herein. Additional assays are also known in the art. In some embodiments, the dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same includes one or more RET inhibitor resistance mutations.

[00674] 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-associated cancer in a patient identified or diagnosed as having a RET-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the patient to determine whether the patient has a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, where the presence of a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, identifies that the patient has a RET-associated 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 RET-associated cancer in a patient identified or diagnosed as having a RET-associated cancer through a step of performing an assayon a sample obtained from the patient to determine whether the patient has a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same where the presence of dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, identifies that the patient has a RET-associated cancer. Some embodiments of any of the methods

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PCT7US2017/055983 or uses described herein further include recording in the patient’s clinical record (e.g., a computer readable medium) that the patient is determined to have a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, through the performance of the assay, 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 break apart FISH analysis. Tn some embodiments, the assay is a regulatory agency-approved assay, e g., FDA-approved kit. In some embodiments, the dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same includes one or more RET inhibitor resistance mutations.

[00675] Also provided is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a cancer in a patient in need thereof or a patient identified or diagnosed as having a RET-associated 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-associated cancer. In some embodiments, the cancer is a RET-associated cancer, for example, a RETassociated cancer having one or more RET inhibitor resistance mutations. In some embodiments, a patient is identified or diagnosed as having a RET-associated cancer through the use of a regulatory' agency-approved, eg., FDA-approved, kit for identifying dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, in a patient or a biopsy sample from the sample. As provided herein, a RET-associated cancer includes those described herein and known in the art.

[00676] 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 dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the patient has a tumor that is positive for a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the patient can be a patient with a tumor(s) that is positive for a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the patient can be a patient whose tumors have a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein,

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PCT7US2017/055983 the patient is suspected of having a RET-associated cancer (e.g., a cancer having one or more RET inhibitor resistance mutations). In some embodiments, provided herein are methods for treating a RET-associated cancer in a patient in need of such treatment, the method comprising a) detecting a dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same 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, the dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same includes 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, the dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same includes 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 mutations/insertions/deletions are selected from the group consisting of M918T, M918V, C634W, V804L, and V804M In some embodiments, the dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same includes 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, the cancer with a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same is determined using a regulatoiy agencyapproved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor that is positive for a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same is a tumor positive for one or more RET inhibitor resistance mutations. In some embodiments, the tumor with a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e g., FDA-approved, assay or kit. [00677] 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 that has a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same (eg., a tumor having 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 ofFormula I or a pharmaceutically acceptable salts or solvates thereof or compositions provided herein. In some embodiments, the

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PCT7US2017/055983 cancer with a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same is a cancer having one or more RET inhibitor resistance mutations. In some embodiments, the cancer with a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDAapproved, assay or kit. In some embodiments, the tumor that is positive for a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same is a tumor positive for one or more RET inhibitor resistance mutations. In some embodiments, the tumor with a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e g., FDA-approved, assay or kit.

[00678] Also provided are methods of treating a patient that include administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to a patient having a clinical record that indicates that the patient has a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. 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 RET-associated cancer in a patient having a clinical record that indicates that the patient has a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. Some embodiments of these methods and uses can further include: a step of performing an on a sample obtained from the patient to determine whether the patient has a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, and recording the information in a patient’s clinical file (e g., a computer readable medium) that the patient has been identified to have a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same. In some embodiments, the assay is an in vitro assay. For example, an assay that utilizes next generation sequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved, kit. In some embodiments, the dysrégulation of a RET gene, RET kinase, or expression or activity or level of any of the same includes one or more RET inhibitor resistance mutations.

[00679] Also provided herein is a method of treating a subject. The method includes performing an assay on a sample obtained from the subject to determine whether the subject has a dysrégulation of a RET gene, a RET protein, or expression or level of any of the same. The method also includes administering to a subject determined to have a dysrégulation of a RET gene, a RET

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PCT7US2017/055983 protein, or expression or activity, or level of any of the same a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the dysrégulation in a RET gene, a RET kinase protein, or expression or activity of the same is a gene or chromosome translocation that results in the expression of a RET fusion protein (e.g., any of the RET fusion proteins described herein). In some embodiments, the RET fusion can be selected from a KIF5B-RET fusion and a CCDC6-RET fusion. In some embodiments, the dysrégulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more point mutation in the RET gene (e.g., any of the one or more of the RET point mutations described herein). The one or more point mutations in a RET gene can result, e.g., in the 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 dysrégulation in a RET gene, a RET kinase protein, or expression or activity or level of any of the same is one or more RET inhibitor resistance mutations (e.g., any combination of the one or more RET inhibitor resistance mutations described herein). Some embodiments of these methods further include administering to the subject 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).

[00680J In some embodiments, the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood brain barrier and inhibiting a RET kinase in the brain and/or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount. For example, treatment of a patient with cancer (e g., a RET-associated cancer such as a RET-associated brain or CNS cancer) can include administration (eg., oral administration) of the compound to the patient. In some such embodiments, the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor. For example, the compounds can be used in the treatment of one or more of gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), and craniopharyngiomas (see, for example, the tumors listed in Louis, D.N. et al. ActaNeuropathol 131(6), 803-820 (June 2016)). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the patient has previously been treated with

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PCT7US2017/055983 another anticancer agent, e.g., another RET inhibitor (e.g., a compound that is not a compound of General Formula 1) or a multi-kinase 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 General Formula I) or a multi-kinase inhibitor.

[00681] Also provided are methods (eg., in vitro methods) of selecting a treatment for a patient identified or diagnosed as having a RET-associated cancer. Some embodiments can further include administering the selected treatment to the patient identified or diagnosed as having a RETassociated cancer. For example, the selected treatment can include administration of a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Some embodiments can further include a step of performing an assay on a sample obtained from the patient to determine whether the patient has a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, and identifying and diagnosing a patient determined to have a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, as having a RET-associated cancer. In some embodiments, the cancer is a RET-associated cancer having one or more RET inhibitor resistance mutations. In some embodiments, the patient has been identified or diagnosed as having a RETassociated cancer through the use of a regulatory agency-approved, e g., FDA-approved, kit for identifying dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, in a patient or a biopsy sample from the patient. In some embodiments, the RETassociated cancers is a cancer described herein or known in the art. In some embodiments, the assay is an in vitro assay. For example, an assay that utilizes the next generation sequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory' agency-approved, e.g., FDA-approved, kit.

[00682] Also provided herein are methods of selecting a treatment for a patient, wherein the methods include a step of performing an assay on a sample obtained from the patient to determine whether the patient has a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same (eg., one or more RET inhibitor resistance mutations), and identifying or diagnosing a patient determined to have a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, as having a RET-associated cancer. Some embodiments further include administering the selected treatment to the patient identified or

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PCT7US2017/055983 diagnosed as having a RET-associated cancer. For example, the selected treatment can include administration of a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof to the patient identified or diagnosed as having a RET-associated cancer. In some embodiments, the assay is an in vitro assay. For example, an assay that utilizes the next generation sequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g, FDA-approved, kit.

[00683] Also provided are methods of selecting a patient for treatment, wherein the methods include selecting, identifying, or diagnosing a patient having a RET-associated cancer, and selecting the patient for treatment including administration of 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-associated cancer can include a step of performing an assay on a sample obtained from the patient to determine whether the patient has a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, and identifying or diagnosing a patient determined to have a dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, as having a RETassociated cancer. In some embodiments, the method of selecting a treatment can be used as a part of a clinical study that includes administration of various treatments of a RET-associated cancer. In some embodiments, a RET-associated cancer is a cancer having one or more RET inhibitor resistance mutations. In some embodiments, the assay is an in vitro assay. For example, an assay that utilizes the next generation sequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e g., FDA-approved, kit. In some embodiments, the dysrégulation of the RET gene, the RET kinase, or expression or activity or level of any of the same includes one or more RET inhibitor resistance mutations.

[00684] In some embodiments of any of the methods or uses described herein, an assay used to determine whether the patient has a dysrégulation of a RET gene, or a RET kinase, or expression or activity or level of any of the same, using a sample from a patient can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one

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PCT7US2017/055983 labelled antibody or antigen-binding fragment thereof. Assays can utilize other detection methods known in the art for detecting dysrégulation of a RET gene, a RET kinase, or expression or activity or levels of any of the same (see, e.g., the references cited herein). In some embodiments, the dysrégulation of the RET gene, the RET kinase, or expression or activity or level of any of the same includes one or more RET inhibitor resistance mutations. In some embodiments, the sample is a biological sample or a biopsy sample (e.g ., a paraffin-embedded biopsy sample) from the patient. In some embodiments, the patient is a patient suspected of having a RET-associated cancer, a patient having one or more symptoms of a RET-associated cancer, and/or a patient that has an increased risk of developing a RET-associated cancer)

[00685] In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies. Compounds of Formula I therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example a chemotherapeutic agent that works by the same or by a different mechanism of action.

[00686] In some embodiments of any the methods described herein, the compound of Formula I (or a pharmaceutically acceptable salt or solvate thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents.

[00687] Non-limiting examples of additional therapeutic agents include: other RETtargeted therapeutic agents (i.e. a first or second RET kinase inhibitor), receptor tyrosine kinasetargeted therapeutic agents, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e g. obataclax); cytotoxic chemotherapeutics, angiogenesistargeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.

[00688] In some embodiments, the other RET-targeted therapeutic is a multikinase inhibitor exhibiting RET inhibition activity. In some embodiments, the other RET-targeted therapeutic inhibitor is selective for a RET kinase. Exemplary RET kinase inhibitors can exhibit inhibition activity (ICso) against a RET kinase of 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

175 about 10 nM, or less than about 1 nM as measured in an assay as described herein. In some embodiments, a RET kinase inhibitors can exhibit inhibition activity (IC50) against a RET kinase of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein.

[00689( Non-limiting examples of RET-targeted therapeutic agents include alectinib, apatinib, cabozantinib (XL-184), dovitinib, lenvatinib, motesanib, nintedanib, ponatinib, regorafenib, sitravatinib (MGCD516), sunitinib, sorafenib, vatalanib, vandetanib, AUY-922 (5(2,4-Dihydroxy-5-isopropyl-phenyl)-N-ethyl-4-[4-(morpholinomethyl)phenyl]isoxazole-3carboxamide), BLU6864, BLU-667, DCC-2157, GSK3179106, NVP-AST487 (1-(4-((4ethylpiperazin-l-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyri midin-4yl]oxyphenyl]urea), PZ-1, RPI-1 (l,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]H-indol-2-one), RXDX-105 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(l,1,1trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), SPP86 (l-Isopropyl-3-(phenylethynyl)-lHpyrazolo[3,4-d]pyrimidin-4-amine), and TG101209 (N-(l,l-dimethylethyl)-3-[[5-methyl-2-[[4(4-methyl-l-piperazinyl)phenyl]amino]-4-pyrimidinyl]amino]-benzenesulfonamide).

[00690[ Additional examples of other RET kinase inhibitors include those described in U. S.

Patent Nos. 9,150,517 and 9,149,464, and International Publication No. WO 2014075035.

For example, in some embodiments the other RET inhibitor is a compound of formula I: Cl

<img file="CA3039760C_D0284.tif" />

wherein Ri is Cô-Cz+alkyl or polyethylene glycol, or a pharmaceutically acceptable salt form thereof. In some embodiments, the other RET inhibitor is 4-{5-[bis-(chloroethyl)-amino]-lmethyl-lH-benzimidazol-2-yl {butyric acid dodecyl ester.

[00691( Additional examples of other RET kinase inhibitors include those described in International Publication No. WO 2016127074. For example, in some embodiments, the other RET inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

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PCT7US2017/055983 (R^B)n (R^A)m wherein Rings A and B are each independently selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;

each L¹ and L² is independently selected from a bond, -(C1-C6 alkylene)-, <C2Côalkenylene)-, -(C2-C6 alkynylene)-, -(C1-C6 haloalkylene)-, -(C1-C6 heteroalkylene)-, -C(O), -0-, -S-, -S(O), -S(O)2-, -NCR¹)-, -O-(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-, -N^j-CCO)-, C(0)N(R*)-, -(C1-C6 alkyleneJ-N/R¹)-, -NiR’XCl-Cô alkylene)-, -N(R¹)-C(O)-(C1-C6 alkylene)-, -(C1-C6 alkylene)-N(R^l)-C(O)-, -^0)-1^)-(0-C6 alkylene)-, -(C1-C6 alkylene)C(O)-N(R’)-, -N(R¹)-S(O)2-, -S(O)2-N(R¹>, -N(R^l)-S(O)2-(Cl-C6 alkylene)-, and-S(O)2-N(R¹)(C1-C6 alkylene)-; wherein each alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene is independently substituted with 0-5 occurrences of R';

each R^a and R^B is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halo, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, and -NfR’XR¹); wherein each alkyl, alkoxy, haloalkyl, hydroxyalkyl, and hydroxyalkyl is independently substituted with 0-5 occurrences of Ra, each R^c and R^D is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, -C(O)R¹, -OC/OjR¹, -C(O)OR*, -(C1-C6 alkylenej-C/OjR¹, -SR¹,-S(O)2R¹, -S(O)2N/R’J/R¹), -(C1-C6 alkylene)-S(O)2R¹, -(C1-C6 alkylene)-S(O)₂-N(R¹)(R¹), -N(R¹)(R¹) -C(O)NiR’XR’j-NiR'j-CiOjR¹, -NiR’j-CiOjOR¹, -(C1-C6 alkylenej-N/R^-C/OjR¹, -N(R¹)S(0)2R^l, and -P/OXR’XR¹), wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R^a; or 2 R^c or 2 R^D together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R^a;

each R¹ is independently selected from hydrogen, hydroxyl, halo, thiol, C1-C6 alkyl, ClC6 thioalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl,

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PCT7US2017/055983 cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R^b, or 2 R¹ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R^b;

each R^a and R^b is independently C1-C6 alkyl, halo, hydroxyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, cycloalkyl, heterocyclyl, or cyano, wherein each of alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, cycloalkyl and heterocyclyl is independently substituted with 0-5 occurrences of R';

each R' is C1-C6 alkyl, C1-C6 heteroalkyl, halo, hydroxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl or cyano, or 2 R’, together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;

mis0, 1,2, or3;

n is 0,1, or 2; and p and q are each independently 0,1,2,3, or 4. For example, a RET inhibitor can be selected from the group consisting of:

<img file="CA3039760C_D0285.tif" />

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<img file="CA3039760C_D0286.tif" />

<img file="CA3039760C_D0287.tif" />

<img file="CA3039760C_D0288.tif" />

Ο

<img file="CA3039760C_D0289.tif" />

<img file="CA3039760C_D0290.tif" />

<img file="CA3039760C_D0291.tif" />

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<img file="CA3039760C_D0292.tif" />

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<img file="CA3039760C_D0293.tif" />

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<img file="CA3039760C_D0294.tif" />

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<img file="CA3039760C_D0295.tif" />

thereof.

[00692] In some embodiments, a RET inhibitor is selected from the group consisting of: ABT

348 (N-[4-[4-Amino-7-[l-(2-hydroxyethyl)-lH-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl]phenyl]N'-(3-fluorophenyl)urea); AD-57, which has the structure:

<img file="CA3039760C_D0296.tif" />

AD-80 ( 1 -(4-(4-amino-1 -isopropyl-1 H-pyrazolo[3,4-d]pyrimidin3-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea); ALW-II-41-27 (N-(5-((4-((4

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PCT7US2017/055983 ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-(thiophen2-yl)ni cotinamide); Amuvatinib (MP470) (N-(benzo[d][l,3]dioxol-5-ylmethyl)-4-(benzofuro[3,2d]pyrimidin-4-yl)piperazine-l-carbothioamide); BPR1J373 (a derivative of 5-phenylthhiazol-2ylamine-pyriminide); CLM3; doramapimod (BIRB-796) (l-(3-(tert-butyl)-l-(p-tolyl)-lHpyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen-l-yl)urea); DS-5010; famitinib (5-[2(diethylamino)ethyl]-2-[(Z)-(5-fluoro-2-oxo-lH-indol-3-ylidene)methyl]-3-methyl-6,7-dihydrolH-pyrrolo[3,2-c]pyridin-4-one); fedratinib (SAR 302503, TG101348) (N-(tert-butyl)-3-((5methyl-2-((4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)amino)pyrimidin-4yl)amino)benzenesulfonamide); GSK3179106; GSK3352589; HG-6-63-01 ((E)-3-(2-(4-chlorolH-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-N-(4-((4-ethylpiperazin-l-yl)methyl)-3(trifluoromethyl)phenyl)-4-methylbenzamide); NVP-BBT594 (5-((6-acetamidopyrimidin-4yl)oxy)-N-(4-((4-methylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)indoline-lcarboxamide); PP2 (4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine), PP242 (2-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)-lH-indol-5-ol); quizartinib (AC220) (l-(5-(tert-butyl)isoxazol-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1b]thiazol-2-yl)phenyl)urea); semaxanib (SU5416, VEGFR2 Kinase Inhibitor ΠΙ) ((Z)-3-((3,5dimethyl-lH-pyrrol-2-yl)methylene)indolin-2-one); SU4984 (3-[4-(l-formylpiperazin-4yl)benzylidenyl]-2-indolinone); Withaferin A ((4p,5p,6p,22R)-4,27-Dihydroxy-5,6:22,26diepoxyergosta-2,24-diene-1,26-dione); XL-999 ((Z)-5-(( 1 -ethylpiperidin-4-yl)amino)-3-((3fluorophenyl)(5-methyl-1 H-imidazol-2-yl)methylene)indolin-2-one); XMD15-44 (N-(4-((4ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyri din-3ylethynyl)benzamide); Y078-DM1 (antibody drug conjugate composed of a RET antibody (Y078) linked to a derivative of the cytotoxic agent maytansine); and Y078-DM1 (antibody drug conjugate composed of a RET antibody (Y078) linked to a derivative of the cytotoxic agent maytansine).

[00693J Further examples of RET inhibitors include: N-(2-fluoro-5-trifluoromethylphenyl)-N'{4'-[(2-benzamido)pyridin-4-ylamino]phenyl}urea; l-isopropyl-3-(phenylethynyl)-lHpyrazolo[3,4-d]pyrimidin-4-amine; 3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-fluoro-2methylphenol; N-(5-(tert-butyl)isoxazol-3-yl)-2-(4-(imidazo[l,2-a]pyridin-6yl)phenyl)acetamide; N-(5-(tert-butyl)isoxazol-3-yl)-2-(3-(imidazo[l,2-b]pyridazin-6yloxy)phenyl)acetamide; 2-amino-6-{ [2-(4-chlorophenyl)-2-oxoethyl]sulfanyl} -4-(3 thienyl)pyridine-3,5-dicarbonitrile; and 3-arylureidobenzylidene-indolin-2-ones.

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[00694( Yet other therapeutic agents include RET inhibitors such as those described, for example, in U.S. Patent Nos. 7,504,509; 8,299,057; 8,399,442; 8,067,434; 8,937,071; 9,006,256; and 9,035,063; U.S. Publication Nos. 2014/0121239; 20160176865; 2011/0053934; 2011/0301157; 2010/0324065; 2009/0227556; 2009/0130229; 2009/0099167; 2005/0209195; International Publication Nos. WO 2016/037578; WO 2016/038519; WO 2016/038552; WO 2014/184069; WO 2014/072220, WO 2012/053606; WO 2009/017838; WO 2008/031551; WO 2007/136103; WO 2007/087245; WO 2007/057399; WO 2005/051366; WO 2005/062795; and WO 2005/044835; and J. Med.Chem. 2012, 55 (10), 4872-4876.

[00695( Non-limiting examples of receptor tyrosine kinase (e g., Trk) targeted therapeutic agents, include afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab, sunitinib, trastuzumab, l-((3S,4R)-4-(3-fluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4methyl-3-(2- methylpyrimidin-5-yl)-l -phenyl- lH-pyrazol-5-yl)urea, AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, Go 6976, GNF-5837, GTx-186, GW 441756, LOXO101, MGCD516, PLX7486, RXDX101, TPX-0005, and TSR-011. Additional Trk targeted therapeutic agents include those described in U.S. Patent No. 8,450,322; 8,513,263; 8,933,084; 8,791,123; 8,946,226; 8,450,322; 8,299,057; and 8,912,194; U.S. Publication No. 2016/0137654; 2015/0166564; 2015/0051222; 2015/0283132; and 2015/0306086; International Publication No. WO 2010/033941; WO 2010/048314; WO 2016/077841; WO 2011/146336; WO 2011/006074; WO 2010/033941; WO 2012/158413; WO 2014078454; WO 2014078417; WO 2014078408; WO 2014078378; WO 2014078372; WO 2014078331; WO 2014078328; WO 2014078325; WO 2014078323; WO 2014078322; WO 2015175788; WO 2009/013126; WO 2013/174876; WO 2015/124697; WO 2010/058006, WO 2015/017533; WO 2015/112806; WO 2013/183578; and WO 2013/074518.

(00696( Further examples of Trk inhibitors can be found in U.S. Patent No. 8,637,516, International Publication No. WO 2012/034091, U.S. Patent No. 9,102,671, International Publication No. WO 2012/116217, U.S. Publication No. 2010/0297115, International Publication No. WO 2009/053442, U.S. Patent No. 8,642,035, International Publication No. WO 2009092049, U.S. Patent No. 8,691,221, International Publication No. WO2006131952

Exemplary Trk inhibitors include GNF-4256,

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[00697( Additional examples of Trk inhibitors include those disclosed in U.S. Publication No. 2010/0152219, U.S. Patent No. 8,114,989, and International Publication No. WO 2006/123113. Exemplary Trie inhibitors include AZ623, described in Cancer 117(6):1321-1391,2011; AZD6918, described in Cancer Biol. Ther. 16(3):477-483, 2015; AZ64, described in Cancer Chemother. Pharmacol. 70:477-486, 2012; AZ-23 ((S)-5-Chloro-N2-(l-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxylH-pyrazol-3-yl)pyrimidine-2,4-diamine), described in Mol. Cancer Ther. 8:1818-1827, 2009; and AZD7451.

[00698( A Trk inhibitor can include those described in U.S. Patent Nos. 7,615,383; 7,384,632; 6,153,189; 6,027,927; 6,025,166; 5,910,574; 5,877,016; and 5,844,092.

(00699( Further examples of Trk inhibitors include CEP-751, described in Int. J. Cancer 72:672-679, 1997; CT327, described in Acta Derm. Venereal. 95:542-548, 2015; compounds described in International Publication No. WO 2012/034095; compounds described in U.S. Patent No. 8,673,347 and International Publication No. WO 2007/022999; compounds described in U.S. Patent No. 8,338,417; compounds described in International Publication No. WO 2016/027754; compounds described in U.S. Patent No. 9,242,977; compounds described in U.S. Publication No. 2016/0000783; sunitinib (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-lH-indol-3ylidene)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide), as described in PLoS One 9:e95628, 2014; compounds described in International Publication No. WO 2011/133637; compounds described in U.S. Patent No. 8,637,256; compounds described in Expert. Opin. Ther. Pat. 24(7):731-744, 2014; compounds described in Expert Opin. Ther. Pat. 19(3):305-319,2009; (R)2-phenylpyrrolidine substituted imidazopyridazines, e.g., GNF-8625, (R)-l-(6-(6-(2-(3fluorophenyl)pyrrolidin-l-yl)imidazo[l,2-b]pyridazin-3-yl)-[2,4'-bipyridin]-2'-yl)piperidin-4-ol as described in ACS Med. Chem. Lett. 6(5):562-567,2015; GTx-186 and others, as described in PLoSOne 8(12):e83380,2013, K252a((9S-(9a,10p,12a))-2,3,9,10,ll,12-hexahydro-10-hydroxy10-(methoxycarbonyl)-9-methyl-9,12-epoxy-lH-diindolo[l,2,3-fg:3',2',r-kl]pyrrolo[3,4

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i][l,6]benzodiazocin-l-one), as described in Mol. Cell Biochem. 339(1-2):201-213, 2010; 4aminopyrazolylpyrimidines, eg., AZ-23 (((S)-5-chloro-N2-(l-(5-fluoropyridin-2-yl)ethyl)-N4(5-isopropoxy-lH-pyrazol-3-yl)pyrimidine-2,4-diamine)), as described in J. Med. Chem. 51(15):4672-4684, 2008; PHA-739358 (danusertib), as described in Mol. Cancer Ther. 6:3158, 2007; Go 6976 (5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole12-propanenitrile), as described in J. Neurochem. 72:919-924, 1999; GW441756 ((3Z)-3-[(lmethylindol-3-yl)methylidene]-lH-pyrrolo[3,2-b]pyridin-2-one), as described in IJAE 115:117, 2010; milciclib (PHA-848125AC), described in J. Carcinog. 12:22, 2013; AG-879 ((2E)-3-[3,5Bis(l, l-dimethylethyl)-4-hydroxyphenyl]-2-cyano-2-propenethioamide); altiratinib (N-(4-((2(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4fluorophenyl)cyclopropane-l, 1 -dicarboxamide); cabozantinib (N-(4-((6,7-Dimethoxyquinolin-4yl)oxy )phenyl )-N’-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide); lestaurtinib ((5 S,6S,8R)-6Hydroxy-6-(hydroxymethyl)-5-methyl-7,8,14,15-tetrahydro-5H-16-oxa-4b,8a,14-triaza-5,8methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacen-l 3(6H)-one); dovatinib (4-amino-5fluoro-3-[6-(4-methylpiperazin-1 -yl)- lH-benzimidazol-2-yl]quinolin-2( lH)-one mono 2hydroxypropanoate hydrate); sitravatinib (N-(3-fluoro-4-((2-(5-(((2methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4fluorophenyl)cyclopropane-l,l-dicaiboxamide); ONO-5390556; regorafenib (4-[4-({[4-Chloro3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2carboxamide hydrate); and VSR-902A.

[00700( The ability of a Trk inhibitor to act as a TrkA, TrkB, and/or Trk C inhibitor may be tested using the assays described in Examples A and B in U.S. Patent No. 8,513,263.

[00701( In some embodiments, signal transduction pathway inhibitors include Ras-RafMEK-ERK pathway inhibitors (e g., binimetinib, selumetinib, encorafinib, sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (e g. everolimus, rapamycin, perifosine, temsirolimus), and other kinase inhibitors, such as baricitinib, brigatinib, capmatinib, danusertib, ibrutinib, milciclib, quercetin, regorafenib, ruxolitinib, semaxanib, AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF 477736 ((R)-amino-N-[5,6-dihydro-2-(l-methyl-lH

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PCT7US2017/055983 pyrazol-4-yl)-6-oxo-lHpyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-cyclohexaneacetamide), PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103, RXDX106, RXDX108, and TG101209 (N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazin-lyl)phenylamino)pyrimidin-4- ylamino)benzenesulfonamide).

[00702] Non-limiting examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pidilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, and pembrolizumab.

[00703] In some embodiments, cytotoxic chemotherapeutics are selected from arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.

[00704] Non-limiting examples of angiogenesis-targeted therapies include aflibercept and bevacizumab.

[00705] The term “immunotherapy” refers to an agent that modulates the immune system. In some embodiments, an immunotherapy can increase the expression and/or activity of a regulator of the immune system. In some embodiments, an immunotherapy can decrease the expression and/or activity of a regulator of the immune system. In some embodiments, an immunotherapy can recruit and/or enhance the activity of an immune cell.

[00706] In some embodiments, the immunotherapy is a cellular immunotherapy (e.g., adoptive T-cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge™; Plosker (2011) Drugs 71(1): 101108). In some embodiments, the cellular immunotherapy includes cells that express a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is a CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is tisagenlecleucel (Kymriah™).

[00707] In some embodiments, the immunotherapy is an antibody therapy (e.g., a monoclonal antibody, a conjugated antibody). In some embodiments, the antibody therapy is bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (MabThera™, Rituxan®), edrecolomab (Panorex), daratumuab (Darzalex®), olaratumab (Lartruvo™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®), obinutuzumab

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PCT7US2017/055983 (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti™)> avelumab (Bavencio®), necitumumab (Portrazza™), cirmtuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab, urelumab, pidilizumab or amatuximab.

[00708] In some embodiments, the immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg™), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (TDM1; Kadcyla®), mirvetuximab soravtansine (IMGN853) or anetumab ravtansine

[00709] In some embodiments, the immunotherapy includes blinatumomab (AMG103; Blincyto®) or midostaurin (Rydapt).

[00710] In some embodiments, the immunotherapy includes a toxin. In some embodiments, the immunotherapy is denileukin diftitox (Ontak®).

[00711]

[00712] In some embodiments, the immunotherapy is a cytokine therapy. In some embodiments, the cytokine therapy is an interleukin 2 (IL-2) therapy, an interferon alpha (IFNa) therapy, a granulocyte colony stimulating factor (G-CSF) therapy, an interleukin 12 (IL-12) therapy, an interleukin 15 (IL-15) therapy, an interleukin 7 (IL-7) therapy or an erythropoietinalpha (EPO) therapy. In some embodiments, the IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, the IFNa therapy is IntronA® (Roferon-A®). In some embodiments, the GCSF therapy is filgrastim (Neupogen®).

[00713] In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, the immunotherapy includes one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor or a PDL1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®) or durvalumab (Imfinzi™).

[00714] In some embodiments, the immunotherapy is mRNA-based immunotherapy. In some embodiments, the mRNA-based immunotherapy is CV9104 (see, e.g., Rausch et al. (2014) Human

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Vaccin Immunother 10(11): 3146-52; and Kubler et al. (2015) J. Immunother Cancer 3:26).

[00715] In some embodiments, the immunotherapy is bacillus Calmette-Guerin (BCG) therapy. [00716] In some embodiments, the immunotherapy is an oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is talimogene alherparepvec (T-VEC; Imlygic®).

[00717] In some embodiments, the immunotherapy is a cancer vaccine. In some embodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine. In some embodiments, the HPV vaccine is Gardasil®, Gardasil9® or Cervarix®. In some embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In some embodiments, the HBV vaccine is Engerix-B®, Recombivax HB® or GI-13020 (Tarmogen®). In some embodiments, the cancer vaccine is Twinrix® or Pediarix®. In some embodiments, the cancer vaccine is BiovaxID®, Oncophage®, GV AX, ADXS11-001, ALV AC-CEA, PROSTVAC®, Rindopepimut®, CimaVax-EGF, lapuleucel-T (APC8024; Neuvenge™), GRNVAC1, GRNVAC2, GRN-1201, hepcortespenlisimut-L (Hepko-V5), DCVAX®, SCIB1, BMT CTN 1401, PrCa VBIR, PANVAC, ProstAtak®, DPX-Survivac, or viagenpumatucel-L (HS-110).

[00718] In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is nelipepimut-S (E75) (NeuVax™), IMA901, or SurVaxM (SVN53-67). In some embodiments, the cancer vaccine is an immunogenic personal neoantigen vaccine (see, e.g., Ott et al. (2017) Nature 547: 217-221; Sahin et al. (2017) Nature 547: 222-226). In some embodiments, the cancer vaccine is RGSH4K, or NEO-PV-01. In some embodiments, the cancer vaccine is a DNA-based vaccine. In some embodiments, the DNA-based vaccine is a mammaglobin-A DNA vaccine (see, e.g., Kim et al. (2016) Oncolmmunology 5(2): el069940).

[00719] In some embodiments, immune-targeted agents are selected from aldesleukin, interferon alfa-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, and sipuleucel-T.

[00720] Non-limiting examples of radiotherapy include radioiodide therapy, external-beam radiation, and radium 223 therapy.

[00721] Additional kinase inhibitors include those described in, for example, U.S. Patent No. 7,514,446; 7,863,289; 8,026,247; 8,501,756; 8,552,002; 8,815,901; 8,912,204; 9,260,437; 9,273,051; U.S Publication No. US 2015/0018336; International Publication No. WO 2007/002325; WO 2007/002433; WO 2008/080001; WO 2008/079906; WO 2008/079903; WO 2008/079909, WO 2008/080015; WO 2009/007748; WO 2009/012283; WO 2009/143018; WO 2009/143024; WO WO 2009/014637; 2009/152083; WO 2010/111527, WO 2012/109075; WO

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2014/194127; WO 2015/112806; WO 2007/110344; WO 2009/071480; WO 2009/118411;WO

2010/031816; WO 2010/145998; WO 2011/092120; WO 2012/101032; WO 2012/139930;WO

2012/143248; WO 2012/152763; WO 2013/014039; WO 2013/102059; WO 2013/050448;WO

2013/050446; WO 2014/019908; WO 2014/072220; WO 2014/184069; and WO 2016/075224.

[00722| Further examples of kinase inhibitors include those described in, for example, WO 2016/081450; WO 2016/022569; WO 2016/011141; WO 2016/011144; WO 2016/011147; WO 2015/191667; WO 2012/101029; WO 2012/113774; WO 2015/191666; WO 2015/161277; WO 2015/161274; WO 2015/108992; WO 2015/061572; WO 2015/058129; WO 2015/057873; WO 2015/017528; WO/2015/017533; WO 2014/160521; and WO 2014/011900.

[00723( Accordingly, also provided herein is a method of treating cancer, comprising administering to a patient in need thereof a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are together effective in treating the cancer.

[00724[ In some embodiments, the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysrégulation of a RET gene, a RET protein, or expression or activity, or level of any of the same.

[00725( These additional therapeutic agents may be administered with one or more doses of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and/or on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.

[00726( Also provided herein is (i) a pharmaceutical combination for treating a cancer in a patient in need thereof, which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally

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PCT7US2017/055983 at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula I or pharmaceutically acceptable salt or solvate thereof and of the additional therapeutic agent are together effective in treating the cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer in a patient in need thereof. In one embodiment the patient is a human. In some embodiments, the cancer is a RET-associated cancer. For example, a RET-associated cancer having one or more RET inhibitor resistance mutations.

[00727] The term pharmaceutical combination, as used herein, refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term fixed combination means that a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent (e g., a chemotherapeutic agent), are both administered to a patient simultaneously in the form of a single composition or dosage. The term non-fixed combination means that a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent (e.g., chemotherapeutic agent) are formulated as separate compositions or dosages such that they may be administered to a patient in need thereof simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient. These also apply to cocktail therapies, e g. the administration of three or more active ingredients [00728] Accordingly, also provided herein is a method of treating a cancer, comprising administering to a patient in need thereof a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula I or pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are together effective in treating the cancer. In one embodiment, the compound of Formula I or pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In one embodiment, the

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PCT7US2017/055983 compound of Formula I or pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e.g. in daily or intermittently dosages. In one embodiment, the compound of Formula I or pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the cancer is a RET-associated cancer. For example, a RET-associated cancer having one or more RET inhibitor resistance mutations.

[00729] Also provided herein is a method of treating a disease or disorder mediated by RET 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. In some embodiments, the disease or disorder mediated by RET is a dysrégulation of RET gene, a RET kinase, or expression or activity or level of any of the same. For example the dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same includes one or more RET inhibitor resistance mutations. A disease or disorder mediated by RET can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of RET, including overexpression and/or abnormal activity levels. In one embodiment, the disease is cancer (e g., a RET-associated cancer). In one embodiment, the cancer is any of the cancers or RET-associated cancers described herein.

[00730] Although the genetic basis of tumorigenesis may vary between different cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar for all solid tumor types. During a metastatic cascade, the cancer cells lose growth inhibitory responses, undergo alterations in adhesiveness and produce enzymes that can degrade extracellular matrix components. This leads to detachment of tumor cells from the original tumor, infiltration into the circulation through newly formed vasculature, migration and extravasation of the tumor cells at favorable distant sites where they may form colonies. A number of genes have been identified as being promoters or suppressors of metastasis For example, overexpression of glial cell-derived neurotrophic factor (GDNF) and its RET receptor tyrosine kinase have been correlated with cancer proliferation and metastasis. See, e.g., Zeng, Q. et al. J. Int. Med. Res. (2008) 36(4): 656-64.

[00731] Accordingly, also provided herein are methods for inhibiting, preventing, aiding in the prevention, or decreasing the symptoms of metastasis of a cancer in a patient in need thereof,

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PCT7US2017/055983 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. Such methods can be used in the treatment of one or more of the cancers described herein. See, e.g., US Publication No. 2013/0029925; International Publication No. WO 2014/083567; and US Patent No. 8,568,998. In some embodiments, the cancer is a RET-associated cancer. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is used in combination with an additional therapy or another therapeutic agent, including a chemotherapeutic agent, such as a kinase inhibitor. For example, a first or second RET kinase inhibitor.

[00732] The term “metastasis” is an art known term and means the formation of an additional tumor (e.g., a solid tumor) at a site distant from a primary tumor in a subject or patient, where the additional tumor includes the same or similar cancer cells as the primary tumor.

[00733] Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a patient having a RET-associated cancer that include: selecting, identifying, or diagnosing a patient as having a RET-associated cancer, and administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to the patient selected, identified, or diagnosed as having a RET-associated cancer. Also provided are methods of decreasing the risk of developing a metastasis or an additional metastasis in a patient having a RET-associated cancer that includes administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvent thereof to a patient having a RET-associated cancer. The decrease in the risk of developing a metastasis or an additional metastasis in a patient having a RET-associated cancer can be compared to the risk of developing a metastasis or an additional metastasis in the patient prior to treatment, or as compared to a patient or a population of patients having a similar or the same RET-associated cancer that has received no treatment or a different treatment. In some embodiments, the RET-associated cancer is a RET-associated cancer having one or more RET inhibitor resistance mutations.

[00734] The phrase “risk of developing a metastasis” means the risk that a subject or patient having a primaiy tumor will develop an additional tumor (e g., a solid tumor) at a site distant from a primary tumor in a subject or patient over a set period of time, where the additional tumor includes the same or similar cancer cells as the primary tumor. Methods for reducing the risk of

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PCT7US2017/055983 developing a metastasis in a subject or patient having a cancer are described herein.

[00735] The phrase “risk of developing additional metastases” means the risk that a subject or patient having a primary tumor and one or more additional tumors at sites distant from the primary tumor (where the one or more additional tumors include the same or similar cancer cells as the primary tumor) will develop one or more further tumors distant from the primary tumor, where the further tumors include the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastasis are described herein.

[00736] As used herein, a “first RET kinase inhibitor” or “first RET inhibitor” is a RET kinase inhibitor as defined herein, but which does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as defined herein. As used herein, a “second RET kinase inhibitor” or a “second RET inhibitor” is a RET kinase inhibitor as defined herein, but which does not include a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof as defined herein. When both a first and a second RET inhibitor are present in a method provided herein, the first and second RET kinase inhibitor are different.

[00737] In some embodiments, the presence of one or more RET inhibitor resistance mutations in a tumor causes the tumor to be more resistant to treatment with a first RET inhibitor. Methods useful when a RET inhibitor resistance mutation causes the tumor to be more resistant to treatment with a first RET inhibitor are described below. For example, provided herein are methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and administering to the identified subject a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. Also provided are methods of treating a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations that include administering to the subject a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. Tn some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance

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PCT7US2017/055983 mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. [00738J For example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation, and (d) administering a compound of Formula I, or a pharmaceutically acceptable salt of solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation, or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a compound of Formula 1 selected from i) Example No. 1-20; ii) Example No. 2140; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480, xxiv) Example No. 481-500, xxv) Example No. 501-520; xxvi)

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Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt of solvate thereof as a monotherapy or in conjunction with another anti cancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Table 2 in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360, xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt of solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first RET inhibitor, wherein the first RET inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib,

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PCT7US2017/055983 sunitinib, foretinib, BLU667, and BLU6864. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof selected from the group consisting of a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No 61-80; v) Example No. 81-100; vi) Example No 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240, xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380, xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460, xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt of solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the first RET inhibitor of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.

[00739] As another example, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt of solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided

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PCT7US2017/055983 herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440, xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500, xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt of solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864, as a monotherapy or in conjunction with another anti cancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Table 2 in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320, xvii) Example No. 321-340, xviii) Example No. 341-360,

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PCT7US2017/055983 xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt of solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x)ExampleNo. 181-200; xi) Example No. 201220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420, xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt of solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering a second RET inhibitor, wherein the second RET inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor

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PCT7US2017/055983 resistance mutation; or (e) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation.

[00740] Also, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a dysrégulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation, and (d) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject as a monotherapy or in conjunction with another anticancer agent (e g., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt thereof, or immunotherapy) or anticancer therapy (e.g., surgery or radiation) if the subject has a cancer cell that has at least one RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a dysrégulation of a RET gene, a RET kinase, or the expression or activity’ or level of any of the same in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I selected from i) Example No. 1-20, ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100, vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161 -180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221 -240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt of solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (d) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject as a monotherapy

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PCT7US2017/055983 or in conjunction with another anticancer agent (e.g., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt thereof, or immunotherapy) or anticancer therapy (e.g., surgery or radiation) if the subject has a cancer cell that has at least one RET inhibitor resistance mutation. In some embodiments, provided herein are methods for treating a RETassociated cancer in a subject in need of such treatment, the method comprising (a) detecting one or more fusion proteins of Table 1 and/or one or more RET kinase protein point mutations/insertions/deletions of Table 2 in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof selected from the group consisting of a compound ofFormula I selected from i) Example No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201220; xii) Example No. 221-240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420, xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt of solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation of Tables 3 or 4; and (d) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject as a monotherapy or in conjunction with another anticancer agent (e g., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt thereof, or immunotherapy) or anticancer therapy (e.g., surgery or radiation) if the subject has a cancer cell that has at least one RET inhibitor resistance mutation. In some embodiments, a second RET inhibitor selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864 is administered in step (d). In some embodiments, provided herein are methods for treating a RET-associated cancer in a subject in need of such treatment, the method comprising (a) detecting the fusion protein KIF5B-RET in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a compound ofFormula I selected from i) Example

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No. 1-20; ii) Example No. 21-40; iii) Example No. 41-60; iv) Example No. 61-80; v) Example No. 81-100; vi) Example No. 101-120; vii) Example No. 121-140; viii) Example No. 141-160; ix) Example No. 161-180; x) Example No. 181-200; xi) Example No. 201-220; xii) Example No. 221240; xiii) Example No. 241-260; xiv) Example No. 261-280; xv) Example No. 281-300; xvi) Example No. 301-320; xvii) Example No. 321-340; xviii) Example No. 341-360; xix) Example No. 361-380; xx) Example No. 381-400; xxi) Example No. 401-420; xxii) Example No. 421-440; xxiii) Example No. 441-460; xxiii) Example No. 461-480; xxiv) Example No. 481-500; xxv) Example No. 501-520; xxvi) Example No. 521-540; or xxvii) Example No. 541-561, or a pharmaceutically acceptable salt of solvate thereof. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has the RET inhibitor resistance mutation V804M; and (d) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (b) to the subject as a monotherapy or in conjunction with another anticancer agent (e g., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt thereof, or immunotherapy) or anticancer therapy (e g., surgery or radiation) if the subject has a cancer cell that has at least one RET inhibitor resistance mutation. In some embodiments, a second RET inhibitor selected from the group consisting of cabozantinib, vandetanib, alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, foretinib, BLU667, and BLU6864 is administered in step (d).

[00741J Also provided are methods of selecting a treatment for a subject having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and selecting a treatment that includes administration of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a first RET inhibitor. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with the first RET inhibitor. Also provided are methods of selecting a treatment for a subject having a cancer that include: selecting a treatment that includes administration of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations. Also provided are methods of selecting a subject having a cancer for a treatment that does not include a first RET inhibitor as a monotherapy that include:

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PCT7US2017/055983 identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and selecting the identified subject for a treatment that includes a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods of selecting a subject having a cancer for a treatment that does not include a first RET inhibitor as a monotherapy that include: selecting a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations for a treatment that includes administration of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. In some embodiments, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. [00742] Also provided are methods of determining the likelihood that a subject having a cancer (e.g., a RET-associated cancer) will have a positive response to treatment with a first RET inhibitor as a monotherapy that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that a subject having a cancer cell that has one or more RET inhibitor resistance mutations has a decreased likelihood of having a positive response (i.e. an increased likelihood of having a negative response) to treatment with a first RET inhibitor as a monotherapy. Also provided are methods of determining the likelihood that a subject having a cancer (e g., a RET-associated cancer) will have a positive response to treatment with a first RET inhibitor as a monotherapy that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that a subject not having a cancer cell that has one or more RET inhibitor resistance mutations has an increased likelihood of having a positive response to treatment with a first RET inhibitor as a monotherapy as compared to a subject having a cancer cell that has one or more RET inhibitor resistance mutations. Also provided are methods of predicting the efficacy of treatment with a first RET inhibitor as a monotherapy in a subject having cancer that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that treatment w'ith a first RET inhibitor as a monotherapy is less likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has one or more RET inhibitor resistance mutations. Also provided are methods of predicting the efficacy of treatment with a first RET inhibitor as a monotherapy in a subject having cancer that include: determining that treatment with a first RET inhibitor as a

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PCT7US2017/055983 monotherapy is less likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has one or more RET inhibitor resistance mutations. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.

[00743] Also provided are methods of treating a subject having a cancer that include: (a) administering one or more doses of a first RET inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (c) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (d) administering additional doses of the first RET inhibitor of step (a) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the first RET inhibitor of step (a), the subject can also be administered another anticancer agent (e g., a second RET inhibitor or a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments of step (c), another RET inhibitor can be the first RET inhibitor administered in step (a). In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e g., V804M, V804L, or V804E.

[00744] Also provided are methods of treating a subject having a cancer that include: (a) administering one or more doses of a first RET inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one

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RET inhibitor resistance mutation; and (c) administering a second RET inhibitor as a monotherapy or in conjunction with another anti cancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (d) administering additional doses of the first RET inhibitor step (a) to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the first RET inhibitor of step (a), the subject can also be administered another anti cancer agent. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the additional anticancer agent is an immunotherapy.

[00745] Also provided are methods of treating a subject having a cancer (eg., a RET-associated cancer) that include: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor, has one or more RET inhibitor resistance mutations; and (b) administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (c) administering additional doses of the first RET inhibitor previously administered to the subject if the subject has cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the first RET inhibitor previously administered to the subject, the subject can also be administered another anticancer agent (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or immunotherapy). In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino

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PCT7US2017/055983 acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments of step (b), another anticancer agent can be the first RET inhibitor administered in step (a).

[00746] Also provided are methods of treating a subject having a cancer that include: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more RET inhibitor resistance mutations; and (b) administering a second RET inhibitor as a monotherapy or in conjunction with another anti cancer agent to the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (c) administering additional doses of the first RET inhibitor previously administered to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the first RET inhibitor previously administered to the subject, the subject can also be administered another anticancer agent. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments of (b), another anticancer agent can be the first RET inhibitor administered in step (a).

[00747] Also provided are methods of selecting a treatment for a subject having a cancer that include (a) administering one or more doses of a first RET inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (c) selecting a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent for the subject if the subject has a cancer cell that has one or more RET

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PCT7US2017/055983 inhibitor resistance mutations; or (d) selecting additional doses of the first RET inhibitor of step (a) for the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, when additional doses of the first RET inhibitor of step (a) are selected for the subject, the method can further include selecting doses of another anti cancer agent for the subject. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments of step (c), another RET inhibitor can be the first RET inhibitor administered in step (a).

(00748] Also provided are methods of selecting a treatment for a subject having a cancer that include (a) administering one or more doses of a first RET inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one RET inhibitor resistance mutation; and (c) selecting a second RET inhibitor as a monotherapy or in conjunction with another anti cancer agent if the subject has a cancer cell that has one or more RET inhibitor resistance mutations; or (d) selecting additional doses of the first RET inhibitor of step (a) for the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, when additional doses of the first RET inhibitor of step (a) are selected for the subject, the method can further include selecting doses of another anticancer agent for the subject. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof).

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In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments, another RET can be the first RET inhibitor administered in step (a).

[00749] Also provided are methods of selecting a treatment for a subject having a cancer that include (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more RET inhibitor resistance mutations; (b) selecting a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent for the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (c) selecting additional doses of the first RET inhibitor previously administered to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, when additional doses of the first RET inhibitor previously administered to the subject are selected for the subject, the method can further include selecting doses of another anticancer agent (e g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereo0 for the subject. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments of step (c), another RET inhibitor can be the first RET inhibitor administered in step (a).

[00750] Also provided are methods of selecting a treatment for a subject having a cancer that include (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first RET inhibitor has one or more RET inhibitor resistance mutations; (b) selecting a second RET inhibitor as a monotherapy or in conjunction with another anticancer agent for the subject if the subject has a cancer cell that has at least one RET inhibitor resistance mutation; or (c) selecting additional doses of the first RET inhibitor previously administered to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, when additional doses of the first

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RET inhibitor previously administered to the subject are selected for the subject, the method can further include selecting doses of another anticancer agent (e.g., a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof, or an immunotherapy) for the subject. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments, another RET can be the first RET inhibitor administered in step (a).

[00751] Also provided are methods of determining a subject's risk for developing a cancer that has some resistance to a first RET inhibitor that include: determining whether a cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and identifying a subject having a cell that has one or more RET inhibitor resistance mutations, as having an increased likelihood of developing a cancer that has some resistance to the first RET inhibitor. Also provided are methods of determining a subject's risk for developing a cancer that has some resistance to a first RET inhibitor that include: identifying a subject having a cell that has one or more RET inhibitor resistance mutations, as having an increased likelihood of developing a cancer that has some resistance to the first RET inhibitor. Also provided are methods of determining the presence of a cancer that has some resistance to a first RET inhibitor that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that the subject having a cancer cell that has one or more RET inhibitor resistance mutations has a cancerthat has some resistance to the first RET inhibitor. Also provided are methods of determining the presence of a cancer that has some resistance to a first RET inhibitor in a subject that include: determining that a subject having a cancer cell that has one or more RET inhibitor resistance mutations, has a cancer that has some resistance to the first RET inhibitor. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first RET inhibitor. In

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PCT7US2017/055983 some embodiments, the one or more RET inhibitor resistance mutations include one or more RET inhibitor resistance mutations listed in Tables 3 and 4. For example, the one or more RET inhibitor resistance mutations can include a substitution at amino acid position 804, e.g., V804M, V804L, or V804E.

[00752] In some embodiments of any of the methods described herein, a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with a first RET inhibitor can be any of the RET inhibitor resistance mutations listed in Table 3 or 4 (e.g., a substitution at amino acid position 804, e g., V804M, V804L, or V804E).

[00753] In some embodiments, the presence of one or more RET inhibitor resistance mutations in a tumor causes the tumor to be more resistant to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Methods useful when a RET inhibitor resistance mutation causes the tumor to be more resistant to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof are described below. For example, provided herein are methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and administering to the identified subject a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e g., a second RET kinase inhibitor). Also provided are methods of treating a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations that include administering to the subject a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e g., a second RET kinase inhibitor). In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.

[00754] Also provided are methods of selecting a treatment for a subject having a cancer that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and selecting a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy for the identified subject (e g., a second RET kinase inhibitor). Also provided are methods of selecting a treatment for a subject having a cancer that include: selecting a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e.g., a second

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RET kinase inhibitor) for a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations. Also provided are methods of selecting a subject having a cancer for a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e.g., a second RET kinase inhibitor) that include: identifying a subject having a cancer cell that has one or more RET inhibitor resistance mutations; and selecting the identified subject for a treatment that does not include a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (eg., a second RET kinase inhibitor). Also provided are methods of selecting a subject having a cancer for a treatment that does not include a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy (e.g., a second RET kinase inhibitor) that include: selecting a subject identified as having a cancer cell that has one or more RET inhibitor resistance mutations for a treatment that does not include a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.

[00755] Also provided are methods of determining the likelihood that a subject having a cancer will have a positive response to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that the subject having the cancer cell that has one or more RET inhibitor resistance mutations has a decreased likelihood of having a positive response to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy. Also provided are methods of determining the likelihood that a subject having cancer will have a positive response to treatment with a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof as a monotherapy that include: determining that a subject having a cancer cell that has one or more RET inhibitor resistance mutations has a decreased likelihood of having a positive response to treatment with a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy. Also provided are methods of predicting the efficacy of treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy in a subject having cancer that include: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and

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PCT7US2017/055983 determining that treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy is less likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has one or more RET inhibitor resistance mutations. Also provided are methods of predicting the efficacy of treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy in a subject having cancer that include: determining that treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy is less likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has one or more RET inhibitor resistance mutations. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.

[00756] Also provided are methods of treating a subject having a cancer that include: (a) administering one or more doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and (c) administering a second RET inhibitor or a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to a subject having a cancer cell that has one or more RET inhibitor resistance mutations; or (d) administering additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (a) to a subject having a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (a), the subject can also be administered another anticancer agent or a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments, another RET can be the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof administered in step (a).

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[00757] Also provided are methods of treating a subject having a cancer that include: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, has one or more RET inhibitor resistance mutations; (b) administering a second RET inhibitor or a second compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to a subject having a cancer cell that has one or more RET inhibitor resistance mutations; or (c) administering additional doses of the compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof previously administered to a subject having a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where the subject is administered additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (a), the subject can also be administered another anticancer agent. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments, another RET can be the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof administered in step (a).

[00758] Also provided are methods of selecting a treatment for a subject having a cancer that include: (a) administering one or more doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and (c) selecting a second RET inhibitor or a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anti cancer agent for the subject if the subject has a cancer cell that has a RET inhibitor resistance mutation; or (d) selecting additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (a) for the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where additional doses of a compound of Formula I or a phannaceutically acceptable salt or solvate thereof of step (a) are selected for the subject, the method can also include further selecting another

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PCT7US2017/055983 anti cancer agent. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anticancer agent is an immunotherapy. In some embodiments, another RET can be the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof administered in step (a).

[00759] Also provided are methods of selecting a treatment for a subject having a cancer that include: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, has one or more RET inhibitor resistance mutations; (b) selecting a second RET inhibitor or a second compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent for the subject if the subject has a cancer cell that has a RET inhibitor resistance mutation; or (c) selecting additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof previously administered to the subject if the subject has a cancer cell that does not have a RET inhibitor resistance mutation. In some embodiments, where additional doses of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof of step (a) are selected for the subject, the method can also include further selecting another anticancer agent. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional anticancer agent is any anticancer agent known in the art. For example, the additional anticancer agent is another RET inhibitor (e.g., a second RET inhibitor). In some embodiments, the additional anti cancer agent is an immunotherapy. In some embodiments, another RET can be the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof administered in step (a).

[00760] Also provided are methods of determining a subject's risk for developing a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof that include: determining whether a cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and identifying the subject if the subject has a cell that has one or more RET inhibitor resistance mutations as having an increased likelihood of

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PCT7US2017/055983 developing a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods of determining a subject's risk for developing a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof that include: identifying a subject having a cell that has one or more RET inhibitor resistance mutations as having an increased likelihood of developing a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods of determining the presence of a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof that includes: determining whether a cancer cell in a sample obtained from the subject has one or more RET inhibitor resistance mutations; and determining that the subject having the cancer cell that has one or more RET inhibitor resistance mutations has a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Also provided are methods of determining the presence of a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof in a subject that include: determining that a subject having a cancer cell that has one or more RET inhibitor resistance mutations has a cancer that has some resistance to a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the one or more RET inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.

[00761] In some embodiments of any of the methods described herein, a RET inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, can be any of the RET inhibitor resistance mutations listed in Table 3 or 4.

[00762] Methods of determining the level of resistance of a cancer cell or a tumor to a RET inhibitor (e g., any of the RET inhibitors described herein or known in the art) can be determined using methods known in the art. For example, the level of resistance of a cancer cell to a RET inhibitor can be assessed by determining the ICso of a RET inhibitor (e.g., any of the RET inhibitors described herein or known in the art) on the viability of a cancer cell. In other examples, the level of resistance of a cancer cell to a RET inhibitor can be assessed by determining the growth rate of the cancer cell in the presence of a RET inhibitor (e.g., any of the RET inhibitors described herein). In other examples, the level of resistance of a tumor to a RET inhibitor can be assessed by

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PCT7US2017/055983 determining the mass or size of one or more tumors in a subject over time during treatment with a RET inhibitor (e.g., any of the RET inhibitors described herein). In other examples, the level of resistance of a cancer cell or a tumor to a RET inhibitor can be indirectly assessed by determining the activity of a RET kinase including one or more of the RET inhibitor resistance mutations (i.e., the same RET kinase expressed in a cancer cell or a tumor in a subject). The level of resistance of a cancer cell or tumor having one or more RET inhibitor resistance mutations to a RET inhibitor is relative to the level of resistance in a cancer cell or tumor that does not have a RET inhibitor resistance mutation (e.g., a cancer cell or tumor that does not have the same RET inhibitor resistance mutations, a cancer cell or a tumor that does not have any RET inhibitor resistance mutations, or a cancer cell or a tumor that expresses a wildtype RET protein). For example, the determined level of resistance of a cancer cell or a tumor having one or more RET inhibitor resistance mutations can be greater than about 1%, greater than about 2%, greater than about 3% ,greater than about 4%, greater than about 5%, greater than about 6%, greater than about 7%, greater than about 8%, greater than about 9%, greater than about 10%, greater than about 11%, greater than about 12%, greater than about 13%, greater than about 14%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, greater than about 150%, greater than about 160%, greater than about 170%, greater than about 180%, greater than about 190%, greater than about 200%, greater than about 210%, greater than about 220%, greater than about 230%, greater than about 240%, greater than about 250%, greater than about 260%, greater than about 270%, greater than about 280%, greater than about 290%, or greater than about 300% of the level of resistance in a cancer cell or tumor that does not have a RET inhibitor resistance mutation (e g., a cancer cell or tumor that does not have the same RET inhibitor resistance mutations, a cancer cell or a tumor that does not have any RET inhibitor resistance mutations, or a cancer cell or a tumor that expresses a wildtype RET protein).

[00763] RET is thought to play an important role in the development and survival of afferent nociceptors in the skin and gut. RET kinase knock-out mice lack enteric neurons and have other nervous system anomalies suggesting that a functional RET kinase protein product is necessary during development (Taraviras, S. et al., Development, 1999, 126:2785-2797). Moreover

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PCT7US2017/055983 population studies of patients with Hirschsprung's disease characterized by colonic obstruction due to lack of normal colonic enervation have a higher proportion of both familial and sporadic loss of function RET mutations (Butler Tjaden N., et al., Transi. Res., 2013, 162: 1-15). Irritable bowel syndrome (IBS) is a common illness affecting 10-20% of individuals in developed countries and is characterized by abnormal bowel habits, bloating and visceral hypersensitivity (Camilleri, M., /V. Engl. J. Med., 2012, 367: 1626-1635). While the etiology of IBS is unknown it is thought to result from either a disorder between the brain and gastrointestinal tract, a disturbance in the gut microbiome or increased inflammation. The resulting gastrointestinal changes affect normal bowel transit resulting in either diarrhea or constipation. Furthermore in many IBS patients the sensitization of the peripheral nervous system results in visceral hypersensitivity or allodynia (Keszthelyi, D., Eur. J. Pain, 2012,16:1444-1454). See, e.g., U.S. Publication No. 2015/0099762. [00764] Accordingly, provided herein are methods for treating a patient diagnosed with (or identified as having) an irritable bowel syndrome (IBS) including diarrhea-predominant, constipation- predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, and inflammatory bowel disease that include administering to the patient a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof.

[00765] Also provided herein are methods for treating a patient identified or diagnosed as having a RET-associated irritable bowel syndrome (IBS) (e g., a patient that has been identified or diagnosed as having a RET-associated irritable bowel syndrome (IBS) through the use of a regulatory' agency-approved, eg., FDA-approved, kit for identifying dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, in a patient or a biopsy sample from the patient) that include administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.

[00766] Also provided herein are methods for treating pain associated with IBS that include administering to the patient a therapeutically effective amount of a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered in combination with another therapeutic agent useful for treating one or more symptoms of IBS.

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[00767] Also provided are methods for treating an irritable bowel syndrome (IBS) in a patient in need thereof, the method comprising: (a) determining if the irritable bowel syndrome (IBS) in the patient is a RET-associated IBS (e g., using a regulatory-agency approved, e.g., FDAapproved, kit for identifying dysrégulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, in a patient or a biopsy sample from the patient, or by performing any of the non-limiting examples of assays described herein); and (b) if the IBS is determined to be a RET-associated IBS, administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.

[00768] In some embodiments, the compounds of the present invention are useful for treating irritable bowel syndrome (IBS) in combination with one or more additional therapeutic agents or therapies effective in treating the irritable bowel syndrome that work by the same or a different mechanism of action. The at least one additional therapeutic agent may be administered with a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.

[00769] Non-limiting examples of additional therapeutics for the treatment of irritable bowel syndrome (IBS) include probiotics, fiber supplements (e g., psyllium, methylcellulose), anti-diarrheal medications (e.g., loperamide), bile acid binders (e.g., cholestyramine, colestipol, colesevelam), anticholinergic and antispasmodic medications (e g., hyoscyamine, dicyclomine), antidepressant medications (e.g., tricyclic antidepressant such as imipramine or notriptyline or a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine or paroxetine), antibiotics (e g., rifaximin), alosetron, and lubiprostone.

[00770] Accordingly, also provided herein are methods of treating irritable bowel syndrome (IBS), comprising administering to a patient in need thereof a pharmaceutical combination for treating IBS which comprises (a) a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of IBS, wherein the amounts of the compound of Formula I or pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are together effective in treating the IBS. In one embodiment, the compound of Formula I or pharmaceutically acceptable salt or solvate

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PCT7US2017/055983 thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In one embodiment, the compound of Formula 1 or pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e.g. in daily or intermittently dosages. In one embodiment, compound of Formula I or pharmaceutically acceptable salt or solvate thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage.

[00771] Also provided herein is (i) a pharmaceutical combination fortreating irritable bowel syndrome in a patient in need thereof, which comprises (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, (b) at least one additional therapeutic agent (e g., any of the exemplary additional therapeutic agents described herein for treating irritable bowel syndrome or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of irritable bowel syndrome, wherein the amounts of the compound of Formula I or pharmaceutically acceptable salt or solvate thereof and of the additional therapeutic agent are together effective in treating the irritable bowel syndrome; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of irritable bowel syndrome; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of irritable bowel syndrome in a patient in need thereof. In one embodiment the patient is a human.

[00772] The term pharmaceutical combination, as used herein, refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term fixed combination means that a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent (e.g., an agent effective in treating irritable bowel syndrome), are both administered to a patient simultaneously in the form of a single composition or dosage. The term non-fixed combination means that a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and at least one additional therapeutic agent (eg., an agent effective in treating irritable bowel syndrome) are formulated as separate compositions or dosages, such that they may be administered to a patient in need thereof simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient.

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In one embodiment, the compound of Formula I and the additional therapeutic agent are formulated as separate unit dosage forms, wherein the separate dosages forms are suitable for either sequential or simultaneous administration. These also apply to cocktail therapies, e.g. the administration of three or more active ingredients.

[00773] In some embodiments, a compound provided herein can be used as an agent for supportive care for a patient undergoing cancer treatment. For example, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, can be useful to reduce one or more symptoms associated with treatment with one or more cancer therapies such as diarrheal or constipations complications and/or abdominal pain. See, for example, U.S. Publication No. 2015/0099762 and Hoffman, J.M. et al. Gastroenterology (2012) 142:844-854. Accordingly, a compound, or a pharmaceutically acceptable salt thereof, or composition provided herein can be administered to a patient to address one or more complications associated with cancer treatment (e.g., gastrointestinal complications such as diarrhea, constipation, or abdominal pain).

[00774] In some embodiments, a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, can be administered to a patient undergoing cancer treatment (e.g., a patient experiencing an adverse event associated with cancer treatment such as an immune-related adverse event or a gastrointestinal complication including diarrhea, constipation, and abdominal pain). For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be used in the treatment of colitis or IBS associated with administration of a checkpoint inhibitor; see, eg., Postow, M.A. et al. Journal of Clinical Oncology (2015) 33: 1974-1982. In some such embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be formulated to exhibit low bioavailability and/or be targeted for delivery in the gastrointestinal tract. See, for example, US Patent No. 6,531,152.

[00775] Also provided is a method for inhibiting RET kinase activity in a cell, comprising contacting the cell with a compound of Formula I. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. In one embodiment, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to a subject having a cell having RET kinase activity. In some embodiments, the cell is a cancer cell. In one embodiment, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a RET-associated cancer cell. In some embodiments, the cell is a gastrointestinal cell.

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[00776] Also provided is a method for inhibiting RET kinase activity in a mammalian cell, comprising contacting the cell with a compound of Formula 1. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. In one embodiment, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof to a mammal having a cell having RET kinase activity. In some embodiments, the mammalian cell is a mammalian cancer cell. In one embodiment, the mammalian cancer cell is any cancer as described herein. In some embodiments, the mammalian cancer cell is a RET-associated cancer cell. In some embodiments, the mammalian cell is a gastrointestinal cell.

[00777] As used herein, the term contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, contacting a RET kinase with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having a RET kinase, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the RET kinase.

[00778] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein

[00779] The phrase effective amount means an amount of compound that, when administered to a patient in need of such treatment, is sufficient to (i) treat a RET kinase-associated disease or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of Formula I that will correspond to such an amount will vaiy depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.

[00780] When employed as pharmaceuticals, the compounds of Formula I can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.

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Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (eg., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration can include a dosage form formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable [00781] Also provided herein are pharmaceutical compositions which contain, as the active ingredient, a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or capsule.

[00782] The compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term unit dosage form refers to physically discrete units suitable as unitaiy dosages for human subjects and other patients, each unit containing a predetermined quantity of active material (i.e., a compound for Formula I as provided herein) calculated to produce the

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PCT7US2017/055983 desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[00783] In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient.

[00784] In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. One having ordinaiy skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient.

[00785] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.

[00786] The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[00787] Tn some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg/kg to about 100 mg/kg. In some embodiments, the compound provided herein can be administered in an amount of about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50 mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45 mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70 mg/kg. For example, about 5

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PCT7US2017/055983 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg. In some embodiments, such administration can be once-daily or twice-daily (BID) administration.

[00788] Provided herein are pharmaceutical kits useful, for example, in the treatment of RET-associated diseases or disorders, such as cancer or irritable bowel syndrome (IBS), which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

[00789] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and/or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[00790] One skilled in the art will further recognize that human clinical trials including firstin-human, dose ranging and efficacy trials, in healthy patients and/or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.

Examples

[00791] The following examples illustrate the invention.

Biological Examples

Example A

RET Enzyme Assay

[00792] Compounds of Formula I were screened for their ability to inhibit wildtype and V804M mutant RET kinase using CisBio’s HTRF® KinEASE™-TK assay technology. Briefly, N-terminal GST tagged recombinant human RET cytoplasmic domain (aa 658-end) from Eurofins (0.25 nM RET, Catalog No. 14-570M) or N-terminal GST tagged recombinant human V804M

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PCT7US2017/055983 mutant RET cytoplasmic domain (aa 658-end) from Millipore (0.25 nM enzyme; Catalog No. 14760) was incubated with 250 nM TK-substrate biotin (CisBio, part of Catalog No. 62TK0PEC) and 1 mM ATP along with test compound in a buffer consisting of 25 mM HEPES pH 7.4, 10 mM MgCh, 0.01% Triton X-100, and 2% DMSO in a volume of 8 gL. Compounds were typicallyprepared in a threefold serial dilution in DMSO and added to the assay to give the appropriate final concentration. After a 30-minute incubation at 22 °C, the reaction was quenched by adding 8 pL of quench solution containing 31.25 nM Sa-XL665 and IX TK-ab-Cryptate in HTRF detection buffer (all from CisBio, part of Cat. No. 62TK0PEC). After a 1 hour incubation at 22°C, the extent of reaction was determined using a PerkinElmer EnVision multimode plate reader via HTRF dual wavelength detection, and the percent of control (POC) was calculated using a ratiometric emission factor. 100 POC was determined using no test compounds and 0 POC was determined using pre-quenched control reactions. The POC values were fit to a 4 parameter logistic curve, and the IC50 is defined as the concentration of inhibitor at which the POC equals 50 for the fitted curve. The ICso values for the compounds tested in this assay are provided in Table 5.

[00793] Example B

[00794] RET cell assay

[00795] The cellular potency of a compound inhibiting RET kinase was determined in HEK-293 cells expressing a Kif5b-RET fusion protein. Briefly, HEK-293 cells expressing a Kif5b-RET fusion protein were plated at 50K cells /well in 96 well poly-D-Lysine coated plates the day prior to the assay. The cells were incubated for 1 hour with test compound in DMEM (Dulbecco's Modified Eagle Medium) at a final DMSO concentration of 0.5%. Compounds were typically prepared in a three fold serial dilution in DMSO and added to the assay to give the appropriate final concentration. After 1 hour the media was removed, the cells were fixed with 3.8% formaldehyde for 20 min, washed with PBS, and permeabilized for 10 min with 100% methanol. The plates were then washed with PBS-0.05% Tween20, and blocked with LI-COR Blocking solution (LI-COR catalog # 927-40000) for 1 hour. Plates were washed with PBS-0.05% Tween20, then incubated with anti-phospho-RET(Tyr1062) (Santa Cruz catalog #sc-20252-R) antibody and anti-GAPDH (Millipore catalog # MAB374) antibody for 2 hours. The plates were washed with PBS-0.05%Tween20, and incubated with anti-rabbit 680 (Molecular Probes catalog No. A21109) and anti-mouse 800 (LI-COR catalog No. 926-32210) secondary antibodies for 1 hour. All antibodies were diluted in LI-COR Block containing 0.05% Tween. The plates were

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PCT7US2017/055983 washed with PBS-0.05% Tween20, 100 pL PBS was added to each well, and the plates were read on a Ll-COR Aerius fluorescent plate reader. The phospho-RET signal was normalized to the GAPDH signal. 100 POC (percent of control) was determined using no test compounds and 0 POC was determined using 1 μΜ of a control inhibitor. The POC values were fit to a 4 parameter logistic curve. The ICso value is the point where the curve crosses 50 POC. The ICso values for the compounds tested in this assay are provided in Table 5.

[00796] Example C

[00797] RET G810R mutant assay

[00798] The potency of a compound inhibiting G81 OR mutant RET kinase was determined using CisBio’s HTRF Kinease-TK assay technology. The assays contained G810R mutant RET produced at Array Biopharma, Inc. (1 nM enzyme - pl982 Lot. No. 160713. The kinase was incubated with 250 nM TK-substrate biotin (CisBio, part of Catalog # 62TK0PEC) and 1 mM ATP along with test compound in a buffer consisting of 25 mM HEPES, pH 7.4, 10 mM MgCb, 0.01% Triton X-100, and 2% DMSO in a volume of 8 pL. Compounds were typically prepared as a threefold serial dilution in DMSO and added to the assay to give the appropriate final concentration. After a 60-min incubation at 22 °C, the reaction was quenched by adding 8 pL of quench solution containing 31.25 nM Sa-XL665 and lx TK-Ab-Cryptate in HTRF detection buffer (all from CisBio, part of cat # 62TK0PEC). After a 1-h incubation at 22 °C, the extent of reaction was determined using a PerkinElmer Envision multimode plate reader via HIRF dual wavelength detection, and the percent of control (POC) was calculated using a ratiometric emission factor. One hundred POC was determined using no test compounds, and 0 POC was determined using pre-quenched control reactions. A 4-parameter logistic curve was fit to the POC values as a function of the concentration of compound, and the ICso value was the point where the best-fit curve crossed 50 POC.

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[00799] Table 5. ICso’s of compounds tested in the assay of Examples A, B and C

<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5B- RET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 1</td><td> 24.0</td><td> 145.2</td><td> 1074.2</td><td> N/A</td>

<td> 2</td><td> 32.1</td><td> 176.2</td><td> 70.3</td><td> 202.3</td>

<td> 3</td><td> 16.1</td><td> 90.2</td><td> 37.8</td><td> N/A</td>

<td> 4</td><td> 92.1</td><td> 10000.0</td><td> 437.2</td><td> N/A</td>

<td> 5</td><td> 15.4</td><td> 66.9</td><td> 30.8</td><td> N/A</td>

<td> 6</td><td> 16.8</td><td> 61.8</td><td> 22.4</td><td> N/A</td>

<td> 7</td><td> 25.2</td><td> 141.4</td><td> 23.3</td><td> N/A</td>

<td> 8</td><td> 66.2</td><td> 315.7</td><td> 95.2</td><td> N/A</td>

<td> 9</td><td> 14.9</td><td> 95.8</td><td> 32.6</td><td> N/A</td>

<td> 10</td><td> 110.1</td><td> 492.8</td><td> N/A</td><td> N/A</td>

<td> 11</td><td> 42.5</td><td> 143.1</td><td> 89.7</td><td> N/A</td>

<td> 12</td><td> 9.5</td><td> 46.6</td><td> 24.0</td><td> N/A</td>

<td> 13</td><td> 19.2</td><td> 95.6</td><td> 38.6</td><td> N/A</td>

<td> 14</td><td> 165.4</td><td> 1135.1</td><td> N/A</td><td> N/A</td>

<td> 15</td><td> 264.0</td><td> 1839.1</td><td> N/A</td><td> N/A</td>

<td> 16</td><td> 14.1</td><td> 45.0</td><td> 133.9</td><td> N/A</td>

<td> 17</td><td> 18.1</td><td> 62.8</td><td> 11.8</td><td> N/A</td>

<td> 18</td><td> 11.7</td><td> 116.4</td><td> 37.4</td><td> N/A</td>

<td> 19</td><td> 11.4</td><td> 40.0</td><td> 40.6</td><td> N/A</td>

<td> 20</td><td> 30.9</td><td> 127.7</td><td> 39.4</td><td> N/A</td>

<td> 21</td><td> 20.2</td><td> 94.2</td><td> 14.5</td><td> 255.1</td>

<td> 22</td><td> 50.3</td><td> 239.1</td><td> 100.2</td><td> N/A</td>

<td> 23</td><td> 39.9</td><td> 463.1</td><td> 111.5</td><td> N/A</td>

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<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 24</td><td> 31.0</td><td> 241.5</td><td> 99.7</td><td> 611.3</td>

<td> 25</td><td> 258.8</td><td> 1693.0</td><td> N/A</td><td> N/A</td>

<td> 26</td><td> 4048.1</td><td> 5174.2</td><td> N/A</td><td> N/A</td>

<td> 27</td><td> 3545.8</td><td> 10000.0</td><td> N/A</td><td> N/A</td>

<td> 28</td><td> 1314.8</td><td> 10000.0</td><td> N/A</td><td> N/A</td>

<td> 29</td><td> 345.1</td><td> 2124.0</td><td> N/A</td><td> N/A</td>

<td> 30</td><td> 433.8</td><td> 4733.4</td><td> N/A</td><td> N/A</td>

<td> 31</td><td> 13.5</td><td> 88.2</td><td> 26.5</td><td> N/A</td>

<td> 32</td><td> 69.6</td><td> 409.7</td><td> 85.6</td><td> N/A</td>

<td> 33</td><td> 9.9</td><td> 88.1</td><td> 21.1</td><td> N/A</td>

<td> 34</td><td> 19.7</td><td> 138.2</td><td> 19.9</td><td> N/A</td>

<td> 35</td><td> 209.8</td><td> 1263.8</td><td> N/A</td><td> N/A</td>

<td> 36</td><td> 62.4</td><td> 534.0</td><td> 120.0</td><td> N/A</td>

<td> 37</td><td> 80.4</td><td> 963.4</td><td> 160.5</td><td> N/A</td>

<td> 38</td><td> 353.4</td><td> 3915.7</td><td> N/A</td><td> N/A</td>

<td> 39</td><td> 15.1</td><td> 97.2</td><td> 23.5</td><td> N/A</td>

<td> 40</td><td> 63.2</td><td> 802.4</td><td> 193.7</td><td> N/A</td>

<td> 41</td><td> 25.2</td><td> 208.7</td><td> 54.1</td><td> N/A</td>

<td> 42</td><td> 33.0</td><td> 188.5</td><td> 107.8</td><td> N/A</td>

<td> 43</td><td> 25.9</td><td> 59.1</td><td> 1991.1</td><td> N/A</td>

<td> 44</td><td> 54.5</td><td> 396.5</td><td> 175.0</td><td> N/A</td>

<td> 45</td><td> 138.2</td><td> 901.3</td><td> N/A</td><td> N/A</td>

<td> 46</td><td> 60.8</td><td> 735.8</td><td> 88.6</td><td> N/A</td>

<td> 47</td><td> 29.5</td><td> 239.7</td><td> 50.5</td><td> N/A</td>

229

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PCT7US2017/055983

<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 48</td><td> 22.1</td><td> 44.3</td><td> 5.4</td><td> 182.4</td>

<td> 49</td><td> 12.5</td><td> 101.3</td><td> 24.1</td><td> N/A</td>

<td> 50</td><td> 12.6</td><td> 60.7</td><td> 18.9</td><td> N/A</td>

<td> 51</td><td> 14.0</td><td> 62.0</td><td> 46.6</td><td> N/A</td>

<td> 52</td><td> 15.4</td><td> 80.6</td><td> 59.8</td><td> N/A</td>

<td> 53</td><td> 15.6</td><td> 181.0</td><td> 54.8</td><td> N/A</td>

<td> 54</td><td> 16.6</td><td> 84.4</td><td> 40.8</td><td> N/A</td>

<td> 55</td><td> 17.2</td><td> 89.1</td><td> 202.1</td><td> N/A</td>

<td> 56</td><td> 20.3</td><td> 222.0</td><td> 99.6</td><td> N/A</td>

<td> 57</td><td> 22.3</td><td> 131.0</td><td> 92.1</td><td> N/A</td>

<td> 58</td><td> 23.2</td><td> 225.2</td><td> 68.0</td><td> N/A</td>

<td> 59</td><td> 24.3</td><td> 147.6</td><td> 95.0</td><td> N/A</td>

<td> 60</td><td> 32.4</td><td> 220.9</td><td> 125.1</td><td> N/A</td>

<td> 61</td><td> 34.6</td><td> 254.8</td><td> 129.3</td><td> N/A</td>

<td> 62</td><td> 38.1</td><td> 253.9</td><td> 133.7</td><td> N/A</td>

<td> 63</td><td> 18.5</td><td> 67.1</td><td> 12.9</td><td> 550.1</td>

<td> 64</td><td> 73.1</td><td> 644.9</td><td> 241.3</td><td> N/A</td>

<td> 65</td><td> 208.7</td><td> 1451.6</td><td> N/A</td><td> N/A</td>

<td> 66</td><td> 54.6</td><td> 250.1</td><td> 157.2</td><td> N/A</td>

<td> 67</td><td> 6588.9</td><td> 10000.0</td><td> N/A</td><td> N/A</td>

<td> 68</td><td> 166.2</td><td> 1329.1</td><td> N/A</td><td> N/A</td>

<td> 69</td><td> 222.7</td><td> 678.9</td><td> N/A</td><td> N/A</td>

<td> 70</td><td> 469.9</td><td> 3978.2</td><td> N/A</td><td> N/A</td>

<td> 71</td><td> 56.4</td><td> 341.5</td><td> 165.7</td><td> N/A</td>

230

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PCT7US2017/055983

<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 72</td><td> 36.3</td><td> 271.3</td><td> 89.0</td><td> N/A</td>

<td> 73</td><td> 107.8</td><td> 601.8</td><td> N/A</td><td> N/A</td>

<td> 74</td><td> 76.3</td><td> 492.4</td><td> 287.0</td><td> N/A</td>

<td> 75</td><td> 128.2</td><td> 768.6</td><td> N/A</td><td> N/A</td>

<td> 76</td><td> 133.0</td><td> 656.6</td><td> N/A</td><td> N/A</td>

<td> 77</td><td> 277.0</td><td> 1133.2</td><td> N/A</td><td> N/A</td>

<td> 78</td><td> 180.1</td><td> 920.8</td><td> N/A</td><td> N/A</td>

<td> 79</td><td> 241.6</td><td> 968.2</td><td> N/A</td><td> N/A</td>

<td> 80</td><td> 1212.3</td><td> 5647.2</td><td> N/A</td><td> N/A</td>

<td> 81</td><td> 728.9</td><td> 4512.1</td><td> N/A</td><td> N/A</td>

<td> 82</td><td> 2656.5</td><td> 8939.1</td><td> N/A</td><td> N/A</td>

<td> 83</td><td> 72.7</td><td> 410.3</td><td> 382.8</td><td> N/A</td>

<td> 84</td><td> 124.1</td><td> 748.4</td><td> N/A</td><td> N/A</td>

<td> 85</td><td> 209.6</td><td> 1003.6</td><td> N/A</td><td> N/A</td>

<td> 86</td><td> 120.8</td><td> 696.6</td><td> N/A</td><td> N/A</td>

<td> 87</td><td> 215.6</td><td> 1075.5</td><td> N/A</td><td> N/A</td>

<td> 88</td><td> 34.3</td><td> 151.2</td><td> 30.0</td><td> N/A</td>

<td> 89</td><td> 261.7</td><td> 1190.6</td><td> N/A</td><td> N/A</td>

<td> 90</td><td> 454.6</td><td> 1712.2</td><td> N/A</td><td> N/A</td>

<td> 91</td><td> 163.3</td><td> 764.6</td><td> N/A</td><td> N/A</td>

<td> 92</td><td> 32.2</td><td> 152.5</td><td> 35.9</td><td> N/A</td>

<td> 93</td><td> 157.5</td><td> 771.8</td><td> N/A</td><td> N/A</td>

<td> 94</td><td> 88.1</td><td> 702.5</td><td> 370.6</td><td> N/A</td>

<td> 95</td><td> 136.6</td><td> 952.6</td><td> N/A</td><td> N/A</td>

231

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PCT7US2017/055983

<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 96</td><td> 62.8</td><td> 593.9</td><td> 271.5</td><td> N/A</td>

<td> 97</td><td> 39.1</td><td> 255.9</td><td> 90.1</td><td> 487.0</td>

<td> 98</td><td> 21.4</td><td> 152.1</td><td> 269.8</td><td> N/A</td>

<td> 99</td><td> 20.0</td><td> 125.2</td><td> 20.7</td><td> N/A</td>

<td> 100</td><td> 14.1</td><td> 91.3</td><td> 43.4</td><td> N/A</td>

<td> 101</td><td> 60.4</td><td> 465.3</td><td> 346.3</td><td> N/A</td>

<td> 102</td><td> 69.0</td><td> 535.9</td><td> 149.7</td><td> N/A</td>

<td> 103</td><td> 95.2</td><td> 786.8</td><td> 224.0</td><td> N/A</td>

<td> 104</td><td> 476.6</td><td> 3574.3</td><td> N/A</td><td> N/A</td>

<td> 105</td><td> 45.4</td><td> 237.2</td><td> 138.3</td><td> N/A</td>

<td> 106</td><td> 33.3</td><td> 360.8</td><td> 58.5</td><td> N/A</td>

<td> 107</td><td> 47.2</td><td> 457.7</td><td> 67.4</td><td> N/A</td>

<td> 108</td><td> 54.6</td><td> 543.1</td><td> 102.95</td><td> N/A</td>

<td> 108</td><td> 25.2</td><td> N/A</td><td> 91.7</td><td> N/A</td>

<td> 110</td><td> 8.1</td><td> 18.5</td><td> 4.5</td><td> 90.0</td>

<td> 111</td><td> 16.4</td><td> 74.9</td><td> 10.5</td><td> N/A</td>

<td> 112</td><td> 25.7</td><td> 162.9</td><td> 40.4</td><td> N/A</td>

<td> 113</td><td> 614.9</td><td> 4754.7</td><td> N/A</td><td> N/A</td>

<td> 114</td><td> 109.9</td><td> 843.6</td><td> N/A</td><td> N/A</td>

<td> 115</td><td> 15.0</td><td> 70.5</td><td> 16.6</td><td> 54.3</td>

<td> 116</td><td> 103.8</td><td> 1255.1</td><td> 221.8</td><td> N/A</td>

<td> 117</td><td> 51.6</td><td> 322.0</td><td> 135.9</td><td> N/A</td>

<td> 118</td><td> 19.2</td><td> 103.8</td><td> 32.8</td><td> N/A</td>

<td> 119</td><td> 32.1</td><td> 147.9</td><td> 48.3</td><td> N/A</td>

232

CA 03039780 2019-04-08

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PCT7US2017/055983

<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 120</td><td> 37.3</td><td> 275.1</td><td> 72.3</td><td> N/A</td>

<td> 121</td><td> 34.3</td><td> 181.8</td><td> 20.3</td><td> N/A</td>

<td> 122</td><td> 80.4</td><td> 790.4</td><td> 213.8</td><td> N/A</td>

<td> 123</td><td> 36.8</td><td> 276.9</td><td> 50.0</td><td> N/A</td>

<td> 124</td><td> 152.6</td><td> 1075.5</td><td> 294.6</td><td> N/A</td>

<td> 125</td><td> 27.5</td><td> 310.4</td><td> 69.2</td><td> N/A</td>

<td> 126</td><td> 91.5</td><td> 708.9</td><td> 181.3</td><td> N/A</td>

<td> 127</td><td> 41.9</td><td> 228.5</td><td> 201.5</td><td> N/A</td>

<td> 128</td><td> 10.2</td><td> 24.0</td><td> 2.5</td><td> 575.7</td>

<td> 129</td><td> 21.6</td><td> 179.2</td><td> 24.1</td><td> N/A</td>

<td> 130</td><td> 30.9</td><td> 183.7</td><td> 20.1</td><td> N/A</td>

<td> 131</td><td> 41.5</td><td> 422.5</td><td> 113.5</td><td> N/A</td>

<td> 132</td><td> 256.3</td><td> 1332.2</td><td> 593.3</td><td> N/A</td>

<td> 133</td><td> 124.4</td><td> 914.8</td><td> N/A</td><td> N/A</td>

<td> 134</td><td> 33.1</td><td> 398.3</td><td> 109.7</td><td> N/A</td>

<td> 135</td><td> 77.0</td><td> 756.1</td><td> 173.9</td><td> N/A</td>

<td> 136</td><td> 13.1</td><td> 26.1</td><td> 3.9</td><td> 386.6</td>

<td> 137</td><td> 43.7</td><td> 252.0</td><td> 27.1</td><td> N/A</td>

<td> 138</td><td> 41.9</td><td> 360.9</td><td> 87.7</td><td> N/A</td>

<td> 139</td><td> 237.5</td><td> 1733.1</td><td> N/A</td><td> N/A</td>

<td> 140</td><td> 23.5</td><td> 219.7</td><td> 96.2</td><td> N/A</td>

<td> 141</td><td> 85.5</td><td> 651.3</td><td> 159.0</td><td> N/A</td>

<td> 142</td><td> 51.0</td><td> 319.0</td><td> 59.1</td><td> N/A</td>

<td> 143</td><td> 36.3</td><td> 276.0</td><td> 46.5</td><td> N/A</td>

233

CA 03039780 2019-04-08

WO 2018/071447

PCT7US2017/055983

<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 144</td><td> 39.3</td><td> 220.6</td><td> 37.4</td><td> N/A</td>

<td> 145</td><td> 55.1</td><td> 560.5</td><td> 115.5</td><td> N/A</td>

<td> 146</td><td> 113.7</td><td> 712.2</td><td> N/A</td><td> N/A</td>

<td> 147</td><td> 84.2</td><td> 867.7</td><td> 256.2</td><td> N/A</td>

<td> 148</td><td> 144.5</td><td> 1206.0</td><td> N/A</td><td> N/A</td>

<td> 149</td><td> 49.4</td><td> 328.1</td><td> 100.8</td><td> N/A</td>

<td> 150</td><td> 432.5</td><td> 5390.5</td><td> N/A</td><td> N/A</td>

<td> 151</td><td> 490.4</td><td> 5556.6</td><td> N/A</td><td> N/A</td>

<td> 152</td><td> 122.8</td><td> 1986.9</td><td> N/A</td><td> N/A</td>

<td> 153</td><td> 36.7</td><td> 283.5</td><td> 69.7</td><td> N/A</td>

<td> 154</td><td> 26.2</td><td> 180.3</td><td> 26.8</td><td> N/A</td>

<td> 155</td><td> 28.0</td><td> 146.1</td><td> 45.0</td><td> N/A</td>

<td> 156</td><td> 31.9</td><td> 157.6</td><td> 20.5</td><td> N/A</td>

<td> 157</td><td> 35.0</td><td> 346.0</td><td> 72.3</td><td> N/A</td>

<td> 158</td><td> 100.6</td><td> 703.4</td><td> 130.9</td><td> N/A</td>

<td> 159</td><td> 270.8</td><td> 1356.1</td><td> N/A</td><td> N/A</td>

<td> 160</td><td> 34.8</td><td> 397.3</td><td> 86.6</td><td> N/A</td>

<td> 161</td><td> 86.3</td><td> 634.0</td><td> 119.6</td><td> N/A</td>

<td> 162</td><td> 67.0</td><td> 562.6</td><td> 246.7</td><td> N/A</td>

<td> 163</td><td> 14.0</td><td> 24.1</td><td> 4.2</td><td> 530.7</td>

<td> 164</td><td> 18.6</td><td> 154.0</td><td> 22.1</td><td> N/A</td>

<td> 165</td><td> 25.3</td><td> 123.1</td><td> 21.6</td><td> N/A</td>

<td> 166</td><td> 29.3</td><td> 84.2</td><td> 22.6</td><td> N/A</td>

<td> 167</td><td> 35.3</td><td> 320.9</td><td> 89.5</td><td> N/A</td>

234

CA 03039790 2019-04-09

WO 2018/071447

PCT7US2017/055983

<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 168</td><td> 50.4</td><td> 212.9</td><td> 50.8</td><td> N/A</td>

<td> 169</td><td> 63.0</td><td> 299.4</td><td> 109.3</td><td> N/A</td>

<td> 170</td><td> 68.6</td><td> 426.2</td><td> 146.2</td><td> N/A</td>

<td> 171</td><td> 144.4</td><td> 912.1</td><td> N/A</td><td> N/A</td>

<td> 172</td><td> 268.6</td><td> 1788.4</td><td> N/A</td><td> N/A</td>

<td> 173</td><td> 46.9</td><td> 244.2</td><td> 44.8</td><td> N/A</td>

<td> 174</td><td> 13.3</td><td> 52.2</td><td> 6.8</td><td> 847.2</td>

<td> 175</td><td> 19.9</td><td> 37.9</td><td> 2.9</td><td> N/A</td>

<td> 176</td><td> 24.5</td><td> 74.5</td><td> 10.1</td><td> N/A</td>

<td> 177</td><td> 134.4</td><td> 839.7</td><td> N/A</td><td> N/A</td>

<td> 178</td><td> 28.4</td><td> 79.8</td><td> 12.2</td><td> N/A</td>

<td> 179</td><td> 32.1</td><td> 110.8</td><td> 25.4</td><td> N/A</td>

<td> 180</td><td> 23.2</td><td> 63.2</td><td> 15.7</td><td> N/A</td>

<td> 181</td><td> 91.0</td><td> 674.8</td><td> 165.4</td><td> N/A</td>

<td> 182</td><td> 634.3</td><td> 3688.8</td><td> N/A</td><td> N/A</td>

<td> 183</td><td> 15.1</td><td> 34.1</td><td> 6.4</td><td> 472.6</td>

<td> 184</td><td> 21.6</td><td> 82.5</td><td> 17.0</td><td> 3097.4</td>

<td> 185</td><td> 27.0</td><td> 185.2</td><td> 36.6</td><td> N/A</td>

<td> 186</td><td> 20.2</td><td> 149.0</td><td> 36.9</td><td> N/A</td>

<td> 187</td><td> 56.2</td><td> 499.6</td><td> 254.5</td><td> N/A</td>

<td> 188</td><td> 69.2</td><td> 692.5</td><td> 160.5</td><td> N/A</td>

<td> 189</td><td> 82.7</td><td> 789.6</td><td> 211.3</td><td> N/A</td>

<td> 190</td><td> 443.6</td><td> 5301.9</td><td> N/A</td><td> N/A</td>

<td> 191</td><td> 37.3</td><td> 207.3</td><td> 111.6</td><td> N/A</td>

235

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PCT7US2017/055983

<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 192</td><td> 12.3</td><td> 282.3</td><td> 44.7</td><td> N/A</td>

<td> 193</td><td> 38.3</td><td> 372.5</td><td> 38.6</td><td> N/A</td>

<td> 194</td><td> 57.8</td><td> 610.2</td><td> 106.8</td><td> N/A</td>

<td> 195</td><td> 30.5</td><td> 178.1</td><td> 73.6</td><td> N/A</td>

<td> 196</td><td> 78.1</td><td> 567.2</td><td> 238.3</td><td> N/A</td>

<td> 197</td><td> 149.4</td><td> 1533.8</td><td> N/A</td><td> N/A</td>

<td> 198</td><td> 59.1</td><td> 356.1</td><td> 193.0</td><td> N/A</td>

<td> 199</td><td> 50.3</td><td> 449.9</td><td> 91.5</td><td> N/A</td>

<td> 200</td><td> 461.7</td><td> 5324.1</td><td> N/A</td><td> N/A</td>

<td> 201</td><td> 59.0</td><td> 273.6</td><td> 90.0</td><td> N/A</td>

<td> 202</td><td> 278.2</td><td> 2284.8</td><td> N/A</td><td> N/A</td>

<td> 203</td><td> 253.6</td><td> 3034.5</td><td> N/A</td><td> N/A</td>

<td> 204</td><td> 103.7</td><td> 581.8</td><td> 131.7</td><td> N/A</td>

<td> 205</td><td> 18.2</td><td> 89.0</td><td> 11.7</td><td> N/A</td>

<td> 206</td><td> 61.3</td><td> 519.1</td><td> 78.0</td><td> N/A</td>

<td> 207</td><td> 27.4</td><td> 123.0</td><td> 18.8</td><td> N/A</td>

<td> 208</td><td> 33.3</td><td> 234.5</td><td> 40.4</td><td> N/A</td>

<td> 209</td><td> 41.3</td><td> 288.1</td><td> 39.7</td><td> N/A</td>

<td> 210</td><td> 34.5</td><td> 196.7</td><td> 57.2</td><td> 786.7</td>

<td> 211</td><td> 113.5</td><td> 901.6</td><td> N/A</td><td> N/A</td>

<td> 212</td><td> 222.7</td><td> 2022.5</td><td> N/A</td><td> N/A</td>

<td> 213</td><td> 25.2</td><td> 253.7</td><td> 78.3</td><td> N/A</td>

<td> 214</td><td> 54.4</td><td> 338.0</td><td> 148.8</td><td> N/A</td>

<td> 215</td><td> 108.5</td><td> 753.1</td><td> N/A</td><td> N/A</td>

236

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<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 216</td><td> 29.1</td><td> 211.8</td><td> 73.3</td><td> N/A</td>

<td> 217</td><td> 27.0</td><td> 189.9</td><td> 68.4</td><td> N/A</td>

<td> 218</td><td> 85.6</td><td> 499.9</td><td> 194.1</td><td> N/A</td>

<td> 219</td><td> 77.8</td><td> 423.7</td><td> 92.3</td><td> N/A</td>

<td> 220</td><td> 101.8</td><td> 661.0</td><td> 181.7</td><td> N/A</td>

<td> 221</td><td> 54.9</td><td> 293.0</td><td> 55.0</td><td> N/A</td>

<td> 222</td><td> 40.8</td><td> 273.9</td><td> 40.9</td><td> N/A</td>

<td> 223</td><td> 57.1</td><td> 438.6</td><td> 62.1</td><td> N/A</td>

<td> 224</td><td> 125.7</td><td> 1033.3</td><td> N/A</td><td> N/A</td>

<td> 225</td><td> 56.7</td><td> 447.9</td><td> 101.7</td><td> N/A</td>

<td> 226</td><td> 36.3</td><td> 382.8</td><td> 95.6</td><td> N/A</td>

<td> 227</td><td> 49.8</td><td> 379.7</td><td> 76.3</td><td> N/A</td>

<td> 228</td><td> 45.3</td><td> 388.9</td><td> 76.4</td><td> N/A</td>

<td> 229</td><td> 100.0</td><td> 946.3</td><td> 124.3</td><td> N/A</td>

<td> 230</td><td> 908.8</td><td> 9120.4</td><td> N/A</td><td> N/A</td>

<td> 231</td><td> 398.9</td><td> 2999.9</td><td> N/A</td><td> N/A</td>

<td> 232</td><td> 41.9</td><td> 223.7</td><td> 60.0</td><td> N/A</td>

<td> 233</td><td> 194.3</td><td> 1040.2</td><td> N/A</td><td> N/A</td>

<td> 234</td><td> 533.5</td><td> 4156.4</td><td> N/A</td><td> N/A</td>

<td> 235</td><td> 306.4</td><td> 3651.1</td><td> N/A</td><td> N/A</td>

<td> 236</td><td> 348.3</td><td> 3801.2</td><td> N/A</td><td> N/A</td>

<td> 237</td><td> 37.7</td><td> 213.2</td><td> 28.7</td><td> N/A</td>

<td> 238</td><td> 42.4</td><td> 347.8</td><td> 87.5</td><td> N/A</td>

<td> 239</td><td> 48.9</td><td> 498.9</td><td> 125.6</td><td> N/A</td>

237

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<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 240</td><td> 62.4</td><td> 566.0</td><td> 137.0</td><td> N/A</td>

<td> 241</td><td> 69.6</td><td> 560.0</td><td> 142.1</td><td> N/A</td>

<td> 242</td><td> 30.5</td><td> 161.4</td><td> 21.3</td><td> N/A</td>

<td> 243</td><td> 46.3</td><td> 150.4</td><td> 70.2</td><td> N/A</td>

<td> 244</td><td> 107.4</td><td> 476.9</td><td> N/A</td><td> N/A</td>

<td> 245</td><td> 543.5</td><td> 10000.0</td><td> N/A</td><td> N/A</td>

<td> 246</td><td> 413.8</td><td> 7839.8</td><td> N/A</td><td> N/A</td>

<td> 247</td><td> 49.6</td><td> 324.3</td><td> 33.8</td><td> N/A</td>

<td> 248</td><td> 21.8</td><td> 42.0</td><td> 7.3</td><td> N/A</td>

<td> 249</td><td> 10.6</td><td> 37.3</td><td> 8.1</td><td> N/A</td>

<td> 250</td><td> 19.8</td><td> 62.6</td><td> 10.5</td><td> N/A</td>

<td> 251</td><td> 35.0</td><td> 222.7</td><td> 22.1</td><td> 1828.5</td>

<td> 252</td><td> 29.9</td><td> 59.0</td><td> 10.9</td><td> 3738.7</td>

<td> 253</td><td> 51.3</td><td> 1141.8</td><td> 85.5</td><td> N/A</td>

<td> 254</td><td> 14.8</td><td> 85.7</td><td> 36.8</td><td> 104.5</td>

<td> 255</td><td> 14.4</td><td> 128.3</td><td> 22.2</td><td> 80.1</td>

<td> 256</td><td> 39.3</td><td> 512.3</td><td> 445.1</td><td> N/A</td>

<td> 257</td><td> 483.3</td><td> 6165.2</td><td> N/A</td><td> N/A</td>

<td> 258</td><td> 660.5</td><td> 1914.1</td><td> N/A</td><td> N/A</td>

<td> 259</td><td> 74.9</td><td> 930.5</td><td> 251.5</td><td> N/A</td>

<td> 260</td><td> 240.5</td><td> 3455.9</td><td> N/A</td><td> N/A</td>

<td> 261</td><td> 30.7</td><td> 61.4</td><td> 10.7</td><td> 58.7</td>

<td> 262</td><td> 92.8</td><td> 549.5</td><td> 58.9</td><td> 872.3</td>

<td> 263</td><td> 93.2</td><td> 1133.3</td><td> 173.0</td><td> N/A</td>

238

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<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 264</td><td> 117.2</td><td> 1326.1</td><td> N/A</td><td> 938.2</td>

<td> 265</td><td> 156.5</td><td> 1451.0</td><td> N/A</td><td> N/A</td>

<td> 266</td><td> 643.9</td><td> 3333.3</td><td> N/A</td><td> N/A</td>

<td> 267</td><td> 121.7</td><td> 1293.1</td><td> N/A</td><td> N/A</td>

<td> 268</td><td> 2835.2</td><td> 8899.5</td><td> N/A</td><td> N/A</td>

<td> 269</td><td> 3789.0</td><td> 10000.0</td><td> N/A</td><td> N/A</td>

<td> 270</td><td> 271.5</td><td> 2977.8</td><td> 1667.0</td><td> N/A</td>

<td> 271</td><td> 514.0</td><td> 4965.8</td><td> N/A</td><td> N/A</td>

<td> 272</td><td> 69.8</td><td> 982.3</td><td> 673.4</td><td> N/A</td>

<td> 273</td><td> 109.4</td><td> 1109.1</td><td> N/A</td><td> N/A</td>

<td> 274</td><td> 223.4</td><td> 1756.1</td><td> N/A</td><td> N/A</td>

<td> 275</td><td> 965.2</td><td> 9236.5</td><td> N/A</td><td> N/A</td>

<td> 276</td><td> 63.2</td><td> 274.7</td><td> 64.3</td><td> N/A</td>

<td> 277</td><td> 9.7</td><td> 80.8</td><td> 76.6</td><td> N/A</td>

<td> 278</td><td> 35.6</td><td> 237.8</td><td> 47.3</td><td> N/A</td>

<td> 279</td><td> 64.9</td><td> 704.7</td><td> 136.8</td><td> N/A</td>

<td> 280</td><td> 10.2</td><td> 90.4</td><td> 9.0</td><td> N/A</td>

<td> 281</td><td> 9.4</td><td> 19.3</td><td> 5.4</td><td> N/A</td>

<td> 282</td><td> 20.0</td><td> 49.1</td><td> 8.1</td><td> N/A</td>

<td> 283</td><td> 31.9</td><td> 107.5</td><td> 8.1</td><td> N/A</td>

<td> 284</td><td> 13.8</td><td> 55.5</td><td> 13.3</td><td> N/A</td>

<td> 285</td><td> 13.1</td><td> 84.9</td><td> 24.1</td><td> N/A</td>

<td> 286</td><td> 28.9</td><td> 150.9</td><td> 27.7</td><td> N/A</td>

<td> 287</td><td> 17.9</td><td> 121.9</td><td> 30.1</td><td> N/A</td>

239

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<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 288</td><td> 26.5</td><td> 215.5</td><td> 47.3</td><td> N/A</td>

<td> 289</td><td> 36.8</td><td> 209.1</td><td> 54.8</td><td> N/A</td>

<td> 290</td><td> 52.2</td><td> 393.1</td><td> 84.6</td><td> N/A</td>

<td> 291</td><td> 43.4</td><td> 547.9</td><td> 86.2</td><td> N/A</td>

<td> 292</td><td> 43.8</td><td> 177.8</td><td> 99.8</td><td> N/A</td>

<td> 293</td><td> 47.7</td><td> 487.0</td><td> 129.3</td><td> N/A</td>

<td> 294</td><td> 59.3</td><td> 430.5</td><td> 134.2</td><td> N/A</td>

<td> 295</td><td> 53.4</td><td> 181.3</td><td> 195.8</td><td> N/A</td>

<td> 296</td><td> 83.7</td><td> 448.4</td><td> 300.8</td><td> N/A</td>

<td> 297</td><td> 102.3</td><td> 1091.2</td><td> 787.6</td><td> N/A</td>

<td> 298</td><td> 33.9</td><td> 234.8</td><td> 31.4</td><td> N/A</td>

<td> 299</td><td> 33.5</td><td> 302.0</td><td> 29.5</td><td> N/A</td>

<td> 300</td><td> 31.0</td><td> 257.6</td><td> 50.2</td><td> N/A</td>

<td> 301</td><td> 24.0</td><td> 181.0</td><td> 113.1</td><td> N/A</td>

<td> 302</td><td> 65.1</td><td> 504.4</td><td> 158.5</td><td> N/A</td>

<td> 303</td><td> 75.0</td><td> 605.4</td><td> 264.1</td><td> N/A</td>

<td> 304</td><td> 100.2</td><td> 652.5</td><td> 383.3</td><td> N/A</td>

<td> 305</td><td> 108.1</td><td> 680.5</td><td> N/A</td><td> N/A</td>

<td> 306</td><td> 125.4</td><td> 881.5</td><td> N/A</td><td> N/A</td>

<td> 307</td><td> 229.0</td><td> 1552.5</td><td> N/A</td><td> N/A</td>

<td> 308</td><td> 255.8</td><td> 2199.0</td><td> N/A</td><td> N/A</td>

<td> 309</td><td> 140.5</td><td> 1056.1</td><td> N/A</td><td> N/A</td>

<td> 310</td><td> 319.2</td><td> 3631.3</td><td> N/A</td><td> N/A</td>

<td> 311</td><td> 117.4</td><td> 215.0</td><td> N/A</td><td> N/A</td>

240

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<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 312</td><td> 20.8</td><td> 287.9</td><td> 26.1</td><td> N/A</td>

<td> 313</td><td> 13.7</td><td> 132.1</td><td> 9.2</td><td> N/A</td>

<td> 314</td><td> 28.9</td><td> 308.4</td><td> 36.1</td><td> N/A</td>

<td> 315</td><td> 9.6</td><td> 23.2</td><td> 4.9</td><td> N/A</td>

<td> 316</td><td> 31.9</td><td> 221.4</td><td> 38.2</td><td> N/A</td>

<td> 317</td><td> 20.7</td><td> 196.6</td><td> 44.3</td><td> N/A</td>

<td> 318</td><td> 69.5</td><td> 345.6</td><td> 142.7</td><td> N/A</td>

<td> 319</td><td> 53.5</td><td> 674.9</td><td> 166.2</td><td> N/A</td>

<td> 320</td><td> 88.8</td><td> 701.8</td><td> 1667.0</td><td> N/A</td>

<td> 321</td><td> 94.7</td><td> 757.0</td><td> 1667.0</td><td> N/A</td>

<td> 322</td><td> 223.4</td><td> 1490.6</td><td> N/A</td><td> N/A</td>

<td> 323</td><td> 9.9</td><td> 21.6</td><td> 4.0</td><td> N/A</td>

<td> 324</td><td> 11.4</td><td> 15.5</td><td> 10.9</td><td> N/A</td>

<td> 325</td><td> 24.2</td><td> 103.6</td><td> 27.8</td><td> N/A</td>

<td> 326</td><td> 41.1</td><td> 368.2</td><td> 78.8</td><td> N/A</td>

<td> 327</td><td> 94.7</td><td> 517.6</td><td> 314.1</td><td> N/A</td>

<td> 328</td><td> 82.4</td><td> 586.8</td><td> 444.5</td><td> N/A</td>

<td> 329</td><td> 106.7</td><td> 337.0</td><td> N/A</td><td> N/A</td>

<td> 330</td><td> 45.4</td><td> 372.1</td><td> 93.2</td><td> N/A</td>

<td> 331</td><td> 9.4</td><td> 30.8</td><td> 10.3</td><td> N/A</td>

<td> 332</td><td> 14.6</td><td> 75.5</td><td> 24.4</td><td> N/A</td>

<td> 333</td><td> 29.4</td><td> 218.1</td><td> 33.2</td><td> N/A</td>

<td> 334</td><td> 38.5</td><td> 251.0</td><td> 46.0</td><td> N/A</td>

<td> 335</td><td> 39.4</td><td> 218.5</td><td> 47.1</td><td> N/A</td>

241

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<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 336</td><td> 45.3</td><td> 334.8</td><td> 164.0</td><td> N/A</td>

<td> 337</td><td> 12.6</td><td> 30.0</td><td> 4.6</td><td> N/A</td>

<td> 338</td><td> 33.6</td><td> 568.2</td><td> 70.4</td><td> N/A</td>

<td> 339</td><td> 51.7</td><td> 756.7</td><td> 236.9</td><td> N/A</td>

<td> 340</td><td> 65.1</td><td> 582.7</td><td> 769.3</td><td> N/A</td>

<td> 341</td><td> 79.2</td><td> 397.2</td><td> 1667.0</td><td> N/A</td>

<td> 342</td><td> 63.8</td><td> 309.7</td><td> 1667.0</td><td> N/A</td>

<td> 343</td><td> 55.3</td><td> 329.9</td><td> 970.1</td><td> N/A</td>

<td> 344</td><td> 65.6</td><td> 552.2</td><td> 175.1</td><td> N/A</td>

<td> 345</td><td> 26.8</td><td> 140.5</td><td> 37.5</td><td> N/A</td>

<td> 346</td><td> 35.2</td><td> 172.7</td><td> 45.9</td><td> N/A</td>

<td> 347</td><td> 77.9</td><td> 832.3</td><td> 161.1</td><td> N/A</td>

<td> 348</td><td> 183.9</td><td> 1196.6</td><td> N/A</td><td> N/A</td>

<td> 349</td><td> 55.7</td><td> 348.7</td><td> 260.8</td><td> N/A</td>

<td> 350</td><td> 77.2</td><td> 225.7</td><td> 96.1</td><td> N/A</td>

<td> 351</td><td> 313.9</td><td> 2730.6</td><td> N/A</td><td> N/A</td>

<td> 352</td><td> 2379.9</td><td> 10000.0</td><td> N/A</td><td> N/A</td>

<td> 353</td><td> 89.3</td><td> 570.5</td><td> 128.6</td><td> N/A</td>

<td> 354</td><td> 3347.1</td><td> 10000.0</td><td> N/A</td><td> N/A</td>

<td> 355</td><td> 405.4</td><td> 5472.6</td><td> N/A</td><td> N/A</td>

<td> 356</td><td> 242.1</td><td> 2291.9</td><td> N/A</td><td> N/A</td>

<td> 357</td><td> 154.1</td><td> 2082.0</td><td> N/A</td><td> N/A</td>

<td> 358</td><td> 50.3</td><td> 710.0</td><td> 150.6</td><td> N/A</td>

<td> 359</td><td> 60.7</td><td> 1477.2</td><td> 100.2</td><td> N/A</td>

242

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<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 360</td><td> 190.6</td><td> 2393.4</td><td> N/A</td><td> N/A</td>

<td> 361</td><td> 62.5</td><td> 288.0</td><td> 102.7</td><td> N/A</td>

<td> 362</td><td> 170.0</td><td> 732.6</td><td> N/A</td><td> N/A</td>

<td> 363</td><td> 31.7</td><td> 88.9</td><td> 24.8</td><td> N/A</td>

<td> 364</td><td> 257.3</td><td> 1895.7</td><td> N/A</td><td> N/A</td>

<td> 365</td><td> 47.8</td><td> 187.1</td><td> 61.0</td><td> N/A</td>

<td> 366</td><td> 22.3</td><td> 47.5</td><td> 19.3</td><td> N/A</td>

<td> 367</td><td> 109.1</td><td> 1098.7</td><td> N/A</td><td> N/A</td>

<td> 368</td><td> 19.8</td><td> 47.2</td><td> 30.3</td><td> N/A</td>

<td> 369</td><td> 16.2</td><td> 36.9</td><td> 12.1</td><td> N/A</td>

<td> 370</td><td> 19.4</td><td> 56.5</td><td> 13.5</td><td> N/A</td>

<td> 371</td><td> 28.9</td><td> 147.3</td><td> 35.7</td><td> N/A</td>

<td> 372</td><td> 33.9</td><td> 78.7</td><td> 35.7</td><td> N/A</td>

<td> 373</td><td> 277.5</td><td> 2974.6</td><td> N/A</td><td> N/A</td>

<td> 374</td><td> 581.6</td><td> 6256.9</td><td> N/A</td><td> N/A</td>

<td> 375</td><td> 113.1</td><td> 1561.6</td><td> N/A</td><td> N/A</td>

<td> 376</td><td> 164.8</td><td> 2788.1</td><td> N/A</td><td> N/A</td>

<td> 377</td><td> 69.9</td><td> 977.2</td><td> 149.0</td><td> N/A</td>

<td> 378</td><td> 110.3</td><td> 1374.6</td><td> N/A</td><td> N/A</td>

<td> 379</td><td> 474.9</td><td> 4809.7</td><td> N/A</td><td> N/A</td>

<td> 380</td><td> 127.5</td><td> 1994.2</td><td> N/A</td><td> N/A</td>

<td> 381</td><td> 147.5</td><td> 1714.8</td><td> N/A</td><td> N/A</td>

<td> 382</td><td> 31.2</td><td> 134.0</td><td> 28.9</td><td> N/A</td>

<td> 383</td><td> 32.8</td><td> 257.8</td><td> 55.3</td><td> N/A</td>

243

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<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 384</td><td> 77.4</td><td> 598.8</td><td> 381.7</td><td> N/A</td>

<td> 385</td><td> 59.5</td><td> 401.8</td><td> 112.0</td><td> N/A</td>

<td> 386</td><td> 193.8</td><td> 2911.9</td><td> N/A</td><td> N/A</td>

<td> 387</td><td> 355.0</td><td> 4202.6</td><td> N/A</td><td> N/A</td>

<td> 388</td><td> 72.6</td><td> 551.6</td><td> 223.5</td><td> N/A</td>

<td> 389</td><td> 44.3</td><td> 236.7</td><td> 50.2</td><td> N/A</td>

<td> 390</td><td> 69.2</td><td> 621.2</td><td> 231.1</td><td> N/A</td>

<td> 391</td><td> 459.9</td><td> 5367.8</td><td> N/A</td><td> N/A</td>

<td> 392</td><td> 170.9</td><td> 3419.8</td><td> N/A</td><td> N/A</td>

<td> 393</td><td> 706.7</td><td> 7376.4</td><td> N/A</td><td> N/A</td>

<td> 394</td><td> 111.6</td><td> 887.1</td><td> N/A</td><td> N/A</td>

<td> 395</td><td> 365.2</td><td> 2494.9</td><td> N/A</td><td> N/A</td>

<td> 396</td><td> 110.9</td><td> 1859.9</td><td> N/A</td><td> N/A</td>

<td> 397</td><td> 75.6</td><td> 668.0</td><td> 51.9</td><td> N/A</td>

<td> 398</td><td> 197.0</td><td> 3411.4</td><td> N/A</td><td> N/A</td>

<td> 399</td><td> 86.8</td><td> 1309.2</td><td> 129.2</td><td> N/A</td>

<td> 400</td><td> 110.0</td><td> 1427.0</td><td> N/A</td><td> N/A</td>

<td> 401</td><td> 94.9</td><td> 1249.8</td><td> 261.5</td><td> N/A</td>

<td> 402</td><td> 114.1</td><td> 1349.6</td><td> N/A</td><td> N/A</td>

<td> 403</td><td> 50.3</td><td> 738.7</td><td> 105.0</td><td> N/A</td>

<td> 404</td><td> 293.8</td><td> 6841.7</td><td> N/A</td><td> N/A</td>

<td> 405</td><td> 48.2</td><td> 331.7</td><td> 70.0</td><td> N/A</td>

<td> 406</td><td> 46.5</td><td> 299.7</td><td> 46.2</td><td> N/A</td>

<td> 408</td><td> 159.2</td><td> 3136.0</td><td> N/A</td><td> N/A</td>

244

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PCT7US2017/055983

<td> Ex#</td><td> RET Enzyme (wild type) ICso (nM)</td><td> RET enzyme (V804M) ICso (nM)</td><td> KIF5BRET pTYR1062 Cell ICso (nM)</td><td> RET enzyme (G810R) ICso (nM)</td>

<td> 409</td><td> 502.1</td><td> 5012.6</td><td> N/A</td><td> N/A</td>

<td> 410</td><td> 69.6</td><td> 1038.4</td><td> 1667.0</td><td> N/A</td>

<td> 411</td><td> 264.3</td><td> 2912.5</td><td> 1667.0</td><td> N/A</td>

<td> 412</td><td> 184.1</td><td> 2524.7</td><td> N/A</td><td> N/A</td>

<td> 413</td><td> 388.6</td><td> 3712.7</td><td> N/A</td><td> N/A</td>

<td> 414</td><td> 298.0</td><td> 3136.0</td><td> 990.0</td><td> N/A</td>

<td> 415</td><td> 61.6</td><td> 767.8</td><td> 146.5</td><td> N/A</td>

<td> 416</td><td> 14.1</td><td> 48.3</td><td> 9.3</td><td> N/A</td>

<td> 417</td><td> 109.3</td><td> 974.6</td><td> N/A</td><td> N/A</td>

<td> 418</td><td> 340.4</td><td> 3890.4</td><td> N/A</td><td> N/A</td>

<td> 419</td><td> 402.4</td><td> 5308.7</td><td> N/A</td><td> N/A</td>

<td> 420</td><td> 280.2</td><td> 4516.5</td><td> N/A</td><td> N/A</td>

<td> 421</td><td> 135.3</td><td> 685.8</td><td> N/A</td><td> N/A</td>

<td> 422</td><td> 27.4</td><td> 101.6</td><td> 256.9</td><td> N/A</td>

<td> 423</td><td> 15.0</td><td> 82.9</td><td> 13.7</td><td> N/A</td>

<td> 424</td><td> 102.3</td><td> 736.4</td><td> N/A</td><td> N/A</td>